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Gonococcal sepsis in a 32-year-old female: a case report

• Michael Owusu 1 ,
• Kwadwo Sarfo Marfo 1 ,
• Godfred Acheampong 1 ,
• Abednego Arthur 1 ,
• Nimako Sarpong 3 ,
• Justin Im 6 ,
• Ondari D. Mogeni 6 ,
• Augustina Annan 1 , 4 ,
• Hsin-Ying Chiang 5 ,
• Chih-Horng Kuo 5 ,
• Se Eun Park 6 ,
• Florian Marks 6 ,
• Ellis Owusu-Dabo 1 , 2 &
• Yaw Adu-Sarkodie 7  

BMC Research Notes volume  11 , Article number:  253 ( 2018 ) Cite this article

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Neisseria gonorrhoeae is a Gram-negative bacterium which affects the urethra, throat, rectum and cervix of patients and often associated with sexually transmitted infections. The global epidemiology of the disease is not well characterised especially in resource constraint countries due to poor diagnostic capacity and inefficient reporting systems. Although important, little is known about the propensity of this bacterium to cause sepsis in immunocompetent individuals.

Case presentation

A 32-year-old female presented with fever and generalised malaise to a rural hospital in Ghana. The patient had previously been diagnosed as having enteric fever from a neighbouring health facility. Blood and urine samples were collected from the patient and cultured using standard microbiological and molecular techniques. Neisseria gonorrhoeae was isolated from the blood which was resistant to penicillin, ciprofloxacin and cotrimoxazole. The patient recovered following ceftriaxone and azithromycin treatment.

This case highlights the importance of N. gonorrhoeae in causing sepsis and emphasises the need for blood culture investigation in diagnosis of patients presenting with fever.

Neisseria gonorrhoeae ( N. gonorrhoeae ) is a Gram-negative intracellular diplococcus bacterium associated with sexually transmitted infections (STIs). The organism causes gonorrhoeae; a disease which affects the urethra, throat, rectum and cervix of patients. The global epidemiology of the disease is not well characterised due to poor diagnostic capacity and inefficient reporting systems. Globally, it is estimated that about 106 million of occur annually [ 1 ]. It is the second commonly reported STI and is most prevalent in the age group of 15–49 years [ 2 ] Although about 87% of N. gonorrhoeae infections occur in symptomatic individuals, few infections (about 13%) progress asymptomatically [ 3 ]. The N. gonorrhoeae bacterium has become a major public health concern because of its increasing resistance to common antibiotics including penicillin, tetracycline, sulphonamides and, more recently, quinolones [ 1 , 2 ].

In rare circumstances, gonococcal infection may result in sepsis and septic shock [ 4 ]. Gonococcal sepsis is most common in young women, but may develop in sexually active persons of any age. Reports on the occurrence of gonococcal sepsis in developing countries, especially within Africa are limited. Here, we report a case of gonococcal sepsis in a 32-year old female from a rural community of Ghana.

A 32-year-old female trader presented to a hospital in the Ashanti region of Ghana, with 3-weeks history of generalised malaise and fever. Prior to her presentation, she was treated in a neighbouring hospital as a presumed case of enteric fever. On direct questioning, the patient had no known history of chronic underlying medical condition.

On examination, she weighed 73.2 kg, was slightly pale and febrile with a temperature of 38.5 °C. Examination of her body systems including the cervix and vagina were all normal. Based on the clinical findings, a provisional diagnosis of enteric fever was made.

Preliminary laboratory test for HIV and malaria were all negative. Her full blood count showed a low haemoglobin concentration of 8.7 g/dL and raised white cell count of 12.4 × 10 3  cells/µL.

Liver function test showed high aspartate transaminase (AST) of 151 U/L and alanine transaminase (ALT) of 74 U/L. Her CD4 count was 1899 cells/mm 3 and CD4/CD3 ratio was 0.71. Pending results for microbiological investigations, the patient was empirically administered with 500 mg of ciprofloxacin 12 hourly daily.

Blood and urine were collected for microbiological cultures. Blood sample was collected into Beckton Dickinson(BD) adult aerobic blood culture bottle (BD, Baltimore, US) and incubated in Bactec Machine at 35 °C (9050, BD).

The blood culture yielded a fastidious bacterium with small sized and creamy non-haemolytic colonies. Gram stain of the colonies showed Gram negative diplococci. Oxidase and catalase tests proved positive. The identity of the bacteria was determined by first using Analytic Profile Index (API) specific for Neisseria spp. and Haemophilus spp. (API NH, Biomerieux) and then confirming with 16S PCR method. The API kit showed a 100% consistency with N. gonorrhoeae.

For molecular identification, the 16S rRNA gene sequence of this bacterium was determined according to the procedure described previously [ 5 ]. Briefly DNA was extracted from the pure culture using Spherolyse extraction kit (Hain Lifesciense GmbH, Germany). The 16S rDNA was amplified using primer pair 8F and 1492R and the resulting sequence was checked using DECIPHER (version 2.2.0).The final sequence generated was deposited in NCBI GenBank under the MF509590 and exhibits 99% (1440/1442) sequence identity to N. gonorrhoeae strain NCTC 8375 (NR_026079.1).

Antimicrobial susceptibility testing was performed on the isolate using the Kirby Baur disc diffusion method and following the Clinical and Laboratory Standards Institute guideline [ 6 ] The isolate showed resistance to ciprofloxacin, cotrimoxazole and penicillin but sensitivity to ceftriaxone, chloramphenicol and azithromycin. The patient’s prescription was amended to include ceftriaxone and azithromycin and her condition improved clinically.

Discussions and conclusions

Gonococcal bacteremia is a rare condition affecting less than 3% of patients with gonorrhoea [ 7 ]. Isolated cases reported in the Korean population identified viral hepatitis and liver cirrhosis as risk factors for gonococcal bacteremia [ 8 ]. Other risk factors identified include the pathogenicity of the infecting strain, pregnancy, acquired complement deficiencies, systemic lupus erythematosus, sickle cell disease and splenectomy [ 8 , 9 , 10 ].

This patient does not have any of the underlying host factors mentioned above. Her HIV test was negative and a further CD4 cell population was also adequate thus ruling out any possibility of immunosuppression. We surmise that our patient might have been infected based on the virulence of the pathogen. It is possible that prolonged asymptomatic carriage of specific bacterial strains increases the risk of invasive diseases leading to sepsis. In the early 1980s, O’Brien determined that specific strains of N. gonorrhoeae with outer membrane porin isoform (PorB1b) seem to have increased permissive host cell invasion compared to others without those factors [ 9 ]. More studies on the pathogenicity and the genetic diversity of gonococcal strains would be helpful in understanding the mechanisms of gonococcal infections.

We also found the liver function markers (AST and ALT) of the patient as abnormal. Some authors have similarly reported abnormalities in liver enzymes of subjects [ 11 , 12 ]. One common complication associated with gonococcal sepsis is perihepatitis [ 13 ]. Perihepatitis occurs by direct extension of the N. gonorrhoeae from the fallopian tubes to the liver capsule resulting in acute inflammation of the liver [ 13 ]. Other studies have similarly identified gonococcal bacteraemia in patients presenting with abnormal liver parameters, thus suggesting a possible association [ 11 , 12 ].

Another important finding in this patient was the apparent lack of urogenital symptoms consistent with genital gonococcal infections. Thorough examination of the vagina and cervix did not show any signs of gonococcal infection. Other authors have similarly identified gonococcal infection in patients without history of urogenital symptoms [ 9 ]. About 50% of blood cultures were found to be positive in those cases although cultures from other body sites such as the synovial fluids and skin, were negative [ 14 ].

The isolated bacterium was also found to be resistant to common therapeutic agents including penicillin, ciprofloxacin and cotrimoxazole. This finding agrees with the recent report issued by the WHO on the growing gonococcal-associated antibiotic resistance and the need to strengthen antimicrobial surveillance of gonococcal infections [ 15 ].

Our report brings to fore the importance of taking blood cultures and administering the right kind of antibiotics for all fever related conditions that present to the hospital. This particular infection could have been missed if a blood culture had not been performed on the patient.

Further surveillance and investigation into the mechanisms of gonococcal invasion is therefore recommended infections.

Abbreviations

sexually transmitted infections

aspartate transaminase

aspartate transaminase (AST)

Beckton Dickenson

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Authors’ contributions

MO, FM, EOD and YAS designed the study and contributed to writing of the manuscript. KSM, AA1, AA2 and GA contributed to routine laboratory analysis of the samples. NS, SEP, JI, ODM contributed to data collection and documentation of clinical findings. HC and CK assisted with sequencing, sequence data interpretation and writing of the manuscript. All authors read and approved the final manuscript.

Acknowledgements

We thank the parents of the child and staff of the hospital. The Sanger sequencing service was provided by the DNA Analysis Core Laboratory (Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan).

Competing interests

The authors declare that they have no competing interests. No author has any proprietary interest in any of the products or ideas mentioned in this article.

Availability of data and materials

All data generated or analysed during this study are included in this published article and sequences deposited in GeneBank under the accession number MF509590.

Consent for publication

Written informed consent was obtained from the patient before participation in the study and publication of this case report.

Ethics approval and consent to participate

Not applicable.

This report is on a subject recruited as part of an on-going study which is a partnership between the Kumasi Centre for Collaborative Research based at the Kwame Nkrumah University of Science and Technology, Kumasi, Ghana and the International Vaccine Institute, Seoul, Korea with sponsorship from the Bill and Melinda Gates Foundation.

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Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Michael Owusu, Kwadwo Sarfo Marfo, Godfred Acheampong, Abednego Arthur, Augustina Annan & Ellis Owusu-Dabo

Department of Global Health, School of Public Health, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Ellis Owusu-Dabo

Agogo Presbyterian Hospital, Agogo, Ashanti Region, Ghana

Nimako Sarpong

Department of Theoretical and Applied Biology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Augustina Annan

Institute of Plant and Microbial Biology, Academia Sinica, Taipei, Taiwan

Hsin-Ying Chiang & Chih-Horng Kuo

Department of Epidemiology, International Vaccine Institute, Seoul, South Korea

Justin Im, Ondari D. Mogeni, Se Eun Park & Florian Marks

Department of Clinical Microbiology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Yaw Adu-Sarkodie

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Correspondence to Ellis Owusu-Dabo .

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Owusu, M., Marfo, K.S., Acheampong, G. et al. Gonococcal sepsis in a 32-year-old female: a case report. BMC Res Notes 11 , 253 (2018). https://doi.org/10.1186/s13104-018-3346-1

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Received : 23 September 2017

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Published : 24 April 2018

DOI : https://doi.org/10.1186/s13104-018-3346-1

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Preventing Antibiotic-Resistant Gonorrhea by Changing Treatment Guidelines and Educating Health Care Providers

What to know.

Gonorrhea, a common STD, can be treated with medicine but may become resistant to the medicine over time. By preventing antibiotic resistance, CDC can prevent more gonorrhea cases from spreading or becoming harder to treat.

Gonorrhea overview

People who are sexually active can get gonorrhea, a common sexually transmitted disease (STD). It usually causes infection in the genitals, rectum, or throat. However, it also can spread to the bloodstream, heart, and nervous system.

A pregnant person with gonorrhea can give the infection to their baby during delivery. This can cause serious health problems, including blindness, for the baby.

In 2019, a total of 616,392 cases of gonorrhea in the United States were reported to CDC. This is a rate of 188.4 gonorrhea cases per 100,000 persons. Moreover, the rate of gonorrhea cases has increased 92% since 2009. 1

Without treatment, gonorrhea can cause serious and permanent health problems, including infertility in women.

CDC treatment guideline updates and antibiotic resistance

Gonorrhea can be treated with medicine, but the bacteria can develop resistance to antibiotics over time. The term antibiotic resistance means that medicines that have been used to treat an infection may no longer work.

CDC's Gonococcal Isolate Surveillance Project monitors gonorrhea's bacterium, Neisseria gonorrhoeae , and how susceptible it is to antibiotics. When CDC learns that gonorrhea has developed resistance to an antibiotic regimen that was working, it will update its recommendations for health care providers.

CDC has updated its gonorrhea treatment recommendations multiple times since 2000 due to increasing resistance. The most recent update was in 2021 (for more information, see STI Treatment Guidelines, 2021 ).

Antibiotic resistance can make treating gonorrhea and preventing its spread much more difficult. By preventing antibiotic resistance, CDC can prevent gonorrhea cases. This limits additional medical complications and saves on the cost of health care.

For example, increasing cephalosporin resistance could lead to:

• 1 million additional gonococcal infections
• 600 additional gonorrhea-attributable human immunodeficiency virus (HIV) infections
• Cost approximately $400 million over 10 years 2

Educating health care providers and changing treatment practices

To prevent antibiotic-resistance gonorrhea, health care providers should update their treatment practices to be consistent with CDC's current STI Treatment Guidelines, 2021 ). Previous evaluations show that health care providers are aware of when CDC publishes new STD treatment guidelines and update their practices as needed. 3 4 5 6 7

For example, 2015 STD Treatment Guidelines recommended ceftriaxone 250 mg plus azithromycin 1 g to treat uncomplicated gonorrhea. In 2016, a review of U.S. surveillance data showed 81% of reported gonorrhea cases were treated with this regimen. The highest rates of clinics following this regimen included:

• STD clinics (91%)
• Family planning or reproductive health clinics (94%)

In 2021, the STD Treatment Guidelines updated recommendations. The new guideline recommends only a higher ceftriaxone dose of 500 mg for a person weighing less than 150 kg as the recommended regimen for uncomplicated gonorrhea.

Data are not yet available for adherence to the 2021 guidelines, which were released in July 2021.

• Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2019. Atlanta: U.S. Department of Health and Human Services; 2021
• Chesson HW, Kirkcaldy RD, Gift TL, Owusu-Edusei K Jr, Weinstock HS. An Illustration of the Potential Health and Economic Benefits of Combating Antibiotic-Resistant Gonorrhea. Sex Transm Dis. 2018;45(4):250-253. doi:10.1097/OLQ.0000000000000725
• Weston EJ, Workowski K, Torrone E, Weinstock H, Stenger MR. Adherence to CDC Recommendations for the Treatment of Uncomplicated Gonorrhea — STD Surveillance Network, United States, 2016. MMWR Morb Mortal Wkly Rep 2018;67:473–476. DOI: http://dx.doi.org/10.15585/mmwr.mm6716a4external icon.
• Kerani RP, Stenger MR, Weinstock H, et al. Gonorrhea treatment practices in the STD Surveillance Network, 2010-2012. Sex Transm Dis 2015;42:6–12.
• Dowell D, Tian LH, Stover JA, et al. Changes in fluoroquinolone use for gonorrhea following publication of revised treatment guidelines. Am J Public Health 2012;102:148–55.
• Lechtenberg RJ, Samuel MC, Bernstein KT, Lahiff M, Olson N, Bauer HM. Variation in adherence to the treatment guidelines for Neisseria gonorrhoeae by clinical practice setting, California, 2009 to 2011. Sex Transm Dis 2014;41:338–44.
• Swails J, Smock L, Hsu K. Provider characteristics associated with guideline-nonadherent gonorrhea treatment, Massachusetts, 2010. Sex Transm Dis 2014;41:133–6
• National Center for HIV, Viral Hepatitis, STD, and TB Prevention

High-Impact Prevention is a cost-effective, proven, scalable public health approach that prevents new infections, saves life-years, and reduces disparities.

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• Published: 11 November 2021

Gonorrhoea: a systematic review of prevalence reporting globally

• Jane Whelan   ORCID: orcid.org/0000-0003-3784-2749 1 ,
• Victoria Abbing-Karahagopian   ORCID: orcid.org/0000-0003-1987-363X 1 ,
• Laura Serino   ORCID: orcid.org/0000-0002-8618-9726 2 &
• Magnus Unemo   ORCID: orcid.org/0000-0003-1710-2081 3  

BMC Infectious Diseases volume  21 , Article number:  1152 ( 2021 ) Cite this article

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The World Health Organization (WHO) recommends periodic gonorrhoea prevalence assessments in the general population or proxies thereof (including pregnant women, women attending family planning clinics, military recruits, and men undergoing employment physicals for example) and in population groups at increased risk, including men-who-have-sex-with-men (MSM) and sex workers.

We evaluated reported prevalence data, including estimates from proxy general population samples to reflect the WHO recommendations. We describe the outcomes from the general population country-by-country and extend previous reviews to include MSM, sex workers, and extragenital infections.

Result and conclusion

In our systematic search, 2015 titles were reviewed (January 2010–April 2019) and 174 full-text publications were included. National, population-based prevalence data were identified in only four countries (the United States of America, the United Kingdom, Peru, New Caledonia) and local population-based estimates were reported in areas within five countries (China, South Africa, Brazil, Benin, and Malawi). The remaining studies identified only reported test positivity from non-probability, proxy general population samples. Due to the diversity of the reviewed studies, detailed comparison across studies was not possible. In MSM, data were identified from 64 studies in 25 countries. Rectal infection rates were generally higher than urogenital or pharyngeal infection rates, where extragenital testing was conducted. Data on sex workers were identified from 41 studies in 23 countries; rates in female sex workers were high. Current prevalence monitoring was shown to be highly suboptimal worldwide. Serial prevalence monitoring of critical epidemiological variables, and guidelines to optimize prevalence study conduct and reporting beyond antenatal settings are recommended.

Peer Review reports

Gonorrhoea is a sexually transmitted infection (STI) caused by Neisseria gonorrhoeae (the gonococcus). In 2016, an estimated 87 million incident cases occurred among persons aged 15–49 years worldwide with an incidence rate of 20 cases/1000 women and 26/1000 men [ 1 ].

Gonorrhoea affects the urogenital tract, oropharynx, rectum, or conjunctiva, and repeat infections are common. Urogenital infections are often asymptomatic, particularly in women, but irrespective of symptoms, gonorrhoea is associated with substantial morbidity. Serious complications and sequelae include pelvic inflammatory disease, chronic pelvic pain, ectopic pregnancy, and infertility in women [ 2 ]. Infection during pregnancy is also associated with low birth weight and neonatal conjunctivitis, which can progress to blindness [ 2 , 3 ]. In men, gonorrhoea can cause epididymitis [ 2 ]. Rectal and pharyngeal gonorrhoea cases, mostly asymptomatic, are prevalent in men-who-have-sex-with-men (MSM), but can be common also in women and, particularly pharyngeal infection, in men who have sex only with women [ 4 ]. The presence of gonorrhoea is also a co-factor in human immunodeficiency virus (HIV) transmission [ 5 ].

Gonorrhoea is substantially underdiagnosed and underreported worldwide [ 3 ]. Even in high-income economies with well-established STI surveillance systems, it is estimated that more than half of infections are unidentified or unreported [ 6 , 7 ]. This underdiagnosis/underreporting is higher in less-resourced settings and settings using syndromic management with limited access to state-of-the-art diagnostics such as nucleic acid amplification tests (NAATs). Though partially explained by the asymptomatic nature of the infection, underreporting is also due to delays in seeking healthcare and inaccessible or inadequate STI testing/treatment in underserved populations or those particularly vulnerable to infection: adolescents and young people, some ethnic and racial groups, communities of lower socioeconomic status, MSM, sex workers, and others [ 8 ].

The World Health Organization (WHO)’s global target is a 90% reduction in gonorrhoea cases by 2030 [ 9 ]. To monitor progress towards this goal, STI trend monitoring at the national level is recommended. This should include routine prevalence assessments (every two to three years) of bacterial STIs among general populations of men and women (e.g. including pregnant women, women attending family planning clinics, military recruits and men undergoing employment physicals) [ 3 ]. Monitoring in high-risk priority populations including MSM and sex workers is also recommended [ 3 , 9 ].

The WHO reports prevalence estimates of curable non-viral STIs at a global and regional level using epidemic models, while recognizing the small number of prevalence data points that are available to generate reliable estimate [ 1 , 3 ]. Notably, for key population groups such as MSM and sex workers, who likely contribute substantially to the worldwide infection burden, gonorrhoea prevalence in global estimates is indirectly accounted for [ 1 ] and estimates do not reflect rectal and pharyngeal infection.

N. gonorrhoeae is progressively developing antimicrobial resistance (AMR) to all therapeutic antibiotics, and the WHO has issued warnings that untreatable gonorrhoea may be on the horizon [ 10 ]. National prevalence estimates are an essential indicator of the state of gonorrhoea and STI control at state level and globally [ 3 ]. In this review, we aimed to evaluate global prevalence reporting in the general population, and proxies thereof, on a country-by-country basis, extending previous reviews to report on key population groups of MSM and female and male sex workers (FSW and MSW), including extragenital as well as urogenital infection.

Search strategy and selection criteria

We conducted a systematic search of PubMed following PRISMA guidelines (Additional file 1 ) for papers published from 1 January 2010 to 11 April 2019. We derived a sensitive search strategy requiring at least one medical subject headings (MeSH) term related to a sexually transmitted disease (STD) or gonorrhoea and at least one reference to the keyword ‘gonorrhoea’ in the title or abstract. We did not specify the population (e.g. MSM, FSW or MSW), as we noted substantial overlap in reporting of risk groups and inclusion of terms such as ‘prevalence’, ‘epidemiology’ or ‘rate’ rendered the search too specific, omitting relevant papers (Additional file 2 ). Two authors (JW and VAK) independently screened all titles and abstracts against pre-specified inclusion and exclusion criteria (Additional file 3 ) and agreed on the selection of articles to be obtained as full text. English-language abstracts were reviewed but the full text was translated as necessary, from Portuguese, Spanish, and Chinese, where relevant. The systematic search was supplemented with an online English-language country-by-country search of websites, data repositories and surveillance reports of public health and/or governmental agencies using the country name, and ‘gonorr*’ or ‘sexually transmitted’ and ‘disease’ or ‘infection’ to identify data sources and provide context to prevalence estimates. We reviewed regional and international health agency data (WHO, European Centre for Disease Prevention and Control [ECDC]) and contacted relevant experts in the field. AMR monitoring, an essential component of gonorrhoea surveillance [ 10 ] and worthy of a separate review, was beyond the scope of this search.

Data analysis

The primary outcome (prevalence of gonorrhoea) was defined as the proportion of persons with laboratory-confirmed (culture and/or NAAT positive) gonorrhoea in the population within a specified time. It became apparent early in the literature search that population-based prevalence estimates were very limited and so to address the WHO recommendation to derive estimates from studies which are not necessarily population-based but nevertheless relevant, we defined a post-hoc secondary objective to report test positivity, categorizing these as proxy general population samples. Data were tabulated by population group (classified as ‘general population’, MSM and sex workers) and summarized per WHO region and country. ‘General population’ samples were identified according to WHO recommendations, to include studies conducted ‘among pregnant women, women attending family planning clinics, male military recruits and men undergoing employment physicals’ [ 3 ]. These samples served as proxies for the general population where population-based sampling was not, or could not, be conducted. The point estimates reported were adjusted for diagnostic test performance by applying a standardization factor for urogenital infection as utilized by WHO (Additional file 4 ) [ 3 , 11 ]. For rectal and pharyngeal infections, a separate literature review was undertaken to derive sensitivity and specificity values (for culture and/or NAAT) and adjustments were applied in the same manner as for the urogenital samples (Additional file 4 ). Due to obvious heterogeneity in study populations and study designs, widespread inclusion of non-representative samples and frequent lack of reporting of key parameters to judge the study quality, a quality score was not assigned. Similarly, a meta-analysis could not be conducted as we were limited in our ability to appropriately compare studies directly. We did not calculate a median summary estimate per country because only a small number of countries had three or more available estimates. Instead, guided by the principles of Campbell et al [ 12 ], we conducted a narrative synthesis, presenting the prevalence and test positivity estimates reported in the context of the source population and the type of sampling conducted, rather than directly comparing estimates. General population estimates were considered ‘population-based’ and representative if participants were sampled from a general population sampling frame and some form of random selection was performed. Studies employing other forms of sampling from proxy general population samples are labelled as such. As MSM and sex workers are defined in terms of their sexual behaviour, population-based denominator samples are generally not available. For these groups, screening and/or enhanced testing is frequently recommended irrespective of symptom status (and thus may be more reflective of prevalence). Therefore, studies conducted at STI clinics and at other venues frequented by MSM and sex workers were eligible for inclusion, excepting studies including persons presenting with symptoms, which were excluded to minimize bias. The median sample size and interquartile range were estimated using Excel’s ‘quartile.exc’ function.

Prevalence reporting in the general population

We identified 2015 citations relating to gonorrhoea ‘prevalence’ (Fig. 1 ), subsequently categorized into (a) the general population or proxy general population groups (men, women, and pregnant women separately), (b) MSM, and (c) FSW and MSW. Following title and abstract screening, we reviewed 424 full-text publications, of which 174 addressed the primary or secondary objective and were eligible for inclusion, reporting data from the following WHO regions: Africa (n=41), the Western Pacific (n=41), high-income North America that is part of the Region of the Americas (n=25), the Americas excluding high-income North America (n=25), Europe (n=19), South-East Asia (n=18), and the Eastern Mediterranean (n=5). The number of countries where prevalence and/or test positivity estimates were identified from the general population was limited, with data points identified from only 18.0% of countries worldwide (35/194) for women and 9.8% (19/194) for men (Fig. 2 ). Prevalence of gonorrhoea in the general population by WHO region and country is summarized in Table 1 and test positivity estimates from proxy general population samples in Table 2 .

PRISMA diagram describing selection of citations reporting gonorrhoea prevalence. Note: Some articles reported outcomes on several of the populations of interest or provided data for >1 country and therefore the total number of included data points does not amount to 174. n=number of articles

Availability of gonorrhoea prevalence reporting globally. Maps represent the availability of prevalence data in general population samples worldwide, including pregnant women, women attending family planning clinics, male military recruits, and work-based health screening programmes and other similar groups. General population estimates were considered ‘national population-based’ or ‘local population-based’ if participants were sampled from a general population sampling frame and some form of random selection was performed. Studies where probability sampling was not conducted, and which may not be generalizable beyond the study, are labelled as ‘non-population based’

For several countries, we did not identify prevalence or test positivity data. The grey literature search led to one additional estimate [ 63 ], but also allowed us to set the prevalence estimates identified in the context of the extent of surveillance otherwise ongoing in the country. To this end, expert consultation led to identification of surveillance data from three international reporting networks (WHO Global, WHO European Regional Office, and ECDC), and national surveillance data or reports from an additional seven countries, the United States of America (USA), Canada, Australia, Singapore, New Zealand, Japan, and the Republic of Korea.

Prevalence data and/or test positivity in general population samples were identified in 13.2% (seven out of 53) of countries in the WHO European region (nine estimates in women, including pregnant women [ 18 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], and five in men [ 18 , 56 , 57 , 58 , 59 ]) (Tables 1 and 2 ). We identified only one representative, population-based prevalence study in the United Kingdom (UK) that was of national scope [ 18 ]. These data were derived from the National Survey of Sexual Attitudes and Lifestyles (NATSAL) in 2010–2012. A probability sample of 15 162 men and women aged 16–74 years was drawn from the general population. Gonorrhoea testing was conducted for 2665 women and 1885 men and an overall prevalence of <0.1% was recorded (Table 1 ), higher in women and men aged 20–24 (0.2% and 0.1%, respectively). Data from all other countries represented test positivity data that were drawn from proxy groups of the general population, mainly non-probability samples, drawn from antenatal/obstetric clinics, primary care, community/youth clinics, with one study in a high school setting [ 56 ]. The median study sample size was 1004 in all women (interquartile range [IQR]: 220–5337) and 1236 in men (IQR: 802–6620). In all general population studies, NAAT testing conducted on urine (men, women) or genital fluid (women) was most common; confirmation by both NAAT and culture was used in pregnant women in France and Portugal [ 61 , 62 ]. Data on both sexes were available in only five studies [ 18 , 56 , 57 , 58 , 59 ]. One study reported samples from the urogenital and rectal site in aggregate [ 57 ]. All other studies included urogenital infection only.

For countries where no prevalence or test positivity estimate from the general population was identified, some degree of surveillance data was discoverable through the grey literature search. Most European Union (EU)/European Economic Area (EEA) Member States have comprehensive surveillance systems and report a national notification rate annually, except for Germany, Liechtenstein, Austria (not since 2014), and Greece (not since 2017) [ 85 , 86 ]. Belgium, France, and the Netherlands have sentinel surveillance systems. In countries outside the EU/EAA region (mostly the eastern European region), data were less discoverable. In 2017, countries including Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Russian Federation, Turkmenistan, and Uzbekistan reported gonorrhoea cases to the WHO European Regional Office (M. Dara and G. Kuchukhidze, personal communication, 24 February 2019). Indicators included the absolute number of cases identified, the male to female ratio, and only for Armenia, the proportion of reported MSM among the cases. Prevalence data or comprehensive syndromic and aetiologic case reporting were not otherwise identified in the wider European region.

High-income North America

In the USA, laboratory-confirmed gonorrhoea is mandatorily notifiable and data collection is comprehensive, from diverse clinical settings including STD clinics, laboratories, family planning and school-based clinics, hospitals, emergency rooms, drug treatment centres, correctional facilities, and the military [ 87 ]. The most recent estimate of nationwide population prevalence identified was from the National Health and Nutrition Examination Survey (NHANES), a series of cross-sectional, bi-annual household surveys representative in terms of sex, age and race/ethnicity of the USA civilian, non-institutionalized population [ 19 ]. Between 1999 and 2008, screening for cervical or urethral gonorrhoea was a study component, and 15 885 persons, aged 14–39 years participated. An extrapolated national prevalence of 0.3% (95% confidence interval [CI]: 0.1%–0.5%) among 14–39-year-olds was estimated, higher in women than in men (Table 1 ). N. gonorrhoeae testing within NHANES stopped at the end of 2008 and, in 2009, gonorrhoea prevalence and notification rates were at an all-time low in the USA [ 19 ].

In terms of non-probability samples, an estimate of prevalence from a sentinel surveillance population of young people at elevated risk for gonorrhoea is provided annually by the Centers for Disease Control and Prevention (CDC), using data from the ‘National Job Training Program’ (NJTP), a nationwide vocational programme for socioeconomically disadvantaged youth aged 16 to 24 years who are considered at risk of STIs [ 63 ]. Participants are offered gonorrhoea and chlamydia screening at programme entry. In 2018, the median state-specific estimated gonorrhoea prevalence for programme entrants aged 16–24 years was 2.2% in women (range 0.4% to 7.6%), and 0.7% in men (range 0.0% to 4.8%) (Table 2 ) [ 63 ].

In the USA, we identified a further seven test positivity estimates from proxy general population samples in women (including one from a chart review of women screened [ 64 ], two studies in high schools [ 65 , 66 ], and four in pregnant women who are routinely tested [ 67 , 68 , 69 , 70 ]) and three data points in men (the same two studies in high schools [ 65 , 66 ] and one study in college students [ 81 ]) that met the inclusion criteria for the secondary objective (Table 2 ). There was a wide range in study sample size and in estimates reported, reflecting diversity in study participants and settings, and study population characteristics. Test positivity estimates from non-probability samples from the two studies in high schools were identified: one reported the proportion positive over almost 8 years (9.0% [3270/36 263] in girls and 4.1% [1588/39 010] in boys) and another yielded a combined estimate of 2.4% in girls and boys (Table 2 ) [ 65 , 66 ]. No comparison could be made across studies. Where reported, studies used NAAT testing.

In Canada, no prevalence study or proxy general population study was identified. Gonorrhoea is mandatorily notifiable, and laboratory-confirmed cases are reported to the Public Health Agency of Canada through the Canadian Notifiable Disease Surveillance System. Summary data are published annually by age and sex, and are available online [ 88 ], and a detailed surveillance report is produced every five years.

Americas (excluding high-income North America)

Prevalence and/or test positivity estimates from the general population were identified in 18.2% (six out of 33) of countries in this WHO region excluding the USA and Canada (12 estimates in women, including pregnant women [ 16 , 17 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ], and four in men [ 17 , 48 , 49 , 80 ]) (Tables 1 and 2 ). One study in Peru could be considered population-based and of national scope. In this study, the substantial sample included 13 925 randomly selected 18–29-year-old men and women who were resident in 24 cities with populations >50 000 people [ 17 ]. Additionally, a local population-based study in Brazil, also urban, was conducted using two-stage sampling of households and young women in middle size cities in Central Brazil [ 16 ]. The remaining studies were non-probability samples, mainly from community settings including educational facilities, primary healthcare, adolescent health clinics and ANCs. The median study sample size was 399 in women (IQR: 309-1719) and 371 in men (IQR: 180-5749). All studies involved NAAT screening of urine (n=4) [ 16 , 44 , 45 , 49 ] and urogenital swab samples (n=7) [ 17 , 46 , 47 , 48 , 50 , 51 , 53 ] for women (clinical specimen not specified, n=1 [ 52 ]), and urine (n=3) [ 17 , 48 , 49 ] for men (clinical specimen not specified, n=1 [ 80 ]).

From the grey literature search, we identified only aetiological or syndromic case reporting in adult men through WHO Global AIDS Monitoring (GAM; known as Global AIDS Response Progress Reporting prior to 2015) for other countries in the region [ 3 ]. No further prevalence or test positivity data were identified in the region.

In the WHO African region, prevalence data and/or test positivity estimates from the general population were identified in 25.5% (12 out of 47) of countries (25 estimates in women, including pregnant women [ 13 , 14 , 15 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], and six in men [ 13 , 14 , 15 , 29 , 31 , 34 ]) (Tables 1 and 2 ). Three of the studies were local population-based, derived from household samples, and none were of national scope. The first was from the urban centre of Cotonou in Benin, where 2507 subjects aged 15–49 years, from 1070 households sampled from 38 census areas, participated [ 13 ]. In Malawi, another estimate was derived from a largely rural population from the eastern lakeside regions of the Mangochi district [ 14 ]. Most recently, 1342 young people aged 15–24 years were selected from a ‘health and demographic surveillance site’ sampling frame in rural South Africa [ 15 ]. The remaining studies (Table 2 ) were derived from non-probability samples with diverse recruitment sites, including antenatal clinic (ANC) settings, schools and universities, primary healthcare sites, and community-based recruitment. The median study sample size was 322 in women (IQR: 200–553) and 422 in men (IQR: 351–755). Laboratory confirmation was mainly by NAAT on urogenital swab samples and, to a lesser extent, on urine for women; in four studies [ 23 , 24 , 30 , 40 ], Gram stain and/or culture only were used. For men, urine samples were tested by NAAT in all cases where reported.

In the African region, 43% of countries reported to WHO in 2013 having STI surveillance systems in place and 40% had national strategies or plans for preventing and controlling STIs [ 89 ], but beyond limited reporting of aetiological surveillance among men and syndromic surveillance in men and women, we did not identify any further prevalence reporting in the region.

Western Pacific

Prevalence data and/or test positivity data from the general population were identified in 22.2% (six out of 27) of countries and territories in the WHO Western Pacific region (11 estimates in women, including pregnant women [ 20 , 21 , 22 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ], and four in men [ 20 , 22 , 73 , 84 ]) (Tables 1 and 2 ). There were three population-based studies. One was of national scope in New Caledonia [ 22 ]. It included men and women selected during a national three-stage random sampling of general practice surgeries and public dispensaries, and the sample was then weighted to reflect the general population aged 18–49 years. The other two population-based studies were local in scope and were both in China. In one study from the Shandong province [ 20 ], men and women were sampled in a complex multi-stage sampling process based on urban and rural communities within geographic regions. The second study, from Shenzhen City [ 21 ], included women only and was designed to be representative of the entire population in the Nanshan District of the city. Beyond these prevalence data, for both men and women, test positivity estimates from non-probability, proxy general population samples were derived from a range of study settings including community settings, primary care, and hospital-based maternity clinics/ANCs. One study was in an occupational group (miners) in men in China [ 84 ]. The median study sample size in the region was 765 in women (IQR: 362–3581) and 1290 in men (IQR: 376–4490). In some countries in the region where no data were identified, gonorrhoea is a notifiable infection; routine national surveillance is conducted and opportunistic/risk-based screening and/or testing is recommended for some population groups (Australia, New Zealand, and Singapore) [ 90 , 91 , 92 ]. Sentinel surveillance is conducted in the Republic of Korea and in Japan, mostly in urology departments. In both countries, reported cases per sentinel are low and have decreased in recent years [ 93 , 94 ]. GAM data for men are also notified to WHO from many countries [ 3 ], but no further prevalence data were identified in the region.

South-East Asia

Among 11 countries in the WHO South-East Asian region, we did not identify any population-based prevalence estimates. Test positivity data in general population samples were identified from 18.2% (two out of eleven) of countries (two estimates in women, including pregnant women [ 71 , 72 ], and two in men [ 82 , 83 ]) (Table 2 ). Non-probability samples from the general population were community-based in women in India, hospital-based in young pregnant women aged <18 years in Thailand, and in occupational groups in men (migrant workers in India and military conscripts in Thailand). The median study sample size was 466 in women (range: 121–811) and 1482 in men (range: 840–2123).

We did not identify further information on gonorrhoea surveillance in the region, with the exception of GAM data from some countries [ 3 ].

Eastern Mediterranean

We identified non-probability samples in 4.8% (one out of 21) of countries in the WHO Eastern Mediterranean region: a single study in a hospital involving pregnant women [ 54 ] (Iran, n=239; standardized prevalence: 0.5%) (Table 2 ). According to the WHO, ten countries surveyed in 2013 reported having an STI surveillance system, four reported conducting aetiological studies, 11 had updated national STI guidelines or recommendations in place and nine had a national strategy or action plan for STI prevention and control [ 89 ], but no further estimates were identified in the region.

Prevalence and test positivity reporting in vulnerable population groups

Men-who-have-sex-with-men

Prevalence and/or non-probability test positivity data on gonorrhoea in the MSM population were identified in 64 studies from 25 countries (seven countries in Africa, five in Europe, two in North America, four in the Americas [excluding high-income North America], four in the Western Pacific, and three in South-East Asia) (Fig. 3 ; Additional file 5 ) [ 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 ]. For 56.0% (14 out of 25) of countries, data originated from a single study in an urban setting. In five studies, men testing HIV-positive were excluded at the outset [ 96 , 119 , 124 , 148 , 149 ]. HIV status was reported in five studies with variable HIV-positivity [ 98 , 100 , 103 , 115 , 127 ]. Three studies included asymptomatic cases only [ 120 , 131 , 150 ]. Urogenital screening and/or opportunistic testing (predominantly on urine samples) was most often performed. An equal proportion of studies involved recruitment from community settings or STI clinics, but there was diversity in terms of the populations included, including HIV status, which was often not reported. Both rectal and urogenital sampling were reported in 26 studies; rates of rectal infection were higher than urogenital rates in 69.2% (n=18) of these studies (Fig. 3 ). NAAT testing was reported in 22 of these studies, culture-only testing in two, and culture or NAAT testing in two. Reported rates of pharyngeal testing from 27 studies were mostly (51.9%) between 5.0% and 10.0%, 22.2% were between 1.0% and 5.0%, and 14.8% were >10.0%. Though variable, on average, the standardized estimate of pharyngeal infection was similar to urogenital positivity where reported in the same study.

Reported prevalence and/or test positivity of urethral (a) and/or rectal (b) gonorrhoea-positive cases in men-who-have-sex-with-men. 1 Prevalence rates for urethral gonorrhoea could not be standardized. 2 Prevalence rates for rectal gonorrhoea could not be standardized

Sex workers

Data on gonorrhoea prevalence and/or test positivity in MSW, FSW or both were available from 23 countries (Table 3 ), with 38 studies reporting on FSW and six on MSW. Of 41 unique studies, 14 were conducted in a clinic setting (including STI clinics, genito-urinary clinics and outreach clinics) and 13 at commercial sites (including hotels, brothels, street and residence). The remainder (n=14) were described as community-based or conducted at other mixed locations. Only urogenital testing was performed except for one study in China that also performed pharyngeal testing [ 184 ]. Overall, the median study sample size was 655 in women (IQR: 323–2165) and 240 in men (IQR: 113–584). The positivity estimates ranged from 0.0% (MSW in the Republic of Korea) to 29.2% (FSW in Indonesia).

Gonorrhoea prevalence monitoring is one of four key components of national STI surveillance programmes that is recommended by WHO to reduce the burden of gonorrhoea infections by 90% between 2018 and 2030 (in addition to case reporting, assessment of the aetiology of STI syndromes, and monitoring of antimicrobial resistance) [ 9 ]. WHO recommends prevalence assessments in the general population every two to three years, and in key populations such as MSM and sex workers [ 3 , 9 ]. From our review, it is clear that substantive prevalence data among representative samples of the general population were seriously lacking on a worldwide basis. We identified national population-based data from only four countries (USA [ 19 ], UK [ 18 ], Peru [ 17 ], and New Caledonia [ 22 ]), all pre-dating 2013. Recent local population-based data were identified from China [ 20 , 21 ] (2016 and 2017) and South Africa [ 15 ] (2018), but otherwise samples used for local population-based estimates were collected more than 10 years ago (Brazil, Benin, and Malawi [ 13 , 14 , 16 ]). The majority of the remaining test positivity estimates were derived from non-probability samples from groups that might be considered proxies of the general population, as proposed by WHO [ 3 ].

Based on our findings, most studies were conducted in single centres or discrete geographic regions or populations. We excluded STI clinic settings to avoid overestimating the prevalence in general population samples. As estimates (mainly from proxy general population groups) tended to be high, albeit with wide variation in the magnitude and precision of the estimate, it is highly likely that the risk profile of proxy populations was also higher than that of the general population. Even within groups, representativeness may not always have been similar (e.g. military conscripts residing in barracks versus those living at home). The median study sample size in the Americas (excluding high-income North America), Africa and the Eastern Mediterranean was <500 in both men and women, which further limits generalizability beyond the study population in question. Where national data were available to comment (e.g. USA), estimates from non-probability samples in defined younger populations [ 63 , 65 , 66 ] were higher than nationwide population-based estimates [ 19 ] or estimates from older populations [ 64 ], further highlighting the need for continued nationally representative population sampling. Diagnostic testing used varied widely and the sensitivity and specificity of these are an essential factor, contributing to differences in reported estimates. We standardized estimates for differences in laboratory methods (NAAT versus culture) and clinical specimens (urine or urogenital samples) where reported [ 3 , 11 ]. For consistency, we also adjusted for NAAT versus culture on rectal and pharyngeal samples, based on reported sensitivities and specificities in the literature and using a similar standardization procedure, to allow for within-study comparison. The specimen and test were not always reported, but NAAT-based testing was most common.

For most countries, no prevalence estimate or test positivity estimate from general population groups was identified. It was clear from our online (English) grey literature search, that surveillance is ongoing more widely, as we retrieved surveillance reports from online national and international data repositories, syndromic surveillance reports in some countries, and intermittent summaries of laboratory surveillance in others. Generally, the quality and quantity of data identified were highly variable and often neither timely nor contemporaneous. In the absence of prevalence data, low case rates reported in some settings likely reflect limited testing and restricted availability of appropriate laboratory diagnostics rather than actual infection rates. In many African countries, for example, prevalence reports (where available) and syndromic surveillance suggest that the very limited aetiological reporting substantially underestimates the true infection burden.

Heterogenous data in MSM were available for only 12.9% (25 out of 194) of countries, mainly single-centre studies in urban, community-based or STI clinic settings. Most studies performed testing at the urogenital site. Where both urogenital and extragenital testing were conducted, rates at rectal sites were typically higher. However, for modern NAATs no evidence-based consensus exists regarding sensitivity and specificity correction factors when using other diagnostic methods or different NAATs for urogenital and especially extragenital infections. International evidence-based consensus regarding these corrections is imperative to develop. Rates among FSW were often many multiples higher than general population estimates in women, in countries where data in both populations were available. Due to the dearth of data on sex workers in some regions, we erred on the side of inclusivity, including small studies of <100 from Iran for example, where no data were otherwise available.

Our review had limitations. There were undoubtedly data from studies not discoverable on PubMed. For example, a systematic review from China, which documented STI risk among MSM [ 189 ], included studies that we could not access through the library systems available to us. Systematic reviews on a regional basis with good local knowledge, including in setting and language, would be a valuable addition. For many countries, only one or two data points were identified. Limited data and marked heterogeneity between studies prohibited us from conducting a meta-analysis or reporting median estimates. Reporting of proportion testing positive was very diverse in terms of variables reported, degree of stratification by demographic and other factors (e.g. HIV status), details regarding diagnostic tests, and anatomic site, often with statistics omitted where data had clearly been collected. With improved reporting from diverse populations, novel methods for synthesizing diverse data may therefore be required.

Conclusions

Gonorrhoea prevalence is a core indicator to properly inform gonorrhoea management and control programmes, international and national guidelines, and policy documents. Gonorrhoea prevalence monitoring and reporting is suboptimal or absent in most countries. Many countries and regions have seen substantial increases in notification rates of gonorrhoea in recent years [ 63 , 85 ]. In the absence of serial prevalence data, however, it is difficult to disentangle how much of this reflects a true increase in the burden of gonorrhoea or some degree of improved awareness among groups at increased risk (in particular MSM), more consistent screening and/or testing, increased availability and use of NAATs, and improved (electronic) reporting. Irrespectively, among key populations such as MSM and sex workers, there is a substantial burden of infection where data are available. To inform STI control programmes at the national and regional level, and to inform innovative epidemiologic modelling initiatives such as SPECTRUM [ 11 ] and the Global Burden of Disease [ 190 ] that attempt to quantify and model the global burden, significantly more data of higher quality are required. There is an urgent need for more resources for researchers to design, conduct and report prevalence studies in a more consistent, standardized, and quality-assured way. Within countries, serial prevalence monitoring at intervals, including assessment and reporting of a minimum set of epidemiological variables, should be considered. Our review showed the need for more testing at extragenital sites, particularly, but not exclusively, among the MSM population. WHO currently provides guidance on the assessment of gonorrhoea and chlamydia prevalence among pregnant women at ANCs [ 191 ]. This guidance could be extended beyond the ANC setting. Consistent adherence to study reporting guidelines (e.g. adapted STROBE checklists [ 192 ] or equivalent), for all researchers is also advised.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article and its additional file (Additional file 6 ).

Abbreviations

Antimicrobial resistance

Antenatal clinic

Centers for Disease Control and Prevention

Confidence interval

European Centre for Disease Prevention and Control

European Economic Area

European Union

Female sex workers

Global AIDS Monitoring

Human immunodeficiency virus

Interquartile range

Medical subject headings

Male sex workers

Nucleic acid amplification tests

National Survey of Sexual Attitudes and Lifestyles

National Health and Nutrition Examination Survey

National Job Training Program

Sexually transmitted disease

Sexually transmitted infection

United Kingdom

United States of America

World Health Organization

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Acknowledgments

The authors thank the Modis platform for editorial assistance and manuscript coordination, on behalf of GSK. Kristel Vercauteren provided medical writing support and Maria Ana de la Grandière and Sara Blancquaert coordinated the manuscript development and provided editorial support. The authors also thank Masoud Dara and Giorgi Kuchukhidze (WHO European Regional Office, Copenhagen, Denmark); Jane Rowley (London, UK); and Nicholas J. Kassebaum (Institute for Health Metrics and Evaluation, IHME, Seattle, USA).

This work was funded by GlaxoSmithKline Biologicals SA. MU was not funded.

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JW supervised this work. JW, VAK, LS and MU contributed to the conceptualization, investigation, methodology, validation, and visualization of this work. JW, VAK, LS and MU participated in the development and the review of the manuscript and approved the final submitted version.

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Supplementary Information

Additional file 1..

PRISMA checklist.

Additional file 2.

Literature search strategy.

Additional file3.

Inclusion and exclusion criteria.

Additional file 4.

Standardizations adopted for urogenital, rectal and pharyngeal laboratory tests.

Additional file 5.

Reported gonorrhoea prevalence and/or test positivity in men-who-have-sex-with-men, by WHO region, country, and anatomic site.

Additional file 6.

Dataset supporting the output of the literature search.

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Whelan, J., Abbing-Karahagopian, V., Serino, L. et al. Gonorrhoea: a systematic review of prevalence reporting globally. BMC Infect Dis 21 , 1152 (2021). https://doi.org/10.1186/s12879-021-06381-4

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DOI : https://doi.org/10.1186/s12879-021-06381-4

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27:  Chlamydia and Gonorrhea

Takova D. Wallace-Gay; Jonathan C. Cho

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Patient presentation.

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Chief Complaint

“I’ve noticed some discharge in my underwear.”

History of Present Illness

TP is a 23-year-old black female who presents to the family medicine clinic with complaints of unusual discharge. She reports a frequent sensation of urination and mentions that she has been having odorless vaginal discharge that is different than usual. Upon questioning she mentions being nervous that she may have an STD because she had unprotected vaginal intercourse with a young man after a fraternity party about 2 weeks ago. Since then, she heard rumors that this particular gentleman has a history of multiple sexual partners, but she was not concerned until noticing the discharge 2 days ago.

Past Medical History

Asthma, prior ankle injury

Surgical History

Tonsillectomy

Family History

Mother and father with HTN

Social History

Active as a college basketball player; occasionally smokes marijuana; (–) tobacco; (+) EtOH (beer and liquor most weekends)

Doxycycline (swelling of lips and tongue as a teenager)

Home Medications

Acetaminophen 500 mg, two tablets PO q4-6h PRN pain

Ibuprofen 200 mg PO q4-6h PRN pain

Albuterol metered-dose-inhaler 2 puffs q4h PRN shortness of breath and prior to exercise

Ethinyl estradiol and norgestimate (Ortho Tri-Cyclen Lo) one tablet PO daily

Physical Examination

Vital signs.

Temp 98.6°F, P 68, RR 18 breaths per minute, BP 116/70 mm Hg, pO 2 97%, Ht 5′8″, Wt 72.7 kg

Well developed, well-nourished female in no acute distress

Non-contributory

Denies shortness of breath

Cardiovascular

NSR, no m/r/g

Soft, non-distended, non-tender, (+) bowel sounds

Genitourinary

Normal female genitalia, denies abnormal bleeding, (+) vaginal discharge

(+) headaches 1–2 times a week, A&O ×3

Extremities

Noncontributory

Laboratory Findings

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Case Study: Antimicrobial Resistant Gonorrhea

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Antimicrobial Resistance in N. gonorrhoeae: A Case Study (PDF Document 938 KB - 6 pages)

Antimicrobial Resistance in N. gonorrhoeae: A Case Study (PPT Document 139 KB - 5 slides)

Objective: This case study has been developed for primary care and public health professionals who provide counselling and care related to sexual health and sexually transmitted infections. The slides may also be shared with colleagues and those who would benefit from the information. The presentations can be used as is or modified for specific needs.

Directions for Use: When you open the presentation, a box named 'Password' will appear. Choose the 'Read Only' option in the bottom right corner. You may:

• View the presentation;
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• Print the presentation as handouts for participants or print on transparencies

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Antimicrobial Resistance in N. gonorrhoeae: A Case Study

Table of contents – presentation slides, patient history, counselling.

Miranda is a 20 year old student who will be returning home in the next few days for a summer job. She became sexually involved with a new partner about a month ago. She has no family physician.

She reports her LNMP being 2 weeks ago, abnormal vaginal discharge, pain during intercourse, and that these symptoms appeared 5-7 days ago.

• How would you diagnose and screen Miranda?
• How would you treat Miranda?

Are there any additional steps you would take?

Slide #1 – Speaker's Notes

• Your patient, Miranda, is a 20 year old student who will be returning home in the next few days for a summer job. She became sexually involved with a new partner about a month ago.
• She has no family physician.
• Abnormal vaginal discharge
• Pain during intercourse
• The date of her last known menstrual period was 2 weeks ago
• Are there any additional steps that you would take?

Slide #2 – Speaker's Notes

In order to diagnose Miranda, the following steps are recommended:

• The rationale is that any patient with lower abdominal pain should receive a complete pelvic examination.
• The rationale is that symptomatic patients should be tested with culture, particularly if the patient is suspected to have pelvic inflammatory disease. Cultures allow for antimicrobial susceptibility testing. They are also important for contact tracing.
• The rationale is that gonorrhea and chlamydia are often concomitant infections.
• The rationale is that colonisation can occur without anal penetration.

Slide #3 – Speaker's Notes

It is recommended that Miranda be treated as follows:

• Note that women are often asymptomatic.
• Combination therapy should be used for the treatment of gonorrhea.

Counsel Miranda on prevention.

Infection with one STI increases the chance of others being present.

HIV transmission and acquisition is enhanced in people with gonococcal infections.

• Empirically treated regardless of clinical findings and without waiting for test results.

Slide #4 – Speaker's Notes

• She should be informed that infection with one sexually transmitted infection increases the chance of other infections.
• Patients with gonorrhea are more likely to transmit and acquire HIV; HIV testing is recommended.
• Untreated gonorrhea in women can result in upper genital tract infection which may result in pelvic inflammatory disease, infertility, or ectopic pregnancy.
• Gonorrhea is efficiently transmitted from males to females via vaginal intercourse, rectal intercourse, and fellatio.
• Gonorrhea can be transmitted from females to males via vaginal intercourse and less efficiently by cunnilingus.
• Patients with gonorrhea are more likely to transmit and acquire HIV.
• Miranda should abstain from intercourse until therapy is completed and until her and her sex partners no longer have symptoms.
• Latex condoms, when used consistently and correctly, can reduce the risk of transmission of gonorrhea.
• Discuss human papillomavirus vaccine Miranda as per the recommendations outlined in the National Advisory Committee on Immunization Update on Human Papillomavirus Vaccines
• Partner notification should be conducted for any sexual partners that Miranda has had within the 60 days prior to her symptom onset. All of her partners should be notified, tested and empirically treated (given that Miranda does have symptoms).

Strongly encourage Miranda to return to repeat her test.

Report the case to local public health authorities.

Treatment failure should also be reported.

Repeat screening for individuals with gonococcal infection is recommended 6 months post-treatment.

Slide #5 – Speaker's Notes

• Miranda should be strongly encouraged to return to a clinic to have herself retested (at the latest in 3 weeks) in order to ensure that the antibiotics were effective.
• She should also be retested in 6 months.
• If you become aware that Miranda's treatment was not effective, this treatment failure should also be reported.

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Recommendations

Public comments and nominations, about the uspstf.

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• Evidence Summary: Chlamydia and Gonorrhea: Screening

Evidence Summary

Chlamydia and gonorrhea: screening, september 14, 2021.

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

By Amy Cantor, MD, MPH; Tracy Dana, MLS; Jessica C. Griffin, MS; Heidi D. Nelson, MD, MPH; Chandler Weeks, MPH; Kevin L. Winthrop, MD, MPH; Roger Chou, MD

The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was published in JAMA on September 14, 2021 ( JAMA . 2021;326(10):957-966. doi:10.1001/jama.2021.10577).

Importance: The 2014 US Preventive Services Task Force (USPSTF) recommendation statement supported the effectiveness of screening for chlamydia and gonorrhea in asymptomatic, sexually active women 24 years or younger and in older women at increased risk for infection, although evidence for screening in men was insufficient.

Objective: To update the 2014 USPSTF review on screening for chlamydial and gonococcal infection in adults and adolescents, including those who are pregnant.  

Data Sources: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE (January 1, 2014, through May 28, 2020) with surveillance through May 21, 2021.

Study Selection: Randomized clinical trials and observational studies of screening effectiveness, accuracy of risk stratification and alternative screening methods, accuracy of tests, and screening harms.

Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently assessed study quality.

Main Outcomes and Measures: Complications of infection; infection transmission or acquisition; diagnostic accuracy of anatomical site–specific testing and collection methods; screening harms.

Results: Twenty-seven studies were included (N = 179,515). Chlamydia screening compared with no screening was significantly associated with reduced risk of pelvic inflammatory disease (PID) in 2 of 4 trials and with reduced hospital-diagnosed PID (0.24% vs 0.38%); relative risk, 0.6 [95% CI, 0.4-1.0]), but not clinic-diagnosed PID or epididymitis, in the largest trial. In studies of risk prediction instruments in asymptomatic women, age younger than 22 years demonstrated comparable accuracy to extensive criteria. Sensitivity of chlamydial testing was similar at endocervical (89%-100%) and self- and clinician-collected vaginal (90%-100%) sites for women and at meatal (100%), urethral (99%), and rectal (92%) sites for men but lower at pharyngeal sites (69.2%) for men who have sex with men. Sensitivity of gonococcal testing was 89% or greater for all anatomical samples. False-positive and false-negative testing rates were low across anatomical sites and collection methods.

Conclusions and Relevance: Screening for chlamydial infection was significantly associated with a lower risk of PID in young women. Risk prediction criteria demonstrated limited accuracy beyond age. Testing for asymptomatic chlamydial and gonococcal infections was highly accurate at most anatomical sites, including urine and self-collected specimens. Effectiveness of screening in men and during pregnancy, optimal screening intervals, and adverse effects of screening require further evaluation.

Chlamydia is the most commonly reported sexually transmitted infection (STI) in the US, followed by gonorrhea. In 2019, 1,808,703 cases of chlamydia were reported to the Centers for Disease Control and Prevention (CDC), corresponding to a rate of 552.8 cases per 100,000 population. 1 Reported cases of chlamydial infections among US women vs men were 698.9 vs 399.9 cases per 100,000, respectively; however, rates among men increased 32.1% from 2015 to 2019. In 2019, there were 616,392 cases of gonococcal infections, corresponding to a rate of 188.4 cases per 100,000 persons. Both infections demonstrate differences in reported cases by geography, race and ethnicity, and HIV status. 1

In women, chlamydial infection is usually asymptomatic but can result in transmission. 2 Untreated chlamydial infections can progress to symptomatic pelvic inflammatory disease (PID) and can result in infertility, chronic pelvic pain, and ectopic pregnancy. 2 , 3 In men, genital chlamydial infection is most often asymptomatic 4 , 5 but can cause nongonococcal urethritis, epididymitis, and if symptomatic, may present as urethritis. 2 Chlamydial infection can facilitate HIV infection in both women and men and may potentiate the risk for cervical cancer. 6 Gonococcal infections in women are often asymptomatic but in men can lead to symptomatic urethritis, epididymitis, and proctitis. 7 , 8 In contrast, the majority of extragenital (eg, pharyngeal, rectal) infections in men are asymptomatic. 9 , 10

In 2014, the US Preventive Services Task Force (USPSTF) reissued B recommendations for screening for chlamydia and gonorrhea in sexually active women 24 years or younger and in older women at increased risk for infection. 11 Evidence was insufficient to assess the balance of benefits and harms of screening for chlamydia and gonorrhea in men. This systematic review was conducted to update prior reviews on this topic for the USPSTF, 12-14 to inform an updated recommendation.

Scope of the Review

Detailed methods and additional information about included studies are available in the full evidence report. 15 Figure 1 shows the analytic framework and key questions (KQs) that guided the review.

Data Sources and Searches

Searches included Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from January 1, 2014, through May 28, 2020 (eMethods 1 in the JAMA Supplement), with surveillance through May 21, 2021. Reference list review of relevant systematic reviews supplemented the searches.

Study Selection

Two investigators independently reviewed English-language titles, abstracts, and full-text articles for inclusion using predefined eligibility criteria (eMethods 2 in the JAMA Supplement). The screening population included asymptomatic, sexually active adults and adolescents, including those who are pregnant. This update primarily evaluated studies published since the prior USPSTF review. 17 However, since the scope, KQs, and inclusion criteria differ from prior reviews, older studies that were not previously reviewed are also included. Specifically, this review included new KQs focused on accuracy of risk stratification and screening strategies for identifying persons at increased risk, and a KQ evaluating the diagnostic accuracy of anatomical site–specific testing and collection methods. We did not rereview the diagnostic accuracy of specific assays or tests, which the prior review found to be highly accurate. 17

For screening effectiveness and harms, randomized clinical trials (RCTs) and controlled observational studies of screening vs no screening in asymptomatic individuals that evaluated health outcomes were included. Outcomes for KQ1 included reduced complications of chlamydial or gonococcal infections and reduced transmission or acquisition of disease, including HIV and, for pregnant individuals, reduced adverse maternal, fetal, or infant outcomes. Studies of risk stratification methods and screening strategies (eg, selective screening of high-risk groups, sampling from various anatomical sites, cotesting for concurrent STIs including HIV, and using different screening intervals) for chlamydia and gonorrhea that reported measures of diagnostic accuracy or discrimination were included for KQ2.

For KQ3, studies of diagnostic accuracy that included measures of discrimination of testing at various anatomical sites or using different collection methods (self- vs clinician-collected) were included if studies used credible reference standards, adequately described the study population, defined positive test results, and reported performance characteristics of tests (eg, sensitivity, specificity) or provided data to calculate them. For KQ4 on harms of screening, uncontrolled observational studies were included in addition to RCTs and controlled observational studies. Harms include labeling, anxiety, false-positive and false-negative test results, and other consequences of testing.

Data Abstraction and Quality Rating

A single investigator abstracted details about study design, patient population, setting, interventions, analysis, follow-up, and results from each study. A second investigator reviewed abstracted data for accuracy. Two independent investigators assessed the quality of each study as good, fair, or poor using predefined criteria developed by the USPSTF (eMethods 3 in the  JAMA  Supplement). 16 Discrepancies were resolved through consensus. In accordance with the USPSTF Procedure Manual, 16 poor-quality studies were excluded due to methodological limitations.

Data Synthesis

Two independent reviewers assessed the internal validity (quality) of the body of evidence for each KQ using methods developed by the USPSTF, based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence. 16 , 18 Statistical meta-analysis was not performed because of methodological limitations of the studies and heterogeneity in study designs, interventions, populations, and other factors.

Of 2356 unique citations and 490 full-text articles reviewed, 20 studies (N = 179,515) met inclusion criteria, including 13 new studies 19-31 and 7 32-38 from the previous USPSTF report ( Figure 2 ).

Screening Effectiveness

Key Question 1. In sexually active, asymptomatic adolescents and adults, including those who are pregnant, what is the effectiveness of screening for chlamydial or gonococcal infections in reducing complications of infection and transmission or acquisition of disease, including gonorrhea, chlamydia, and HIV?

Four randomized trials evaluated the effects of screening for chlamydial infection vs no screening on risk of complications of infection ( Table 1 ), 25 , 32 , 33 , 36 including 3 trials 32 , 33 , 36 from the prior review. 17 As in the previous reviews, no study evaluated the effectiveness of screening for gonorrhea.

Sample sizes ranged from 1700 to 63,338 (total n = 70,174). Three trials enrolled exclusively women, 32 , 33 , 36 1 trial enrolled both women and men, 25 1 trial enrolled exclusively adolescents, 33 and 3 enrolled a mix of adolescents and adults (16 to 34 years) from a rural primary care setting, 25 a university setting, 32 and a population of higher-risk women. 36 Trials were conducted in the US, 36 Europe, 32 , 33 and Australia 25 and compared screening vs usual care, 25 home sampling, 33 or clinic-based testing. 36 One trial compared immediate vs deferred screening. 32 Three trials used self-collected vaginal 25 , 32 , 33 or male urine testing. 25 Two trials were rated good-quality[[25,32] and 2 fair-quality (eTable 1 in the  JAMA  Supplement), 33 , 36 because of unclear randomization methods and high loss to follow-up.

The Australian Chlamydia Control Effectiveness Pilot trial (ACCEPt), was a new, good-quality cluster randomized trial that evaluated the effectiveness of screening for chlamydia compared with usual care in 180,355 men and women aged 16 to 29 years in 130 rural Australian primary care clinics. 25 While screening was significantly associated with reduced risk of hospital-diagnosed primary PID (relative risk [RR], 0.6 [95% CI, 0.4-1.0]), the absolute difference was small (0.24% [57/23,527] vs 0.38% [88/23,219]). Screening was not significantly associated with reduced repeat chlamydia infection within 6 weeks to 6 months of a positive test result (odds ratio [OR], 3.1 [95% CI, 0.7-13.8]), clinic-diagnosed PID (RR, 1.1 [95% CI, 0.7-1.8]; 0.45% [293/65,519] vs 0.39% [237/ 60,384]), or clinic-diagnosed epididymitis (RR, 1.1 [95% CI, 0.7-1.8]; 0.26% [106/41,168] vs 0.27% [106/38,717]).

Three trials included in the prior USPSTF review indicated an association between screening and decreased risk of PID, although results were statistically significant in only 1 trial. 32 Chlamydia screening was significantly associated with reduced risk for PID in a fair-quality RCT of 2607 women aged 18 to 34 years at increased risk for chlamydia who were recruited from a health maintenance organization in the US (RR, 0.44 [95% CI, 0.20-0.90]). 36 In the Prevention of Pelvic Infection (POPI) trial, a good-quality RCT of 2529 sexually active symptomatic (35%) or asymptomatic (65%) young women in the UK, screening was not associated with a statistically significant reduced risk of PID (RR, 0.65 [95% CI, 0.34-1.22]). 32 However, 79% (30/38) of PID cases occurred in women who had tested negative at baseline. A fair-quality RCT of 1761 Danish high school students indicated that risk of PID was not significantly associated with a reduction of PID for screening vs home sampling (RR, 0.50 [95% CI, 0.23-1.08]). 33

Risk Stratification

Key Question 2. What is the accuracy of risk stratification methods or alternative screening strategies for identifying persons at increased risk for chlamydial or gonococcal infections (such as younger persons or men who have sex with men)?

Seven fair-quality studies (n = 93,137) evaluated accuracy of strategies for identifying individuals at increased risk for chlamydial or gonococcal infections using different criteria to select patients for testing (eTables 2 and 3 in the  JAMA  Supplement). 20-22 , 24 , 26-28 No study compared screening intervals or alternative screening strategies, such as testing for concurrent infection with HIV.

Two studies enrolled only women, 27 , 28 and 5 included both men and women. 20-22 , 24 , 26 Participants were asymptomatic in 3 studies, 20-22 symptom status was not reported in 3 studies, 24 , 26 , 27 and 1 study included both asymptomatic (52%) and symptomatic (47%) participants. 28 Studies were conducted in Canada, 20-22 the US, 24 , 26 , 28 and Europe 27 in family planning clinics, 28 STI or sexual health clinics, 20-22 , 26 , 28 university or community clinics, 24 and a pregnancy termination clinic. 27 Six studies were cross-sectional, 20-22 , 24 , 27 , 28 and 1 was a case-control study. 26 Key limitations included inadequate selection of patients and measurement of exposures or outcomes, including retrospective data collection, 20-22 , 27 and baseline between-group differences between intervention and control groups. 28

In asymptomatic patients, 2 cross-sectional studies (n = 35,818) of the Vancouver risk estimation tool, an instrument for identifying asymptomatic women and heterosexual men at increased risk for chlamydial or gonococcal infection, demonstrated fair discrimination (area under the receiver operating characteristics curve [AUC], 0.64-0.73). 20 , 21 Factors in the model included age, sex, race, number of partners, and other known STI risk factors. A cross-sectional study of a 3-item (age, indicators of risk, and injection drug use) risk score (n = 35,818) reported an AUC of 0.73 (95% CI, 0.71-0.74) in a population of asymptomatic men and women attending STI testing clinics in Canada. 22

A cross-sectional study of women attending family planning or STI clinics in the US (n = 6672) compared 9 sets of selective screening criteria for chlamydial infection. 28 In family planning clinics, 69% of women were asymptomatic, while nearly 80% of women in STI clinics reported genitourinary symptoms. 28 Age alone ( < 22 years) performed nearly as well as multiple criteria in predicting chlamydial infection, demonstrating similar sensitivity (74%-77%), specificity (51%-56%), and AUC (0.69 [95% CI, 0.67-0.71]), compared with multi-item screening criteria (AUC, 0.72-0.73). Risk prediction tools evaluated in other settings, such as with intrauterine device insertion or surgical abortion, demonstrated poor accuracy in 2 other studies. 24 , 27

A case-control study conducted in 12 STI clinics in Los Angeles County (n = 245) evaluated the proportion of gonorrhea cases missed by limiting testing to urogenital gonorrhea in men or women aged 15 to 29 years reporting oral intercourse in the last 3 months with an opposite-sex partner. 26 The multivariable model demonstrated a strong association between higher number of oral sex partners in the last 3 months (adjusted OR, 5.7 [95% CI, 1.3-25.6]) and the presence of concurrent urogenital gonorrhea (adjusted OR, 6.2 [95% CI, 2.6-14.3]) and risk of pharyngeal gonorrhea, after adjusting for age, sex, and number of sex partners. 26

Diagnostic Accuracy of Tests

Key Question 3. What is the diagnostic accuracy of anatomical site–specific testing and collection methods for identifying persons with chlamydial or gonococcal infections?

Nine studies 19 , 23 , 29-31 , 34 , 35 , 37 , 38 evaluated the diagnostic accuracy of anatomical site–specific testing, and 6 studies 23 , 29 , 34 , 35 , 37 , 38 compared collection methods for identifying chlamydial or gonococcal infections (eTable 4 in the  JAMA  Supplement). 19 , 23 , 29-31 , 34 , 35 , 37 , 38 Four studies were in the 2014 USPSTF review. 34 , 35 , 37 , 38 All studies were conducted in the US,[[23,29,34,37 UK,19,30,31,35,38]] or Canada and were fair quality (eTable 5 in the  JAMA  Supplement). 34 Sample sizes ranged from 133 to 3974 (total n = 16,204). 19 , 23 , 29-31 , 34 , 35 , 37 , 38 Studies enrolled exclusively female participants; 23 , 30 , 34 , 35 , 37 , 38 exclusively male participants, 19 , 31 including 1 study that enrolled MSM; 31 or both male and female participants. 29 Infection prevalence infection ranged from 1.5% to 26.6% for chlamydial infection and 1.5% to 11.7% for gonococcal infection. Methodological limitations included unclear methods of enrollment 19 , 23 , 29-31 , 34 , 35 , 37 , 38   and unclear description of independent interpretation of index test results compared with a reference standard. 19 , 23 , 29-31 , 34 , 35 , 37 , 38

Anatomical Site–Specific Testing

The sensitivity of site-specific testing for chlamydial infection ranged from 89% to 100% for endocervical 23 , 29 , 30 , 34 , 35 and 90% to 100% for vaginal testing, 23 , 29 , 30 , 34 , 35 excluding 1 outlier study with lower sensitivities ( Figure 3 ; eTable 6 in the  JAMA  Supplement). 37 Specificities were 99% to 100% for endocervical 23 , 29 , 30 , 34 , 35 , 37 and 95% to 100% for vaginal 23 , 29 , 30 , 34 , 35 , 37 testing. The sensitivity of urine testing was more variable than anatomical site testing in 5 studies (range, 44%-100%; median, 85%), with specificities ranging from 96% to 100%. 23 , 29 , 30 , 34 , 37 Vaginal testing using patient and clinician-collected samples showed similar sensitivities (range, 90%-100%); specificity was also high (range, 95%-100%). 23 , 29 , 30 , 34 , 35 , 37 Three studies of testing in males (eTable 7 in the  JAMA  Supplement) 19 , 29 , 31 indicated high sensitivity for urine (89%-100%), 19 , 29 , 31 meatal (92%), 19 urethral (99%), 31 and rectal (92%) 31 samples. Pharyngeal testing had lower sensitivity (69%) in men who have sex with men (MSM). 31 Specificity was not reported in studies of males.

Three studies of site-specific testing for gonorrhea in females (eTable 8 in the  JAMA  Supplement) 23 , 29 , 38 indicated sensitivities of 90% to 98% for endocervical, 23 , 29 , 38 98% to 100% for vaginal (both self- and clinician-collected), 23 , 29 , 38 and 91% to 100% for urine samples. 29 Specificity was also high for all sites (range, 99%-100%). 23 , 29 , 38 Three studies of testing in males (eTable 9 in the  JAMA  Supplement) 19 , 29 , 31 indicated high sensitivity (range, 93%-100%) and specificity (>99%) for urine 19 , 31 and high sensitivity for meatal (100%), 19 urethral (98%), 31 rectal (93%), 31 and pharyngeal (89%) 31 samples.

Clinician and Self-Collected Testing

One new study 29 and 2 studies 34 , 37 from the prior USPSTF review compared the accuracy of clinician- and self-collected vaginal samples for diagnosis of chlamydial infection in females ( Figure 3 ; eTable 6 in the  JAMA  Supplement). In 2 studies, sensitivity was 90% to 100% for clinician-collected samples and 90% to 98% for self-collected samples. 29 , 34 An additional study reported sensitivities of 56% for clinician-collected samples and 52% for self-collected samples using a different study methodology. 37 One study compared clinician- and self-collected vaginal samples for diagnosis of gonorrhea infection in females (eTable 8 in the  JAMA  Supplement). 29 In this study, sensitivities were 100% for both methods, and specificities were 100% for clinician-collected and 99.7% for self-collected samples. No study compared clinician- and self-collected testing for chlamydial or gonorrhea infections at other anatomical sites or in males.

Screening Harms

Key Question 4. What are the harms of screening for chlamydial or gonococcal infections (such as labeling, anxiety, false-positive/ false alarm results, false-negative results/reassurance, or changes in risk behaviors or risk perception)?

Eight studies of diagnostic accuracy reported false-positive and false-negative rates for anatomical site–specific testing, and 6 studies reported rates for collection methods (eTables 10-13 in the  JAMA  Supplement). 19 , 23 , 29 , 30 , 34 , 35 , 37 , 38 As in prior USPSTF reviews, no study evaluated psychosocial harms related to screening or evaluated effects of screening on changes in risk behaviors or risk perceptions.

For chlamydia testing in females, false-positive rates (1 – specificity) ranged from 0% to 2% across anatomical sites in 6 studies, 23 , 29 , 30 , 34 , 35 , 37 including 0% to 0.7% for endocervical, 0% to 1.2% for vaginal, 0.2% to 1.7% for urethral, and 0% to 2% for urine testing. False-negative rates (1 – sensitivity) ranged from 0% to 28% in 5 studies 23 , 29 , 30 , 34 , 35 ; a sixth study 37 reported higher false-negative rates (44%-56%). False-positive rates in studies that compared self-collected and clinician-collected samples ranged from 0% to 1.2%. 29 , 34 , 37 For chlamydia testing in males, false-positive rates were 0.4% for meatal testing 19 and 0.3% to 0.7% for urine testing, 19 , 29 while false-negative rates ranged from 0% to 8%. 19 , 29

For gonorrhea testing in females, false-positive rates were less than 1% and false-negative rates ranged from 0% to 10% across anatomical sites 23 , 29 , 38 and were 0% for self-collected and 0.3% for clinician-collected samples 29 (eTables 10, 11, 12, and 13 in the  JAMA  Supplement). In males, false-positive rates were similarly low (<1% across sites). 19 , 29 No study reported rates by collection method for chlamydia or gonorrhea in males.

The evidence reviewed for this report on screening for chlamydial and gonococcal infection is summarized in Table 2 . New data on screening were generally consistent with those from prior trials that found screening associated with decreased risk of PID. Evidence evaluating risk prediction tools indicated suboptimal accuracy and require validation in US primary care populations. Prior findings regarding high accuracy of diagnostic testing at various anatomical sites and home-based testing was largely confirmed by newer evidence that demonstrated low false-positive and false-negative rates. Important gaps include lack of studies on psychosocial or other harms related to screening, studies comparing screening intervals or alternative screening strategies, and studies evaluating changes in risk behaviors or risk perception.

Results of 4 screening trials demonstrated that screening for chlamydia was associated with decreased risk of PID, although effects were not statistically significant in most trials and the magnitude of benefit was relatively small. No studies reported on the effectiveness of screening in men, other than 1 study that reported rates of epididymitis, 25 and there were no studies conducted among pregnant individuals for any outcome. In contrast to screening trials from the prior review, 32 , 33 , 36 the newest trial included young men and women in primary care settings at average risk and found a reduction in hospital-diagnosed PID associated with chlamydia screening, although absolute effects were small. 25

This report included studies on the accuracy of risk criteria, which was not addressed in prior USPSTF reviews. Three studies 20-22 in asymptomatic patients that found fair discrimination require further validation in diverse clinical and geographic settings. Age 22 years or younger alone vs multi-item risk criteria demonstrated similar discrimination in 1 study that included symptomatic and asymptomatic women. 28 A study reporting high rates of pharyngeal gonorrhea in a population of high-risk persons attending STI clinics, correlated increasing numbers of oral sex partners in the 3-month period with rates of pharyngeal gonorrhea. 26 Screening both urogenital and pharyngeal sites to increase sensitivity of case detection in certain populations may have implications for extragenital testing in other higher-risk populations.

Diagnostic testing for chlamydia was highly accurate across all genitourinary anatomical sites in both male and female anatomical samples, with vaginal and endocervical testing demonstrating the highest accuracy in females. 23 , 29 , 30 , 34 , 35 , 37 Gonococcal testing was also highly accurate across anatomical sites for females, with endocervical and vaginal sites demonstrating the highest accuracy, 23 , 29 , 38 and urine testing demonstrating the highest sensitivity in males compared with meatal testing. 19 , 29 Extragenital (pharyngeal) testing in MSM demonstrated low sensitivity for chlamydial infection but higher sensitivity for gonococcal infection based on 1 study. 31 In females, self-and clinician-collected vaginal samples for chlamydia and gonorrhea diagnosis were both highly sensitive, 29 , 34 , 37 but no studies meeting inclusion criteria compared collection methods in males. These results were largely based on asymptomatic patient populations, increasing relevance to screening populations in the US.

In addition to diagnostic accuracy, other factors that may inform testing at extragenital sites include higher prevalence of extragenital chlamydial and gonococcal infection in MSM and persons attending STI clinics, as well as persons engaging in sexual contact at extragenital sites. Recent data on the association between rectal STI and HIV acquisition in men may also inform decisions around extragenital testing. 6 , 39 A small observational study of MSM in Australia demonstrated direct transmission of antibiotic-resistant strains of gonorrhea to partners of asymptomatic MSM in association with pharyngeal and rectal infection. 40 In the US, prevalence data indicate that MSM are disproportionately affected by STIs, including HIV. 41 In a report of prevalence data from STI and HIV clinic attendees, approximately 1 in 8 men had an extragenital chlamydial or gonococcal infection. 41 Given the reported rates of antibiotic resistant strains of gonococcal infection for MSM, 42 expanding the range of specimen types for screening may increase identification of infected individuals, especially for asymptomatic MSM, in whom nearly 90% of all gonorrhea infections are in nongenital sites. 43

There are few harms of screening based on findings from this review, including low rates of false-positive or false-negative findings. However, no studies provided data about other potential adverse effects of screening for any population groups, including anxiety; changes in risk behaviors; or risk perception. Further research is needed to determine the effectiveness of screening in multiple populations and on various clinical outcomes; trials of gonorrhea screening, including screening high-risk groups; effective screening strategies and intervals; and harms of screening.

Despite many years of relatively consistent screening recommendations, rates of chlamydial and gonococcal infections continue to rise. 1 This trend is likely due in part to changes in risk behaviors, although there may be other contributors. Screening tests for chlamydial and gonococcal infections are accurate regardless of anatomical site or collection method. The clinical significance of asymptomatic extragenital infections and the effectiveness of screening at those sites warrants further evaluation. While most studies were primarily conducted in heterosexual populations, several groups continue to experience increased risk for sexually transmitted infections including MSM, gender minority populations, and transgender populations, 44 , 45 but data are limited. Additional screening studies evaluating extragenital testing may also inform strategies for expanded screening in various settings and among target groups or those at increased risk.

Limitations

This review had several limitations. First, inclusion criteria considered settings and tests relevant to current US practice and did not reevaluate the accuracy of nucleic acid amplification testing, reducing the available evidence. However, this approach improved the relevance of the evidence to the USPSTF screening recommendation. Second, there was variation in the quality and applicability of studies. A number of studies were conducted in STI clinics or other high-risk clinical settings or in persons at higher risk for infection, reducing potential applicability to primary care settings or persons at lower risk. Third, evidence for men was limited and there were no studies of pregnant individuals, despite the need for additional research in these populations. Fourth, screening trials focused on PID and epididymitis as the main outcome; other health outcomes such as infertility, chronic pelvic pain, and ectopic pregnancy are also relevant but may be more challenging to correlate. Detection of PID and epididymitis in 1 trial may have been limited by relatively low screening rates (17%-25%). 25 Differences in assay sensitivity may have contributed to a differential effect on PID prevention, given that less sensitive assays may detect only patients with higher bacterial load, which has been linked in some studies to greater likelihood of developing PID. Fifth, there were no screening studies that reported disease acquisition or transmission. Sixth, meta-analysis was not performed due to relatively small numbers of studies and heterogeneity in populations, settings, comparisons, and outcomes. Formal graphical or statistical assessments for publication bias were not performed because of small numbers of studies.

Screening for chlamydial infection was significantly associated with a lower risk of PID in young women. Risk prediction criteria demonstrated limited accuracy beyond age. Testing for asymptomatic chlamydial and gonococcal infections was highly accurate at most anatomical sites, including urine and self-collected specimens. Effectiveness of screening in men and during pregnancy, optimal screening intervals, and adverse effects of screening require further evaluation.

Source:  Published in  JAMA on September 14, 2021 ( JAMA . 2021;326(10):957-966. doi:10.1001/jama.2021.10577).

Conflict of Interest Disclosures: Dr Winthrop reported receiving personal fees from Insmed, Paratek, RedHill, and Spero and receiving grants from Insmed. No other disclosures were reported.

Funding/Support: This research was funded under contract HHSA 290201500009-I, Prism No. HHSA29032014T, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the US Preventive Services Task Force (USPSTF).

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight; reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Information: A draft version of this evidence report underwent external peer review from 4 federal partners representing the US Centers for Disease Control and Prevention, US Food and Drug Administration, and the National Institutes of Health and 3 content experts (Charlotte A. Gaydos, DrPH, MPH, MS; Katherine K. Hsu, MD, MPH; Susan Tuddenham, MD, MPH). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review.

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• Lavoué V, Morcel K, Voltzenlogel MC, et al. Scoring system avoids Chlamydia trachomatis overscreening in women seeking surgical abortions. Sex Transm Dis . 2014;41(8):470-474. doi:10.1097/OLQ.0000000000000153
• Miller WC, Hoffman IF, Owen-O’Dowd J, et al. Selective screening for chlamydial infection: which criteria to use? Am J Prev Med . 2000;18(2):115-122. doi:10.1016/S0749-3797(99)00146-4
• Nye MB, Osiecki J, Lewinski M, et al. Detection of Chlamydia trachomatis and Neisseria gonorrhoeae with the cobas CT/NG v2.0 test: performance compared with the BD probetec CT Q and GC Q amplified DNA and aptima AC2 assays. Sex Transm Infect . 2019;95(2):87-93. doi:10.1136/sextrans-2018-053545
• Skidmore S, Kaye M, Bayliss D, Devendra S. Validation of COBAS Taqman CT for the detection of chlamydia trachomatis in vulvo-vaginal swabs. Sex Transm Infect . 2008;84(4):277-278. doi:10.1136/sti.2007.029587
• Sultan B, White JA, Fish R, et al. The “3 in 1” study: pooling self-taken pharyngeal, urethral, and rectal samples into a single sample for analysis for detection of Neisseria gonorrhoeae and Chlamydia trachomatis in men who have sex with men. J Clin Microbiol . 2016;54(3):650-656. doi:10.1128/JCM.02460-15
• Oakeshott P, Kerry S, Aghaizu A, et al. Randomised controlled trial of screening for Chlamydia trachoma tis to prevent pelvic inflammatory disease: the POPI (Prevention Of Pelvic Infection) trial. BMJ . 2010;340:c1642. doi:10.1136/bmj.c1642
• Østergaard L, Andersen B, Møller JK, Olesen F. Home sampling versus conventional swab sampling for screening of Chlamydia trachomati s in women: a cluster-randomized 1-year follow-up study. Clin Infect Dis . 2000;31(4):951-957. doi:10.1086/318139
• Shrier LA, Dean D, Klein E, Harter K, Rice PA. Limitations of screening tests for the detection of Chlamydia trachomatis in asymptomatic adolescent and young adult women. Am J Obstet Gynecol . 2004;190(3):654-662. doi:10.1016/j.ajog.2003.09.063
• Detels R, Green AM, Klausner JD, et al. The incidence and correlates of symptomatic and asymptomatic Chlamydia trachomatis and Neisseria gonorrhoeae infections in selected populations in five countries. Sex Transm Dis . 2011;38(6):503-509. doi:10.1097/OLQ.0b013e318206c288

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line indicates a health outcome that immediately follows an intermediate outcome. For additional information see the USPSTF Procedure Manual. 16

KQ indicates key question; USPSTF, US Preventive Services Task Force. a Articles may be included for multiple key questions.

a See eTable 6 in the JAMA Supplement for values from the individual studies. b One study (Schachter et al 34 ) reported sensitivity and specificity for 3 tests.

Abbreviations: NR, not reported; PID, pelvic inflammatory disease; RR, relative risk.

a Denominator is the number of females aged 16 to 33 years with at least 1 consultation during the intervention period. b Denominator is the number of men aged 16 to 29 years with at least 1 consultation during the intervention period. c Included in prior US Preventive Services Task Force evidence review.

Abbreviations: AUC, area under the receiving operating characteristic curve; KQ, key question; MSM, men who have sex with men; NA, not applicable; PID, pelvic inflammatory disease; RCT, randomized clinical trial; RR, relative risk.

The website may be down at times on Saturday, August 24, and Sunday, August 25, for maintenance. 

DAVID MEYERS, M.D., Medical Officer, Agency for Healthcare Research and Quality

Am Fam Physician. 2005;72(9):1799-1800

A more recent USPSTF on this topic is available .

A 22-year-old woman comes to your office for her routine well-woman examination. She says that she is currently sexually active in a long-term monogamous relationship. She had a chlamydial infection two years ago. Her only concern today is that her menstrual period is late.

Case Study Questions

Based on information from the U.S. Preventive Services Task Force (USPSTF), which one of the following statements is correct in relation to the patient’s care?

A. Local patterns of gonorrhea infection should not affect whether you screen for gonorrhea infection.

B. Vaginal culture is not an accurate gonorrhea screening test.

C. Even if the patient did not have a history of chlamydia, she is at increased risk for gonorrhea infection.

D. You will need to perform a pelvic examination to adequately screen the patient for gonorrhea infection.

E. If a gonorrhea screening test is performed, there is no need to perform a chlamydia screening test.

The patient’s urine test for pregnancy is positive. Which one of the following statements about gonorrhea screening during pregnancy is correct?

A. The USPSTF recommends screening all pregnant women for gonorrhea infection at an early prenatal visit.

B. The definition of increased risk is different for pregnant women than for nonpregnant women.

C. Gonorrhea infection is not associated with adverse pregnancy outcomes.

D. Infants of women with negative third trimester gonorrhea screening tests do not need ocular prophylaxis.

E. There is a low prevalence of gonorrhea infection in pregnant women without risk factors.

If the patient’s gonorrhea screening test is positive, which of the following actions is/are appropriate next steps?

A. Arrange testing or presumptive treatment for the patient’s sexual partner.

B. Treat the patient with a third-generation cephalosporin.

C. Consider a second gonorrhea screening test during the third trimester.

D. Delay treatment until the second trimester.

1. The correct answer is C

The USPSTF recommends that physicians screen all sexually active women for gonorrhea infection if they are at increased risk for infection. The USPSTF considers all women younger than 25 years to be at increased risk for gonorrhea infection. Thus, the patient’s age is the primary factor to consider when deciding to screen her. Additional risk factors for gonorrhea include a history of sexually transmitted infection, new or multiple sex partners, inconsistent condom use, sex work, and drug use.

Recognizing that individual risk for gonorrhea depends on local epidemiology of the disease, the USPSTF notes that in communities with high prevalence rates, broader screening may be warranted. Similarly, in areas with low community prevalence of gonorrhea infection, more targeted screening may be appropriate. The USPSTF encourages physicians to work with local public health authorities to identify populations at increased and decreased risk within their communities and to report all cases of gonorrhea to public health authorities to allow for more accurate estimations of gonorrhea prevalence.

Vaginal culture remains an accurate screening test when transport conditions are suitable. Nucleic acid probes have demonstrated improved sensitivity and comparable specificity when compared with cervical cultures, and some newer tests may be used with urine and vaginal swabs, enabling screening without a full pelvic examination.

Although patients with gonorrhea should be tested for or presumptively treated for chlamydia, screening for gonorrhea infection is not an acceptable screening strategy for chlamydia. Women at risk for gonorrhea and chlamydia infections should be screened for both.

2. The correct answer is E

The USPSTF found insufficient evidence to recommend for or against routine screening for gonorrhea infection in pregnant women who are not at increased risk of infection. The USPSTF could not determine the balance of benefits and harms of screening in this population because it has a low prevalence of infection.

The USPSTF recommends, however, that physicians screen pregnant women for gonorrhea infection if they are at increased risk for infection. Risk factors for pregnant women are the same as for nonpregnant women (see answer no. 1) .

Gonorrhea infection during pregnancy is associated with adverse outcomes including chorioamnionitis, premature rupture of membranes, and preterm labor.

Screening is recommended at the first prenatal visit for pregnant women who are in a high-risk group for gonorrhea infection. For pregnant patients who are at continued risk, and for those who acquire a new risk factor, screening also should be conducted in the third trimester.

The USPSTF strongly recommends prophylactic ocular topical medication for gonococcal ophthalmia neonatorum for all newborns. There is good evidence that blindness caused by gonococcal ophthalmia neonatorum has become rare in the United States since the implementation of universal prophylaxis of infants.

3. The correct answers are A, B, and C

In order to prevent recurrent gonorrhea transmission, sexual partners of infected persons should be tested and treated if infected, or treated presumptively.

Genital gonorrhea infections in men and nonpregnant women may be treated with a third-generation cephalosporin (intramuscular ceftriaxone [Rocephin]) or fluoroquinolone antibiotic. Pregnant women with gonorrhea infections should be treated with a third-generation cephalosporin. Women who continue to be at high risk for infection or who develop a new risk factor during pregnancy should be screened during the third trimester. There is no indication for delaying gonorrhea treatment during pregnancy.

Glass N, Nelson HD, Villemyer K. Screening for gonorrhea: update of the evidence for the U.S. Preventive Services Task Force. Rockville, Md.: Agency for Healthcare Research and Quality, 2005. Accessed online July 21, 2005, at: http://www.ahrq.gov/clinic/uspstf05/gonorrhea/gonup.htm .

U.S. Preventive Services Task Force. Screening for gonorrhea: recommendation statement. Rockville, Md.; Agency for Healthcare Research and Quality, 2005. Accessed online July 1, 2005, at: http://www.ahrq.gov/clinic/uspstf05/gonorrhea/gonrs.htm .

This series is coordinated by Joanna Drowos, DO, contributing editor.

A collection of Putting Prevention Into Practice published in AFP is available at https://www.aafp.org/afp/ppip.

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August 21, 2024

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Collaborative study brings effective gonorrhea vaccine step closer

by Mike Addelman, University of Manchester

A study involving Kenyan sex workers illuminates the immune response to gonorrhea, paving the way for more effective vaccines.

Carried out by scientists at the Universities of Manchester and Oxford working in collaboration with the KEMRI/Wellcome Trust Unity in Kenya, the study is published in the journal Nature Communications .

The findings come amid recent reports showing gonorrhea —a sexually transmitted disease —is becoming increasingly resistant to antibiotics and could become untreatable in the future.

People infected with gonorrhea may experience pain or burning though, if untreated, they may go on to develop more serious problems including infertility, systemic infection and increased risk of HIV/AIDS. There are now multidrug resistant strains of the Neisseria gonorrheae (Ng) bacterium—which causes gonorrhea—making many antibiotics ineffective as first-line treatments.

The bacterium has a range of mechanisms to dampen immune responses, meaning there is insufficient immunological 'memory' to combat subsequent infections.

Attempts to develop a vaccine against gonorrhea have been largely unsuccessful. However, in 2017, a study showed that vaccination against a related bacterium Neisseria meningitidis (Nm) led to a reduction in the incidence of gonorrhea. Although the efficacy of the Nm vaccine against Ng was limited, it provided an important clue to making an effective Ng vaccine.

Working with a marginalized community of sex workers in coastal Kenya who have high exposure to gonorrhea, Prof Ed Sanders and his team in Kenya conducted a trial of an Nm vaccine to examine their immune responses. Prof Jeremy Derrick and the team in Manchester then identified the pattern of antibody responses in the vaccine recipients and compared them to individuals infected with gonorrhea.

To unpick the complicated antibody responses, the Manchester team fabricated a 'microarray'—a library of the different components, or antigens, which could react with the antibodies induced by the Nm vaccine. Using this powerful technology, the complex profiles of antibodies against the different components were determined for each vaccinee, or each infected individual.

Comparison of the profiles revealed a detailed picture of the antibody responses to the vaccine, and showing how they differ to those following infection.

The project lead Professor Chris Tang from the University of Oxford said, "This work takes an important step along the road to developing Ng vaccines, as we have a better idea of which responses are generated by partially protective vaccination compared with infection."

Professor Derrick added, "This study has wide implications about revisiting vaccine design for other bacterial pathogens using these new methods, including those where antimicrobial resistance is a problem. We hope that the application of these technologies will enable progress towards vaccines against other pathogens."

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Differential Diagnoses

Young adult patients who engage in unprotected sex are at risk of contracting a number of sexually transmitted infections (STIs). The risk of STIs is especially high when people engage in unprotected sexual activities with many partners or partners that are not monogamous (McCance & Huether, 2019). Before a diagnosis of chlamydia is confirmed, the clinician must first rule out other sexually transmitted infections. 

Figure 1: Cervicitis and vaginal discharge caused by N. gonorrhoeae .

Figure 2: Penile discharge as a result of urethritis from a N. gonorrhoeae infection.

Images taken from https://www.sexandu.ca/stis/gonorrhea/

The patient admits to sexual intercourse without a condom, making gonorrhea a likely infection. Chlamydial and gonorrheal infections cause similar clinical manifestations because each of the bacteria are able to infect and cause inflammation within the same structures of urogenital tract, and the infections may be indistinguishable from each other without proper screening. It is important to note that both diseases can be asymptomatic in both males and females. Gonorrhea is a sexually transmitted bacterial infection caused by Gram-negative Neisseria gonorrhoeae cocci bacteria. The patient complains of painful urination (dysuria), and vaginal discharge. Infection and inflammation of the cervix in female patients leads to mucopurulent discharge and physical examination would reveal a red and swollen cervix, in both Chlamydia and Gonorrhea infections. In addition to the cervix, the bacteria can infect and cause inflammation of the urethra, causing pain or burning with urination, as seen in the patient. Urethritis and cervicitis often lead to patient complaints of discomfort during sexual intercourse. While intermittent bleeding can occur with a Chlamydia infection, gonorrhea is more likely to cause changes to menstrual patterns, patients may complain of increased pain from cramps and heavier menstrual flow. If left untreated, both diseases can lead to the development of pelvic inflammatory disease. Pelvic inflammatory disease (PID) occurs when the bacteria are able to move up the urogenital tract and infect the ovaries, and fallopian tubes. Patients will experience symptoms common of infection including fever, chills, nausea, and vomiting, along with pain of the lower abdomen. In men, bacteria infecting the urethra will also cause inflammation leading to discharge and pain while urinating. Penile discharge can vary slightly between the diseases, with chlamydia causing a clear mucoid discharge, and gonorrhea a pus-filled discharge. Untreated gonorrhea infections have a risk of bacteremia leading to a systemic disseminated gonococcal infection. Although rare, the widespread infection could lead to the development of joint pain, rashes, meningitis, and endocarditis. Diagnostic testing is required to differentiate the two infections. Nucleic acid amplification testing of urine, cervical, urethral, or vaginal samples can inform the clinician of the infecting bacterial organism (McCance & Huether, 2019).

Mycoplasma genitalium Infection

Figure 3: Computer generated image of M. gentialium bacteria.

Image taken from https://www.shfpact.org.au/about-us/30-info-sheets/sti-s/57-mycoplasma-genitalium

Due to the patient’s complaints of dysuria, and vaginal discharge, another possible diagnosis is infection by Mycoplasma genitalium. Mycoplasma genitalium is a type of bacteria that is able to cause infection of the urogenital organs and is transmitted through unprotected sexual intercourse, much like the patient reports. Research continues to uncover information about the structures M. genitalium is able to infect and the resulting symptomatology, but has proven difficult due to lack of growth in bacterial laboratory cultures. Unlike in Chlamydia infections, it has not yet been confirmed that M. genitalium causes inflammation of the urethra in females. However, it has been linked to cervicitis. Inflammation of the cervix is responsible for mild mucopurulent vaginal discharge, and pain with urination, as exhibited in the patient. The cervicitis can also lead to vaginal pruritus, and generalized pelvic pain and discomfort (Martin, 2019). Even when patients present with symptoms, vaginal pruritus and generalized pelvic pain, without the complication of pelvic inflammatory disease, are not often seen in Chlamydia infections (McCance & Huether, 2019). Although studies have not shown a strong link, it is believed that M. genitalium can lead to PID. If PID develops from a M. genitalium infection, patients will present with symptoms similar to those caused by PID from a Chlamydia infection. In men, M. genitalium infection has been linked to urethritis which results in itching, dysuria, and mucopurulent penile discharge. M. genitalium bacterial cells do not have a cell wall, so gram-staining and microscopic evaluation of the specimen does not allow for visualization. To differentiate from gonorrhea and chlamydia, clinicians will use vaginal or cervical swabs for nucleic acid amplification tests to determine the specific organism present in women. In men, urine or urethral swabs will be used for nucleic acid amplification test results (Martin, 2019).

Trichomoniasis

Figure 4: Vaginal discharge caused by a T. vaginalis infection.

Figure 5: Penile discharge caused by a T. vaginalis infection.

Images taken from https://www.sexandu.ca/stis/trichomoniasis/

Trichomoniasis is a genitourinary disease caused by a flagellated protozoan called Trichomonas vaginalis .  Worldwide, trichomoniasis is the most prevalent nonviral sexually transmitted disease. While Chlamydia tends to infect the cervix in females, T. vaginalis more often infects the squamous epithelium of the vagina, urethra, and paraurethral glands.  Similar to chlamydia, trichomoniasis is often asymptomatic. When symptoms are present, trichomoniasis in women often presents with redness around the vulva and vaginal mucosa, as well as a “green-yellow, frothy, malodorous discharge” in 10-30% of symptomatic women (Sobel, 2019).  This mucosal texture/color combination distinguishes trichomoniasis from chlamydia. Other symptoms in women can include “burning, pruritus, dysuria, frequency, lower abdominal pain, or dyspareunia” (Sobel, 2019). Many of these symptoms can also be seen in chlamydia. Unlike chlamydia, trichomoniasis does not progress to pelvic inflammatory disease (PID), and therefore infection with T. vaginalis will not likely show up as PID-typical symptoms such as abdominal or pelvic pain.  In men, Trichomonas most commonly affects the urethra. Symptoms of trichomoniasis are the same as would be for any other cause of urethritis (dysuria, urethral discharge) and therefore are not reliable for differential diagnosis in males. Overall, both men and women are often asymptomatic and symptoms can be variable, so the gold standard for differential diagnosis is lab testing.  Since chlamydia is caused by a bacteria and trichomoniasis is caused by a mobile, flagellated protozoan, microscopy may be useful in observing the jerky motion of the T. vaginalis.  However, the most reliable method for distinguishing the two is Nucleic Acid Amplification Testing (NAAT) in which RNA unique to the microorganism is amplified using polymerase chain reaction (PCR) in order to be detected (Sobel, 2019).  With a 98-99% sensitivity, the NAAT is the best available option for diagnosing both chlamydia and trichomoniasis (Hsu, n.d.). While chlamydia is most likely to be detected in females ages 16-20, trichomoniasis is more likely to be detected at ages 47 to 53, so advanced age may be an indicator of trichomoniasis ( Sobel, 2019).

“Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone” (2011), by Makoto Ohnishi, Daniel Golparian, Ken Shimuta, Takeshi Saika, et al.

In July 2011, Makoto Ohnishi and colleagues published the article “ Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone,” hereafter, “Untreatable Gonorrhea,” in the journal Antimicrobial Agents and Chemotherapy . Gonorrhea is a sexually transmitted disease, or STD, caused by the bacterium Neisseria gonorrhoeae . In 2009, Ohnishi and a few of his co-authors found the first ceftriaxone-resistant strain of gonorrhea, called H041. That strain demonstrated resistance to ceftriaxone, one of the last remaining and effective first-line antibiotic treatment drugs for N. gonorrhoeae. In “Untreatable Gonorrhea,” Ohnishi and Colleagues confirm that the H041 strain is resistant to ceftriaxone and analyze the bacterium’s mechanism of resistance. “Untreatable Gonorrhea” was one of the first publications to characterize the H041strain and highlights a need for global public health interventions to prevent the rapid spread of gonorrhea.

Background and Context

Article roadmap, detailed content.

The authors of “Untreatable Gonorrhea” hail from multiple academic institutions and laboratories across Japan and Sweden. At the time of the article’s publication in 2011, Ohnishi, the first author, worked as a researcher at the National Institute of Infectious Diseases in Tokyo, Japan. The corresponding author, Magnus Unemo, was a researcher at the Swedish Reference Laboratory for Pathogenic Neisseria of Örebro University in Örebro, Sweden. As of 2024, Unemo is the Director of the World Health Organization Collaborating Centre for Gonorrhea and other Sexually Transmitted Infections. The remaining authors were affiliated with the same research institutions, as well as the Mitsubishi Chemical Medience Corporation in Tokyo and the Hoshina Clinic and Kyoto Prefectural University of Medicine, both located in Kyoto, Japan. Following the publication of “Untreatable Gonorrhea,” the members of the research group continued to research and publish articles about gonorrhea.

“Untreatable Gonorrhea” includes discussion of the STD called gonorrhea, which can infect and cause symptomology in men, women, and babies. Gonorrhea typically is transmitted from one individual to another during sexual intercourse with an infected partner. Gonorrhea can infect the eyes, throat, and rectum, though it primarily affects the female and male reproductive tracts. Symptoms of gonorrhea, or gonococcal infection, typically appear within one to fourteen days after infection, and symptoms vary between men and women. Men are often asymptomatic but can sometimes display symptoms such as abnormal discharge from the urethra, pain and swelling of the testicles, and dysuria or painful urination. Women, like men, are often asymptomatic, but they can experience symptoms such as abnormal vaginal discharge, dysuria, pelvic or abdominal pain, and vaginal bleeding in between periods. Without treatment, women can develop pelvic inflammatory disease, or PID, a condition where the female reproductive organs became inflamed due to infection. Untreated PID can cause scarring of the fallopian tubes, which can lead to infertility. Additionally, a pregnant woman infected with gonorrhea can pass the infection to her child during childbirth, potentially causing severe illness in the infant if untreated.

Prior to the publication of “Untreatable Gonorrhea,” researchers typically treated gonorrhea with a variety of antibiotic drugs , yet various gonococcal strains developed antibiotic resistance to most of those drugs. Antibiotic, or antimicrobial, resistance occurs when pathogens such as bacteria develop the ability to overcome the drug therapies designed to kill them. During the bacterial replication process, mutations arise, and some of those mutations confer traits that allow for antibiotic resistance. Those bacteria with mutations coding for antibiotic resistance typically survive and continue to reproduce. Antibiotic resistance is more likely to occur when people misuse antibiotics by not taking the entire dose of their prescribed antibiotics, taking antibiotics not prescribed to them, or taking antibiotics when they do not have a bacterial infection. 

In the twentieth and twenty-first centuries, researchers observed antibiotic resistance of gonococcal strains to various drugs that previously treated the disease, including sulfonamides, penicillin, tetracycline, spectinomycin, and cefixime. In 1935, researchers developed sulfanilamide, one of the first antibiotics produced and part of the sulfonamide drug class. During the 1930s and 1940s, researchers continued to develop other antimicrobials of the sulfonamide class, and those drugs successfully treated gonorrhea cases. By 1944, over ninety percent of strains in circulation were resistant to the sulfonamide drugs. For the next forty years, physicians continued to treat gonorrhea with different antibiotics, such as penicillin, tetracycline, and spectinomycin, but N. gonorrhoeae repeatedly developed resistance to those treatments. In the late 1960s, the antibiotic drug class of cephalosporins, which includes the drugs cefixime and ceftriaxone, became available as first-line treatments for gonorrhea. By the late 1990s and early 2000s, though, gonorrhea strains evolved resistance to cefixime, which closely resembles ceftriaxone. According to a 2014 publication from Unemo, the resistant strains first appeared in Japan, then spread to the United States, Canada, and multiple countries in Europe. Following that, physicians primarily relied on ceftriaxone as a first-line treatment for gonorrhea, since there were no longer any other antimicrobials effective against the disease.

Prior to the publication of “Untreatable Gonorrhea,” first-line treatment guidelines by the Centers for Disease Control and Prevention, or CDC, recommended dual therapy with a cephalosporin drug and an azithromycin or doxycycline antimicrobial. At that time, researchers had not yet identified clinical cases of ceftriaxone resistance, but cefixime-resistant cases were present. Medical physicians recommended that regimen to patients through 2011.

In 2009, Ohnishi and a few of his coauthors identified the first recorded case of a ceftriaxone-resistant strain of gonorrhea, later called H041, in a thirty-one-year-old female sex worker in Kyoto, Japan, and they reported their findings in the article “Ceftriaxone-Resistant Neisseria gonorrhoeae , Japan.” According to that article, the woman with gonorrhea sought out routine sexually transmitted infection, or STI, testing at a clinic in Kyoto, and physicians found that although the woman was asymptomatic, her throat swab revealed she had a pharyngeal gonorrhea infection, or gonococcal infection of the throat. Two weeks later, she received STI testing again, which yielded another positive result. The authors state that medical providers subsequently treated the woman with one gram of ceftriaxone delivered intravenously. Typically, people treated with ceftriaxone completely clear N. gonorrhoeae from their body within two weeks of receiving treatment, but the woman tested positive again two weeks later. The woman then received further treatment with ceftriaxone, but, according to the article, physicians did not perform an additional test to see if the treatment was successful because of the woman’s high risk of reinfection due to her occupation. A few months later, in April 2009 the woman returned to the clinic for STI testing and she tested negative for gonorrhea. In “Untreatable Gonorrhea,” the authors analyze the strain of gonorrhea found in that woman and relate that strain, which they call H041, to other known strains to quantify its level of resistance and describe its mechanism of resistance.

“Untreatable Gonorrhea” contains four sections. In the untitled introductory section, the authors detail that gonorrhea maintains a high global prevalence and many strains have evolved antibiotic resistance to first-line treatments. Thus, they chose to study the recently discovered ceftriaxone-resistant H041 strain and its mechanism. Next, in “Materials and Methods,” the authors explain that they conducted antimicrobial resistance testing as well as a series of additional tests to characterize the H041 strain. In “Results,” the authors emphasize that their test results confirmed that H041 is a strain of gonorrhea and is resistant to multiple drug classes including cephalosporins like ceftriaxone due to specific mutations in its genome. The authors also explain that that H041is a descendant of ST7363, a cefixime-resistant strain previously discovered in Japan. In the final section, “Discussion,” the research group characterizes H041 as four- to eight-times more resistant to ceftriaxone than other strains of gonorrhea and propose that H041 will likely initiate an era of untreatable gonorrhea. Finally, the authors conclude by stating that global public health interventions will be necessary to monitor and control transmission of H041.

In the unlabeled introduction, Ohnishi and colleagues explain that gonorrhea has developed antibiotic resistance to many previously developed first-line treatments, and thus, the disease continues to infect individuals worldwide. The authors first claim that gonorrhea is the second most common bacterial STI and is a serious global public health problem. They state that since there is no vaccine therapy available for the disease, diagnostic testing and antibiotic treatment are essential for reducing the transmission of gonorrhea as well as preventing severe illness in individuals who do contract the bacteria. The authors elaborate that the use of those treatment options has rapidly decreased because N. gonorrhoeae has achieved antibiotic resistance to many first-line drug therapies, including penicillin and spectinomycin. They explain that physicians can no longer use those therapies to effectively treat gonococcal infections. Then, they assert that gonorrhea has globally become less susceptible to the last few remaining first-line treatments, which are the injectable antibiotic ceftriaxone and the oral cefixime.

Also in the introductory section, the authors discuss that their paper focuses on understanding and treating H041, a newly observed strain of gonorrhea that they explain has high levels of resistance to ceftriaxone. Ohnishi and colleagues explain that physicians previously found the strain in the pharynx, or throat, of a commercial sex worker in Kyoto, Japan. According to the paper, those physicians could not definitively determine if ceftriaxone failed to treat H041 in that woman because they did not have a posttreatment sample of H041 available to test and compare to. However, the authors state that H041 is closely related to ST7363, a common strain of gonorrhea in Japan and Europe that is resistant to the antibiotic cefixime. They elaborate that antibiotic resistance is quite prevalent in Japan and the Western Pacific Region, and previous resistant strains have spread from those regions to other parts of the world, in large part due to sex tourism, migration, and long-distance truck drivers. The researchers predict that ceftriaxone-resistant gonorrhea will follow a similar distribution pattern as its predecessors, thus, they argue that it is essential to study H041 and its mechanism of resistance in detail. Then, the authors describe what researchers already knew about those gonococcal resistance mechanisms, including that it involves alterations in the penA gene. The penA gene codes for the protein that allows N. gonorrhoeae to bind to penicillin and other antibiotics to create resistance. The research team concludes that the aim of the study is to conduct an in-depth characterization of H041 to examine and treat its antibiotic-resistant mechanisms.

In the second section, “Materials and Methods,” the authors explain that in their study, they compared H041 to nine other strains of gonorrhea using the Etest method to quantify its levels of resistance and determine which antibiotics it is resistant to. First, the research group explains that they performed seven species confirmatory tests to verify that is H041 is indeed a strain of gonorrhea. They then detail that they tested ceftriaxone and twenty-nine additional antimicrobials against H041 and the other strains of gonorrhea to discern which antimicrobials each strain was resistant to. They performed that testing using the Etest method, which is a standardized lab test in which researchers place a plastic strip containing antimicrobial agent onto a plate of bacteria and examine if the bacteria grow near the strip. If bacteria grow, then the strain is resistant to that antimicrobial. The Etest measures the minimal inhibitory concentration, or MIC, which is the lowest concentration of an antimicrobial substance required to prevent visible growth of a bacteria in a laboratory setting. MIC can measure how susceptible or resistant a particular bacterial strain is to a specific antimicrobial agent.

At the end of the “Materials and Methods,” section, the research group states that they tested H041 and the other gonorrheal strains to discover that a mutation in the penA gene , called penAH041 , causes high ceftriaxone resistance. First, the authors detail that they performed genetic and phylogenetic, or evolutionary, analyses to understand the characteristics of each strain. Then, they explain that they performed transformation assays, or lab tests that clone genetic material, in which they inserted the penAH041 allele, the variation of the penA gene uniquely found in H041, into the other nine strains of gonorrhea to determine how penAH041 affects those strains’ antibiotic susceptibility. They performed the transformation assay three times for each strain to confirm that penAH041 allele caused high levels of ceftriaxone resistance.

In the third section, “Results,” the research group explain that from the tests they ran, they found that H041 is a strain of gonorrhea and is resistant to a majority of the thirty antibiotics they tested, including ceftriaxone. They state that after they performed all seven species confirmatory tests, they were able to confirm that H041 is indeed a strain of gonorrhea. They explain that they found H041 is resistant to seven major antimicrobial classes, including penicillin and other antibiotics that physicians previously used to treat gonorrhea before it acquired widespread resistance to them. The research team then states that H041 was resistant to all cephalosporins, the drug class containing ceftriaxone. The researchers highlight H041’s ceftriaxone MIC, a value between two and four micrograms per milliliter, which was at a level of resistance that they describe as very high. They explain that only one other strain of gonorrhea globally had previously demonstrated a ceftriaxone MIC greater than the threshold 0.25 micrograms per milliliter. They also emphasize that H041 demonstrated a high MIC towards all other cephalosporins when they performed antimicrobial susceptibility testing. However, the authors did disclose that H041 is susceptible to the antibiotics spectinomycin and rifampin, neither of which are typical first-line therapies for the treatment of gonorrhea. They also state that the MIC for the antibiotics tigecycline and those in the aminoglycoside class were low, though as of 2024, doctors consider none of those drugs as first-line therapies. The authors include a table in “Results” that presents information regarding the H041’s MIC for various antibiotics as determined by the Etest method.

Next, Ohnishi and colleagues describe the relationship of H041 to other known gonorrheal strains and explicate that the penAH041 allele confers H041’s high levels of resistance to ceftriaxone. They declare that after conducting phylogenetic analyses, they found that H041 is closely related to other cephalosporin-resistant gonorrhea strains. They elaborate that H041 has the penAH041 , which is unique to its strain, and, thus, that allele must be responsible for the strain’s increased resistance to ceftriaxone. They further support that claim by explaining that after they inserted the penAH041 allele into other gonorrheal strains, eight of the nine tested strains had a MIC above the antibiotic resistance threshold of 0.25 micrograms per microliter for ceftriaxone. The authors conclude the “Results” by definitively stating that the penAH041 allele is responsible for high-level ceftriaxone resistance in their study.

In the final section, “Discussion,” the authors explain that the antibiotic resistance of H041 to ceftriaxone and other antimicrobials complicates the available treatment options for gonorrhea and could potentially lead to uncontrollable spread of the disease worldwide. Ohnishi and colleagues begin by reaffirming that ceftriaxone is the last remaining first-line therapy for N. gonorrhoeae, and the discovery and study of the H041 strain has demonstrated that N. gonorrhoeae is able to evolve and lower its susceptibility to that drug. They go on to explain that when medical providers typically treat a gonorrheal infection with ceftriaxone, the treatment eliminates all presence of N. gonorrhoea e genetic material from the host within two weeks. Unlike typical cases of gonorrhea, the female reported to have the first recorded clinical case of H041 retained gonorrheal genetic material after the two-week period. The authors emphasize that based on their results, if a person infected with the H041 strain of gonorrhea receives the standard one-gram dose of ceftriaxone, then the medication will not eradicate the H041 strain in most cases. The authors argue that due to the development of ceftriaxone resistance in the H041 strain, N. gonorrhoeae could potentially become what they define as a superbug, meaning it could initiate an era of untreatable gonorrhea.

The researchers also use the “Discussion” section to emphasize that their study revealed that other alleles, in addition to the penAH041 allele, are responsible for creating ceftriaxone resistance in the H041 strain and demonstrated that the resistance can spread across the N. gonorrhoeae strains. The research team reiterates that the penAH041 allele causes the resistance, and the insertion of the penAH041 allele into the other nine gonococcal strains led those strains to also develop high ceftriaxone MIC. They detail that in order for the other strains to reach the same levels of ceftriaxone MIC as the H041 strain, additional resistance determinants must be present, including the mtrR and penB genes, as well as an unidentified agent, which the authors call factor X. Although high ceftriaxone MIC levels as found in the H041 strain require other determinants, the authors conclude that the penAH041 allele successfully transformed into the other gonococcal strains, and, therefore, ceftriaxone resistance can rapidly spread within the N. gonorrhoeae population.

Next, the authors explain that they theorize that H041 evolved from the previously identified S7363 strain, and that due to the possibility of the spread of H041, they strongly recommend that Japan implement surveillance programs to prevent global transmission. They explain that they suspect that the H041 strain represents a subclone of the ST7363 strain, the gonococcal strain that previously expressed resistance to other drugs in the cephalosporin class and evolved from it. The group explicitly states that they fear H041 may disseminate globally, given that previous strains of antibiotic-resistant pathogens have spread worldwide within one to two decades. The research team asserts that the discovery of H041 is important because experts identified the first clinical case of H041 in a commercial sex worker, a member of a high-risk population that frequently transmits STIs, and the presence of H041 in that population could mean a faster infection rate. Furthermore, Ohnishi and colleagues also emphasize that Japan does not have a national antimicrobial resistance surveillance program. Due to its initial prevalence in the sex work population, where STIs typically rapidly spread, as well as the lack of a national surveillance program, the researchers believe that the H041 strain can rapidly proliferate. The team explains that following the initial discovery of H041 in 2009, experts did create an antibiotic resistance surveillance program in Kyoto, the city where researchers first identified H041, but as of 2011, they had not identified any additional cases of H041 transmission or cases of treatment failure.

The authors conclude “Untreatable Gonorrhea” by arguing for the implementation of global public health interventions to combat the spread of antimicrobial-resistant gonorrhea. They explain that although the survival capacity of the H041 strain remains unknown, there is a possibility that it may lead to a superbug. According to Ohnishi and colleagues, therefore, it is important for countries worldwide to enhance their disease prevention and control activities to reduce the spread of the antibiotic-resistant strains.

As of 2024, researchers have cited “Untreatable Gonorrhea” 795 times according to Google Scholar, and those studies highlight the importance of understanding antibiotic resistance in gonorrhea and the implementation of global surveillance programs. In 2012, shortly after the team published “Untreatable Gonorrhea,” authors Daniel Golparian and Unemo, among others, published a study about F89, an additional highly cephalosporin-resistant strain of gonorrhea that researchers identified in France in 2010. The authors of that article cite “Untreatable Gonorrhea” to explain that F89 has a similar mechanism of resistance to H041 that involves the penAH041 allele, a penB DNA sequence, as well as the unknown factor X. However, they found that F89 derived from the ST1901 strain, a different strain of gonorrhea from H041. In 2017, a group of researchers, including Unemo, from various research institutions worldwide, published “Antimicrobial Resistance in Neisseria gonorrhoeae : Global surveillance and a Call for International Collaborative Action.” In that article, the authors discuss that many countries in Eastern Europe, Central Asia, parts of Latin, and Africa lack global gonococcal assistance surveillance programs. They explain that many of those setting have high rates of gonorrhea and lack of medical access to microbials, which fosters ideal conditions for gonococcal spread. The researchers cite “Untreatable Gonorrhea” and other studies describing ceftriaxone-resistant strains of gonorrhea as evidence to explain that all documented cases of scientists detecting ceftriaxone-resistant gonorrhea have taken place in well-resourced countries. Thus, the researchers argue that the current documentation does not represent the true global health burden of antimicrobial resistance by gonorrhea, since resource-constrained countries have limited programs and data. The authors state that surveillance resources must be in place in those countries to stop the gonococcal spread.

As of 2024, antibiotic-resistant gonorrhea continues to proliferate worldwide, but the CDC still recommends ceftriaxone as a first-line treatment. Gonorrhea continues to be a public health concern since the publication of “Untreatable Gonorrhea,” with 82 million new occurrences of gonorrhea globally in 2020. As of 2024, the CDC recommends that professionals treat gonorrhea with a 500-milligram single dose intramuscular injection. That is because only a few cases of ceftriaxone resistance have been reported in several countries, including Japan, Australia, France, and Spain, meaning it has not spread wide enough to prohibit the use of the medication. Although the CDC still recommends ceftriaxone as a first-line treatment, they do not advise cefixime as a treatment for gonorrhea. On 10 August 2012, shortly after the publication of “Untreatable Gonorrhea,” the CDC recommended stopping cefixime as a treatment for gonorrhea. As of 2024, researchers are working to develop other antibiotic agents and treatment strategies to address the potential spread of ceftriaxone resistance.

“Untreatable Gonorrhea” was one of the first publications to characterize the H041 strain of gonorrhea. The H041 strain demonstrated a high level of ceftriaxone resistance, thus limiting treatment of ceftriaxone as a first-line treatment drug for gonorrhea. “Untreatable Gonorrhea” allows researchers to understand the mechanism of H041 antimicrobial resistance and create new antibiotic drugs to treat gonorrhea and limit its spread.

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• Health and social care
• Public health
• Health protection
• Infectious diseases

Antibiotic resistant gonorrhoea cases are on the rise

Between June 2022 and May 2024, 15 ceftriaxone-resistant gonorrhoea cases were detected in England

New data from the UK Health Security Agency (UKHSA) highlights a concerning rise in antibiotic-resistant gonorrhoea infections in England.   

In 2023, over 85,000 gonorrhoea diagnoses were reported in England, the highest number since records began in 1918. This highlights the importance of regular STI testing, especially if you have condomless sex with new or casual partners. While the infection can usually be easily treated, some strains are resistant to commonly used antibiotics and are harder to treat. A type that poses a particular threat is ceftriaxone-resistant gonorrhoea. Ceftriaxone is the ‘first line’ antibiotic used to treat gonorrhoea in this country and so resistance to the drug can make treatment difficult, especially for gonorrhoea infections in the throat.   

Between June 2022 and May 2024, 15 ceftriaxone-resistant gonorrhoea cases were detected in England, including 5 that were found to be extensively drug-resistant (resistant to both first- and second-line treatment options and to other antibiotics).  Since the first case detected in England in 2015, there have now been a total of 31 ceftriaxone-resistant gonorrhoea cases, 7 of which were extensively drug-resistant.   

To date, all detected cases have been among heterosexual individuals, mostly in their 20s, and most acquired the infection abroad. There has been limited transmission within England, but the increasing number of cases in recent years is concerning as it increases the chance of wider spread and treatment challenges.   

Dr Helen Fifer, Consultant Microbiologist at UKHSA, said:  

Gonorrhoea is becoming increasingly resistant to antibiotics, risking the possibility of it becoming untreatable in the future. Untreated gonorrhoea can lead to serious health issues, including pelvic inflammatory disease and infertility. Condoms are the best defence, but if you didn’t use one with a recent new or casual partner, get tested to detect the infection and prevent onwards transmission.

Professor Matt Phillips, President of the British Association for Sexual Health and HIV, said:  

The rise of antibiotic-resistant gonorrhoea infections in England is a worrying trend that must be addressed with immediate action. Antibiotic resistance of STIs poses an increasingly major public health threat, which can create physical and psychological harms and place additional demands on other parts of the NHS. BASHH, alongside sector partners, has repeatedly called for a sexual health strategy for England; this must be a priority if our expert sexual health workforce are to effectively meet these growing and changing needs in sexual health.

Meanwhile, the latest data from UKHSA show that syphilis rates are still rising. Syphilis can cause severe, irreversible, and potentially life-threatening damage to the brain, heart, or nerves if not treated. In 2023, diagnoses of infectious syphilis rose to 9,513, a 9.4% increase from 2022 (8,693). The highest rates were among gay, bisexual and other men who have sex with men, however, the largest proportional rise between 2022 and 2023 was in heterosexual individuals. UKHSA is also reminding healthcare professionals to be alert to the signs of syphilis, because it can cause a range of symptoms affecting multiple organ systems and, without treatment, can lead to serious and permanent harm.   

While the increase in gonorrhoea and syphilis diagnoses will in part be due to increases in testing, it may also be due to more transmission of these STIs within the population.  

Both of these STIs are easy to catch and are on the rise. If you are having condomless sex with new or casual partners, regular testing for STIs and HIV is essential to maintain good sexual health. Testing is free and can be accessed through  local sexual health clinics , university and college medical centres or through self-sampling kits sent discreetly through the post.

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Gonorrhea persistent foe as other STIs plunge in SF

• by John Ferrannini, Assistant Editor
• Wednesday August 14, 2024

Rates of syphilis and chlamydia in San Francisco have been trending down since the start of 2023, city data shows. But gonorrhea is proving to be a much more pernicious opponent for public health.

The city's department of public health issued the last 2023 monthly sexually transmitted infection report in June of this year, and has also released the first four months of data for 2024. Reported chlamydia cases went from 6,465 at the end of 2022 to 5,634 at the end of 2023, including cases of rectal chlamydia, which went from 2,064 to 1,438.

Reported adult syphilis cases went from 1,559 to 1,162 from the end of 2022 to the end of 2023. (Cases in cisgender females went up, from 153 to 176.)

From January through April of 2024, there were 323 reported cases of chlamydia compared with 465 in the first four months of 2023 (for rectal cases that's 70 in 2024 compared to 123 in 2023). Turn to adult syphilis and it's 78 reported cases compared with 101 (with cisgender women, cases went up, from 13 to 15).

But the numbers for gonorrhea tell a different story — 5,247 reported cases at the end of 2022 became 5,012 reported cases at the end of 2023. By April 2024 there were 1,555 reported cases compared to 1,647 at the same time in 2023. That's a slight decline but not at the same level as the other infections.

The San Francisco Department of Public Health declined to provide an expert to speak with the Bay Area Reporter for this report, but did provide a statement from the director of health, Dr. Grant Colfax, who is gay.

"The sharp decline in chlamydia and early syphilis infections in San Francisco demonstrates just how effective doxyPEP is as a sexual health tool," Colfax stated. "The San Francisco Department of Public Health, including the San Francisco City Clinic, played a critical role in the implementation of doxyPEP, and our community outreach and education continues."

Mayor London Breed's bond measure — including funding for City Clinic — will be included on the November ballot after it was approved by the San Francisco Board of Supervisors June 25.

Medical experts the B.A.R. has spoken with think the introduction of doxyPEP in late 2022 — a novel way of treating bacterial sexually transmitted infections with the antibiotic doxycycline (a type of tetracycline) after unprotected sex — is the key to understanding what's happening.

DoxyPEP has been approved for men who have sex with men and for trans women, which explains the concurrent rise in cases in cis women even as cases go down generally.

It also explains why gonorrhea isn't budging as much.

"Gonorrhea has a real potential to develop [antibiotic] resistance, although doxycycline is not something we use for gonorrhea anymore because the cat is out of the bag there," Dr. Matt Spinelli, a UCSF assistant professor and medical lead of the PrEP clinic at Ward 86 told the B.A.R.

Jorge Roman, a gay man who oversees clinical services at Magnet, the sexual health clinic at the San Francisco AIDS Foundation's Strut health center in the Castro LGBTQ neighborhood, told the B.A.R. that "tetracyclines have not been used for or against gonorrhea for a very long time, and so I think that's part of it; that's a big piece of it. It's not necessarily a surprise."

A study of doxyPEP efficacy showed an 80% drop in syphilis and chlamydia but only a 55% drop in gonorrhea, according to findings presented by Dr. Annie Luetkemeyer of UCSF at the 2022 International AIDS Conference, as reported on by the B.A.R. earlier this year, and which Spinelli cited.

Health Commissioner Cecilia Chung, a trans woman who is a longtime HIV/AIDS advocate who is HIV-positive, agreed with Spinelli and Roman in a statement to the B.A.R. and thanked the LGBTQ community for embracing doxyPEP.

"The reduction in chlamydia and syphilis rates in MSM [men who have sex with men] and trans women is a testament to the innovation of the San Francisco Department of Public Health, which was the first in the nation to research and put out guidelines for this innovative prevention tool," Chung stated. "Credit must also be given to our MSM and trans women communities, who were quick to adopt DoxyPEP as part of their sexual practices."

Rectal cases of gonorrhea showed some improvement last year — 1,597 cases in 2023 compared to 1,916 in 2022. But this year it's slightly up — 562 in 2024 compared to 549 at the same point in 2023.

Dr. Dan O'Neill, the chief medical officer at the San Francisco Community Health Center, was less bullish than Spinelli or Roman on doxyPEP — but he did state, as a potential explanation for the gonorrhea persistence, that it's possible the bacteria is becoming more resistant to tetracyclines in the population.

"While I feel certain doxyPEP is a contributing factor, causality can be tricky to pin down with such a complex topic," O'Neill stated in an email to the B.A.R. "It is also still relatively early to know how this new intervention will play out, as the full story of doxyPEP is yet untold. In particular, evidence of growing population-level tetracycline resistance is concerning for both the STD gonorrhea, which doxyPEP has been less helpful in curbing."

This isn't just a problem for the bacteria that causes gonorrhea but also Staphylococcal aureus, or MRSA, a common staph bacteria that causes skin infections, O'Neill said, among the health center's patient population, which he stated is "largely houseless folks or those struggling with addiction."

'Really exciting time for STI prevention'

Roman said that the general trends the city is seeing are also the case at Magnet, saying his was the first of San Francisco's larger providers to see more doxyPEP uptake before primary care doctors started prescribing it. Roman and Spinelli agreed it's a compelling time for the frontlines of combatting sexually transmitted infections.

"It's a really exciting time for STI prevention — there was a lot of frustration our public health efforts [condoms, asymptomatic testing] were not making an impact, and it's such a great time to have a highly effective, biomedical preventative tool making improvements on the population level," Spinelli said.

There is even hope for the fight against gonorrhea, Spinelli said.

"There was hope a Meningitis group B vaccine — they [meningitis and gonorrhea] have some similarities in that they are the same genus — there was hope a vaccine would have an impact on gonorrhea, and the data was presented and, unfortunately, it did not have an effect but it trended toward benefit," he said, adding that now researchers are working on a gonorrhea vaccine, which is currently on an FDA fast-track following a phase 1 trial .

Roman said that in the interim, doctors and the public should build on the momentum they are gaining in the fight against STIs. One way Magnet does that is by having clinicians have "conversations with all of our clients in shared decision making as to whether it'd [doxyPEP] help on an independent basis in their sexual networks, who they are engaging in sexual relationships with, and so understanding that and having open dialogue with our clients will help build on that momentum in terms of who would benefit from it."

Spinelli said that work needs to be done to see how cisgender women would benefit from doxyPEP.

"Globally, it's a really important population," he said. "Some providers are speaking with women who've had a prior STI and doing patient-centered decision-making. We measured the adherence in the study in women and that adherence was very low — that's why the study failed."

A study of female sex workers in Tokyo Spinelli referred to showed evidence of doxyPEP efficacy in that population without affecting vaginal bacteria.

Spinelli said another potential field of study is whether a 200-milligram dose of doxycycline could be taken before unprotected sex.

"There is a lot of plausibility it would work that way," he said.

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COVID vaccine mandates linked to increased uptake among healthcare workers

A new study in JAMA Network Open shows that state COVID-19 vaccine mandates for healthcare workers (HCWs) issued in 17 states in 2021 were associated with increased vaccine uptake.

The authors found that states with vaccines mandates had a nearly 4% increase in vaccination rates compared with non-mandate states, with even bigger gains in states with no test-out options.  

The study included 31,142 HCWs sampled across 45 states, including 16 states with vaccine mandates issued in mid-2021. The outcomes measured were increases in the proportions of vaccinated HCWs and those who completed or intended to complete the vaccination series 2 weeks after mandate announcement relative to baseline proportions of 88% and 86% vaccinated HCWs, respectively.

Test-out option tied to higher uptake

The authors found a mandate-associated 3.46 percentage point (pp) (95% confidence interval [CI], 0.29 to 6.63 pp) increase in the proportion of HCWs ever vaccinated against COVID-19 and a 3.64 pp (95% CI, 0.72 to 6.57 pp) increase in the proportion that completed or intended to complete the primary vaccination series 2 weeks after a mandate announcement in states with mandates.  

A stratified analysis showed that, in states with a no test-out option and among HCWs aged 25 to 49 years, vaccination increased 3.32% to 7.09% compared to baseline proportions. There were no significant uptake increases in states that offered both vaccine mandates and a test-out option.  

In an editorial on the study, John B. Lynch, MD, PhD, of the University of Washington in Seattle, said vaccine mandates are often unpopular and can be politicized, so understanding just how much benefit they yield is important for policy makers.  

Researchers are gaining more information on the specific tools that can be used for employer vaccine mandate policies, including not having a test-out option.

"Importantly, researchers are gaining more information on the specific tools that can be used for employer vaccine mandate policies, including not having a test-out option," he said.

COVID activity shows signs of slowing in parts of US

COVID-19 activity remains elevated across most of the United States, but some regions of the country are seeing some declines, as the proportion of KP.3.1.1 variant continues to rise, the Centers for Disease Control and Prevention (CDC) said today in its latest updates .

Nationally, wastewater detections of SARS-CoV-2 are at the very high level for the second straight week. The highest levels are still in the West and South, followed by the Midwest and the Northeast. The CDC's latest update, however, shows downward trends from high levels in the South and Midwest. 

For respiratory virus activity in general, the nation's levels are low, with most illnesses caused by COVID, with flu and respiratory syncytial virus (RSV) levels still low, the CDC said in its latest snapshot. It noted an upward trend for RSV, though.

COVID indicators show that the burden is highest in people ages 65 and older and in children younger than 2 years old.

KP.3.1.1 variant continues to rise

The proportion of KP.3.1.1 variant continues to rise, the CDC said in its latest variant proportion estimates . KP.3.1.1, one of many JN.1 offshoots, is thought to more easily evade immunity from earlier infection and vaccination. The variant now makes up 36.8% of sequences, up from 22.8% in the previous 2 weeks.

Among the CDC's other metrics, test positivity rose slightly last week and is at 18.1% nationally, but was highest in Texas and surrounding states. Emergency department visits for COVID declined a bit from the previous week, but are still at the moderate level in parts of the South.

Hospitalization levels are declining from an early-August peak. Deaths from COVID continue to rise, however, up 18.7% from the previous week. 

WHO, UNICEF call for cease-fire in Gaza to allow polio vaccination

The World Health Organization (WHO) and UNICEF today called for a humanitarian pause in Gaza for 7 days to allow two rounds of polio vaccination to take place, following the recent detection of virus in environmental samples and the identification of three suspected cases of acute flaccid paralysis (AFP) in children.

Stool samples from the children with AFP have been sent for testing to Jordan's national polio lab. 

The agencies have plans to launch two rounds of vaccination at the end of August and September across the Gaza Strip, targeting 640,000 children younger than 10 with novel oral polio vaccine type 2 (nOPV2). More than 1.6 million doses are earmarked for the vaccination response.

According to finalized plans, vaccination will be delivered by 708 teams made up of 2,700 health workers total and will take place at hospitals, field hospitals, and primary healthcare centers. 

The WHO said that, before the hostilities, Gaza had been free of polio for 25 years. "Its reemergence, which the humanitarian community has warned about for the last ten months, represents yet another threat to the children in the Gaza Strip and neighboring countries," the group said. " A ceasefire is the only way to ensure public health security in the Gaza Strip and the region."

More cases in 3 countries

In other developments, three countries reported more polio cases this week, according to the latest update from the Global Polio Eradication Initiative. 

Pakistan reported 2 more wild poliovirus type 1 (WPV1) cases, both in Balochistan, raising its total for the year to 14, up sharply from the 6 cases it reported in 2023.   Two African countries reported more cases involving circulating vaccine-derived poliovirus type 2 (cVDPV2). Liberia reported its first case since 2021, which was in Sinoe. Angola reported one case in Moxico.

UK health officials warn of rise in ceftriaxone-resistant gonorrhea

UK health officials are warning of a rise in cases of ceftriaxone-resistant gonorrhea.

In a report released yesterday, the UK Health Security Agency (UKHSA) said 15 cases of infection with ceftriaxone-resistant Neisseria gonorrhoeae were detected in England from June 2022 to May 2024, including 5 that were extensively drug-resistant (XDR). A total of 31 ceftriaxone-resistant gonorrhea cases, 7 of them XDR, have been reported in England since 2015.

Ceftriaxone is the first-line recommended antibiotic for gonorrhea infections in England and most countries. But it's the last remaining effective treatment option for the N gonorrhoeae bacterium, which has developed resistance to every class of antibiotic used to treat it, and ceftriaxone-resistant strains have been spreading, particularly in parts of Asia.

Concerns about wider spread

All case-patients have been heterosexual men, mostly in their 20s, and most have acquired the infection abroad. While transmission within England has been limited, UKHSA officials say they're concerned about the potential for wider spread as gonorrhea cases rise. The 85,223 gonorrhea cases reported in England in 2023 is the most annual cases in the country since officials began keeping records in 1918.

"Gonorrhoea is becoming increasingly resistant to antibiotics, risking the possibility of it becoming untreatable in the future," UKHSA consultant microbiologist Helen Fifer said in a  news release . "Untreated gonorrhoea can lead to serious health issues, including pelvic inflammatory disease and infertility."

Fifer added that the best defense against gonorrhea is to use condoms.

UKHSA sent a clinical alert to sexual health clinics advising them to culture gonococcal isolates, perform test-of-cure, and to refer all ceftriaxone-resistant strains or potential treatment failures to UKHSA.

Gonorrhoea is becoming increasingly resistant to antibiotics, risking the possibility of it becoming untreatable in the future.

More than 4 billion worldwide lack access to safe drinking water

A new study indicates more than 4 billion people in low- and middle-income countries (LMICs) lack access to safe drinking water, Swiss researchers reported yesterday in Science.

Combining household surveys and earth observation data (including satellite, airborne, and land-based data) with geospatial modelling techniques, a team led by researchers from the Swiss Federal Institute of Aquatic Science and Technology estimated that only 33% of the total population of 135 LMIC's used a safely managed drinking water service (SMDWS) in 2020, leaving approximately 4.4 billion without access to safe drinking water. That's more than twice the number of people estimated to lack access to safe drinking water in a 2020 by the World Health Organization and the United Nations (UN) Children's Fund Joint Monitoring Programme for Water Supply, Sanitation and Hygiene.

The lowest national rates of SMDWS use were in sub-Saharan Africa. The study estimates that, in 12 countries in the region, less than 10% of the population used SMDWS in 2020.

Safe drinking water a 'basic human right'

The study also found that access to safe drinking water in LMICs is primarily limited by fecal contamination, which affects nearly half the population in those countries and is indicated by Escherichia coli contamination in the primary drinking water source. 

"Detection of fecal contamination in drinking water is concerning, as ingestion of fecal pathogens is a major driver of diarrheal disease, one of the leading causes of under-five child mortality globally," the study authors wrote.

The authors note that access to safe drinking water is recognized as a basic human right and plays a core role in the UN's 2030 Agenda for Sustainable Development. They add that drawing attention to the many regions lacking safe water could "inform the mobilization and effective allocation of financial resources and human capacity" to address the issue.

"By filling crucial data gaps, our results point toward a substantial underestimation of the number of people whose basic human rights to safe drinking water are not being met and provide information on which subcomponents may be limiting use of SMDWS regionally," they wrote.

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• Open access
• Published: 21 August 2024

A Brief Alcohol Intervention (BAI) to reduce alcohol use and improve PrEP outcomes among men who have sex with men in Vietnam: study protocol for a randomized controlled trial

• Hao T. M. Bui 1 ,
• Le Minh Giang 1 , 2 ,
• Jane S. Chen 3 ,
• Teerada Sripaipan 3 ,
• Ha T. T. Nong 4 ,
• Ngan T. K. Nguyen 4 ,
• Sophia M. Bartels 3 ,
• Sarah L. Rossi 3 ,
• Heidi Hutton 5 ,
• Geetanjali Chander 6 ,
• Hojoon Sohn 7 ,
• Olivia Ferguson 3 ,
• Ha V. Tran 4 ,
• Minh X. Nguyen 2 , 3 ,
• Khanh D. Nguyen 1 , 3 ,
• Sarah E. Rutstein 8 ,
• Sara Levintow 9 ,
• Irving F. Hoffman 8 ,
• Byron J. Powell 10 ,
• Brian W. Pence 9 ,
• Vivian F. Go 3   na1 &
• William C. Miller   ORCID: orcid.org/0000-0002-1934-7827 9   na1  

Trials volume  25 , Article number:  552 ( 2024 ) Cite this article

Metrics details

In Vietnam and other global settings, men who have sex with men (MSM) have become the population at greatest risk of HIV infection. Although HIV pre-exposure prophylaxis (PrEP) has been implemented as a prevention strategy, PrEP outcomes may be affected by low persistence and adherence among MSM with unhealthy alcohol use. MSM have a high prevalence of unhealthy alcohol use in Vietnam, which may affect PrEP outcomes.

Design:  We will conduct a two-arm hybrid type 1 effectiveness-implementation randomized controlled trial of a brief alcohol intervention (BAI) compared to the standard of care (SOC) at the Sexual Health Promotion (SHP) clinic Hanoi, Vietnam.

Participants: Sexually active MSM ( n =564) who are newly initiating PrEP or re-initiating PrEP and have unhealthy alcohol use will be recruited and randomized 1:1 to the SOC or BAI arm. A subgroup of participants ( n =20) in each arm will be selected for longitudinal qualitative interviews; an additional subset ( n =48) in the BAI arm will complete brief quantitative and qualitative interviews after completion of the BAI to assess the acceptability of the intervention. Additional implementation outcomes will be assessed through interviews with clinic staff and stakeholders ( n =35).

Intervention: Study participants in both arms will receive standard care for PrEP clients. In the BAI arm, each participant will receive two face-to-face intervention sessions and two brief booster phone sessions, based on cognitive behavioral therapy and delivered in motivational interviewing informed style, to address their unhealthy alcohol use.

Outcomes: Effectiveness (PrEP and alcohol use) and cost-effectiveness outcomes will be compared between the two arms. Intervention implementation outcomes (acceptability, feasibility, adoption) will be assessed among MSM participants, clinic staff, and stakeholders.

This proposed trial will assess an alcohol intervention for MSM with unhealthy alcohol use who initiate or re-initiate PrEP, while simultaneously preparing for subsequent implementation. The study will measure the effectiveness of the BAI for increasing PrEP persistence through reducing unhealthy alcohol use in a setting where excessive alcohol consumption is a normative behavior. If effective, implementation-focused results will inform future scale-up of the BAI in similar settings.

Trial registration

NCT06094634 on clinicaltrials.gov. Registered 16 October 2023.

Peer Review reports

In Asia, the HIV epidemic has shifted from people who inject drugs (PWID) to men who have sex with men (MSM) [ 1 , 2 ]. HIV prevalence among Vietnamese MSM tripled from 2011 (4%) to 2021 (13.5%) [ 3 ]. The prevalence is even higher in urban areas, at 15% [ 4 , 5 ]. In 2021, MSM comprised 43% of new HIV cases in Vietnam [ 6 ].

In 2018, Vietnam was the second country in Asia to start a program for HIV pre-exposure prophylaxis (PrEP), which is a medication that if taken as prescribed, is highly effective for preventing HIV. By the end of 2022, over 60,000 people at high risk for HIV had access to PrEP in Vietnam; 80% of those using PrEP were MSM. Effective PrEP use requires persistence in care and adherence to the prescribed regimen, whether daily oral, event-driven, or injectable. PrEP persistence (maintaining PrEP use over time) has been a challenge for Vietnamese MSM. In Hanoi, PrEP persistence among MSM is only 42 and 33% at 6 and 12 months, respectively.

Unhealthy alcohol use may contribute to poor PrEP persistence [ 7 , 8 ]. Unhealthy alcohol use is defined as a spectrum of use from risky/hazardous (drinking more than the recommended daily, weekly or per-occasion amounts resulting in increased risk for health consequences) to alcohol use disorder [ 9 ]. In Asia, unhealthy alcohol use is common among MSM with about 25–50% of MSM engaging in heavy alcohol use (defined as having 5 or more drinks on any day or 15 or more per week) and binge drinking (defined as having 6 standard drinks for men, 4 for women). Unhealthy alcohol use is normative in Vietnam—men often feel pressured to drink and drink to excess. In Hanoi, 63% of MSM attending a sexual health clinic reported unhealthy alcohol use [ 10 ], which is higher than data from a national survey on alcohol use. These data indicated that 40.1% men in urban and 40.9% men in rural drank alcohol at hazardous (4–6 standard drinks) or harmful (≥ 6 standard drinks) levels in the last year [ 11 ].

Unhealthy alcohol use impairs cognition and affects behavior, often leading to poor decision making [ 12 , 13 , 14 ]. Unhealthy alcohol use also causes substantial morbidity and mortality and affects every step of the HIV prevention and care cascade [ 15 ], including PrEP persistence and PrEP adherence (using PrEP consistently as prescribed). In multiple settings, unhealthy alcohol use has been found to be associated with reduced oral PrEP persistence [ 16 , 17 ], thereby potentially impairing PrEP’s effectiveness in preventing HIV infection. Thus, an effective alcohol intervention for MSM using PrEP is needed to address both unhealthy alcohol use and low PrEP persistence issues. In addition to causing consequences related to PrEP, alcohol use at high levels before sex is consistently linked to condomless anal intercourse [ 8 ], more sex partners, and commercial sex acts [ 18 , 19 , 20 , 21 ], increasing the risk of HIV and sexually transmitted infections (STIs) among MSM [ 22 , 23 , 24 , 25 ]. People with unhealthy alcohol use are also less likely to engage in health care and to take medications appropriately [ 26 ]. Yet, few interventions to reduce alcohol use in MSM have been evaluated [ 7 ].

The brief alcohol intervention (BAI) is an alcohol reduction intervention that was developed [ 27 ] and piloted in primary care settings [ 28 , 29 , 30 , 31 ]. Studies in the USA [ 31 ] and Vietnam [ 28 , 29 , 30 ] have found that the BAI is an effective intervention for reducing alcohol use and improving HIV-related outcomes among people with HIV (PWH). In our randomized controlled trial (RCT) of the BAI among 440 Vietnamese PWH on antiretroviral therapy (ART) with unhealthy alcohol use, PWH who received the intervention were more likely to be virally suppressed 12 months [ 28 ]. Since findings from our previous study suggested that the BAI reduced alcohol use, which in turn improved ART adherence among PWH, we hypothesize that the BAI would also help improve adherence and persistent of PrEP among MSM. In two-arm effectiveness-implementation type 1 hybrid RCT, we will extend the use of the BAI to improve PrEP use. Our aims are (1) to assess the effectiveness of the BAI for increasing PrEP persistence and adherence among MSM in Vietnam; (2) to assess the impact of the BAI on alcohol use among MSM; (3) to estimate the cost-effectiveness, feasibility, and acceptability of scaling up the BAI in PrEP clinics throughout Vietnam via in-depth interviews with relevant stakeholders.

In this paper, we describe the guiding theories and conceptual frameworks, study setting, design, randomization, and types of participants involved in this study. We discuss the interventions, study outcomes, data collection, and analysis plan. We end this paper by describing this study’s innovations and potential challenges. We follow the SPIRIT checklist in reporting the protocol for this study [ 32 ].

Study setting

This study will be based at the SHP (Sexual Health Promotion) clinic at the Hanoi Medical University hospital, Hanoi, Vietnam. The clinic offers comprehensive sexual health care services to key populations, with a focus on MSM. Since May 2019, the clinic has provided oral PrEP free of charge to people at risk of HIV infection. As of February 2024, the clinic has provided oral PrEP to 5025 clients, 95% of whom are MSM. Unhealthy alcohol use is common in this population. In Hanoi, 72% of MSM PrEP clients drink alcohol at risky levels based on the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) scale [ 33 ]. In addition, data from the SHP clinic indicated that almost 50% of MSM discontinued PrEP within 6 months.

The BAI will be delivered to SHP clinic MSM PrEP clients initiating or reinitiating PrEP who report unhealthy alcohol use based on the AUDIT-C (The Alcohol Use Disorders Identification Test-Concise) score [ 34 ]. In-person BAI sessions will be administered in a private room in a building adjacent to the SHP clinic. Evaluation activities to measure BAI effectiveness will be conducted in a separate room in the same building to mask PrEP clinic staff from study participants’ assigned trial arm and minimize potential contamination. Intervention (e.g., BAI counselors) and evaluation teams will also not overlap.

Study design

This study is a hybrid type 1, two-arm effectiveness-implementation randomized controlled trial (RCT). A total of 564 MSM participants will be recruited and randomly assigned to either the BAI (target n =282) or standard of care (SOC) (target n =282) arms.

Prior to RCT implementation, the BAI as well as the outcome assessment tools will be adapted and piloted among MSM from other PrEP clinics in Hanoi (Fig. 1 ).

Randomization

Randomization will be conducted following the completion of study consent and baseline data collection. Randomization will use a stratified, permuted block design with randomly assigned block sizes. Details of blocking will be provided to the data manager who has no direct role in the study. Stratification will account for initiation or re-initiation of PrEP. Random allocation will be implemented by study statisticians, who use a random number generator to assign each participant to an arm at a single point in time. The randomization sequence is concealed from study team members and allocation is determined from a randomization list generated prior to study start. RCT enrollment is completed upon allocation to the study arm.

Study arm allocation will be masked to PrEP clinic staff, data analysts, and investigators. Emergency unblinding would only occur in the case of a severe adverse event that might have been related to the intervention. As the intervention is behavioral, we expect this to be extremely rare. Unblinding would require the clinic staff caring for the person to contact the study team that has access to the allocation assignments.

Participants

Msm participants.

MSM newly initiating PrEP or reinitiating PrEP who have unhealthy alcohol use will be recruited ( N =564). A subgroup of participants from both study arms ( N =20 for each arm) will be purposively selected and enrolled in a qualitative cohort to evaluate their change in alcohol use and PrEP use over 12 months. An additional subset of MSM in the intervention arm ( N =48) will be selected to assess the acceptability of the BAI. We will engage MSM-focused community-based organizations in Hanoi to encourage PrEP-eligible MSM to present to the SHP PrEP clinic.

Eligibility criteria for MSM participants includes (1) newly initiating PrEP or re-initiating PrEP after at least 3 months from a missed PrEP appointment, based on Vietnamese PrEP guidelines; (2) assigned male sex at birth; (3) identifying as male; (4) receptive or penetrative anal intercourse with a man in the past 6 months; (5) AUDIT-C≥4, indicating unhealthy alcohol use [ 34 ]; (6) 16 years of age or older; (7) intention to receive PrEP care in Hanoi for 12 months; and (7) willingness to provide informed consent. In accordance with the Vietnam law on medical examination and treatment [ 35 ], which requires parental consent for PrEP initiation of minors, participants from 16–17 years old will be eligible for study participation with parental written informed consent. MSM will not be enrolled if they meet one of these criteria: (1) psychological disturbance, cognitive impairment, or threatening behavior; (2) unwilling to provide locator information; (3) current participation in alcohol programs or studies; (4) current participation in other research studies unless specifically approved by the principal investigators; (5) current or previous participation in an HIV vaccine study; or (6) Clinical Institute Withdrawal Assessment for Alcohol (CIWA) ≥ 10, indicating risk for alcohol withdrawal.

Stakeholder participants for pre and post implementation assessment

We will recruit health care staff working in PrEP clinics in Hanoi for in-depth interviews on alcohol use among MSM PrEP users, availability of alcohol screening and intervention services, and their comments for the BAI manual at pre-implementation phase. Staff from the Vietnam Authority for HIV/AIDS Control (VAAC) (which directs and provides support for initiatives in HIV/AIDS prevention and care in Vietnam), Hanoi Center for Disease Control, and the SHP PrEP clinic will be recruited prior to and upon completion of the main RCT to examine implementation-related outcomes. Stakeholders will be recruited through referral and well-established connections with governmental HIV agencies in Vietnam.

Intervention: BAI

The BAI is based on Project TrEAT [ 27 ]—an effective alcohol intervention was adapted for PWH in the USA [ 31 ]. In 2016, the BAI was further adapted in Vietnam as part of REDART, a 3-arm RCT among 440 adults with unhealthy alcohol use receiving ART in 7 HIV outpatient clinics in Thai Nguyen, Vietnam [ 28 , 29 , 30 ]. Results of the study showed that the BAI significantly reduced alcohol use compared to the SOC. The BAI arm also increased viral suppression compared to the SOC and was found to be cost-effective [ 29 ].

Guiding conceptual frameworks

The BAI draws from motivational interviewing (MI) [ 36 ]/motivational enhancement therapy (MET) [ 37 , 38 ] and cognitive behavioral therapy (CBT) [ 39 ]. The BAI leads to increased alcohol-related readiness to change and coping skills, which will, in turn, decrease alcohol use [ 28 ]. Since our previous study suggested that reduced alcohol use increases ART adherence among PWH, we extended these findings to hypothesize that the BAI will reduce alcohol use and increase PrEP uptake among MSM. As the BAI is implemented in the real world, its effectiveness will depend, in part, on its acceptability and feasibility from the perspective of MSM and stakeholders.

MI [ 36 ] and MET [ 37 , 38 ]

MI is a therapeutic approach that is directive, yet client-centered, and is based in enhancing individuals’ intrinsic motivation to change behavior by exploring and resolving their ambivalence [ 36 , 37 , 38 ]. The goal of MI is to elicit self-motivational statements and behavioral change from the client through four principles: empathy, collaboration, evocation, and autonomy support. MET, based on the MI approach and practice, provides clients with normative-based feedback on alcohol use, explores client motivation to change in light of this feedback, and consolidates client commitment to change [ 37 , 38 ]. In Vietnamese settings where drinking is normative, this feedback supports change [ 30 ].

Cognitive behavioral therapy (CBT) [ 39 ]

CBT emphasizes clients’ development of skills to modify problematic cognitions and maladaptive behaviors. Specifically, CBT targets cognitive, affective, and environmental risks for alcohol use and develops clients’ behavioral skills to cope with these risks (Figs. 2 and 3 ) [ 39 ].

Conceptual model

Schedule of enrolment, intervention, and assessment

Intervention components

The BAI comprises two in-person sessions and two booster telephone sessions. The two in-person, face-to-face sessions are approximately 45 min each, and occur about 1 month apart. The two booster telephone sessions are approximately 20 min each, and each telephone session occurs 2 to 3 weeks after each face-to-face session. The sequence and schedule of BAI sessions are in-person session 1 (~0–2 weeks following study enrollment), booster session 1 (~2–4 weeks), in-person session 2 (~4–6 weeks), and booster session 2 (~6–8 weeks).

The BAI’s core components (Table 1 ) reflect the theoretical and empirical mechanisms responsible for behavior change.

In session 1, the BAI includes information about personalized feedback, alcohol facts, decisional balance, managing risky moods and situations, target behaviors, and optional goal setting. In session 2, events since session 1 and previously set goals are reviewed, followed by discussion of developing an alcohol independent lifestyle, engaging supportive others, and building coping skills. Booster phone sessions check the participant’s perception of progress towards goals (or needed goal revisions), elicit self-motivational statements and strategies for coping with high-risk situations, and/or review effective coping skills.

Intervention arm

BAI counselors, who were not working as PrEP counselors at the SHP clinic, were identified and trained. MSM will receive BAI sessions delivered by BAI counselors with timeframe and contents describe above. In addition, MSM in the BAI arm will receive the same procedures with participants in the standard of care arm. A counseling supervisor from UNC Vietnam will provide specific feedback on BAI competencies that meet or need improvement as well as on adherence to the BAI content. This supervisor will in turn be supervised by protocol team members with expertise in behavioral interventions and alcohol use.

Standard of care arm

Participants in the SOC arm will receive all counseling sessions that are normally offered within the PrEP clinic, including PrEP counseling. Those identified with substance use disorders (exclusive of alcohol use disorder) or mental health problems will receive care, as needed, using a four-tiered approach currently in place at SHP: (1) information and leaflets focusing on the specific issue; (2) brief intervention; (3) intensive intervention; (4) referral. None of these activities address alcohol use or alcohol use disorder.

All MSM participants will have regular screening for HIV and STI (gonorrhea, chlamydia, and syphilis) at baseline and months 3, 6, and 12. They will also receive HIV testing at 9 months. Any positive tests will be treated (STI) or referred for treatment (HIV) according to Vietnamese guidelines. All participants will receive pre- and post-test counseling for HIV testing and brief counseling for STI risk reduction. Condoms and lubricant will be offered to all participants.

Study procedure

As a part of routine clinic activities at SHP clinic, clients who would like to initiate or re-initiate PrEP will be pre-screened for risk behaviors including a brief screening for alcohol use. Those who have elected to start PrEP and are eligible for the study will have the study explained to them. Screening for study participants may occur at their PrEP initiation visit or within 1 month of PrEP initiation. For each potential MSM participant, independent informed consent for screening will be obtained before screening procedures are initiated.

During screening, MSM will undergo a brief screening questionnaire, including the AUDIT-C and CIWA. MSM will also be offered condoms and lubricant. Sobriety will be clinically assessed. MSM identified as acutely intoxicated will not be able to proceed with the screening or enrollment process. MSM who screen positive for unhealthy alcohol use (AUDIT-C ≥ 4) will be assessed for severe alcohol use disorder with the Mini International Neuropsychiatric Interview (MINI) [ 40 ]. Individuals in danger of alcohol withdrawal (CIWA ≥ 10) will be further evaluated with the CIWA and will not be able to proceed with enrollment at that time. For these individuals, rescreening for study eligibility may occur after the danger of alcohol withdrawal has passed—participants will be asked to be re-screening following completion of their withdrawal treatment.

Participants who meet all the eligibility criteria for enrollment will proceed with enrollment visit procedures, including written informed consent for RCT study procedures. Study participants are requested to remain in the study for 12 months with study visits at months 3, 6, 9, and 12. However, participants may voluntarily withdraw from the study for any reason at any time. The enrollment visit will typically occur on the same day but may occur up to 1 month after screening. If enrollment occurs on a different date from screening, the CIWA will be administered again prior to enrollment.

As part of each study visit, participants will complete a standardized questionnaire on topics including demographic information, PrEP use, alcohol use, and sexual behaviors. At enrollment, 3 months, and 12 months, participants will be asked to complete a 30-day Timeline Followback (TLFB) to assess recent alcohol use and they will be asked to provide dried blood spots (DBS).

We will use a variety of procedures to maximize retention, including compensating participants for their time to complete study visit, tracking of scheduled and missed visits in a computerized follow-up program, updating locator information at every study visit and using appropriate and timely visit reminder mechanisms.

Stakeholder participants

In the RCT phase, implementation outcomes will be assessed prior to and following completion of the RCT. All stakeholders will provide informed consent prior to participation in study interviews.

Effectiveness outcomes

Prep use and sexual behavior/stis (aim 1).

The primary effectiveness outcome among MSM participants is PrEP persistence (Table 2 , Table 3 ). The secondary effectiveness outcomes are PrEP adherence and risk-aligned PrEP use. Risk-aligned PrEP use is defined as persistent oral, event-driven (2+1+1) [ 41 ] or injectable PrEP, or clinician-supervised PrEP discontinuation for reduced sexual risk. Supplemental effectiveness outcomes, which are pre-specified for analyses, include condomless anal intercourse, as well as incident HIV, gonorrhea, chlamydia, and syphilis.

All PrEP outcomes will be measured at 3, 6, and 12 months. Because self-report may overestimate adherence, we will also measure PrEP metabolites in DBS at 3 and 12 months. Condomless anal intercourse will be measured at baseline and every quarterly study visit. Incident HIV will be measured at 3, 6, 9, and 12 months, and incident gonorrhea, chlamydia, and syphilis will be measured at 3, 6, and 12 months.

Alcohol use (Aim 2)

The primary alcohol-related effectiveness outcome is heavy drinking days (binge drinking), measured by self-report with the TLFB (Table 2 ). Secondary alcohol-related effectiveness outcomes include self-reported number of drinking days and self-reported drinks per drinking day. Supplemental alcohol-related effectiveness outcomes include self-reported alcohol before sex and alcohol abstinence stigma.

Alcohol outcomes will each be measured at 0, 3, and 12 months. Phosphatidyl ethanol (PEth) levels, a biomarker of alcohol consumption [ 42 , 43 , 44 ], will be measured using DBS as a process measure.

Implementation outcomes

The study has two primary implementation outcomes: acceptability of the BAI among clinic staff and MSM, and feasibility of the BAI at the clinic level. Secondary implementation outcomes include adoption and penetration.

Acceptability will be measured both qualitatively and quantitatively. MSM and clinic staff will complete the 4-item Acceptability of Intervention Measure (AIM) [ 45 ] after receiving the BAI, and after BAI implementation, respectively. The 15-item Mental Health Implementation Science Tools Acceptability Scale (mhIST), consumer version [ 46 ] and the mhIST 13-item provider version will also be administered simultaneously. Clinic staff will address acceptability in in-depth interviews as well.

Feasibility will be measured qualitatively among clinic staff at within 6 months of the final BAI delivery to an MSM participant, and quantitatively based on the BAI completion rate among MSM participants. The BAI completion rate will be defined as (1) completion of all four sessions among those who initiated at least one session and (2) completion of all four sessions among those who were assigned to the BAI arm; (3) completion of at least two sessions among those who were assigned to the BAI arm.

Adoption will be measured qualitatively among clinic staff within 6 months of the final BAI delivery to an MSM participant. Penetration will be measured among all MSM participants and defined as completion of at least one session among those assigned to the BAI arm.

Economic evaluation and measurements

The BAI has been found to be cost-effective for PWH [ 29 ]; however, implementation costs and its value in MSM clients with alcohol use problems has not been studied. In our study, we incorporated a suite of economic evaluation sub-studies to assess (1) the cost of BAI implementation, (2) the intervention delivery, (3) patient perspective costs during their care, (4) health-related quality of life (HRQoL), and (5) the cost-effectiveness of the BAI in the study’s target population. For the health systems costing, key outcome measure will be total implementation process cost of the BAI and per-patient intervention delivery cost. For patient cost, the primary outcome will be cumulative total direct and indirect patient costs associated with care-seeking from screening to maintaining PrEP. For HRQoL, we will use EQ-5D-5L-based health profiles collected for each patient into a value on a scale anchored at 1 (full health) and 0 (worst health state = death) based on the value set for Vietnam, which will represent the quality-adjusted-life years (QALY) estimate for each participant on average during the study participation [ 47 ]. For the cost-effectiveness analysis, we will estimate the incremental cost-effectiveness ratio (ICER), defined as [C i − C a ]/[E i − E a ] with C i and C a being the respective health systems costs of the intervention [i], inclusive of implementation costs, and assessment only [a], and E i and E a the corresponding effectiveness, measured in terms of QALY [ 48 ]. The ICER estimates will be measured against varied levels of the willingness to pay thresholds (WTP) to assess the overall cost-effectiveness of the BAI in our study population. Costs will be measured using direct observation and time-and-motion (TAM) studies, detailed prospective budgetary analysis, and surveys of both participants and key staff.

We will estimate the human resource requirements (using activity-based time estimates) and costs of all intervention-related activities, including the BAI, PrEP (including long-acting injectable, event-driven, and risk-aligned approaches, accounting for adherence), screening for and treatment of HIV, and management of HIV-associated complications.

Data collection and analysis

Formative data collection and bai adaptation.

Prior to RCT recruitment, adaptive and pilot phases were conducted to adapt intervention package and study tools to the context of MSM on PrEP in Vietnam. In-depth interviews were conducted with clinic staff and MSM PrEP clients to ensure that concepts, language, examples, and context of the BAI is culturally relevant to MSM, HIV risk, and PrEP persistence in adaptive phase. Data were analyzed to systematically adapt key BAI characteristics to MSM in Vietnam acceptability while maintaining the core structure [ 30 , 49 , 50 , 51 ]. Key characteristics were the population-specific elements and structural factors that increase intervention efficacy, relevance. Two focus group discussions, one with MSM on PrEP and one with counselors from PrEP clinics from the four clinics (around 8 participants per focus group) to test component of the adapted BAI. Feedback from the focus groups was utilized to further revise the adapted intervention package for pilot.

In the pilot phase, trained BAI counselors delivered the adapted BAI package to eight MSM on PrEP to assess intervention flow, comprehension, utility of information, motivation changes, and utility of behavioral skill training. We also did pilot survey items, interview procedures to assess survey length, check response distribution, item comprehension, and data collection procedures with up to 10 MSM on PrEP. The results informed refinement and finalization of the BAI package and assessment tools for use in the RCT. Individuals who take part in the pilot did not participate in the RCT phase.

Quantitative data

At baseline and each quarterly visit, we will measure PrEP use, alcohol use, and sexual behaviors. PrEP use will be monitored from the participant’s medical record, and from self-report at each study visit. HIV screening status will be conducted at every quarterly visit and STI testing for gonorrhea, chlamydia, and syphilis will be performed at baseline, and months 3, 6, and 12.

Analytically, we will conduct intention-to-treat comparisons between the two arms to assess effectiveness of the BAI at months 3, 6, and 12 for the PrEP outcomes and months 3 and 12 for the alcohol outcomes. All tests will be based on a nominal 5% two-sided type 1 error probability. Confidence intervals (CI) will have a nominal 95% coverage. Additional multivariable analyses will adjust for potentially important predictors of persistence, determined a priori, which include age, prior PrEP use, partner living with HIV, perceived PrEP need, use of event-driven PrEP, AUDIT-C score, number of sex partners, and frequency of condomless sex. Alternative predictors may be chosen if any of the proposed predictors have substantial statistical issues, such as low response frequency or substantial missing data. We will also examine overall persistence using a generalized estimating equations (GEE) model with a logit link function and binomial error distribution to assess the outcome across time at 3, 6, and 12 months.

TLFB hand-on training was conducted online in total nine 1-hour sessions at the beginning of the pilot phase to equip knowledge and skill for assessment team of study. To examine the primary outcome of number of heavy drinking days, we will use GEE with a Gaussian error distribution and identity link to compare the means of heavy drinking days between the two arms at 3 and 12 months. The primary model will estimate effects across all time points; a secondary model will include an interaction term with time.

Quantitative tools used to measure acceptability were described above. Although a specific AIM cutoff has not been established [ 45 ], we provisionally consider an AIM score of ≥ 16 to reflect adequate acceptability. We will use descriptive analysis to determine if the intervention is acceptable and feasible.

For assessment of health systems perspective costs, we will perform an activity-based cost analysis for both implementation costs and intervention delivery costs using ingredients approach scale-up planning. Capital assets and start-up costs will be annuitized based on their expected useful life years (between 2 and 15 years) and discounted at 3–10%. All other resource use will be assessed as costs using ingredients approach. Common costs multiple activities and procedures will be apportioned based on ratios of cumulative human resource time commitment measured from time assessment study. Patient costs include data on socio-economic status, costs associated with the participants’ alcohol use, direct health care costs, and indirect costs associated with the participants’ illness. Cumulative total costs for each period and overall follow-up will be assessed for individual patients. We will calculate the differences in the proportion of participants experiencing patient costs exceeding 20% (sensitivity analysis performed at different % levels) of individual and household income as well as income levels assessed based on the social capital approach between the intervention and control arms of the trial.

Leveraging individual participant level data on costs and effectiveness, we will evaluate the cost-effectiveness of the BAI intervention against the SOC, from the health systems perspective. Cumulative health systems costs measured for individual participants in the study will be used to estimate the differences in health systems costs between the BAI and SOC groups. Differences in effectiveness will be assessed based on differences in HRQoL estimate obtained from EQ-5D-5L between the two groups, as an estimated number of QALYs gained by the BAI among MSM initiating PrEP relative to the SOC. As the WTP is largely unknown for the BAI in our study population context, we will explore a range of WTPs, starting with 1 x Vietnam’s Gross Domestic Product (GDP) per capita in the “net benefits” (NB) or “net-monetary benefit” (NMB) approach (via generalized linear models with log-link) [ 52 , 53 ] and generate the cost-effectiveness acceptability curve.

For PrEP persistence and adherence, MSM lost to follow-up will be considered not persistent and non-adherent. For other outcomes, if there are missing >10% of observations, we will assess predictors of loss to follow-up and apply multiple imputation under the assumption that data are missing at random conditional on observed data.

Qualitative data

To monitor the process of change in PrEP and alcohol-related outcomes, as well as BAI acceptability, we will conduct qualitative interviews with a subset of 40 RCT study participants, with 20 MSM in each arm. In this qualitative cohort, qualitative interviews will be conducted at months 3 and 12. At each in-depth interview, we will ask participants about personal drinking and sexual behaviors, attitudes towards and perceptions around drinking, PrEP use, and if and how they have changed over time as well as their experiences in the study. Participants in the BAI arm will also be asked about BAI acceptability, including how they experience BAI, if the BAI is useful and acceptable for them and if the BAI would be applied for those with unhealthy alcohol.

We will also conduct in-depth interviews with SHP clinic staff (up to 15) and stakeholders from policy-oriented agencies (up to 20) in Hanoi to explore feasibility and adoption of the BAI. In-depth interviews with SHP staff, including those who are BAI counselors, will be conducted after BAI training and within approximately 1 month prior RCT initiation. These interviews will focus on BAI implementation barriers and facilitators, staff’s intent to sustain use of the BAI, and competing health priorities, resources, counselor skills, and clinic space for intervention implementation. We will also conduct in-depth interviews with staff from policy-oriented agencies when the BAI is completed for all MSM participants. These interviews will explore and assess the feasibility of scaling up the BAI throughout Vietnam and intention to adopt the BAI, if it is effective.

All qualitative interviews will be audiotaped, transcribed, and translated, for analysis using NVivo or similar software. Analysis will begin as data are collected so that topics for further exploration can be incorporated into ongoing fieldwork. Textual data analysis will involve five steps: (1) reading for content; (2) deductive and inductive coding; (3) data display to identify emerging themes; (4) data reduction; and (5) interpretation. Coded interviews will be compared and triangulated within study participants with multiple interviews and across all study participants. Findings from qualitative interviews will inform our understanding of the context and processes that may underlie successful mechanisms for the BAI to be effectively delivered to MSM PrEP clients as well as refinements that may be needed for future scale-up efforts.

Data management, safety monitoring, and adverse event reporting

Standard operating procedures (SOPs) will be created to outline procedures for data and forms processing, adverse event assessment, management, and other study operations. Data will be transferred to the central UNC-Vietnam office in Hanoi, processed, and cleaned. The data manager will be responsible for coordinating Quality Control reports and data queries resolutions. All participant information will be stored in locked file cabinets in areas with access limited to study staff. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems.

Safety monitoring will be performed by an independent Data and Safety Monitoring Board (DSMB) committee comprised of researchers and persons in Hanoi with expertise in issues relevant to this study. The committee will meet before the trial begins, 1 year of commencing enrollment and at least annually thereafter. Blind interim analyses of the data will be conducted halfway through the follow-up period, when virtually all participants will have provided 6-month behavioral interim endpoints and presented blinded for the DSMB by an external statistician. All adverse events and social harms will be documented and reported to the principal investigators (PIs), Institutional Review Board (IRB), and DSMB according to the SOPs.

Trial conduct is reviewed regularly by independent boards as well as the study team. The trial will be monitored by an independent DSMB at least annually. The university and local IRBs review the trial progress annually to ensure ethical conduct and participant safety. The DSMB and IRB members and their review processes are independent from investigators and the sponsor. Additionally, the data management and assessment teams conduct various study procedures and data quality checks at each participant study visit. The data management team submits quality assurance/quality control (QA/QC) reports monthly to the Evaluation Team and Operational Coordinating Center and biannually to the Protocol Committee for review and feedback.

Study committees’ roles and responsibilities

The study team comprises the Protocol Committee, Operations Team, and Community Advisory Board (CAB). The Protocol Committee leads the study and consists of the PIs and co-investigators. The Protocol Committee has primary responsibilities of overseeing and facilitating the overall conduct of the study, developing the study protocol, making study decisions, and reporting the study results.

The Operations Team consists of the Operational Coordinating Center, Evaluation Team, and Clinical Team. The Operational Coordinating Center is primarily responsible for reviewing all study materials and procedures; facilitating regular meetings among the Protocol Committee and Operations Team; facilitating and/or leading staff trainings; ensuring study activities are meeting protocol requirements; tracking study progress, timelines, and decisions; preparing progress reports for the sponsor; and ensuring that all relevant IRB regulations are followed. The Evaluation Team directly oversees all day-to-day study activities, with primary responsibilities of conducting the study assessment visits and obtaining informed consent with study participants; developing SOPs; data management; quality assurance and quality control of data and procedures; and coordinating local IRB approvals. The Evaluation Team Research Manager supervises this team. The Clinical Team is responsible for conducting all recruitment and intervention activities with study participants and managing the intervention team. The Clinical Team Research Manager supervises this team.

The Protocol Committee meets weekly with the Operations Team to discuss study conduct, progress, and challenges. Additionally, the Operational Coordinating Center meets weekly with the Evaluation Team to discuss specific study issues and operations, and the Evaluation Team and Clinical Team meet weekly to coordinate day-to-day study activities.

The CAB includes MSM eligible for PrEP, organizations serving MSM in Hanoi, and community and health leaders from Hanoi, and meets every 2 months. The CAB serves as a voice for the community and study participants and provides input on how the study can best serve and protect the interests and welfare of study participants and the community.

Sample size

Rct sample size and power calculation.

For the primary effectiveness outcomes, the total number of MSM participants enrolled into the RCT will be 564, with a target of 282 participants in each of the two arms. Power calculations are based on a two-sided α =0.05, 80 and 90% power, and a minimum clinically important difference in proportions of 0.15 for our primary outcome of PrEP persistence. We estimate study retention to be 80% at 12 months, based on data retention in our previous trials [ 28 ]. With these assumptions, a sample of 564 provides an analytical sample of 450 and 90% power to detect a prevalence proportion difference of 0.15 for our primary outcomes. Power for secondary outcomes is greater. For the number of heavy drinking days, we have sufficient power to detect a difference of ~0.3 days.

To the best of our knowledge, this study is the first to assess the effectiveness and cost-effectiveness of the BAI among MSM with unhealthy alcohol use who initiate PrEP in Vietnam or similar settings where alcohol use is widely accepted. This trial will simultaneously test the effectiveness of the BAI for addressing two important public health issues for MSM: PrEP persistence and unhealthy alcohol use. The BAI was effective, cost-effective, and feasible for PWH on ART in Vietnam [ 28 ]—extending the use of the BAI to MSM initiating or re-initiating PrEP is a logical step. The study population of our previous BAI trial with PWH on ART was primarily people with a history of injection drug use; this BAI trial with MSM who initiate PrEP will develop a culturally acceptable manual for this new population. This trial will also assess appropriate mechanisms for the BAI to be effectively delivered to MSM initiating PrEP and provide information needed for future scale-up if the intervention is shown to be effective.

In our previous trial, the effect of the BAI on PWH on ART was mediated through alcohol use and increased ART adherence. We expect there to be a similar mechanism for the BAI among MSM initiating/re-initiating PrEP. We hypothesize that the BAI will lead to reduced alcohol use, better alcohol-related decision-making which in turn increase PrEP persistence. If MSM’s behavioral risks change after receiving the BAI, we will identify those changes through HIV and STI testing, as well as detailed behavioral assessments. We anticipate that through its impact on alcohol use, the BAI may also lead to fewer STIs. Taken together, we believe that the BAI may have important health implications for MSM with unhealthy alcohol use.

This study addresses priorities for the future health of MSM in several ways:

First, the BAI has the potential to alter multiple health outcomes among MSM. Interventions to address alcohol reduction among MSM are “alarmingly scarce” [ 54 , 55 ]. Yet, excessive alcohol use is both common and consequential among MSM. This proposed study has the potential to improve three interlinking health outcomes [ 7 ] for MSM: excessive alcohol use, STIs, and HIV prevention.

Second, this intervention study is designed as a type 1 hybrid RCT to expedite scale up of this study if the BAI is found effective. Many interventions are never taken to scale after their effectiveness is shown. Bringing an evidence-based intervention to scale requires careful implementation assessment. By combining the effectiveness evaluation with preparation for implementation, the timeline for scale up is shortened dramatically, allowing a greater impact on MSM health in a shorter time.

Third, the study will evaluate a cost-effective and likely sustainable intervention model. As seen in REDART with PWH on ART, the short duration, feasibility, and acceptability of the BAI are keys to its potential for sustained impactful benefit to MSM in resource-limited settings.

Finally, the trial is designed to be integrated into an existing structure within the SHP clinic and enroll MSM who initiate or re-initiate PrEP at the clinic, providing an opportunity to evaluate the intervention in a real-world clinic setting to inform future scale-up [ 56 ]. By integrating the BAI into an existing structure and enrolling current PrEP clients, we will have the opportunity to access BAI acceptability among both MSM and the clinic staff.

Since the study is being conducted in a setting where alcohol use is considered a normative behavior, MSM PrEP clients with unhealthy alcohol use may not realize that their alcohol consumption is at a level that requires intervention. As a result, they may be reluctant to undergo the BAI. To help address this concern, our study staff will provide complete information about what excessive alcohol use is, potential consequences of excessive alcohol use, and how the BAI is delivered, including its relatively short duration in screening session.

One of the expected benefits of the BAI is that MSM will reduce their alcohol use. If alcohol-related decision-making is positively affected, MSM may also reduce their sexual risk behaviors, potentially eliminating their need for PrEP or shifting the need to event-driven PrEP. We will measure these changes in behavior and conduct secondary analyses to describe the potential mediators of changes in PrEP use over time.

Currently in Vietnam, long-acting injectable PrEP (LAI-PrEP) is not available. LAI-PrEP may become available during the study and the protocol has included adaptations for that possibility. Recently, the United State President's Emergency Plan for AIDS Relief (PEPFAR) has proposed a donation of long acting injectable cabotegravir for conducting a demonstration study evaluating acceptability and feasibility of LAI-PrEP implementation in Vietnam. While we have not seen challenges when the demonstrated study is conducted, our study team will keep eyes on preparation process for this demonstration study and decide on adjustment for our study if needed.

Conclusions

PrEP is an effective HIV prevention strategy for MSM when it is used as prescribed and persistently. Interventions to support PrEP adherence and persistence are crucial to ensure effective implementation of PrEP worldwide. In regions where heavy alcohol use is normative, alcohol reduction interventions may be needed to improve PrEP adherence among MSM PrEP clients. The BAI, which improved HIV outcomes among PWH with unhealthy alcohol use, is a logical intervention to adapt to the context of MSM using PrEP. This study will provide insight regarding the adaptation of the BAI to a new population. The trial will also shed light on the potential impact of targeting alcohol use reduction to improve PrEP persistence among MSM worldwide.

Trial status

Protocol version 4.0 (2/22/2024). Recruitment is expected to begin on April 3, 2024, and complete in February 28, 2026.

Availability of data and materials

Data collection for this study is ongoing, so no data and materials are currently available. During study implementation, deidentified data will be made available in accordance with NIAAA policies. This study will comply with all NIH and U.S. Federal governments requirements related to the dissemination of the research findings upon completion of the study. The International Committee of Medical Journal Editors (ICMJE) guidelines for authorship will be applied. In addition to publications, primary results of the study will be presented to stakeholders and study participants through a dissemination workshop and/or dissemination materials. All informed consent forms will include a statement referencing that this study will be registered in clinicaltrials.gov and will provide a link to the site to enable interested participants to review the trial information on the website.

Abbreviations

Acceptability of intervention measure

Alcohol use disorders identification test

Antiretroviral therapy

Brief alcohol intervention

Community advisory board

Cognitive behavioral therapy

Clinical Institute Withdrawal Assessment for Alcohol

Dried blood spot

Data and safety monitoring board

Generalized estimating equation

Human immunodeficiency virus

Health-related quality of life

Incremental cost-effectivenes ratio

Institutional review boards

Motivational enhancement therapy

Mental health implementation science tools acceptability scale

Men who have sex with men

Long acting injectable

Motivational interview

Mini International Neuropsychiatric Interview

Principal investigators

People living with HIV

Pre-Exposure Prophylaxis

Quality-adjusted life-year

Randomized controlled trial

Timeline follow back

Sexual Health Promotion

Standard of care

Standard operating procedure

Sexually transmitted infections

University of North Carolina

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Acknowledgements

We would like to thank all staff in the BAI implementation team at the UNC Project Vietnam and HMU for their work in preparing and conducting this trial (Pham Dieu Linh Thi, Nguyen Thanh Van, Tran Thi Van Anh, Pham Quang Loc, Mai Quang Anh, Nguyen Huu Anh, Nguyen Cong Thanh and Dau Sy Nguyen). We also thank staff and clients at four PrEP clinics in Hanoi, including Nam Tu Liem health district center, Lighthouse clinic, ASK Minh Ngoc clinic, and GLINK clinic for their support and participation in the adaptive phase of the study.

This study was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism ([email protected]) US National Institutes of Health, 1R01AA030479. HTMB was supported by the Fogarty International Center and the Office of Disease Prevention of the National Institutes of Health (NIH) under Award Number D43TW009343 and the University of California Global Health Institute (UCGHI). VFG was in part supported by the University of North Carolina at Chapel Hill Center for AIDS Research (P30 AI50410). The funders had no role in the data collection, analysis, manuscript preparation, or decision to publish.

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Vivian F. Go and William C. Miller are co-last authors.

Authors and Affiliations

Center for Training and Research on Substance Abuse -HIV (CREATA-H), Hanoi Medical University, Hanoi, Vietnam

Hao T. M. Bui, Le Minh Giang & Khanh D. Nguyen

Department of Epidemiology, School of Preventive Medicine and Public Health, Hanoi Medical University, Hanoi, Vietnam

Le Minh Giang & Minh X. Nguyen

Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA

Jane S. Chen, Teerada Sripaipan, Sophia M. Bartels, Sarah L. Rossi, Olivia Ferguson, Minh X. Nguyen, Khanh D. Nguyen & Vivian F. Go

University of North Carolina Project Vietnam, Van Phuc Diplomatic Compound, Apartment 407-408, A2 Building298 Kim Ma Street, Ba Dinh District, Hanoi, Vietnam

Ha T. T. Nong, Ngan T. K. Nguyen & Ha V. Tran

Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, USA

Heidi Hutton

Division of General Internal Medicine, School of Medicine, University of Washington, Seatle, USA

Geetanjali Chander

Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea

Hojoon Sohn

Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, USA

Sarah E. Rutstein & Irving F. Hoffman

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA

Sara Levintow, Brian W. Pence & William C. Miller

George Warren Brown School of Social Work, Washington University, St. Louis, MO, USA

Byron J. Powell

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WCM, VFG, and LMG conceived the study and obtained the funding. WCM, VFG, LMG, HTMB, JSC, TS, HTTN, NTKN, SMB, SLR, HS, OF, HVT, MXN, KDN, SER, SL, IFH, BJP, and BWP contributed to research design and protocol development. HH and GC helped conceptualize the intervention conditions, contributed to the grant writing, and informed all implementation materials. HTMB drafted the manuscript, and VFG, WCM, LMG, and MXN revised it critically with important intellectual contents. All authors read and approved the final manuscript.

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Correspondence to William C. Miller .

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The study was approved by the IRBs at the University of North Carolina, Chapel Hill and Hanoi Medical University. The study will be conducted in full compliance with the protocol. The protocol will not be amended without prior written approval by the PIs. All protocol amendments must be submitted to and approved by the relevant IRB(s)/Ethical Committees prior to implementing the amendment. Informed consent for both MSM participants and stakeholders will be obtained by research staff in the assessment team who have prior experience with obtaining informed consent. All consent forms will be translated into Vietnamese. The informed consent procedures will be conducted with all MSM who are eligible and interested in participating in the study, prior to participation in any study visit activities. Stakeholder participants will be consented prior to any quantitative or qualitative interviews.

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Bui, H.T.M., Giang, L.M., Chen, J.S. et al. A Brief Alcohol Intervention (BAI) to reduce alcohol use and improve PrEP outcomes among men who have sex with men in Vietnam: study protocol for a randomized controlled trial. Trials 25 , 552 (2024). https://doi.org/10.1186/s13063-024-08382-5

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Rigour after gonorrhea treatment in a 55-year-old man

The incidence of syphilis has increased, primarily among men who have sex with men. Syphilis presentation can be difficult to discern and might be missed, but should be suspected in persons who experience the classic Jarisch-Herxheimer reaction after treatment with β-lactam antibiotics. This case describes a 55-year-old male patient with negative test results for HIV who presented to the clinic as a contact of a recent male sexual partner who was diagnosed with gonorrhea. This case suggests that ceftriaxone and azithromycin treatment of persons with unknown infectious syphilis infections might cause a classic posttreatment syphilis reaction (rigour that spontaneously resolves). Patients should be informed to look for these Jarisch-Herxheimer reaction symptoms, and clinicians should assess for the symptoms of this reaction in patients who are at risk of syphilis.

Visit 1. A 55-year-old man presented to the sexually transmitted infection (STI) clinic after a recent casual male partner informed him he had been diagnosed with gonorrhea. The patient engaged in condomless receptive and penetrative oral and anal sex with this man. Table 1 provides a summary of the patient’s case. Table 1. Case summary TIME PATIENT’S HISTORY AND ASSESSMENTS, PLANS, AND RESULTS Past medical history Gonorrhea (no other previous STIs) Negative test results for HIV Taking HIV PrEP Insomnia GERD Hypertension Visit 1 Assessment Presented to clinic as a gonorrhea contact Reported a painless 1-cm 2 penile lesion about 4–6 wk earlier that resolved without marking Asymptomatic at time of visit Unremarkable findings on examination Plan Tested for chlamydia and gonorrhea (urine sample, oral and rectal swabs), HIV, and syphilis Treated empirically for gonorrhea Results Rectal gonorrhea detected Syphilis testing: CMIA result reactive, RPR titre 1:4, TPPA result reactive Visit 2 (8 d after visit 1) Assessment Asymptomatic Reported rigour about 2 h after empiric gonorrhea treatment at visit 1 Plan Syphilis stage determined as early latent; treatment administered Repeated syphilis serology Results Syphilis testing: CMIA results reactive, RPR titre 1:8, TPPA results reactive Follow-up Reported same rigour about 2 h after treatment Open in a separate window CMIA—chemiluminescent microparticle immunoassay, GERD—gastroesophageal reflux disease, PrEP—preexposure prophylaxis, RPR—rapid plasma reagin, STI—sexually transmitted infection, TPPA— Treponema pallidum passive particle agglutination assay. Review of systems: The patient was asymptomatic when he presented for care, but reported having had a painless genital lesion that was less than 1 cm 2 approximately 4 to 6 weeks earlier; it resolved spontaneously after 7 to 10 days. The patient suspected the lesion was an “ingrown hair.” He denied rashes, hair loss, and mucous lesions. He denied current or recent rigour, fatigue, weight loss, lymphadenopathy, myalgia, arthralgia, headaches, and vision or hearing changes. Past medical history: The patient’s past medical history included insomnia, gastroesophageal reflux disease, and hypertension, for which he took trazodone, esomeprazole, and the telmisartan-amlodipine combination, respectively. He had been taking these drugs for longer than 12 months. He had started taking a fixed-dose combination of emtricitabine (200 mg) and tenofovir (300 mg) daily for HIV preexposure prophylaxis (PrEP) 5 months earlier. The patient had similarly presented to the STI clinic 5 months previously as a contact of a gonorrhea case and was treated with 1 intramuscular dose of 250 mg of ceftriaxone (reconstituted with 0.9 mL of 1% lidocaine) plus 1 oral dose of 1 g of azithromycin. 1 , 2 This treatment was administered at the clinic. He experienced no reaction after treatment (both immediately after treatment and during the following day): no nausea, no emesis, no diarrhea, and no rigour. His test results at that time were negative for gonorrhea and chlamydia (urine nucleic acid amplification testing [NAAT], and pharyngeal and rectal cultures). He did not undergo serology testing at the clinic, but had documented negative HIV and syphilis test results from this time. On examination: The patient was afebrile and had no perceptible rashes on his hands, feet, or trunk. His cervical nodes were not palpable or tender; he had no oral lesions or erythema. He had no palpable inguinal nodes or tenderness, and no lesions, erythema, or tenderness of his penis or genital area; no urethral discharge was present. He had no scrotal lesions or testicular tenderness. He had no external anal erythema, lesions, or discharge. Anoscopy was not performed. Plan: The nurse practitioner who saw this patient at his initial visit collected pharyngeal and rectal swabs and urine for gonorrhea and chlamydia testing, as well as blood for HIV and syphilis testing. As the patient was a contact of a gonorrhea case, this same provider treated the patient in the clinic with 1 intramuscular dose of 250 mg of ceftriaxone (reconstituted with 0.9 mL of 1% lidocaine) plus 1 oral dose of 1 g of azithromycin. 1 , 2 The patient remained in the clinic after the injection without reaction. A fourth-generation antigen-antibody combination assay was used for HIV testing. 3 Syphilis testing was done using the reverse screening algorithm, starting with a chemiluminescent microparticle immunoassay (CMIA), followed by a rapid plasma reagin (RPR) test and a Treponema pallidum passive particle agglutination assay (TPPA) for samples with positive screening results. 4 , 5 Gonorrhea and chlamydia samples underwent NAAT. 6 – 8 Of note, between the patient’s previous and current presentation for care, in Ontario, NAAT for extragenital samples was validated by the Public Health Ontario laboratory. This occurred owing to a greater than 2-fold increase in sensitivity of NAAT compared with culture, and because the test swabs required were reduced from 2 swabs to 1. Moreover, extragenital testing is done with the same type of swab used for endocervical gonorrhea and chlamydia testing and is thus likely more readily available in many clinics. Test results: The patient had negative results for HIV, pharyngeal and urine gonorrhea and chlamydia, and rectal chlamydia. His rectal gonorrhea test result was positive. For syphilis, the CMIA result was reactive, the RPR titre was 1:4, and the TPPA result was reactive. The STI clinic nurses contacted the patient and requested that he return to the clinic. Visit 2. On returning to the clinic 8 days after the first visit, the patient was asymptomatic. To determine the need for gonorrhea re-treatment, I inquired if he had had issues with treatment. He denied nausea, emesis, and diarrhea, and he denied sexual contact with untreated partners. He reported rigour about 2 hours after receiving gonorrhea treatment; rigour lasted less than 12 hours and resolved spontaneously. He denied rashes, mucosal irritation and pain, myalgia, and arthralgia. He denied experiencing such symptoms when he was treated empirically for gonorrhea 5 months earlier. I repeated the syphilis bloodwork, determined the patient’s stage of infectious syphilis (early latent phase owing to no symptoms, a confirmed negative result 5 months earlier, and no known contacts with any sexual partners recently diagnosed with infectious syphilis). I treated him with 1 intramuscular dose of 2.4 million units of benzathine penicillin G. 1 , 2 He tolerated the injection well and had no reactions during the 15 minutes he remained in the clinic. Interestingly, he reported a similar Jarisch-Herxheimer–like reaction after this treatment as well. Patients who receive more than 1 dose of antibiotics for syphilis typically only experience the Jarisch-Herxheimer reaction with the first treatment; it is possible that the second reaction occurred in this case because, in the first instance, the nurse practitioner had not actually treated him for syphilis. Instead, the nurse practitioner had treated him for gonorrhea, and potentially induced this reaction with a dose of medication that was appropriate for gonorrhea but subtherapeutic for syphilis. It is thus possible that he experienced the Jarisch-Herxheimer reaction twice. Syphilis bloodwork from this second visit revealed reactive CMIA results, an RPR titre of 1:8, and reactive TPPA results, supporting the diagnosis of infectious syphilis. The change in syphilis titre might suggest the infection was primary (with a possible chancre in an undetected location such as the rectum); however, it might also be normal laboratory variation in the measurement of a serofast state.

It is possible this patient experienced a Jarisch-Herxheimer reaction, which is common after treatment of spirochete infections (eg, syphilis, yaws, pinta, Lyme disease). 1 , 2 , 9 This reaction typically starts 2 hours after treatment and resolves within 24 hours; it can occur during any stage of syphilis. 1 , 2 , 9 It is hypothesized that this reaction is due to mass release of lipoproteins from destroyed bacteria that induce rigour, myalgia, arthralgia, and headache. 9 The Jarisch-Herxheimer reaction is not a hypersensitivity, and the patient does not need to avoid penicillin. No treatment is required, although antipyretics can alleviate symptoms. 2 Systemic corticosteroids can be used for severe reactions, but only with expert consultation. 2

The postulation here is that this patient experienced such a reaction after receiving treatment for gonorrhea with a cephalosporin and macrolide. This is fitting, seeing as cephalosporins have a similar mechanism of action to penicillin, 10 and because these 2 medications can cure syphilis, although in higher doses and for a longer duration than what this patient received. 1 , 2 It is possible that such a reaction occurred here from a subtherapeutic dose of these drugs. Supporting this assertion is that the patient had a similar reaction when treated with benzathine penicillin G.

One similar case report exists. In this other case, the patient was an HIV-positive 32-year-old man who, similar to this case, was diagnosed with rectal gonorrhea, was treated with ceftriaxone and azithromycin, and experienced rigour 6 hours later. 11 The patient returned to the clinic with a classic syphilis rash and received treatment for syphilis. Serology results supported the syphilis diagnosis.

Another possible explanation for this patient’s symptoms is HIV seroconversion, 2 although this is unlikely based on his use of HIV PrEP, which can prevent HIV transmission in more than 90% of those who take it. 12 The patient’s symptoms might also have been the result of an unrelated concomitant viral infection (eg, influenza), although the timing and duration of symptoms makes this unlikely. Likewise, drug-drug interactions are an unlikely cause of the patient’s symptoms, as the only possible interaction is a category C interaction between azithromycin and trazodone (potential corrected QT interval prolongation), 13 and he had no flulike reaction with concurrent use of these medications 5 months previously. The patient’s reaction might also have been a Jarisch-Herxheimer reaction to a different spirochete, such as Borrelia burgdorferi, which is prevalent locally. 14 No testing was done to rule out Lyme disease, so this infection is possible, although the patient did not have any related symptoms including erythema migrans or neurologic findings. 15 As I work in an STI clinic, testing for Lyme disease is not available. Instead, I encouraged the patient to follow up with his family physician for further assessment.

Recommendations for practice

This case highlights 3 points. The first is the need for clinicians to include syphilis in the differential diagnosis of oral, genital, and perianal lesions. 1 , 2 This is particularly important owing to increasing rates of syphilis, primarily among men who have sex with men. 16 , 17 In such cases, it is ideal to consider (and provide) empiric treatment at the point of care, plus appropriate testing including serology and the consideration of direct fluorescent antibody (DFA) or polymerase chain reaction (PCR) testing of syphilitic lesions. 1 , 2 Specifically, DFA and PCR testing involve specimen collection from a potential syphilitic lesion, whether a chancre, condyloma latum, or mucous patch. When results are positive, DFA and PCR confirm the presence of syphilis organisms. Of note, DFA and PCR testing of syphilis lesions can detect primary infection before the development of systemic markers that can be detected in serology.

Second, the symptoms of Jarisch-Herxheimer reaction should be communicated to patients who are at risk of syphilis who receive treatment for gonorrhea with ceftriaxone and azithromycin. This involves explicitly listing these symptoms to patients at the time of treatment as part of reviewing posttreatment precautions (eg, reviewing the symptoms of anaphylaxis, recommending avoiding sexual activity until no longer infectious, recommending avoiding sexual contact with untreated partners). Patients should be instructed to return to the clinic for assessment if they experience Jarisch-Herxheimer–like symptoms, and clinicians should consider providing empiric treatment while investigations are pending for patients with these symptoms. This approach aligns with the previous case report, 11 in which the clinicians aptly suspected and empirically treated syphilis based on the patient’s risk factors for syphilis plus a Jarisch-Herxheimer–like reaction after receiving ceftriaxone and azithromycin treatment for gonorrhea. Similarly, clinicians who examine patients who were recently treated with these medications should also explicitly inquire about Jarisch-Herxheimer reaction symptoms, and not assume that patients would necessarily report such symptoms without explicit inquiry. Although the patient in this case volunteered this information without being precisely asked about the symptoms of this reaction, he only provided this information once I inquired if he had experienced any symptoms after his gonorrhea treatment. This highlights the need for clinicians to positively review these symptoms.

Third, although less applicable to this case because the patient was already taking HIV PrEP, syphilis is an established risk factor for HIV acquisition, meaning that a syphilis diagnosis should signal clinicians to ensure HIV testing is performed and, if test results are negative for HIV, to consider HIV PrEP. In the existing PrEP studies, 18 seroconversion rates within 12 months of syphilis diagnosis ranged between 1 in 20 and 1 in 30 persons. 19 , 20 Data from Vancouver, BC, also found elevated HIV incidence after syphilis diagnosis (3.6 per 100 person-years), which increased to 17 per 100 person-years for patients with concurrent gonorrhea and syphilis diagnoses. 21 Thus, nearly 1 in 5 such persons would acquire HIV within 12 months of this presentation, highlighting the importance of PrEP for such patients. Recent Canadian guidelines 12 detail how to provide this intervention.

This article reviews the case of an asymptomatic 55-year-old man with negative test results for HIV who presented as a contact of a gonorrhea case, experienced rigour after ceftriaxone and azithromycin administration, and was subsequently diagnosed with syphilis. This case supports a previous case report of a similar situation, 11 and highlights that clinicians should inform patients about Jarisch-Herxheimer reaction symptoms and consider these symptoms as indicators of syphilis in otherwise asymptomatic patients. Finally, clinicians should discuss HIV PrEP with patients diagnosed with syphilis, considering the elevated HIV seroconversion rates that occur after this diagnosis. This helps ensure comprehensive sexual health service provision.

Editor’s key points

• ▸ The incidence of syphilis has increased, primarily among men who have sex with men. This article reviews the case of an asymptomatic 55-year-old man with negative test results for HIV who presented as a contact of a sexual partner with gonorrhea, experienced rigour after ceftriaxone and azithromycin administration, and was subsequently diagnosed with syphilis.
• ▸ Syphilis should be suspected in persons who experience the classic Jarisch-Herxheimer reaction (rigour that spontaneously resolves) after treatment with β-lactam antibiotics. The symptoms of Jarisch-Herxheimer reaction should be communicated to patients who are at risk of syphilis who receive treatment for gonorrhea with ceftriaxone and azithromycin. Patients should be instructed to return to the clinic for assessment if they experience these symptoms, and clinicians should consider providing empiric treatment while investigation results are pending.
• ▸ Clinicians should discuss HIV preexposure prophylaxis with patients diagnosed with syphilis, considering the elevated HIV seroconversion rates that frequently occur after this diagnosis.

Competing interests

None declared

This article has been peer reviewed.

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Not Applicable

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from the NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide , follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

• Use the NIH ASSIST system to prepare, submit and track your application online.
• Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

Part 2. Full Text of Announcement

Section i. notice of funding opportunity description.

The purpose of this NOFO is to support the Pediatric HIV/AIDS Cohort Study (PHACS) cohorts as a transformative, streamlined, and agile program addressing the developmental and clinical course of persons living with HIV and perinatally  acquired HIV in the United States. The integration of investigators with experience using streamlined scientific and administrative methods and approaches to enhance the function and scientific vision of the cohorts is encouraged.

The goals of this initiative are to support research on the developmental and clinical course of persons living with HIV and perinatally acquired HIV, including the effects of HIV and HIV treatment on fertility, pregnancy and post-partum outcomes, complications, co-morbidities, and co-infections including gynecologic conditions and sexually transmitted infections (STI's) for example syphilis, chlamydia, gonorrhea, HPV, trichomoniasis and CMV. The transition to adulthood of youth living with vertically acquired HIV who have been on ART for an extended period provides an important opportunity to understand many early developing health issues, including cardiovascular, metabolic, and immune. Early changes in oral health, alcohol, and substance use, behavioral, mental, social, health outcomes may also be evaluated.

The WHO has reported that in 2022 there were approximately 1.2 M pregnant women and 1.5 M children living with HIV. At the end of 2022 there were 9.9K women and 8.8K children accessing ART globally. Individuals with perinatally acquired HIV live with a chronic illness and face the developmental consequences of prolonged HIV, associated co-morbidities, and long-term ART that can affect health, starting with the development of the immune system and over the life course into young adulthood. Of the >1 M people in the US diagnosed with HIV at the end of 2019, 12,355 were among people diagnosed with vertically acquired HIV. The total number of people diagnosed with vertically acquired HIV in the US is disproportionate and occurs among certain racial and ethnic groups with the largest number among Black and Hispanic populations. People with vertically acquired HIV face the developmental consequences of exposure to HIV in utero, long-term antiretroviral therapy (ART) use and associated co-morbidities and co-infections, that affect health throughout life.

There were 2.5 million new cases of syphilis, chlamydia, and gonorrhea reported by the CDC in 2022, with a 555% increase in syphilis reported. These STIs are syndemic with HIV and affect similar populations. Included in the groups most affected by STI's and HIV are pregnant people, those who misuse substances and those aged 13-24.

The findings from United States (US) based initiatives have great relevance internationally since millions of children living with HIV in resource-constrained settings receive treatment and survive into adolescence and adulthood, and many pregnant people with HIV have access to and use combination antiretroviral therapy to prevent transmission of HIV to their infants and preserve their own health. The increased availability of antiretrovirals for HIV treatment and prevention has allowed for an increased number of children with perinatally acquired HIV to age into adulthood globally. There is limited clinical data on the long-term impact of HIV and its treatments on this population as they enter reproductive age and have children of their own.

Building on the infrastructure, community connections, and data obtained in the PHACS and similar US cohorts for perinatally acquired HIV individuals, opportunities to study the generational consequences of lifelong ART therapy is critical. For example, the PHACS Adolescent Master Protocol Cohort (AMP Series) includes youth who received very early treatment and may have had nearly lifelong HIV suppression. These data may also inform HIV cure research. Collaborations will continue to be encouraged with other similar cohorts in both resource-rich and resource-constrained settings for data harmonization and sharing.

Cohorts of Interest:

Cohorts of 500 to 1,000 individuals at risk for or living with perinatally or behaviorally acquired HIV, including youth and women of reproductive age are of interest. Recruitment of pregnant and non-pregnant individuals at high risk for or living with HIV (including perinatally acquired) and their children will continue to be encouraged. New enrollments will continue to capture the evolving type and timing of antiretrovirals used as youth transition to adulthood and during pregnancy. The impact of new HIV regimens in these populations will inform the future direction of long-acting antiretrovirals, multipurpose prevention technologies, and vaccines. Activities to support the maintenance and enrichment of the foundational cohorts proposed for study will continue to follow the needed numbers of participants in proposed protocols, but at least 200 new individuals, including children, will be recruited as an addition to the active cohorts each year.

It is expected appropriate control groups, pertinent to the cohorts being studied are included.

Cohorts will also be used in focused Research Pilots (sub-studies) to answer new questions as the research landscape evolves. This will enable the study of priority scientific investigations more rapidly than could be accomplished by individual projects alone.

The collection of basic information in areas of interest is expected to continue through base protocols and in other supported studies and should include but not be limited to:

• The outcomes and the generational consequences of lifelong ART therapy on:
• Reproductive system pathology and other gynecologic conditions, fertility, sexual maturation, nutrition, growth, endocrine, and bone development
• Cardiovascular, pulmonary, and renal disease risk and complications
• Genomic and metabolomic outcomes of exposure to ART and HIV in reproductive age people
• Correlates of immune system development, breath and HIV control.
• Studies on epigenetic aging on the early development of co-morbidities, and complications.
• Studies on neurodevelopmental, cognitive, and behavioral, outcomes including central nervous system imaging, and peripheral nervous system complications.
• Studies evaluating biomarker correlates of cognitive, cerebrovascular, neuro-inflammatory, neurodegenerative, behavioral and substance exposures use.
• Research on the effects of ART treatment on oral cells/tissues, bone mineral density, and tooth development; mucosal immunity; disease biomarkers; persistence, latency and reservoirs for HIV and pathogens causing oral diseases.
• Studies on the effect of Human Papillomavirus (HPV) vaccine on mucosal immunity and HPV acquisition, clearance, and persistence among those living with HIV.
• Studies on alcohol and drug exposure outcomes in individuals living with perinatally acquired HIV.
• Studies of HIV persistence, latency, reservoirs, and vaccines in reproductive age people
• Research on the effects of HIV and HIV treatment on fertility, pregnancy and post-partum outcomes, complications, co-morbidities, and co-infections including sexually transmitted infections (STI's) (for example syphilis, chlamydia, gonorrhea, HPV, trichomoniasis and CMV).

Examples of activities supported and encouraged under this NOFO include, but are not limited to:

• Development and implementation of a quality assurance and quality control plan spanning the full data life cycle
• Development of a centralized data storage system for site data.
• Creation and roll-out of a searchable web-based platform to enrich data sharing and broader integration
• Development and utilization of standard, unambiguous terminology for data linkage and integration with multiple data sets, including data dictionaries
• Development of methodologies to support the interoperability of PHACS data with other data sets such as common and metadata standards.
• Establishment of scientific collaborations with investigators.  

Essential Features of the U19 Structure

Scientific Administrative Core (SAC) (required)

The Scientific Administrative Core (SAC) provides overall management, communication, coordination, and supervision of the Program. The SAC administers the plan provided in the application to address the short- and long-term management of the Program. The SAC will monitor progress, develop, and implement a project management plan, and define timelines. Additionally, the Scientific Administrative Core will coordinate detailed communication of efforts and progress with NICHD and participating NIH program staff.

The SAC will provide outreach and establish collaborations with other networks and studies, develop and maintain bylaws and policies and mitigate conflicts of interest. In addition, the SAC will convene a Scientific Leadership Group and an Executive Committee, recruit and support the activities of an External Advisory Group (EAG).

The SAC will bring necessary expertise and resources for collaborative protocol development that will ensure feasible and acceptable study design(s), with proven ability to recruit and retain these unique populations through 5-15 competitive subcontracts to clinical sites with demonstrated high level prior performance .

The SAC will maintain discretionary funds to support the Emerging Research Pilots (ERPs) and may conduct an annual competition for an Early Career Investigator Award. The SAC will also be responsible for developing plans to mentor new and early-stage investigators to develop independent research careers.

The SAC will also be responsible for holding an annual group meeting to review accomplishments and plan the project agenda.

Data Management and Analysis Core (DMAC) (required)

The Data Management and Analysis Core (DMAC) will be responsible for providing central data storage, data management with safeguards to protect the integrity of the data to all projects within a U19 application and will be responsible for ensuring the submission of data, meta-data and related data analyses to DASH, or other appropriate public databases approved by NICHD. The core will also provide analytic support and development of methods, as needed, to integrate and/or harmonize data and methods for activities across research projects.The DMAC must demonstrate that existing datasets pertinent to the research proposed are usable and accessible through DASH or other publicly accessible data systems.

The DMAC will develop and direct the overarching Project Management Plan for the Cores and Research Projects.  The project management plan must include a transition plan to another responsible steward and long-term archival of the data. This is required if the current team no longer manages the data resource, or the entire resource is sunset.

The DMAC will:

• Execute and manage subcontracts for collaborating partners and clinical sites 
• Provide support to the Single IRB (sIRB) process and regulatory and compliance management for clinical sites.
• Utilize its relationship with and direct access to clinical sites, personnel, including Clinical Investigators, Study Staff and Community Board (CB) members, to implement all Research Projects and manage and monitor performance efficiently and effectively.
• Serve as the centralized data and resource management entity.
• Provide sample tracking, manage sample storage, oversee laboratory data management and data storage and access.
• Oversee and execute the sharing and transfer of samples and data and the receipt of data for collaborations.
• Provide programming and analytical core services for integrated data analysis. 
• Serve as a shared resource to all Cores and Research Projects.

The Core Lead is responsible for ensuring that shared scientific and analytic resources/facilities are available and utilized to the maximum extent possible and that procedures are developed to ensure that such resources are available to members of the research team in a timely manner. The data management and analysis core will also be responsible for ensuring compliance with data sharing policies.  The DMAC is encouraged to provide data as it becomes available.  To achieve the goal of data sharing from large epidemiologic studies in which data are collected over several discrete time periods or waves, it is reasonable to expect that these data would be released in waves as data become available or main findings from waves of the data are published.

It is expected and encouraged that the DMAC will lead an effort to engage the community to inform the research project, implementation, and dissemination of research findings. This may include translation of findings into resources of interest, coordination of dissemination activities with community members, partner organizations, and relevant service organizations or policymakers.

The effort may also include the support of a community advisory board and/or utilization of a community-based participatory research approach as applicable. Using plain language strategies, dissemination activities should include an effort to translate findings from projects and strategic planning into sustainable community and system-level changes.

The PHACS U19 Research Projects

Each U19 will include a maximum of 3 Research Projects along with Core(s) necessary to support the projects. Research projects should focus on the effects of antiretroviral treatment (ART) treatment on HIV during reproductive years and/or the developmental and clinical course of persons living with perinatally transmitted HIV. The U19 research program will be facilitated by the sharing of ideas, data, and specialized resources, such as equipment, services, and clinical facilities. The Research Projects proposed must be scientifically meritorious, and complement one another, be synergistic, and support the program's overall theme. Thus, the program's overall scientific merit should be greater than the sum of its parts.

Research Projects require the participation of established investigators in several disciplines or investigators with special expertise in several areas of one discipline. All Senior/Key Personnel (PDs/PIs, Project Leads, Core Leads) must contribute to, and share in, the responsibilities of fulfilling the program objectives.

Each Research Project should contribute materially and intellectually to the specific goals and objectives of the Program Project, contribute expertise and/or resources toward the aims of the Program Project and emphasize collaboration across all components of the U19. Each Research Project should contain the scientific vision which anticipates the ongoing evolution of the field and an emerging scientific agenda by briefly addressing the current state of knowledge on the clinical course of vertically transmitted HIV in children and adolescents, and the critical scientific questions in the clinical course of HIV from preconception to post-partum including the significant scientific gaps and opportunities, and the research, tools, resources and collaborations needed to progress toward filling those gaps to improve health outcomes in these populations.

Research Projects should be supported by the Scientific Administrative Core (SAC), Data Management and Analysis Core (DMAC) and any other optional appropriate Cores to enhance the research objectives.

The PD/PI must possess recognized scientific and administrative competence, devote a substantial commitment of effort to the program, and exercise leadership in maintaining program quality.

Optional Core (Optional) 

Up to 2 optional cores may be proposed to support the research projects proposed for the U19.

Cores are optional and may be included to provide investigators with core resources and/or facilities that are essential for the activities of two or more Research Projects. Core activities must not overlap with each other or with the activities of a Research Project.  The Core (optional) will be evaluated as Acceptable or Not Acceptable based on whether it is essential for the proposed research and has the capability to fulfill the proposed function. 

Annual Programmatic Meetings

A one- or two-day annual meeting will be held at a location at or near Bethesda, MD or at another NICHD-approved site or may be held virtually as needed. Costs associated with this meeting(s) should be included in the budget.

External Advisory Group (EAG)

An independent external advisory Group (EAG) of investigators who are not current collaborators of the funded programs is expected to be constituted by the PD/PI(s) of the U19 program project and the NIH. The advisory board will meet at least biannually to review the progress in achieving the goals of all research projects participating in the program. The EAG will make recommendations in writing for the continuation or re-direction of any or all projects and activities. Costs associated with the EAG should be included in the budget.

 NICHD Data Sharing Expectations and Requirements

The NIH Policy for Data Management and Sharing (Policy) expects researchers maximize the sharing of scientific data and data be accessible as soon as possible and no later than the time of an associated publication or the end of the award period, whichever comes first. NIH requires all applications submitted in response to this NOFO to include a Data Management and Sharing Plan (DMS Plan). The DMS Plan is expected to address the Elements as described in Supplemental Information to the NIH Policy for Data Management and Sharing: Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014) The DMS Plan will be reviewed and approved by NIH Program Staff prior to award. Awardees will be required to comply with their approved DMS Plan and any approved updates.

For human data, NICHD encourages the use of the Data and Specimen Hub (DASH), a centralized resource for researchers to store and access de-identified data from studies funded by NICHD. Information about DASH may be obtained at https://dash.nichd.nih.gov/. For projects generating large-scale human genetic data, applicants should provide a Provisional or Institutional Certification specifying whether the individual-level data can be shared through an NIH approved repository, such as dbGaP and the Sequence Read Archive, in line with the NIH Genomic Data Sharing Policy.

If use of DASH is not feasible, NICHD expects awardees to share data through other equivalent broad-sharing data repositories. For applications that aim to analyze existing data, DMS Plans should describe where and how other researchers can access that data to enable reproducibility and reuse. Additional information on the Data Management and Sharing Policy is available on the NICHD Office of Data Science and Sharing website.

See Section VIII. Other Information for award authorities and regulations.

Plan for Enhancing Diverse Perspectives (PEDP) The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust. To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done. This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review. The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials .

Section II. Award Information

Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this NOFO.

The  OER Glossary  and the How to Apply - Application Guide provides details on these application types. Only those application types listed here are allowed for this NOFO.

Not Allowed: Only accepting applications that do not propose clinical trials.

Issuing IC, NICHD, and partner  components intend to commit an estimated total of $11M to fund 1-2 awards.

Application budgets may not exceed $5.5 M direct costs per year but need to reflect the actual needs of the proposed project.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III. Eligibility Information

1. eligible applicants eligible organizations higher education institutions public/state controlled institutions of higher education private institutions of higher education the following types of higher education institutions are always encouraged to apply for nih support as public or private institutions of higher education: hispanic-serving institutions historically black colleges and universities (hbcus) tribally controlled colleges and universities (tccus) alaska native and native hawaiian serving institutions asian american native american pacific islander serving institutions (aanapisis) nonprofits other than institutions of higher education nonprofits with 501(c)(3) irs status (other than institutions of higher education) nonprofits without 501(c)(3) irs status (other than institutions of higher education) for-profit organizations small businesses for-profit organizations (other than small businesses) local governments state governments county governments city or township governments special district governments indian/native american tribal governments (federally recognized) indian/native american tribal governments (other than federally recognized) federal governments eligible agencies of the federal government u.s. territory or possession other independent school districts public housing authorities/indian housing authorities native american tribal organizations (other than federally recognized tribal governments) faith-based or community-based organizations regional organizations foreign organizations non-domestic (non-u.s.) entities (foreign organization) are not eligible to apply. non-domestic (non-u.s.) components of u.s. organizations are not eligible to apply. foreign components, as defined in the nih grants policy statement , are not allowed.  required registrations applicant organizations applicant organizations must complete and maintain the following registrations as described in the how to apply- application guide to be eligible to apply for or receive an award. all registrations must be completed prior to the application being submitted. registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference  nih grants policy statement section 2.3.9.2 electronically submitted applications  for additional information. system for award management (sam) – applicants must complete and maintain an active registration, which requires renewal at least annually . the renewal process may require as much time as the initial registration. sam registration includes the assignment of a commercial and government entity (cage) code for domestic organizations which have not already been assigned a cage code. nato commercial and government entity (ncage) code – foreign organizations must obtain an ncage code (in lieu of a cage code) in order to register in sam. unique entity identifier (uei) - a uei is issued as part of the sam.gov registration process. the same uei must be used for all registrations, as well as on the grant application. era commons - once the unique organization identifier is established, organizations can register with era commons in tandem with completing their grants.gov registration; all registrations must be in place by time of submission. era commons requires organizations to identify at least one signing official (so) and at least one program director/principal investigator (pd/pi) account in order to submit an application. grants.gov – applicants must have an active sam registration in order to complete the grants.gov registration. program directors/principal investigators (pd(s)/pi(s)) all pd(s)/pi(s) must have an era commons account.  pd(s)/pi(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in era commons. if the pd/pi is also the organizational signing official, they must have two distinct era commons accounts, one for each role. obtaining an era commons account can take up to 2 weeks. eligible individuals (program director/principal investigator) any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the program director(s)/principal investigator(s) (pd(s)/pi(s)) is invited to work with his/her organization to develop an application for support. individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for nih support. see, reminder: notice of nih's encouragement of applications supporting individuals from underrepresented ethnic and racial groups as well as individuals with disabilities, not-od-22-019 .  for institutions/organizations proposing multiple pds/pis, visit the multiple program director/principal investigator policy and submission details in the senior/key person profile (expanded) component of the how to apply - application guide . 2. cost sharing.

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement  Section 1.2- Definitions of Terms.

3. Additional Information on Eligibility

Number of applications.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application . This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications ).

Section IV. Application and Submission Information

1. requesting an application package.

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this NOFO. See the administrative office for instructions if planning to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide , except where instructed in this notice of funding opportunity to do otherwise and where instructions in the How to Apply - Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Denise Russo, Ph.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Telephone: 301-435-6871  Email:   [email protected]  

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

Instructions for the Submission of Multi-Component Applications The following section supplements the instructions found in How to Apply- Application Guide and should be used for preparing a multi-component application. The application should consist of the following components: Overall: required, page limit 12 Scientific Administrative Core (SAC): required, page limit 12 Cores: optional, page limit 6, maximum 2 Data Management and Analysis Core (DMAC): required, page limit 12 Projects: required, page limit 12, minimum 2, maximum 3 Overall Component

When preparing the application, use Component Type ‘Overall’.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions, as noted.

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
• Description of how the PEDP will advance the scientific and technical merit of the proposed project;
• Anticipated timeline of proposed PEDP activities;
• Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP guidance materials .

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this NOFO) for the entire application.

The U19 Program Project PD/PI (s)

• Should be established investigator(s) with demonstrated leadership and administrative capabilities in multidisciplinary research.
• Will be responsible for the projects and cores within the U19 and for communication, collaboration and coordination with other research networks and investigators.
• Will participate and collaborate with the Research Project leads, Core leads and others within the U19 to guide the Program in implementing scientific and administrative decisions.
• Should demonstrate a capacity to ensure participant recruitment based on demonstrated prior site experience and performance.
• Should demonstrate a track record of proactive community engagement in development of research activities.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

PEDP implementation costs: Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Specific Aims should comprehensively address the overall goals of the U19  

Research Strategy: Summarize the overall research objectives and strategic plan for the multi-project application. Applications responding to this FOA should describe the central theme of the proposed Program and explain how the proposed Research Projects are synergistic and fit under the overarching Program theme.

• Describe the conceptual wholeness to the overall program project by giving a statement of the general problem area and by laying out a broad strategy for addressing the problems.
• As the strategy develops, cite each research project and core to describe its place in the overall scheme.
• Concisely describe the hypothesis or hypotheses to be tested.
• Highlight the innovation, approach, and significance across the Program Project, including in the research projects.
• Explain ongoing, planned, and potential collaborations nationally to conduct epidemiologic and clinical research.
• Describe the program project's plan and timeline for  dissemination of  the research data and resources generated. t
• Include an overview of the program project's outreach activities.
• Describe the program project's commitment and plan for developing and mentoring new talent, including new PIs and early stage investigators, toward leadership roles in the cohort and as PIs of R01's.
• Describe prior collaborative arrangements between investigators in the group to explain the development of the current application.
• Describe a Project Management Plan that articulates the strategies and processes that will be used to manage the U19 and achieve the overall goals, including monitoring progress on achievement of Milestones, implementation of the Plan, and proposed Timelines.
• Explain how the proposed program project would enable the stated objectives of the proposed research to be addressed more efficiently and effectively than by a group of individual research project grants.
• Briefly describe the components of the Program Project and how they will interact and synergize to provide a program that is greater than the sum of its parts.
• Explain the strategy for achieving the goals defined for the overall program and how each Core and Research Project relate to that strategy.
• Demonstrate how partnerships between academia and the community have influenced and will continue to facilitate the design and implementation of interventions that leverage new and existing relationships (e.g., academic-based clinical and research sites, and community-based organizations, public health authorities and other private organizations) to optimize the research objectives. 

Letters of Support: Include letters of support/agreement for any collaborative/cooperative arrangements, subcontracts, or consultants. Letter of support for the U19 Cooperative Multi-Program Projects overall should be included with the Overall Component. Letter of support for individual Research Projects or Cores should be included with those components of the applications. For program activities to be conducted off site, i.e., at an institution other than the application institution, a letter of assurance or comparable documentation, signed by the collaborator as well as the off-site institutional officials, must be submitted with the application. 

Resource Sharing Plan : Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide .

Other Plan(s):  

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in How to Apply- Application Guide ; any instructions provided here are in addition to the How to Apply - Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide , with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

Delayed Onset Study

Note:  Delayed onset  does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form (Overall)

All instructions in the How to Apply- Application Guide must be followed.

Scientific Administrative Core 

When preparing your application, use Component Type ‘[ Administrative Core] ’

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions, as noted. 

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages. If required, the Data Management and Sharing (DMS) Plan must be provided in the Overall component.

SF424 (R&R) Cover (Scientific Administrative Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement ( Scientific Administrative Core )

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information ( Scientific Administrative Core )

Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) ( Scientific Administrative Core )

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile ( Scientific Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used. 
• The applicant should assemble the necessary multidisciplinary team of established investigators to establish the Scientific Leadership Committee (SLC). Disciplines should be included as required to support the purposes of this initiative .   

Budget (Scientific Administrative Core)

Funding for the overall administrative efforts, including secretarial, and/or other administrative services, expenses for publications demonstrating collaborative efforts, and communication expenses should be requested in the budget for this core. Additionally,

• The U19 PD(s)/PI(s) will be expected to provide at least 25% FTE (3 person-months) to the Program and will lead this Core; increased effort is expected if the U19 PD(s)/PI(s) plan to also lead a research project within the U19.
• The U19 PD(s)/PI(s) should provide a discretionary budget to be used for funding of the focused Emerging Research Pilots (sub-studies), for supporting collaboration or co-endorsement agreements with other research networks as indicated, and for accommodating central sub-study-mandated requirements (e.g., specimen shipping costs) on an as-needed basis.
• Funds for one yearly meeting should be included in the budget

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan ( Scientific Administrative Core)

Specific Aims: List in priority order, the broad, long-range objectives, and goals of the Scientific Administrative Core. State the Core’s relationship to the multi-project program goals and how it relates to the Research Projects and any other Cores in the application. Include a brief list of Specific Aims outlining the objectives and functions of the Scientific Administrative Core.

Research Strategy: The overview of the Scientific Administrative Core should articulate the strategy that the Program Project will adopt to achieve the scientific goals and describe the processes/approaches that will be used in decision-making and implementation of activities, including the establishment of scientific priorities, strategies used to manage the Program Project.

• As part of the Core, describe the structure and plans for coordination, administration, fiscal accountability, allocation of funds and other resources, problem identification and resolution, and training.
• Describe the services provided and how the SAC resources will contribute to the objectives of the Research Projects.
• Provide information on how the SAC will provide oversight of the Cores and Research Projects and will promote coordination and collaboration within the program and with investigators and organizations outside the program. 
• A plan for determining how the research pilots will be selected should be included.

Letters of Support: Provide letters of support specific to this component.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide , The Data Management and Sharing (DMS) Plan must be provided in the Overall component.

Only limited items are allowed in the Appendix. Follow all instructions for the How to Apply- Application Guide ; any instructions provided here are in addition to those in the Application Guide instructions.

PHS Human Subjects and Clinical Trials Information ( Scientific Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information  form or a Delayed Onset Study record.

Delayed Onset Study:

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

Data Management and Analysis Core (DMAC)

When preparing your application, use Component Type ‘ Data Core .’ 

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Data Management and Analysis Core)

Phs 398 cover page supplement (data management and analysis core), research & related other project information (data management and analysis core).

Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) Data Management and Analysis Core

Research & related senior/key person profile (data management and analysis core).

• In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Core Lead’ and provide a valid eRA Commons ID in the Credential field.

Budget (Data Management and Analysis Core)

Phs 398 research plan (data management and analysis core).

Specific Aims : List in priority order, the broad, long-range objectives, and goals of the proposed Core. In addition, state the Core's relationship to the Program Project and how it relates to the individual Research Projects or other Cores in the application.  Include a brief list of Specific Aims outlining the objectives and functions of the Scientific Administrative Core.    

Research Strategy: Describe the organizational structure and role of the Data Management and Analysis Core in the overall Program Project research activities and include a strategy for management of data activities that describes internal and external data acquisition strategies to achieve harmonization of systems and procedures for data management, data quality, data analyses, and dissemination for all data and data-related materials. Provide information on innovative capabilities in data analysis and visualization and how these will be developed. Describe the strategies and processes that will be used to manage the DMAC and achieve the overall goals, including monitoring progress on milestones, implementation of the Project Management Plan and proposed Timelines. The DMAC must demonstrate that existing datasets pertinent to the research proposed are usable and accessible through DASH or other publicly accessible data systems.

Describe the utilization of the Core and include the following :

• The Project Management Plan for the Cores and Research Projects.
• A plan for executing and managing subcontracts for collaborating partners. 
• Clinical site Single IRB (sIRB) process, regulatory and compliance management.
• DMAC relationship with and direct access to clinical sites, personnel, including Clinical Investigators, Study Staff and Community Board (CB) members, to implement all Research Projects and manage and monitor performance efficiently and effectively.
• The plan for serving as the centralized data and resource management entity.
• How sample tracking, management of sample storage, oversight of laboratory data management and data storage and access will be provided.
• How oversight and execution of the sharing and transfer of samples/data and the receipt of data for collaborations will be managed.
• How programming and analytical core services for integrated data analysis will be provided and how DMAC will serve as a shared resource to all Cores and Research Projects. 

Describe how DMAC will demonstrate that existing datasets pertinent to the research proposed are usable and accessible through DASH or other publicly accessible data systems.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide. The Data Management and Sharing (DMS) Plan must be provided in the Overall component.

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

PHS Human Subjects and Clinical Trials Information (Data management and Analysis Core )

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed

Research Project

When preparing your application, use Component Type ‘ Project .’

SF424 (R&R) Cover Research project)

Phs 398 cover page supplement (research project), research & related other project information (research project), project /performance site location(s) (research project), research & related senior/key person profile (research project).

• In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘ Core Lead’ and provide a valid eRA Commons ID in the Credential field.

Budget (Research Project)

Phs 398 research plan (research project).

Specific Aims:  Provide Specific Aims for the Research Project

Research Strategy: Following the instructions in the SF424 (R&R) Application Guide, start each section with the appropriate section heading—Significance, Innovation, Approach.

• Clearly describe the project's objectives and explain its relevance to the overall program's theme.
• As part of the Research Strategy, include information on preliminary studies, data, and/or prior experience pertinent to this application.
• Specify the scientific hypotheses and biomedical significance of the work proposed.
• Describe the Research Project's use of Core services, including why the services are needed and the advantages and cost-effectiveness of Core usage for the Project.
• Provide a timeline and recruitment objectives if pertinent.
• Describe the strategies, techniques and processes that will be used to manage the research project and achieve the overall goals, including monitoring progress with respect to Milestones, and proposed Timelines.

Letters of Support: Provide letters of support specific to the Research Projects.

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.  The Data Management and Sharing (DMS) Plan must be provided in the Overall component.

PHS Human Subjects and Clinical Trials Information (Research Project)

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

Optional Core

When preparing your application, use Component Type ‘CORE.’

Cores are optional and may be included to provide investigators with core resources and/or facilities that are essential for the activities of two or more Research Projects. Core activities must not overlap with each other or with the activities of a Research Project. 

SF424 (R&R) Cover Optional Core )

Phs 398 cover page supplement (optional core ), research & related other project information (optional core).

The Core (optional) will be evaluated as Acceptable or "Not Acceptable based on whether it is essential for the proposed research and has the capability to fulfill the proposed function.

Project /Performance Site Location(s) (Optional Core)

Research & related senior/key person profile (optional core), budget (optional core ), phs 398 research plan (optional core).

Specific Aims: 

Include a brief list of Specific Aims outlining the objectives and functions of the Core.

Research Strategy:

Provide the following information:

• Objectives: Description of the objectives of the Core.
• Staffing: Brief description of scientific, technical, and support staff.
• Resources: Description of how Core resources will contribute to the objectives of the Research Projects, SAC, DMAC.    
• Services provided: Description of current and projected services to other Core and Research Components, as well as the process for prioritizing requests for use of Core facilities by the various Research Projects.
• Management: Description of overall management of the Core, decision-making process for use of Core services, and plans for cost-effectiveness and quality control.
• Utilization of Core: Provide a summary of past and/or projected usage of Core services (e.g., assays performed, etc.).  Include estimates of the percentage use of Core unit by the affiliated Research Project components.       

Letters of Support: Include letters of support specific to this component.

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.    

PHS Human Subjects and Clinical Trials Information (Optional Core)

3. unique entity identifier and system for award management (sam).

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons , NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications .

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review .

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Pre-award costs are allowable only as described in the  NIH Grants Policy Statement  Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - Application Guide . Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide . If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII .

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form . Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide .

See more tips for avoiding common errors.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" ( http://cde.nih.gov/ ) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures,  2 CFR 200.113 and  NIH Grants Policy Statement Section 4.1.35 .

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the  HHS Office of Inspector Grant Self Disclosure Program at  [email protected] .

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy .

Section V. Application Review Information

1. criteria.

Only the review criteria described below will be considered in the review process. Applications submitted to NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the program to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the program proposed).

As part of the overall impact score, reviewers should consider and indicate how the Plan to Enhance Diverse Perspectives affects the scientific merit of the program.

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a program that by its nature is not innovative may be essential to advance a field.

Significance

Does the program address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed program rigorous? If the aims of the program are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the program? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the program is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the program?

Specific to this NOFO :  Are Early stage investigators (ESI) involved in different components of the program application? If a multi PD/PI application, are they part of the leadership plan?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the program? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed program? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the program is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the program involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO :

Is there robust synergy/integration across the programs proposed including the projects and cores? 

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the program proposed? Will the program benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria - Overall

As applicable for the program proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects .

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed program involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research .

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Additional review considerations - overall.

As applicable for the program proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Select agent research.

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms ) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For programs involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Review Criteria - Scientific Administrative Core 

Reviewers will evaluate the following items in determining scientific and technical merit. Reviewers will provide a single impact score for the Science Administrative Core. Reviewers will not give separate scores for the individual items. Reviewers will not provide criteria scores.

• Have the planning and coordination of research activities been adequately described?
• Have the strategies and processes to be used for U19 management to achieve the overall goals, including monitoring progress with respect to Milestones, implementation of the overall Project Management Plan, and proposed Timelines been discussed?
• Are the plans for ongoing communication, and plans for evaluation of the Program Project by internal or external advisory board clearly delineated?
• Are the qualifications, experience, and commitment of the Core director and other Core personnel appropriate? 

Review Criteria - Data Management and Analysis Core

Reviewers will evaluate the following items in determining scientific and technical merit. Reviewers will provide a single impact score for the Data Management and Analysis Core. Reviewers will not give separate scores for the individual items. Reviewers will not provide criteria scores.

• Is the plan for services and the process for prioritizing requests for use of Core facilities by the various Research Projects adequately formulated?
• Has information been provided on innovative capabilities in data analysis and visualization, including, GPS and artificial intelligence (AI) strategies to enhance data integration workflows and pipelines, and how these will be developed to serve as community accepted standards?
• Has a description of plans for data harmonization between research projects and cores been provided?
• Has a description of plans for statistical and data management support and for creating and maintaining the necessary clinical infrastructure been provided?
• Is there a description of how DMAC has provided to the public, existing datasets pertinent to the research proposed, that are usable and accessible through DASH or other publicly accessible data systems?
• Are the qualifications, experience, and commitment of the Core director and other Core personnel appropriate?
• Are Core's governance and organizational structure appropriate?
• Has a plan for the development of a centralized information center been described?

Review Criteria - Optional Core

Reviewers will rate the Optional Core as Acceptable or Not Acceptable based on whether it is essential and justified for the proposed research and has the capability to fulfill the proposed function (reviewers will evaluate the number of Projects serviced by the Core; the Core must service two or more Projects).

Reviewers will evaluate the following items in determining scientific and technical merit. 

The following items should be considered in providing an overall evaluation of the optional Core(s) as Acceptable or Unacceptable

• Are the cores sufficiently justified?
• Do they support at least two research projects?
• Are the cores adequately connected to the focus of the overall program?
• Are the facilities or services provided by the cores (including procedures, techniques, and quality control) high quality and appropriate?
• Will the services be used effectively?
• Are the core leader(s) and key personnel well qualified and is there an adequate commitment of time?

Review Criteria - Research Projects

Overall impact - research projects.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria - Research Projects

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous?  If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?   

Are the Project Leads, collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?  

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed?  Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility, and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed? 

Specific to this NOFO : Has the research project's use of the Core services, including why they are needed, been adequately explained?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?      

Additional Review Criteria - Cores and Research Projects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects' involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the  Guidelines for the Review of Human Subjects .

Inclusion of Women, Minorities, and Individuals Across the Lifespan   

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed.  For additional information on review of the Inclusion section, please refer to the  Guidelines for the Review of Inclusion in Clinical Research .

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section .

 Not Applicable

Additional Review Considerations - Cores and Research Projects 

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g.,  Sharing Model Organisms ) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

2. Review and Selection Process Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NICHD, in accordance with NIH peer review policies and practices , using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons. As part of the scientific peer review, all applications will receive a written critique. Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score. Appeals  of initial peer review will not be accepted for applications submitted in response to this NOFO. Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions: Scientific and technical merit of the proposed project, including the PEDP, as determined by scientific peer review Availability of funds. Relevance of the proposed project to program priorities. If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the  NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures . This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships. 3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access their Summary Statement (written critique) via the  eRA Commons . Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications .

Section VI. Award Administration Information

1. award notices.

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in  Section IV.6. Funding Restrictions . Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the  NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see  Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Prior Approval of Pilot Projects

Recipient-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval .
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies .

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200 , Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities .
• HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in  NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See  2 CFR Part 200.340 Termination and  NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support .

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The structure of this cooperative agreement encourages interaction and discussion among NIH staff and all involved investigators leading to more robust and innovative research strategies and methods for clinical research to enroll and retain vulnerable reproductive age young adult populations at risk for and living with HIV or at high risk for HIV. Substantive and frequent scientific and administrative involvement of the NICHD and the co-funding ICs (Institutes) Project Scientists will assist the investigators in developing the scientific agenda, refining study protocols, monitoring the progress of the clinical research and participant safety, and coordinating the activities of the Cohorts, including plans for data harmonization, curating, archiving and utilization. The cooperative agreement mechanism will also serve to facilitate cross-Cohort and multi-agency Collaborations, including efforts to ensure participants are prioritized in behavioral and biomedical clinical research.

PD(s)/PI(s) Responsibilities

PD(s)/PI(s) will have the primary responsibility for coordinating the Projects and Cores within the overall Program. Specifically, the PD(s)/PI(s) have primary responsibility as described below.

• The PD(s)/PI(s) will be responsible for defining the research objectives, approaches, and details of the projects within the guidelines of the NOFO and retains primary responsibility for the planning, directing, and executing the proposed scientific activities.
• The PD(s)/PI(s) will monitor all Research Projects and actively promote efforts that foster integration, collaboration, and synergy across the projects.
• The PD(s)/PI(s) will be responsible for ensuring timely compliance with data sharing requirements.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.  The PD(s)/PI(s) will be responsible for ensuring optimal dissemination of research results by expedient data analysis and key publications within 1 year of study completion and implement explicit data sharing policies for public use thereafter.
• The PD(s)/PI(s) is responsible for the timely presentation/publication of work supported in part or in whole by this Cooperative Agreement. Prior notification to the NICHD regarding any presentations or publications and appropriate acknowledgement of NICHD support are required.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The NIH Project Scientists, representing each of the Institutes co-sponsoring the NOFO, will:

• Provide technical assistance, advice, and coordination, and interact with the PD(s)/PI(s) on a regular basis to monitor study progress, regulatory compliance, and quality assurance to ensure the production of high-quality, unbiased results. Monitoring may include: (1) regular communication with the PD(s)/PI(s) and staff, (2) periodic site visits for discussions with recipients' research teams, and (3) observation of activities, quality control, and other relevant matters, as well as (4) attendance at and participation in annual meetings.
• The Project Scientist will work closely with the PD(s)/PI(s) and other Program member scientists to facilitate collaborations and to leverage the resources available to the Program Project.
• Assist PD/PI and SAC in monitoring the progress of ongoing studies, including field data collection, standardization of methods across study sites, and adherence to protocol and quality control measures.
• Assist in data analyses, interpretation, and publication of study results.
• Assist in identifying the need to terminate or curtail the study (or an individual award) in the event of non-participation in the committee/group activities, substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of protocol or substantive protocol changes without prior approval from NIH.
• Collaborate with PD(s)/PI(s) and SAC in overseeing the establishment, maintenance and collaborative scientific efforts of the Program Project and its progress in achieving program goals.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The duties of the agency Program Official include:

• Carrying out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines.
• Having the option to withhold support to a participating institution if technical performance requirements are not met.
• Performing other duties required for normal program stewardship of grants.

Areas of Joint Responsibility include:

The Project Scientist and the PD(s)/PI(s) will hold regular program-wide discussions to facilitate the achievement of program goals.

The Project Scientist and the PD(s)/PI(s) will collaborate during the course of the award to revise and/or update project milestones as appropriate.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online:  https://www.era.nih.gov/need-help  (preferred method of contact) Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources) Email:  [email protected]  (preferred method of contact) Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace) Contact Center Telephone: 800-518-4726 Email:  [email protected]

Denise Russo, Ph.D. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Telephone: 301-435-6871  Email: [email protected]    

Kathleen Ruth Borgmann NIDA - NATIONAL INSTITUTE ON DRUG ABUSE Phone: (301) 594-6561 E-mail: [email protected]

Anais Stenson, PhD National Institute of Mental Health (NIMH) Telephone: 240-926-7572 Email: [email protected]

Hiroko Iida, DDS, MPH NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH Phone: 301-594-7404 E-mail: [email protected]

Tia Morton, RN, MS   National Institute of Allergy and Infectious Diseases (NIAID) Telephone: 240-627-3073 Email: [email protected]

Joanna Kubler-Kielb, PhD Eunice Kennedy Shriver  National Institute of Child Health and Human Development (NICHD) Telephone: 301-435-6916 Email:  [email protected]

Rehana A. Chowdhury Eunice Kennedy Shriver  National Institute of Child Health and Human Development (NICHD) Telephone: 301-979-0259 Email:  [email protected]

Pamela G Fleming NIDA - NATIONAL INSTITUTE ON DRUG ABUSE Phone: 301-480-1159 E-mail: [email protected]

Rita Sisco National Institute of Mental Health (NIMH) Telephone: 301-443-2805 Email: [email protected]

Gabriel Hidalgo, MBA NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH Phone: 301-827-4630 E-mail: [email protected]

Ann Devine National Institute of Allergy and Infectious Diseases (NIAID) Telephone: 240-669-2988 Email:  [email protected]  

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts . All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement .

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.