Vaccine value profile for herpes simplex virus.

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are chronic, highly prevalent viral infections that cause significant morbidity around the world. HSV-2 is sexually transmitted and is the leading cause of genital ulcer disease (GUD). It also increases the risk of HIV acquisition, fueling the HIV epidemic. HSV-1 is typically acquired in childhood through nonsexual contact and contributes to oral and ocular disease, but it can also be sexually transmitted to cause GUD. Both HSV-1 and HSV-2 cause neonatal herpes and neurologic disease. Given the ubiquitous nature of HSV-1 and HSV-2 infections and the limited existing prevention and control measures, vaccination would be the most efficient strategy to reduce the global burden of morbidity related to HSV infection. Vaccine strategies include prophylactic vaccination, which would prevent infection among susceptible persons and would likely be given to adolescents, and therapeutic vaccinations, which would be given to people with symptomatic genital HSV-2 infection. This document discusses the vaccine value profile of both types of vaccines. This 'Vaccine Value Profile' (VVP) for HSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by subject matter experts from academia, non-profit organizations, government agencies and multi-lateral organizations. All contributors have extensive expertise on various elements of the HSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Financial incentives to improve uptake of partner services for sexually transmitted infections in Zimbabwe antenatal care: protocol for a cluster randomised trial.

Introduction: Sexually transmitted infections (STIs) such as chlamydia, gonorrhoea, trichomoniasis, and syphilis, are associated with adverse birth outcomes. Treatment should be accompanied by partner services to prevent re-infection and break cycles of transmission. Partner services include the processes of partner notification (PN) as well as arranging for their attendance for testing and/or treatment. However, due to a complex mix of cultural, socio-economic, and health access factors, uptake of partner services is often very low, in many settings globally. Alternative strategies to facilitate partner services are therefore needed.The aim of this study is to assess the impact of a small financial incentive on uptake of partner services for STIs as part of antenatal care (ANC) services in Zimbabwe. Methods and analysis: This trial will be embedded within a prospective interventional study in Harare, aiming to evaluate integration of point-of-care diagnostics for STIs into ANC settings. One thousand pregnant women will be screened for chlamydia, gonorrhoea, trichomoniasis, and syphilis. All individuals with STIs will be offered treatment, risk reduction counselling, and client PN. Each clinic day will be randomised 1:1 to be an incentive or non-incentive day. On incentive days, participants diagnosed with a curable STI will be offered a PN slip, that when returned will entitle their partners to $3 (USD) in compensation. On non-incentive days, regular PN slips with no incentive are provided.The primary outcome measure is the proportion of individuals with at least one partner who returns for partner services based on administrative records. Secondary outcomes will include the number of days between index case diagnosis and the partner attending for partner services, uptake of PN slips by pregnant women, adverse birth outcomes in index cases, partners who receive treatment, and intervention cost. Registration: Pan African Clinical Trials Registry: PACTR202302702036850 (Approval date 18 th February 2022).

Investigating point-of-care diagnostics for sexually transmitted infections and antimicrobial resistance in antenatal care in Zimbabwe (IPSAZ): protocol for a mixed-methods study.

INTRODUCTION: Sexually transmitted infections (STIs) can cause serious morbidity, including pelvic inflammatory disease, and adverse pregnancy outcomes. In low/middle-income countries, limited laboratory infrastructure has resulted in a syndrome-based approach being used for management of STIs, which has poor sensitivity and specificity, leading to considerable underdiagnosis and overtreatment. The WHO has called for development and evaluation of strategies to inform replacement of syndromic management by diagnostic testing.The aim of this project is to evaluate a strategy of point-of-care testing for six STIs in antenatal care (ANC) in Zimbabwe. METHODS AND ANALYSIS: A prospective interventional study will be conducted in ANC clinics in Harare province, Zimbabwe. One thousand pregnant women will be recruited when registering for routine ANC. Alongside routine HIV and syphilis testing, participants will be offered an integrated screening package including testing for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV) and hepatitis B. All individuals with STIs will receive treatment, partner notification services, risk reduction counselling and referral if needed according to national guidelines. Gonorrhoea samples will be cultured and tested for antimicrobial resistance as per WHO enhanced gonococcal antimicrobial surveillance programme guidelines.The primary outcome measure is the composite prevalence of CT, NG, TV, syphilis and hepatitis B. A mixed-methods process evaluation and economic evaluation will be conducted to understand the acceptability, feasibility and cost-effectiveness of integrated STI testing, compared with standard of care (syndromic management). ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Research Council of Zimbabwe, the Biomedical Research and Training Institute Institutional Review Board, and the London School of Hygiene & Tropical Medicine Research Ethics Committee. Results will be submitted to open-access peer-reviewed journals, presented at academic meetings and shared with participating communities and with national and international policymaking bodies. TRIAL REGISTRATION NUMBER: NCT05541081.

Bibliometric Analysis of Authorship of Publications About Sub-Saharan Africa Published in the Journal Sexually Transmitted Diseases , 2011 to 2020.

BACKGROUND: As a potential indicator of equity in research partnerships, we conducted a bibliometric analysis of author affiliations and author order in publications about sub-Saharan Africa published in the journal Sexually Transmitted Diseases . METHODS: We identified articles in the journal Sexually Transmitted Diseases that were about sub-Saharan Africa and published from 2011 to 2020. Medical Subject Heading terms in PubMed were used to identity articles about sub-Saharan Africa. Authors with at least 1 affiliation in sub-Saharan Africa were characterized as sub-Saharan Africa-affiliated authors. RESULTS: Of the 1439 articles that were published in Sexually Transmitted Diseases from 2011 to 2020, 148 (10%) had a Medical Subject Heading term for a sub-Saharan African country. Of the 604 authors of these 148 articles, 53 (36%) of the first authors, 493 (53%) of the middle authors, and 58 (40%) of the last authors had a sub-Saharan African affiliation; 13 (8.8%) of the articles had no authors with a sub-Saharan African affiliation. The proportions of sub-Saharan African-affiliated authors in first and last authorship positions did not change significantly from 2011-2015 (77 articles) to 2016-2020 (71 articles). CONCLUSIONS: The underrepresentation of Africans in first and last authorship positions suggests power imbalances in global scientific partnerships. Funders, researchers, editors, publishers, and grant and manuscript reviewers each have roles in promoting equity in global health research. This study may serve as an example for journals to establish benchmarks and monitor progress toward a more equitable research environment.

Cutaneous squamous cell carcinoma in vertically acquired HIV and epidermodysplasia verruciformis.

Introduction: Acquired epidermodysplasia verruciformis (EV) is a skin disorder that has been described in individuals with perinatally acquired HIV. Many cases have been identified in sub-Saharan Africa in keeping with the epidemiology of HIV infection compared to the rest of the world, where cases are rare. Epidermodysplasia verruciformis skin lesions may undergo malignant transformation. There are few documented cases of malignant transformation of these skin lesions. We describe a patient with an EV-like skin rash who developed cutaneous squamous cell carcinoma (SCC). Patient presentation: A 25-year-old man, on antiretroviral treatment for 12 years, presented with a generalised skin rash since the age of 11 years, and a 7-month history of a persistent scalp ulcer. He had no history of trauma, radiation or other chronic conditions. Despite an undetectable HIV viral load, he had failed to immune reconstitute (CD4 42 cells/µL). Physical examination revealed a generalised hypopigmented, papular skin rash resembling verruca plana and a 3 cm × 3 cm ulcer with rolled edges on the right parietal region of the scalp. There were no palpable lymph nodes in the head and neck areas. Biopsy of the ulcer revealed moderately differentiated SCC. Management and outcome: Wide local excision of the lesion was done under local anaesthesia and histological analysis confirmed completely excised moderately differentiated SCC. Further examination four weeks later revealed two, smaller, histologically similar scalp lesions which were completely excised. Conclusion: Patients with acquired EV require thorough, frequent examination for skin lesions with possible malignant transformation. Early identification of malignant transformation and treatment with surgical intervention is curative.

WHO global antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017-18: a retrospective observational study.

BACKGROUND: Gonorrhoea and antimicrobial resistance (AMR) in Neisseria gonorrhoeae are major health concerns globally. Increased global surveillance of gonococcal AMR is essential. We aimed to describe the 2017-18 data from WHO's global gonococcal AMR surveillance, and to discuss priorities essential for the effective management and control of gonorrhoea. METHODS: We did a retrospective observational study of the AMR data of gonococcal isolates reported to WHO by 73 countries in 2017-18. WHO recommends that each country collects at least 100 gonococcal isolates per year, and that quantitative methods to determine the minimum inhibitory concentration of antimicrobials, interpreted by internationally standardised resistance breakpoints, are used. FINDINGS: In 2017-18, 73 countries provided AMR data for one or more drug. Decreased susceptibility or resistance to ceftriaxone was reported by 21 (31%) of 68 reporting countries and to cefixime by 24 (47%) of 51 reporting countries. Resistance to azithromycin was reported by 51 (84%) of 61 reporting countries and to ciprofloxacin by all 70 (100%) reporting countries. The annual proportion of decreased susceptibility or resistance across countries was 0-21% to ceftriaxone and 0-22% to cefixime, and that of resistance was 0-60% to azithromycin and 0-100% to ciprofloxacin. The number of countries reporting gonococcal AMR and resistant isolates, and the number of examined isolates, have increased since 2015-16. Surveillance remains scarce in central America and the Caribbean and eastern Europe, and in the WHO African, Eastern Mediterranean, and South-East Asian regions. INTERPRETATION: In many countries, ciprofloxacin resistance was exceedingly high, azithromycin resistance was increasing, and decreased susceptibility or resistance to ceftriaxone and cefixime continued to emerge. WHO's global surveillance of gonococcal AMR needs to expand internationally to provide imperative data for national and international management guidelines and public health policies. Improved prevention, early diagnosis, treatment of index patients and partners, enhanced surveillance (eg, infection, AMR, treatment failures, and antimicrobial use or misuse), and increased knowledge on antimicrobial selection, stewardship, and pharmacokinetics or pharmacodynamics are essential. The development of rapid, accurate, and affordable point-of-care gonococcal diagnostic tests, new antimicrobials, and gonococcal vaccines is imperative. FUNDING: None.

Gonococcal vaccines: Public health value and preferred product characteristics; report of a WHO global stakeholder consultation, January 2019.

Renewed interest in developing vaccines against Neisseria gonorrhoeae has been sparked by the increasing threat of gonococcal antimicrobial resistance (AMR) and growing optimism that gonococcal vaccines are biologically feasible. Evidence suggests serogroup B Neisseria meningitidis vaccines might provide some cross-protection against N. gonorrhoeae, and new gonococcal vaccine candidates based on several approaches are currently in preclinical development. To further stimulate investment and accelerate development of gonococcal vaccines, greater understanding is needed regarding the overall value that gonococcal vaccines might have in addressing public health and societal goals in low-, middle-, and high-income country contexts and how future gonococcal vaccines might be accepted and used, if available. In January 2019, the World Health Organization (WHO) convened a multidisciplinary international group of experts to lay the groundwork for understanding the potential health, economic, and societal value of gonococcal vaccines and their likely acceptance and use, and for developing gonococcal vaccine preferred product characteristics (PPCs). WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper describes the main discussion points and conclusions from the January 2019 meeting of experts. Participants emphasized the need for vaccines to control N. gonorrhoeae infections with the ultimate goals of preventing adverse sexual and reproductive health outcomes (e.g., infertility) and reducing the impact of gonococcal AMR. Meeting participants also discussed important PPC considerations (e.g., vaccine indications, target populations, and potential immunization strategies) and highlighted crucial research and data needs for guiding the value assessment and PPCs for gonococcal vaccines and advancing gonococcal vaccine development.

Gonorrhoea.

The bacterium Neisseria gonorrhoeae causes the sexually transmitted infection (STI) gonorrhoea, which has an estimated global annual incidence of 86.9 million adults. Gonorrhoea can present as urethritis in men, cervicitis or urethritis in women, and in extragenital sites (pharynx, rectum, conjunctiva and, rarely, systemically) in both sexes. Confirmation of diagnosis requires microscopy of Gram-stained samples, bacterial culture or nucleic acid amplification tests. As no gonococcal vaccine is available, prevention relies on promoting safe sexual behaviours and reducing STI-associated stigma, which hinders timely diagnosis and treatment thereby increasing transmission. Single-dose systemic therapy (usually injectable ceftriaxone plus oral azithromycin) is the recommended first-line treatment. However, a major public health concern globally is that N. gonorrhoeae is evolving high levels of antimicrobial resistance (AMR), which threatens the effectiveness of the available gonorrhoea treatments. Improved global surveillance of the emergence, evolution, fitness, and geographical and temporal spread of AMR in N. gonorrhoeae, and improved understanding of the pharmacokinetics and pharmacodynamics for current and future antimicrobials in the treatment of urogenital and extragenital gonorrhoea, are essential to inform treatment guidelines. Key priorities for gonorrhoea control include strengthening prevention, early diagnosis, and treatment of patients and their partners; decreasing stigma; expanding surveillance of AMR and treatment failures; and promoting responsible antimicrobial use and stewardship. To achieve these goals, the development of rapid and affordable point-of-care diagnostic tests that can simultaneously detect AMR, novel therapeutic antimicrobials and gonococcal vaccine(s) in particular is crucial.

Diagnosing sexually transmitted infections in resource-constrained settings: challenges and ways forward.

INTRODUCTION: Sexually transmitted infections (STIs) remain prevalent and are increasing in several populations. Appropriate STI diagnosis is crucial to prevent the transmission and sequelae of untreated infection. We reviewed the diagnostic accuracy of syndromic case management and existing point-of-care tests (POCTs), including those in the pipeline, to diagnose STIs in resource-constrained settings. METHODS: We prioritized updating the systematic review and meta-analysis of the diagnostic accuracy of vaginal discharge from 2001 to 2015 to include studies until 2018. We calculated the absolute effects of different vaginal flowcharts and the diagnostic performance of POCTs on important outcomes. We searched the peer-reviewed literature for previously conducted systematic reviews and articles from 1990 to 2018 on the diagnostic accuracy of syndromic management of vaginal and urethral discharge, genital ulcer and anorectal infections. We conducted literature reviews from 2000 to 2018 on the existing POCTs and those in the pipeline. RESULTS AND DISCUSSIONS: The diagnostic accuracy of urethral discharge and genital ulcer disease syndromes is relatively adequate. Asymptomatic Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections limit the use of vaginal discharge and anorectal syndromes. The pooled diagnostic accuracy of vaginal syndromic case management for CT/NG is low, resulting in high numbers of overtreatment and missed treatment. The absolute effect of POCTs was reduced overtreatment and missed treatment. Findings of the reviews on syndromic case management underscored the need for low-cost and accurate POCTs for the identification, first, of CT/NG, and, second, of Mycoplasma genitalium (MG) and Trichomonas vaginalis (TV) and NG and MG resistance/susceptibility testing. Near-patient POCT molecular assays for CT/NG/TV are commercially available. The prices of these POCTs remain the barrier for uptake in resource-constrained settings. This is driving the development of lower cost solutions. CONCLUSIONS: The WHO syndromic case management guidelines should be updated to raise the quality of STI management through the integration of laboratory tests. STI screening strategies are needed to address asymptomatic STIs. POCTs that are accurate, rapid, simple and affordable are urgently needed in resource-constrained settings to support the uptake of aetiological diagnosis and treatment.

World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a serious public health problem, compromising the management and control of gonorrhoea globally. Resistance in N. gonorrhoeae to ceftriaxone, the last option for first-line empirical monotherapy of gonorrhoea, has been reported from many countries globally, and sporadic failures to cure especially pharyngeal gonorrhoea with ceftriaxone monotherapy and dual antimicrobial therapies (ceftriaxone plus azithromycin or doxycycline) have been confirmed in several countries. In 2018, the first gonococcal isolates with ceftriaxone resistance plus high-level azithromycin resistance were identified in England and Australia. The World Health Organization (WHO) Global Gonococcal Antimicrobial Surveillance Program (GASP) is essential to monitor AMR trends, identify emerging AMR and provide evidence for refinements of treatment guidelines and public health policy globally. Herein we describe the WHO GASP data from 67 countries in 2015-16, confirmed gonorrhoea treatment failures with ceftriaxone with or without azithromycin or doxycycline, and international collaborative actions and research efforts essential for the effective management and control of gonorrhoea. In most countries, resistance to ciprofloxacin is exceedingly high, azithromycin resistance is present and decreased susceptibility or resistance to ceftriaxone has emerged. Enhanced global collaborative actions are crucial for the control of gonorrhoea, including improved prevention, early diagnosis, treatment of index patient and partner (including test-of-cure), improved and expanded AMR surveillance (including surveillance of antimicrobial use and treatment failures), increased knowledge of correct antimicrobial use and the pharmacokinetics and pharmacodynamics of antimicrobials and effective drug regulations and prescription policies (including antimicrobial stewardship). Ultimately, rapid, accurate and affordable point-of-care diagnostic tests (ideally also predicting AMR and/or susceptibility), new therapeutic antimicrobials and, the only sustainable solution, gonococcal vaccine(s) are imperative.

Antimicrobial susceptibility in Neisseria gonorrhoeae isolates from five sentinel surveillance sites in Zimbabwe, 2015-2016.

OBJECTIVES: Gonorrhoea and antimicrobial resistance (AMR) in Neisseria gonorrhoeae are major public health concerns worldwide. Enhanced AMR surveillance for gonococci is essential globally. In Zimbabwe, very limited gonococcal AMR data were reported. Our aims were to (i) implement quality-assured gonococcal AMR surveillance in Zimbabwe and (ii) investigate gonococcal AMR at five health centres in 2015-2016. METHODS: Gonococcal isolates from 104 men with urethral discharge were tested for susceptibility to kanamycin, ceftriaxone, cefixime, ciprofloxacin and azithromycin using Etest. RESULTS: All isolates (102 possible to test) were susceptible to ceftriaxone and cefixime. The level of resistance (intermediate resistance) to kanamycin and ciprofloxacin was 2.0% (2.0%) and 18.6% (27.5%), respectively. The two kanamycin-resistant isolates (R≥128 mg/L) had a kanamycin minimum inhibitory concentration (MIC) of >256 mg/L. The ciprofloxacin resistance ranged from 9.5% to 30.8% in the five sentinel sites. Only 10 (9.6%) of the isolates were tested for susceptibility to azithromycin and 1 (10.0%) was resistant (MIC=4 mg/L). CONCLUSIONS: The emergence of multidrug-resistant gonorrhoea internationally is a major public health concern and gonococcal AMR surveillance is crucial globally. In Zimbabwe, gonococcal AMR surveillance has now been implemented and quality assured according to WHO standards. The results of this first surveillance will be used to directly inform revisions of the national treatment guidelines. It is imperative to further strengthen the surveillance of gonococcal AMR, and ideally also treatment failures, in Zimbabwe and most countries in the WHO African region, which requires continuous national and international support, including technical support, and political and financial commitment.

Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines.

Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.

Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action.

In a Policy Forum, Teodora Wi and colleagues discuss the challenges of antimicrobial resistance in gonococci.

Estimating prevalence trends in adult gonorrhoea and syphilis in low- and middle-income countries with the Spectrum-STI model: results for Zimbabwe and Morocco from 1995 to 2016.

OBJECTIVE: To develop a tool for estimating national trends in adult prevalence of sexually transmitted infections by low- and middle-income countries, using standardised, routinely collected programme indicator data. METHODS: The Spectrum-STI model fits time trends in the prevalence of active syphilis through logistic regression on prevalence data from antenatal clinic-based surveys, routine antenatal screening and general population surveys where available, weighting data by their national coverage and representativeness. Gonorrhoea prevalence was fitted as a moving average on population surveys (from the country, neighbouring countries and historic regional estimates), with trends informed additionally by urethral discharge case reports, where these were considered to have reasonably stable completeness. Prevalence data were adjusted for diagnostic test performance, high-risk populations not sampled, urban/rural and male/female prevalence ratios, using WHO's assumptions from latest global and regional-level estimations. Uncertainty intervals were obtained by bootstrap resampling. RESULTS: Estimated syphilis prevalence (in men and women) declined from 1.9% (95% CI 1.1% to 3.4%) in 2000 to 1.5% (1.3% to 1.8%) in 2016 in Zimbabwe, and from 1.5% (0.76% to 1.9%) to 0.55% (0.30% to 0.93%) in Morocco. At these time points, gonorrhoea estimates for women aged 15-49 years were 2.5% (95% CI 1.1% to 4.6%) and 3.8% (1.8% to 6.7%) in Zimbabwe; and 0.6% (0.3% to 1.1%) and 0.36% (0.1% to 1.0%) in Morocco, with male gonorrhoea prevalences 14% lower than female prevalence. CONCLUSIONS: This epidemiological framework facilitates data review, validation and strategic analysis, prioritisation of data collection needs and surveillance strengthening by national experts. We estimated ongoing syphilis declines in both Zimbabwe and Morocco. For gonorrhoea, time trends were less certain, lacking recent population-based surveys.

Gonococcal antimicrobial resistance: perspectives from the African region.

Many countries in Africa have weak surveillance systems for data collection of sexually transmitted infections, and hardly any programmes for gonococcal antimicrobial susceptibility assessment. The widespread adoption of the syndromic approach to the diagnosis and management of sexually transmitted infections has also meant that the collection of a genital specimen for laboratory analysis is no longer routinely done when patients present with genital complaints, and clinical staff and laboratory technicians have lost the skill to collect genital specimens and processing them for culture and antimicrobial susceptibility testing. Following reports of gonococcal antimicrobial resistance to quinolones, WHO urged countries to monitor gonococcal antimicrobial resistance in a more systematic and regular manner. Although the response in Africa has been slow to take off, a number of studies have been conducted in a few countries and plans for implementation are in place in others. However, the number of isolates studied has been small in nearly all the countries except one, and the barriers to scaling up gonococcal antimicrobial resistance surveys seem overwhelming. In spite of the studies being few and of small sample sizes, enough information can be discerned to indicate that quinolones can no longer be a medicine of choice for the treatment of gonorrhoea in Africa and the threat of antimicrobial resistance developing in Neisseria gonorrhoeae to third-generation cephalosporins is real and imminent.

Antimicrobial resistance monitoring in Neisseria gonorrhoeae and strategic use of funds from the Global Fund to set up a systematic Moroccan gonococcal antimicrobial surveillance programme.

OBJECTIVES: The aims of this study were to assess antimicrobial resistance in Neisseria gonorrhoeae infections and update the treatment in the national guidelines for the syndromic management of sexually transmitted infections in Morocco. METHODS: 171 men complaining of urethral discharge were recruited from basic health services during 2009. Urethral swab samples were collected and N gonorrhoeae identification was performed by culture. Antimicrobial susceptibility testing was performed using the Etest method and the antimicrobial agents tested were ciprofloxacin, penicillin, spectinomycin, tetracycline, ceftriaxone and cefixime. RESULTS: A total of 72 isolates were examined. Significant resistance to tetracycline (92.8%) and ciprofloxacin (86.8%), which was used as first-line treatment in gonococcal infections, was noted. No resistance to spectinomycin, ceftriaxone or cefixime was detected in all the isolates. CONCLUSIONS: Following these results the Ministry of Health of Morocco replaced ciprofloxacin and introduced ceftriaxone 250 mg as a single dose in the treatment of gonococcal infections. Using funds from the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund), a surveillance programme was set up for antimicrobial resistance testing in N gonorrhoeae.