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Background: Syphilis is a curable sexually transmitted infection that, untreated, is associated with significant morbidity and mortality. In people living with HIV (PLWH), syphilis carries greater risks of disease progression. We estimated syphilis prevalence among PLWH in the general population in sub-Saharan Africa and compared the prevalence among PLWH and without HIV., Methods: We searched for studies published January 1, 2011, to March 28, 2022, reporting syphilis prevalence among PLWH in sub-Saharan Africa (PROSPERO No. CRD42020167328). We excluded studies in high-risk subpopulations. We estimated pooled syphilis prevalence among PLWH using random-effects modeling and compared the prevalence with people without HIV when included in the same study. We examined influences of region, study setting, and test type in subgroup analyses., Results: We identified 926 studies; 53 were included in the meta-analysis. Pooled syphilis prevalence among PLWH was 7.3% (95% confidence interval [CI], 6.3%-8.5%). Prevalence differed by region: 3.1% (95% CI, 2.2%-4.0%) in Southern, 5.5% (95% CI, 2.3%-9.3%) in West/Central, and 10.5% (95% CI, 8.0%-13.1%) in Eastern Africa. Prevalence also differed by study setting: 13.8% (95% CI, 5.7%-23.0%) in sexual and reproductive health/sexually transmitted infection care, 8.7% (95% CI, 5.0%-12.8%) in HIV care, 7.1% (95% CI, 5.8%-8.5%) in antenatal care, and 3.8% (95% CI, 2.0%-5.8%) in household/community-based settings. Syphilis prevalence was higher among PLWH than without HIV (relative risk, 3.5; 95% CI, 2.8-4.5)., Conclusions: Syphilis is highly prevalent among PLWH in sub-Saharan Africa and is more common among PLWH than without HIV. Integration of syphilis screening and management into HIV care may reduce complications of HIV-syphilis coinfection among PLWH in sub-Saharan Africa., Competing Interests: Conflict of Interest and Sources of Funding: J.J. has received in-kind research support from binx health. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Objectives: Sexually transmitted infections (STIs) cause significant morbidity among women with HIV and increase HIV transmission. We estimated the prevalence of four STIs among women with HIV in sub-Saharan Africa (SSA) and compared prevalence among women with and without HIV., Design: Systematic review and meta-analysis., Methods: We searched for studies published 1 January 1999 to 19 December 2019 reporting prevalence of gonorrhea, chlamydia, trichomoniasis, or Mycoplasma genitalium among women with HIV in SSA. We excluded studies conducted in high-risk groups (e.g. female sex workers). We extracted data on laboratory-confirmed STIs among women with HIV, and when included, among women without HIV. We estimated pooled prevalence for each STI among women with HIV using inverse variance heterogeneity meta-analysis, compared prevalence to women without HIV, and examined the influences of region, clinical setting, and pregnancy status in subgroup analyses., Results: We identified 3756 unique records; 67 studies were included in the meta-analysis. Prevalence of gonorrhea, chlamydia, trichomoniasis, and M. genitalium was 3.5, 4, 15.6, and 10.2%, respectively. Chlamydia prevalence was lower in Eastern (2.8%) than in Southern (12.5%) and West/Central (19.1%) Africa combined. Prevalence of chlamydia and trichomoniasis was higher among pregnant (8.1%, 17.6%) than nonpregnant (1.7%, 12.3%) women. All STIs were more prevalent among women with than without HIV (relative risks ranging 1.54-1.89)., Conclusion: STIs are common among women with HIV in SSA, and more common among women with than without HIV. Integrated STI and HIV care could substantially impact STI burden among women with HIV, with potential downstream impacts on HIV transmission., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known., Methods: In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin., Results: A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log 10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log 10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%)., Conclusions: Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.)., (Copyright © 2022 Massachusetts Medical Society.)

HIV substantially worsens human papillomavirus (HPV) carcinogenicity and contributes to an important population excess of cervical cancer, particularly in sub-Saharan Africa (SSA). We estimated HIV- and age-stratified cervical cancer burden at a country, regional and global level in 2020. Proportions of cervical cancer (a) diagnosed in women living with HIV (WLHIV), and (b) attributable to HIV, were calculated using age-specific estimates of HIV prevalence (UNAIDS) and relative risk. These proportions were validated against empirical data and applied to age-specific cervical cancer incidence (GLOBOCAN 2020). HIV was most important in SSA, where 24.9% of cervical cancers were diagnosed in WLHIV, and 20.4% were attributable to HIV (vs 1.3% and 1.1%, respectively, in the rest of the world). In all world regions, contribution of HIV to cervical cancer was far higher in younger women (as seen also in empirical series). For example, in Southern Africa, where more than half of cervical cancers were diagnosed in WLHIV, the HIV-attributable fraction decreased from 86% in women ≤34 years to only 12% in women ≥55 years. The absolute burden of HIV-attributable cervical cancer (approximately 28 000 cases globally) also shifted toward younger women: in Southern Africa, 63% of 5341 HIV-attributable cervical cancer occurred in women <45 years old, compared to only 17% of 6901 non-HIV-attributable cervical cancer. Improved quantification of cervical cancer burden by age and HIV status can inform cervical cancer prevention efforts in SSA, including prediction of the impact of WLHIV-targeted vs general population approaches to cervical screening, and impact of HIV prevention., (© 2021 World Health Organization. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Introduction: Individuals recruited into clinical trials for life-threatening illnesses are particularly vulnerable. This is especially true in low-income settings. The decision to enrol may be influenced by existing inequalities, poor healthcare infrastructure and fear of death. Where patients are confused or unconscious the responsibility for this decision falls to relatives. This qualitative study is nested in the ongoing AMBIsome Therapy Induction OptimisatioN (AMBITION) Trial. AMBITION is recruiting participants from five countries in sub-Saharan Africa and is trialling a novel treatment approach for HIV-associated cryptococcal meningitis, an infection known to affect brain function. We aim to learn from the experiences of participants, relatives and researchers involved in AMBITION., Methods and Analysis: We will collect data through in-depth interviews with trial participants and the next of kin of participants who were confused at enrolment and therefore provided surrogate consent. Data will be collected in Gaborone, Botswana; Kampala, Uganda and Harare, Zimbabwe. Interviews will follow a narrative approach including participatory drawing of participation timelines. This will be supplemented by direct observation of the research process at each of the three recruiting hospitals. Interviews will also take place with researchers from the African and European institutions that form the partnership through which the trial is administered. Interviews will be transcribed verbatim, translated (if necessary) and organised thematically for narrative analysis., Ethics and Dissemination: This study has been approved by the Health Research Development Committee, Gaborone (Reference: HPDME:13/18/1); Makerere School of Health Sciences Institutional Review Board, Kampala (Reference: 2019-061); University of Zimbabwe Joint Research Ethics Committee, Harare (Reference: 219/19), and the London School of Hygiene and Tropical Medicine (Reference: 17957). Study findings will be shared with research participants from the sites, key stakeholders at each research institution and ministries of health to help inform the development and implementation of future trials. The findings of this study will be published in journals and presented at academic meetings., Trial Registration: Registered at www.clinicaltrials.gov:NCT04296292., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Africa bears a disproportionately high burden of globally significant disease but has lagged in knowledge production to address its health challenges. In this contribution, we discuss the challenges and approaches to health research capacity strengthening in sub-Saharan Africa and propose that the recent shift to an African-led approach is the most optimal., Methods and Findings: We introduce several capacity building approaches and recent achievements, explore why African-led research on the continent is a potentially paradigm-shifting and innovative approach, and discuss the advantages and challenges thereof. We reflect on the approaches used by the African Academy of Sciences (AAS)-funded Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) consortium as an example of an effective African-led science and capacity building programme. We recommend the following as crucial components of future efforts: 1. Directly empowering African-based researchers, 2. Offering quality training and career development opportunities to large numbers of junior African scientists and support staff, and 3. Effective information exchange and collaboration. Furthermore, we argue that long-term investment from international donors and increasing funding commitments from African governments and philanthropies will be needed to realise a critical mass of local capacity and to create and sustain world-class research hubs that will be conducive to address Africa's intractable health challenges., Conclusions: Our experiences so far suggest that African-led research has the potential to overcome the vicious cycle of brain-drain and may ultimately lead to improvement of health and science-led economic transformation of Africa into a prosperous continent.

Background: Intensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies., Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load., Results: Coverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%)., Discussion: Although further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Introduction: HIV-associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub-Saharan Africa (SSA). We performed a systematic review and meta-analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings., Methods: We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized-controlled trials (RCTs) or investigator-managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short-term (in-hospital or two weeks), medium-term (up to 10 weeks) and long-term (up to six months)., Results and Discussion: Seventy-nine studies met inclusion criteria. In routine care settings, pooled short-term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole-based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short-term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short-term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized-controlled trials. Few studies evaluated long-term outcomes., Conclusions: Mortality rates from HIV-associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV-associated meningitis in the region., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare no competing interests. This article was funded by the South African Medical Research Council and Unicef. Research reported in this publication was also supported by the Fogarty International Center of the National Institutes of Health under Award Number 1K43TW010683 to ALS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development under Award Number 1R21HD093531 to KMP. ALS receives salary support through the CIPHER Grantee Programme of the International AIDS Society (2017/518-SLO) while VR receives support from the SAMRC Intramural Postdoctoral Fellowship Programme. The content of this paper is the sole responsibility of the authors and does not necessarily represent the official views of the organisations and funders.

Introduction: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation., Methods and Analysis: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial., Ethics and Dissemination: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings., Trial Registration: ISRCTN 7250 9687; Pre-results., Competing Interests: Competing interests: JNJ and TSH were the recipients of a Gilead Investigator Initiated Award (completed). TSH has received speaker fees from Gilead Sciences and Pfizer., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen)., Methods: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance., Discussion: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment., Trial Registration: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Design: Universal voluntary HIV counselling and testing followed by prompt initiation of antiretroviral therapy (ART) for all those diagnosed HIV-infected (universal test and treat, UTT) is now a global health standard. However, its population-level impact, feasibility and cost remain unknown. Five community-based trials have been implemented in sub-Saharan Africa to measure the effects of various UTT strategies at population level: BCPP/YaTsie in Botswana, MaxART in Swaziland, HPTN 071 (PopART) in South Africa and Zambia, SEARCH in Uganda and Kenya and ANRS 12249 TasP in South Africa. This report describes and contrasts the contexts, research methodologies, intervention packages, themes explored, evolution of study designs and interventions related to each of these five UTT trials., Methods: We conducted a comparative assessment of the five trials using data extracted from study protocols and collected during baseline studies, with additional input from study investigators. We organized differences and commonalities across the trials in five categories: trial contexts, research designs, intervention packages, trial themes and adaptations., Results: All performed in the context of generalized HIV epidemics, the trials highly differ in their social, demographic, economic, political and health systems settings. They share the common aim of assessing the impact of UTT on the HIV epidemic but differ in methodological aspects such as study design and eligibility criteria for trial populations. In addition to universal ART initiation, the trials deliver a wide range of biomedical, behavioural and structural interventions as part of their UTT strategies. The five studies explore common issues, including the uptake rates of the trial services and individual health outcomes. All trials have adapted since their initiation to the evolving political, economic and public health contexts, including adopting the successive national recommendations for ART initiation., Conclusions: We found substantial commonalities but also differences between the five UTT trials in their design, conduct and multidisciplinary outputs. As empirical literature on how UTT may improve efficiency and quality of HIV care at population level is still scarce, this article provides a foundation for more collaborative research on UTT and supports evidence-based decision making for HIV care in country and internationally., (© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.)