Efficient regulatory approval of two novel HIV prevention interventions in a resource-limited setting: experiences from Zimbabwe.

The global burden of HIV remains unacceptably high despite significant progress made in HIV treatment and prevention. There is an urgent need to scale up the comprehensive HIV prevention strategies that include pre-exposure prophylaxis (PrEP). Oral PrEP is highly effective in preventing HIV acquisition when taken regularly, but this remains a challenge for some at-risk individuals. Therefore, there is a need for other HIV prevention options. The dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA) are novel biomedical interventions that are safe and efficacious for HIV pre-exposure prophylaxis, as demonstrated in recently completed clinical trials. Timely roll-out and scalability of efficacious interventions depend on the registration process with the national medicine regulatory authorities (NMRAs). The Medicines Control Authority of Zimbabwe (MCAZ) was the first NMRA globally to approve the DVR in July 2021 and the first in Africa to approve CAB-LA for HIV prevention in July 2022. The regulatory review process for DVR and CAB-LA by MCAZ took 4.5 and 5.5 months, respectively. This efficient review process of the two interventions by MCAZ, a regulatory body in a resource-limited setting, provides important lessons to shorten timelines between the completion of the clinical development process and the registration of essential medicines.

Antenatal depression: Associations with birth and neonatal outcomes among women attending maternity care in Harare, Zimbabwe.

INTRODUCTION: Antenatal depression is highly prevalent and is associated with negative birth and neonatal outcomes. However, the mechanisms and causality behind these associations remain poorly understood as they are varied. Given the variability in whether associations are present, there is need to have context-specific data to understand the complex factors that go into these associations. This study aimed to assess the associations between antenatal depression and birth and neonatal outcomes among women attending maternity care in Harare, Zimbabwe. METHODS: We followed 354 pregnant women in second or third trimester, attending antenatal care services in two randomly selected clinics in Harare, Zimbabwe. Antenatal depression was assessed using the Structured Clinical Interview for DSM-IV. Birth outcomes included birth weight, gestational age at delivery, mode of delivery, Apgar score, and initiation of breastfeeding within one-hour postdelivery. Neonatal outcomes at six weeks postdelivery included infant's weight, height, illness, feeding methods and maternal postnatal depressive symptoms. The association between antenatal depression and categorical and continuous outcomes were assessed by logistic regression and point-biserial correlation coefficient, respectively. Multivariable logistic regression determined the confounding effects on statistically significant outcomes. RESULTS: Prevalence of antenatal depression was 23.7%. It was associated with low birthweight [AOR = 2.30 (95% CI: 1.08-4.90)], exclusive breastfeeding [AOR = 0.42 (95%CI: 0.25-0.73)] and postnatal depressive symptoms [AOR = 4.99 (95%CI: 2.81-8.85)], but not with any other birth or neonatal outcomes measured. CONCLUSIONS: The prevalence of antenatal depression in this sample is high with significant associations demonstrated for birth weight, maternal postnatal depressive symptoms and infant feeding methods Effective management of antenatal depression is thus crucial to the promotion of maternal and child health.

Strategic actions to advance multipurpose prevention technologies in low- and middle-income countries.

Background: HIV, other sexually transmitted infections (STIs) and unintended pregnancies are critical and interlinked health risks for millions of women of reproductive age worldwide. Multipurpose prevention technologies (MPTs) offer an innovative approach for expanding combined pregnancy and/or disease prevention. So far, MPT development efforts have focused mostly on HIV prevention, but about half of product candidates comprise compounds active against non-HIV STIs as well. This review aims to provide a framework that promotes the efficient advancement of the most promising preclinical products through the development pathway and into the hands of end-users, with a focus on women in low- and middle-income countries (L/MICs). Methods: This mini review provides a summary of the current landscape of the MPT field. It comprises a landscape assessment of MPTs in development, complemented by a series of 28 in-depth, semi-structured key informant interviews (KIIs) with experts representing different L/MIC perspectives. Main results: We identified six primary action strategies to advance MPTs for L/MICs, including identification of key research gaps and priorities. For each action strategy, progress to date and key recommendations are included. Conclusions: To realize the life-saving potential of MPTs and maximize the momentum made to date, a strategic, collaborative and well-funded response to the gaps and next steps outlined in this paper is critical. A coordinated response can add rigor and efficiency to the development process, to successfully advance the most promising MPT products to the hands of end-users.

Alignment of PrEP adherence with periods of HIV risk among adolescent girls and young women in South Africa and Zimbabwe: a secondary analysis of the HPTN 082 randomised controlled trial.

BACKGROUND: Adolescent girls and young women in southern and eastern Africa have adherence challenges with daily oral HIV pre-exposure prophylaxis (PrEP). High adherence is most important during periods of HIV risk (prevention-effective adherence). We aimed to describe HIV risk behaviour and to understand patterns in PrEP adherence during periods of risk among adolescent girls and young women from sub-Saharan Africa. METHODS: We did a secondary analysis of the HPTN 082 trial, an open-label, interventional, randomised controlled trial of sexually active adolescent girls and young women (aged 16-25 years) testing negative for HIV in Johannesburg and Cape Town, South Africa, and in Harare, Zimbabwe. The primary outcomes were high cumulative PrEP adherence, dichotomised as intracellular tenofovir diphosphate concentrations of at least 700 fmol/punch in dried blood spots at weeks 13, 26, and 52, and high recent PrEP adherence, dichotomised as plasma tenofovir concentrations of at least 40 ng/mL at weeks 13, 26, and 52, among participants who accepted PrEP. We collected data on sexual behaviour every 3 months. We categorised visits into a binary variable of any HIV risk based on condomless sex, more than one sexual partner, primary partner's HIV status and antiretroviral use, transactional sex, drug or alcohol use around sexual activity, and laboratory-diagnosed STIs. We used generalised estimating equations to evaluate associations between HIV risk (reflecting behaviour during the previous 3 months) and high cumulative and recent adherence to PrEP and any PrEP use (quantifiable drug concentrations). The trial is registered with ClinicalTrials.gov, NCT02732730. FINDINGS: Between Oct 12, 2016, and Oct 25, 2018, 451 women were recruited, and 427 participants (median age 21·0 years [IQR 19·0-22·0]) were eligible for inclusion in this analysis. The proportion of participants reporting at least one HIV risk factor decreased significantly over follow-up, from 364 (85%) participants at enrolment, 226 (60%) at week 13, and 243 (65%) at week 26, to 224 (61%) at week 52 (p<0·0001). Any HIV risk was significantly associated with high PrEP adherence, measured by both tenofovir diphosphate concentrations of at least 700 fmol/punch (adjusted relative risk 1·57 [95% CI 1·09-2·25]; p=0·014) and plasma tenofovir concentrations of at least 40 ng/mL (1·36 [1·11-1·65]; p=0·0025). Any HIV risk was also associated with quantifiable concentrations of tenofovir diphosphate (1·15 [1·03-1·29]; p=0·013) and tenofovir (1·27 [1·09-1·49]; p=0·0022). We observed significant dose-response relationships between number of HIV risk factors and PrEP drug concentrations. INTERPRETATION: The association between any HIV risk and high PrEP adherence suggests that adolescent girls and young women were able to use PrEP during periods of risk, an indicator of prevention-effective PrEP adherence. Our findings support a shift in the PrEP framework to acknowledge prevention-effective adherence practices, which might improve PrEP delivery and adherence support for adolescent girls and young women in HIV-endemic settings. FUNDING: US National Institutes of Health.

Understanding the public health value and defining preferred product characteristics for therapeutic human papillomavirus (HPV) vaccines: World Health Organization consultations, October 2021-March 2022.

The World Health Organization (WHO) global strategy to eliminate cervical cancer (CxCa) could result in >62 million lives saved by 2120 if strategy targets are reached and maintained: 90% of adolescent girls receiving prophylactic human papillomavirus (HPV) vaccine, 70% of women receiving twice-lifetime cervical cancer screening, and 90% of cervical pre-cancer lesions and invasive CxCa treated. However, the cost and complexity of CxCa screening and treatment approaches has hampered scale-up, particularly in low- and middle-income countries (LMICs), and new approaches are needed. Therapeutic HPV vaccines (TxV), which could clear persistent high-risk HPV infection and/or cause regression of pre-cancerous lesions, are in early clinical development and might offer one such approach. During October 2021 to March 2022, WHO, in collaboration with the Bill and Melinda Gates Foundation, convened a series of global expert consultations to lay the groundwork for understanding the potential value of TxV in the context of current CxCa prevention efforts and for defining WHO preferred product characteristics (PPCs) for TxV. WHO PPCs describe preferences for vaccine attributes that would help optimize vaccine value and use in meeting the global public health need. This paper reports on the main discussion points and findings from the expert consultations. Experts identified several ways in which TxV might address challenges in current CxCa prevention programmes, but emphasized that the potential value of TxV will depend on their degree of efficacy and how quickly they can be developed and implemented relative to ongoing scale-up of existing interventions. Consultation participants also discussed potential use-cases for TxV, important PPC considerations (e.g., vaccine indications, target populations, and delivery strategies), and critical modelling needs for predicting TxV impact and cost-effectiveness.

Patient experiences of living with cancer before interaction with palliative care services in Zimbabwe: A qualitative secondary data analysis.

OBJECTIVE: Cancer patients in Zimbabwe typically access health services with advanced disease, limiting treatment choices and lessening the likelihood of positive treatment outcomes. We outline experiences of patients with advanced cancer prior to interaction with palliative care services to identify targets for future intervention development to enhance care delivery in Zimbabwe. METHODS: Participants were purposively sampled adult patients with advanced cancer. We adopted a thematic approach to guide a qualitative secondary data analysis exploring factors influencing support sought by participants, external factors influencing decision making across the disease trajectory and the process for seeking and accessing palliative care. RESULTS: Participants reported fragmented and uncoordinated care, from initial symptom experience and throughout disease progression. A recurring notion of disjuncture was present through participants' experiences of gaps, breaks and discontinuity across the disease trajectory. Each step had a beginning and end without clear routes for transition with movement between steps as a result of happenstance or informal encounters. CONCLUSION: Targets for intervention development at the patient and family level exist that may reduce the disjuncture currently experienced between need and care provision. A holistic response that incorporates engagement with policy actors is critical to addressing prominent financial constraints for patients.

Population-Level Correlation Between Incidence of Curable Sexually Transmitted Infections and Human Immunodeficiency Virus (HIV)-1 Among African Women Participating in HIV-1 Pre-Exposure Prophylaxis Trials.

BACKGROUND: Highly efficacious oral pre-exposure prophylaxis (PrEP) is the global standard for human immunodeficiency virus (HIV)-1 prevention, including in clinical trials of novel PrEP agents using active-comparator designs. The analysis assessed whether incident sexually transmitted infections (STIs) can serve as a surrogate indicator of HIV-1 incidence that might occur in the absence of PrEP. METHODS: We analyzed data from 3256 women randomized to placebo groups of oral and vaginal PrEP trials (MTN-003/VOICE and MTN-020/ASPIRE). Regression modeling assessed the correlation between incident individual STIs (Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, each considered separately) and incident HIV-1. RESULTS: Across 18 sites in 4 countries (Malawi, South Africa, Uganda, Zimbabwe), STI and HIV-1 incidences were high: HIV-1 4.9, N gonorrhoeae 5.3, C trachomatis 14.5, and T vaginalis 7.1 per 100 person-years. There was limited correlation between HIV-1 incidence and incidence of individual STIs: N gonorrhoeae (r = 0.02, P = .871), C trachomatis (r = 0.49, P = <.001), and T vaginalis (r = 0.10, P = .481). The modest association with C trachomatis was driven by country-level differences in both C trachomatis and HIV-1, with no statistically significant association within countries. CONCLUSIONS: Sexually transmitted infection incidence did not reliably predict HIV-1 incidence at the population level among at-risk African women participating in 2 large PrEP trials.

Treatment approaches for women with positive cervical screening results in low-and middle-income countries.

The primary goal of cervical screening is to identify women with cervical precancers who need treatment to prevent invasive cervical cancer. Cervical cancer screening programs in high-resource settings rely on a multi-step process to reassure the majority of women of low cancer risk and treat the small number of women at high risk of precancer and cancer. The requirement of major resource investment for training and capacity building of multi-step cervical cancer screening programs prevents their introduction in low- and middle-income countries (LMICs). Screen-and-treat programs have been evaluated and introduced in some countries that use mainly ablative treatment as primary treatment options. Ablative treatment with cryotherapy and thermal ablation has a favorable tradeoff of benefits and harms and can be introduced more widely than excisional treatment in LMICs. While most women below 40 are eligible for ablative procedures, fewer than 50% are eligible by age 50 and ablative treatment is not appropriate over age 50. Excisional treatment is required for women ineligible for ablative treatment. Since screening programs in LMICs necessarily detect invasive cancers, cancer treatment and palliative care needs to be considered as well.

Prevalence and Incidence of Sexually Transmitted Infection in Injectable Progestin Contraception Users in South Africa.

Introduction: Whether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection. Materials and Methods: Prospective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users. Results: Among 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%, p= 0.54; gonorrhea: 3.4 vs. 3.7%, p= 0.70; trichomoniasis: 5.7 vs.5.0%, p= 0.40; or syphilis: 1.5 vs. 0.7%, p= 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%, p < 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85-1.25), gonorrhea (aHR 0.88, 95% CI 0.60-1.31), trichomoniasis (aHR 1.07, 95% CI 0.74-1.54), syphilis (aHR 0.41, 95% CI 0.15-1.10), and HSV-2 (aHR 0.83, 95% CI 0.45-1.54, p= 0.56)]. Discussion: Among South African participants enrolled in VOICE, DMPA-IM and NETEN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

Understanding data and information needs for palliative cancer care to inform digital health intervention development in Nigeria, Uganda and Zimbabwe: protocol for a multicountry qualitative study.

INTRODUCTION: Palliative care is a clinically and cost-effective component of cancer services in sub-Saharan Africa (SSA). Despite the significant need for palliative cancer care in SSA, coverage remains inadequate. The exploration of digital health approaches could support increases in the quality and reach of palliative cancer care services in SSA. However, there is currently a lack of any theoretical underpinning or data to understand stakeholder drivers for digital health components in this context. This project addresses this gap through engaging with key stakeholders to determine data and information needs that could be supported through digital health interventions. METHODS AND ANALYSIS: This is a multicountry, cross-sectional, qualitative study conducted in Nigeria, Uganda and Zimbabwe. In-depth interviews will be conducted in patients with advanced cancer (n=20), caregivers (n=15), health professionals (n=20) and policy-makers (n=10) in each of the three participating countries. Data from a total of 195 interviews will transcribed verbatim and translated into English before being imported into NVivo software for deductive framework analysis. The analysis will seek to understand the acceptability and define mechanisms of patient-level data capture and usage via digital technologies. ETHICS AND DISSEMINATION: Ethics approvals have been obtained from the Institutional Review Boards of University of Leeds (Ref: MREC 18-032), Research Council of Zimbabwe (Ref: 03507), Medical Research Council of Zimbabwe (Ref: MRCZ/A/2421), Uganda Cancer Institute (Ref: 19-2018), Uganda National Council of Science and Technology (Ref: HS325ES) and College of Medicine University of Lagos (Ref: HREC/15/04/2015). The project seeks to determine optimal mechanisms for the design and development of subsequent digital health interventions to support development, access to, and delivery of palliative cancer care in SSA. Dissemination of these findings will occur through newsletters and press releases, conference presentations, peer-reviewed journals and social media. TRIAL REGISTRATION NUMBER: ISRCTN15727711.

Social harms in female-initiated HIV prevention method research: state of the evidence.

OBJECTIVES: Assessment of safety is an integral part of real-time monitoring in clinical trials. In HIV prevention research, safety of investigational products and trial participation has been expanded to include monitoring for 'social harms', generally defined as negative consequences of trial participation that may manifest in social, psychological, or physical ways. Further research on social harms within HIV prevention research is needed to understand the potential safety risks for women and advance the implementation of prevention methods in real-world contexts. METHODS: Secondary analysis of quantitative data from three randomized, double-blind, placebo-controlled trials of microbicide candidates in sub-Saharan Africa was conducted. Additionally, we assessed data from two prospective cohort studies that included participants who became HIV-positive or pregnant during parent trials. RESULTS: Social harms reporting was low across the largest and most recent microbicide studies. Social harm incidence per 100 person-years ranged from 1.10 (95% CI 0.78-1.52) to 3.25 (95% CI 2.83-3.74) in the phased trials. Reporting differed by dosing mechanism (e.g. vaginal gel, oral tablet, ring) and study, most likely as a function of measurement differences. Social harms were most frequently associated with male partners, rather than, for example, experiences of stigma in the community. CONCLUSION: Measurement and screening for social harms is an important component of conducting ethical research of novel HIV prevention methods. To date, social harm incidence reported in microbicide trials has been relatively low (<4% per 100 person-years), and the majority have been partner-related events. However, any incidence of social harm within the context of HIV prevention is important to capture and understand for the safety of individuals, and for the successful impact of prevention methods in a real-world context.

End-user preference for and choice of four vaginally delivered HIV prevention methods among young women in South Africa and Zimbabwe: the Quatro Clinical Crossover Study.

INTRODUCTION: Adherence to HIV prevention methods is a challenge, particularly for young women in Sub-Saharan Africa. End-user research during product development can inform modifiable factors to increase future uptake and adherence. METHODS: Preferences for four vaginally inserted placebo HIV prevention methods were assessed among Zimbabwean and South African young women using a crossover clinical design. For each of months 1 to 4, participants were asked to use a pre-coitally inserted film, insert (vaginal tablet) and gel once/week for a month, and a monthly ring in a randomly assigned sequence. Participants subsequently chose one preferred product to use as directed for the final study month. Women ranked the four products from most preferred to least preferred at enrolment and after trying all products. RESULTS: A total of 200 women aged 18 to 30 (mean 23) were enrolled; 178 (89%) completed follow-up. At baseline, 41% of participants selected the gel as their most preferred product and 61% selected the ring as least preferred. During the crossover period, most (82% to 85%) self-reported using each product at least once a week, although only half the time with sex. Objective biomarker data confirmed adequate use of all products. After trying each product, rankings changed with the film, ring, insert and gel being selected by 29%, 28%, 26% and 16% respectively. Choice varied significantly by country (p < 0.001): More Zimbabweans chose the film (45%), and more South Africans chose the insert (34%). Among women choosing the ring, 88% reported using it every time with sex. By contrast, self-reported adherence was lower for "on-demand" (coitally associated) products, with 40% to 55% using them every time during sex (p < 0.001). CONCLUSIONS: Preferences for these four dosage forms varied before and after use, and both within and across countries - there was no clear favourite - indicating the need for a range of options for end-users The ring's popularity increased the most with use, was the second most preferred delivery system, and per self-report, provided more coverage during sex. These end-user perspectives provide important information to product developers and funding agencies.

Mentored postdoctoral training in Zimbabwe: A report on a successful collaborative effort.

Low-and-middle-income countries (LMICs) have high disease burdens, necessitating increased research. However, LMIC research output constitutes only 2% of global total. To increase output, researchers must be capacitated. The University of Zimbabwe (UZ) and the University at Buffalo (UB), developed and implemented the AIDS International Research Training Program (AITRP), in 2008, that focused on graduate scholars. The subsequent HIV Research Training Program (HRTP), begun in 2016, and piloted post-doctoral training to enhance research productivity at UZ. This report discusses the collaboration. As of 2016, prospective candidates applied by submitting letters of intent, research proposals, curriculum vitae and biographical sketches. The scholars research training included hypothesis and project development, completion of grant applications, research project budgets, research presentations to diverse audiences and the application of advanced statistics to research data. The first cohort of five postdoctoral scholars were trained at UZ and UB, between 2016 and 2019. Through the formalized postdoctoral training approach, scholars identified areas of focus. In 2017, one of the scholars obtained a National Institutes of Health (NIH) Emerging Global Leader Award and is now a highly-rated researcher based in South Africa. A second scholar made NIH D43 and K43 grant applications, while the remaining three are academicians and early researchers at UZ. Although research output in Africa and many LMICs is low, it can be built through cooperation similar to the UZ-UB HRTP. This manuscript reports on an effort aimed at building individual and institutional research capacity in Zimbabwe. This can serve as a model for building other similar training programs.

HIV infection in patients with sexually transmitted infections in Zimbabwe - Results from the Zimbabwe STI etiology study.

BACKGROUND: HIV and other sexually transmitted infections (STI) frequently co-occur. We conducted HIV diagnostic testing in an assessment of the etiologies of major STI syndromes in Zimbabwe. METHODS: A total of 600 patients were enrolled at six geographically diverse, high-volume STI clinics in Zimbabwe in 2014-15: 200 men with urethral discharge, 200 women with vaginal discharge, and 100 men and 100 women each with genital ulcer disease (GUD). Patients completed a questionnaire, underwent a genital examination, and had specimens taken for etiologic testing. Patients were offered, but not required to accept, HIV testing using a standard HIV algorithm in which two rapid tests defined a positive result. RESULTS: A total of 489 participants (81.5%) accepted HIV testing; 201 (41.1%) tested HIV-1-positive, including 16 (11.9%) of 134 participants who reported an HIV-negative status at study enrollment, and 58 (28.2%) of 206 participants who reported their HIV status as unknown. Of 147 who self-reported being HIV-positive at study enrollment, 21 (14.3%) tested HIV negative. HIV infection prevalence was higher in women (47.3%) than in men (34.8%, p<0.01), and was 28.5% in men with urethral discharge, 40.5% in women with vaginal discharge, 45.2% in men with GUD, and 59.8% in women with GUD (p<0.001). CONCLUSIONS: The high prevalence of HIV infection in STI clinic patients in Zimbabwe underscores the importance of providing HIV testing and referral for indicated prevention and treatment services for this population. The discrepancy between positive self-reported and negative study HIV test results highlights the need for operator training, strict attention to laboratory quality assurance, and clear communication with patients about their HIV infection status.

The Etiology of Vaginal Discharge Syndrome in Zimbabwe: Results from the Zimbabwe STI Etiology Study.

INTRODUCTION: Symptomatic vaginal discharge is a common gynecological condition managed syndromically in most developing countries. In Zimbabwe, women presenting with symptomatic vaginal discharge are treated with empirical regimens that commonly cover both sexually transmitted infections (STIs) and reproductive tract infections, typically including a combination of an intramuscular injection of kanamycin, and oral doxycycline and metronidazole regimens. This study was conducted to determine the current etiology of symptomatic vaginal discharge and assess adequacy of current syndromic management guidelines. METHODS: We enrolled 200 women with symptomatic vaginal discharge presenting at 6 STI clinics in Zimbabwe. Microscopy was used to detect bacterial vaginosis and yeast infection. Nucleic acid amplifications tests were used to detect Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis, and Mycoplasma genitalium. In addition, serologic testing was performed to detect human immunodeficiency virus (HIV) infection. RESULTS: Of the 200 women, 146 (73%) had an etiology detected, including bacterial vaginosis (24.7%); N. gonorrhoeae (24.0%); yeast infection (20.7%); T. vaginalis (19.0%); C. trachomatis (14.0%) and M. genitalium (7.0%). Among women with STIs (N = 90), 62 (68.9%) had a single infection, 18 (20.0%) had a dual infection, and 10 (11.1%) had 3 infections.Of 158 women who consented to HIV testing, 64 (40.5%) were HIV infected.The syndromic management regimen covered 115 (57.5%) of the women in the sample who had gonorrhea, chlamydia, M. genitalium, or bacterial vaginosis, whereas 85 (42.5%) of women were treated without such diagnosis. CONCLUSIONS: Among women presenting with symptomatic vaginal discharge, bacterial vaginosis was the most common etiology, and gonorrhea was the most frequently detected STI. The current syndromic management algorithm is suboptimal for coverage of women presenting with symptomatic vaginal discharge; addition of point of care testing could compliment the effectiveness of the syndromic approach.

How Presentation of Drug Detection Results Changed Reports of Product Adherence in South Africa, Uganda and Zimbabwe.

Accurate estimates of study product use are critical to understanding and addressing adherence challenges in HIV prevention trials. The VOICE trial exposed a significant gap between self-reported adherence and drug detection. The VOICE-D qualitative study was designed to better understand non-adherence during VOICE, and was conducted in 2 stages: before (stage 1) and after (stage 2) drug detection results were provided to participants. Transcripts from 44 women who participated in both stages were analysed to understand the effect of presenting drug detection data on narratives of product use. Thirty-six women reported high adherence in stage 1, yet admitted non-use in stage 2, three reported high adherence in both stages (contrary to their drug detection results) and five had consistent responses across both stages and drug results. Presenting objective measures of use may facilitate more accurate product use reporting and should be evaluated in future prevention trials.

Differences in Cumulative Exposure and Adherence to Tenofovir in the VOICE, iPrEx OLE, and PrEP Demo Studies as Determined via Hair Concentrations.

Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) prevented HIV acquisition among men and women in several trials and is broadly recommended. In the VOICE and FEM-PrEP trials, however, TDF/FTC-based PrEP did not prevent HIV acquisition among women in eastern and southern Africa. Tenofovir was detected in plasma, reflecting exposure and adherence in recent days, in fewer than one-third of participants. Drug concentrations in hair, which represent cumulative exposure and adherence over weeks to months, have never previously been examined among women on PrEP. We compared tenofovir hair concentrations among women assigned to oral TDF/FTC in the VOICE trial to those among men and transgender women enrolled in 2 open-label PrEP studies, the iPrEx open-label extension (OLE) study and the U.S. PrEP Demonstration Project (PrEP Demo). Tenofovir hair concentrations were detectable in 55% of person-visits in VOICE, 75% of person-visits in iPrEx OLE (p = .006), and 98% of person-visits in PrEP Demo (p < .001). Median tenofovir hair concentrations corresponded to an estimated 0.2, 2.9, and 6.0 TDF/FTC doses taken per week in the three studies, respectively. In VOICE, combining tenofovir concentration data from plasma and hair suggested inconsistent, low-level product use. Incorporation of both short- and long-term adherence measures may allow for an improved understanding of patterns of drug-taking among women during global PrEP roll-out.

Bone Mineral Density Changes Among Young, Healthy African Women Receiving Oral Tenofovir for HIV Preexposure Prophylaxis.

BACKGROUND: Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial. METHODS: HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks. RESULTS: Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH. CONCLUSIONS: TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

Pharmacological Measures of Treatment Adherence and Risk of HIV Infection in the VOICE Study.

BACKGROUND: None of the 3 regimens tested in the VOICE study showed protection against human immunodeficiency virus (HIV) infection in intent-to-treat analyses. Plasma tenofovir concentrations demonstrated poor adherence to the study product among study subjects. Statistical analyses to explore the causal treatment effect on the prevention of HIV infection among adherent individuals are needed. METHODS: We developed an analytical strategy to evaluate whether conventional covariate adjustment removes confounding and thereby reveals a prevention effect among adherent individuals. We applied this strategy to the VOICE study, using 2 dichotomized proxy measures of product use: detection of tenofovir in plasma at least once during follow-up and detection of tenofovir in plasma at the 3-month follow-up visit. RESULTS: After adjustment for a set of baseline predictors of the risk of HIV transmission, the confounding associated with comparison of adherent individuals in the tenofovir gel arm to placebo recipients was nearly eliminated. The relative risk for a prevention effect among those ever having tenofovir detected was 0.53 (P = .038); the relative risk among those having tenofovir detected at 3 months was 0.40 (P = .045). CONCLUSIONS: A novel regression approach was proposed for causal as-treated analyses in the VOICE study. While intent-to-treat analyses yield null results, this exploratory approach presented evidence suggesting a prevention effect among gel users. CLINICAL TRIALS REGISTRATION: NCT00705679.