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Background: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-β1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date.Methods: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-β1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948.Findings: Between March 22, 2020, and Jan 29, 2021, 14304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82–1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89–1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76–0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46–1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76–0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77–1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75–0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings.Interpretation: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both).

The extent to which Omicron infection1–9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3–9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19–27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.

Background: Previous WHO guidance on tenofovir disoproxil fumarate-based oral pre-exposure prophylaxis (PrEP) suggests measuring creatinine levels at PrEP initiation and regularly afterwards, which might represent barriers to PrEP implementation and uptake. We aimed to systematically review published literature on kidney toxicity among tenofovir disoproxil fumarate-based oral PrEP users and conducted an individual participant data meta-analysis (IPDMA) on kidney function among PrEP users in a global implementation project dataset. Methods: In this systematic review and meta-analysis we searched PubMed up to June 30, 2021, for randomised controlled trials (RCTs) or cohort studies that reported on graded kidney-related adverse events among oral PrEP users (tenofovir disoproxil fumarate-based PrEP alone or in combination with emtricitabine or lamivudine). We extracted summary data and conducted meta-analyses with random-effects models to estimate relative risks of grade 1 and higher and grade 2 and higher kidney-related adverse events, measured by elevated serum creatinine or decline in estimated creatinine clearance or estimated glomerular filtration rate. The IPDMA included (largely unpublished) individual participant data from 17 PrEP implementation projects and two RCTs. Estimated baseline creatinine clearance and creatinine clearance change after initiation were described by age, gender, and comorbidities. We used random-effects regressions to estimate the risk in decline of creatinine clearance to less than 60 mL/min. Findings: We identified 62 unique records and included 17 articles reporting on 11 RCTs with 13 523 participants in meta-analyses. PrEP use was associated with increased risk of grade 1 and higher kidney adverse events (pooled odds ratio [OR] 1·49, 95% CI 1·22–1·81; I2=25%) and grade 2 and higher events (OR 1·75, 0·68–4·49; I2=0%), although the grade 2 and higher association was not statistically significant and events were rare (13 out of 6764 in the intervention group vs six out of 6782 in the control group). The IPDMA included 18 676 individuals from 15 countries (1453 [7·8%] from RCTs) and 79 (0·42%) had a baseline estimated creatinine clearance of less than 60 mL/min (increasing proportions with increasing age). Longitudinal analyses included 14 368 PrEP users and 349 (2·43%) individuals had a decline to less than 60 mL/min creatinine clearance, with higher risks associated with increasing age and baseline creatinine clearance of 60·00–89·99 mL/min (adjusted hazard ratio [aHR] 8·49, 95% CI 6·44–11·20) and less than 60 mL/min (aHR 20·83, 12·83–33·82). Interpretation: RCTs suggest that risks of kidney-related adverse events among tenofovir disoproxil fumarate-based oral PrEP users are increased but generally mild and small. Our global PrEP user analysis found varying risks by age and baseline creatinine clearance. Kidney function screening and monitoring might focus on older individuals, those with baseline creatinine clearance of less than 90 mL/min, and those with kidney-related comorbidities. Less frequent or optional screening among younger individuals without kidney-related comorbidities may reduce barriers to PrEP implementation and use.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

This report was undertaken to determine whether researchers in South Africa who publish within large consortia are appropriately recognised in the South African context, including the systems by which authors are evaluated and rewarded, with specific reference to multi-authored publications. The study sought to establish the current practices in South Africa and compare these with international best practice. Lastly the report provides a number of recommendations to improve this aspect of the current system.

Summary Background The incidence of HIV infection in young women in Africa is very high. We did a large-scale community-wide phylogenetic study to examine the underlying HIV transmission dynamics and the source and consequences of high rates of HIV infection in young women in South Africa. Methods We did a cross-sectional household survey of randomly selected individuals aged 15–49 years in two neighbouring subdistricts (one urban and one rural) with a high burden of HIV infection in KwaZulu-Natal, South Africa. Participants completed structured questionnaires that captured general demographic, socioeconomic, psychosocial, and behavioural data. Peripheral blood samples were obtained for HIV antibody testing. Samples with HIV RNA viral load greater than 1000 copies per mL were selected for genotyping. We constructed a phylogenetic tree to identify clusters of linked infections (defi ned as two or more sequences with bootstrap or posterior support ≥90% and genetic distance ≤4·5%). Findings From June 11, 2014, to June 22, 2015, we enrolled 9812 participants, 3969 of whom tested HIV positive. HIV prevalence (weighted) was 59·8% in 2835 women aged 25–40 years, 40·3% in 1548 men aged 25–40 years, 22·3% in 2224 women younger than 25 years, and 7·6% in 1472 men younger than 25 years. HIV genotyping was done in 1589 individuals with a viral load of more than 1000 copies per mL. In 90 transmission clusters, 123 women were linked to 103 men. Of 60 possible phylogenetically linked pairings with the 43 women younger than 25 years, 18 (30·0%) probable male partners were younger than 25 years, 37 (61·7%) were aged 25–40 years, and fi ve (8·3%) were aged 41–49 years: mean age diff erence 8·7 years (95% CI 6·8–10·6; p linked pairings with the 56 women aged 25–40 years, the age diff erence dropped to 1·1 years (95% CI –0·6 to 2·8; p=0·111). 16 (39·0%) of 41 probable male partners linked to women younger than 25 years were also linked to women aged 25–40 years. Of 79 men (mean age 31·5 years) linked to women younger than 40 years, 62 (78·5%) were unaware of their HIV-positive status, 76 (96·2%) were not on antiretroviral therapy, and 29 (36·7%) had viral loads of more than 50 000 copies per mL. Interpretation Sexual partnering between young women and older men, who might have acquired HIV from women of similar age, is a key feature of the sexual networks driving transmission. Expansion of treatment and combination prevention strategies that include interventions to address age-disparate sexual partnering is crucial to reducing HIV incidence and enabling Africa to reach the goal of ending AIDS as a public health threat. Funding President’s Emergency Program for AIDS Relief, US Centers for Disease Control and Prevention, South African Medical Research Council, and MAC AIDS Fund.

Summary Eliciting antibodies that neutralize a broad range of circulating HIV strains (broadly neutralizing antibodies [bnAbs]) represents a key priority for vaccine development. HIV superinfection (re-infection with a second strain following an established infection) has been associated with neutralization breadth, and can provide insights into how the immune system responds to sequential exposure to distinct HIV envelope glycoproteins (Env). Characterizing the neutralizing antibody (nAb) responses in four superinfected women revealed that superinfection does not boost memory nAb responses primed by the first infection or promote nAb responses to epitopes conserved in both infecting viruses. While one superinfected individual developed potent bnAbs, superinfection was likely not the driver as the nAb response did not target an epitope conserved in both viruses. Rather, sequential exposure led to nAbs specific to each Env but did not promote bnAb development. Thus, sequential immunization with heterologous Envs may not be sufficient to focus the immune response onto conserved epitopes., Graphical Abstract, Highlights • HIV superinfection does not efficiently recruit cross-reactive memory B cells • Superinfection results in antibody responses specific to each infecting strain • No evidence that superinfection drives the development of bnAbs, HIV-infected individuals can be re-infected with a second strain (superinfection), providing a model that informs the use of sequential immunizations in future vaccines. Sheward et al. find that superinfection fails to boost memory B cells primed by the first infection and does not promote broadly neutralizing antibodies to HIV.

Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections.

ARV-based HIV prevention methods available in pill, gel or ring formulations (broadly referred to as microbicides) offer the possibility of protection against HIV for women who find it difficult because they cannot ask their partners to use condoms or even refuse sex. Partial efficacy of ARV-based medications has been demonstrated in a number of clinical trials around the world among various populations, building the evidence that ARV-based technologies will contribute to reducing the AIDS epidemic worldwide. Disappointing results, however, from two trials in sub-Saharan Africa, where poor adherence contributed to study closure due to futility, have raised questions about whether women at the centre of the epidemic are able to effectively use products that require routine use. Also, there are fears by some of risk compensation by decreased condom use because of the availability of microbicides when only partial efficacy has been demonstrated in microbicide trials to date. Of note, sub-analyses of biologic measures of adherence in trials where this was possible have shown a strong correlation between good adherence and efficacy, reinforcing the necessity of good adherence. Research conducted in conjunction with clinical trials and post-trials in advance of possible rollout of ARV-based products have examined social and cultural factors, gender-related and otherwise, influencing adherence and other aspects of women's use of products. These include HIV stigma, women's perception of risk, partner and community influences and the differing needs of women in various stages of life and in different circumstances. It is the purpose of this supplement to give voice to the needs of women who can benefit from woman-initiated methods by presenting research results and commentary to contribute to the global conversation about optimizing women's experience with ARV-based prevention., Introduction Antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) is a promising new HIV prevention strategy. However, variable levels of adherence have yielded mixed results across several PrEP trials and populations. It is not clear how taking ARV – traditionally used for HIV treatment – is perceived and how that perception may affect the use of these products as preventives. We explored the views and experiences of VOICE participants, their male partners and community members regarding the use of ARV as PrEP in the VOICE trial and the implications of these shared meanings for adherence. Methods VOICE-C was a qualitative ancillary study conducted at the Johannesburg site of VOICE, a multisite, double-blind, placebo-controlled randomised trial testing tenofovir gel, oral tenofovir and oral Truvada® for HIV PrEP. We interviewed 102 randomly selected female VOICE participants, 22 male partners and 40 community members through in-depth interviews, serial ethnography, or focus group discussions. All interviews were audiotaped, transcribed, translated and coded thematically for analysis. Results The concept of ARV for prevention was understood to varying degrees across all study groups. A majority of VOICE participants understood that the products contained ARV, more so for the tablets than for the gel. Although participants knew they were HIV negative, ARV was associated with illness. Male partners and community members echoed these sentiments, highlighting confusion between treatment and prevention. Concerned that they would be mistakenly identified as HIV positive, VOICE participants often concealed use of or hid their study products. This occasionally led to relationship conflicts or early trial termination. HIV stigma and its association with ARV, especially the tablets, was articulated in rumour and gossip in the community, the workplace and the household. Although ARV were recognised as potent and beneficial medications, transforming the AIDS body from sickness to health, they were regarded as potentially harmful for those uninfected. Conclusions VOICE participants and others in the trial community struggled to conceptualise the idea of using ARV for prevention. This possibly influenced willingness to adopt ARV-based prevention in the VOICE clinical trial. Greater investments should be made to increase community understanding of ARV for prevention and to mitigate pervasive HIV stigma., Introduction Risk perception is a core construct in many behaviour change theories in public health. Individuals who believe they are at risk of acquiring an illness may be more likely to engage in behaviours to reduce that risk; those who do not feel at risk may be unlikely to engage in risk reduction behaviours. Among participants who seroconverted in two FEM-PrEP sites – Bondo, Kenya, and Pretoria, South Africa – we explored perceived HIV risk and worry about acquiring HIV prior to HIV infection. Methods FEM-PrEP was a phase III clinical trial of once-daily, oral emtricitabine and tenofovir disoproxil fumarate for HIV prevention among women in sub-Saharan Africa. We asked all participants about their perceived HIV risk in the next four weeks, prior to HIV testing, during a quantitative face-to-face interview at enrolment and at quarterly follow-up visits. Among participants who seroconverted, we calculated the frequencies of their responses from the visit conducted closest to, but before, HIV acquisition. Also among women who seroconverted, we conducted qualitative, semi-structured interviews (SSIs) at weeks 1, 4 and 8 after participants’ HIV diagnosis visit to retrospectively explore feelings of HIV worry. Applied thematic analysis was used to analyse the SSI data. Results Among participants who seroconverted in Bondo and Pretoria, 52% reported in the quantitative interview that they had no chance of acquiring HIV in the next four weeks. We identified four processes of risk rationalization from the SSI narratives. In “protective behaviour,” participants described at least one risk reduction behaviour they used to reduce their HIV risk; these actions made them feel not vulnerable to HIV, and therefore they did not worry about acquiring the virus. In “protective reasoning,” participants considered their HIV risk but rationalized, based on certain events or beliefs, that they were not vulnerable and therefore did not worry about getting HIV. In “recognition of vulnerability,” participants described reasons for being worried about getting HIV but said no or limited action was taken to reduce their perceived vulnerability. Participants with “no rationalization or action” did not describe any HIV worry or did not engage in HIV risk reduction behaviours. Conclusions Women who are at substantial risk of acquiring HIV may underestimate their actual risk. Yet, others who accurately understand their HIV risk may be unable to act on their concerns. Perceived HIV risk and risk rationalization are important concepts to explore in risk reduction counselling to increase the use of HIV prevention strategies among women at risk of HIV., Women continue to be at special risk for HIV acquisition due to a complex mix of biological, behavioural, structural, cultural and social factors, with unacceptable rates of new infection. Scientific advances over the past decade have highlighted the use of antiretroviral (ARV) drugs as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition (sexually, parenterally and vertically) and ARV treatment (ART) for HIV-positive patients to prevent onward transmission (treatment as prevention – TasP). This paper reviews the evidence base for PrEP and TasP, describes new products in development and the need to translate research findings into programmes with impact at the population level., Introduction Constructively engaging male partners in women-centred health programs such as family planning and prevention of mother-to-child HIV transmission has resulted in both improved health outcomes and stronger relationships. Concerted efforts to engage men in microbicide use could make it easier for women to access and use microbicides in the future. This paper synthesizes findings from studies that investigated men's role in their partners’ microbicide use during clinical trials to inform recommendations for male engagement in women's microbicide use. Methods We conducted primary and secondary analyses of data from six qualitative studies implemented in conjunction with microbicide clinical trials in South Africa, Kenya, and Tanzania. The analyses included data from 535 interviews and 107 focus groups with trial participants, male partners, and community members to answer research questions on partner communication about microbicides, men's role in women's microbicide use, and potential strategies for engaging men in future microbicide introduction. We synthesized the findings across the studies and developed recommendations. Results The majority of women in steady partnerships wanted agreement from their partners to use microbicides. Women used various strategies to obtain their agreement, including using the product for a while before telling their partners, giving men information gradually, and continuing to bring up microbicides until resistant partners acquiesced. Among men who were aware their partners were participating in a trial and using microbicides, involvement ranged from opposition to agreement/non-interference to active support. Both men and women expressed a desire for men to have access to information about microbicides and to be able to talk with a healthcare provider about microbicides. Conclusions We recommend counselling women on whether and how to involve their partners including strategies for gaining partner approval; providing couples’ counselling on microbicides so men have the opportunity to talk with providers; and targeting men with community education and mass media to increase their awareness and acceptance of microbicides. These strategies should be tested in microbicide trials, open-label studies, and demonstration projects to identify effective male engagement approaches to include in eventual microbicide introduction. Efforts to engage men must take care not to diminish women's agency to decide whether to use the product and inform their partners., Introduction Product adherence and its measurement have emerged as a critical challenge in the evaluation of new HIV prevention technologies. Long-acting ARV-based vaginal rings may simplify use instructions and require less user behaviour, thereby facilitating adherence. One ARV-based ring is in efficacy trials and others, including multipurpose rings, are in the pipeline. Participant motivations, counselling support and measurement challenges during ring trials must still be addressed. In previous HIV prevention trials, this has been done largely using descriptive and post-hoc methods that are highly variable and minimally evaluated. We outline an interdisciplinary framework for systematically investigating promising strategies to support product uptake and adherence, and to measure adherence in the context of randomized, blinded clinical trials. Discussion The interdisciplinary framework highlights the dual use of adherence measurement (i.e. to provide feedback during trial implementation and to inform interpretation of trial findings) and underscores the complex pathways that connect measurement, adherence support and enacted adherence behaviour. Three inter-related approaches are highlighted: 1) adherence support – sequential efforts to define motivators of study product adherence and to develop, test, refine and evaluate adherence support messages; 2) self-reported psychometric measures – creation of valid and generalizable measures based in easily administered scales that capture vaginal ring use with improved predictive ability at screening, baseline and follow-up that better engage participants in reporting adherence; and 3) more objective measurement of adherence – real-time adherence monitoring and cumulative measurement to correlate adherence with overall product effectiveness through innovative designs, models and prototypes using electronic and biometric technologies to detect ring insertion and/or removal or expulsion. Coordinating research along these three pathways will result in a comprehensive approach to product adherence within clinical trials. Conclusions Better measurement of adherence will not, by itself, ensure that future effectiveness trials will be able to address the most basic question: if the product is used per instructions, will it prevent HIV transmission? The challenges to adherence measurement must be addressed as one component of a more integrated system that has as its central focus adherence as a behaviour emerging from the social context of the user., Introduction Despite the disproportionate impact of HIV on women, and adolescents in particular, those below age 18 years are underrepresented in HIV prevention trials due to ethical, safety and logistical concerns. This study examined and compared the sexual risk contexts of adolescent women aged 15–17 to young adult women aged 18–21 to determine whether adolescents exhibited similar risk profiles and the implications for their inclusion in future trials. Methods We conducted a two-phase, mixed-method study to assess the opportunities and challenges of recruiting and retaining adolescents (aged 15–17) versus young women (18–21) in Tanzania. Phase I, community formative research (CFR), used serial in-depth interviews with 11 adolescent and 12 young adult women from a range of sexual risk contexts in preparation for a mock clinical trial (MCT). For Phase II, 135 HIV-negative, non-pregnant adolescents and young women were enrolled into a six-month MCT to assess and compare differences in sexual and reproductive health (SRH) outcomes, including risky sexual behaviour, incident pregnancy, sexually transmitted infections (STIs), reproductive tract infections (RTIs) and HIV. Results In both research phases, adolescents appeared to be at similar, if not higher, risk than their young adult counterparts. Adolescents reported earlier sexual debut, and similar numbers of lifetime partners, pregnancy and STI/RTI rates, yet had lower perceived risk. Married women in the CFR appeared at particular risk but were less represented in the MCT. In addition, adolescents were less likely than their older counterparts to have accessed HIV testing, obtained gynaecological exams or used protective technologies. Conclusions Adolescent women under 18 are at risk of multiple negative SRH outcomes and they underuse preventive services. Their access to new technologies such as vaginal microbicides or pre-exposure prophylaxis (PrEP) may similarly be compromised unless greater effort is made to include them in clinical trial research., Introduction Current HIV prevention options are unrealistic for most women; however, HIV prevention research has made important strides, including on-going development of antiretroviral-based vaginal microbicide gels. Nevertheless, social-behavioural research suggests that women's ability to access and use new HIV prevention technologies will be strongly influenced by a range of socio-cultural, gender and structural factors which should be addressed by communications and marketing strategies, so that these products can be positioned in ways that women can use them. Methods Based on an extensive literature review and in-country policy consultation, consisting of approximately 43 stakeholders, we describe barriers and facilitators to HIV prevention, including potential microbicide use, for four priority audiences of Kenyan women (female sex workers [FSWs], women in stable and discordant relationships, and sexually active single young women). We then describe how messages that position microbicides might be tailored for each audience of women. Results We reviewed 103 peer-reviewed articles and reports. In Kenya, structural factors and gender inequality greatly influence HIV prevention for women. HIV risk perception and the ability to consistently use condoms and other prevention products often vary by partner type. Women in stable relationships find condom use challenging because they connote a lack of trust. However, women in other contexts are often able to negotiate condom use, though they may face challenges with consistent use. These women include FSWs who regularly use condoms with their casual clients, young women in the initial stages of a sexual relationship and discordant couples. Thus, we consider two approaches to framing messages aimed at increasing general awareness of microbicides – messages that focus strictly on HIV prevention and ones that focus on other benefits of microbicides such as increased pleasure, intimacy or sexual empowerment, in addition to HIV prevention. Conclusions If carefully tailored, microbicide communication materials may facilitate product use by women who do not currently use any HIV prevention method. Conversely, message tailoring for women with high-risk perception will help ensure that microbicides are used as additional protection, together with condoms., Introduction Stakeholders continue to discuss the appropriateness of antiretroviral-based pre-exposure prophylaxis (PrEP) for HIV prevention among sub-Saharan African and other women. In particular, women need formulations they can adhere to given that effectiveness has been found to correlate with adherence. Evidence from family planning shows that contraceptive use, continuation and adherence may be increased by expanding choices. To explore the potential role of choice in women's use of HIV prevention methods, we conducted a secondary analysis of research with female sex workers (FSWs) and men and women in serodiscordant couples (SDCs) in Kenya, and adolescent and young women in South Africa. Our objective here is to present their interest in and preferences for PrEP formulations – pills, gel and injectable. Methods In this qualitative study, in Kenya we conducted three focus groups with FSWs, and three with SDCs. In South Africa, we conducted two focus groups with adolescent girls, and two with young women. All focus groups were audio-recorded, transcribed and translated into English as needed. We structurally and thematically coded transcripts using a codebook and QSR NVivo 9.0; generated code reports; and conducted inductive thematic analysis to identify major trends and themes. Results All groups expressed strong interest in PrEP products. In Kenya, FSWs said the products might help them earn more money, because they would feel safer accepting more clients or having sex without condoms for a higher price. SDCs said the products might replace condoms and reanimate couples’ sex lives. Most sex workers and SDCs preferred an injectable because it would last longer, required little intervention and was private. In South Africa, adolescent girls believed it would be possible to obtain the products more privately than condoms. Young women were excited about PrEP but concerned about interactions with alcohol and drug use, which often precede sex. Adolescents did not prefer a particular formulation but noted benefits and limitations of each; young women's preferences also varied. Conclusions The circumstances and preferences of sub-Saharan African women are likely to vary within and across groups and to change over time, highlighting the importance of choice in HIV prevention methods., Introduction Clinical trials of new vaginal products require careful communication with participants about trial requirements. Most microbicide trials have been multi-site studies conducted among women in sub-Saharan Africa, where literacy levels and understanding of scientific methods differ from those designing and conducting the trials. Microbicide trials require women to insert objects in their vagina and ensure they are present in the vagina during sex. For many women, this is a novel behaviour. These behaviours take place within the context of clinical trial participation, which is an additional novelty. Research teams must develop informational materials to help participants understand the clinical trial and input from local research staff and community members can improve the content and format of these materials. Methods This paper discusses the development of illustrated materials developed for microbicide trial participants, presenting examples from two studies. In both studies, research staff and community advisory groups collaborated to review and revise materials. Results Collaborative efforts revealed insights about how to convey information about clinical trial participation and microbicide use. These insights highlighted realities of the local context, details that might be misunderstood, illustrations of a sensitive nature and concerns about blood testing. In particular, information about blood testing and product use instructions required careful consideration. Although the research team anticipated needing advice on how best to convey information on these topics to participants, some aspects of potential participant concerns about these topics were also new to the research team. Community advisors and local research staff suggested better ways to convey this information, and provided guidance on how to use the materials. Conclusions The collaboration served to develop informational materials for microbicide trial participants. Furthermore, staff gained a better understanding of issues and concerns that could influence trial participation. A collaborative engagement process can provide important insights into local culture and knowledge beyond what is needed for development of clinical trial participant information materials. Research teams should be sensitive to this possibility, avail themselves of information and take appropriate action., Introduction In planning for the introduction of vaginal microbicides and other new antiretroviral (ARV)-based prevention products for women, an in-depth understanding of potential end-users will be critically important to inform strategies to optimize uptake and long-term adherence. User-centred private sector companies have contributed to the successful launch of many different types of products, employing methods drawn from behavioural and social sciences to shape product designs, marketing messages and communication channels. Examples of how the private sector has adapted and applied these techniques to make decisions around product messaging and targeting may be instructive for adaptation to microbicide introduction. Discussion In preparing to introduce a product, user-centred private sector companies employ diverse methods to understand the target population and their lifestyles, values and motivations. ReD Associates’ observational research on user behaviours in the packaged food and diabetes fields illustrates how ‘tag along’ or ‘shadowing’ techniques can identify sources of non-adherence. Another open-ended method is self-documentation, and IDEO's mammography research utilized this to uncover user motivations that extended beyond health. Mapping the user journey is a quantitative approach for outlining critical decision-making stages, and Monitor Inclusive Markets applied this framework to identify toilet design opportunities for the rural poor. Through an iterative process, these various techniques can generate hypotheses on user drop-off points, quantify where drop-off is highest and prioritize areas of further research to uncover usage barriers. Although research constraints exist, these types of user-centred techniques have helped create effective messaging, product positioning and packaging of health products as well as family planning information. These methods can be applied to microbicide acceptability testing outside of clinical trials to design microbicide marketing that enhances product usage. Conclusions The introduction of microbicide products presents an ideal opportunity to draw on the insights from user-centred private sector companies’ approaches, which can complement other methods that have been more commonly utilized in microbicide research to date. As microbicides move from clinical trials to real-world implementation, there will be more opportunities to combine a variety of approaches to understand end-users, which can lead to a more effective product launch and ultimately greater impact on preventing HIV infections., Introduction Two new microbicide products based on topical (vaginal) application of antiretroviral drugs – 1% tenofovir gel and the dapivirine ring – are currently in late-stage clinical testing, and results on their safety and effectiveness are expected to become available in early 2015. WHO guidelines on the use of topical pre-exposure prophylaxis (topical PrEP) are important in order to ensure that these new prevention products are optimally used. Discussion Given that these new topical PrEP products are designed to be woman initiated and will likely be delivered in reproductive health settings, it is important to ensure that the guidance be framed in the context of comprehensive sexual and reproductive health and human rights. In addition to the safety and effectiveness data resulting from clinical trials, and the regulatory approval required for new products, the WHO normative guidelines on the use of topical PrEP will be essential for rapid roll-out in countries. Conclusions Human rights standards and principles provide a framework for the provision of woman-initiated HIV prevention products. These include addressing issues related to the gender inequities which are linked to the provision of HIV-prevention, treatment and care for young girls and women. Effective programming for women and girls must therefore be based on understanding the local, social and community contexts of the AIDS epidemic in the country, and adapting HIV strategies and programmes accordingly. Such a framework therefore is needed not only to ensure optimal uptake of these new products by women and girls but also to address sociocultural barriers to women's and girls’ access to these products.

BACKGROUND: Eight decades ago, the ratio of monocytes to lymphocytes (hereafter, the "ML ratio") was noted to affect outcomes of mycobacterial infection in rabbits. Recent transcriptomic studies support a role for relative proportions of myeloid and lymphoid transcripts in tuberculosis outcomes. The ML ratio in peripheral blood is known to be governed by hematopoietic stem cells with distinct biases. METHODS: The predictive value of the baseline ML ratio was modeled in 2 prospective cohorts of HIV-infected adults starting cART in South Africa (primary cohort, 1862 participants; replication cohort, 345 participants). Incident tuberculosis was diagnosed with clinical, radiographic, and microbiologic methods per contemporary guidelines. Kaplan-Meier survival analyses and Cox proportional hazards modeling were conducted. RESULTS: The incidence rate of tuberculosis differed significantly by baseline ML ratio: 32.61 (95% confidence interval [CI], 15.38-61.54), 16.36 (95% CI, 12.39-21.23), and 51.80 (95% CI, 23.10-101.71) per 1000 patient-years for ML ratios of less than the 5th percentile, between the 5th and 95th percentiles, and greater than the 95th percentile, respectively (P = .007). Neither monocyte counts nor lymphocyte counts alone were associated with tuberculosis. After adjustment for sex, World Health Organization human immunodeficiency virus disease stage, CD4(+) T-cell counts, and previous history of tuberculosis, hazards of disease were significantly higher for patients with ML ratios of less than the 5th percentile or greater than the 95th percentile (adjusted hazard ratio, 2.47; 95% CI, 1.39-4.40; P = .002). CONCLUSIONS: The ML ratio may be a useful, readily available tool to stratify the risk of tuberculosis and suggests involvement of hematopoietic stem cell bias in tuberculosis pathogenesis.

The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. This is a two-arm, open-label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at-risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. This trial was registered with the South Africa Department of Health (reference: DOH-27-0812-4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012.

Background Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial. Methods and Results We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein downregulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis. Conclusion Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.

The impact of HIV on maternal mortality and more broadly on the health of women, remains poorly documented and understood. Two recent reports attempt to address the conceptual and methodological challenges that arise in estimating HIV-related maternal mortality and trends. This paper presents and compares the methods and discusses how they affect estimates at global and regional levels. Country examples of likely patterns of mortality among women of reproductive age are provided to illustrate the critical interactions between HIV and complications of pregnancy in high-HIV-burden countries. The implications for collaboration between HIV and reproductive health programmes are discussed, in support of accelerated action to reach the Millennium Development Goals and improve the health of women.

Background: In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant's safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants. Experiences: Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n = 135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n = 50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants' safety and validity of the trial results was implemented. Shared electronic database between research units was established to enable verification of each volunteer's trial participation and to prevent future co-enrollments. Lessons learnt: Interviews with ineligible enrolled women revealed that high-quality care, financial incentives, altruistic motives, preference for sex with gel, wanting to increase their likelihood of receiving active gel, perceived low risk of discovery and peer pressure are the reasons for their enrollment in the CAPRISA 004 trial. Conclusion: Instituting education programs based on the reasons reported by women for seeking enrollment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.

BACKGROUND: Tenofovir gel, an antiretroviral-based vaginal microbicide, reduced HIV acquisition by 39% in women in a recent randomized controlled clinical trial in South Africa. METHODS: To inform policy, we used a dynamical model of HIV transmission, calibrated to the epidemic in South Africa, to determine the population-level impact of this microbicide on HIV incidence, prevalence, and deaths and to evaluate its cost-effectiveness. RESULTS: If women use tenofovir gel in 80% or more of sexual encounters (high coverage), it could avert 2.33 (0.12 to 4.63) million new infections and save 1.30 (0.07 to 2.42) million lives and if used in 25% of sexual encounters (low coverage), it could avert 0.50 (0.04 to 0.77) million new infections and save 0.29 (0.02 to 0.44) million deaths, over the next 20 years. At US $0.50 per application, the cost per infection averted at low coverage is US $2392 (US $562 to US $4222) and the cost per disability-adjusted life year saved is US $104 (US $27 to US $181); at high coverage the costs are about 30% less. CONCLUSIONS: Over 20 years, the use of tenofovir gel in South Africa could avert up to 2 million new infections and 1 million AIDS deaths. Even with low rates of gel use, it is highly cost-effective and compares favorably with other control methods. This female-controlled prevention method could have a significant impact on the epidemic of HIV in South Africa. Programs should aim to achieve gel use in more than 25% of sexual encounters to significantly alter the course of the epidemic.

The early closure of a clinical trial assessing the effectiveness of oral antiretroviral pre-exposure prophylaxis (PrEP) in women, FEM-PrEP, is a substantial setback for HIV prevention. Expectations of this trial were high in view of favourable results from the pre-exposure prophylaxis initiative (iPrEX) trial, which studied the same drug and dosing strategy in men who have sex with men, and the Centre for the AIDS Programme of Research in South Africa (CAPRISA 004) trial,3 which tested tenofovir gel (a topical PrEP formulation) in heterosexual women. As a result, the interim FEM-PrEP trial results, announced on April 18, 2011, which showed no protection against HIV infection, were disappointing. Using publicly available information and data from other PrEP studies, we offer a potential explanation for the results of the FEM-PrEP trial.

A defining moment in the global AIDS response has been reached. The discourse is no longer about HIV prevention or HIV treatment; it is now about HIV control through the implementation of antiretrovirals as key components of combination interventions. Barely a year ago, visions of HIV control would have been considered far-fetched. The impetus for this change in mindset, which has been building since the XVIII International AIDS Conference in Vienna last year, emanates from the compelling evidence that antiretroviral drugs prevent HIV infection in the general heterosexual population, which is released this week and presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome by the Partners PrEP and Botswana TDF2 trials.

Reliable data from South Africa emanating from WHO recommendations for the Safe Motherhood programme underscores HIV/AIDS as the most common cause of maternal deaths. The strengthening of HIV services for pregnant women especially in countries with a high burden of HIV infection will reduce HIV-related and un-related maternal mortality rates. High-quality and complete data on maternal deaths is a critical foundation for reliably monitoring temporal trends in maternal deaths, and causes thereof, but needs substantial strengthening in many resource-constrained settings. HIV/AIDS is an increasing contributor to direct and indirect causes of maternal deaths in sub-Saharan Africa. A review of published data on maternal deaths and its association with HIV shows that reliable data come from the Confidential Enquiries into Maternal Deaths from South Africa, population-based surveys in sentinel populations, and facility-based data. Despite an increase in knowledge of the HIV status of pregnant women and the initiation of antiretroviral treatment, reversals in trends towards increased maternal deaths are not being observed. The strengthening of HIV services provides an opportunity to alter HIV epidemic trajectories and reduce maternal deaths.

OBJECTIVES: The aim of this study was to evaluate the HIV-1 RNA pooled nucleic acid amplification testing (NAAT) strategy to screen pregnant women in the 'window period' of acute HIV infection (AHI) in rural South Africa. METHODS: In 2007 and 2008, 750 consecutive pregnant women on their first antenatal care visit to a primary health care clinic were tested anonymously for HIV infection. HIV-1 RNA pooled NAAT was performed on HIV antibody-negative samples. All positive pools were tested individually and positive samples were classified as incident cases to calculate HIV incidence. RESULTS: The overall HIV prevalence was 37.3% [95% confidence interval (CI) 34.3-41.3]. Of the 467 HIV antibody-negative samples, four (0.9%) were HIV-1 RNA-positive. The mean viral load in the four samples was 386 260 HIV-1 RNA copies/mL (range 64 200-1 228130). The HIV incidence was 11.2%per year (95% CI 0.3-22.1) and all women with AHI were 21 years of age. CONCLUSIONS: Identifying AHI in pregnancy is important for health interventions to reduce perinatal and heterosexual transmission of HIV, and to estimate HIV incidence for epidemiological surveillance.

This study assessed the uptake of provider-initiated HIV testing and counseling (PITC) among women attending an urban sexually transmitted diseases (STD) clinic in South Africa. From July 2005 to June 2006, women were offered HIV testing following group information and education on HIV and STDs in the clinic waiting area. Of those who were provided with education, information, and offered HIV testing, uptake was 43.5% (2439/5612). The overall HIV prevalence among those tested was 56.5% and the prevalence of acute HIV infection was 1.2%. Of the 56.5% (3173/5612) refusing to test, the reasons for not testing were having already been tested for HIV (61.8%), being afraid to test or felt unready to test (32.5%), the need to consult with partner (0.9%), and refusing with no explanation (4.8%). In settings where high-risk patients await health care services, such as an STD clinic, failure to implement PITC is a missed opportunity for patients to benefit from counseling, prevention, early diagnosis, and referral into care and treatment for HIV infection.

Women account for approximately one-half of all human immunodeficiency virus (HIV) infections worldwide. Sexual transmission is the dominant mode of HIV transmission to women, and there is a concomitant associated epidemic of transmission to infants. The majority of HIV infections in women are in sub-Saharan Africa, with a disproportionate burden in young women < 25 years of age. Acquisition and prevention of HIV infection in women is complex and influenced by biological, behavioral, and structural factors. Efforts to reduce the incidence of HIV infection among women in sub-Saharan African could play a substantial role in altering global trajectories of HIV infection. Increasing access to sexual and reproductive health services, addressing gender-based violence and social instability, reducing poverty and the need to engage in sex for survival, and encouraging greater male responsibility are critical short-to-medium-term interventions. Efforts to find a microbicide and HIV vaccine need to be matched with efforts to deepen understanding of acquisition of HIV in the female genital tract to inform development of targeted molecules for prevention of HIV infection.

HIV research in South Africa is world class. To halt the country's epidemic, scientists need to shift focus from global problems to priorities at home.

The United Nations' (UN's) eight Millennium Development Goals (MDGs) (1) are widely accepted as the primary path to alleviating poverty worldwide. This month, world leaders convene to assess progress toward these goals (2). In the countdown to the MDG 2015 deadline and amid protracted economic recession, we need the most efficient, effective, and evidence-based means to accelerate progress toward all MDGs. Challenges must be considered in concert, and solutions must provide multidimensional dividends for the world's poor, or we risk unwisely dividing limited resources and diluting their impact. As authors from diverse communities, we emphasize here the influence that investments in rights-based family planning can have on achieving the MDGs.

OBJECTIVES: To describe the baseline demographic data, clinical characteristics and HIV-incidence rates of a cohort at high risk for HIV infection in South Africa as well as the challenges experienced in establishing and maintaining the cohort. METHODOLOGY/PRINCIPLE FINDINGS: Between August 2004 and May 2005 a cohort of HIV-uninfected women was established for the CAPRISA 002 Acute Infection Study, a natural history study of HIV-1 subtype C infection. Volunteers were identified through peer-outreach. The cohort was followed monthly to determine HIV infection rates and clinical presentation of early HIV infection. Risk reduction counselling and male and female condoms were provided. After screening 775 individuals, a cohort of 245 uninfected high-risk women was established. HIV-prevalence at screening was 59.6% (95% CI: 55.9% to 62.8%) posing a challenge in accruing HIV-uninfected women. The majority of women (78.8%) were self-identified as sex-workers with a median of 2 clients per day. Most women (95%) reported more than one casual sexual partner in the previous 3 months (excluding clients) and 58.8% reported condom use in their last sexual encounter. Based on laboratory testing, 62.0% had a sexually transmitted infection at baseline. During 390 person-years of follow-up, 28 infections occurred yielding seroincidence rate of 7.2 (95% CI: 4.5 to 9.8) per 100 person-years. Despite the high mobility of this sex worker cohort retention rate after 2 years was 86.1%. High co-morbidity created challenges for ancillary care provision, both in terms of human and financial resources. CONCLUSIONS/SIGNIFICANCE: Challenges experienced were high baseline HIV-prevalence, lower than anticipated HIV-incidence and difficulties retaining participants. Despite challenges, we have successfully accrued this cohort of HIV-uninfected women with favourable retention, enabling us to study the natural history of HIV-1 during acute HIV-infection. Our experiences provide lessons for others establishing similar cohorts, which will be key for advancing the vaccine and prevention research agenda in resource-constrained settings.

Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners. Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables. The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p = 0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups. The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services.

Background Understanding sexual activity is necessary to prevent sexually transmitted infections. Evidence from Sub-Saharan Africa suggests that 10–20% of youth aged 15–24 are sexually active before reaching 15 years, yet estimating sexual activity remains challenging. This study explored the use of multiple sexual health outcomes to identify sexually-active young women in rural KwaZulu-Natal, South Africa. Methods Using a multi-component sexual activity profile (MSAP), we aimed to identify sexually active students. Based on data from 2675 grade 9 and 10 students attending 14 high schools) in rural KwaZulu-Natal, we constructed a descriptive diagram identifying students who were sexually active by self-report vs MSAP profile. T-tests for two independent samples was performed to compare by sex and ecological variables that characterise students newly-identified as sexually active. Results Using self-report only, 40.3% self-reported as sexually active, whilst the MSAP identified 48.7% (223 additional students). More females were identified than males. Younger adolescents were more likely to underreport sexual activity but were identified using MSAP. Newly-identified as sexually active were more likely to be female (p =

Sex and gender differences influence the health and wellbeing of men and women. Although studies have drawn attention to observed differences between women and men across diseases, remarkably little research has been pursued to systematically investigate these underlying sex differences. Women continue to be underrepresented in clinical trials, and even in studies in which both men and women participate, systematic analysis of data to identify potential sex-based differences is lacking. Standards for reporting of clinical trials have been established to ensure provision of complete, transparent and critical information. An important step in addressing the gender imbalance would be inclusion of a gender perspective in the next Consolidated Standards of Reporting Trials (CONSORT) guideline revision. Uniform Requirements for Manuscripts Submitted to Biomedical Journals, as a set of well-recognized and widely used guidelines for authors and biomedical journals, should similarly emphasize the ethical obligation of authors to present data analyzed by gender as a matter of routine. Journal editors are also promoters of ethical research and adequate standards of reporting, and requirements for inclusion of gender analyses should be integrated into editorial policies as a matter of urgency.

Background: Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose: This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods: This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results: HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001). Conclusion: The populations selected provide suitable diverse target groups for HIV prevention intervention studies.

Background A blood-based assay that could quantify HIV susceptibility would be very valuable for HIV prevention research. Previously, we developed and validated an ex vivo, flow-based, HIV entry assay to assess genital HIV susceptibility in endocervical CD4+ T cells. Methods Here we assessed whether this tool could be used to predict HIV risk using blood-derived CD4+ T cells in a rigorously-blinded, nested case-control study using blood samples collected from high-risk, HIV-uninfected South African women enrolled in the CAPRISA 004 clinical trial. Cases, subsequently acquiring HIV were sampled prior to HIV infection and compared with controls, who remained HIV-uninfected. The primary endpoint was ex vivo entry of a CCR5-tropic HIV founder virus into blood CD4+ T cells. Secondary endpoints included HIV entry into CD4+ central (TCM) and effector (TEM) memory T cells, and into CD4+ T cell subsets expressing CCR5, CD69, CCR6, α4β1 or α4β7. Results Compared to bulk CD4+ T cells (4.9% virus entry), CD4+ T cells expressing CCR5, CCR6 or α4β1 and TEM were highly susceptible (15.5%, 8.8%, 8.2% and 10.8% entry, respectively, all p

Background: Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection. Methodology/Principal Findings: Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α4β7). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p less than 0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p less than 0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIRpos) NK cells increased following HIV acquisition (p = 0.006), and KIRpos NK cells were less activated than KIRneg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p less than 0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p less than 0.0001). Conclusions/Significance: Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.

Background: Epidemiological data from South Africa demonstrate that risk of human immunodeficiency virus (HIV) infection in males increases dramatically after adolescence. Targeting adolescent HIV-negative males may be an efficient and cost-effective means of maximising the established HIV prevention benefits of voluntary medical male circumcision (VMMC) in high HIV prevalence���, low circumcision practice���settings. This study assessed the feasibility of recruiting male high school students for VMMC in such a setting in rural KwaZulu-Natal. Methods and Findings: Following community and key stakeholder consultations on the acceptability of VMMC recruitment through schools, information and awareness raising sessions were held in 42 high schools in Vulindlela. A three-phase VMMC demand-creation strategy was implemented in partnership with a local non-governmental organization, ZimnadiZonke, that involved: (i) community consultation and engagement; (ii) in-school VMMC awareness sessions and centralized HIV counselling and testing (HCT) service access; and (iii) peer recruitment and decentralized HCT service access. Transport was provided for volunteers to the Centre for the AIDS Programme of Research in South Africa (CAPRISA) clinic where the forceps-guided VMMC procedure was performed on consenting HIV-negative males. HIV infected volunteers were referred to further care either at the CAPRISA clinic or at public sector clinics. Between March 2011 and February 2013, a total of 5165 circumcisions were performed, the majority (71%) in males aged between 15 and 19 years. Demand-creation strategies were associated with an over five-fold increase in VMMC uptake from an average of 58 procedures/month in initial community engagement phases, to an average of 308 procedures/month on initiation of the peer recruitment���decentralized service phase. Post-operative adverse events were rare (1.2%), mostly minor and self-resolving. Conclusions: Optimizing a high volume, adolescent-targeted VMMC program was feasible, acceptable and safe in this setting. Adaptive demand-creation strategies are required to sustain high uptake.

BACKGROUND World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

In July 2010, the World Health Organization (WHO) issued formal revisions of its guidelines on the use of highly active antiretroviral therapy for HIV. The new guidelines greatly expand eligibility for treatment of adults and children, as well as for pregnant women seeking prophylaxis for vertical HIV transmission. WHO's new recommendations bring the guidelines closer to practices in developed countries, and its shift to earlier treatment alone will increase the number of treatment-eligible people by 50% or more. Scaling up access to HIV treatment is revealing important gaps in our understanding of how best to provide for all those in need. This knowledge gap is especially significant in developing countries, where women and children comprise a majority of those living with HIV infection. Given the magnitude and significance of these populations, the International AIDS Society, through its Industry Liaison Forum, prioritized HIV treatment and prophylaxis of women and children. In March 2010, the International AIDS Society and 15 partners launched a Consensus Statement outlining priority areas in which a relative lack of knowledge impedes delivery of optimal prevention of mother to child transmission (PMTCT) and treatment to women and children. The Consensus Statement, "Asking the Right Questions: Advancing an HIV Research Agenda for Women and Children", makes a special appeal for a more gender-sensitive approach to HIV research at all stages, from conception to design and implementation. It particularly emphasizes research to enhance the understanding of sex-based differences and paediatric needs in treatment uptake and response. In addition to clinical issues, the statement focuses on programmatic research that facilitates access and adherence to antiretroviral regimens. Better coordination of HIV management with sexual and reproductive healthcare delivery is one such approach. We discuss here our knowledge gaps concerning effective, safe PMTCT and treatment for women and children in light of the expansion envisioned by WHO's revised guidelines. The guideline's new goals present an opportunity for advancing the women and children's agenda outlined in the Consensus Statement.

Background: Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy. Methods: We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel. Pregnancy was assessed with monthly urine tests. Adherence was measured monthly and defined as proportion of sex acts covered by two returned, used applicators based on pre- and post-coital dosing. High adherence was defined as a median adherence score of greater than 80%, that is, more than 80% of sex acts were covered by two applications of study gel. A multivariate generalized estimating equations (GEE) model with a binomial distribution was used to assess covariates associated with high adherence (greater than 80%) over time. Median adherence before and after pregnancy was compared using Wilcoxon signed rank test. Results: Among 868 women, 53 had at least 1 pregnancy (4.06 per 100 woman years, 95% CI: 3.04, 5.31). Women with pregnancies had lower median adherence compared to women without pregnancies (50% [IQR: 45–83] vs. 60% [IQR: 50–100], p = 0.02). Women with pregnancies also had a 48% lower odds of high adherence compared to women without pregnancies when adjusting for confounders (aOR 0.52, 95%CI: 0.41–0.66, p less than 0.0001). Among women with pregnancies, adherence before and after pregnancy was not different (50% [IQR: 46–83] vs. 55% [IQR: 20–100], p = 0.68). Conclusions: Women with pregnancies were less likely to have high adherence to study gel compared to women without pregnancies. Understanding these differences may inform findings from HIV prevention trials and future implementation of antiretroviral prophylaxis for at-risk women who choose to conceive. The protocol for the parent trial is registered on ClinicalTrials.gov, NCT00441298, http://www.clinicaltrials.gov/ct2/show/N​CT00441298.

In attaining UNAIDS targets of 90-90-90 to achieve epidemic control, understanding who the current utilizers of HIV treatment services are will inform efforts aimed at reaching those not being reached. A retrospective chart review of CAPRISA AIDS Treatment Program (CAT) patients between 2004 and 2013 was undertaken. Of the 4043 HIV-infected patients initiated on ART, 2586 (64.0%) were women. At ART initiation, men, compared to women, had significantly lower median CD4+ cell counts (113 vs 131 cells/mm3, p