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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.

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.