on behalf of the CAPRISA 004 Trial Group ‡ The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18-to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use. W omen are disproportionately affected by the Acquired Immunodeficiency Syndrome (AIDS) epidemic in Africa, the region that accounts for 70% of global burden of Human Immunodeficiency Virus (HIV) infection (1). Current HIV prevention behavioral messages on abstinence, faithfulness, and condom promotion have had limited impact on HIV incidence rates in women, especially in sub-Saharan Africa, where young women bear the greatest HIV burden (2). The search for new technologies to prevent sexually transmitted HIV infection over the past three decades has had limited success. Only five of 37 randomized controlled trials, which tested 39 HIV prevention strategies, have demonstrated protection against sexual transmission of HIV infection (3). The successful trials tested medical male circumcision in South Africa (4), Kenya (5), and Uganda (6) (combined effectiveness in reducing HIV acquisition was 57%), sexually transmitted infection (STI) treatment in Tanzania (effectiveness in reducing HIV acquisition was 42%) (7), and a HIV vaccine combination in Thailand (effectiveness in reducing HIV acquisition was 31%) (8). Hence, HIV prevention technologies that women can use and control remain a pressing priority (9).Microbicides are products that can be applied to the vagina or rectum with the intention of reducing the acquisition of STIs, including HIV. An effective microbicide has the potential to alter the trajectory of the global HIV pandemic (10). Over the ...

On Nov 25, 2021, about 23 months since the first reported case of COVID-19 and after a global estimated 260 million cases and 5•2 million deaths, 1 a new SARS-CoV-2 variant of concern (VoC), omicron, 2 was reported. Omicron emerged in a COVID-19-weary world in which anger and frustration with the pandemic are rife amid widespread negative impacts on social, mental, and economic wellbeing. Although previous VoCs emerged in a world in which natural immunity from COVID-19 infections was common, this fifth VoC has emerged at a time when vaccine immunity is increasing in the world.The emergence of the alpha, beta, and delta SARS-CoV-2 VoCs were associated with new waves of infections, sometimes across the entire world. 3 For example, the increased transmissibility of the delta VoC was associated with, among others, a higher viral load, 4 longer duration of infectiousness, 5 and high rates of reinfection, because of its ability to escape from natural immunity, 6 which resulted in the delta VoC rapidly becoming the globally dominant variant. The delta VoC continues to drive new waves of infection and remains the dominant VoC during the fourth wave in many countries. Concerns about lower vaccine efficacy because of new variants have changed our understanding of the COVID-19 endgame, disabusing the world of the notion that global vaccination is by itself adequate for controlling SARS-CoV-2 infection. Indeed, VoCs have highlighted the importance of vaccination in combination with existing public health prevention measures, such as masks, as a pathway to viral endemicity. 7

Elevated genital concentrations of HIV target cell-recruiting chemokines and a genital inflammatory profile contributes to the high risk of HIV acquisition in these African women.

Despite high mortality rates in tuberculosis patients with HIV co-infection, there is continued controversy on when to initiate antiretroviral therapy (ART) in these patients. Methods-We conducted an open-label randomized controlled trial in Durban, South Africa to determine optimal timing of ART initiation in relation to TB treatment. Acid-fast bacilli (AFB) smear positive tuberculosis patients with HIV infection and CD4+ counts <500 cells/mm 3 (n=642) were randomized to one of two integrated treatment arms (ART initiation during tuberculosis treatment) or to a sequential treatment arm (ART initiation upon tuberculosis treatment completion). Participants received standard tuberculosis therapy, cotrimoxazole prophylaxis and once daily didanosine, lamivudine and efavirenz ART regimen. The primary endpoint was allcause mortality.

Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial. Two major vaginal bacterial community types-one dominated by (59.2%) and the other where predominated with other anaerobic bacteria (40.8%)-were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61% ( = 0.013) in dominant women but only 18% ( = 0.644) in women with non- bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non- women, negatively correlating with and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism.

Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful1-3, a minority of individuals naturally develop these antibodies after many years of infection4-7. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly underrepresented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.

Background We previously reported that integrating antiretroviral therapy (ART) with tuberculosis treatment reduces mortality. However, optimal time to initiate ART during tuberculosis treatment remains contentious. Methods To address this, we conducted a 3-arm, open-label randomized controlled trial in South Africa in acid-fast bacilli smear positive patients (n=642) with HIV and CD4+ counts <500 cells/mm3. Findings on the early therapy group (ART initiated within 4 weeks of tuberculosis treatment initiation, n=214) and late therapy group (ART initiated within the first 4 weeks of the continuation phase of tuberculosis treatment, n=215) are presented here. Results Median CD4+ count and viral load at baseline was 150 cells/mm3 and 161000 copies/ml, being similar in both groups. Incidence rate of AIDS or death was 6.9 (18/259.4) and 7.8 (19/244.2) per 100 person-years in the early and late therapy groups respectively (Incidence Rate Ratio (IRR)=0.89; 95%Confidence Interval (95%CI): 0.44,1.79; P=0.73). However, in patients with CD4+ counts <50 cells/mm3, the incidence rates of AIDS or death were 8.5 (early) and 26.3 (late) per 100 person-years (IRR=0.32; 95%CI: 0.07,1.13; P=0.06). Immune reconstitution inflammatory syndrome (IRIS) incidence rates were 20.2 (early) and 7.7 (late) per 100 person-years (IRR=2.62; 95%CI: 1.48,4.82; P<0.001). Adverse events requiring antiretroviral drug switches occurred in 10 (early) and 1 (late) patients (P=0.006). Conclusions The benefits of AIDS-free survival balanced against the risks of IRIS and ART-related adverse events, support early ART initiation in patients with CD4+ counts <50 cells/mm3 and deferred ART initiation to the continuation phase of tuberculosis treatment when CD4+ counts are higher.

ObjectivesTo 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 FindingsBetween 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/SignificanceChallenges 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.