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Abstract:Several safe and effective COVID-19 vaccines were developed, evaluated, and made available in record time during the pandemic. But hopes of equitable access to COVID-19 vaccines were dashed by corporate greed, political expediency, global trade agreements, and intellectual property ownership, delaying or denying access for poor countries. Once vaccines became widely available, their benefits were curtailed by anti-science sentiment and anti-vaccine conspiracy theories. Building trust in science is key to preparing for the next pandemic.

Several clinical trials have demonstrated that antiretroviral (ARV) drugs taken as pre-exposure prophylaxis (PrEP) can prevent HIV infection, with the magnitude of protection ranging from −49 to 86% (refs. ). Although these divergent outcomes are thought to be due primarily to differences in product adherence, biological factors likely contribute. Despite selective recruitment of higher-risk participants for prevention trials, HIV risk is heterogeneous even within higher-risk groups. To determine whether this heterogeneity could influence patient outcomes following PrEP, we undertook a post hoc prospective analysis of results from the CAPRISA 004 trial for 1% tenofovir gel (n = 774 patients), one of the first trials to demonstrate protection against HIV infection. Concentrations of nine proinflammatory cytokines were measured in cervicovaginal lavages at >2,000 visits, and a graduated cytokine score was used to define genital inflammation. In women without genital inflammation, tenofovir was 57% protective against HIV (95% confidence interval (CI): 7–80%) but was 3% protective (95% CI: −104–54%) if genital inflammation was present. Among women who highly adhered to the gel, tenofovir protection was 75% (95% CI: 25–92%) in women without inflammation compared to −10% (95% CI: −184–57%) in women with inflammation. Immunological predictors of HIV risk may modify the effectiveness of tools for HIV prevention; reducing genital inflammation in women may augment HIV prevention efforts.

Background We assessed whether women who acquired HIV during tenofovir gel prophylaxis trials can be safely and effectively treated with tenofovir-containing anti-retroviral therapy (ART).Methods Between May 2011 and October 2014, HIV seroconvertors from two tenofovir gel trials were recruited when eligible for ART (CD4+T-cell count <350 cells/ml, pregnancy or AIDS-defining illness). Women were randomized to tenofovir-containing (tenofovir + lamivudine/emtricitabine + efavirenz) or tenofovir-sparing (zidovudine + lamivudine/emtricitabine + efavirenz) antiretroviral treatment regimens. The proportion with virological suppression, adverse events and drug switches were compared.Results Fifty-nine women were enrolled and followed-up for median 18 months (IQR 6–24). Twenty-nine women (7 tenofovir gel exposed, 22 tenofovir gel unexposed) were randomized to a tenofovir-containing and 30 (9 tenofovir gel exposed, 21 tenofovir gel unexposed) to a tenofovir-sparing regimen. Median baseline CD4+T-cell count and viral load (VL) were 345 cells/ml (IQR 280–423) and 4.5 log copies/ml (sd0.79), and did not differ by ART assignment. Overall VL suppression rates were 88.0% and 78.3% at 6 months (P=0.454) and 85.7% and 79.0% at 12 months (P=0.689) in women on the tenofovir-containing and tenofovir-sparing regimens, respectively. Toxicity-related drug switches were more frequent in women on the tenofovir-sparing than tenofovir-containing regimen (36.7% versus 0.0%, P<0.001).Conclusions Preliminary data show that tenofovir-containing ART was effective and more tolerable in HIV seroconvertors from tenofovir gel prophylaxis trials and may be considered for use in women with prior tenofovir gel exposure. Clinical trials.gov NCT01387022.

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.

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Background: A provider-initiated counselling and testing (PICT) strategy replaced the voluntary counselling and testing (VCT) strategy with respect to the provision of human immunodeficiency virus (HIV) counselling and testing (HCT) in KwaZulu-Natal province with the aim of increasing the uptake of HIV services. VCT depended on clients requesting HCT, whereas HCT is routinely offered to all persons utilising health facilities, regardless of the reason for the visit with the provision of PICT. This study reports on the feasibility and early outcomes of using the PICT strategy in KwaZulu-Natal.Method: Health workers were trained to provide PICT to patients presenting at the outpatient department (OPD) of two public health institutions in KwaZulu-Natal from December 2010 to May 2011. Data on the offering and uptake of HIV services were recorded and analysed using univariate and multivariate analysis to compare HCT uptake and other systematic barriers before and after the introduction of PICT.Results: A significant change in the uptake of HCT after the introduction of PICT at both sites (p = 0.242 and p = 0.224) and in the uptake of HIV testing (p = 0.062 and p = 0.224) was not observed. PICT offering was weakest at the OPDs (p< 0.001), and was solely provided by counsellors (85.5%). Few (29.2%) clients were screened for tuberculosis. Immunological and clinical staging was performed on 29.8% and 1.0% of HIV-positive patients, respectively. The linkage to prevention services was low with 12.2% of clients referred for further care.Conclusion: PICT implementation and integration with other services faces human resource, infrastructural and conceptual barriers, and is not currently feasible at OPDs. The urgent provision of operational guidance and training for providers is needed.

Background Tenofovir gel, used vaginally before and after coitus, reduced women's acquisition of HIV by 39%. This is a safety assessment of tenofovir gel, including renal, bone, gastrointestinal, genital and haematological parameters.Methods In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, a double-blind, randomized placebo-controlled trial, 445 of the 889 eligibly enrolled women were assigned to tenofovir gel. All participants were advised to use the gel vaginally only, with one dose of gel within 12 h before and a second dose as soon as possible after sex, with no more than two doses in 24 h. Clinical and laboratory safety data were collected at monthly and quarterly visits, respectively. Genital assessments were undertaken at enrolment and quarterly thereafter, or as indicated.Results Women assigned to tenofovir gel were exposed to an average monthly vaginal dose of 240 mg of tenofovir (six applications). In total, six women, three in each group, had mild creatinine elevations, all of which occurred in July/ August 2008. The incidence of anaemia was 3.5 and 3.8 per 100 women-years in tenofovir and placebo groups, respectively (P=0.80). Of the six women (four tenofovir and two placebo) experiencing bone fractures, none were associated with abnormal phosphate or calcium values. The proportion of women with diarrhoea was higher in the tenofovir gel group (17% versus 11%; P=0.026). There was no significant increase of any genital adverse event in the tenofovir group.Conclusions No significant renal, haematological, genital or bone effects were associated with the use of tenofovir gel. Aside from a puzzling increase in diarrhoea, tenofovir gel has an excellent safety profile.

The HIV Prevention Trials Network (HPTN) is supported by the NIH to conduct randomized clinical trials to assess the efficacy of HIV prevention strategies and technologies to reduce HIV transmission between adults. A special focus of attention is on the use of antiretroviral drugs to prevent HIV transmission, both by reducing infectiousness among HIV-uninfected persons taking combination antiretroviral therapy (cART) and also by reducing susceptibility among HIV-infected persons taking antiretrovirals for pre-exposure prophylaxis. Studies may be developmental in nature to assess novel ideas for interventions or for assessing trial feasibility. However, pivotal efficacy trials to test HIV-specific prevention strategies and technologies are the main HPTN priority. Examples include a major protocol investigating the impact of expanded testing and linkage to care on HIV surveillance indicators in the USA (HPTN 065). Another protocol is addressing similar issues while also investigating how combinations of prevention approaches are best deployed to make a community-level impact in southern Africa (HPTN 071). HPTN 068 is evaluating a novel conditional cash transfer structural intervention to increase school completion rates in young girls and thereby reduce their HIV risk. Studies outside the US address the epidemic in most at-risk populations and include an assessment of opiate agonist therapy to reduce risk of HIV seroconversion among injection drug users (HTPN 058), methods to increase HIV testing rates (HTPN 043), as well as methods for reducing high-risk behaviors, and increasing adherence to cART in HIV-infected individuals (HPTN 062 and HPTN 063, respectively). The recent HPTN 052 study demonstrated that a 96% reduction in HIV transmission could be achieved between serodiscordant sexual partners by providing the infected partners with cART at a CD4+cell count (350–550/µl) above the level that would usually qualify them for therapy in low- and middle-income countries. The immediate relevance to public health policy showcased in these trials is a paradigm for the HPTN: design and conduct of clinical trials using available licensed tools that can be rapidly translated for implementation (‘Prevention NOW!’).

Introduction:Integrating HIV and tuberculosis (TB) treatment can reduce mortality substantially. Practical barriers to treatment integration still exist and include safety concerns related to concomitant drug use because of drug interactions and additive toxicities. Altered therapeutic concentrations may influence the chances of treatment success or toxicity.Areas covered:The available data on drug––drug interactions between the rifamycin class of anti-mycobacterials and the non-nucleoside reverse transcriptase inhibitor and the protease inhibitor classes of antiretrovirals are discussed with recommendations for integrated use. Additive drug toxicities, the impact of immune reconstitution inflammatory syndrome (IRIS) and the latest data on survival benefits of integrating treatment are elucidated.Expert opinion:Deferring treatment of HIV to avoid drug interactions with TB treatment or the occurrence of IRIS is not necessary. In the integrated management of TB––HIV co-infection, rational drug combinations aimed at reducing toxicities while effecting TB cure and suppressing HIV viral load are possible.

The first part of this paper provides a brief overview of the global situation, the second will describe several scenarios that capture the key features of the emerging epidemics, and the third will present the specific challenges that these scenarios pose to us in terms of preventing the further spread of HIV.