HIV epidemiology, prevention, treatment, and implementation strategies for public health.

The global HIV response has made tremendous progress but is entering a new phase with additional challenges. Scientific innovations have led to multiple safe, effective, and durable options for treatment and prevention, and long-acting formulations for 2-monthly and 6-monthly dosing are becoming available with even longer dosing intervals possible on the horizon. The scientific agenda for HIV cure and remission strategies is moving forward but faces uncertain thresholds for success and acceptability. Nonetheless, innovations in prevention and treatment have often failed to reach large segments of the global population (eg, key and marginalised populations), and these major disparities in access and uptake at multiple levels have caused progress to fall short of their potential to affect public health. Moving forward, sharper epidemiologic tools based on longitudinal, person-centred data are needed to more accurately characterise remaining gaps and guide continued progress against the HIV epidemic. We should also increase prioritisation of strategies that address socio-behavioural challenges and can lead to effective and equitable implementation of existing interventions with high levels of quality that better match individual needs. We review HIV epidemiologic trends; advances in HIV prevention, treatment, and care delivery; and discuss emerging challenges for ending the HIV epidemic over the next decade that are relevant for general practitioners and others involved in HIV care.

Implementation preferences for the management of sexually transmitted infections in the South African health system: a discrete choice experiment.

OBJECTIVES: Despite strengthening HIV prevention with the introduction of pre-exposure prophylaxis (PrEP), STI services have remained relatively unchanged and the standard of care remains syndromic management. We used a discrete choice experiment to investigate service users' preferences for the diagnosis and treatment of STIs in South Africa. METHODS: Between 1 March 2021 and 20 April 2021, a cross-sectional online questionnaire hosted on REDCap was administered through access links sent to WhatsApp support groups for HIV PrEP users and attendees of two primary healthcare clinics and two mobile facilities in the Eastern Cape and Gauteng provinces aged between 18 and 49 years. Participants either self-completed the questionnaire or received support from a research assistant. We used a conditional logit model for the initial analysis and latent class model (LCM) to establish class memberships, with results displayed as ORs and probabilities. RESULTS: We enrolled 496 individuals; the majority were female (69%) and <30 years (74%). The LCM showed two distinct groups. The first group, comprising 68% of the participants, showed a strong preference for self-sampling compared with no sampling (OR 2.16, 95% CI 1.62 to 2.88). A clinic follow-up appointment for treatment was less preferable to same-day treatment (OR 0.78, 95% CI 0.63 to 0.95). Contact slip from index patient (OR 0.86, 95% CI 0.76 to 0.96) and healthcare professional (HCP)-initiated partner notification (OR 0.63, 95% CI 0.55 to 0.73) were both less preferable than expedited partner treatment (EPT). The second group included 32% of participants with a lower preference for self-sampling compared with no sampling (OR 0.65, 95% CI 0.41 to 1.04). There was no treatment option that was significantly different from the others; however, there was a strong preference for HCP-initiated partner notification to EPT (OR 1.53, 95% CI 1.10 to 2.12). CONCLUSIONS: Our results suggest that service users preferred STI testing prior to treatment, with the majority preferring self-taken samples and receiving aetiology-based treatment on the same day.

The viral load monitoring cascade in HIV treatment programmes in sub-Saharan Africa: a systematic review.

BACKGROUND: The United Nations' 95-95-95 (95% of people with HIV being aware of their diagnosis, 95% of those aware of their diagnosis being on treatment and 95% achieving viral suppression) target aims to reduce morbidity and mortality of HIV. However, with 60% of new HIV infections occurring in sub-Saharan Africa (SSA), achieving this target in the region is challenging. Viral load (VL) monitoring is the gold-standard approach of assessing treatment efficacy, and its implementation into national health systems is a global health priority if elimination of HIV as a public health threat is to be achieved by 2030. This systematic review aims to investigate VL monitoring outcomes in SSA, and to identify gaps and possible interventions to help nations meet their 2030 targets. METHODS: A literature search of three electronic platforms (MEDLINE, EMBASE and Global Health) was undertaken from 1 January to 9 August 2024 to identify studies published in English and conducted in SSA. The primary outcome was the proportion of people living with HIV (PLHIV) on antiretroviral therapy (ART) with routine VL monitoring at the recommended time points (initially, 6 months, 12 months and annually). Secondary outcomes reported proportions of PLHIV who received routine VL monitoring who went on to complete the cascade of care after identified virological failure [enhanced adherence counselling (EAC), switch to second-line ART, and finally viral suppression]. RESULTS: The initial search identified 342 papers, of which 35 studies were included for narrative synthesis. Included studies reported on findings from 14 African countries and demonstrated extensive variation in rates of VL monitoring (range: 24.3-99.7%, mean: 63.8%). Results were more unfavourable in the latter steps of the viral load monitoring cascade, with a range of 0-88%, and a switch to second-line ART mean of 42% (range: 4.4-93%). Studies with additional support, and those with community-based models of care, had higher rates of VL testing and viral suppression. CONCLUSIONS: VL monitoring and management of virological failure are suboptimal in many SSA countries due to individual and health system-related challenges. Health system strengthening is vital to ensure the sustainability of HIV treatment programmes and the achievement of 95-95-95 targets by 2030.

Associations of inter-annual rainfall decreases with subsequent HIV outcomes for persons with HIV on antiretroviral therapy in Southern Africa: a collaborative analysis of cohort studies.

BACKGROUND: Periods of droughts can lead to decreased food security, and altered behaviours, potentially affecting outcomes on antiretroviral therapy (ART) among persons with HIV (PWH). We investigated whether decreased rainfall is associated with adverse outcomes among PWH on ART in Southern Africa. METHODS: Data were combined from 11 clinical cohorts of PWH in Lesotho, Malawi, Mozambique, South Africa, Zambia, and Zimbabwe, participating in the International epidemiology Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration. Adult PWH who had started ART prior to 01/06/2016 and were in follow-up in the year prior to 01/06/2016 were included. Two-year rainfall from June 2014 to May 2016 at the location of each HIV centre was summed and ranked against historical 2-year rainfall amounts (1981-2016) to give an empirical relative percentile rainfall estimate. The IeDEA-SA and rainfall data were combined using each HIV centre's latitude/longitude. In individual-level analyses, multivariable Cox or generalized estimating equation regression models (GEEs) assessed associations between decreased rainfall versus historical levels and four separate outcomes (mortality, CD4 counts < 200 cells/mm3, viral loads > 400 copies/mL, and > 12-month gaps in follow-up) in the two years following the rainfall period. GEEs were used to investigate the association between relative rainfall and monthly numbers of unique visitors per HIV centre. RESULTS: Among 270,708 PWH across 386 HIV centres (67% female, median age 39 [IQR: 32-46]), lower rainfall than usual was associated with higher mortality (adjusted Hazard Ratio: 1.18 [95%CI: 1.07-1.32] per 10 percentile rainfall rank decrease) and unsuppressed viral loads (adjusted Odds Ratio: 1.05 [1.01-1.09]). Levels of rainfall were not strongly associated with CD4 counts < 200 cell/mm3 or > 12-month gaps in care. HIV centres in areas with less rainfall than usual had lower numbers of PWH visiting them (adjusted Rate Ratio: 0.80 [0.66-0.98] per 10 percentile rainfall rank decrease). CONCLUSIONS: Decreased rainfall could negatively impact on HIV treatment behaviours and outcomes. Further research is needed to explore the reasons for these effects. Interventions to mitigate the health impact of severe weather events are required.

CD4+ T-Cell Count at Antiretroviral Therapy Initiation in the "Treat-All" Era in Rural South Africa: An Interrupted Time Series Analysis.

BACKGROUND: South Africa implemented universal test and treat (UTT) in September 2016 in an effort to encourage earlier initiation of antiretroviral therapy (ART). METHODS: We therefore conducted an interrupted time series (ITS) analysis to assess the impact of UTT on mean CD4 count at ART initiation among adults aged ≥16 years attending 17 public sector primary care clinics in rural South Africa, between July 2014 and March 2019. RESULTS: Among 20 599 individuals (69% women), CD4 counts were available for 74%. Mean CD4 at ART initiation increased from 317.1 cells/µL (95% confidence interval [CI], 308.6 to 325.6) 1 to 8 months prior to UTT to 421.0 cells/µL (95% CI, 413.0 to 429.0) 1 to 12 months after UTT, including an immediate increase of 124.2 cells/µL (95% CI, 102.2 to 146.1). However, mean CD4 count subsequently fell to 389.5 cells/µL (95% CI, 381.8 to 397.1) 13 to 30 months after UTT but remained above pre-UTT levels. Men initiated ART at lower CD4 counts than women (-118.2 cells/µL, 95% CI, -125.5 to -111.0) throughout the study. CONCLUSIONS: Although UTT led to an immediate increase in CD4 count at ART initiation in this rural community, the long-term effects were modest. More efforts are needed to increase initiation of ART early in those living with human immunodeficiency virus, particularly men.

A systematic review of antimicrobial resistance in Neisseria gonorrhoeae and Mycoplasma genitalium in sub-Saharan Africa.

OBJECTIVES: Limited antimicrobial resistance (AMR) surveillance coupled with syndromic management of sexually transmitted infections (STIs) in sub-Saharan Africa (SSA) could be contributing to an increase in AMR in the region. This systematic review aimed to synthesize data on the prevalence of AMR in common STIs in SSA and identify some research gaps that exist. METHODS: We searched three electronic databases for studies published between 1 January 2000 and 26 May 2020. We screened the titles and abstracts for studies that potentially contained data on AMR in SSA. Then we reviewed the full text of these studies to identify articles that reported data on the prevalence of AMR in Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and Mycoplasma genitalium in SSA. We summarized the data using a narrative synthesis. RESULTS: The 40 included studies reported on AMR data from 7961 N. gonorrhoeae isolates from 15 countries in SSA and 350 M. genitalium specimens from South Africa. All four SSA regions reported very high rates of ciprofloxacin, tetracycline and penicillin resistance in N. gonorrhoeae. Resistance to cefixime or ceftriaxone was observed in all regions except West Africa. Azithromycin resistance, recommended as part of dual therapy with an extended-spectrum cephalosporin for gonorrhoea, was reported in all the regions. Both macrolide and fluoroquinolone-associated resistance were reported in M. genitalium in South Africa. Studies investigating AMR in C. trachomatis and T. vaginalis were not identified. CONCLUSIONS: There is a need to strengthen AMR surveillance in SSA for prompt investigation and notification of drug resistance in STIs.

Early HIV treatment and survival over six years of observation in the ANRS 12249 Treatment as Prevention Trial.

OBJECTIVES: Population-based universal test and treat (UTT) trials have shown an impact on population-level virological suppression. We followed the ANRS 12249 TasP trial population for 6 years to determine whether the intervention had longer-term survival benefits. METHODS: The TasP trial was a cluster-randomized trial in South Africa from 2012 to 2016. All households were offered 6-monthly home-based HIV testing. Immediate antiretroviral therapy (ART) was offered through trial clinics to all people living with HIV (PLHIV) in intervention clusters and according to national guidelines in control clusters. After the trial, individuals attending the trial clinics were transferred to the public ART programme. Deaths were ascertained through annual demographic surveillance. Random-effects Poisson regression was used to estimate the effect of trial arm on mortality among (i) all PLHIV; (ii) PLHIV aware of their status and not on ART at trial entry; and (iii) PHLIV who started ART during the trial. RESULTS: Mortality rates among PLHIV were 9.3/1000 and 10.4/1000 person-years in the control and intervention arms, respectively. There was no evidence that the intervention decreased mortality among all PLHIV [adjusted rate ratio (aRR) = 1.10, 95% confidence interval (CI) = 0.85-1.43, p = 0.46] or among PLHIV who were aware of their status but not on ART. Among individuals who initiated ART, the intervention decreased mortality during the trial (aRR = 0.49, 95% CI = 0.28-0.85, p = 0.01), but not after the trial ended. CONCLUSIONS: The 'treat all' strategy reduced mortality among individuals who started ART but not among all PLHIV. To achieve maximum benefit of immediate ART, barriers to ART uptake and retention in care need to be addressed.

How long should clinicians spend sampling the pharynx for gonorrhoea culture specimens?

There are few data on the length of time clinicians should take sampling the pharynx to optimise the sensitivity of gonorrhoea culture specimens and we aimed to gain a consensus on sampling time. The estimated mean time clinicians reported that they spent sampling the pharynx for gonorrhoea culture specimens was 4.63 s (s.d.±2.04). There was no significant difference in sampling times between clinicians who had worked in sexual health for over and under 10 years, (4.7 (s.d.±2.02) vs 4.6 (s.d.±2.3); P =0.45). We are now using these findings to design an educational tool with the aim of improving pharyngeal gonorrhoea culture sensitivity.

Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor-Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis.

BACKGROUND: Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC). METHODS: We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR). RESULTS: Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR. CONCLUSIONS: This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization's recommendation to avoid using NNRTIs in countries where levels of PDR are high.

Early ART Initiation Improves HIV Status Disclosure and Social Support in People Living with HIV, Linked to Care Within a Universal Test and Treat Program in Rural South Africa (ANRS 12249 TasP Trial).

We investigated the effect of early antiretroviral treatment (ART) initiation on HIV status disclosure and social support in a cluster-randomized, treatment-as-prevention (TasP) trial in rural South Africa. Individuals identified HIV-positive after home-based testing were referred to trial clinics where they were invited to initiate ART immediately irrespective of CD4 count (intervention arm) or following national guidelines (control arm). We used Poisson mixed effects models to assess the independent effects of (a) time since baseline clinical visit, (b) trial arm, and (c) ART initiation on HIV disclosure (n = 182) and social support (n = 152) among participants with a CD4 count > 500 cells/mm3 at baseline. Disclosure and social support significantly improved over follow-up in both arms. Disclosure was higher (incidence rate ratio [95% confidence interval]: 1.24 [1.04; 1.48]), and social support increased faster (1.22 [1.02; 1.46]) in the intervention arm than in the control arm. ART initiation improved both disclosure and social support (1.50 [1.28; 1.75] and 1.34 [1.12; 1.61], respectively), a stronger effect being seen in the intervention arm for social support (1.50 [1.12; 2.01]). Besides clinical benefits, early ART initiation may also improve psychosocial outcomes. This should further encourage countries to implement universal test-and-treat strategies.

Optimised electronic patient records to improve clinical monitoring of HIV-positive patients in rural South Africa (MONART trial): study protocol for a cluster-randomised trial.

BACKGROUND: There is poor viral load monitoring (VLM) and inadequate management of virological failure in HIV-positive individuals on antiretroviral therapy in rural KwaZulu-Natal, South Africa. This could be contributing to increasing HIV drug resistance in the setting. This study aims to investigate the clinical and process impediments in VLM within the health system and to evaluate a quality improvement package (QIP) to address the identified gaps. The QIP comprises (i) a designated viral load champion responsible for administrative management and triaging of viral load results (ii) technological enhancement of the routine clinic-based Three Interlinked Electronic Register (TIER.Net) to facilitate daily automatic import of viral load results from the National Health Service Laboratory to TIER.Net (iii) development of a dashboard system to support VLM. METHODS/DESIGN: The study will evaluate the effectiveness of the QIP compared to current care for improving VLM and virological suppression using an effectiveness implementation hybrid type 3 design. This will use a cluster-randomised design with the primary healthcare clinics as the unit of randomisation with ten clinics randomised in a 1:1 ratio to either the intervention or control arm. We will enrol 150 HIV-positive individuals who had been on ART for ≥ 12 months from each of the ten clinics (750 in 5 intervention clinics vs. 750 in 5 control clinics) and follow them up for a period of 12 months. The primary outcome is the proportion of all patients who have a viral load (VL) measurement and are virally suppressed (composite outcome) after 12 months of follow up. Secondary outcomes during follow up include proportion of all patients with at least one documented VL in TIER.Net, proportion with VL ≥ 50 copies/mL, proportion with VL ≥ 1000 copies/mL (virological failure) and subsequent switch to second-line ART. DISCUSSION: We aim to provide evidence that a staff-centred quality improvement package, designated viral load monitoring champion, and augmentation of TIER.Net with a dashboard system will improve viral load monitoring and lead to improved virological suppression. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov on 8 Oct 2021. Identifier: NCT05071573; https://clinicaltrials.gov/ct2/show/NCT05071573?term=NCT05071573&draw=2&rank=1.

Investigation of post-trial access views among study participants and stakeholders using photovoice and semistructured interviews.

PURPOSE: We examine the levels of post-trial responsibility ascribed to different stakeholders, following a community-based clinical trial and how the 'responsibility' is understood. METHODS: We employed photovoice, unstructured observations and key informant interviews to gain insights into contexts of access to care following transition to the public health system post trial. We used an inductive narrative analysis to explore experiences and understandings of post-trial access (PTA). RESULTS: In their photovoice stories, many participants expressed a sense of abandonment after the trial. This was viewed as a contributing factor to failing to re-engage with care available in the public health system. This led to the experiences of loss as some trial participants defaulted and died. Research investigators, department of health participants and sponsor agreed that PTA was especially important for communities in resource-limited settings. The government has an obligation towards its citizens while researchers have a responsibility to ensure a smooth transition of patients to public clinics. Sponsors have a responsibility to ensure that the trial is conducted in accordance with the protocol and post-trial agreements are in place and adhered to. Research partnerships among stakeholders were affected by power imbalances making it difficult to negotiate and plan for post-trial care responsibilities. CONCLUSIONS: The research community still struggles with understanding the scope of PTA responsibilities. Power dynamics between public health actors and research sponsors need to be managed to ensure that government involvement is not tokenistic. The responsibility of trial participants and ethics committees needs to be investigated further.

Opportunities and Challenges in HIV Treatment as Prevention Research: Results from the ANRS 12249 Cluster-Randomized Trial and Associated Population Cohort.

PURPOSE OF REVIEW: The ANRS 12249 treatment as prevention (TasP) trial investigated the impact of a universal test and treat (UTT) approach on reducing HIV incidence in one of the regions of the world most severely affected by the HIV epidemic-KwaZulu-Natal, South Africa. We summarize key findings from this trial as well as recent findings from controlled studies conducted in the linked population cohort quantifying the long-term effects of expanding ART on directly measured HIV incidence (2004-2017). RECENT FINDINGS: The ANRS TasP trial did not-and could not-demonstrate a reduction in HIV incidence, because the offer of UTT in the intervention communities did not increase ART coverage and population viral suppression compared to the standard of care in the control communities. Ten controlled studies from the linked population cohort-including several quasi-experimental study designs-exploit heterogeneity in ART exposure to show a consistent and substantial impact of expanding provision of ART and population viral suppression on reduction in HIV incidence at the couple, household, community, and population levels. In this setting, all of the evidence from large, population-based studies (inclusive of the ANRS TasP trial) is remarkably coherent and consistent-i.e., higher ART coverage and population viral suppression were repeatedly associated with clear, measurable decreases in HIV incidence. Thus, the expanded provision of ART has plausibly contributed in a major way toward the dramatic 43% decline in population-level HIV incidence in this typical rural African population. The outcome of the ANRS TasP trial constitutes a powerful null finding with important insights for overcoming implementation challenges in the population delivery of ART. This finding does not imply lack of ART effectiveness in blocking onward transmission of HIV nor its inability to reduce HIV incidence. Rather, it demonstrates that large increases in ART coverage over current levels will require health systems innovations to attract people living with HIV in early stages of the disease to participate in HIV treatment. Such innovations and new approaches are required for the true potential of UTT to be realized.

A phase IV randomised, open-label pilot study to evaluate switching from protease-inhibitor based regimen to Bictegravir/Emtricitabine/Tenofovir Alafenamide single tablet regimen in Integrase inhibitor-naïve, virologically suppressed HIV-1 infected adults harbouring drug resistance mutations (PIBIK study): study protocol for a randomised trial.

BACKGROUND: Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC). METHODS/DESIGN: A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures. DISCUSSION: We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations. TRIAL REGISTRATION: ISRCTN 44453201 , registered 19 June 2019 and EudraCT 2018-004732-30.

Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial.

BACKGROUND: Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. METHODS: Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. RESULTS: PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91-2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12-0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82-1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. CONCLUSIONS: NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. CLINICAL TRIALS TEGISTRATION: NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974.

Predicted antiviral activity of tenofovir versus abacavir in combination with a cytosine analogue and the integrase inhibitor dolutegravir in HIV-1-infected South African patients initiating or failing first-line ART.

Objectives: The WHO recently recommended the use of a new first-line ART containing dolutegravir. We investigated the efficacy of NRTI backbones (tenofovir or abacavir with a cytosine analogue) in low- and middle-income countries where there is significant prior exposure to antiretrovirals and drug resistance to NRTIs. Methods: Within the treatment-as-prevention study in South Africa, we selected participants with available next-generation sequencing (NGS) data for the HIV-1 pol gene at trial entry; they were either ART initiators (n = 1193) or already established on ART (n = 94). NGS of the HIV-1 pol gene was carried out using MiSeq technology; reverse transcriptase drug resistance mutations (DRMs) were detected at 5% (DRM5%) and 20% (DRM20%) for all 1287 participants. Genotypic susceptibility was assessed using the Stanford HIVDB resistance interpretation algorithm. Results: NRTI DRM20% and DRM5% were detected among 5/1193 (0.4%) and 9/1193 (0.8%) of ART initiators, respectively. There was tenofovir exposure in 73/94 (77.7%) of those established on ART, with full susceptibility to abacavir in 57/94 (60.6%) and 56/94 (59.6%) for DRM20% and DRM5%, respectively, while 67/94 (71.3%) and 64/94 (68.1%) were fully susceptible to tenofovir, respectively. The differences between tenofovir and abacavir were not statistically significant at the 20% or 5% variant level (P = 0.16 and 0.29, respectively). NGS detection of variants at the 5% level increased detection of K65R in both naive and treated groups. One of 607 integrase sequences carried a DRM20% (Q148R). Conclusions: Dolutegravir with a cytosine analogue plus tenofovir or abacavir appears to have similar efficacy in South Africans naive to ART. NGS should be considered in HIV drug resistance surveillance.

Virological Outcomes of Second-line Protease Inhibitor-Based Treatment for Human Immunodeficiency Virus Type 1 in a High-Prevalence Rural South African Setting: A Competing-Risks Prospective Cohort Analysis.

Background: Second-line antiretroviral therapy (ART) based on ritonavir-boosted protease inhibitors (bPIs) represents the only available option after first-line failure for the majority of individuals living with human immunodeficiency virus (HIV) worldwide. Maximizing their effectiveness is imperative. Methods: This cohort study was nested within the French National Agency for AIDS and Viral Hepatitis Research (ANRS) 12249 Treatment as Prevention (TasP) cluster-randomized trial in rural KwaZulu-Natal, South Africa. We prospectively investigated risk factors for virological failure (VF) of bPI-based ART in the combined study arms. VF was defined by a plasma viral load >1000 copies/mL ≥6 months after initiating bPI-based ART. Cumulative incidence of VF was estimated and competing risk regression was used to derive the subdistribution hazard ratio (SHR) of the associations between VF and patient clinical and demographic factors, taking into account death and loss to follow-up. Results: One hundred one participants contributed 178.7 person-years of follow-up. Sixty-five percent were female; the median age was 37.4 years. Second-line ART regimens were based on ritonavir-boosted lopinavir, combined with zidovudine or tenofovir plus lamivudine or emtricitabine. The incidence of VF on second-line ART was 12.9 per 100 person-years (n = 23), and prevalence of VF at censoring was 17.8%. Thirteen of these 23 (56.5%) virologic failures resuppressed after a median of 8.0 months (interquartile range, 2.8-16.8 months) in this setting where viral load monitoring was available. Tuberculosis treatment was associated with VF (SHR, 11.50 [95% confidence interval, 3.92-33.74]; P < .001). Conclusions: Second-line VF was frequent in this setting. Resuppression occurred in more than half of failures, highlighting the value of viral load monitoring of second-line ART. Tuberculosis was associated with VF; therefore, novel approaches to optimize the effectiveness of PI-based ART in high-tuberculosis-burden settings are needed. Clinical Trials Registration: NCT01509508.

Towards control of the global HIV epidemic: Addressing the middle-90 challenge in the UNAIDS 90-90-90 target.

In a Perspective, Collins Iwuji and Marie-Louise Newell discuss early findings from Richard Hayes and colleagues' PopART study on HIV testing and treatment.

Antiretroviral Therapy to Prevent HIV Acquisition in Serodiscordant Couples in a Hyperendemic Community in Rural South Africa.

BACKGROUND: Antiretroviral therapy (ART) was highly efficacious in preventing human immunodeficiency virus (HIV) transmission in stable serodiscordant couples in the HPTN-052 study, a resource-intensive randomized controlled trial with near-perfect ART adherence and mutual HIV status disclosure among all participating couples. However, minimal evidence exists of the effectiveness of ART in preventing HIV acquisition in stable serodiscordant couples in "real-life" population-based settings in hyperendemic communities of sub-Saharan Africa, where health systems are typically resource-poor and overburdened, adherence to ART is often low, and partners commonly do not disclose their HIV status to each other. METHODS: Data arose from a population-based open cohort in KwaZulu-Natal, South Africa. A total of 17 016 HIV-uninfected individuals present between January 2005 and December 2013 were included. Interval-censored time-updated proportional hazards regression was used to assess how the ART status affected HIV transmission risk in stable serodiscordant relationships. RESULTS: We observed 1619 HIV seroconversions in 17 016 individuals, over 60 349 person-years follow-up time. During the follow-up period, 1846 individuals had an HIV-uninfected and 196 had an HIV-infected stable partner HIV incidence was 3.8/100 person-years (PY) among individuals with an HIV-infected partner (95% confidence interval [CI], 2.3-5.6), 1.4/100 PY (.4-3.5) among those with HIV-infected partners receiving ART, and 5.6/100 PY (3.5-8.4) among those with HIV-infected partners not receiving ART. Use of ART was associated with a 77% decrease in HIV acquisition risk among serodiscordant couples (adjusted hazard ratio, 0.23; 95% CI, .07-.80). CONCLUSIONS: ART initiation was associated with a very large reduction in HIV acquisition in serodiscordant couples in rural KwaZulu-Natal. However, this "real-life" effect was substantially lower than the effect observed in the HPTN-052 trial. To eliminate HIV transmission in serodiscordant couples, additional prevention interventions are probably needed.