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The epidemic in South Africa is characterized by high genetic diversity driven by multiple independent introductions. The bulk of these introductions occurred between 1985-2000 during which time HIV prevalence increased exponentially. Epidemic growth has stabilized in recent years with the implementation of several interventions. Here we identified distinct HIV clades from a large sequence dataset of southern African HIV sequences (n = 15,332). Each clade was characterized using phylodynamic and phylogeographic methods to infer their growth through time and space. The estimated date of origin for the 18 clades that were found, fell between 1979-1992 with strong growth during the 1990's. Phylogeographic reconstruction revealed wide dispersal of clades throughout the country with the city of Johannesburg as the focal point of viral dispersal. We found clear signs of decreasing growth rate in four of the clades since the advent of interventions, while other clades have continued to growth and expand. Our results demonstrate that interventions do not affect the HIV epidemic universally with major difference between different clades over time and space. Here we demonstrate the utility and flexibility of molecular epidemiological methods and demonstrate how they can potentially be a powerful tool in HIV epidemic monitoring in South Africa.

Introduction: Novel point‐of‐care assays which measure urine tenofovir (TFV) concentrations may have a role in improving adherence monitoring for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). However, further studies of their diagnostic accuracy, and whether results are associated with viraemia and drug resistance, are needed to guide their use, particularly in the context of the global dolutegravir rollout. Methods: We conducted a cross‐sectional evaluation among PLHIV receiving first‐line ART containing tenofovir disoproxil fumarate at enrolment into a randomized trial in two South African public sector clinics. We calculated the diagnostic accuracy of the Abbott point‐of‐care immunoassay to detect urine TFV compared to liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). We evaluated the association between point‐of‐care urine TFV results and self‐reported adherence, viraemia ≥1000 copies/ml and HIV drug resistance, among people receiving either efavirenz or dolutegravir‐based ART. Results: Between August 2020 and March 2022, we enrolled 124 participants. The median age was 39 (IQR 34–45) years, 55% were women, 74 (59.7%) were receiving efavirenz and 50 (40.3%) dolutegravir. The sensitivity and specificity of the immunoassay to detect urine TFV ≥1500 ng/ml compared to LC‐MS/MS were 96.1% (95% CI 90.0−98.8) and 95.2% (75.3−100.0), respectively. Urine TFV results were associated with short (p<0.001) and medium‐term (p = 0.036) self‐reported adherence. Overall, 44/124 (35.5%) had viraemia, which was associated with undetectable TFV in those receiving efavirenz (OR 6.01, 1.27−39.0, p = 0.014) and dolutegravir (OR 25.7, 4.20−294.8, p<0.001). However, in those with viraemia while receiving efavirenz, 8/27 (29.6%) had undetectable urine TFV, compared to 11/17 (64.7%) of those receiving dolutegravir. Drug resistance was detected in 23/27 (85.2%) of those receiving efavirenz and only 1/16 (6.3%) of those receiving dolutegravir. There was no association between urine TFV results and drug resistance. Conclusions: Among PLHIV receiving ART, a rapid urine TFV immunoassay can be used to accurately monitor urine TFV levels compared to the gold standard of LC‐MS/MS. Undetectable point‐of‐care urine TFV results were associated with viraemia, particularly among people receiving dolutegravir. Trial registration: Pan‐African Clinical Trials Registry: PACTR202001785886049. [ABSTRACT FROM AUTHOR]

HIV drug resistance (HIVDR) can become a public health concern, especially in low- and middle-income countries where genotypic testing for people initiating antiretroviral therapy (ART) is not available. For first-line regimens to remain effective, levels of transmitted drug resistance (TDR) need to be monitored over time. To determine the temporal trends of TDR in Mozambique, a search for studies in PubMed and sequences in GenBank was performed. Only studies covering the pol region that described HIVDR and genetic diversity from treatment naïve patients were included. A dataset from seven published studies and one novel unpublished study conducted between 1999 and 2018 were included. The Calibrated Population Resistance tool (CPR) and REGA HIV-1 Subtyping Tool version 3 for sequences pooled by sampling year were used to determine resistance mutations and subtypes, respectively. The prevalence of HIVDR amongst treatment-naïve individuals increased over time, reaching 14.4% in 2018. The increase was most prominent for non-nucleoside reverse transcriptase inhibitors (NNRTIs), reaching 12.7% in 2018. Subtype C was predominant in all regions, but a higher genetic variability (19% non-subtype C) was observed in the north region of Mozambique. These findings confirm a higher diversity of HIV in the north of the country and an increased prevalence of NNRTI resistance among treatment naïve individuals over time. [ABSTRACT FROM AUTHOR]

Background: HIV self-testing (HIVST) is one of the recommended approaches for HIV testing services, particularly for helping reach populations who would not normally access facility-based HIV testing. Key stakeholder engagement is paramount in tailoring health interventions to ensure uptake by target populations. Objective: The main objective of this study was to collaborate with key stakeholder in the co-creation of an acceptable HIVST delivery strategies to help improve urban men's engagement with HIV services. Methods: We invited key stakeholders for urban men's HIV services to participate in a co-creation workshop aimed at developing HIVST delivery approaches for urban men, using eThekwini municipality as a study setting. We conducted purposive sampling to include health care users and health care providers, representing a range of views across the public sector and voluntary sector. We employed the nominal group technique (NGT) method for data collection. The NGT workshop was conducted in two consecutives: phase 1 was focused on determining barriers for men's engagement with the current/facility-based HIV testing services; phase 2 was aimed at determining HIVST delivery strategies. Results: Participants identified the following factors as the most important barriers to uptake of HIV testing services by urban men: stigma, ignorance about the importance of testing, and testing process as well as fear of positive test results. Key stakeholders suggested internal motivation strategies as a potentially effective approach to support HIVST delivery strategy. Guided by the NGT results, we designed a HIVST delivery strategy that is supported by a risk communication approach. Conclusion: The NGT enabled successful collaboration with key stakeholders in the co-creation of HIVST delivery strategies to guide implementation and strategy improve urban men's engagement with HIV services. A follow-up study to evaluate the feasibility of implementing these approaches is recommended. [ABSTRACT FROM AUTHOR]

Background: Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. Methods: We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. Results: From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7–96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1–97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3–97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). Conclusions: Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens. [ABSTRACT FROM AUTHOR]

Participatory visual research can offer critical insight into the experiences of those most affected by health issues. As these methods are increasingly used to research sensitive topics, there is a need for a clear ethical framework to guide best practice on the part of researchers and research ethics committees. Here we reflect on a project where we used digital storytelling as a participatory visual methodology to explore HIV treatment adherence in rural South Africa, with a focus on the ethical issues we encountered during the lifetime of the project. To ground our reflections, we use the framework for ethical research developed by Emanuel et al., and the adaptation of this framework for social science proposed by Wassenaar and Mamotte. We suggest that fellow PVM practitioners and REC members draw on this holistic framework to support the optimal application of PVM in health research. [ABSTRACT FROM AUTHOR]

Background We aimed to estimate the prevalence of and explore risk factors for Mycobacterium tuberculosis infection among adolescents in a high tuberculosis (TB) and human immunodeficiency virus (HIV) prevalence setting. Methods A cross-sectional study of adolescents (10–19 years) randomly selected from a demographic surveillance area (DSA) in rural KwaZulu-Natal, South Africa. We determined M tuberculosis infection status using the QuantiFERON-TB Gold-plus assay. We used HIV data from the DSA to estimate community-level adult HIV prevalence and random-effects logistic regression to identify risk factors for TB infection. Results We enrolled 1094 adolescents (548 [50.1%] female); M tuberculosis infection prevalence (weighted for nonresponse by age, sex, and urban/rural residence) was 23.0% (95% confidence interval [CI], 20.6–25.6%). Mycobacterium tuberculosis infection was associated with older age (adjusted odds ratio [aOR], 1.37; 95% CI, 1.10–1.71, for increasing age-group [12–14, 15–17, and 18–19 vs 10–11 years]), ever (vs never) having a household TB contact (aOR, 2.13; 95% CI, 1.25–3.64), and increasing community-level HIV prevalence (aOR, 1.43 and 95% CI, 1.07–1.92, for increasing HIV prevalence category [25%–34.9%, 35%–44.9%, ≥45% vs <25%]). Conclusions Our data support prioritizing TB prevention and care activities in TB-affected households and high HIV prevalence communities. [ABSTRACT FROM AUTHOR]

Objectives: To determine the impact of pretreatment low-abundance HIV-1 drug-resistant variants (LA-DRVs) on virological failure (VF) among HIV-1/TB-co-infected individuals treated with NNRTI first-line ART.Methods: We conducted a case-control study of 170 adults with HIV-1/TB co-infection. Cases had at least one viral load (VL) ≥1000 RNA copies/mL after ≥6 months on NNRTI-based ART, and controls had sustained VLs <1000 copies/mL. We sequenced plasma viruses by Sanger and MiSeq next-generation sequencing (NGS). We assessed drug resistance mutations (DRMs) using the Stanford drug resistance database, and analysed NGS data for DRMs at ≥20%, 10%, 5% and 2% thresholds. We assessed the effect of pretreatment drug resistance (PDR) on VF.Results: We analysed sequences from 45 cases and 125 controls. Overall prevalence of PDR detected at a ≥20% threshold was 4.7% (8/170) and was higher in cases than in controls (8.9% versus 3.2%), P = 0.210. Participants with PDR at ≥20% had almost 4-fold higher odds of VF (adjusted OR 3.7, 95% CI 0.8-18.3) compared with those without, P = 0.104. PDR prevalence increased to 18.2% (31/170) when LA-DRVs at ≥2% were included. Participants with pretreatment LA-DRVs only had 1.6-fold higher odds of VF (adjusted OR 1.6, 95% CI 0.6-4.3) compared with those without, P = 0.398.Conclusions: Pretreatment DRMs and LA-DRVs increased the odds of developing VF on NNRTI-based ART, although without statistical significance. NGS increased detection of DRMs but provided no additional benefit in identifying participants at risk of VF at lower thresholds. More studies assessing mutation thresholds predictive of VF are required to inform use of NGS in treatment decisions. [ABSTRACT FROM AUTHOR]

Objectives: Optimising medication adherence is one of the essential factors in reversing the tide of a TB-HIV syndemic in sub-Saharan Africa, especially South Africa. Impairment in key neurocognitive domains may impair patients' ability to maintain adherence to treatment, but the level of cognition and its relationship to HIV status has not been examined in individuals with drug-resistant TB. We therefore investigated performance on several key neurocognitive domains in relationship to HIV status in a multidrug-resistant tuberculosis patients (MDR-TB) sample.Methods: We enrolled microbiologically confirmed MDR-TB inpatients at a TB-specialist referral hospital in KwaZulu-Natal province, South Africa. We collected cross-sectional data on sociodemographic, clinical and neurocognitive function (e.g. attention, memory, executive functioning, language fluency, visual-spatial, eye-hand coordination). For the primary analysis, we excluded participants with major depressive episode/substance use disorder (MDE/SUD). We fitted adjusted Poisson regression models to explore the association between HIV and neurocognitive function.Results: We enrolled 200 people with MDR-TB; 33 had MDE/SUD, and data of 167 were analysed (151 HIV+, 16 HIV-). The mean age of participants was 34.2 years; the majority were female (83%), and 53% had not completed secondary school. There was evidence of impaired neurocognitive functioning across all domains in both HIV+/- study participants. Based on the regression analyses, individuals with co-infection (MDR-TB/HIV+), as well as those who had longer duration of hospital stays experienced significantly lower cognitive performance in several domains. Poor cognitive performance was significantly related to older age and lower educational attainment. The presence of major depression or substance use disorders did not influence the significance of the findings.Conclusions: Adults with MDR-TB have significant neurocognitive impairment, especially if HIV positive. An integrated approach is necessary in the management of MDR-TB as cognitive health influences the ability to adhere to chronic treatment, clinical outcomes and functionality. [ABSTRACT FROM AUTHOR]

There is evidence of increasing levels of pretreatment HIV drug resistance (PDR) in Southern Africa. We used data from two large population-based HIV surveillance studies to estimate prevalence of PDR in KwaZulu-Natal, the province with the highest HIV prevalence in South Africa. Sanger sequencing was performed on samples obtained from a longitudinal HIV surveillance program (study A, 2013–2014) and the HIV Incidence Provincial Surveillance System (study B, 2014–2015). Sequences were included for adult HIV positive participants (age ≥15 years for study A, age 15–49 years for study B) with no documented prior exposure to antiretroviral therapy (ART). Overall and drug class-specific PDR was estimated using the World Health Organization 2009 surveillance drug resistance mutation (SDRM) list, and phylogenetic analysis was performed to establish evidence of drug resistance transmission linkage. A total of 1,845 sequences were analyzed (611 study A; 1,234 study B). An overall PDR prevalence of 9.2% [95% confidence interval (CI) 7.0–11.7] was observed for study A and 11.0% (95% CI 8.9–13.2) for study B. In study B, the prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR exceeded 10% for sequences collected in 2014 (10.2%, 95% CI 7.5–12.9). The most prevalent SDRMs were K103NS (7.5%), M184VI (2.4%), and V106AM (1.4%). There was no evidence of large transmission chains of drug-resistant virus. High level NNRTI PDR (>10%) suggests a need to modify the standard first-line ART regimen and to focus attention on improving the quality of HIV prevention, treatment, and care. [ABSTRACT FROM AUTHOR]

Background: Data are required regarding the feasibility of conducting a randomized trial of point-of-care viral load (VL) testing to guide management of HIV viremia and to provide estimates of effect to guide potential future trial design. Setting: Two public South African clinics during the dolutegravir-based antiretroviral therapy (ART) rollout. Methods: We randomized adults receiving first-line ART, with recent VL ≥1000 copies/mL, in a 1:1 ratio to receive point-of-care Xpert HIV-1 VL versus standard-of-care laboratory VL testing after 12 weeks. Feasibility outcomes included proportions of eligible patients enrolled and completing follow-up and VL process outcomes. Estimates of effect were assessed using the trial primary outcome of VL <50 copies/mL after 24 weeks. Results: From August 2020 to March 2022, we enrolled 80 eligible participants, an estimated 24% of those eligible. 47 of 80 (58.8%) were women, and the median age was 38.5 years (interquartile range [IQR], 33–45). 44 of 80 (55.0%) were receiving dolutegravir, and 36 of 80 (465.0%) were receiving efavirenz. After 12 weeks, point-of-care participants received VL results after median 3.1 hours (IQR 2.6–3.8), versus 7 days (IQR 6–8, P < 0.001) in standard of care. Twelve-week follow-up VL was ≥1000 copies/mL in 13 of 39 (33.3%) point-of-care participants and in 16 of 41 (39.0%) standard-of-care participants; 11 of 13 (84.6%) and 12 of 16 (75.0%) switched to second-line ART. After 24 weeks, 76 of 80 (95.0%) completed follow-up. 27 of 39 (69.2% [95% CI: 53.4 to 81.4]) point-of-care participants achieved VL <50 copies/mL versus 29 of 40 (72.5% [57.0 to 83.9]) standard-of-care participants. Point-of-care participants had median 3 (IQR, 3–4) clinical visits versus 4 (IQR, 4–5) in standard-of-care participants (P < 0.001). Conclusions: It was feasible to conduct a trial of point-of-care VL testing to manage viremia. Point-of-care VL lead to quicker results and fewer clinical visits, but estimates of 24-week VL suppression were similar between arms. Trial Registration: Pan African Clinical Trials Registry: PACTR202001785886049. [ABSTRACT FROM AUTHOR]

Near-perfect adherence to antiretroviral therapy (ART) is required to achieve the best possible prevention and treatment outcomes. Yet, there have been particular concerns about the challenges of adherence among patients living in resource-limited settings in sub-Saharan Africa. The primary objective of this study was to explore adherence in a low-resourced, rural community of high HIV prevalence in South Africa and to identify specific individual and structural factors that can either challenge or support adherence in this context. We applied digital stories as a qualitative research tool to gain insights into personal contexts of HIV and ART adherence. Through an inductive thematic analysis of twenty story texts, soundtracks and drawings, we explored experiences, understandings, and contexts of the participants and identified potential barriers and facilitators for those on lifelong treatment. We found that many of the stories reflected a growing confidence in the effectiveness of ART, which should be viewed as a key facilitator to successful adherence since this attitude can promote disclosure and boost access to social support. Nevertheless, stories also highlighted the complexity of the issues that individuals and households face as they deal with HIV and ART in this setting and it is clear that an overburdened local healthcare system has often struggled to meet the demands of a rapidly expanding epidemic and to provide the necessary medical and emotional support. Our analysis suggests several opportunities for further research and the design of novel health interventions to support optimal adherence. Firstly, future health promotion campaigns should encourage individuals to test together, or at least accompany each other for testing, to encourage social support from the outset. Additionally, home-based testing and ART club interventions might be recommended to make it easier for individuals to adhere to their treatment regimens and to provide a sense of support and solidarity. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: We aimed to evaluate the analytic performance of 3 rapid HIV viral load assays: the novel Xpert HIV-1 VL XC (Xpert XC), Xpert HIV-1 VL (Xpert VL), and m-PIMA HIV-1/2 VL (m-PIMA). Setting: Two South African clinics. Methods: We conducted a prospective diagnostic accuracy study. Site-laboratory technicians and nurses used the Xpert XC, Xpert VL, and m-PIMA to test plasma samples from people with HIV receiving antiretroviral therapy. We compared results with the Roche cobas HIV-1 reference assay. We determined accuracy to detect viraemia at the World Health Organization (WHO) failure threshold of 1000 copies/mL on all 3 assays, and 50 and 200 copies/mL on the Xpert assays. We assessed the agreement using Bland–Altman plots. Results: We enrolled 140 participants (98 [70%] women, median age 37 years), who provided 189 paired samples at one or more timepoints. We tested 174 samples with the Xpert XC, 188 with the Xpert VL, and 128 with the m-PIMA. At 1000 copies/mL, sensitivity and specificity (95% confidence intervals) were 97% (82 to 100) and 98% (93 to 99) (Xpert XC), 100% (87 to 100) and 96% (91 to 98) (Xpert VL), and 92% (72 to 99) and 99% (93 to 100) (m-PIMA) respectively. At 50 copies/mL, sensitivity and specificity were 93% (81 to 98) and 96% (91 to 99) (Xpert XC), and 95% (84 to 99) and 95% (90 to 98) (Xpert VL) respectively. Mean bias was −0.10 (−0.54 to 0.34) log10 copies/mL (Xpert XC), 0.07 (−0.37 to 0.52) log10 copies/mL (Xpert VL), and −0.26 (−0.83 to 0.31) log10 copies/mL (m-PIMA). Conclusions: In these South African clinics, the accuracy of all 3 assays was clinically acceptable to detect viraemia at the WHO failure threshold, whereas both Xpert assays were also accurate at detecting low-level viraemia. [ABSTRACT FROM AUTHOR]