Final 192-Week Efficacy and Safety Results of the ADVANCE Trial, Comparing 3 First-line Antiretroviral Regimens.

Background: ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive. Methods: This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks. Results: Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm. Conclusions: High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes.

Regional variation in weight change after the transition to dolutegravir: a prospective cohort study in Uganda and South Africa.

BACKGROUND: People with HIV (PWH) on integrase inhibitor-based regimens may be at risk of excess weight gain, but it is unclear if this risk is consistent across settings. We assessed weight change over 48 weeks among PWH who were transitioned to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD). DESIGN: We conducted a prospective cohort study at public-sector HIV clinics in Uganda and South Africa. METHODS: Eligible participants were adults who were transitioned to TLD. Weight was measured at enrollment, 24-, and 48-weeks post TLD transition. Our outcomes were (1) weight change, (2) change in waist circumference, and (3) clinically significant weight gain, defined as ≥10% increase in weight from baseline, over 48 weeks. We used linear mixed-effects regression models, adjusted for demographic factors, to estimate weight gain and identify risk factors. RESULTS: Weight data were available for 428 participants in Uganda and 367 in South Africa. The mean weight change was 0.6 kg [95%CI: 0.1-1.0] in Uganda and 2.9 kg [2.3-3.4] in South Africa (p < 0.001). The mean change in waist circumference was 0.8 cm [95%CI: 0.0-1.5]) in Uganda and 2.3 cm [95%CI: 1.4-3.2] in South Africa (p = 0.012). Clinically significant weight gain occurred in 9.8% [7.0-12.6] of participants in Uganda and 18.0% [14.1-21.9] in South Africa (p < 0.001). After adjustment, PWH gained significantly less weight in Uganda than in South Africa. CONCLUSIONS: PWH in South Africa experienced significantly greater weight gain and increases in waist circumference compared to Uganda. Strategies to address weight gain in PWH should be carefully considered and may vary by region.

Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Does Engagement in HIV Care Affect Screening, Diagnosis, and Control of Noncommunicable Diseases in Sub-Saharan Africa? A Systematic Review and Meta-analysis.

Low- and middle-income countries are facing a growing burden of noncommunicable diseases (NCDs). Providing HIV treatment may provide opportunities to increase access to NCD services in under-resourced environments. We conducted a systematic review and meta-analysis to evaluate whether use of antiretroviral therapy (ART) was associated with increased screening, diagnosis, treatment, and control of diabetes, hypertension, chronic kidney disease, or cardiovascular disease among people living with HIV in sub-Saharan Africa (SSA). A comprehensive search of electronic literature databases for studies published between 01 January 2011 and 31 December 2022 yielded 26 studies, describing 13,570 PLWH in SSA, 61% of whom were receiving ART. Random effects models were used to calculate summary odds ratios (ORs) of the risk of diagnosis by ART status and corresponding 95% confidence intervals (95% CIs), where appropriate. ART use was associated with a small but imprecise increase in the odds of diabetes diagnosis (OR 1.07; 95% CI 0.71, 1.60) and an increase in the odds of hypertension diagnosis (OR 2.10, 95% CI 1.42, 3.09). We found minimal data on the association between ART use and screening, treatment, or control of NCDs. Despite a potentially higher NCD risk among PLWH and regional efforts to integrate NCD and HIV care, evidence to support effective care integration models is lacking.

Perceptions of Health, Body Size, and Nutritional Risk Factors for Obesity in People with HIV in South Africa.

Metabolic disease is increasing in people with HIV (PWH) in South Africa, but little is known about self-perceptions of body size, health, and nutritional behavior in this population. We performed a cross-sectional analysis of individual-level data from the 2016 South Africa Demographic and Health Survey. This survey measured HIV serostatus and body mass index (BMI). We categorized participants into six BMI groups: 18.5-22 kg/m2, 22-25 kg/m2, 25-27.5 kg/m2, 27.5-30 kg/m2, 30-35 kg/m2, and ≥ 35 kg/m2 and stratified them by HIV serostatus. Our outcomes were self-reported (1) body size and (2) health status among all participants, and intake of (3) chips and (4) sugar-sweetened beverages (SSB) in PWH. We described these metrics and used multivariable regression to evaluate the relationship between the nutritional behaviors and BMI ≥ 25 kg/m2 in PWH only, adjusting for age, sex, educational attainment, and household wealth quintile. Of 6138 participants, 1163 (19.7%) were PWH. Among PWH, < 10% with a BMI 25-30 kg/m2, < 20% with a BMI 30-35 kg/m2 and < 50% with a BMI ≥ 35 kg/m2 self-reported as overweight or obese. PWH reported being in poor health at higher rates than those without HIV at each BMI category except ≥ 35 kg/m2. In adjusted models, SSB consumption was associated with BMI ≥ 25 kg/m2 (1.13 [1.01-1.25], t-statistic = 2.14, p = 0.033) in PWH. Perceptions of body size may challenge efforts to prevent weight gain in PWH in South Africa. SSB intake reduction should be further explored as a modifiable risk factor for obesity.

Weight Gain After HIV Therapy Initiation: Pathophysiology and Implications.

Rapid advances in the potency, safety, and availability of modern HIV antiretroviral therapy (ART) have yielded a near-normal life expectancy for most people living with HIV (PLWH). Ironically, considering the history of HIV/AIDS (initially called "slim disease" because of associated weight loss), the latest dilemma faced by many people starting HIV therapy is weight gain and obesity, particularly Black people, women, and those who commenced treatment with advanced immunodeficiency. We review the pathophysiology and implications of weight gain among PLWH on ART and discuss why this phenomenon was recognized only recently, despite the availability of effective therapy for nearly 30 years. We comprehensively explore the theories of the causes, from initial speculation that weight gain was simply a return to health for people recovering from wasting to comparative effects of newer regimens vs prior toxic agents, to direct effects of agents on mitochondrial function. We then discuss the implications of weight gain on modern ART, particularly concomitant effects on lipids, glucose metabolism, and inflammatory markers. Finally, we discuss intervention options for PLWH and obesity, from the limitations of switching ART regimens or specific agents within regimens, weight-gain mitigation strategies, and potential hope in access to emerging antiobesity agents, which are yet to be evaluated in this population.

Clinical consequences of weight gain during treatment for HIV infection.

PURPOSE OF REVIEW: The introduction of dolutegravir, an oral integrase inhibitor, within public health HIV programs has been a success, with excellent sustained viral load suppression, persistence, and safety. Initial concerns around integrase-inhibitors being implicated in safety concerns around immune reconstitution inflammatory syndromes (IRIS), neural tube defects, and weight gain, have been largely laid to rest, but new concerns about cardiovascular risk have arisen, including a link between hypertension and this antiretroviral class. RECENT FINDINGS: We review the pertinent studies here, and while we find both observational and randomized controlled study associations in some but not all studies, these are often confounded by associated weight gain and aging. In addition, definitions of hypertension, as well as measurement within the studies (such as cuff size), were not consistent within studies. SUMMARY: Careful analysis will be needed, as with the weight-gain signal, before assigning causation, especially as plausible physiological mechanisms for this rise in blood pressure are unclear.

From Evidence to Effectiveness: Implications of the Randomized Trial to Prevent Vascular Events in HIV Study for People With Human Immunodeficiency Virus in Low- and Middle-Income Settings.

The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) study found a 35% reduction in major adverse cardiovascular events for people with human immunodeficiency virus who received daily pitavastatin. However, how this evidence will change practice is far from certain. Here, we outline evidence gaps and political and healthcare delivery challenges that will need to be addressed for REPRIEVE to offer public health benefits in low- and middle-income countries.

Integration of point-of-care screening for type 2 diabetes mellitus and hypertension into the COVID-19 vaccine programme in Johannesburg, South Africa.

BACKGROUND: South Africa grapples with a substantial burden of non-communicable diseases (NCDs), particularly type 2 diabetes (diabetes) and hypertension. However, these conditions are often underdiagnosed and poorly managed, further exacerbated by the strained primary healthcare (PHC) system and the disruptive impact of the COVID-19 pandemic. Integrating NCD screening with large-scale healthcare initiatives, such as COVID-19 vaccination campaigns, offers a potential solution, especially in low- and middle-income countries (LMICs). We investigated the feasibility and effectiveness of this integration. METHODS: A prospective cohort study was conducted at four government health facilities in Johannesburg, South Africa. NCD screening was incorporated into the COVID-19 vaccination campaign. Participants underwent COVID-19 rapid tests, blood glucose checks, blood pressure assessments, and anthropometric measurements. Those with elevated blood glucose or blood pressure values received referrals for diagnostic confirmation at local PHC centers. RESULTS: Among 1,376 participants screened, the overall diabetes prevalence was 4.1%, combining previously diagnosed cases and newly identified elevated blood glucose levels. Similarly, the hypertension prevalence was 19.4%, comprising pre-existing diagnoses and newly detected elevated blood pressure cases. Notably, 46.1% of participants displayed waist circumferences indicative of metabolic syndrome, more prevalent among females. Impressively, 7.8% of all participants screened were potentially newly diagnosed with diabetes or hypertension. Approximately 50% of individuals with elevated blood glucose or blood pressure successfully linked to follow-up care within four weeks. CONCLUSION: Our study underscores the value of utilizing even brief healthcare interactions as opportunities for screening additional health conditions, thereby aiding the identification of previously undiagnosed cases. Integrating NCD screenings into routine healthcare visits holds promise, especially in resource-constrained settings. Nonetheless, concerted efforts to strengthen care linkage are crucial for holistic NCD management and control. These findings provide actionable insights for addressing the NCD challenge and improving healthcare delivery in LMICs.

Community-based management of a five-arm randomised clinical trial in COVID-19 outpatients in South Africa: challenges and opportunities.

BACKGROUND: Repeated COVID-19 waves and corresponding mitigation measures have impacted health systems globally with exceptional challenges. In response to the pandemic, researchers, regulators, and funders rapidly pivoted to COVID-19 research activities. However, many clinical drug studies were not completed, due to often complex and rapidly evolving research conditions. METHODS: We outline our experience of planning and managing a randomised, adaptive, open-label, phase 2 clinical trial to evaluate the safety and efficacy of four repurposed drug regimens versus standard-of-care (SOC) in outpatients with 'mild to moderate' COVID-19 in Johannesburg, South Africa, in the context of a partnership with multiple stakeholders. The study was conducted between 3 September 2020 and 23 August 2021 during changing COVID-19 restrictions, significant morbidity and mortality waves, and allied supply line, economic, and political instability. RESULTS: Our clinical study design was pragmatic, including low-risk patients who were treated open label. There was built-in flexibility, including provision for some sample size adjustment and a range of secondary efficacy outcomes. Barriers to recruitment included the timing of waves, staff shortages due to illness, late presentation of patients, COVID-19 misinformation, and political unrest. Mitigations were the use of community health workers, deployment of mobile clinical units, and simplification of screening. Trial management required a radical reorganisation of logistics and processes to accommodate COVID-19 restrictions. These included the delivery of staff training and monitoring remotely, electronic consent, patient training and support to collect samples and report data at home, and the introduction of tele-medicine. These measures were successful for data collection, safe, and well received by patients. CONCLUSION: Completing a COVID-19 trial in outpatients during the height of the pandemic required multiple innovations in nearly every aspect of clinical trial management, a high commitment level from study staff and patients, and support from study sponsors. Our experience has generated a more robust clinical research infrastructure, building in efficiencies to clinical trial management beyond the pandemic.

Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV.

BACKGROUND: Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest. OBJECTIVE: We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). METHODS: Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations. RESULTS: A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10-8) and intergenic rs142693425 (P = 1.4 × 10-8), respectively. CONCLUSION: Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.

Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans.

OBJECTIVE: Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans. METHODS: Genetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine ß2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations. RESULTS: 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 ( P  = 0.022), ABCC10 rs2125739 ( P  = 0.07), and ABCC4 rs1059751 ( P  = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 ( P  = 0.0013), rs691857 ( P  = 0.00039), and PKD2 rs72659631 ( P  = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 ( P  = 3.4 × 10 -9 ), CDH4 rs66494466 ( P  = 5.6 × 10 -8 ), and ITGA4 rs3770126 ( P  = 6.1 × 10 -7 ). CONCLUSION: Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.

Population pharmacokinetics of tenofovir given as either tenofovir disoproxil fumarate or tenofovir alafenamide in an African population.

Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of the nucleotide analogue tenofovir, which acts intracellularly to inhibit HIV replication. Whereas TDF converts to tenofovir in plasma and may cause kidney and bone toxicity, TAF mostly converts to tenofovir intracellularly, so it can be administered at lower doses. TAF leads to lower tenofovir plasma concentrations and lower toxicity, but there are limited data on its use in Africa. We used data from 41 South African adults living with HIV from the ADVANCE trial and described, with a joint model, the population pharmacokinetics of tenofovir given as TAF or TDF. The TDF was modeled to appear in plasma as tenofovir with a simple first-order process. Instead, two parallel pathways were used for a TAF dose: an estimated 32.4% quickly appeared as tenofovir into the systemic circulation with first-order absorption, whereas the rest was sequestered intracellularly and released into the systemic circulation as tenofovir slowly. Once in plasma (from either TAF or TDF), tenofovir disposition followed two-compartment kinetics and had a clearance of 44.7 L/h (40.2-49.5), for a typical 70-kg individual. This semimechanistic model describes the population pharmacokinetics of tenofovir when dosed as either TDF or TAF in an African population living with HIV and can be used as a tool for exposure prediction in patients, and to simulate alternative regimes to inform further clinical trials.

Change in body weight and risk of hypertension after switching from efavirenz to dolutegravir in adults living with HIV: evidence from routine care in Johannesburg, South Africa.

Background: The integrase strand transfer inhibitor (INSTI) dolutegravir is recommended in World Health Organization guidelines, but is associated with weight gain. We evaluated weight change in patients switching from efavirenz to dolutegravir in first-line antiretroviral therapy (ART) in Johannesburg, South Africa. Methods: We conducted a prospective cohort study of adults (≥16 years) of black African ancestry with HIV who initiated ART between January 2010-December 2020. Patients were propensity score-matched 1:1 (unexposed i.e. remaining on efavirenz: exposed i.e. switched from efavirenz to dolutegravir) on sex, age, months on ART, first ART regimen, haemoglobin, body mass index (BMI), blood pressure, viral load and CD4 count. We used linear regression to assess the effect of switching from efavirenz to dolutegravir on weight change and hypertension 12 months after exposure. Findings: We matched 794 patients switching to dolutegravir to 794 remaining on efavirenz. Exposed patients had a higher mean change in weight (1.78 kg; 95% confidence interval (CI):1.04,2.52 kg) from start of follow-up to 12 months vs. unexposed. We also found a 14.2 percentage point increase (95% CI: 10.6,17.7) in the risk of hypertension in those exposed to dolutegravir vs those that remained on efavirenz. Interpretation: In a real-world population, patients gained more weight and were at higher risk of hypertension after switching from efavirenz to dolutegravir than those remaining on efavirenz. Longer follow-up is needed, however, to determine if INSTI-associated weight gain is associated with changes in non-communicable disease risk over the long-term, or whether weight gain is sustained, as seen in clinical trials. Funding: This study has been made possible by the generous support of the American People and the President's Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID), under the terms of cooperative agreement cooperative Agreement 72067419CA00004. In addition to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 1K01MH105320-01A1.

Does engagement in HIV care affect screening, diagnosis, and control of noncommunicable diseases in sub-Saharan Africa? A systematic review and meta-analysis.

Objective: Low- and middle-income countries are facing a growing burden of noncommunicable diseases (NCDs). Providing HIV treatment may also provide opportunities to increase access to NCD services in under-resourced environments. We sought to investigate whether reported use of antiretroviral therapy (ART) was associated with increased screening, diagnosis, treatment, and/or control of diabetes, hypertension, chronic kidney disease, or cardiovascular disease among people living with HIV (PLWH) in sub-Saharan Africa (SSA). Design: Systematic review and meta-analysis. Methods: We searched 10 electronic literature databases for studies published between 01 January 2011 and 31 December 2022 using a comprehensive search strategy. We sought studies reporting on screening, diagnosis, treatment, and/or control of NCDs of interest by ART use among non-pregnant adults with HIV ≥16 years of age in SSA. Random effects models were used to calculate summary odds ratios (ORs) of the risk of diagnosis by ART status and corresponding 95% confidence intervals (95% CIs), where appropriate. Results: Twenty-six studies, describing 13,570 PLWH in SSA, 61% of whom were receiving ART, were included. ART use was associated with a small but imprecise increase in the odds of diabetes diagnosis (OR: 1.07; 95% CI: 0.71, 1.60) and an increase in the odds of hypertension diagnosis (OR: 2.10, 95% CI: 1.42, 3.09). We found minimal data on the association between ART use and screening, treatment, or control of NCDs. Conclusion: Despite a potentially higher NCD risk among PLWH and regional efforts to integrate NCD and HIV care, evidence to support effective care integration models is lacking.

Impact of rilpivirine cross-resistance on long-acting cabotegravir-rilpivirine in low and middle-income countries.

Baseline rilpivirine drug resistance mutations (DRMs) are a risk factor for virological failure in patients treated with long-acting cabotegravir and rilpivirine (CAB/RPV LA). We investigated rilpivirine cross-resistance in treatment-naive and experienced patients in South Africa. One in 10 treatment-naive patients and 74.5% of patients failing treatment presented with rilpivirine DRMs. Our data suggest targeted genotyping may be required for patients initiating CAB/RPV LA, which significantly complicates the currently used public health approach.

Impact and cost-effectiveness of the national scale-up of HIV pre-exposure prophylaxis among female sex workers in South Africa: a modelling analysis.

INTRODUCTION: In 2016, South Africa (SA) initiated a national programme to scale-up pre-exposure prophylaxis (PrEP) among female sex workers (FSWs), with ∼20,000 PrEP initiations among FSWs (∼14% of FSW) by 2020. We evaluated the impact and cost-effectiveness of this programme, including future scale-up scenarios and the potential detrimental impact of the COVID-19 pandemic. METHODS: A compartmental HIV transmission model for SA was adapted to include PrEP. Using estimates on self-reported PrEP adherence from a national study of FSW (67.7%) and the Treatment and Prevention for FSWs (TAPS) PrEP demonstration study in SA (80.8%), we down-adjusted TAPS estimates for the proportion of FSWs with detectable drug levels (adjusted range: 38.0-70.4%). The model stratified FSW by low (undetectable drug; 0% efficacy) and high adherence (detectable drug; 79.9%; 95% CI: 67.2-87.6% efficacy). FSWs can transition between adherence levels, with lower loss-to-follow-up among highly adherent FSWs (aHR: 0.58; 95% CI: 0.40-0.85; TAPS data). The model was calibrated to monthly data on the national scale-up of PrEP among FSWs over 2016-2020, including reductions in PrEP initiations during 2020. The model projected the impact of the current programme (2016-2020) and the future impact (2021-2040) at current coverage or if initiation and/or retention are doubled. Using published cost data, we assessed the cost-effectiveness (healthcare provider perspective; 3% discount rate; time horizon 2016-2040) of the current PrEP provision. RESULTS: Calibrated to national data, model projections suggest that 2.1% of HIV-negative FSWs were currently on PrEP in 2020, with PrEP preventing 0.45% (95% credibility interval, 0.35-0.57%) of HIV infections among FSWs over 2016-2020 or 605 (444-840) infections overall. Reductions in PrEP initiations in 2020 possibly reduced infections averted by 18.57% (13.99-23.29). PrEP is cost-saving, with $1.42 (1.03-1.99) of ART costs saved per dollar spent on PrEP. Going forward, existing coverage of PrEP will avert 5,635 (3,572-9,036) infections by 2040. However, if PrEP initiation and retention doubles, then PrEP coverage increases to 9.9% (8.7-11.6%) and impact increases 4.3 times with 24,114 (15,308-38,107) infections averted by 2040. CONCLUSIONS: Our findings advocate for the expansion of PrEP to FSWs throughout SA to maximize its impact. This should include strategies to optimize retention and should target women in contact with FSW services.

Roadmap for Achieving Universal Antiretroviral Treatment.

Modern antiretroviral therapy safely, potently, and durably suppresses human immunodeficiency virus (HIV) that, if left untreated, predictably causes acquired immunodeficiency syndrome (AIDS), which has been responsible for tens of millions of deaths globally since it was described in 1981. In one of the most extraordinary medical success stories in modern times, a combination of pioneering basic science, innovative drug development, and ambitious public health programming resulted in access to lifesaving, safe drugs, taken as an oral tablet daily, for most of the world. However, substantial challenges remain in the fields of prevention, timely access to diagnosis, and treatment, especially in pediatric and adolescent patients. As HIV-positive adults age, treating their comorbidities will require understanding the course of different chronic diseases complicated by HIV-related and antiretroviral toxicities and finding potential treatments. Finally, new long-acting antiretrovirals on the horizon promise exciting new options in both the prevention and treatment fields.