Blood pressure increases are associated with weight gain and not antiretroviral regimen or kidney function: a secondary analysis from the ADVANCE trial in South Africa.

INTRODUCTION: Recent evidence has raised questions about whether newer HIV treatment regimens, including dolutegravir (DTG) and tenofovir alafenamide (TAF), are associated with increases in blood pressure (BP). METHODS: We assessed changes in BP by treatment regimen and evaluated the relative contribution of kidney function and weight gain to these changes among participants in the ADVANCE phase-3 trial clinical trial in South Africa (study dates: January 2017-February 2022). Our primary outcome of interest was a change in systolic BP (SBP) at 96 and 192 weeks, among those not receiving antihypertensive medication. The secondary outcome was treatment-emergent hypertension at these same time points, defined as BP ≥140/90 mmHg on two occasions, or initiation of antihypertensive medication after week 4 among individuals without hypertension at enrolment. We used linear regression to evaluate the relationship between change in estimated glomerular filtration rate (eGFR) and change in SBP; and Poisson regression to evaluate the relationship between change in eGFR and treatment-emergent hypertension at each time point. All models were adjusted for age, sex, treatment group and change in body mass index (BMI). RESULTS: Over 96 weeks, the average changes in SBP were 1.7 mmHg (95% CI: 0.0-3.4), -0.5 mmHg (95% CI: -2.2 to 1.7) and -2.1 mmHg (95% CI: -3.8 to 0.4) in the TAF/emtricitabine (FTC)/DTG, tenofovir disoproxil fumarate (TDF)/FTC/DTG and TDF/FTC/efavirenz (EFV) groups, respectively. This difference was significant for the TAF/FTC/DTG compared to the TDF/FTC/EFV group (p = 0.002). Over 96 weeks, 18.2% (95% CI: 13.4-22.9), 15.4% (95% CI: 11.0-19.9) and 13.3% (95% CI: 8.9-17.6) of participants developed treatment-emergent hypertension, respectively. In adjusted models, there was no significant relationship between change in eGFR and either outcome. Change in BMI was significantly associated with an increase in SBP, while age was associated with an increased risk of treatment-emergent hypertension. Adjustment for BMI also mitigated the unadjusted relationship between HIV treatment regimen and SBP where present. CONCLUSIONS: In the ADVANCE cohort, weight gain and age accounted for increases in BP and risk of treatment-emergent hypertension. HIV treatment programmes may need to integrate the management of obesity and hypertension into routine care. CLINICAL TRIAL NUMBER: NCT03122262.

Low CD4 counts predict excessive weight gains during first-line treatment for HIV.

BACKGROUND: Weight gain is common after antiretroviral initiation, especially among females, those of black race and lower baseline CD4, although this may potentially be due to lower baseline weight. Use of tenofovir disoproxil fumarate or efavirenz can suppress weight gain. METHODS: Data were pooled from the ADVANCE (n = 1053), NAMSAL (n = 613) and WHRI001 (n = 536) trials investigating first-line regimen. Week 96 weight and body mass index (BMI) was stratified by baseline CD4. Multivariable models of weight change and incident obesity (BMI ≥30 kg/m2) were adjusted for baseline CD4, age, sex, tenofovir disoproxil fumarate, efavirenz, baseline BMI and trial. RESULTS: Participants across all treatment arms experienced weight gain from baseline to week 96, with baseline CD4 count, baseline HIV RNA, tenofovir alafenamide and dolutegravir use, and female sex significant predictors. Mean unadjusted weight change was highest with CD4 < 100 (+8.6 kg; SD = 8.2) and lowest with CD4 ≥ 350 (+3.0 kg; SD = 6.5). This weight gain in CD4 < 100 was highest for participants on tenofovir alafenamide-inclusive treatment, such that absolute weight at week 96 was highest in the CD4 < 100 group. Although not statistically significant, obesity rate (BMI ≥ 30 kg/m2) in those taking TAF/FTC + DTG with CD4 < 100 overtook that seen in CD4 ≥ 350, despite lower baseline obesity prevalence. The unadjusted findings were corroborated in multivariable longitudinal models. CONCLUSIONS: Participants with low CD4 may demonstrate significant 'overshoot' weight gain, in addition to 'return to health', with a trend towards increased risk of obesity when initiated on TAF/FTC + DTG. Use of tenofovir disoproxil fumarate and efavirenz were associated with smaller weight gains. Effective weight management strategies are needed, especially for individuals with low baseline CD4.

The cost of adding rapid screening for diabetes, hypertension, and COVID-19 to COVID-19 vaccination queues in Johannesburg, South Africa.

BACKGROUND: Non-communicable diseases (NCDs) are responsible for 51% of total mortality in South Africa, with a rising burden of hypertension (HTN) and diabetes mellitus (DM). Incorporating NCDs and COVID-19 screening into mass activities such as COVID-19 vaccination programs could offer significant long-term benefits for early detection interventions. However, there is limited knowledge of the associated costs and resources required. We evaluated the cost of integrating NCD screening and COVID-19 antigen rapid diagnostic testing (Ag-RDT) into a COVID-19 vaccination program. METHODS: We conducted a prospective cost analysis at three public sector primary healthcare clinics and one academic hospital in Johannesburg, South Africa, conducting vaccinations. Participants were assessed for eligibility and recruited during May-Dec 2022. Costs were estimated from the provider perspective using a bottom-up micro-costing approach and reported in 2022 USD. RESULTS: Of the 1,376 enrolled participants, 240 opted in to undergo a COVID-19 Ag-RDT, and none tested positive for COVID-19. 138 (10.1%) had elevated blood pressure, with 96 (70%) having no prior HTN diagnosis. 22 (1.6%) were screen-positive for DM, with 12 (55%) having no prior diagnosis. The median cost per person screened for NCDs was $1.70 (IQR: $1.38-$2.49), respectively. The average provider cost per person found to have elevated blood glucose levels and blood pressure was $157.99 and $25.19, respectively. Finding a potentially new case of DM and HTN was $289.65 and $36.21, respectively. For DM and DM + HTN screen-positive participants, diagnostic tests were the main cost driver, while staff costs were the main cost driver for DM- and HTN screen-negative and HTN screen-positive participants. The median cost per Ag-RDT was $5.95 (IQR: $5.55-$6.25), with costs driven mainly by test kit costs. CONCLUSIONS: We show the cost of finding potentially new cases of DM and HTN in a vaccine queue, which is an essential first step in understanding the feasibility and resource requirements for such initiatives. However, there is a need for comparative economic analyses that include linkage to care and retention data to fully understand this cost and determine whether opportunistic screening should be added to general mass health activities.

Two-drug regimens for the treatment of HIV in Africa.

Two-drug regimens for the treatment of HIV are increasingly available. The oral regimen of dolutegravir plus lamivudine is recommended as a preferred option in multiple national guidelines but is not currently included in WHO HIV treatment guidelines nor widely used in Africa. Long-acting injectable cabotegravir and rilpivirine is being rolled out in the USA, Europe, and Australia but its use in sub-Saharan Africa is currently restricted to clinical trials. Given the increasing life expectancy, rising prevalence of non-communicable diseases, and resulting polypharmacy among people living with HIV, there are potential advantages to the use of two-drug regimens, particularly in African women, adolescents, and older adults. This Viewpoint reviews existing evidence and highlights the risks, benefits, and key knowledge gaps for the use of two-drug regimens in settings using the public health approach in Africa. We suggest that a two-drug regimen of dolutegravir and lamivudine can be safely used as a switch option for virologically suppressed individuals in settings using the public health approach once chronic hepatitis B has been excluded. Individuals with HIV who are switched to two-drug regimens should receive a full course of hepatitis B vaccinations. More efficacy data is needed to support dolutegravir plus lamivudine combination in the test and treat approach, and long-acting cabotegravir and rilpivirine in the public health system in sub-Saharan Africa.

Switch to long-acting cabotegravir and rilpivirine in virologically suppressed adults with HIV in Africa (CARES): week 48 results from a randomised, multicentre, open-label, non-inferiority trial.

BACKGROUND: Long-acting injectable cabotegravir and rilpivirine is licensed for individualised treatment of HIV-1 infection in resource-rich settings. Additional evidence is required to support use in African treatment programmes where demographic factors, viral subtypes, previous treatment, and delivery and monitoring approaches differ. The aim of this study was to determine whether switching to long-acting therapy with injections every 8 weeks is non-inferior to daily oral therapy in Africa. METHODS: CARES is a randomised, open-label, non-inferiority trial being conducted at eight sites in Uganda, Kenya, and South Africa. Participants with HIV viral load below 50 copies per mL on oral antiretroviral therapy and no history of virological failure were randomly assigned (1:1; web-based, permuted blocks) to receive cabotegravir (600 mg) and rilpivirine (900 mg) by intramuscular injection every 8 weeks, or to continue oral therapy. Viral load was monitored every 24 weeks. The primary outcome was week 48 viral load below 50 copies per mL, assessed with the Food and Drug Administration snapshot algorithm (non-inferiority margin 10 percentage points) in the intention-to-treat exposed population. This trial is registered with the Pan African Clinical Trials Registry (202104874490818) and is ongoing up to 96 weeks. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 512 participants (295 [58%] female; 380 [74%] previous non-nucleoside reverse transcriptase inhibitor exposure). Week 48 viral load was below 50 copies per mL in 246 (96%) of 255 participants in the long-acting therapy group and 250 (97%) of 257 in the oral therapy group (difference -0·8 percentage points; 95% CI -3·7 to 2·3), demonstrating non-inferiority (confirmed in per-protocol analysis). Two participants had virological failure in the long-acting therapy group, both with drug resistance; none had virological failure in the oral therapy group. Adverse events of grade 3 or greater severity occurred in 24 (9%) participants on long-acting therapy and ten (4%) on oral therapy; one participant discontinued long-acting therapy (for injection-site reaction). INTERPRETATION: Long-acting therapy had non-inferior efficacy compared with oral therapy, with a good safety profile, and can be considered for African treatment programmes. FUNDING: Janssen.

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.

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.

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.

Risks of metabolic syndrome in the ADVANCE and NAMSAL trials.

Introduction: The ADVANCE and NAMSAL trials evaluating antiretroviral drugs have both reported substantial levels of clinical obesity in participants. As one of the main risk factors for metabolic syndrome, growing rates of obesity may drive metabolic syndrome development. This study aims to evaluate the risk of metabolic syndrome in the ADVANCE and NAMSAL trials. Methods: The number of participants with metabolic syndrome was calculated at baseline and week 192 as central obesity and any of the following two factors: raised triglycerides, reduced HDL-cholesterol, raised blood pressure and raised fasting glucose. Differences between the treatment arms were calculated using the χ2 test. Results: Across all visits to week 192, treatment-emergent metabolic syndrome was 15% (TAF/FTC + DTG), 10% (TDF/FTC + DTG) and 7% (TDF/FTC/EFV) in ADVANCE. The results were significantly higher in the TAF/FTC + DTG arm compared to the TDF/FTC/EFV arm (p < 0.001), and the TDF/FTC + DTG vs. the TDF/FTC/EFV arms (p < 0.05) in all patients, and in females. In NAMSAL, the incidence of treatment-emergent metabolic syndrome at any time point was 14% (TDF/3TC + DTG) and 5% (TDF/3TC + EFV) (p < 0.001). This incidence was significantly greater in the TDF/3TC/DTG arm compared to the TDF/3TC/EFV arm in all patients (p < 0.001), and in males (p < 0.001). Conclusion: In this analysis, we highlight treatment-emergent metabolic syndrome associated with dolutegravir, likely driven by obesity. Clinicians initiating or monitoring patients on INSTI-based ART must counsel for lifestyle optimisation to prevent these effects.

The cost of adding rapid screening for diabetes, hypertension, and COVID-19 to COVID-19 vaccination queues in Johannesburg, South Africa.

Background: Non-communicable diseases (NCDs) are responsible for 51% of total mortality in South Africa, with a rising burden of hypertension (HTN) and diabetes mellitus (DM). Incorporating NCD and COVID-19 screening into mass activities such as COVID-19 vaccination programs could offer significant long-term benefits for early detection interventions. However, there is limited knowledge of the associated costs and resources required. We evaluated the cost of integrating NCD screening and COVID-19 antigen rapid diagnostic testing (Ag-RDT) into a COVID-19 vaccination program. Methods: We conducted a prospective cost analysis at three public sector primary healthcare clinics and one academic hospital in Johannesburg, South Africa, conducting vaccinations. Participants were assessed for eligibility and recruited during May-Dec 2022. Costs were estimated from the provider perspective using a bottom-up micro-costing approach and reported in 2022 USD. Results: Of the 1,376 enrolled participants, 240 opted in to undergo a COVID-19 Ag-RDT, and none tested positive for COVID-19. 138 (10.1%) had elevated blood pressure, with 96 (70%) having no prior HTN diagnosis. 22 (1.6%) were screen-positive for DM, with 12 (55%) having no prior diagnosis. The mean and median costs per person screened for NCDs were $2.53 (SD: 3.62) and $1.70 (IQR: $1.38-$2.49), respectively. The average provider cost per person found to have elevated blood glucose levels and blood pressure was $157.99 and $25.19, respectively. Finding a new case of DM and HTN was $289.65 and $36.21, respectively. For DM and DM + HTN screen-positive participants, diagnostic tests were the main cost driver, while staff costs were the main cost driver for - and HTN screen-positive and screen-negative participants. The mean and median cost per Ag-RDT was $6.13 (SD: 0.87) and $5.95 (IQR: $5.55-$6.25), with costs driven mainly by test kit costs. Conclusions: We show the cost of finding new cases of DM and HTN in a vaccine queue, which is an essential first step in understanding the feasibility and resource requirements for such initiatives. However, there is a need for comparative economic analyses that include linkage to care and retention data to fully understand this cost and determine whether opportunistic screening should be added to general mass health activities.

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.

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.

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.

Weight and Metabolic Changes After Switching From Tenofovir Alafenamide/Emtricitabine (FTC)+Dolutegravir (DTG), Tenofovir Disoproxil Fumarate (TDF)/FTC + DTG, and TDF/FTC/Efavirenz to TDF/Lamivudine/DTG.

Participants randomized to first-line tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC + DTG, or TDF/FTC/efavirenz (EFV) for 192 weeks were then switched to TDF/lamivudine (3TC)/DTG for 52 weeks. Participants switching either TAF/FTC + DTG or TDF/FTC/EFV to TDF/3TC/DTG showed statistically significant reductions in weight, low-density lipoprotein, triglycerides, glucose and glycated hemoglobin.

Comparing Prospective Incident Severe Acute Respiratory Syndrome Coronavirus 2 Infection Rates During Successive Waves of Delta and Omicron in Johannesburg, South Africa.

In high-risk individuals in Johannesburg, during the Delta coronavirus disease 2019 wave, 22% (125/561) were positive, with 33% symptomatic (2 hospitalizations; 1 death). During Omicron, 56% (232/411) were infected, with 24% symptomatic (no hospitalizations or deaths). The remarkable speed of infection of Omicron over Delta poses challenges to conventional severe acute respiratory syndrome coronavirus 2 control measures.

Coronavirus Host Genomics Study: South Africa (COVIGen-SA).

Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa's response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA-a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing and targeted sequencing of important genomic loci. This project will promote and enhance partnerships, build skills, and develop resources needed to address the COVID-19 burden and associated risk factors in South African communities.

Pharmacokinetic and pharmacogenetic associations with dolutegravir neuropsychiatric adverse events in an African population.

BACKGROUND: Dolutegravir has been associated with neuropsychiatric adverse events (NPAEs), but relationships between dolutegravir concentrations and NPAEs are unclear. OBJECTIVES: To determine in an African population whether a concentration-response relationship exists between dolutegravir and treatment-emergent NPAEs, and whether selected loss-of-function polymorphisms in genes encoding UDP-glucuronosyltransferase-1A1 (the major metabolizing enzyme for dolutegravir) and organic cation transporter-2 (involved in neurotransmitter transport and inhibited by dolutegravir) are associated with NPAEs. METHODS: Antiretroviral therapy-naive participants randomized to dolutegravir-based therapy in the ADVANCE study were enrolled into a pharmacokinetic sub-study. Primary outcome was change in mental health screening [modified mini screen (MMS)] and sleep quality from baseline to weeks 4, 12 and 24. Dolutegravir exposure was estimated using a population pharmacokinetic model. Polymorphisms analysed were UGT1A1 rs887829 and SLC22A2 rs316019. RESULTS: Data from 464 participants were available for pharmacokinetic analyses and 301 for genetic analyses. By multivariable linear regression, higher dolutegravir exposure was associated with worsening sleep quality only at week 12 [coefficient  = -0.854 (95% CI -1.703 to -0.005), P = 0.049], but with improved MMS score at weeks 12 and 24 [coefficient = -1.255 (95% CI -2.250 to -0.261), P = 0.013 and coefficient = -1.199 (95% CI -2.030 to -0.368), P = 0.005, respectively]. The UGT1A1 and SLC22A2 polymorphisms were not associated with change in MMS score or sleep quality. CONCLUSIONS: Only at week 12 did we find evidence of a relationship between dolutegravir exposure and worsening sleep quality. However, higher dolutegravir exposure was associated with improved MMS scores, suggesting a possible beneficial effect.