Effect of antiretroviral treatment strategies on retention in care, viral suppression, and non-communicable diseases in a large South African cohort: an emulated trial framework approach
Embargo Date
2028-01-15
OA Version
Citation
Abstract
As HIV is now a chronic disease due to improved access to treatment and improved antiretroviral therapies (ART), there is a growing need for evidence regarding the long-term impact of ART use on the health of people living with HIV (PLWH) on treatment and how the risk of weight gain, changes in blood pressure, and other chronic non-communicable diseases (NCDs) like hypertension are impacted by the specific ART regimens are on. This is particularly important as HIV-NCD comorbidity reduces engagement in care and decreases quality of life. With almost eight million PLWH, South Africa has the world’s largest HIV burden and HIV treatment program. In 2019, South Africa’s treatment guidelines were updated to replace efavirenz with dolutegravir, due to clinical trials demonstrating dolutegravir’s efficacy. However, clinical trial populations are often healthier with better retention than real-world populations, in part due to a trial’s intensive follow-up procedures and their selective inclusion/exclusion criteria. As dolutegravir use has expanded, there is growing concern that dolutegravir increases the risk of NCDs. However, the magnitude and severity of this risk remain unclear. While observational studies can offer important insights, they are often limited by bias. Robust causal inference methods can help reduce the risk of bias. In this dissertation, we aim to evaluate the impact of different HIV treatment strategies on long-term retention in care and viral suppression, as well as to assess the association between dolutegravir use and adverse health outcomes—including weight gain, elevated blood pressure, and the development of hypertension.In aim one, using the Target Trial Emulation Framework we estimated, among treatment-naïve PLWH initiating treatment from 2019–2022 in South Africa, the effect of initiating a dolutegravir-based regimen compared to an efavirenz-based regimen on 12- and 24-month retention and viral suppression using data from the Themba Lethu HIV Clinical Cohort (TLC), a prospective cohort of PLWH receiving care at a clinic in Johannesburg, South Africa. Linear regression was conducted to estimate the causal risk difference on 12- and 24-month retention and viral suppression. Baseline characteristics were balanced via inverse probability of treatment weighting. Initiation of dolutegravir was associated with a 5-percentage point increase (95% Confidence Interval (CI): -0.02, 0.11) in retention and 4-percentage point increase (95% CI: -0.06, 0.16) in viral suppression among those with a viral load at 12-months. At 24-months, dolutegravir was associated with a 10-percentage point (95% CI: 0.03, 0.16) increase in retention and a 14-percentage point (95% CI: -0.02, 0.30) increase in viral suppression. Initiation of dolutegravir led to an appreciable increase in retention over 24 months when compared to efavirenz. A moderate but imprecise increase in viral suppression was found among those who initiated dolutegravir compared to efavirenz over the 24-month period.
In aim two, utilizing the Target Trial Emulation Framework we evaluated, among ART-naïve individuals initiating treatment from 2019–2022, the impact of initiating a dolutegravir-based regimen versus initiating an efavirenz-based regimen on 12- and 24-month weight, body mass index (BMI), blood pressure, and incident hypertension, also using TLC data. Generalized linear models were used to estimate the mean difference in weight, BMI, blood pressure at 12- and 24-months and a log-binomial model was used to estimate the causal risk difference of 12- and 24-month incident hypertension were used. At 12-months, mean difference comparing dolutegravir to efavirenz in weight was 2.9 kilograms (95% Confidence Interval (CI): -0.3, 5.5), BMI was 0.8 kg/m2 (95% CI: -0.3, 1.9), diastolic BP was 1.6 mmHg (95% CI: -0.7, 3.9) and systolic BP was 3.9 mmHg (95% CI: 1.2, 6.6). Individuals who initiated a dolutegravir-based regimen had 1.35 times the risk (95% CI: 0.04, 0.5) of incident hypertension at 12 months compared individuals who initiated an efavirenz-based regimen. At 24-months, mean weight difference was 1.9 kilograms (95% CI: -1.3, 5.1), BMI was 0.6 kg/m2 (95% CI: -0.6, 1.9), diastolic BP was -0.4 mmHg (95% CI: -1.8, 5.1) and systolic BP was 1.7 mmHg (95% CI: -1.8, 5.1). Risk of incident hypertension was 22% higher among dolutegravir initiators compared to efavirenz initiators (95% CI: -0.1, 0.4). Dolutegravir was associated with greater increases in weight and systolic blood pressure over 24 months compared to efavirenz, with the greatest increase in the first 12 months. A moderate increase in incident hypertension was also observed.
In aim three, using data from TLC we emulated nine sequential target trials, among treatment-experienced PLWH, to estimate the effect of switching to a dolutegravir-based regimen versus remaining on an efavirenz-based regimen on 12- and 24-month retention and viral suppression from 2019–2022. At 12-months, switching to a dolutegravir-based regimen was associated with a 14-percentage point (95% CI: 0.10, 0.19) increase in retention and a 2-percentage point (95% CI: -0.04, 0.08) increase in viral suppression. By 24-months, we observed a 1-percentage point (95% CI: -0.05, 0.07) increase in retention and an 8-percentage point (95% CI: 0.02, 0.14) increase in viral suppression. Switching to dolutegravir led to an appreciable increase in retention at 12-months and a moderate but imprecise increase in viral suppression at 24-months. Findings suggest that switching to dolutegravir does not harm and might improve retention and viral suppression over a 24-month period.
Overall, we observed that initiating dolutegravir compared to initiating efavirenz led to improvements in retention and viral suppression at 12 and 24 months among PLWH who were treatment-naïve. However, initiating dolutegravir may also be associated with increased weight and systolic blood pressure, and subsequent increased risk of hypertension over the first 24 months of treatment initiation. Among treatment-experienced individuals while we found no appreciable difference in retention for those who switched to dolutegravir compared to not switching, our results suggest that it may potentially lead to improvements in viral suppression. Findings from this dissertation provide further evidence of the benefits of initiating treatment-naïve individuals onto dolutegravir but also highlights the importance of continuing to screen individuals for NCDs after ART initiation as dolutegravir may be associated with increased risk of weight gain and hypertension. Furthermore, our findings suggest switching individuals to dolutegravir does not adversely impact retention and may lead to improvements in viral suppression.
Description
2026
License
Attribution-NonCommercial-NoDerivatives 4.0 International