CHARACTERISE - A Cross-sectional, Observational Study to Characterise the Transition to Dolutegravir-based Regimens in South Africa in Terms of the Emergence of Obesity, Viral Re-suppression and Integration Into Routine Programme Care

Dolutegravir

The ADVANCE clinical trial, weight gain, viral re-suppression, regimens

The ADVANCE clinical trial compared three recommended first-line regimens two containing dolutegravir head-to-head and demonstrated virological non-inferiority at 48- and 96-weeks respectively1,2, paving the way for the mass- introduction of dolutegravir-containing regimens across low- and- middle-income countries. The dolutegravir-containing regimens in ADVANCE were very well tolerated and demonstrated remarkable viral re-suppression in patients with viraemia when adherence measures were instituted, even in the presence of genotypically-documented resistance1,2. Across Africa, including South Africa, and in many other low- and middle-income countries, the combination of tenofovir disoproxil fumarate/lamivudine (or emtricitabine) /dolutegravir has been rolled out to millions of patients, much of this with Unitaid support to research, programmes and communities. Most ADVANCE patients have since transitioned out of the study and are on tenofovir disoproxil fumarate/lamivudine/dolutegravir in South African public sector clinics in central Johannesburg. One of the unanticipated findings of ADVANCE and the concomitant Unitaid-supported NAMSAL3 study in Cameroon, as well as analyses of registration studies and observational studies, was the consistent finding that patients on dolutegravir experience significant weight gain and new-onset obesity. It remains unclear whether this is a feature of the integrase inhibitor class (and aggravated by tenofovir alafenamide), or whether other factors are at play - it is possible that HIV infection itself may predispose to weight gain in successfully treated patients, and other antiretrovirals may alter weight trajectories. The signal has been met with alarm by the public health community, as many countries where TLD is being rolled out are experiencing a parallel obesity epidemic. Obesity is strongly associated with adverse outcomes, including diabetes, cardio-vascular-disease (CVD), sleep apnoea, gastrointestinal and muscular-skeletal disorders, asthma, poor pregnancy outcomes, many cancers, mental health issues, and poor COVID-19 outcomes. In many countries with large antiretroviral programmes, these concurrent epidemics have significant public health and financial implications, and clarification of the extent of the obesity signal is urgent.

This is a single centre, follow-up, observational, cross-sectional study reviewing two cohorts of patients who have transitioned to routine care on tenofovir disoproxil fumarate/lamivudine/dolutegravir . The first cohort will include ADVANCE patients, in which participants were randomised to one of three arms including either DTG+TAF/FTC, DTG+TDF/FTC or EFV/TDF/FTC. The second cohort will include patients previously on tenofovir disoproxil fumarate/lamivudine/emtricitabine or tenofovir disoproxil fumarate/emtricitabine/efavirenz who have since transitioned to routine care on tenofovir disoproxil fumarate/lamivudine/dolutegravir. The medium 5-year data in the ADVANCE cohort and longer 9-year data in the other cohort metabolic and virologic consequences of those on long-term antiretrovirals will be described and compared in the above cohorts. After obtaining informed consent from potential participants, a single cross-sectional, baseline visit will be conducted for each participant. Demographic data, clinical history, and details of previous and concomitant medications will be collected. Questionnaires including a food diary, Weight Bias Internalization Scale and Berlin questionnaire will be administered. Bone density and weight distribution will be assessed through use of a dual-energy X-ray absorptiometry DXA scan, and cardiac function assessed by conduction of a baseline electrocardiogram. Laboratory evaluations will include a liver function test, glycated haemoglobin , plasma HIV-1 RNA viral load, lipid panel, C-peptide, both serum glucose and oral glucose tolerance test, and DNA extraction for genotyping in those with unsuppressed viral loads above 1000 copies/mL. Plasma samples will be stored locally for possible future analysis. After the baseline visit, participants who are suitable for one, or more, sub-study will be identified. A randomly selected sub-group for each of the following sub-studies and additional investigations will be drawn from eligible participants within each cohort: * Sleep evaluation: actigraphy and polysomnography * Glucose metabolism evaluation: oral glucose tolerance test including assessment of glucose, insulin, and C-peptide to estimate insulin sensitivity and beta cell function * Experiences of users and providers in the roll out of tenofovir disoproxil fumarate/lamivudine/dolutegravir in South Africa. Abnormalities detected in the assessments will be managed by on-study medical personnel with referral as appropriate.

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South Africa