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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Dolutegravir

Intervention / Treatment
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* Behavioral: CHARACTERISE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults of at least 18 years of age with HIV-1 infection who are currently on the TLD state programme who satisfy the below eligibility criteria. The following eligibility criteria will be used to select study participants for the main study (baseline visit only): Inclusion criteria (baseline visit/main study): Able and willing to provide written or electronic informed consent for the baseline visit prior to any study-specific assessment or procedure. Age at least 18 years at the time of signing the informed consent form. Previously enrolled in the ADVANCE trial and have been on the TLD state programme for more than one year [Cohort 1] or, part of an existing cohort of patients initiating TLE (and switched to TEE) more than 9 years ago, who have been transitioned to TLD within the state programme for more than one year [Cohort 2]. Access to a reliable telephone or other device permitting information transfer. Exclusion Criteria: Exclusion criteria (baseline visit/main study): Personnel (e.g., investigator, sub-investigator, research assistant, pharmacist, study coordinator or anyone mentioned in the delegation log) directly involved in the conduct of the study. Any physical, mental, or social condition, that, in the Investigator's judgment, might interfere with the completion of the baseline assessments and evaluations. The Investigator should make this determination in consideration of the volunteer's medical history. Participant is judged by the Investigator to be at significant risk of failing to comply with the provisions of the protocol as to cause harm to self or seriously interfere with the validity of the study results. Additional eligibility criteria will be used to identify study participants who are eligible for random selection for any of the sub-studies: Inclusion criteria (sub-studies): Enrolled into main study and completed baseline visit. Able and willing to provide written or electronic informed consent for the relevant sub-study. Identified as high risk for development of OSA based on the Berlin Questionnaire responses [Sleep sub study only]. Exclusion criteria (sub-studies): Self-reported diabetic or on treatment for diabetes mellitus (Type 1 or 2) [Glucose metabolism sub-study only]. Serum glucose and/or HbA1C assessment at baseline consistent with a diagnosis of diabetes mellitus [Glucose metabolism sub-study only].

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1<br>ADVANCE patient cohort, who have been on the TLD state programme for more than one year | Behavioral: CHARACTERISE<br>* Cohort 1 Cohort 2<br>|
| Cohort 2<br>Existing cohorts of patients initiating TLE (and subsequently switched to TEE) more than 9 years ago and who have since transitioned to TLD within the state programme for more than one year. | Behavioral: CHARACTERISE<br>* Cohort 1 Cohort 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterisation of weight gain and metabolic consequences associated with long-term TLD use | Weight measurement with body mass index calculation | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term TLD use | Blood pressure which will measured using both systolic and diastolic | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | Plasma glucose | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | Oral glucose tolerance test | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | C-peptide measurements | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | Lipid panel | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | The liver function test will be performed to determine where damage may be occurring in the liver | 60 Days | 
| Characterisation of weight gain and metabolic consequences associated with long-term | Dual-energy X-ray absorptiometry (DXA) scan | 60 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of factors contributing to, and individual perception on weight gain | Food diary questionnaire there is no min and max values assessments will be done based upon participant diet | 60 Days | 
| Assessment of factors contributing to, and individual perception on weight gain | Weight Bias Internalization Scale through averaging 10 items (rated on a 1-7 scale), with higher scores indicating greater weight bias internalization | 60 Days | 
| Description of the presence of viraemia | Plasma HIV-1 RNA levels | 60 Days | 
| Description of the presence and patterns of HIV-1 resistance mutations in participants with viral loads > 1000 copies/mL | HIV-1 genotyping | 60 Days | 
| Description and occurrence of associated sleep quality and disorders | Berlin Questionnaire for risk of sleep apnoea | 60 Days | 
| Description and occurrence of associated sleep quality and disorders | Polysomnography in randomly selected 20% of participants at high risk of developing obstructive sleep apnoea based on the Berlin Questionnaire | 60 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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The ADVANCE clinical trial, weight gain, viral re-suppression, regimens