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 Clinical Trial

— CHARACTERISE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05502692
• Other study ID #: EZ-FV-030
• Status: Completed
• Start date: July 12, 2022
• Est. completion date: March 30, 2023

Study information

• Verified date: May 2023
• Source: University of Witwatersrand, South Africa
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: March 30, 2023
• Est. primary completion date: December 30, 2022
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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):

1. Able and willing to provide written or electronic informed consent for the baseline visit prior to any study-specific assessment or procedure.

2. Age at least 18 years at the time of signing the informed consent form.

3. 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].

4. Access to a reliable telephone or other device permitting information transfer.

Exclusion Criteria:

• Exclusion criteria (baseline visit/main study):

1. 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.

2. 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.

3. 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):

1. Enrolled into main study and completed baseline visit.

2. Able and willing to provide written or electronic informed consent for the relevant sub-study.

3. Identified as high risk for development of OSA based on the Berlin Questionnaire responses [Sleep sub study only].

Exclusion criteria (sub-studies):

1. Self-reported diabetic or on treatment for diabetes mellitus (Type 1 or 2) [Glucose metabolism sub-study only].

2. Serum glucose and/or HbA1C assessment at baseline consistent with a diagnosis of diabetes mellitus [Glucose metabolism sub-study only].

Related Conditions & MeSH terms

• Dolutegravir
• Obesity

Intervention

Behavioral:
• CHARACTERISE
Cohort 1 Cohort 2

Locations

Country	Name	City	State
South Africa	Sunnyside Office Park	Johannesburg	Gauteng

Sponsors (2)

Lead Sponsor	Collaborator
University of Witwatersrand, South Africa	UNITAID

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Characterisation of weight gain and metabolic consequences associated with long-term TLD use	Weight measurement with body mass index calculation	60 Days
Primary	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
Primary	Characterisation of weight gain and metabolic consequences associated with long-term	Plasma glucose	60 Days
Primary	Characterisation of weight gain and metabolic consequences associated with long-term	Oral glucose tolerance test	60 Days
Primary	Characterisation of weight gain and metabolic consequences associated with long-term	C-peptide measurements	60 Days
Primary	Characterisation of weight gain and metabolic consequences associated with long-term	Lipid panel	60 Days
Primary	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
Primary	Characterisation of weight gain and metabolic consequences associated with long-term	Dual-energy X-ray absorptiometry (DXA) scan	60 Days
Secondary	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
Secondary	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
Secondary	Description of the presence of viraemia	Plasma HIV-1 RNA levels	60 Days
Secondary	Description of the presence and patterns of HIV-1 resistance mutations in participants with viral loads > 1000 copies/mL	HIV-1 genotyping	60 Days
Secondary	Description and occurrence of associated sleep quality and disorders	Berlin Questionnaire for risk of sleep apnoea	60 Days
Secondary	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