Children with HIV in Africa – pharmacokinetics and acceptability of simple second-line antiretroviral regimens

• Register: ISRCTN
• Last refreshed on: 2 August 2023
• Main ID: ISRCTN22964075
• Date of registration: 20/10/2017
• Prospective Registration: Yes
• Primary sponsor: University College London (UK)
• Public title: Children with HIV in Africa – pharmacokinetics and acceptability of simple second-line antiretroviral regimens
• Scientific title: Children with HIV in Africa – pharmacokinetics and acceptability of simple second-line antiretroviral regimens (CHAPAS-4 trial): a randomised controlled trial
• Date of first enrolment: 17/12/2018
• Target sample size: 1000
• Recruitment status: Completed
• URL: https://www.isrctn.com/ISRCTN22964075
• Study type: Interventional
• Study design: 4x2 open-label factorial multi-centre randomised controlled trial (Treatment)
• Phase: Phase III

Countries of recruitment

Uganda, Zambia, Zimbabwe

Contacts

• Name: Diana Gibb

Key inclusion & exclusion criteria

Inclusion criteria:
Current inclusion criteria as of 17/07/2019:
1. HIV-infected currently receiving NNRTI containing regimen with abacavir-, zidovudine- or stavudine-containing NRTIbackbone and failing according to current WHO criteria:
1.1. Confirmed VL >1000 copies/ml after adherence counselling (confirmatory may be at screening) OR
1.2. CD4 criteria for failure OR
1.3. Clinical criteria for failure
2. Aged 3-15 years inclusive
3. Weight 14 kg or higher
4. Viral load >400 copies/ml at screening visit
5. Able to swallow trial drug tablets (all children will have been receiving tablets within first-line ART)
6. If female and reached menses, then negative pregnancy test at screening (and randomisation if randomisation >2 weeks from screening) and willing to adhere to highly effective methods of contraception if sexually active
7. Parents/carers give informed written consent; child provides informed written assent as appropriate based on age, knowledge of HIV status and local country guidelines

Previous inclusion criteria:
1. HIV-infected failing first-line treatment with abacavir-, zidovudine- or stavudine-containing NRTI+NNRTI regimens as per current WHO criteria
2. Aged 3-15 years inclusive
3. Weight 14 kg or higher
4. Viral load >400 copies/ml at screening visit
5. Able to swallow trial drug tablets (all children will have been receiving tablets within first-line ART)
6. Parents/carers give informed written consent; child provides informed written assent as appropriate based on age, knowledge of HIV status and local country guidelines

Exclusion criteria:
Current exclusion criteria as of 17/07/2019:
1. History or presence of known allergy or other contraindication to the study drugs or their components
2. Treatment of co-morbidities, except TB, with significant drug interactions with the study drugs, requiring their dose adjustment
3. Breastfeeding
4. More than 3 months (>91 days) from the screening visit
5. Evidence of previous failure on LPV/r
6. Evidence of previous failure on both abacavir and zidovudine
7. Alanine aminotransferase (ALT) =5 times the upper limit of normal (ULN), OR ALT =3xULN and bilirubin =2xULN
8. Patients with severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

Previous exclusion criteria:
1. History or presence of known allergy or other contraindication to the study drugs or their components
2. Treatment of co-morbidities, except TB, with significant drug interactions with the study drugs, requiring their dose adjustment
3. More than 3 months (>91 days) from the screening visit


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

HIV infection
Infections and Infestations
Human immunodeficiency virus [HIV] disease

Intervention(s)

Current interventions as of 12/05/2021:
A screening visit involving blood tests will be carried out to confirm that the child is eligible. Consented participants will then be randomly assigned to one ‘third-drug’ and one ‘NRTI based regimen’. Randomisation lists will be prepared by the trial statistician using permuted blocks and sites will randomise using the trial database.

Specifically, one third drug from (randomised in a 1:1:1 ratio):
1. Research: dolutegravir (DTG) once-daily (OD) (an integrase inhibitor, INI)
2. Research: atazanavir/ritonavir (ATV/r) OD (boosted protease inhibitor, bPI)
3. Research: darunavir/ritonavir (DRV/r) OD (boosted protease inhibitor, bPI)
4. Standard of care: lopinavir/ritonavir (LPV/r) twice-daily (BD) (bPI)

Together with one nucleoside reverse transcriptase inhibitor (NRTI) backbone from (randomised in a 1:1 ratio):
1. Research: tenofovir-alafenamide (TAF) plus emtricitabine (FTC) OD
2. Standard of care: whichever of abacavir (ABC) (OD) or zidovudine (ZDV) (BD) has not been used first-line, plus lamivudine (3TC)

The route of administration will be oral and each drug will be dosed according to weight bands.

Enough ART will be prescribed for the participant to take daily until they are seen at their next clinic visit. Participants will be followed up for a minimum of 2 years with clinic visits every 3 months. At the visits side effects and responses to treatment will be carefully checked by a nurse and a doctor. A small amount of blood will be collected and stored at each visit. The first children enrolled into the study, plus children who recei

Primary Outcome(s)

Percentage of children alive with viral load <400 copies/ml, measured with lab test at baseline and weeks 6, 24, 48, 72, 96

Secondary Outcome(s)

Secondary outcome measures through 96 weeks are:
1. Percentage of children alive with viral load <50 and <1000 copies/ml, measured with lab test at baseline and weeks 6, 24, 48, 72, 96
2. Change in Stanford drug resistance, accumulation of new NRTI, PI and INI resistance-associated mutations in those with viral load > 400 copies/ml, measured with lab test at weeks 48, 96
3. Percentage modifying ART due to adverse events (AEs), incidence/type of grade 3/4 AEs and serious AEs, measured throughout the study as they occur (investigator reported, reviewed by blinded Endpoint Review Committee)
4. Changes in total, LDL, HDL cholesterol and triglycerides, measured using lab test at baseline, weeks 48, 96
5. Changes in renal function (creatinine clearance estimated using bedside-Schwartz) and bilirubin, measured using lab test at baseline, weeks 6, 24, 48, 96
6. Changes in absolute and percentage CD4, measured using lab test at baseline, weeks 24, 48, 72, 96
7. New or recurrent WHO 3 or 4 events or death, reported on an event form by the site clinician and initially clinically reviewed at MRC CTU by the trial physician and finally reviewed and adjudicated by an independent endpoint committee
8. Self-reported adherence and acceptability, measured using nurse-led questionnaires and pill counts at all visits (baseline, weeks 2, 6, 12, 24, 36, 48, 60, 72, 84, 96)

Other outcome measures are:
1. Hospital inpatient episodes and total days admitted through 96 weeks, measured throughout the study as they occur (investigator reported)
2. Changes in bone mineral density Z-scores assessed by calcaneal ultrasound at baseline, weeks 6, 24, 48, 72, 96 and in a sub-set of patients measured by DEXA scan at baseline, weeks 48, 96
3. Changes in weight-for-age, height-for-age and body mass index-for-age Z scores, measured at all visits (baseline, weeks 2, 6, 12, 24, 36, 48, 60, 72, 84, 96)
4. Body composition, measured by bioelectrical impedance analysis
5. Population pharmacokinetics, measured using lab test at weeks 6, 24, 48, 72, 96
6. Cost-effectiveness: at the end of the trial health economists will analyse data collected on medical resource utilisation (e.g. hospital stays, drug usage) with data on clinical, virological and quality of life outcomes

Secondary ID(s)

N/A

Source(s) of Monetary Support

European and Developing Countries Clinical Trials Partnership, Janssen Pharmaceutica NV

Ethics review

Status:
Approval date:
Contact:

Old ethics approval format; 1. UCL Research Ethics Committee, 21/07/2017, ref: 11205/001 2. Ethics approval sought from the appropriate national ethics committees in Uganda, Zambia and Zimbabwe

Results

• Results available: Yes
• Date Completed: 01/02/2023