Children with HIV in Africa – pharmacokinetics and acceptability of simple second-line antiretroviral regimens
| ISRCTN | ISRCTN22964075 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN22964075 |
| Secondary identifying numbers | N/A |
- Submission date
- 11/08/2017
- Registration date
- 20/10/2017
- Last edited
- 17/06/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
Human immunodeficiency virus (HIV) is a virus that damages the cells in the immune system and weakens the body’s ability to fight everyday infections and disease. HIV is treated with antiretroviral medications which stop the virus replicating in the body. In 2014, an estimated 823,000 HIV-infected children and adolescents aged up to 15 years were receiving anti-retroviral therapy (ART) in low- and middle-income countries. From 2015, World Health Organisation (WHO) guidelines recommended all HIV-infected adults and children take ART, regardless of the strength of their immune system (CD4 count) or their clinical status. The numbers of HIV-infected children on first-line ART in low-income countries is therefore likely to continue to increase, despite reductions in many countries of new infections through mother-to child transmission. The growing number of children on ART, coupled with increased detection of ART treatment failure, will increase the number of children needing to switch from their first ART drug treatment (first line) to second-line treatment. This raises the question of whether current second-line ART is optimal in terms of maximising children’s health gains and minimising toxicity (side effects) from the treatment long-term, given the need for children to receive life-long ART. The current WHO-recommended second-line ART for children failing standard first-line treatment is not ideal, as it is based on a fixed dose combination drug which needs to be taken as whole (non-crushed) pills, mini-pill pellets or unpalatable liquid, and also interacts with anti-tuberculosis drugs. The aim of this study is to optimise second-line treatment in HIV-infected children by testing new antiretroviral drugs/formulations, in order to maximise long-term health gains.
Who can participate?
HIV-infected children aged 3-15 years weighing 14 kg or higher and failing first-line antiretroviral treatment
What does the study involve?
A screening visit involving blood tests is carried out to confirm that the child is eligible. Participants are then randomly allocated to one ‘third-drug’ and one ‘NRTI based regimen’.
The four ‘third-drug’ options are:
1. The current standard of care, called lopinavir/ritonavir (LPV/r)
2. A different drug which belongs to the same family as LPV/r, called atazanavir/ritonavir (ATV/r). This drug is used a lot in adults but has not previously been available as a single pill for children
3. A different drug that also belongs to the same drug family as LPV/r, called darunavir/ritonavir (DRV/r)
4. A drug which belongs to a different family, called dolutegravir (DTG)
The two ‘NRTI based regimens’ are:
1. The current standard of care, which is lamivudine (3TC) combined with whichever of abacavir (ABC) or zidovudine (ZDV) is not taken as first-line ART
2. A new drug called‘TAF (tenofovir alafenamide) combined with a drug very similar to lamivudine called emtricitabine (FTC). TAF is a new type of an existing ART drug called tenofovir which is much kinder on people’s bones and kidneys and so can be tested in children
Enough ART is prescribed for the participant to take daily until they are seen at their next clinic visit. Participants are followed up for a minimum of 2 years with clinic visits every 3 months. At the visits side effects and responses to treatment are carefully checked by a nurse and a doctor. A small amount of blood is collected and stored at each visit. The first children enrolled into the study, plus children who receive anti-tuberculosis treatment during the study have additional blood tests to look at levels of the antiretroviral drugs in their blood.
What are the possible benefits and risks of participating?
There may be no direct benefit to the children participating in the study. However, the information from this study will help to improve treatment for children with HIV in the future. These children need to be treated with second-line ART regardless of whether or not they participate in the study, and all treatment has risks and side effects. The common side effects of ART are stomach upsets, changes in the liver, problems with kidney and bones, difficulty sleeping, hypersensitivity reactions and tiredness. Participating children need to attend the clinic more frequently than if they were receiving treatment outside of the study. In addition there are some extra blood tests.
Where will the study be run?
1. University of Zimbabwe Clinical Research Centre (UZCRC), Harare (Zimbabwe)
2. University Teaching Hospital, Lusaka (Zambia)
3. Joint Clinical Research Centre (JCRC), Kampala (Uganda)
4. Mbarara Regional Referral Hospital (Uganda)
5. Arthur Davison Children’s Hospital (Zambia)
6. Mpilo Central Hospital (Zimbabwe)
7. It is coordinated by the Medical Research Council Clinical Trials Unit at UCL, London (UK)
When is the study starting and how long is it expected to run for?
April 2017 to February 2023
Who is funding the study?
European and Developing Countries Clinical Trials Partnership (EU) with additional funding from Janssen Pharmaceutica (Belgium) and Gilead Sciences (USA)
Who is the main contact?
CHAPAS-4 Trial Management Team
mrcctu.chapas4@ucl.ac.uk
Contact information
Scientific
MRC Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
90 High Holborn
2nd Floor
London
WC1V 6LJ
United Kingdom
 ORCID ID |
0000-0002-9738-5490 |
|---|
Study information
| Study design | 4x2 open-label factorial multi-centre randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | Children with HIV in Africa – pharmacokinetics and acceptability of simple second-line antiretroviral regimens (CHAPAS-4 trial): a randomised controlled trial |
| Study acronym | CHAPAS-4 |
| Study hypothesis | The CHAPAS-4 trial will evaluate four new drugs/formulations (dolutegravir (DTG), tenofovir alafenamide (TAF), darunavir/ritonavir (DRV/r) and atazanavir/ritonavir (ATV/r)) to optimise treatment for children, and better harmonise with adult anti-retroviral therapy (ART). CHAPAS-4 will also evaluate options for second-line treatment given concomitantly with anti-tuberculosis drugs. There are four main hypotheses: 1. DTG will provide superior virological suppression 96 weeks after starting second-line ART compared to second-line ART based on the bPIs LPV/r or ATV/r 2. DRV/r will provide superior virological suppression 96 weeks after starting second-line ART compared to second-line ART based on the bPIs LPV/r or ATV/r 3. ATV/r will provide non-inferior virological efficacy compared to lopinavir/ritonavir (LPV/r) in second-line ART 4. TAF will provide non-inferior virological efficacy compared to standard of care NRTIs in second-line ART |
| Ethics approval(s) | 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 |
| Condition | HIV infection |
| Intervention | 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 receive anti-TB treatment during the study will have additional blood tests to look at levels of the antiretroviral drugs in their blood. Children will be enrolled over 18 months and followed for 96 weeks, where they will be invited to enrol in extended follow-up for up to a further 2 years. Treatment will continue throughout the trial. Previous interventions: 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 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 receive anti-TB treatment during the study will have additional blood tests to look at levels of the antiretroviral drugs in their blood. Children will be enrolled over 18 months and followed for 96 weeks. Treatment will continue throughout the trial. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Dolutegravir, atazanavir, darunavir, ritonavir, lopinavir, tenofovir, alafenamide, emtricitabine, abacavir, lamivudine, zidovudine |
| Primary outcome measure | 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 measures | 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 |
| Overall study start date | 01/04/2017 |
| Overall study end date | 01/02/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Lower age limit | 3 Years |
| Upper age limit | 15 Years |
| Sex | Both |
| Target number of participants | 1000 |
| Total final enrolment | 919 |
| Participant 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 |
| Participant 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 |
| Recruitment start date | 17/12/2018 |
| Recruitment end date | 01/04/2021 |
Locations
Countries of recruitment
- Uganda
- Zambia
- Zimbabwe
Study participating centres
1578 Avondale
Zimbabwe
PO Box 10005
Uganda
PO Box 50110
Zambia
Mbarara
-
Uganda
Box 240227
Ndola
-
Zambia
Mzilikazi
PO Box 2096
Bulawayo
-
Zimbabwe
Sponsor information
University/education
Gower Street
London
WC1E 6BT
England
United Kingdom
"ROR" |
https://ror.org/02jx3x895 |
|---|
Funders
Funder type
Research organisation
Private sector organisation / International organizations
- Alternative name(s)
- Le partenariat Europe-Pays en développement pour les essais cliniques, A Parceria entre a Europa e os Países em Desenvolvimento para a Realização de Ensaios Clínicos, The European & Developing Countries Clinical Trials Partnership, European and Developing Countries Clinical Trials, EDCTP
- Location
- Netherlands
No information available
Results and Publications
| Intention to publish date | 01/06/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | 1. The protocol will be available on the MRC CTU at UCL webpage 2. Planned publication of study results in a high-impact peer reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Gibb (mrcctu.chapas4@ucl.ac.uk) after main publication following the Unit’s Data Sharing SOP and after approval from the Trial Steering Committee, which has majority independent membership, for any approved analyses, all data is anonymised. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Interim results article | Pharmacokinetic substudy secondary outcome results | 06/06/2023 | 07/06/2023 | Yes | No |
| Other publications | Substudy results | 09/05/2023 | 15/06/2023 | Yes | No |
| Other publications | Substudy results | 20/07/2023 | 21/07/2023 | Yes | No |
| Preprint results | Second-line anchor drugs | 15/04/2024 | 09/01/2025 | No | No |
| Preprint results | Second-line tenofovir alafenamide | 21/04/2024 | 09/01/2025 | No | No |
| Results article | Second-line anchor drugs | 14/05/2025 | 09/06/2025 | Yes | No |
| Other publications | Pharmacokinetic sub-study | 16/06/2025 | 17/06/2025 | Yes | No |
Editorial Notes
17/06/2025: Publication reference added.
09/06/2025: Publication reference added.
09/01/2025: Preprints added.
10/05/2024: The intention to publish date was changed from 01/03/2023 to 01/06/2024.
21/07/2023: Publication reference added.
15/06/2023: Publication reference added.
07/06/2023: Publication reference added.
13/05/2021: Total final enrolment number added.
12/05/2021: The following changes were made to the trial record:
1. The interventions were updated.
2. The recruitment end date was changed from 01/03/2021 to 01/04/2021.
3. The overall trial end date was changed from 31/12/2022 to 01/02/2023.
4. The plain English summary was updated accordingly.
14/12/2020: Janssen Pharmaceutica NV has been added as a funder and the plain English summary updated accordingly.
01/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/10/2020 to 01/03/2021.
2. The overall trial end date was changed from 01/03/2022 to 31/12/2022.
17/07/2019: The inclusion and exclusion criteria and trial participating centres were updated.
08/03/2019: The recruitment start date was changed from 01/11/2018 to 17/12/2018.
01/10/2018: The recruitment start date was changed from 01/04/2018 to 01/11/2018.
