A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa
Overview
- Phase
- Phase 4
- Intervention
- Clinically Driven Monitoring (CDM)
- Conditions
- Human Immunodeficiency Virus
- Sponsor
- Medical Research Council
- Enrollment
- 1206
- Locations
- 4
- Primary Endpoint
- LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART):
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Whether clinically driven monitoring (CDM) will have a similar outcome in terms of disease progression or death as routine laboratory and clinical monitoring (LCM) for toxicity (haematology/biochemistry) and efficacy (CD4)?
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Whether induction with four drugs from two ART classes followed by maintenance with three drugs after 36 weeks be more effective than a continuous non-nucleoside reverse transcriptase inhibitors (NNRTI)-based triple drug regimen in terms of CD4 and clinical outcome?
Two secondary objectives were to determine
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Whether changing from twice daily lamivudine+abacavir to once daily lamivudine+abacavir after 48 weeks on ART will have a similar outcome in terms of virological suppression and will result in improvements in adherence to ART?
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Whether stopping daily cotrimoxazole prophylaxis in children over 3 years of age who have been on ART for at least 96 weeks has a similar outcome in terms of hospitalisation or death as continuing daily cotrimoxazole?
Detailed Description
The ARROW (AntiRetroviral Research fOr Watoto) protocol describes an open-label randomised trial primarily evaluating two strategic approaches for management of antiretroviral therapy (ART) in 1200 symptomatic HIV-infected infants and children initiating ART following WHO guidelines in Uganda and Zimbabwe. The first strategy compares clinically driven monitoring (CDM) with laboratory plus clinical monitoring (LCM). In both groups, tests for toxicity (standard haematology and biochemistry panels) and efficacy (lymphocyte subsets including CD4 count) will be done every 12 weeks. In LCM, all results will be returned for patient management. In CDM, physicians may request results from routine haematology/biochemistry panels if needed for clinical management, but results will not be returned routinely, and lymphocyte subsets will never be returned. Extra laboratory tests may be requested outside of the scheduled visits at any time in either group (except for lymphocyte subsets in CDM). The second strategy compares a continuous WHO-recommended first-line ART three-drug two-class regimen, comprising two Nucleoside Reverse Transcriptase Inhibitors (NRTIs) plus one Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), with induction with four drugs (two classes) for 36 weeks followed by maintenance with three drugs. After at least 36 and 96 weeks on ART respectively, two further randomisations will assess simplification strategies which could improve long-term ART adherence (i) once versus twice daily lamivudine+abacavir NRTI drugs (ii) stopping versus continuing daily cotrimoxazole prophylaxis.
Investigators
Diana M Gibb
Professor of Epidemiology
Medical Research Council
Eligibility Criteria
Inclusion Criteria
- •Children should have an adult carer in the household who is either:
- •participating in the DART trial OR
- •being treated with ART OR
- •HIV positive but not yet needing treatment but with access to a treatment programme when ART is required OR
- •HIV negative. Children of DART participants should have first priority on any available remaining slots to enter ARROW.
- •Parents or guardians, and children where appropriate according to age and knowledge of HIV status, must be willing and able to give informed consent for randomisation to CDM or LCM and to first-line ART strategy.
- •Participants must have a confirmed documented diagnosis of HIV-1 infection:
- •For children aged under 18 months: two separate peripheral blood specimens from different days, both results being positive with HIV-DNA polymerase chain reaction (PCR).
- •For children aged 18 months or over: antibody positive serology by ELISA test (confirmed by licensed second ELISA or Western Blot) or WHO approved rapid test (performed in series) both on the same sample. Any child previously tested at another clinic should have a repeat test at an ARROW screening laboratory to confirm their status.
- •Age 3 months to 17 years (13-17 years to be capped at 10%)
Exclusion Criteria
- •Cannot, or unlikely to attend regularly (e.g. usual residence too far from study centre)
- •Likelihood of poor adherence
- •Presence of acute infection (e.g. malaria, helminthiasis, acute hepatitis, acute pneumonia, septicaemia, meningitis). Children may be admitted after recovery of an acute infection. Children with chronic lung disease, including recurrent respiratory infections, are eligible. Children with tuberculosis (TB) will not be enrolled while on the intensive phase of anti-tuberculosis therapy, but should be re-evaluated after the intensive phase and a decision made then about starting ART (see 4 below)
- •In receipt of medication contraindicated by ART
- •children under three years of age receiving anti-tuberculosis therapy should not be enrolled (as they will have to receive nevirapine).
- •on chemotherapy for malignancy
- •Laboratory abnormalities which are a contra-indication for the child to start ART (haemoglobin \<8.5g/dL; neutrophils \<0.50x109/L; aspartate transaminase (AST) or alanine transaminase (ALT) \>5 x the upper limit of normal (ULN); grade 3 renal dysfunction - creatinine \>1.9 x ULN).
- •N.B. causes of anaemia, such as concurrent bacterial infection, malaria, helminthiasis and/or malnutrition should be investigated, and treatment for anaemia and its causes commenced prior to re-screening for eligibility.
- •Being pregnant or breast-feeding an infant
- •Perinatal exposure to nevirapine (either through prevention of mother-to-child transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only
Arms & Interventions
Clinically Driven Monitoring (CDM)
Intervention: Clinically Driven Monitoring (CDM)
Laboratory plus Clinical Monitoring (LCM)
Intervention: Laboratory plus Clinical Monitoring (LCM)
Once-daily ABC+3TC
ABC \[abacavir\]: syrup or tablet, dosed once-daily according to weight-bands following WHO 3TC \[lamivudine\]: syrup or tablet, dosed once-daily according to weight-bands following WHO
Intervention: Once-daily ABC+3TC
Twice-daily ABC+3TC
ABC \[abacavir\]: syrup or tablet, dosed twice-daily according to weight-bands following WHO 3TC \[lamivudine\]: syrup or tablet, dosed twice-daily according to weight-bands following WHO
Intervention: Twice-daily ABC+3TC
Continued cotrimoxazole prophylaxis
Once-daily doses 5-\<15 kg: 200 mg of trimethoprim + 40 mg sulfamethoxazole 15-\<30 kg: 400 mg trimethoprim + 80 mg sulfamethoxazole \>=30 kg: 800 mg trimethoprim + 160 mg sulfamethoxazole
Intervention: Continued cotrimoxazole prophylaxis
Stopped cotrimoxazole prophylaxis
Children had been taking once-daily cotrimoxazole prophylaxis since at least ART initiation. Children randomised to this experimental arm stopped taking cotrimoxazole prophylaxis.
Intervention: Stopped cotrimoxazole prophylaxis
Outcomes
Primary Outcomes
LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or Death
Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Number of participants with disease progression to a new WHO stage 4 event or death, to be analysed using time-to-event methods
LCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Number of participants with a new Grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation
Time Frame: Baseline, 72 weeks
Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation
Time Frame: Baseline, 144 weeks
Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Time Frame: Median 4 years (from randomization to 16 March 2012; maximum 5 years)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation
Time Frame: 48 weeks
Number of participants with HIV RNA viral load \<80 copies/ml at 48 weeks. Measured retrospectively on stored plasma specimens: due to low stored volumes from some children, samples had to be diluted and therefore a threshold of \<80 copies/ml was used to indicate suppression.
Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV, Judged Definitely/Probably or Uncertain Whether Related to Lamivudine or Abacavir
Time Frame: Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, judged definitely/probably or uncertain whether related to lamivudine or abacavir, to be analysed using time-to-event methods
Cotrimoxazole: New Hospitalisation or Death
Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Number of participants with a new hospitalisation or death, to be analysed using time-to-event methods
Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Time Frame: Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years)
Number of participants with a new grade 3 or 4 adverse event (AE), not solely related to HIV, to be analysed using time-to-event methods
Secondary Outcomes
- LCM vs CDM, Induction ART: All-cause Mortality(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- Induction ART: New WHO Stage 4 Event or Death(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72(Baseline, week 72)
- LCM vs CDM, Induction ART: Weight-for-age Z-score(Baseline and a median of 4 years (maximum 5 years))
- LCM vs CDM, Induction ART: Height-for-age Z-score(Baseline and a median of 4 years (maximum 5 years))
- LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score(Baseline and a median of 4 years (maximum 5 years))
- LCM vs CDM: Change From Baseline in CD4% to Week 72(Baseline, week 72)
- LCM vs CDM: Change From Baseline in CD4% to Week 144(Baseline, week 144)
- LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144(Baseline, week 144)
- CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline(72 weeks)
- CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline(144 weeks)
- LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: New ART-modifying Adverse Event(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)(Median 4 years (from randomization to 16 March 2012; maximum 5 years))
- Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation(96 weeks)
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48(Randomisation to once vs twice daily, week 48)
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72(Baseline, week 72)
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96(Randomisation to once vs twice daily, week 96)
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48(Randomisation to once vs twice daily, week 48)
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72(Baseline, week 72)
- Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality(Median 2 years (from randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96(Randomisation to once vs twice daily, week 96)
- Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death(Median 2 years (from randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death(Median 2 years (from randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score(Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score(Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score(Baseline and a median of 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV(Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV(Median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72(Baseline, week 72)
- Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 48 Weeks(48 weeks after randomization to once- versus twice-daily)
- Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) at 96 Weeks(96 weeks after randomization to once- versus twice-daily)
- Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)(Mean over median 2 years (from once vs twice daily randomization to 16 March 2012; maximum 2.6 years))
- Cotrimoxazole: New Clinical and Diagnostic Positive Malaria(Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: New Severe Pneumonia(Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: New WHO Stage 3 or 4 Event or Death(Median 2 years (from randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea(Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: New WHO Stage 4 Event or Death(Median 2 years (from randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: All-cause Mortality(Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: Weight-for-age Z-score(Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: Height-for-age Z-score(Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: Body Mass Index-for-age Z-score(Baseline and a median of 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: Change From Baseline in CD4% to Week 72(Baseline, week 72)
- Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV(Median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))
- Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)(Mean over median 2 years (from cotrimoxazole randomization to 16 March 2012; maximum 2.5 years))