Efficacy Study of Different Laboratory Management Strategies and Drug Regimens in HIV-infected Children in Africa
Information source: Medical Research Council
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Human Immunodeficiency Virus
Intervention: Clinically Driven Monitoring (CDM) (Other); Laboratory plus Clinical Monitoring (LCM) (Other); Arm A: ABC+3TC+NNRTI (Drug); Arm B: ZDV+ABC+3TC+NNRTI->ABC+3TC+NNRTI maintenance (Drug); Arm C: ZDV+ABC+3TC+NNRTI->ZDV+ABC+3TC maintenance (Drug); Once-daily ABC+3TC (Drug); Twice-daily ABC+3TC (Drug); Continued cotrimoxazole prophylaxis (Drug); Stopped cotrimoxazole prophylaxis (Other)
Phase: Phase 4
Status: Completed
Sponsored by: Medical Research Council Official(s) and/or principal investigator(s): Diana M Gibb, MD, Principal Investigator, Affiliation: Medical Research Council Peter Mugyenyi, PhD, Principal Investigator, Affiliation: Joint Clinical Research Centre, Kampala, Uganda Kusum Nathoo, PhD, Principal Investigator, Affiliation: University of Zimbabwe, Harare, Zimbabwe Adeodata Kekitiinwa, MD, Principal Investigator, Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda Paula Munderi, MBChB, Principal Investigator, Affiliation: MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda Victor Musiime, PhD, Principal Investigator, Affiliation: Joint Clinical Research Centre, Kampala, Uganda Mutsa F Bwakura-Dangarembizi, MBChB, Principal Investigator, Affiliation: University of Zimbabwe, Harare, Zimbabwe Philippa Musoke, PhD, Principal Investigator, Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda Sabrina Bakeera-Kitaka, MBChB, Principal Investigator, Affiliation: Baylor College of Medicine Children's Foundation, Mulago, Uganda Patricia Nahirya-Ntege, MBChB, Principal Investigator, Affiliation: MRC/UVRI Uganda Research Unit on Aids
Summary
The two original objectives were to determine in HIV-infected children initiating
antiretroviral therapy (ART):
1. 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)?
2. 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
3. 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?
4. 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?
Clinical Details
Official title: A Randomised Trial of Monitoring Practice and Induction Maintenance Drug Regimens in the Management of Antiretroviral Therapy in Children With HIV Infection in Africa
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: LCM vs CDM: Disease Progression to a New WHO Stage 4 Event or DeathLCM vs CDM: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV Induction ART: Change From Baseline in CD4% 72 Weeks After ART Initiation Induction ART: Change From Baseline in CD4% to 144 Weeks From ART Initiation Induction ART: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV Once Versus Twice Daily Abacavir+Lamivudine: Suppressed HIV RNA Viral Load 48 Weeks After Randomisation 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 Cotrimoxazole: New Hospitalisation or Death Cotrimoxazole: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV
Secondary outcome: LCM vs CDM, Induction ART: All-cause MortalityInduction ART: New WHO Stage 4 Event or Death LCM vs CDM, Induction ART: New WHO Stage 3 or 4 Event or Death LCM vs CDM, Induction ART: New or Recurrent WHO Stage 3 or 4 Event or Death LCM vs CDM, Induction ART: Weight-for-age Z-score LCM vs CDM, Induction ART: Height-for-age Z-score LCM vs CDM, Induction ART: Body Mass Index-for-age Z-score LCM vs CDM: Change From Baseline in CD4% to Week 72 LCM vs CDM: Change From Baseline in CD4% to Week 144 LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 72 LCM vs CDM, Induction ART: Change From Baseline in Absolute CD4 to Week 144 CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 72 Weeks After Baseline CDM vs LCM, Induction ART: Suppression of HIV RNA Viral Load 144 Weeks After Baseline LCM vs CDM, Induction ART: Cessation of First-line Regimen for Clinical/Immunological Failure LCM vs CDM, Induction ART: New Grade 3 or 4 Adverse Event Definitely/Probably or Uncertainly Related to ART LCM vs CDM, Induction ART: New Serious Adverse Events Not Solely Related to HIV LCM vs CDM, Induction ART: New ART-modifying Adverse Event LCM vs CDM, Induction ART: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) Once Versus Twice Daily Abacavir+Lamivudine: Suppression of HIV RNA Viral Load 96 Weeks After Randomisation Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 48 Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 72 Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in CD4% to Week 96 Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 48 Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 72 Once Versus Twice Daily Abacavir+Lamivudine: Change From Baseline in Absolute CD4 to Week 96 Once Versus Twice Daily Abacavir+Lamivudine: All-cause Mortality Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 4 Event or Death Once Versus Twice Daily Abacavir+Lamivudine: New WHO Stage 3 or 4 Event or Death Once Versus Twice Daily Abacavir+Lamivudine: Height-for-age Z-score Once Versus Twice Daily Abacavir+Lamivudine: Weight-for-age Z-score Once Versus Twice Daily Abacavir+Lamivudine: Body Mass Index-for-age Z-score Once Versus Twice Daily Abacavir+Lamivudine: New Grade 3 or 4 Adverse Event (AE), Not Solely Related to HIV Once Versus Twice Daily Abacavir+Lamivudine: New Serious Adverse Events Not Solely Related to HIV 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 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 Once Versus Twice Daily Abacavir+Lamivudine: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks) Cotrimoxazole: New Clinical and Diagnostic Positive Malaria Cotrimoxazole: New Severe Pneumonia Cotrimoxazole: New WHO Stage 3 or 4 Event or Death Cotrimoxazole: New WHO Stage 3 Severe Recurrent Pneumonia or Diarrhoea Cotrimoxazole: New WHO Stage 4 Event or Death Cotrimoxazole: All-cause Mortality Cotrimoxazole: Weight-for-age Z-score Cotrimoxazole: Height-for-age Z-score Cotrimoxazole: Body Mass Index-for-age Z-score Cotrimoxazole: Change From Baseline in CD4% to Week 72 Cotrimoxazole: Change From Baseline in Absolute CD4 to Week 72 Cotrimoxazole: New Serious Adverse Events Not Solely Related to HIV Cotrimoxazole: Adherence to ART as Measured by Self-reported Questionnaire (Missing Any Pills in the Last 4 Weeks)
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.
Eligibility
Minimum age: 3 Months.
Maximum age: 17 Years.
Gender(s): Both.
Criteria:
For initial randomisation to CDM vs LCM, and to ART induction strategy:
Inclusion Criteria:
1. 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.
2. 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.
3. Participants must have a confirmed documented diagnosis of HIV-1 infection:
1. 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).
2. 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.
4. Age 3 months to 17 years (13-17 years to be capped at 10%)
5. ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child
HIV transmission).
6. Meeting criteria for requiring ART according to WHO stage and CD4 percent or count:
- WHO paediatric clinical stage IV disease: treat regardless of CD4 percent or
count
- WHO paediatric clinical stage III disease:
- <12 months: treat all
- >12 months: treat all children irrespective of the CD4 percent or count;
however, in children aged > 12 months with tuberculosis, lymphocytic
interstitial pneumonia (LIP), oral hairy leukoplakia (OHP) or
thrombocytopenia (low platelet count treat) be guided by CD4 cell assays
(see below).
- WHO paediatric clinical stage II or I disease: treat guided by CD4 percent or
count
- CD4%<25% for infants <12 months;
- CD4%<20% for children 1-<3 years;
- CD4% <15% for children 3-<5years;
- CD4% <15% for children > 5years (consideration should also be taken of the
CD4 count. A CD4 count <200 cells/mm3 can be used to guide starting ART and
CD4 should generally be <350 cells/mm3.)
Exclusion Criteria:
1. Cannot, or unlikely to attend regularly (e. g. usual residence too far from study
centre)
2. Likelihood of poor adherence
3. 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)
4. 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
5. 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.
6. Being pregnant or breast-feeding an infant
7. Perinatal exposure to nevirapine (either through prevention of mother-to-child
transmission (pMTCT) or breastfeeding) for children aged 3 - 6 months only
Eligibility criteria for the secondary randomisation to once vs twice daily
lamivudine+abacavir Inclusion criteria
1. Participating in ARROW
2. On ART for at least 36 weeks
3. Currently taking lamivudine+abacavir twice daily as part of their ART regimen and
expected to stay on these two drugs for at least the next 12 weeks
4. 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
once or twice daily lamivudine+abacavir
Exclusion criteria
5. Likely to switch to second-line therapy in the next 12 weeks
Eligibility criteria for the secondary randomisation to stop or continue cotrimoxazole
prophylaxis randomisation Inclusion criteria
1. Participating in ARROW
2. Aged at least 3 years
3. Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART
allowing for any interruptions in ART
4. Currently prescribed daily cotrimoxazole as primary prophylaxis
5. 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
stop or continue daily cotrimoxazole prophylaxis
6. If living in a malaria endemic area, has an insecticide treated bednet and prepared
to use this for the child.
Exclusion criteria
7. Previous diagnosis of Pneumocystis jiroveci pneumonia (cotrimoxazole is secondary
prophylaxis and should not be discontinued)
Locations and Contacts
MRC /UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
Joint Clinical Research Centre, Kampala, Uganda
Baylor College of Medicine Children's Foundation, Mulago, Uganda
University of Zimbabwe Medical School, Harare, Zimbabwe
Additional Information
main ARROW trial webpage
Starting date: March 2007
Last updated: June 4, 2014
|