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About
The two original objectives were to determine in HIV-infected children initiating antiretroviral therapy (ART):
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)?
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
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?
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?
Full 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.
Enrollment
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Inclusion and exclusion criteria
For initial randomisation to CDM vs LCM, and to ART induction strategy:
Inclusion Criteria:
Children should have an adult carer in the household who is either:
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:
Age 3 months to 17 years (13-17 years to be capped at 10%)
ART naïve (except for exposure to perinatal ART for the prevention of mother-to-child HIV transmission).
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:
WHO paediatric clinical stage II or I disease: treat guided by CD4 percent or count
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
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
Eligibility criteria for the secondary randomisation to once vs twice daily lamivudine+abacavir Inclusion criteria
Participating in ARROW
On ART for at least 36 weeks
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
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
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
Participating in ARROW
Aged at least 3 years
Initiated ART at least 96 weeks previously, and received at least 96 weeks of ART allowing for any interruptions in ART
Currently prescribed daily cotrimoxazole as primary prophylaxis
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
If living in a malaria endemic area, has an insecticide treated bednet and prepared to use this for the child.
Exclusion criteria
Previous diagnosis of Pneumocystis jiroveci pneumonia (cotrimoxazole is secondary prophylaxis and should not be discontinued)
Primary purpose
Allocation
Interventional model
Masking
1,206 participants in 9 patient groups
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Data sourced from clinicaltrials.gov
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