Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial

Abstract

Background: No trials have investigated routine laboratory monitoring for children with HIV, nor four-drug induction strategies to increase durability of first-line antiretroviral therapy (ART). Methods: In this open-label parallel-group trial, Ugandan and Zimbabwean children or adolescents with HIV, aged 3 months to 17 years and eligible for ART, were randomly assigned in a factorial design. Randomisation was to either clinically driven monitoring or routine laboratory and clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4 cell counts; non-inferiority monitoring randomisation); and simultaneously to standard three-drug or to four-drug induction first-line ART, in three groups: three-drug treatment (non-nucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C; superiority ART-strategy randomisation). For patients assigned to routine laboratory monitoring, results were returned every 12 weeks to clinicians; for clinically driven monitoring, toxicity results were only returned for requested clinical reasons or if grade 4. Children switched to second-line ART for WHO stage 3 or 4 events or (routine laboratory monitoring only) age-dependent WHO CD4 criteria. Randomisation used computer-generated sequentially numbered tables incorporated securely within the database. Primary efficacy endpoints were new WHO stage 4 events or death for monitoring and change in CD4 percentage at 72 and 144 weeks for ART-strategy randomisations; the co-primary toxicity endpoint was grade 3 or 4 adverse events. Analysis was by intention to treat. This trial is registered, ISRCTN24791884. Findings: 1206 children were randomly assigned to clinically driven (n=606) versus routine laboratory monitoring (n=600), and groups A (n=397), B (n=404), and C (n=405). 47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1·13, 95% CI 0·73-1·73, p=0·59; non-inferiority criterion met). However, in years 2-5, rates were higher in children on clinically driven monitoring (1·3 vs 0·4 per 100 child-years, difference 0·99, 0·37-1·60, p=0·002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0·98, 0·83-1·16, p=0·83). Mean CD4 percentage change did not differ between ART groups at week 72 (16·5% [SD 8·6] vs 17·1% [8·5] vs 17·3% [8·0], p=0·33) or week 144 (p=0·69), but the four-drug groups (B, C) were superior to three-drug group A at week 36 (12·4% [7·2] vs 14·1% [7·1] vs 14·6% [7·3], p

Citation

ARROW trial team. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet (2013) 381 (9875) 1391-1403. [DOI: 10.1016/S0140-6736(12)62198-9]

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