ATLANTA – HIV treatment can be delivered safely to children with good clinical care alone, without any need for routine laboratory monitoring of side effects, according to researchers involved in the ARROW Trial.
Routine CD4 and toxicity laboratory monitoring every 12 weeks had no impact on HIV disease progression during the first year of antiretroviral therapy (ART). There was a small, but significant impact on progression after the first year, but overall event rates were very low and occurred mostly in older children whose adherence to therapy may have played a role in the poorer outcomes, Dr. Adeodata Kekitiinwa said at the Conference on Retroviruses and Opportunistic Infections.
The findings indicate that expensive lab monitoring is not essential to good outcomes for children, especially those in impoverished countries.
"Resources should be focused on getting as many children onto treatment as possible, rather than providing routine laboratory monitoring to the few on ART," Dr. Kekitiinwa said, noting that 90% of HIV-infected children live in Sub-Saharan Africa, and only 28% of those in need of ART are receiving it.
Trials in adults have shown routine CD4 monitoring provides small, but significant benefits on disease progression and death, while routine toxicity monitoring has no impact on toxicity outcomes, observed Dr. Kekitiinwa of the pediatric infectious diseases clinic, Baylor College of Medicine, Children’s Foundation–Uganda in Mulago.
The ARROW (Anti-Retroviral Research for Watoto) trial randomized 1,206 antiretroviral-naive children and adolescents in Uganda and Zimbabwe to either clinically or laboratory-driven monitoring and to one of three groups of standard three- or four-drug induction ART. Group A received a non-nucleoside reverse transcriptase inhibitor (NNRTI), lamivudine, and abacavir. Groups B and C received an NNRTI, lamivudine, abacavir, and zidovudine therapy; after week 36, the regimen was reduced to a three-drug NNRTI, lamivudine plus abacavir in group B and lamivudine, abacavir plus zidovudine in group C.
Both groups received 12 weekly biochemistry profiles and full blood counts to monitor for toxicity and CD4 counts to monitor for efficacy. The laboratory arm, however, had their results returned every 12 weeks, while the clinical arm received toxicity results only if requested or a grade 4-toxicity occurred and never had their CD4 counts returned, Dr. Kekitiinwa explained.
More than 30% of the children were less than 3 years old (range, 4 months to 17 years); 70% had grade 3/4 disease. Median follow-up was 4 years and 3% of children were lost to follow-up.
The primary endpoint of grade 4 toxicity or death occurred in 39 patients in the lab arm and 47 in the clinical arm (1.7 vs. 2.0 events/100 child-years). This resulted in a hazard ratio of 1.13 (95% confidence interval 0.73-1.53; P = .59), and translated into an absolute difference of 0.3 (95% CI –0.5-1.1), which fell within the prespecified noninferiority margin, she said.
In years 2-5, the number of events increased significantly in the clinical care arm (1.3 vs. 0.4/100 child-years). Once again, the absolute difference remained within the noninferiority margin (1.0/100 child-years; P = .002; 95% CI 0.4-1.6), although Dr. Kekitiinwa acknowledged that "there may be a role for targeted, as opposed to routine, laboratory monitoring from the second year of ART."
Mortality was low, with 96% of the clinical arm and 95% of the lab arm still alive at the end of 4 years. Two deaths occurred in the lab arm vs. 14 in the clinical arm, of which 12 were in children 8 years or older.
Excess grade 3 and 4 adverse events were reported in 40% of children in group A, 47% in group B and 54% in group C. These events were driven by asymptomatic neutropenia in children receiving zidovudine-containing regimens, and by failure to thrive in group A.
"Monitoring of weight gain should be emphasized as an important clinical aid for identifying first-line failure," Dr. Kekitiinwa said.
Viral load suppression did not differ by monitoring strategy. Full details of ARROW were simultaneously published online (Lancet 2013 [doi:10.1016/S0140-6736(12)62198-9])
ARROW is funded by the U.K. Department for International Development and U.K. Medical Research Council. Study drugs were donated and viral load assays funded by ViiV Healthcare and GlaxoSmithKline. Dr. Kekitiinwa reported having no financial disclosures.