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To evaluate the toxicity, tolerability and effect on laboratory markers of adding lamivudine (3TC) to nucleoside analogue reverse transcriptase inhibitors (NRTI) in children with HIV-1 infection.Randomized double-blind trial.HIV-1-infected children on stable NRTI therapy were randomized to receive 3TC syrup or tablets (4 mg/kg twice daily) or matching placebo in addition to existing therapy. Endpoints were serious adverse events, and changes in CD4 cell count and plasma HIV-1 RNA. Analyses were on an intention-to-treat basis.A total of 162 (81 on 3TC, 81 on placebo) children [median age, 6.5 years; interquartile range (IQR), 4.1–10.1 years] were included. At randomization, 52 were receiving zidovudine (ZDV), 39 didanosine (ddl), 54 ZDV–ddl and 17 ZDV–zalcitabine (ddC); 32 (20%) had AIDS; median CD4 cell count was 328 × 106/l (IQR, 127–696 × 106/l), and median HIV-1 RNA was 4.9 log10 copies/ml (IQR, 4.3–5.4 log10 copies/ml). Median follow-up was 40 weeks (IQR, 29–49 weeks) and 76% of follow-up was on blinded therapy for both 3TC and placebo groups. There were 11 serious adverse events in the blinded phase [two clinical (both placebo) and nine laboratory (five 3TC, four placebo)], five (two 3TC, three placebo) resulting in stopping trial drug. At 24 weeks, the CD4 cell count was greater in the 3TC group by a median of 47 × 106/l and HIV-1 RNA was lower by 0.30 log10 copies/ml (P = 0.03 and 0.002, respectively, versus the placebo group). The difference in reduction in HIV-1 RNA up to 24 weeks, as measured by area under the curve minus baseline, between 3TC and placebo groups was 0.38 log10 copies/ml (95% confidence interval, 0.12–0.65) greater in children taking ZDV–containing regimens at baseline, compared with those on ddl monotherapy (P = 0.005), after adjusting for other factors at baseline. Thirteen children developed new AIDS events (six on 3TC, four on placebo) of whom three died (all placebo).The addition of 3TC to current NRTI therapy in children was safe and well-tolerated. There was evidence that treatment changes in HIV-1 RNA viral load were greater in children taking regimens that included ZDV.