A randomized double-blinded trial of the addition of lamivudine or matching placebo to current nucleoside analogue reserve transcriptase inhibitor therapy in HIV-onfected children. The PENTA 4 trial.

Objectives: 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. Design: Randomized double-blind trial. Methods: HIV-l-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. Results: 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 x 10(6)/l (IQR, 127-696 x 10(6)/l), and median HIV-1 RNA was 4.9 log(10) copies/ml (IQR, 4.3-5.4 log(10) 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 x 10(6)/l and HIV-1 RNA was lower by 0.30 log(10) 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 log(10) 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). Conclusions: 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