Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children

Abstract: Objective: To describe the long-term efficacy over 5 years of regimens including combinations of abacavir, lamivudine and/or zidovudine in previously untreated children in the PENTA 5 trial. Design: PENTA 5 was a 48-week randomised controlled trial comparing three dual nucleoside reverse transcriptase inhibitor (NRTI) combinations as part of first triple antiretroviral therapy (ART). Methods: 128 ART-naive children were randomised to zidovudine\lamivudine (n = 36), zidovudine\abacavir (45) or lamivudine\abacavir (47). Asymptomatic children (n = 55) were also randomised to nelfinavir or placebo; all other children received open-label nelfinavir. Analyses are intent-to-treat and adjusted for minor baseline imbalances and receipt of nelfinavir/placebo. Results: Median follow-up was 5.8 years. By 5 years, 17 (47%), 28 (64%) and 18 (39%) children had changed their randomised NRTIs in the zidovudine\lamivudine, zidovudine\abacavir and lamivudine\abacavir groups respectively, but 18%, 50% and 50% of these changes were either early single drug substitutions for toxicity or switches with viral suppression (HIV-1 RNA < 400 copies/ml; e.g. to simplify regimen delivery). At 5 years, 55%/32% zidovudine\lamivudine, 50%/25% zidovudine\abacavir and 79%/ 63% lamivudine\abacavir had HIV-1 RNA <400/<50 copies/ml respectively (p=0.03/p=0.003). Mean increase in height-for-age 0.42, 0.68, 1.05 (p = 0.02); weight-for-age 0.03, 0.13, 0.75 (p = 0.02). Reverse transcriptase resistance mutations emerging on therapy differed between the groups: zidovudine\lamivudine (M41L, D67N, K70R, M184V, L210W, T215Y); zidovudine\abacavir (M41L, D67N, K70R, L21 OW, T215F/Y, K219Q); lamivudine\abacavir (K65R, L74V, Y115F, M184V). Conclusions: Five year data demonstrate that lamivudine\abacavir is more effective in terms of HIV-1 RNA suppression and growth changes, with lower rates of switching with detectable HIV-1 RNA than zidovudine\lamivudine or zidovudine\abacavir, and should be preferred as first-line NRTI backbone. (C) 2007 Lippincott Williams & Wilkins

A randomized controlled trial of genotypic HIV drug resistance testing in HIV-1-infected children: The PERA (PENTA 8) trial

Objective: To evaluate the longer-term utility of genotypic resistance testing in HIV-1-infected children with virological failure. Methods: Children aged 3 months-18 years switching antiretroviral therapy (ART) with HIV-1 RNA > 2,000 copies/ml were randomized between genotypic testing (Virtual Phenotype (TM)) and no testing at baseline and subsequent virological failures. Children were followed to at least 96 weeks. Results: One hundred and seventy eligible children, from 24 clinical centres in six countries, were randomized to resistance testing (n=87) or no testing (n=83) between June 2000-July 2003. At baseline, mean HIV-1 RNA and CD4(+) T-cell percentage were 4.7 log(10) copies/ml and 20%, respectively. Children had taken ART for a mean of 5 years; 24% had received all three classes, 53% nucleoside reverse transcriptase inhibitors (NRTIs)+protease inhibitors (PIs), 9% NRTIs+non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 14% NRTIs only. There was no difference between the arms in the drug classes or the individual PIs/NNRTIs prescribed. However, 49% in the resistance test arm (RT) versus 19% in the no-test arm (NT) continued at least one NRTI from their failing regimen; 56% versus 19% were prescribed didanosine+stavudine as their NRTI backbone. Adjusting for baseline HIV-1 RNA, mean reductions in HIV-1 RNA at 48 weeks were 1.51 log(10) copies/ml in the RT arm and 1.23 in the NT arm (P=0.3); the difference between the arms was smaller at week 96 (RT: 1.50, NT: 1.47; P=0.9). Conclusion: In this first paediatric trial of resistance testing, we observed a substantial difference in NRTI-prescribing behaviour across arms. However statistically significant evidence of a long-term virological or immunological benefit was not observed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN14367816