PURPOSE AND METHODS: To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (VIRCO: phenotyping and genotyping with 'Virtual Phenotype' interpretation).
RESULTS: At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare.
CONCLUSIONS: Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
INTRODUCTION: Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dual-nucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1.
METHODS: In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptom-free (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat.
FINDINGS: Children had a median CD4 percentage of 22% (IQR 15-29) and a mean HIV-1 RNA concentration of 5.0 log copies/mL (SD 0.8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1.71, 2.19, and 2.63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0.02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events--six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir.
INTERPRETATION: Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.
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-naïve 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, L210W, 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.
To describe the evolution of resistance to zidovudine (ZDV), lamivudine (3TC), abacavir (ABC) and nelfinavir (NFV), 113 previously untreated children in the PENTA 5 trial had resistance assayed at baseline, rebound and/or 24, 48, 72 weeks (
VIRCO:
phenotyping and genotyping with 'Virtual Phenotype' interpretation).
RESULTS:
At baseline, few reverse transcriptase mutations and no primary protease inhibitor mutations were observed. Time to detectable HIV-1 RNA with reduced phenotypic susceptibility to any drug was shortest in the ZDV+3TC arm (overall logrank P=0.02). Through a median follow-up of 55 weeks, at their last assessment 11 (28%), 16 (40%) and 13 (32%) children with detectable HIV-1 RNA and a resistance test available had mutations conferring resistance to none, one, or two or more trial drugs, respectively, according to the virtual phenotype. Reduced phenotypic susceptibility to ABC only occurred in the 3TC+ABC arm and required K65R and/or L74V in addition to M184V. NFV-resistant virus was selected slowly through D30N or L90M pathways, and selection of ZDV-resistant virus was rare.
CONCLUSIONS:
Selection of 3TC-resistant virus was most frequent, followed by NFV and/or ABC; selection of ZDV-resistant virus was rare. Importantly, although in vitro, ABC selects for M184V as the first mutation, ABC did not select for M184V when combined with ZDV without 3TC. The most sustained HIV-1 RNA response was in the 3TC+ABC arm, but mutations conferring reduced susceptibility to 3TC and/or ABC evolved more frequently if virological failure occurred with 3TC+ABC than with ZDV+ABC.
