Elsevier

The Lancet

Volume 359, Issue 9308, 2 March 2002, Pages 733-740
The Lancet

Articles
Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial*

https://doi.org/10.1016/S0140-6736(02)07874-1Get rights and content

Summary

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 symptomfree (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.

Introduction

Combination antiretroviral treatment is the standard care for adults1, 2 and children3, 4 needing treatment for HIV-1 infection in well-resourced countries. However, therapeutic options for children are limited by unsuitable formulations and inadequate pharmacokinetic data for many drugs. Volume, taste, and dose frequency also need consideration, as does the ability of any combination to control the high concentrations of HIV-1 RNA in plasma that are seen in young children. Data for use of protease inhibitors in children were few when this trial began. The risks and benefits of these drugs as first-line treatment had not been defined in previously untreated children. Paediatric formulations of protease inhibitors, when available, were not accepted well by children. A powder formulation of nelfinavir has been developed with a recommended dose of 60–90 mg/kg daily for children aged older than 2 years.5

Abacavir is a new nucleoside-analogue reverse-transcriptase inhibitor (NRTI) with a liquid formulation.6, 7 Data for use of abacavir with lamivudine as a dual NRTI backbone in adults or children were few at the start of the study. However, because both drugs were available as small-volume, palatable, liquid formulations to be given twice daily without dietary restrictions, this combination was thought to be suitable for children. Although both drugs had been associated with development of the M184V mutation,8, 9 whether such an association would affect the efficacy of the drugs in combination was unknown. We aimed to assess the antiviral activity and safety of three dual NRTI treatment combinations and the safety and tolerability of the protease inhibitor nelfinavir in children with HIV-1 who had not previously been treated.

Section snippets

Participants

Children were eligible if they were aged 3 months to 16 years, had evidence of HIV-1 infection, and had received no antiretroviral treatment unless given as in-utero or perinatal prophylaxis up to 6 weeks after delivery. They were not eligible if they were receiving cytotoxic treatment for malignant disease or had haematological, hepatic, or renal contraindications to abacavir, zidovudine, lamivudine, or nelfinavir. The protocol was approved by the ethics committee for each participating

Results

130 children were randomised between January, 1998, and April, 1999. Two were excluded before starting trial drugs because one had an abnormal concentration of amino-transferases, and the other had parental consent withdrawn. 73 children were enrolled in part B and 55 in part A. 36 children received zidovudine and lamivudine, 45 zidovudine and abacavir, and 47 lamivudine and abacavir. In part A, 30 children were allocated to nelfinivir and 25 to placebo. Two children who were randomly allocated

Discussion

In Europe and the USA, successful interventions to reduce mother-to-child transmission of HIV-1 have resulted in a sharp decrease in the number of children born with HIV-1 infection, and few infected children in these countries remain untreated. PENTA 5 assessed highly active antiretroviral treatment in children who have not previously been treated, and was designed to address more than one question. By chance, the number of children allocated to the NRTI groups differed; some differences in

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