ArticlesComparison 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*
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
References (28)
British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals
Lancet
(1997)- et al.
Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA Panel
JAMA
(1997) Guidelines for the use of antiretroviral agents in pediatric HIV infection
MMWR Morb Mortal Wkly Rep
(1998)- et al.
Current evidence for the use of paediatric antiretroviral therapy—a PENTA analysis
Eur J Paediatr
(2000) - et al.
Treatment of human immunodeficiency virus 1 -infected children with the protease inhibitor nelfinavir mesylate
Clin Infect Dis
(1999) - et al.
Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children
Antimicrob Agents Chemother
(1999) - et al.
A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection
Pediatrics
(1999) - et al.
The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT Inhibitors
AIDS
(1998) - et al.
Combination of mutations in HIV-1 reverse transcriptase required for resistance to carbocyclic nucleoside 1592U89
Antimicrob Agents Chemother
(1997) - et al.
Design and analysis of randomised clinical trials requiring prolonged observation of each participant, II: analysis and examples
Br J Cancer
(1977)
Regression analysis when the dependent variable is truncated normal
Econometrica
Age related reference ranges: significance test for models and confidence intervals for centiles
Stat Med
Cross-sectional stature and weight reference curves for the UK 1990
Arch Dis Child
Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial- PACTG-377
AIDS Res Hum Retroviruses
Cited by (105)
Adverse events associated with abacavir use in HIV-infected children and adolescents: A systematic review and meta-analysis
2016, The Lancet HIVCitation Excerpt :None reported any screening of HLA B5701 allele. Four provided details on timing of hypersensitivity reaction, three of which reported hypersensitivity reaction in the first 2 weeks of ART19,20,25 one in the first month of ART.21 One study included children substituted onto ART.21
Can abacavir be used safely in children without HLA testing?
2016, The Lancet HIVAbacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): An open-label, parallel-group, randomised controlled trial
2016, The Lancet Infectious DiseasesCitation Excerpt :No IMPAACT/PACTG trial has directly compared abacavir, zidovudine, or stavudine head-to-head within combination therapy. Our results differ from the only previous randomised, smaller trial of zidovudine versus abacavir (PENTA-5), which showed virological superiority of abacavir versus zidovudine over 5 years in children in well-resourced settings.27,28 However, children received two NRTIs alone or with nelfinavir; with a potent third drug, as in CHAPAS-3, any superiority of abacavir over zidovudine could well be masked.
CHAPAS-3 fills the gap
2016, The Lancet Infectious DiseasesRoutine versus clinically driven laboratory monitoring and fi rst-line antiretroviral therapy strategies in African children with HIV (ARROW): A 5-year open-label randomised factorial trial
2013, The LancetCitation Excerpt :1200 children followed up for 3·5–5·0 years with less than 10% loss to follow-up provided 90% power to establish that clinically driven monitoring was not inferior to routine laboratory monitoring on the primary efficacy outcome, defined as the upper 95% confidence limit for the difference (clinically driven minus routine laboratory monitoring) in rate of first new WHO stage 4 event or deaths per 100 child-years being no greater than 1·6 per 100 child-years (assumed rate for routine laboratory monitoring of 2·5 per 100 child-years). For the ART-strategy randomisation, 1200 children provided 80% power to detect differences in change in CD4 percentage of more than 2·5% across the three groups (F test, two-sided α=0·05) assuming 20% missing data (loss to follow-up, missed visit or test) and standard deviation 10%.23 Interim data were reviewed annually by an independent data monitoring committee (four meetings) using the Haybittle-Peto criterion (p<0·001).
Effect of Vitamin D Supplementation on CD4 Count in HIV-Infected Children and Adolescents in North India: A Non-Randomized Comparative Study
2022, Journal of Tropical Pediatrics
- *
Members listed at end of report