Violari A, Lindsey JC, Hughes MD, Mujuru HA, Barlow-Mosha L, Kamthunzi P, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med. 2012 Jun 21;366(25):2380-9. PubMed PMID: 22716976.
To compare the relative efficacy of nevirapine (NVP)-based antiretroviral therapy (ART) vs. ritonavir-boosted lopinavir (LPV/r)-based ART in treating children aged 2 to 36 months without previous NVP exposure.
Four sites in South Africa; one site each in India, Tanzania, Uganda, Zambia and Zimbabwe.
Randomized controlled equivalency trial (RCT).
HIV-infected children aged 2-36 months meeting the 2006 World Health Organization (WHO) clinical criteria for treatment,(1) with baseline plasma HIV-1 RNA level above 5000 copies per mL, and no previous exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as NVP or efavirenz (EFV).
Primary: Treatment failure (virologic failure or permanent discontinuation of regimen for any reason) by week 24. Virologic failure was defined as confirmed plasma HIV-1 RNA level < 1 log10 copies/mL below baseline at 12-24 weeks, or confirmed HIV- RNA level >400 copies/mL at 24 weeks. Secondary: Confirmed virologic failure or death by week 24; confirmed virologic failure or death during the follow-up period; and a composite of virologic failure or discontinuation of regimen during the follow-up period. Confirmed virologic failure was defined as above, or as viral rebound to >4000 copies/mL after week 24. Toxicity(2) endpoints included ≥grade 3 hepatotoxicity, ≥grade 2b rash, neutropenia, anemia and thrombocytopenia.
Children were stratified by age (2 to <6 months, 6 to <12 months, or 12 to 36 months) and randomly assigned to either NVP or LPV/r, combined with zidovudine (ZDV) and lamivudine (3TC). NVP dosage was 4 mg per kg of body weight once daily for 14 days, then increasing to 7 mg/kg twice daily. The study protocol(3) was amended in September 2007 to meet new WHO recommendations for NVP dosage of 160-200 mg per square meter (m2) of body-surface area, once daily for 14 days and twice daily thereafter. Characteristics and timing of the LPV/r regimen were not reported in this paper or its supplementary materials,(4) but the study protocol required a dosage of lopinavir 12 mg/kg with ritonavir 3 mg/kg every 12 hours in subjects weighing <15 kg; lopinavir 10 mg/kg with ritonavir 2.5 mg/kg every 12 hours in subjects weighing ≥15 to <40 kg; and lopinavir 400 mg with ritonavir 100 mg every 12 hours in subjects weighing ̥40 kg. All subjects also received ZDV 180 mg per m2 of body surface every 12 hours and 3TC 4 mg/kg every 12 hours.
Between November 2006 and March 2010, 288 children were randomized either to an NVP-based regimen (n=147) or an LPV/r-based regimen (n=141). One child randomized to LPV/r did not begin treatment and was excluded from analysis. Four children with previous NVP exposure were incorrectly enrolled in the trial. While their outcome data were included in the analysis, sensitivity analyses excluding them showed similar results. Median follow-up was for 72 weeks (interquartile range [IQR], 48 to 120 weeks). At baseline, 210 children (73.2%) were age >12 months, with median age of 20 months (1.7 years). Median HIV-1 RNA level was 535,632 copies/mL; median of 15% CD4+ T cells; median z-scores of -2.6 for weight and -2.3 for height. Most HIV infections (212 of 265 [80.0%]) were subtype C. Median caregiver-reported adherence to therapy was 100% for the initial 24 weeks; there were no significant differences in adherence between the two treatment groups (p= 0.16). Caregivers reported ≥95% adherence for 80.3% of the children receiving NVP vs. 90% of those receiving LPV/r.
Significantly more children in the NVP arm (n=60, 40.8%) than in the LPV/r arm (n=27, 19.3%) experienced virologic failure or discontinued treatment for any reason, including death, by week 24 (p<0.001). Between-group differences across age strata were similar (age <12 months: 22%, 95% confidence interval [CI] 2.2% to 41.9%; p=0.03; age =12 months: 21.3%, 95% CI 9.3% to 33.4%; p=0.001).(5) Children in the NVP arm were much more likely to have died or had virologic failure by week 24 (hazard ratio [HR] 2.51 (95% CI, 1.41 to 4.47; p<0.01). By week 48, 81/108 children (75%) in the NVP arm had HIV-1 RNA levels below 400 copies/mL, vs. 101/119 children (85%) in the LPV/r arm (p=0.06).
At study entry, 58/287 (20.2%) mothers were breastfeeding their infants (18.4% of mothers of infants in the NVP arm, and 22.1% of those in the LPV/r arm); none of the mothers were on ART. During follow-up, mothers of six NVP infants and five LPV/r infants started ART, which in all cases included NVP. Only one of these children (a child in the LPV/r arm) had virologic failure.
Thirteen children (4.6%) died by week 24, 10 (6.8%) in the NVP arm and three (2.1%) in the LPV/r arm. Seven of the NVP arm's deaths occurred by week 12. Causes of death in the NVP arm included gastroenteritis and diarrhea with marasmus (n=4), pneumonia (n=2), sepsis associated with burns and kwashiorkor (n=2), malaria (n=1), and unknown (n=1). Causes of death in the LPV/r arm included measles (n=1), pneumonia and cardiac failure (n=1), and gastroenteritis and marasmus (n=1).
Children in the NVP arm had significantly more protocol-defined toxicity endpoints. Toxicity occurred in 14 children in the NVP arm (6.8%) and five (3.6%) in the LPV/r arm. In the NVP arm, two children had grade 2b rash, two had grade 3 hepatotoxicity, two had grade 4 hepatotoxicity, two had grade 3 neutropenia, two had grade 4 neutropenia, and one had grade 3 anemia. In the LPV/r arm, two children had grade 3 neutropenia, one had grade 4 neutropenia, one had grade 3 anemia, and one had grade 4 thrombocytopenia.
Ten (6.8%) subjects in the NVP arm and eight (5.7%) in the LPV/r arm, in addition to the child in the LPV/r arm who never started treatment, were lost to follow-up or left the study for other reasons.
The authors conclude that for initial therapy in HIV-infected infants and young children, LPV/r-based regimens are more efficacious and safer than NVP-based regimens.
The overall risk of bias in this trial is low. Randomization was done using a dynamic permuted block system, stratifying by age. Allocation was concealed with a web-based system that assigned treatment based on a permuted block algorithm. The trial was not blinded to participants, personnel or outcome assessors, but outcomes were unlikely to have been affected by this. Analysis was by intention to treat, and attrition bias is unlikely. The trial's protocol is available, so selective outcome reporting is unlikely. Although the trial's data and safety monitoring board recommended releasing results in October 2010, when week 24 endpoints had been reached by all participants, patient follow-up continued for a median 72 weeks. Overestimation of treatment effects is thus unlikely.
This was "cohort 2" of the P1060 trials, two concurrent open-label RCTs comparing NVP-based regimens with LPV/r-based regimens in young children. The study population in the "cohort 1" trial(6) had peripartum NVP exposure. Results were consistent between the two trials. A different trial,(7) however, while its study population, methods and other aspects were different to those of the P1060 trials, found no significant differences in the outcomes of children on first-line NNRTI-based ART compared to those on protease inhibitor (PI)-based ART.
HIV-infected infants and young children without previous NVP exposure should receive the current ART regimen recommended by WHO,(8) which varies depending on age and other considerations. New WHO guidance on ART for infants and children is expected in 2013.
- World Health Organization (WHO). Antiretroviral therapy of HIV infection in infants and children. Geneva, 2006
- National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS, Table for Grading Adult and Pediatric Adverse Events (Toxicity Table), 2009 clarification. Accessed 4 August 2012]
- Protocol: Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 2012;366:2380-9. Accessed 4 August 2012]
- Supplement to: Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children. N Engl J Med 2012;366:2380-9. Accessed 4 August 2012]
- The between-group difference is the rate in the NVP arm minus the rate in the LPV/r arm.
- Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with peripartum nevirapine exposure. N Engl J Med 2010;363:1510-1520
- PENPACT-1 (PENTA 9/PACTG 390) Study Team. First-line antiretroviral therapy with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial. The Lancet Infectious Diseases 2011;11(4):273-283.
- WHO. Antiretroviral therapy for HIV infection in infants and children: Towards universal access. Recommendations for a public health approach: 2010 revision. Accessed 4 August 2012]