Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children

Violari, Avy; Lindsey, Jane C.; Hughes, Michael D.; Mujuru, Hilda; Barlow‐Mosha, Linda; Kamthunzi, Portia; Benjamin, H.; Cotton, Mark F.; Moultrie, Harry; Khadse, Sandhya; Schimana, Werner; Bobat, Raziya; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne; Jean‐Philippe, Patrick; Palumbo, Paul

doi:10.1056/nejmoa1113249

Cited by 179 publications

(206 citation statements)

References 15 publications

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“…These findings, reported in early analyses [11,12], remained consistent over a median follow-up of >5 years. Separation of treatment effect by arm occurred early; thereafter, children on both treatment arms experienced relative stability.…”

Section: Discussionsupporting

confidence: 75%

“…A full description of study procedures is published elsewhere [11,12]. In brief, infants and young children aged 2 months to 3 years were recruited once ART eligibility was established.…”

Section: Methodsmentioning

confidence: 99%

“…In October 2010 the DSMB recommended results be released in the NVP-unexposed cohort, which also showed that LPV/ r-based ART was superior to the NVP treatment arm for the primary study endpoint [12]. With closure of each cohort, clinicians and caregivers had the choice to switch from NVPbased ART to LPV/r-based ART.…”

Section: Study Historymentioning

confidence: 99%

“…By 12 months, the lopinavir/ritonavir (LPV/r)-based regimen was associated with fewer virologic treatment failures or deaths compared with the NVP-based regimen. However, improvements in CD4 percentage (CD4%) and growth (weight-for-age and height-for-age z score) marginally favored NVP [11,12]. To better understand the comparative long-term effect of these 2 ART regimens in an HIV-infected pediatric population, we present data from extended follow-up in this multicenter clinical trial.…”

mentioning

confidence: 99%

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Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

et al. 2016

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Background. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1060 study demonstrated short-term superiority of lopinavir/ritonavir (LPV/r) over nevirapine (NVP) in antiretroviral therapy (ART), regardless of prior NVP exposure. However, NVP-based ART had a marginal benefit in CD4 percentage (CD4%) and growth. We compared 5-year outcomes from this clinical trial.Methods. Human immunodeficiency virus (HIV)-infected, ART-eligible children were enrolled into 2 cohorts based on prior NVP exposure and randomized to NVP-or LPV/r-based ART. The data safety monitoring board recommended unblinding results in both cohorts due to superiority of LPV/r for the primary endpoint: stopping randomized treatment, virologic failure (VF), or death by 6 months. Participants were offered a switch in regimens (if on NVP) and continued observational follow-up. We compared time to VF or death, death, and CD4% and growth changes using intention-to-treat analyses. Additionally, inverse probability weights were used to account for treatment switching and censoring.Results. As of September 2014, 329 of the 451 (73%) enrolled participants were still in follow-up (median, 5.3 years; interquartile range [IQR], 4.3-6.4), with 52% on NVP and 88% on LPV/r as originally randomized. NVP arm participants had significantly higher risk of VF or death (adjusted hazard ratio [aHR], 1.90; 95% confidence interval [CI], 1.37-2.65) but not death alone (aHR, 1.65; 95% CI, .72-3.76) compared with participants randomized to LPV/r. Mean CD4% was significantly higher in the NVP arm up to 1 year after ART initiation, but not beyond. Mean weight-for-age z scores were marginally higher in the NVP arm, but height-for-age z scores did not differ. Similar trends were observed in sensitivity analyses.Conclusions. These findings support the current World Health Organization recommendation of LPV/r in first-line ART regimens for HIV-infected children.Clinical Trials Registration. NCT00307151.

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Section: Discussionsupporting

confidence: 75%

“…A full description of study procedures is published elsewhere [11,12]. In brief, infants and young children aged 2 months to 3 years were recruited once ART eligibility was established.…”

Section: Methodsmentioning

confidence: 99%

Section: Study Historymentioning

confidence: 99%

mentioning

confidence: 99%

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Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

et al. 2016

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“…Children randomized to an NVP‐containing regimen were twice as likely as those on an LPV/r‐based regimen to reach a composite endpoint of: virological failure, treatment discontinuation or death at 24 weeks of follow‐up (40.8% versus 19.3%, respectively; P < 0.001) 68. Transmitted NVP resistance, emergence of NVP resistance because of high VL in infancy and possible low NVP levels during lead‐in dosing 69 may have played a role.…”

Section: Which Art Regimen To Start As First‐line Therapymentioning

confidence: 99%

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

et al. 2015

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The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV‐1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short‐term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long‐term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first‐ and second‐line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

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Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa

Coovadia

Abrams

Strehlau

et al. 2015

JAMA

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Importance Advantages of using efavirenz as part of treatment for HIV-infected children include once-daily dosing, simplification of co-treatment for tuberculosis, preserving ritonavir-boosted lopinavir for second-line treatment, and harmonization of adult and pediatric treatment regimens. However, there have been concerns about possible reduced viral efficacy of efavirenz in children exposed to nevirapine for prevention of mother-to-child transmission (PMTCT). Objective To evaluate whether nevirapine-exposed children, initially virally-suppressed on ritonavir-boosted lopinavir-based therapy, can transition to efavirenz-based therapy without risk of viral failure. Design, Setting, Participants Randomized, open-label, non-inferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, June 2010 to December 2013. Three hundred HIV-infected children exposed to nevirapine for PMTCT, ≥ 3 years of age, and with plasma HIV RNA <50 copies/ml on ritonavir-boosted lopinavir-based therapy were enrolled; 298 were randomized, and 292 (98%) were followed to 48 weeks post-randomization. Intervention Switch to efavirenz-based therapy (n=150) or continue on ritonavir-boosted lopinavir-based therapy (n=148). Main Outcomes and Measures Risk difference (delta) between groups in (1) viral rebound; i.e., one or more HIV RNA >50 copies/ml, and (2) viral failure; i.e., confirmed HIV RNA >1000 copies/ml; with a non-inferiority bound for the delta of −0.10. Immunologic and clinical responses were secondary endpoints. Results The Kaplan-Meier probability of viral rebound by 48 weeks was 0.176 (n=26) in the efavirenz group and 0.284 (n=42) in the ritonavir-boosted lopinavir group. Probabilities of viral failure were 0.027 (n=4) in the efavirenz and 0.020 (n=3) in the ritonavir-boosted lopinavir group. The risk difference of viral rebound was 0.107 (1-sided 95% CI: 0.028,∞) and −0.007 (1-sided 95% CI: −0.036, ∞) for viral failure. We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (p<.001) for both endpoints. By 48 weeks, CD4 percentage was 2.88 (95% CI: 1.26, 4.49) units higher in the efavirenz than in the ritonavir-boosted lopinavir group. Conclusions and Relevance Among HIV-infected children exposed to nevirapine for PMTCT and initially virally-suppressed on ritonavir-boosted lopinavir-based therapy, switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound or viral failure. This therapeutic approach may offer advantages in children such as these.

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Nevirapine versus Ritonavir-Boosted Lopinavir for HIV-Infected Children

Cited by 179 publications

References 15 publications

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

Nevirapine- Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy in HIV-Infected Infants and Young Children: Long-term Follow-up of the IMPAACT P1060 Randomized Trial

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

Efavirenz-Based Antiretroviral Therapy Among Nevirapine-Exposed HIV-Infected Children in South Africa

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