Can nevirapine-exposed children switch to efavirenz?

Efavirenz-based antiretroviral therapy among nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial.

Coovadia A, Abrams EJ, Strehlau R, Shiau S, Pinillos F, Martens L, Patel F, Hunt G, Tsai WY, Kuhn L. JAMA. 2015 Nov 3;314(17):1808-17. doi: 10.1001/jama.2015.13631.

Importance: Advantages of using efavirenz as part of treatment for children infected with human immunodeficiency virus (HIV) include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of 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.

Objective: To evaluate whether nevirapine-exposed children achieving initial viral suppression with ritonavir-boosted lopinavir-based therapy can transition to efavirenz-based therapy without risk of viral failure.

Design, setting, and participants: Randomized, open-label noninferiority trial conducted at Rahima Moosa Mother and Child Hospital, Johannesburg, South Africa, from June 2010 to December 2013, enrolling 300 HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission who were aged 3 years or older and had plasma HIV RNA of less than 50 copies/mL during ritonavir-boosted lopinavir-based therapy; 298 were randomized and 292 (98%) were followed up to 48 weeks after randomization.

Interventions: Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148).

Main outcomes and measures: Risk difference between groups in (1) viral rebound (ie, ≥1 HIV RNA measurement of >50 copies/mL) and (2) viral failure (ie, confirmed HIV RNA >1000 copies/mL) with a noninferiority bound of -0.10. Immunologic and clinical responses were secondary end points.

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 group and 0.020 (n = 3) in the ritonavir-boosted lopinavir group. The risk difference for viral rebound was 0.107 (1-sided 95% CI, 0.028 to infinity) and for viral failure was -0.007 (1-sided 95% CI, -0.036 to infinity). We rejected the null hypothesis that efavirenz is inferior to ritonavir-boosted lopinavir (P < .001) for both end points. By 48 weeks, CD4 cell percentage was 2.88% (95% CI, 1.26%-4.49%) higher in the efavirenz group than in the ritonavir-boosted lopinavir group.

Conclusions and relevance: Among HIV-infected children exposed to nevirapine for prevention of mother-to-child transmission and with initial viral suppression with 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.

Abstract [1] Full-text [free] access [2]

Editor’s notes: For infants and young children (aged under three years), World Health Organization recommends ritonavir-boosted lopinavir therapy as the first-line antiretroviral therapy regimen. This is because of concerns about the increased risk of virologic failure with non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based regimens among infants previously exposed to NNRTIs for prevention of mother-to-child HIV transmission, and better virologic efficacy of a lopinavir-based regimen even in unexposed HIV-positive infants and young children. However, there are several significant issues associated with use of boosted lopinavir therapy in children. Firstly, the syrup form of the drug has an unpleasant taste posing major adherence challenges. Secondly, there are pharmacokinetic constraints restricting its use in children who are also being treated for tuberculosis. Thirdly, there are metabolic toxicities associated with the use of boosted lopinavir therapy.

In this open-labelled non-inferiority trial, the investigators examined whether efavirenz can be used in children aged over three years, previously exposed to nevirapine as part of prevention of mother-to-child HIV transmission, who have achieved virologic suppression with lopinavir-based therapy. Efavirenz was found to be non-inferior for both the trial endpoints, namely risk of viral rebound and risk of virologic failure. There were no differences in CD4 counts or other clinical endpoints such as height- or weight-for age, anaemia or neutropenia, skin reactions or serious elevations in transaminases between the groups. In addition, children randomised to switch to efavirenz had a significantly better lipid profile than people who continued to take lopinavir-based therapy. Children randomised to receive efavirenz had significantly higher rates of neuropsychiatric disturbances, but these did not persist beyond eight weeks and notably there were no differences in proportions with behavioural problems between the two arms at the end of follow-up.

The findings of this study strongly support the switch to efavirenz in children who have achieved virologic suppression. Some caveats of this study are that the findings cannot be generalised to children who are aged under three years or to children failing boosted lopinavir therapy. In addition, it is not clear how long children can be maintained on lopinavir-based therapy before a switch to efavirenz can be made.

There is currently no guidance on managing children aged over three years taking lopinavir therapy. This study provides strong evidence to support the switch to efavirenz among virally-suppressed children aged over three years. This is important given the considerable advantages of efavirenz, including preservation of protease inhibitor-based regimens for second line treatment, harmonising paediatric with adult guidelines that recommend efavirenz as first-line therapy, once-daily dosing, better palatability and lower cost.

Africa [8]
South Africa [9]
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