Switching to efavirenz-based therapy

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Dr Louise Kuhn of Columbia University, New York, and colleagues have evaluated whether HIV-infected children in South Africa who had achieved viral suppression with one treatment could transition to efavirenz-based therapy without risk of viral failure.

Implementation of paediatric antiretroviral treatment (ART) programmes in sub-Saharan Africa has resulted in significant reductions in morbidity and mortality among children infected with human immunodeficiency virus (HIV), changing a rapidly fatal disease into a chronic condition.

For infants and young children, ritonavir-boosted lopinavir-based therapy is recommended as first-line ART. In adults and older children, efavirenz is recommended as part of first-line ART. Advantages of this regimen include once-daily dosing, simplification of co-treatment for tuberculosis, preservation of ritonavir-boosted lopinavir for second-line treatment, and alignment 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.

This study, conducted at a hospital in Johannesburg, South Africa, included HIV-infected children 3 years of age or older exposed to nevirapine for prevention of mother-to-child transmission and who had plasma HIV RNA of less than 50 copies/ml during ritonavir-boosted lopinavir-based therapy. Participants were randomly assigned to switch to efavirenz-based therapy (n = 150) or continue ritonavir-boosted lopinavir-based therapy (n = 148). The children were followed up to 48 weeks after randomisation.

The researchers found that switching to efavirenz-based therapy compared with continuing ritonavir-boosted lopinavir-based therapy did not result in significantly higher rates of viral rebound (HIV RNA >50 copies/mL) or viral failure (confirmed HIV RNA >1000 copies/mL). “This therapeutic approach may offer advantages in children such as these.”

“There is little guidance available as to what clinicians ought to do when confronted with a child older than 3 years who has begun treatment with ritonavir-boosted lopinavir. As a result, it has been left to individual interpretation, and there are anecdotal reports of clinicians switching to efavirenz in the absence of data to support such a practice. This study provides evidence to support the safety and efficacy of switching to efavirenz, the recommended drug for children older than 3 years, among children with viral suppression,” the authors write.

In an accompanying editorial, Dr Ram Yogev, of Lurie Children’s Hospital, Chicago, said: “The study by Coovadia et al is an important contribution in the evolving science of how to treat perinatally HIV¬infected children. Even when combination ART controls the viral load, HIV-related complications remain (cardiovascular disease), and strategies to improve patient outcomes are needed that include early treatment and chemoprophylaxis as well as research on vaccines and an effective cure.”

Abstract
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 ∞) and for viral failure was −0.007 (1-sided 95% CI, −0.036 to ∞). 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.

JAMA material
JAMA abstract
JAMA editorial


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