First-line HIV drugs not equal for kids
HIV-infected children may do better with an anti-retroviral regimen that includes ritonavir-boosted lopinavir.
HIV-infected children may do better with an anti-retroviral regimen that includes ritonavir-boosted lopinavir (Kaletra), even if they had not previously received the usual first-line nevirapine (Viramune), a clinical trial showed.
Use of ritonavir-boosted lopinavir resulted in fewer infants and toddlers with virologic failure or treatment discontinuation by week 24 than was seen with nevirapine (19.3% versus 40.8%, P<0.001), Paul Palumbo, MD, of Dartmouth–Hitchcock Medical Center in Lebanon, N.H., and colleagues found.
The nevirapine regimen also led to more toxicity and a trend for higher mortality compared with the ritonavir-boosted lopinavir regimen, the group reported in the June 21 issue of the New England Journal of Medicine.
Those findings present policymakers with some tough choices, the group acknowledged.
"Nevirapine is an important component of long-term therapy because it is stable at high temperatures, available in fixed-dose combinations, and relatively inexpensive, and its use is based on extensive experience and an acceptable safety profile in the pediatric population," they wrote.
For resource-limited regions, "nevirapine-based anti-retroviral therapy is the predominant (and often the only) regimen available for children," they added.
The World Health Organization recommends ritonavir-boosted lopinavir for children under age 2 previously exposed to single-dose nevirapine, since resistance is common after its use to prevent mother-to-child transmission.
The cheaper drug, though, is still recommended as initial therapy for children not previously exposed to it at birth.
The P1060 trial included two cohorts of HIV-infected children under age 3, divided by prior exposure to nevirapine.
The results in children whose mothers took nevirapine to protect the baby during delivery were previously reported in the New England Journal of Medicine, as that arm of the trial was stopped early. It showed a higher rate of virologic failure or discontinuation of the study drug for death or any other reason with nevirapine compared with ritonavir-lopinavir (36.9% versus 21.7%, P=0.02).
The parallel unexposed cohort included 288 Indian and African children 2 months to 3 years of age randomized to an anti-retroviral treatment regimen of zidovudine and lamivudine (Combivir) plus either nevirapine or ritonavir-boosted lopinavir.
Their HIV was relatively advanced, with a median 15% CD4+ T cells and a median plasma HIV type 1 RNA level of 5.7 log10 copies/mL.
These high viral levels may have been one reason for the poorer results with nevirapine in the previously unexposed children, the researchers noted.
"It is plausible that the use of agents for which single-gene mutations result in resistance (e.g., nevirapine) may be sub-optimal in the presence of high viral replication and a prolonged time to viral suppression, which may confer a predisposition to the emergence of resistance," they wrote.
More than half of the virologic failures examined with nevirapine showed resistance (19 of 32).
Death was nearly three and a half times more common with nevirapine, at ten cases versus three with ritonavir-boosted lopinavir, but the difference just missed statistical significance (P=0.06).
Protocol-defined toxicity likewise occurred more often with nevirapine (14 versus five events, hazard ratio 3.00, P=0.04), largely rash and liver toxicity.
The ramp-up dosing strategy with nevirapine, designed to reduce dermatologic reactions, may also have contributed to virologic failure, Palumbo's group noted.
"These data support ritonavir-boosted lopinavir as the basis for first-line anti-retroviral therapy in all children younger than 3 years of age, regardless of whether they have had prior NNRTI exposure," they wrote.
Challenges to implementation worldwide are likely to temper enthusiasm, though, they acknowledged, pointing to the bad taste of liquid ritonavir-lopinavir that may suppress appetite. Its use also doubles the cost of a treatment regimen for young children.
"In the absence of a confirmatory study, policymakers are left to weigh the costs and benefits of these two different first-line regimens as they develop national and regional pediatric treatment guidelines," the group concluded.
The study was supported by a grant from the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health and by cooperative agreements with the NIAID.
GlaxoSmithKline and Abbott provided anti-retroviral agents used in the study.
Palumbo reported grant and travel support funds to his institution from the NIH.
Coauthors reported relationships with Abbott, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, Medicines Development, Merck, ViiV Healthcare, and Tibotec.
By Crystal Phend
Primary source: New England Journal of Medicine Source reference: Violari A, et al "Nevirapine versus Ritonavir-boosted Lopinavir for HIV-infected children"N Engl J Med 2012; DOI:10.1056/NEJMoa1113249.
Source: MedPage Today