The results of this randomized clinical trial, which compared nevirapine-based ART and ritonavir-boosted lopinavir–based ART for the initial treatment of HIV-infected children, challenge our current approach. For infants and young children, regardless of whether they were previously exposed to nevirapine, we now have evidence of the superiority of ritonavir-boosted lopinavir– based regimens over nevirapine-based regimens in terms of both efficacy and safety.
Nevirapine-based treatment is currently the choice for first-line ART in most countries where resources are limited and is often the only readily available option. Recent data in HIV-infected women have provided support for the continued use of nevirapine as a first-line treatment option. The Optimal Combination Therapy after Nevirapine Exposure (OCTANE) A5208 trial, which had a design parallel to that of the P1060 study, showed that nevirapine, administered as the initial treatment in HIV-infected women without prior exposure to single-dose nevirapine, was noninferior to ritonavir-boosted lopinavir with respect to virologic failure or death2
; however, nevirapine was associated with a poorer safety profile. The treatment regimen included tenofovir and emtricitabine, which may be more potent than zidovudine and lamivudine, the agents used in the P1060 study. In addition, the PENPACT 1 (Paediatric European Network for Treatment of AIDS [PENTA 9]/Pediatric AIDS Clinical Trials Network [PACTG] 390) trial, conducted in Europe, the United States, and South America, showed equivalent outcomes when treatment was initiated with an NNRTI-based regimen or a proteaseinhibitor– based regimen.4
The PENPACT 1 trial differed substantially from the P1060 trial in several respects: it enrolled children at a median age of 6.5 years, with a median viral load of 5.1 log10
copies per milliliter; the primary end point was virologic only (without consideration of treatment changes); and it allowed investigators to choose the NNRTIs (efavirenz was chosen in 62% of the cases) and protease inhibitors (which were equally divided between nelfinavir and ritonavir-boosted lopinavir). The P1060 study directly compared nevirapine-based treatment and ritonavir-boosted lopinavir–based treatment in children who were younger than 3 years of age.
Why did nevirapine fare less well than ritonavir-boosted lopinavir among the infants in our study? One important factor may be the high plasma HIV-1 RNA levels commonly seen during infancy (median for the overall cohort, 536,000 copies per milliliter), which make viral suppression difficult. Even with optimal ART viral decay kinetics, the time to achievement of an undetectable plasma virus level will be longer for infants than for older children and adults, who have lower viral loads.5,6
It is plausible that the use of agents for which single-gene mutations result in resistance (e.g., nevirapine) may be suboptimal in the presence of high viral replication and a prolonged time to viral suppression, which may confer a predisposition to the emergence of resistance. In the P1060 study, more than half the children in the nevirapine group who had virologic failure had nevirapine resistance at the time of failure. The results of the PENPACT 1 study showed that NNRTI resistance in children with no response to NNRTI-based ART occurs early and at low levels of viral rebound (<1000 copies per milliliter).4
Another potential contributing factor may have been the ramp-up dosing strategy, in which nevirapine is given once daily at half the final target dose for 2 weeks and is then increased to the full dose on a twice-daily schedule. This strategy was designed to minimize the risk of dermatologic reactions during the initiation of nevirapine therapy (seen primarily in adults during drug development) and to accommodate the induction of cytochrome P-450 metabolizing enzymes after exposure to nevirapine. However, this may result in suboptimal levels of nevirapine during the ramp-up period, a time when viral levels in infected infants are profoundly elevated. This hypothesis is consistent with the finding that virologic failure in the nevirapine group tended to be an early event, occurring in the first 12 to 24 weeks of therapy. The Children with Human Immunodeficiency Virus (HIV) in Africa — Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS 1) study compared the initiation of full-dose nevirapine in fixed-dose combination tablets to simplify administration in children with a median age of 5 years.7
Rash occurred at a higher frequency when nevirapine was initiated at the full dose (11%, vs. 2% with dose escalation) but was considered to be manageable.
Baseline resistance to NNRTIs due to unrecognized exposure to drugs for preventing mother-to-child transmission in cohort 2 is not likely to be responsible for the results; the frequency of baseline nevirapine resistance was less than 1% (1 of 132 children) in the nevirapine group. Resistance was determined with the use of an HIV-genotyping system based on population sequencing and approved by the Food and Drug Administration. Low-frequency NNRTI mutations, which can be detected only by means of high-sensitivity assays, have been implicated in treatment failure in adults.8,9
It is not known whether low-frequency mutations at baseline affected treatment outcomes in the P1060 cohort; this question will require further research. However, in the Nevirapine Resistance Study (NEVEREST), virologic failure in infants who were switched to nevirapine-based ART was associated with an increased frequency of baseline resistance, as detected by population sequencing, but not with low-frequency baseline resistance.10
Data from P1060 cohort 1 (infants exposed to single-dose nevirapine)1
and from NEVEREST11
previously showed that CD4 counts and weight gain improved more slowly from baseline levels with ritonavir-boosted lopinavir than with nevirapine despite efficacy data favoring ritonavir-boosted lopinavir. Although somewhat counter-intuitive, this observation was partially confirmed in the present study, in which adjusted increases in the z score for weight and in BMI from baseline to week 24 and to week 48 were significantly larger in the nevirapine-treated group; however, changes in CD4+ counts over time appeared to be similar in the two groups. The mechanism underlying the smaller weight gain in the ritonavir-boosted lopinavir group remains unclear, but leading hypotheses are poor palatability and appetite suppression, as well as the metabolic consequences of ritonavir, excipients, or both in the liquid formulation (15.3% propylene glycol and 42.4% alcohol) or both.1,12–15
The path forward for pediatric first-line treatment guidelines in resource-limited settings is not simple. Identification of HIV infection early in infancy, with prompt initiation of ART, is critical for increasing survival among HIV-infected children.3,16
The data from the P1060 cohort 2 study show superior outcomes with ritonavir-boosted lopinavir, as compared with nevirapine, for the composite end point, as well as for virologic failure or death, toxicity, and death alone. These data support ritonavir-boosted lopinavir as the basis for first-line ART in all children younger than 3 years of age, regardless of whether they have had prior NNRTI exposure. Enthusiasm for such an approach, however, may be tempered by the inherent challenges to its implementation worldwide. For example, the liquid formulation of ritonavir-boosted lopinavir has an unpleasant taste and does not withstand high ambient temperatures. Today, the cost of a ritonavir-boosted lopinavir–based treatment regimen for young children is approximately twice that of a nevirapine-based regimen. It is important to note that 75% of the children who were randomly assigned to nevirapine had HIV-1 RNA levels below 400 copies per milliliter after 48 weeks of therapy, although the percentage was higher for the children randomly assigned to ritonavir-boosted lopinavir. 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. New approaches to monitoring treatment and new drug formulations are urgently needed to address this emerging gap in global pediatric HIV treatment.