Andrew Wiznia

Enfuvirtide is the only entry inhibitor approved for the treatment of human immunodeficiency virus (HIV)-1 infection. It is approved for use in adults and dosage recommendations exist for children aged 6 years or older. T20-310 was a multicenter, open-label, nonrandomized, noncomparative study of the safety and efficacy of 2.0 mg/kg (maximum 90 mg) twice-daily subcutaneous enfuvirtide for 48 weeks in 52 treatment-experienced, HIV-1-infected pediatric patients (3–16 years) receiving optimized background therapy. Enfuvirtide was generally well tolerated, and no new patterns of adverse events compared with adults were observed. Mild-to-moderate injection-site reactions were the most common adverse event. Of those participants on treatment for 48 weeks, the median change from baseline in HIV-1 RNA was −1.17 log10 copies/mL (n = 32), and there was a median CD4 change of +106 (n = 25) cells/mm3 and +4.7 CD4%. Seventeen (32.7%) patients achieved a viral load decrease of ≥1 log10 copies/mL and 11 (21.2%) achieved HIV-1 RNA <400 copies/mL. Virologic and immunologic treatment responses were substantially better for children (<11 years) than adolescents. Steady-state mean enfuvirtide Ctrough levels were stable during 24 weeks with no differences between children and adolescents. Enfuvirtide is an effective treatment for HIV-1 infection in children and adolescents receiving optimized background therapy and has a favorable safety profile. Efficacy in adolescents was inferior; probably related to unique adherence challenges. The long-term safety and efficacy of enfuvirtide in pediatric patients is comparable to that observed in adults.

The association between baseline drug resistance mutations and subsequent increase in viral failure has not been established for HIV-infected children. We evaluated drug resistance mutations at 39 codon sites (21 protease inhibitor (PI) resistant codons and 18 nucleoside reverse transcriptase inhibitor (NRTI) resistant codons) for 92 clinically stable NRTI-experienced, PI-naive HIV-infected children 2 to 17 years of age who were initiating new therapy with ritonavir plus zidovudine (ZDV) and lamivudine or plus stavudine. The association between baseline drug resistance mutations and subsequent viral failure after 12 and 24 weeks of highly active antiretroviral therapy (HAART) was studied. There were few primary PI associated mutations in this PI-naïve population, but 84% had NRTI mutations – codons 215 (66%), 41 (42%), 67 (37%), 210 (33%) and 70 (32%). None of the specific baseline drug resistance mutations were associated with a higher rate of virologic failure after 12 or 24 weeks of HAART. Median week 12 viral load decreased as the total number of NRTI mutations at baseline increased (P = 0.006). Specifically, a higher level of baseline ZDV resistance mutation was associated with a decrease in viral failure after 12 weeks on a ZDV-containing HAART regimen (P = 0.017). No increase was seen in the rate of viral failure after HAART associated with the presence of resistance mutations at baseline. This paradoxical result may be due to adherence, replicative capacity, or ZDV hypersusceptibility to the new regimen.

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy–experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance (^R) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv^R, ddI^R, and ddC^R mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp^R and 3TC^R mutations were detected frequently at virologic failure, and Nvp^R mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp^R and 3TC^R mutations plus Rtv^R and Nfv^R mutations. However, Rtv^R and Nfv^R mutations were detected at unexpectedly low rates

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (≤400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.

The response of 40 immunologic parameters was studied for 147 clinically stable, protease inhibitor-naive, human immunodeficiency virus (HIV)-infected children aged 2–17 years when antiretroviral therapy was changed to either a dual nucleoside analogue regimen or a protease inhibitor-containing regimen. Immunologie response to therapy, as measured by lymphocyte subsets, 3-color flow cytometric measures, and lymphoproliferative assays, were investigated for changes in weeks 44 and 48. The most significant changes after baseline that were associated with the administration of a protease inhibitor-containing regimen were seen for percentages of CD8⁺/CD38⁺/HLA-DR⁺, CD8⁺/CD95⁺/CD28⁻, and CD8. The percentages of CD8⁺/CD38⁺/HLA-DR⁺ and CD8⁺/CD95⁺/CD28⁻ decreased from baseline medians of 33% and 46% to medians of 18% and 30% at week 44 (P < .0001 for both). Median CD4 cell count increased 168 cells/μL (from 694 cells/μL to 862 cells/μL; P = .02) by week 48 in this clinically stable population. Changes in lymphoproliferative responses to HIV antigens and recall antigens did not increase over time and between groups.