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Background: The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier., Design/methods: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as 'very cost-effective,' interventions with ICERs below 3× gross domestic product/YLS as 'cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as 'cost-saving'., Results: Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective., Conclusions: On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.

Treatment failure and drug resistance create obstacles to long-term management of HIV-1 infection. Nearly 60% of infected persons fail their first highly active antiretroviral therapy (HAART) regimen, partially because of nonadherence, requiring a switch to a second regimen to prevent drug resistance. Among HIV-infected youth, a group with rising infection rates, treatment switch is often delayed; virologic and immunologic consequences of this delay are unknown. We conducted a retrospective, longitudinal study of drug resistance outcomes of initial HAART in U.S. youth enrolled between 1999-2001 in a multicenter, observational study and experiencing delayed switch in their first nonsuppressive treatment regimen for up to 3 years. HIV-1 genotyping was performed on plasma samples collected longitudinally, and changes in drug resistance mutations, CD4+ T cell numbers and viral replication capacity were assessed. Forty-four percent (n = 18) of youth in the parent study experiencing virologic nonsuppression were maintained on their initial HAART regimen for a median of 144 weeks. Drug resistance was detected in 61% (11/18) of subjects during the study. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (8/10) drug resistance mutations than those on protease-inhibitor (PI) regimens (2/7) (p = 0.058). Subjects developing NNRTI-resistance (NNRTI-R), showed a trend toward lower CD4+ T cell gains (median: -6 cells/mm(3) per year) than those without detectable NNRTI-R (median: +149 cells/mm(3) per year) (p = 0.16). HIV-1-infected youth maintained on initial nonsuppressive NNRTI-based HAART regimens are more likely to develop drug-resistant viremia than with PI-based HAART. This finding may have implications for initial treatment regimens and transmission risk in HIV-infected youth, a group with rising infection rates.

The PACTG 381 cohort included 120 adolescents infected via high-risk behaviors and treated with at least two NRTIs plus either a protease inhibitor or an efavirenz-containing HAART regimen. After 24 weeks of therapy, only 69 of 118 (59%) evaluable subjects had undetectable viral loads. We now present findings of the study after 3 years of follow-up. Virologic, immunologic, and treatment information were collected from subjects every 12 weeks beyond the first 24 weeks of therapy through 156 weeks. Of the 120 subjects starting HAART, 44 (37%) stayed on study treatment for the 3 years of observation. Twenty-nine (24%) subjects reached and maintained undetectable viral loads. Poorer adherence (p = 0.016), higher baseline viral load (p = 0.010), and CD8 naive counts (p = 0.034) predicted virologic failure. Immunologic measurements improved from entry to the end of follow-up in the subjects with undetectable viral loads. CD4 counts at the end of study were not significantly different from HIV-uninfected youth, but CD4%, CD8 counts and percent, and CD8 activation markers remained significantly different. Adolescents infected with HIV via high-risk behaviors have less than optimal responses to HAART therapy with only 24% achieving and maintaining undetectable viral loads over 3 years. Immunologic improvement was demonstrated and CD4 counts in subjects with virologic control reached levels in HIV-uninfected adolescents. Interventions, especially those focused on adherence, are necessary to improve HAART outcomes in adolescents.

The responses to HAART in HIV-infected adolescents infected through risk behaviors are not well defined. PACTG 381 collected intensive immunologic and virologic data on youth naive to or with minimal exposure to antiretroviral therapy who began HAART. Subjects were evaluated according to their weeks 16-24 virologic response. Comparisons with a cohort of HIV-uninfected adolescents from the REACH cohort were performed. Cox proportional hazards models were used to identify baseline and week 24 predictors of virologic failure. Only 69 of 120 subjects (58%) achieved virologic suppression by weeks 16-24, whereas 55 of 69 (80%) demonstrated control to week 60. Higher CD4+ naive T cells (CD4+/62L+/RA+: hazard ratio [HR], 2.13; p = 0.018), higher CD8+ activated T cells (CD8+/CD38+/DR+: HR, 1.40, p = 0.028 per 100 cells/mm3) and higher CD8+ naive T cells (CD8+/62L+/RA+: HR, 1.72; p = 0.005) at weeks 16-24 in subjects with early viral success were predictive of subsequent failure. By week 60, total CD4+ T cells remained significantly lower than in uninfected controls. Adolescents beginning HAART achieve moderate rates of viral suppression by weeks 16-24. In those who do achieve early virologic control, suppression to week 60 is high although total CD4+ T cells remain significantly lower than in uninfected controls. Several T cell markers were predictive of subsequent virologic failure in subjects achieving short-term success. Further study is warranted to determine whether these predictors provide any benefit to clinical management.

Background: Weight and height growth of HIV-infected children tends to lag behind that of uninfected children of similar age. Previous reports of the effect of highly active antiretroviral therapy (HAART) on the growth of HIV-infected children have been contradictory., Methods: Age- and gender-adjusted height and weight z scores were studied for 192 HIV-infected children, 4 months to 17 years of age, who had been treated with antiretroviral therapy for at least 16 weeks. These children, in clinically and immunologically stable condition, were enrolled into one of 4 HAART regimens and evaluated for 96 weeks., Results: At baseline, these HIV-infected children were significantly shorter than uninfected children (mean z score, -0.57; 95% confidence interval, -0.73 to -0.41; P < 0.001). Children with greater viral loads at baseline were significantly shorter and lighter than children with smaller viral loads (both P < 0.001). Administration of HAART led to an increase in mean weight z scores to normal values (mean z score increase, from -0.16 to >0) by week 48 and an increase in mean height z scores of 72% toward normal values (mean z score increase, from -0.57 to -0.16) by week 96. Younger children gained height more rapidly (P < 0.001), and children with greater baseline viral loads gained weight more rapidly (P < 0.001). There was no evidence of differential height or weight changes in 48 weeks between children with different degrees of virologic control., Conclusions: HAART improved the average weight gain of HIV-infected children from subnormal to normal after 1 year and improved average height growth to nearly normal after 2 years.

Background: Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy., Methods: We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy., Results: Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads., Conclusions: Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Background: Human immunodeficiency virus (HIV)-infected children often suffer from impaired growth. Highly active antiretroviral therapy (HAART) successfully reduces HIV 1 (HIV-1) RNA to 400 copies/mL or less in many children., Objectives: To determine if age- and sex-adjusted growth z scores correlate with HIV-1 RNA level and if control of viral load for 48 and 96 weeks results in improved growth in children receiving highly active antiretroviral therapy., Design: Secondary analysis of the cohort of children receiving ritonavir nested in a randomized, open-label, clinical trial., Subjects and Methods: The Pediatric AIDS Clinical Trials Group Protocol 338 enrolled clinically stable, antiretroviral therapy-experienced, HIV-infected subjects aged 2 through 17 years. Using data from subjects randomized to ritonavir-containing regimens (n = 197), the association of growth z scores and HIV-1 RNA levels were examined., Main Outcome Measures: Age- and sex-adjusted weight and height z scores., Results: Enrollment weights were comparable with age- and sex-adjusted norms, but subjects receiving ritonavir-containing antiretroviral therapy were significantly shorter (mean z score, -0.57 [29th percentile]; 95% confidence interval, -0.73 to -0.40). Higher HIV-1 RNA levels correlated with lower growth z scores (P<.01). Subjects achieving and maintaining HIV-1 RNA of 400 copies/mL or less through 48 and 96 weeks experienced worse growth than subjects with a less controlled viral load., Conclusions: In this pediatric cohort, a significant decline in height and weight z scores was found despite control of viral replication. Further studies of growth are necessary to assess if nutritional and hormonal adjuvants to highly active antiretroviral therapy should be considered to improve growth in HIV-infected children.