Multicentre analysis of second-line antiretroviral treatment in HIV-infected children: adolescents at high risk of failure.

INTRODUCTION: The number of HIV-infected children and adolescents requiring second-line antiretroviral treatment (ART) is increasing in low- and middle-income countries (LMIC). However, the effectiveness of paediatric second-line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second-line ART outcomes for children and assessed the need for paediatric third-line ART. METHODS: We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second-line ART in LMIC, contacting the corresponding study groups and including patient-level data on virologic and clinical outcomes. Kaplan-Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second-line treatment. RESULTS: We included 12 cohorts representing 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9-19.4) of children experienced virologic failure. Adolescents (10-18 years) had failure rates of 14.5 (95% CI 11.9-17.6) per 100 person-years compared to 4.5 (95% CI 3.4-5.8) for younger children (3-9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first-line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24-48 months and >48 months, respectively, compared to <24 months). CONCLUSIONS: In LMIC, paediatric PI-based second-line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI-based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.

Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver disease in HIV-infected Asian children.

BACKGROUND: We determined the prevalence and incidence of liver dysfunction before and after initiation of combination antiretroviral therapy (cART) in the TREAT Asia Pediatric HIV Observational Database. METHODS: Data from children initiated on cART between 2 and 18 years of age with baseline alanine aminotransferase (ALT) available before and at least once after cART initiation in TREAT Asia Pediatric HIV Observational Database between 2008 and 2012 were analyzed. Prevalence and incidence of liver dysfunction and biomarkers including the aspartate aminotransferase to platelet ratio index and FIB4 index (a noninvasive panel to stage liver disease) were assessed. RESULTS: Data from 1930 children were included. Their median age was 6.9 years; 49% were male; 98% were perinatally infected and 94% were initiated on non-nucleoside reverse transcriptase-based cART regimens. Before cART, the prevalence of ALT ≥3 times the upper limit of normal (×ULN) was 5.8%. There were 8.5% of children with aspartate aminotransferase to platelet ratio index >1.5 (suggestive of liver fibrosis) and 2.7% with FIB4 index >1.3 (predictive of possible cirrhosis). Among the 1143 cases with normal baseline ALT (≤1×ULN), the incidence of ALT 3×ULN after cART was 1.19 of 1000 person-months (95% confidence interval: 0.93-1.51). Two of 350 with available tests (0.6%) met Hy's law (ALT >3×ULN and total bilirubin >2×ULN). By multivariate analysis, baseline hemoglobin <7.5 g/dL was a predictor of ALT >3×ULN, whereas age 5-9 years at cART initiation was protective for liver dysfunction. CONCLUSIONS: We demonstrated a low prevalence and incidence of liver dysfunction before and after cART initiation in children with normal baseline chemistries. In this population facing life-long cART, prospective surveillance for emergence of liver disease is warranted.

Virologic and immunologic outcomes in HIV-infected Cambodian children after 18 months of highly active antiretroviral therapy (HAART).

This observational cohort study was conducted among HIV-infected, antiretroviral therapy (ART) naive children in Phnom Penh, Cambodia, to evaluate the feasibility and efficacy of highly active antiretroviral therapy (HAART) delivered using a modified directly observed therapy (MDOT) protocol. From August 2004 to March 2006, 26 children were enrolled and started on a first-line HAART regimen, which was continued for 18 months. The study included a directly observed therapy phase (months 1-3) and a medication self-administration phase (months 4-18). CD4 percentage (CD4%) and HIV-1 RNA plasma viral load (PVL) were measured at baseline and at months 6, 12, and 18. At baseline, the median age was 5.5 years (range: 13 months-12 years), the median CD4% was 4, and the median PVL was 7.5x10(5) copies/ml. At 18 months, 23 (88%) children were alive and participating in the study. Of these children, 20 (87%) had a PVL <400 copies/ml and 12 (52%) had PVL < 50 copies/ml. The median CD4% increased to 23, while the median change in height-for-weight z-score was 0.64. Genotypic resistance typing in 2 children with PVL > 400 copies/ml at 18 months demonstrated mutations associated with resistance to lamivudine (M184V) and non-nucleoside reverse transcriptase inhibitors (Y181C and G190A). The virologic and immunologic outcomes achieved in this study compare favorably with those reported by other pediatric HIV treatment programs worldwide. The study results suggest that MDOT may be effective for HAART administration in limited-resource settings like Cambodia.