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Objective: HIV-infected adolescents are a heterogeneous population; source of infection, immunodeficiency severity and antiretroviral (ARV) experience vary. Here, we describe youth followed in an observational study at Latin American sites of the NICHD International Site Development Initiative (NISDI).Methods: The NISDI pediatric protocol is an ongoing prospective cohort study that collects demographic, clinical, immunologic, virologic and medication data. Youth were enrolled at 15 sites in Brazil, Argentina and Mexico between 2002 and 2006. HIV-infected subjects aged 12–21 years at the time of enrollment were analyzed.Results: Data from 120 HIV-infected youth were analyzed. Sixty-nine (58%) had acquired HIV through vertical transmission (VT); 51(42%) via horizontal transmission (HT). Twenty-eight percent of the VT group were not diagnosed until they were ≥10 years of age. Ninety-one percent of the VT group and 46% of the HT were receiving ARV at enrollment. Modes of HT included sexual (ST), blood product transfusion (BPT) and unknown (U). Severe immunodeficiency was frequent (21%) in the ST group. Low BMI was frequent in the VT and BPT sub-groups. Utilization of HAART increased over the course of the study, but viral suppression was present in only 38% of the VT group and 37% of the HT group at study end.Conclusions: This cohort of HIV-infected adolescents in Latin America displayed a diverse epidemiologic pattern. Care providers must be prepared to address the diverse needs and challenges of this population. The levels of virologic suppression achieved were inadequate. Further research into appropriate interventions for this population is urgently needed.