The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study

et al. (2011) The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV- Infected Children in a Resource-Deprived Setting: A Cohort Study. PLoS Med 8(6): e1001044. doi:10.1371/journal.pmed.1001044 The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study Andrew Edmonds 0 Marcel Yotebieng 0 Jean Lusiama 0 Yori Matumona 0 Faustin Kitetele 0 Sonia 0 Napravnik 0 Stephen R. Cole 0 Annelies Van Rie 0 Frieda Behets 0 David R. Bangsberg, Massachusetts General Hospital, United States of America 0 1 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America, 2 School of Public Health, University of Kinshasa , Kinshasa , Democratic Republic of the Congo, 3 School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina , United States of America Background: The effect of highly active antiretroviral therapy (HAART) on the survival of HIV-infected children has not been well quantified. Because most pediatric HIV occurs in low- and middle-income countries, our objective was to provide a first estimate of this effect among children living in a resource-deprived setting. Methods and Findings: Observational data from HAART-nave children enrolled into an HIV care and treatment program in Kinshasa, Democratic Republic of the Congo, between December 2004 and May 2010 were analyzed. We used marginal structural models to estimate the effect of HAART on survival while accounting for time-dependent confounders affected by exposure. At the start of follow-up, the median age of the 790 children was 5.9 y, 528 (66.8%) had advanced or severe immunodeficiency, and 405 (51.3%) were in HIV clinical stage 3 or 4. The children were observed for a median of 31.2 mo and contributed a total of 2,089.8 person-years. Eighty children (10.1%) died, 619 (78.4%) initiated HAART, six (0.8%) transferred to a different care provider, and 76 (9.6%) were lost to follow-up. The mortality rate was 3.2 deaths per 100 person-years (95% confidence interval [CI] 2.4-4.2) during receipt of HAART and 6.0 deaths per 100 person-years (95% CI 4.1-8.6) during receipt of primary HIV care only. The mortality hazard ratio comparing HAART with no HAART from a marginal structural model was 0.25 (95% CI 0.06-0.95). Conclusions: HAART reduced the hazard of mortality in HIV-infected children in Kinshasa by 75%, an estimate that is similar in magnitude but with lower precision than the reported effect of HAART on survival among children in the United States. Please see later in the article for the Editors' Summary. - Funding: The HIV care and treatment program at Kalembe Lembe Pediatric Hospital and Bomoi Healthcare Center, conducted in collaboration with the Kinshasa School of Public Health and the National AIDS Control Program, was funded by the US Centers for Disease Control and Prevention Global AIDS Program (http:// www.cdc.gov/globalaids; grant number U62/CCU422422) and the Presidents Emergency Plan for AIDS Relief (http://www.pepfar.gov; grant number 5U2GPS001179-01), with additional support from the Elizabeth Glaser Pediatric AIDS Foundation (http://www.pedaids.org), the Belgian Development Cooperation (http://diplomatie.belgium.be/en/policy/development_cooperation), the William J. Clinton Foundation (http://www.clintonfoundation.org), the United Nations Childrens Fund (http://www.unicef.org), and the Global Fund to Fight AIDS, Tuberculosis, and Malaria (http://www.theglobalfund.org/en). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: CI, confidence interval; DRC, Democratic Republic of the Congo; HAART, highly active antiretroviral therapy; HR, hazard ratio; IPTC, inverse probability of treatment and censoring; IPTCV, inverse probability of treatment, censoring, and visit attendance; IQR, interquartile range; NVP, nevirapine; WHO, World Health Organization Highly active antiretroviral therapy (HAART) clearly improves the survival of adults living with HIV [1,2], even when initiated at higher CD4 cell counts [3,4], but less is known about the degree to which HAART affects the survival of HIV-infected children. The course of HIV disease in children, in part because of deleterious impacts of the virus on the immature thymus [5], leading to high HIV RNA viremia [6] and rapid death [7], is distinct from that in adults [8]. Response to antiretroviral treatment also differs across age groups [9]. Given that the natural history of HIV and response to therapy vary by age and that more than two million children worldwide are living with HIV [10], the extrapolation of results from studies of adults to pediatric populations is not appropriate. It is imperative that the effect of HAART on survival is specifically quantified in children. Most observational studies on the effects of treatment on survival in children have not used the epidemiological methods necessary to account for potential biases inherent to their design, including confounding by indication. One study not employing methods necessary to account for such possible biases found that HAART, relative to no therapy, decreased the mortality rate by 71% among 1,142 Italian children [11]. A recent study of 1,236 children in the United States [12], which used optimal analytical methods, observed a result similar to that of the Italian study. More than 90% of children receiving HAART live in lowresource areas [10,13]. Because multiple factors that may adversely affect treatment outcomes including delayed presentation to care and a higher incidence of co-occurring infectious and non-infectious conditions such as undernutrition are more common in such environments [14], there is a specific need for information on the effects of HAART on patients living in these areas. Studies in adults have revealed higher mortality after HAART initiation in resource-poor settings than in resourceprivileged settings after adjusting for age, CD4 cell count, and disease stage [15,16]. Although investigations in pediatric cohorts from Zambia [17], Haiti [18], and Cote dIvoire [19] have shown that treatment improves immunological, hematological, and growth outcomes, and results in mortality rates lower than those observed in the pre-antiretroviral era [7], an estimate of the effect on mortality of HAART, compared to no HAART, has never been accurately quantified among children in a resource-deprived setting. This is true of two recent multi-site studies in sub-Saharan Africa [20,21], as well as studies in Thailand [22], Zambia [23], Co te dIvoire [24], and Lesotho [25] that have provided valuable information on mortality among children receiving HAART, including rates during the early and late therapeutic periods. In this study, we (...truncated)