Antiretroviral therapy in children with tuberculosis: progress toward defining the issues.

Received 20 November 2009; accepted 20 November 2009; electronically published 9 March 2010. Potential conflicts of interest: none reported. Financial support: none reported. Reprints or correspondence: Prof Mark F. Cotton, Stellenbosch University, Francie van Zyl Ave, Tygerberg, Western Cape 7505, South Africa (mcot@sun.ac.za). The Journal of Infectious Diseases 2010;201:1113–1114 2010 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2010/20108-0001$15.00 DOI: 10.1086/651455 Compared with adults, children have always presented treatment challenges. The coexisting pandemics of human immunodeficiency virus (HIV) infection and tuberculosis in high-prevalence settings such as sub-Saharan Africa have been especially devastating for infants and young children. The difficulties are well illustrated in the thoughtful article by Reitz et al [1] in this issue of the Journal, in which they report on the virological outcomes in children ! 2 years of age in the Nevirapine Resistance (NEVEREST) antiretroviral strategy study in Johannesburg, South Africa. Fourteen percent of children died and 39% required cotreatment for tuberculosis. The difficulties of diagnosing tuberculosis in infants are also well illustrated in this article and reflect “reality on the ground,” where clinicians initiate treatment on the basis of a constellation of symptoms such as failure to thrive, suggestive radiological findings, and contact with a source case. The appropriateness of this strategy is supported by the recent documentation of a culture-confirmed tuberculosis incidence rate of 1596 per 100,000 HIV-infected infants as opposed to 65.9 per 100,000 in HIV-uninfected infants ! 1 year of age in the South African Western Cape [2]. The children were in the prerandomization phase of an antiretroviral strategy study and were treated according to South African guidelines from 2005 [3]. At the time, a single dose of nevirapine was used to prevent vertical transmission. Because there was already evidence of compromised virological outcome in mothers exposed to this strategy [4], the South African guidelines recommended the protease inhibitor lopinavir-ritonavir for infants 6 months of age and ritonavir alone for younger infants. Subsequent to the study, the correct lopinavir-ritonavir dosage for infants ! 6 months of age was established [5]. In the NEVEREST study, infants were switched to lopinavir-ritonavir at 6 months of age. The induction of subtherapeutic levels of many protease inhibitors (such as nevirapine and efavirenz) through rifampicin-induced enhanced cytochrome P450 activity, as well as the ability of ritonavir at high dosage to limit this interaction, is well known, which is why children who require rifampicin cotreatment for tuberculosis were given ritonavir alone until recently [6]. Overall, Reitz et al [1] showed that 84% of children achieved viral suppression to HIV RNA loads of ! 400 copies/mL by 9 months of age, a remarkable achievement, in keeping with the best outcomes in children elsewhere. Their key finding in this study, however, was that those children cotreated for tuberculosis had statistically significantly poorer virological outcomes, more so when antituberculosis therapy was initiated during, rather than prior to, antiretroviral therapy. The majority of infants had advanced HIV disease at entry. The most important question is how to explain these findings. Is the poorer virological outcome due to either tuberculosis or factors such as failure to thrive, respiratory symptoms, and radiological abnormalities that trigger the initiation of antituberculosis treatment, or are they due to suboptimal antiretroviral therapy? The authors found that factors such as poorer adherence to antiretroviral therapy regimens (possibly aggravated by the need for additional antituberculosis therapy), decreased CD4 cell percentage, failure to thrive, and increased viral load contributed to, but did not fully explain, the poorer viral suppression with concurrent treatment for tuberculosis. An important issue, also addressed by Reitz et al [1], is the potential contribution of ritonavir, a medication well known for its intolerability, especially in the liquid formulation. The authors argue against a medication effect by citing a recent study of 50 children in whom 72% (84% as