Research Article: HIV Drug Resistance-Associated Mutations in Antiretroviral Naïve HIV-1-Infected Latin American Children

Date Published: January 18, 2010

Publisher: Hindawi Publishing Corporation

Author(s): Luis E. Soto-Ramirez, Roberto Rodriguez-Diaz, D. Robert Harris, Rohan Hazra.


Our goal was to describe the presence of HIV drug resistance among HIV-1-infected, antiretroviral (ARV) naïve children and adolescents in Latin America and to examine resistance in these children in relation to drug exposure in the mother. Genotyping was performed on plasma samples obtained at baseline from HIV-1-infected participants in a prospective cohort study in Brazil, Argentina, and Mexico (NISDI Pediatric Study). Of 713 HIV-infected children enrolled, 69 were ARV naïve and eligible for the analysis. At enrollment, mean age was 7.3 years; 81.2% were infected with HIV perinatally. Drug resistance mutations (DRMs) were detected in 6 (8.7%; 95% confidence interval 3.1–18.2%) ARV-naïve subjects; none of the mothers of these 6 received ARVs during their pregnancies and none of the children received ARV prophylaxis. Reverse transcriptase mutations K70R and K70E were detected in 3 and 2 subjects, respectively; protease mutation I50 V was detected in 1 subject. Three of the 6 children with DRMs initiated ARV therapy during followup, with a good response in 2. The overall rate of primary drug resistance in this pediatric HIV-infected population was low, and no subjects had more than 1 DRM. Mutations associated with resistance to nucleoside reverse transcriptase inhibitors were the most prevalent.

Partial Text

Primary HIV-1 drug resistance has been reported in up to 20% of HIV-infected adults in the United States and Europe [1–3] and has led to recommendations that all treatment-naïve adults undergo resistance testing when they enter care [4]. Data on primary (or initial) resistance in HIV-infected infants and children are more limited but have led to similar recommendations [5]. Recent studies of infected infants in the United States have demonstrated rates of primary resistance to at least one antiretroviral (ARV) in the range of 19–24%, with most being mutations associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance [6, 7]. Rates reported from older children in the United Kingdom are lower (3 of 44, 6.8%) [8]. In a study from Brazil, primary resistance was seen in 7 of 26 (27%) perinatally infected children [9], and a study from Argentina demonstrated primary resistance in 5 of 22 (23%) infected infants but much lower rates (1 of 45, 2.2%) in infected children 1–14 years of age [10]. When examined in some of these studies, maternal ARV history did not generally provide a clear explanation for the results seen in the infants and children.

In 2002, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) began enrollment to the NICHD International Site Development Initiative (NISDI) pediatric protocol at 15 sites in Brazil, Mexico, and Argentina [11]. The NICHD IRB, the data management and statistical center IRB, separate in-country ethics committees, and national review boards (where required, i.e., Brazil) reviewed and approved the protocol. Informed consent was obtained from either parents or guardians or from subjects who were able to provide consent based upon local laws. Assent was obtained from subjects >8 years of age when developmentally appropriate.

Of the 713 HIV-infected children and adolescents enrolled in the NISDI Pediatric Protocol at clinical sites in Argentina, Brazil, and Mexico as of February 1, 2005, a total of 85 subjects were ARV naïve and eligible for inclusion in this study. Sixteen were excluded because they either did not have a sample in the repository or viral DNA could not be amplified from their specimen, leaving 69 subjects eligible for the final analysis.

Among this population of HIV-1-infected children and adolescents from Latin America who were ARV naïve at time of enrollment with relatively low plasma viral loads and relatively high CD4+ counts, DRMs were detected in repository samples from 6 of 69 subjects (8.7%, 95% CI 3.1–18.2%). The population we studied is likely representative of the pediatric HIV population at these sites with expertise in pediatric HIV and availability of ARVs, but we cannot comment on how representative our population is of the whole region. In comparison to other studies, this rate of primary drug resistance is lower than that reported in children in Northeast Brazil [9] and higher than the 0% rate reported in 24 children in Sao Paulo, Brazil [13] (although reverse transcriptase mutation K219N was seen in one subject in the latter study, which, by our definition [12], yields a rate of 4.2%). Studies from the United States and Argentina have shown higher rates in HIV-infected infants [6, 7, 10]. However, all of these studies are quite small and larger cohorts and datasets are necessary to document these rates around the world and to examine changes in them as access to ARVs expands. In addition, in several of these other studies and in ours, specimen collection was performed long enough after infection that some DRMs may have become undetectable, thus underestimating the true rate of resistance and also helping to explain the wide range of results seen.