Genotyping for Guiding Drug Choice in Human Immunodeficiency Virus-Infected Children Failing Multiple Antiretroviral Treatment Regimens

Abstract

To the Editors: The use of human immunodeficiency virus (HIV) genotyping for identifying the most effective regimens in HIV-infected adults failing highly active antiretroviral therapy led to improved virologic response as compared with regimens selected on the basis of antiretroviral exposure history. In contrast, similar studies conducted in small cohorts of HIV-infected children failed to demonstrate a clear advantage of antiretroviral resistance testing over antiretroviral exposure history. In this study, we have genotyped HIV reverse transcription and protease genes in 17 children (ages 4.5–11.3 years) between 2000 and 2001, at treatment failure and have changed antiretroviral drugs according to HIV genotype profiles. All 17 children who were included showed an elevated viral load (>1000 copies/mL) for at least 9 months during the last year before genotyping and had failed from 1–5 regimens during that time. All the HIV-infected children had received a combination of at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) (17 of 17) and while 8 of 17 had been treated with a PI containing regimen; none of them was previously treated with non-NRTIs (Table 1). Adherence to therapy was based on reports from children and caretakers and on calculation of quantities of drugs that were requested at each visit. At the time of treatment failure, we identified substitutions in both the reverse transcription and the protease genes in samples from 94% of children.TABLE 1: Nucleoside Reverse Transcription Inhibitors Used in HIV TreatmentWild-type sequences could not be identified in any sample from this cohort of HIV-infected children. Drug-specific genotypic resistance, identified on the basis of the IAS mutation list,4 was commonly observed for all the NRTIs as shown in detail in Table 1. Antiretroviral therapy was changed by substitution of at least one antiretroviral medication in all patients, except in patient 17. Since none of the patients had been previously exposed to non-NRTI drugs whereas 8 of 17 had received a drug of the protease inhibitor class, we introduced efavirenz in the therapeutic regimens of 11 children. Virologic and immunologic data were collected at 2- to 3-month intervals for at least 12 months. We observed a significant suppression of viral load (<1000 copies) 3-6 months after treatment change. HIV suppression was detected in 8 of the 17 patients from 6 to 35 months (stably undetectable in 5 cases), whereas in another 5 children viral load remained elevated through 12 months of follow-up. CD4+ percentages showed a significant increase from baseline levels in the same children who showed virologic suppression, except in patient 10 who had already started the treatment with 44% of CD4, suggesting that their treatment regimens were effective to induce immunologic reconstitution. The remaining patients (patients 1, 3, 4 and 13) showed a rapid, but transient, decline of viral load after treatment change. Because of the high risk of false negatives, we have performed an additional HIV genotyping in the remaining 9 patients who showed an unsatisfactory response to medication changes. In patients 1 and 13, we detected additional mutations in reverse transcription gene (Table 1) that conferred resistance to efavirenz, thereby accounting for the inadequate response to the previous change of antiretroviral treatment. HIV genotyping did not reveal any resistance-associated mutation in 7 children who had failed 2 changes of treatment regimens, suggesting that limited adherence may account for this observation. Our study demonstrates that HIV genotyping based treatment choices in 17 infected pretreated children led to persistent viral suppression and immunologic reconstitution in 10 children, suggesting that use of this assay improves clinical outcome of antiretroviral-experienced children. A previous study failed to show benefit of HIV resistance testing in a cohort of 18 children. We believe that the limited availability of novel antiretroviral medications and variable adherence to therapeutic regimens may account the different results that are observed in these studies. Drs Badolato and Schumacher contributed equally to this work. Raffaele Badolato, MD, PhD R. Fabian Schumacher, MD Elisabetta Rodella, MD Franco Gargiulo, MD Carlo Torti, MD Luigi D. Notarangelo, MD Marzia Duse, MD Istituto di Medicina Molecolare “Angelo Nocivelli” Clinica Pediatrica Cattedra di Malattie Infettive Laboratorio di Microbiologia University of Brescia Brescia, Italy