Drug Resistance Mutations During Structured Interruptions of HAART in HIV-1 Infected Children

Gerardo      C. Palacios-Saucedo; Lydia      G. Rivera-Morales; Jose      M. Vazquez-Guillen; Luz      M. Sanchez; Teresa      J. Ramirez; Evangelina      Briones; Rocio      Ortiz-Lopez; Carlos      A. Vazquez; Cristina      Rodriguez-Padilla

Abstract

Information concerning structured treatment interruptions (STI) of the Highly Active Antiretroviral Therapy (HAART) and the associated risk of this strategy for selecting antiretroviral resistance in children is scarce. In this study, we have searched for antiretroviral resistance mutations at the end of five viral rebounds of two HIV-1-infected children who underwent an STI program. The HAART of two children with HIV and a chronically undetectable viral load (VL) was interrupted for 4 weeks and then restarted and continued for 12 weeks for three cycles. VL, CD4+/CD8+ lymphocytes, and clinical status were evaluated at the end of each STI and at 6 and 12 weeks after HAART was resumed. Treatment of both the patients based on AZT+3TC+RTV remained identical during the study. The reverse transcriptase (RT)- and protease (PR)-coding regions were sequenced searching for antiretroviral resistance mutations at the end of each viral rebound. Genotyping analysis was performed using the Stanford University HIV Drug Resistance Database (HIV-DB). One patient experienced progressively lower viral rebounds (269000 – 31300 at the first and third rebounds, respectively), while the other patient did not experience such a reduction, and the VL of both the patients fell to undetectable levels during therapy. In the five viral rebounds examined, no mutations for major or minor resistance to protease inhibitors (PIs) were found and the analysis indicated susceptibility to all PIs currently in clinical use. Although the mutation K103R associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was found in two viral rebounds of one patient, the analysis indicated the absence of resistance to reverse transcriptase inhibitors in all the sequences evaluated. As no mutation related to antiretroviral resistance was found, our results suggest that the STI program used in this study may have a low risk of selecting antiretroviral resistance. Nevertheless, further studies evaluating larger cohorts over longer periods, and above all, controlled clinical trials, are required before definitive conclusions about the safety of STI of HAART in children may be drawn.

Keywords: AIDS (acquired immunodeficiency syndrome), antiretroviral resistance, HAART (highly active antiretroviral therapy), STI (structured treatment interruptions), HIV-DB, APOBEC, Reverse Transcriptase Inhibitor, Protease Inhibitors, HIV-1