Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy

Diana Averbuch, Jonathan M. Schapiro, E. Randall Lanier, Serge Gradstein, Giora Gottesman, Eynat Kedem, Menachem Einhorn, Galia Grisaru-Soen, Michal Ofir, Dan Engelhard, Zehava Grossman

    Research output: Contribution to journalArticlepeer-review

    20 Scopus citations

    Abstract

    BACKGROUND: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome. METHODS: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured. RESULTS: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 ± 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns. CONCLUSIONS: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

    Original languageEnglish
    Pages (from-to)1049-1056
    Number of pages8
    JournalPediatric Infectious Disease Journal
    Volume25
    Issue number11
    DOIs
    StatePublished - 1 Nov 2006

    Keywords

    • African children
    • M184V
    • NRTI
    • Phenotype and genotype resistance testing
    • Subtype C HIV-I-infected children
    • Thymidine analog mutations (TAMs)

    ASJC Scopus subject areas

    • Pediatrics, Perinatology, and Child Health
    • Microbiology (medical)
    • Infectious Diseases

    Fingerprint

    Dive into the research topics of 'Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy'. Together they form a unique fingerprint.

    Cite this