The Body PRO Covers: The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy

Antiretroviral Resistance (Poster Session 176)

December 18, 2001

  • Impact of M184V/I Mutation on HIV Phenotypic Resistance to Nucleoside Analogs (NRTIs) in NRTI-Experienced Patients
    Abstract 1759
    Authored by N. Shulman, R. Bosch, N. Wang, M. Albrecht, N. Hellmann, D. Katzenstein, (ACTG 364 Study Team, Bethesda, MD)
    View the original abstract

Emerging information suggests that some mutations conferring primary drug resistance to one HIV drug may reduce drug resistance (increase susceptibility) to another drug. This has been described with the M184V mutation seen in the HIV reverse transcriptase gene, which confers resistance to 3TC (lamivudine) but can rescue AZT's activity despite the presence of AZT-associated mutations.

This poster discusses the impact of this mutation on other NRTI medications, namely d4T (stavudine), and considers the long-term viral load impact in patients who had the M184V mutation and subsequently started a d4T-containing regimen.

Baseline plasma samples were obtained from patients who enrolled in ACTG 364. These patients had several years of NRTI experience, although only six percent had received prior d4T. Over 75 percent had more than two AZT or thymidine-associated mutations (TAMs). Genotypic and phenotypic resistance testing was performed. Fifty-five patients had virus with the normal (wild type) amino acid (M, methionine) at the 184 position, and 75 patients had the V (valine) substitution, which confers resistance to 3TC. Presence of the M184V mutation resulted in a significant reduction in AZT resistance (as defined as an IC50 fold reduction), and in addition resulted in a significant reduction in d4T resistance (reduction in fold change).

However, there was a significant increase in ddI and abacavir resistance (increased fold change) in the presence of M184V. After analyzing viral load results in those patients on d4T-containing regimens, the presence of M184V did not seem to offer a virologic advantage compared to those patients who did not have the M184V mutation. This may be because the virus contained other mutations which could have adversely affected the activity of d4T, or that many patients also had 3TC included in their regimens, which may result in a sub-optimal viral load response masking the potential benefits toward d4T.

This study indicates that the presence of the M184V mutation may have a beneficial effect toward d4T, despite the presence of thymidine-associated mutations, which are now known to confer resistance to d4T. The biologic and clinical cut points for d4T and ddI in phenotypic assays continue to be defined.

Interestingly, this mutation had a negative impact for ddI, decreasing its susceptibility slightly. Some previous studies have found no reduced effect of ddI in the presence of the M184V mutation, although the viral load impact on ddI containing regimens was not specifically reported here. Although increased phenotypic susceptibility for d4T was clearly found, the clinical significance remains to be defined.

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