Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy

Abstract

Background and objective: The optimal time for changing failing antiretroviral therapy (ART) is not known. It involves balancing the risk of exhausting future treatment options against the risk of developing increased drug resistance. The frequency with which new drug-resistance mutations (DRM) developed and their potential consequences in patients continuing unchanged treatment despite persistent viremia were assessed.

Design: A retrospective study of consecutive sequence samples from 106 patients at one institution with viral load (VL) of more than 400 copies/ml, with no change in ART for more than 2 months despite virologic failure.

Methods: Two consecutive pol sequences, CD4 cell counts and VL were analyzed to quantify the development of new DRM and to identify changes in immunologic and virologic parameters. Genotypic susceptibility scores (GSS) and viral drug susceptibilities were calculated by a computer program (HIVDB). Poisson log-linear regression models were used to predict the expected number of mutations at the second time point.

Results: : After a median of 14 months of continued ART, 75% (80 of 106) of patients acquired new DRM and were assigned a significantly lower GSS, potentially limiting the success of future ART. The development of new DRM was proportional to the time between the two sequences and inversely proportional to the number of DRM in the first sequence. However, the development of DRM was not associated with significant changes in CD4 or VL counts.

Conclusions: Despite stable levels of CD4 and VL over time, maintaining a failing therapeutic regimen increases drug resistance and may limit future treatment options.

Fig. 1. Study timeline

Median duration of exposure to antiviral therapy prior to the maintenance regimen (gray square), and during the maintenance regimen (black square), and how these relate to the time of the first and second sequences (bottom arrows). CD4 (cells × 10⁶/l) and viral load (log₁₀ copies/ml) at the three time-points are shown.

Fig. 2. Drug resistance mutations that were acquired in the time period between the first and second sequences (acquired mutations, black bars in descending order), and prevalence of mutations at these positions at the first time-point (baseline mutations, white bars), in patients continuing a failing antiretroviral regimen

PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitors related mutations.

Fig. 3. Mutations that were gained, ‘maintenance regimen’ genotypic susceptibility score (GSS) and ‘other drugs’ GSS according to CD4 (cells × 10⁶/l) and VL (log₁₀ copies/ml) level patterns between the two sequence time-points (solid lines)

Dashed lines indicate median CD4 and VL levels between the start of the maintenance regimen and the first sequence time-point. (a) CD4 increase, VL decrease; (b) CD4 decrease, VL decrease; (c) CD4 increase, VL increase; (d) CD4 decrease, VL increase (67, 87, 74 and 75% gained resistance mutations, respectively). Data were available for 103 of 106 patients.