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

Kantor, Ramia; Shafer, Robert Wa; Follansbee, Stephenb; Taylor, Jonathanc; Shilane, Davidc; Hurley, Leob; Nguyen, Dong-Phuongb; Katzenstein, Davida; Fessel, W Jeffreyb

Basic Science: Opinion

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.

From the aDivision of Infectious Diseases, Center for AIDS Research, Stanford University, Stanford, the bClinical Trials Unit, Kaiser Permanente, San Francisco and the cDepartment of Statistics, Stanford University, Stanford, California, USA.

Correspondence to Rami Kantor, MD, Division of Infectious Diseases and Center for AIDS Research, 300 Pasteur Drive, room S-156, Stanford, CA 94305, USA.

Tel: +1 650 7360436; fax: +1 208 9751490; e-mail:

Received: 15 September 2003; revised: 22 April 2004; accepted: 4 May 2004.

© 2004 Lippincott Williams & Wilkins, Inc.