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Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs

Katzenstein, David Aa; Bosch, Ronald Jb; Hellmann, Nicholasc; Wang, Nanb; Bacheler, Leed; Albrecht, Mary Ae; for the ACTG 364 Study Team

Clinical Science

Objective: To evaluate phenotypic drug susceptibility and non-nucleoside reverse transcriptase inhibitor hypersusceptibility as predictors of the time to virological failure.

Design: In a randomized clinical trial, phenotypic susceptibility was retrospectively determined among 131 exclusively nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients with baseline HIV-RNA levels greater than 2000 copies/ml. Subjects were assigned two NRTI drugs and were randomly assigned to nelfinavir, efavirenz, or both. Virological failure was defined as two HIV-RNA measurements of 2000 copies/ml or greater at or after week 16 and before treatment discontinuation.

Methods: Using biological cut-offs to define resistance, assigned NRTI and randomized drug regimens, continuous and dichotomous phenotypic susceptibility scores (PSS) were calculated for each virus. Efavirenz hypersusceptibility as a dichotomous value was defined as less than 0.4-fold resistance. Associations between virological failure and continuous and dichotomous PSS were evaluated using Kaplan–Meier curves and Cox proportional hazards regression models.

Results: A higher baseline viral load (P < 0.02) and lower dichotomous or continuous baseline PSS (P = 0.004 and P < 0.001, respectively) were independently associated with virological failure. In the 85 subjects who received efavirenz, efavirenz hypersusceptibility (P = 0.042, hazard ratio 0.43, 95% confidence interval 0.19–0.97) was independently associated with a reduced risk of virological failure.

Conclusion: Reduced phenotypic susceptibility was a significant independent risk factor for virological failure. The presence of efavirenz hypersusceptibility appeared to enhance virological responses during treatment with efavirenz in combination with NRTIs. The retrospective calculation of continuous PSS accurately identified treatment regimens containing sufficient drug activity to prevent virological failure.

From the aCenter for AIDS Research, Stanford, CA, USA: bCenter for Biostatistics in AIDS, Harvard School of Public Health, Boston, MA, USA; cViroLogic, South San Francisco, CA, USA; dBristol-Myers Squibb, Wilmington, DE, USA: and eBeth Israel Deaconess Medical Center, Boston, MA, USA.

Correspondence to: David Katzenstein, S-156, Division of Infectious Disease, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94035-5107, USA. Tel: +1 650 725 8304; fax: +1 650 725 2395; e-mail: davidkk@leland.stanford.edu

Received: 19 April 2002; revised: 25 October 2002; accepted: 5 November 2002.

© 2003 Lippincott Williams & Wilkins, Inc.