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Loss of antiretroviral drug susceptibility at low viral load during early virological failure in treatment-experienced patients

Parkin, Neil T.a; Deeks, Steven G.b; Wrin, M. Terria; Yap, Joycea; Grant, Robert M.c; Lee, Kok H.b; Heeren, Dorieb; Hellmann, Nicholas S.a; Petropoulos, Christos J.a

Clinical Science

Background: Clinical studies have demonstrated a correlation between the response to second-line antiretroviral therapy and the number of drugs in the regimen to which the virus is susceptible. These studies have largely been performed in patients with viral loads over 1000 copies/ml.

Objectives: To examine the evolution of resistance during early virological failure, and the potential role of susceptibility testing in patients with low viral loads (below 1000 copies/ml), in treatment-experienced patients.

Methods: Drug susceptibility and genotypes of HIV-1 from indinavir-experienced patients undergoing therapy with nelfinavir, saquinavir, abacavir and either a second nucleoside reverse transcriptase inhibitor (NRTI) or nevirapine were determined.

Results: Sixteen subjects were studied. Five of the ten subjects treated with nevirapine, and one of six treated with a second NRTI, achieved and maintained plasma HIV RNA < 500 copies/ml. Virus from the treatment failures lost susceptibility to one or more treatment drugs, including nelfinavir and/or saquinavir, after 4 to 36 weeks of treatment. In six of the ten failures, virus with new reductions in drug susceptibility was detected prior to failure. In five of the six failures who had at least one plasma sample with a viral load between 50 and 1000 copies/ml, reductions in susceptibility to one or more treatment drugs were detected (viral load range: 260 to 630 copies/ml).

Conclusions: Drug resistance can be detected at viral loads below 1000 copies/ml which may be predictive of treatment failure. Failure of a second line regimen was typically associated with early evolution of resistance in HIV protease.

From aViroLogic Inc., South San Francisco, California, USA, bUniversity of California San Francisco AIDS Program, and cGladstone Institute of Virology, San Francisco, California, USA.

Correspondence to Neil T. Parkin, ViroLogic, Inc., 270 East Grand Ave., South San Francisco, CA 94080, USA. Tel: +1 650 866 7438; Fax: +1 650 742 0993; e-mail: nparkin@virologic.com

Received: 14 June 2000;

revised: 14 August 2000; accepted: 23 August 2000.

Sponsorship: Supported in part by grants from the National Institutes of Health, University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research, P30 MH59037 and the California AIDS Research Center, CC99-SF-001.

© 2000 Lippincott Williams & Wilkins, Inc.