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Connection Domain Mutations in Treatment-Experienced Patients in the OPTIMA Trial

Dau, Birgitt MD*; Ayers, Dieter MSc; Singer, Joel PhD; Harrigan, P Richard PhD; Brown, Sheldon MD§; Kyriakides, Tassos PhD; Cameron, D William MD; Angus, Brian MD#; Holodniy, Mark MD***

JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1st, 2010 - Volume 54 - Issue 2 - p 160-166
doi: 10.1097/QAI.0b013e3181cbd235
Clinical Science

Objectives: To determine the frequency of mutations in the connection domain (CD) of HIV reverse transcriptase in treatment-experienced patients in the Options in Management with Antiretrovirals trial, their impact on susceptibility to antiretroviral (ARV) drugs, and their impact on virologic outcomes.

Methods: Baseline plasma ARV genotypes and inferred resistance phenotypes were obtained. Frequencies of E312Q, Y318F, G333D, G333E, G335C, G335D, N348I, A360I, A360V, V365I, A371V, A376S, and E399G were compared with a treatment-naive population. The association of CD mutations with inferred IC50 fold changes to nucleos(t)ide reverse transcriptase inhibitors was evaluated. Univariate and multivariate analyses examined the association of CD mutations with a >1 log10 per milliliter decrease in HIV viral load after 24 weeks on a new ARV regimen.

Results: Higher CD mutation rates were seen in Options in Management with Antiretrovirals patients (n = 345) compared with a treatment-naive population. CD mutations were associated with increased inferred IC50 fold changes to abacavir, stavudine, tenofovir, and zidovudine. On univariate analysis, A371V was associated with lack of virologic response, as was having any CD mutation on multivariate analysis.

Conclusions: CD mutations are frequent in treatment-experienced populations. They are associated with reduced susceptibility to some nucleos(t)ide reverse transcriptase inhibitors and with a diminished response to ARV therapy.

From the *AIDS Research Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; †Canadian Institutes for Health Research, Canadian HIV Trials Network, Vancouver, BC, Canada; ‡British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; §Division of Infectious Diseases, Bronx Veterans Affairs Medical Center, New York, NY; ∥Cooperative Studies Program Coordinating Center, Veterans Affairs, West Haven, CT; ¶Division of Infectious Disease, Department of Medicine, Ottawa General Hospital, Ottawa, Ontario, Canada; #Department of Medicine, University of Oxford, Oxford, United Kingdom; and **Department of Medicine, Stanford University, Division of Infectious Diseases and Geographic Medicine, Stanford, CA.

Received for publication July 25, 2009; accepted November 2, 2009.

The Options in Management with Antiretrovirals study was funded in part by the Cooperative Studies Program of the US Department of Veterans Affairs Office of Research and Development, the Canadian Institutes for Health Research, the Canadian HIV Trials Network, and the UK Medical Research Council. This substudy was funded in part by a Veterans Affairs grant to M.H. and by the Canadian HIV Trials Network.

Correspondence to: Birgitt Dau, MD, 3801 Miranda Ave. (132), VA Palo Alto Health Care System, Palo Alto, CA 94304 (e-mail: birgitt.dau@gmail.com).

© 2010 Lippincott Williams & Wilkins, Inc.