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Adherenceresistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness

Bangsberg, David Ra,b; Acosta, Edward Pc; Gupta, Reenad; Guzman, Davida; Riley, Elise Da; Harrigan, P Richardf; Parkin, Neile; Deeks, Steven Gb

doi: 10.1097/01.aids.0000199825.34241.49
Clinical Science

Objective: To compare the prevalence of resistance by adherence level in patients treated with non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI). Also to examine the mechanism of differential class-specific adherence–resistance relationships, focusing on the patient-derived capacity of wild-type and drug-resistant recombinant variants to replicate in vitro in the presence of variable drug levels.

Methods: Participants received unannounced pill count measures to assess adherence, viral load monitoring, and genotypic resistance testing. The replicative capacity of drug-susceptible and drug-resistant recombinants was determined using a single-cycle recombinant phenotypic susceptibility assay. Drug exposure was estimated using population-averaged pharmacological measurements adjusted by participant-specific levels of adherence.

Results: In the NNRTI-treated group, 69% had resistance at 0–48% adherence compared to 13% at 95–100% (P = 0.01). PI resistance was less common than NNRTI resistance at 0–48% adherence (69% versus 23%; P = 0.01). In multivariate analysis, the odds for PI resistance increased (P = 0.03) while the odds for NNRTI resistance decreased (P = 0.04) with improving adherence. Individuals with drug-resistant variants were more likely to have levels of drug exposure where the resistant variant was more fit than the drug-susceptible variant in vitro, while those with drug-susceptible virus were more likely to have levels of drug exposure where the drug-susceptible virus was more fit than the drug-resistant variant (P = 0.005).

Conclusions: NNRTI resistance was more common than PI resistance at low levels of adherence. Class-specific adherence–resistance relationships are associated with the relative replicative capacity of drug-resistant versus wild-type variants to replicate in the presence of clinically relevant drug levels.

From the aEpidemiology and Prevention Interventions Center, Division of Infectious Diseases and

bPositive Health Program, San Francisco General Hospital, UCSF, San Francisco, California

cUniversity of Alabama at Birmingham, Birmingham, Alabama

dHarvard Medical School, Boston, Massachusetts

eMonogram Biosciences, Inc, South San Francisco, California, USA

fBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.

Received 11 March, 2005

Revised 25 July, 2005

Accepted 26 September, 2005

Correspondence to Dr D. R. Bangsberg, Epidemiology and Prevention Interventions Center, PO Box 1372, UCSF, San Francisco, California 94143-1372, USA. e-mail: db@epi-center.ucsf.edu

© 2006 Lippincott Williams & Wilkins, Inc.