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Reverset Resistance
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Baseline Genotype/Phenotype, Virological Response, and Lack of de novo Resistance Mutation Generation during Therapy with Dexelvucitabine (Formerly Reverset) in Study RVT-203
Reported by Jules Levin
13th CROI, Denver, Feb 5-8, 2006
Susan Erickson-Viitanen*1, K Hou1, R Lloyd Jr2, R Mathis2, D Burns2, R Goyvaerts3, and R Levy1
1Incyte, Wilmington, DE, US; 2Research Think Tank, Alpharetta, GA, US; and 3Virco, Mechelen, Belgium
Study RVT-203 was a randomized, placebo-controlled, 24-week study to examine efficacy and safety of 50-, 100-, and 200-mg once-daily doses of dexelvucitabine (DFC), in nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients. Previous efficacy analyses revealed that 200 mg DFC, when used without concurrent cytidine analogs lamivudine/emtricitabine (3TC/FTC), decreased viral load with a significantly greater proportion of subjects achieving >1 log reduction in viral load at week 16 compared to placebo. The current study assessed the role of specific genotype in predicting virological response, and the emergence of DFC resistance.
Genotypes were determined using the TRUGENE assay at baseline, and after 2, 4, 12, 16, and 24 weeks of therapy; phenotypes were determined using the Antivirogram Phenotype assay on plasma samples collected at the study screening visit, and at 16, 20, or 24 weeks in patients experiencing virological failure.
Results
Screening genotypes from 199 subjects were examined, and stratified according to number of thymidine analogue mutations (TAM); 58% of the study population had either 3 or 4 TAM. K65R was present in 11 patients, Q151M was present in 5 patients, and M184V in 129 patients.
Baseline phenotyping revealed a mean reduced susceptibility of 2.3-fold over reference HIV-1 strain; virus with the Q151M mutation showed >18-fold reduced susceptibility.
The most prevalent genotypes were M41L/D67N/T215Y/F/K219Q/E ± M184V (45 patients) and M41L/L210W/T215Y/F ± M184V (34 patients). For subjects with these genotypes, after 16 weeks of therapy, mean change in viral load, median change in viral load and percentage >1 log decline in viral load were: -1.1, -0.93, and 41%, respectively, for 200 mg DFC (n = 22) vs -0.66, -0.17 and 30%, respectively, for placebo (n = 23).
Of subjects taking 200 mg DFC without concurrent 3TC/FTC, 71% had viral load decline >1 log; responders included 5 of 6 patients with M41L-containing genotypes, 2 of 2 subjects with K65R, and 3 of 5 subjects with 70 of 219±67 for 215 genotypes. No novel mutations were detected in samples after 24 weeks of therapy. No K65R mutations emerged, even in 5 patients taking NRTI-only regimens that excluded AZT. A rare variant, L210S, was observed in 2 patients taking 100 mg DFC after 12 to 24 weeks of therapy; both subjects were also taking abacavir and 3TC.
The authors concluded that - other than the Q151M mutation, no other genotypes were associated with baseline phenotypic resistance or poor virological outcome at week 16. No specific resistance to DFC emerged during the study.
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