|
13th International HIV Drug Resistance Workshop8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain |
BACKGROUND: The safety and efficacy of capravirine, a novel NNRTI, were evaluated in combination with nelfinavir and two NRTIs in two Phase 2 studies in HIV-infected, NNRTI-experienced patients. Although both studies were discontinued early, patients with a viral load <400 copies/ml were given the option of continuing on open-label capravirine, nelfinavir and NRTIs. Of the 36 patients who elected to continue therapy, 16 (44%) remain virologically suppressed (VL <50 copies/ml) following 39–49 months of therapy. There were 20 cases in which the patient discontinued from the study early: six were due to virological failure, five were due to adverse events, and nine were for non-study related reasons.
METHODS: HIV phenotype and genotype were determined for each patient at study entry and at the time of virological failure (TOF).
RESULTS: Six of the 36 patients (17%) have discontinued from the study due to virological failure. The median time to virological failure was 19 months (range 4–27 months). Two of the six patients did not develop any new genotypic changes or further reduction in susceptibility to either capravirine or nelfinavir, despite receiving therapy for 11 and 15 months. Three of the six patients developed new or increased levels of resistance to both capravirine and nelfinavir at TOF. Virus isolated from these patients contained one, two or three new NNRTI-resistance associated substitutions located at different positions in reverse transcriptase (101, 108, 190 and/or 188) as well as substitutions at positions 20, 30, 36 and/or 88 of protease. TOF genotype data is not available for the one remaining patient; however, phenotype data indicate the development of nelfinavir resistance (8.2-fold), and no measurable change in NRTI or capravirine susceptibility.
CONCLUSIONS: NNRTI-experienced patients treated with capravirine as part of a HAART regimen can achieve long-term suppression of viraemia. Results from the present study support previous in vitro and in vivo findings demonstrating that a single mutation conferring high-level resistance does not rapidly emerge during capravirine therapy. Rather, varied patterns of substitutions slowly emerge, indicating a high genetic barrier to resistance. Phase 2b studies evaluating capravirine in NNRTI-experienced patients are currently underway.
PRESENTING AUTHOR: J Hammond
Download PDF of this abstract.
2004-06-08
15
Copyright © 2004 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.