Correlation of response to treatment and HIV genotypic changes during phase III trials with saquinavir and reverse transcriptase inhibitor combination therapy.
| Autor: | Race E; Department of Virology, Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, UK., Gilbert SM, Sheldon JG, Rose JS, Moffatt AR, Sitbon G, Dissanayeke SR, Cammack N, Duncan IB |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | AIDS (London, England) [AIDS] 1998 Aug 20; Vol. 12 (12), pp. 1465-74. |
| DOI: | 10.1097/00002030-199812000-00008 |
| Abstrakt: | Objectives: Assessment of genotypic change in HIV protease during treatment with saquinavir (SQV) in combination with zidovudine (ZDV) and/or zalcitabine (ddC), to determine the influence of such changes on viral phenotype and response to treatment. Design: Virologic substudies of Phase III clinical trials NV14256 and SV14604. Methods: Population sequencing of HIV protease genes amplified from pre- and post-treatment plasma. Phenotyping of peripheral blood mononuclear cell (PBMC)-derived virus isolates, and genotyping of proviral DNA clones amplified from PBMC used in the expansion of virus isolates. Results: In both trials the incidence of Met90 remained at < or = 20% in subjects receiving SQV in combination with ddC (with or without ZDV) for 1 year. A Val48 substitution was observed in two out of 81 subjects after 24 weeks and in two out of 75 subjects after 48 weeks. In 12 out of 13 NV14256 subjects with viral load rebound during SQV monotherapy these substitutions were associated with the rebound. In subjects treated with SQV plus ddC, rebound was associated with SQV resistance in six out of 22 cases and ddC resistance in five out of 22 cases. The incidences of non-BRU residues at positions 10, 63 and 71 were increased significantly (P < 0.05, Fisher's exact test) after SQV treatment with or without ZDV. However, comparison of genotypic and phenotypic data showed that these changes were not associated with reduced sensitivity to SQV. Conclusions: Virological failure during combination therapy can be due to resistance to either treatment drug, emphasising the need to change both the reverse transcriptase inhibitor and the protease inhibitor. Only Val48 and Met90 correlated directly with the development of reduced drug sensitivity during treatment with SQV in vivo. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|