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Genetic Variability of the HCV NS3 Protease in HIV/HCV Co-infected Patients Treated with HIV Protease Inhibitors
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Reported by Jules Levin
CROI 2010 Feb 16-19 SF
Marcelle Bottecchia*, A Madejon, M Sanchez-Carrillo, P Labarga, J García-Samaniego, and V Soriano
Hosp Carlos III, Madrid, Spain
Background: Rapid selection of resistance seems to be one of the most challenging aspects in the development of new antivirals against HCV (STAT-C). This concern might be even more pronounced in the treatment of HIV-HCV co-infected patients, in whom higher serum HCV-RNA levels and increased proportion of HCV genotype 1a are characteristically seen. Moreover, preliminary data have suggested that HIV protease inhibitors might induce changes in the HCV protease potentially linked to some STAT-C drug susceptibility. The aim of this study was to investigate NS3 sequences of HCV in HIV-co-infected patients who had received protease inhibitors as part of HAART.
Methods: Sequences covering the whole NS3 gene were obtained from HIV+ patients with HCV genotype 1 co-infection. Two specimens per patient were examined, one before beginning protease inhibitor therapy and another after at least 6 months of protease inhibitor-based treatment. Protease inhibitors used were atazanavir and lopinavir. Serum HCV-RNA was measured using real-time PCR. Sequencing of the HCV NS3 protease was carried out using a commercial assay (Trugene). HCV genotyping was performed using Inno-LIPA (Innogenetics).
Results: A total of 32 samples from 16 distinct patients were examined. All patients were Caucasian, 75% male, 50% IDU. There was no statistical significant difference in synonymous (33.6% baseline vs 35.32% final) and non-synonymous (6.10% baseline x 7.63% final) amino acid changes. Overall 7 positions out of 200 showed amino acid changes comparing baseline and final specimens (positions 40, 46, 80, 86, 89, and 91). However, there was no specific amino acid shift in any of these positions. In one subject, the T54S mutation, which has been associated to intermediate level of resistance to telaprevir and boceprevir, was observed in both baseline and final specimens.
Conclusions: The use of HIV PIs does not seem to select for changes in the NS3 protease of HCV. This is consistent with the substantially divergent structure of these proteases. The recognition of naturally occurring polymorphisms in the HCV NS3 protease, as T54S in one of our patients, must be interpreted with caution and larger studies assessing the prevalence of natural polymorphisms are warranted.
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