|Title / Titel||Prevalence and relevance of HCV drug resistance in the SHCS|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||2. Summary
Coinfection with the Hepatitis C Virus (HCV) is common in HIV-1 infected patients, with approximately 30% SHCS participants with a positive HCV serology (1, 2). The current standard of care therapy with pegylated interferon and ribavirin operates through unspecific antiviral effects and eradicates infection in only around 40% of cases. By the end of this year, two potent HCV-specific antiviral drugs that inhibit HCV protease (telaprevir and boceprevir (3-6)) will be approved in Switzerland. In the near future, more directly acting antiviral drugs (DAAs) will be licensed for the treatment of HCV infection. DAAs can substantially increase viral eradication rates, but are also associated with important limitations and uncertainties. An important drawback of DAAs is the rapid emergence of resistance associated variants (RAVs) in patients with virological failure (7). RAVs impair the efficacy of HCV DAAs and might compromise future therapies due to cross-resistance with next generation DAAs. There is only limited information on the prevalence and relevance of HCV resistance in HIV/HCV-coinfected patients. We therefore propose to first investigate the baseline prevalence of DAAs in 500 exemplary HIV/HCV-coinfected patients, and then to analyse the relevance and evolution of RAVs in the first 50 SHCS participants starting an HCV therapy with a DAA.
2.2 Study Aims
1) To assess the baseline prevalence of HCV RAVs in the HCV protease and polymerase (NS3 and NS5B) in 500 exemplary DAA-naive SHCS participants using ultra-deep sequencing.
2) To assess the impact of immunodeficiency and of further clinical characteristics on the prevalence of HCV-RAVs.
3) To study longitudinally the frequency and relevance of RAVs during HCV therapy with DAAs. We aim to assess whether baseline and on-treatment RAVs influence virological response, and whether host and viral characteristics influence the evolution of RAVs during DAA therapy.
4) To study the dynamics of replacement of RAVs with wild-type variants after cessation of DAAs.
2.3 Study Design
Aim 1) HCV genotypes from 500 HIV/HCV-coinfected SHCS participants will be analyzed by 454 pyrosequencing, a new next generation sequencing (NGS) technology including all major HCV genotypes (1, 3, and 4).
Aim 2) The impact of CD4+ T cell counts and further clinical and demographic characteristics on RAVs will be assessed using 2-tests and multivariate linear regression.
Aim 3) HCV-RNA decay during therapy and the frequency of RAVs will be assessed longitudinally in 50 patients starting HCV therapy with a DAA. Analyses will be performed at days 0, 7, 14, 28 and then monthly as long as HCV-RNA remains detectable.
Aim 4) The replacement of RAVs by wild-type viruses will be assessed 6 and 12 months after stopping DAA-therapy in 20 individuals.
|Keywords / Suchbegriffe||HCV, HIV, HIV-HIV coinfection|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
|SNF (Personen- und Projektförderung), Others
Swiss HIV Cohort Study
|In collaboration with /
In Zusammenarbeit mit
|Duration of Project / Projektdauer||Oct 2011 to Oct 2016|