Coinfection of hepatitis C virus (HCV) with human immunodeficiency virus (HIV) occurs in 20-30% of HIV infected patients. Patients with HCV/HIV coinfection tend to have higher HCV viral loads than controls. Furthermore, there is now evidence that initiation of effective antiretroviral therapy (ART) may be associated with paradoxical increases in HCV viral load. HCV viral flare may be associated with increases in serum tranaminases which affect clinical decision making, vis a vis discontinuation of ART. Previous studies have failed to prospectively evaluate these issues in a systematic, progressive manner. The mechanisms responsible for viral load increase during effective immune reconstitution have also not undergone detailed evaluation. We propose the following Specific Aims to address these issues: 1. To develop and perform a clinical intervention trial in HCV/HIV coinfected subjects treated with ART in order to characterize early/late HCV viral kinetics as well as the prevalence, significance, and pathogenesis of HCV viral load increase. 2. To prospectively evaluate the significance and role of HCV quasispecies emergence following ART initiation between treatment responders and nonresponders. 3. To define immunologic correlates during immune reconstitution that are associated with development of increased HCV viral load and/or liver injury. We will test specific, hypothesis-driven questions to help achieve the broader goals described within our Specific Aims. In an effort to develop a conceptual framework for the relationship between hepatitis C infection and HIV, we will use the tools of mathematical modeling, molecular epidemiology and immunology to study viral selection, mutation and replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065256-05
Application #
7797657
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Brobst, Susan W
Project Start
2006-04-15
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$552,261
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Blackard, Jason T; Ma, Gang; Polen, Clarissa et al. (2016) Recombination among GB virus C (GBV-C) isolates in the United States. J Gen Virol 97:1537-44
Blackard, Jason T; Ma, Gang; Sengupta, Satarupa et al. (2014) Evidence of distinct populations of hepatitis C virus in the liver and plasma of patients co-infected with HIV and HCV. J Med Virol 86:1332-41
Sherman, Kenneth E; Guedj, Jeremie; Shata, Mohamed Tarek et al. (2014) Modulation of HCV replication after combination antiretroviral therapy in HCV/HIV co-infected patients. Sci Transl Med 6:246ra98
Dahari, Harel; Cotler, Scott J; Layden, Thomas J et al. (2013) Understanding triphasic HCV decline during treatment in the era of IL28B polymorphisms and direct acting antiviral agents via mathematical modeling. J Hepatol 58:840-2
Guedj, Jeremie; Dahari, Harel; Uprichard, Susan L et al. (2013) The hepatitis C virus NS5A inhibitor daclatasvir has a dual mode of action and leads to a new virus half-life estimate. Expert Rev Gastroenterol Hepatol 7:397-9
Guedj, H; Guedj, J; Negro, F et al. (2012) The impact of fibrosis and steatosis on early viral kinetics in HCV genotype 1-infected patients treated with Peg-IFN-alfa-2a and ribavirin. J Viral Hepat 19:488-96
Chatterjee, Anushree; Guedj, Jeremie; Perelson, Alan S (2012) Mathematical modelling of HCV infection: what can it teach us in the era of direct-acting antiviral agents? Antivir Ther 17:1171-82
Guedj, Jeremie; Dahari, Harel; Pohl, Ralf T et al. (2012) Understanding silibinin's modes of action against HCV using viral kinetic modeling. J Hepatol 56:1019-24
Guedj, Jeremie; Dahari, Harel; Shudo, Emi et al. (2012) Hepatitis C viral kinetics with the nucleoside polymerase inhibitor mericitabine (RG7128). Hepatology 55:1030-7
Dahari, Harel; Guedj, Jeremie; Perelson, Alan S (2011) Silibinin mode of action against hepatitis C virus: a controversy yet to be resolved. Hepatology 54:749

Showing the most recent 10 out of 26 publications