title: Immunodeficiency and intrinsic IFN resistance are associated with viral breakthrough to HCV therapy in HIV-coinfected patients.
abstract: Viral breakthroughs (VB), defined as having detectable HCV VL while on anti-HCV therapy after achieving maximal suppression, have not yet been characterized with the use of PEG-IFN in HIV/HCV-coinfected patients. We evaluated possible mechanisms for VB among HIV/HCV-coinfected patients receiving PEG-IFN/RBV. Thirty HIV/HCV coinfected patients were treated with PEG-IFN (1.5 mug/kg sc qwk) and RBV (1-1.2 g daily) for 48 weeks. Liver chemistry, HCV VL, genotyping, DNA microarray, and sequencing of HCV E-2 envelope were performed before and during treatment. VB had lower baseline HCV VL but higher ALT and AST than relapsers (ETR) (p < 0.05) and lower CD4+ T lymphocytes (%) than patients with sustained virological responses (SVR), but similar first and second phase HCV viral kinetics (vs. ETR and SVR; p > 0.05). HCV genotypes and envelope sequences were similar for patients with VB pretreatment and at break-through. VB had higher levels of interferon-induced gene (IFIG) expression pretreatment than patients with ETR (p < 0.01). HIV/HCV-coinfected patients have a high rate of VB on PEG-IFN/RBV therapy characterized by higher levels of IFIG expression, immunodeficiency, and hepatic inflammation. Novel strategies are required for the treatment of persons with VB.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Nussenblatt
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Rehm
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lempicki
authors.forename: Terry
authors.initials: T
authors.lastname: Brann
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Proschan
authors.forename: Helene C
authors.initials: HC
authors.lastname: Highbarger
authors.forename: Robin L
authors.initials: RL
authors.lastname: Dewar
authors.forename: Tom
authors.initials: T
authors.lastname: Imamichi
authors.forename: Chad
authors.initials: C
authors.lastname: Koratich
authors.forename: Avidan U
authors.initials: AU
authors.lastname: Neumann
authors.forename: Henry
authors.initials: H
authors.lastname: Masur
authors.forename: Michael A
authors.initials: MA
authors.lastname: Polis
authors.forename: Shyam
authors.initials: S
authors.lastname: Kottilil
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000276:immunology; D016174:Hepacivirus / Q000187:drug effects* / Q000276:immunology; D006526:Hepatitis C / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012254:Ribavirin / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase