Immunodeficiency and intrinsic IFN resistance are associated with viral breakthrough to HCV therapy in HIV-coinfected patients.
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.
Nussenblatt
Veronique
V
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
McLaughlin
Mary
M
Rehm
Catherine A
CA
Lempicki
Richard A
RA
Brann
Terry
T
Yang
Jun
J
Proschan
Michael
M
Highbarger
Helene C
HC
Dewar
Robin L
RL
Imamichi
Tom
T
Koratich
Chad
C
Neumann
Avidan U
AU
Masur
Henry
H
Polis
Michael A
MA
Kottilil
Shyam
S
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
D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase