Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h.
OBJECTIVE
This study explored gene expression differences in predicting response to pegylated interferon (IFN-PEG) and ribavirin (RBV) in hepatitis C infection. Current treatment for hepatitis C virus (HCV) with IFN-PEG alpha-2a/b and RBV is an expensive regimen with frequent significant side-effects where less than 60% of patients ultimately achieve a sustained virological response. Responders and nonresponders may not be identified for up to 6 months post-treatment. This dichotomy may be because of differences in the molecular genetic response.


METHODS
Peripheral blood mononuclear cell samples were obtained from a cohort of 31 infected individuals within the first 24 h of treatment and the extracted RNA was hybridized to genome expression microarrays. Hepatitis C viral kinetics was also examined in these patients. The ability of differentially regulated genes to predict response to therapy was assessed with treatment outcome.


RESULTS
Distinct patterns of gene expression distinguished responders from nonresponders to HCV treatment. The ultimate response to treatment with IFN-PEG and RBV was observed within the first 24 h of treatment by a greater drop in viral load (mean HCV RNA decline of 1.92+/-1.26 log10 IU/ml) in responders compared with nonresponders (P<0.007). Induced genes achieved maximal response within 12 h of therapy which coincided with a rapid decline in HCV RNA between 12 and 24 h. This study revealed that peripheral blood mononuclear cell metallothionein 2A, CCRL2, tumour necrosis factor-alpha-induced protein 6 (TNFAIP6) and IFN-induced protein with tetratricopeptide repeats 2 expression predicted viral treatment response to therapy verified by quantitative real time polymerase chain reaction.


CONCLUSIONS
This study has identified a noninvasive gene microarray pattern and a set of verified genes to be predictive of hepatitis C patient response to IFN-PEG and RBV treatment within the first 24 h. The potential of this noninvasive diagnostic approach and identified genes as biomarkers of response to treatment warrants further investigation.
Devitt
Emma
E
Centre for Liver Disease, Mater Misericordiae University Hospital, Dublin, Ireland. emma.devitt@ucd.ie
Lawless
Matthew W
MW
Sadlier
Denise
D
Browne
John A
JA
Walsh
Caroline
C
Crowe
John
J
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology / Q000821:virology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D013997:Time Factors
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin