ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.
On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR.


CONCLUSIONS
ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.
St Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
Jacinta A
JA
Holmes
Stuart K
SK
Roberts
Rachel J
RJ
Ali
Gregory J
GJ
Dore
William
W
Sievert
Geoffrey W
GW
McCaughan
Darrell H
DH
Crawford
Wendy S
WS
Cheng
Martin D
MD
Weltman
Sara
S
Bonanzinga
Kumar
K
Visvanathan
Vijaya
V
Sundararajan
Paul V
PV
Desmond
D Scott
DS
Bowden
Gail V
GV
Matthews
Alexander J
AJ
Thompson
D000328:Adult; D000743:Anemia, Hemolytic / Q000139:chemically induced* / Q000235:genetics / Q000821:virology; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D017327:Clinical Trials, Phase IV as Topic; D004359:Drug Therapy, Combination; D005260:Female; D006526:Hepatitis C / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011755:Pyrophosphatases / Q000172:deficiency / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000008:administration & dosage; D012189:Retrospective Studies; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D000097630:Inosine Triphosphatase
D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; D000097630:Inosine Triphosphatase; C100416:peginterferon alfa-2a