ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response

Holmes, Jacinta A., Roberts, Stuart K., Ali, Rachel J., Dore, Gregory J., Sievert, William, McCaughan, Geoffrey W., Crawford, Darrell H., Cheng, Wendy S., Weltman, Martin D., Bonanzinga, Sara, Visvanathan, Kumar, Sundararajan, Vijaya, Desmond, Paul V., Bowden, D. Scott, Matthews, Gail V. and Thompson, Alexander J. (2014) ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response. Hepatology, 59 6: 2152-2160. doi:10.1002/hep.27022

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Author Holmes, Jacinta A.
Roberts, Stuart K.
Ali, Rachel J.
Dore, Gregory J.
Sievert, William
McCaughan, Geoffrey W.
Crawford, Darrell H.
Cheng, Wendy S.
Weltman, Martin D.
Bonanzinga, Sara
Visvanathan, Kumar
Sundararajan, Vijaya
Desmond, Paul V.
Bowden, D. Scott
Matthews, Gail V.
Thompson, Alexander J.
Title ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response
Journal name Hepatology   Check publisher's open access policy
ISSN 1527-3350
0270-9139
Publication date 2014-06
Year available 2014
Sub-type Article (original research)
DOI 10.1002/hep.27022
Open Access Status
Volume 59
Issue 6
Start page 2152
End page 2160
Total pages 9
Place of publication Hoboken NJ, United States
Publisher John Wiley & Sons
Collection year 2015
Language eng
Formatted abstract
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. Conclusion: 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.
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Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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