ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection

Abstract

Background & aim: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin.

Methods: HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression.

Results: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12.

Conclusions: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes.

Trial registration: ClinicalTrials.gov: NCT01132313.

Conflict of interest statement

Competing Interests: TA has received consultancy fees from BMS, Boehringer Ingelheim, Roche, Merck-Schering Plough, Gilead, and Janssen. SZ has received consultancy fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Idenix, Janssen, Merck, Novartis, Presidio, Roche, Santaris, and Vertex. VS has received grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, and Merck, has served on speaker bureaus for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, and Merck, and has received compensation for educational presentations from Gilead, Janssen, Merck, and ViiV. J-PB has received consultancy fees from Boehringer Ingelheim, BMS, Gilead, Janssen, MSD, and Novartis, and has received speaker fees from BMS, Gilead, Janssen, MSD, and Roche. AWL has received grant support from Boehringer Ingelheim, BMS, Falk, Gilead, MSD and Roche. BM has received grant support from MSD and Roche and is an advisor for Gilead, Janssen, MSD, and Roche. MS has received consultancy fees and speaker honoraria from Roche, Gilead, BMS, Merck, Boehringer Ingelheim, Janssen and Falk. M. Bourlière has served on advisory boards for Boehringer Ingelheim, Merck, Vertex, Janssen, Gilead, Abbott, GSK and Roche, and has also received lecture fees from Merck, Janssen, Boehringer Ingelheim, and Gilead. M. Buti has served as consultant for Boehringer Ingelheim, and has received payment for lectures from BMS, Gilead, Janssen, MSD, and Novartis. SKR is a consultant for BMS, Gilead, Janssen, and Roche. EJG is member of advisory boards for Abbot, Gilead, Janssen, Roche, and Tibotec. He has received speaker fees for Gilead, Janssen, AbbVie, Novartis, and Roche. JOS, FV, PB, J-PG, WOB, and FJM are employees of Boehringer Ingelheim. These commercial affiliations do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Hemoglobin levels over time.

Mean hemoglobin by treatment group over time is shown. The mean reduction at the end of treatment for the pooled ribavirin-containing arms was approximately 2.5 g/dL. TID16W/TID28W/TID40W, faldaprevir 120 mg once daily, deleobuvir 600 mg three times daily, and ribavirin for 16, 28, and 40 weeks, respectively; BID28W, faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and ribavirin for 28 weeks; TID28W-NR, faldaprevir 120 mg once daily and deleobuvir 600 mg three times daily without ribavirin for 28 weeks.

Fig 2. Probability of anemia over time.

Among patients in the pooled ribavirin-containing arms with anemia, the median time to the first occurrence of anemia was 42 days.

Fig 3. Mean hemoglobin levels by inosine triphosphatase (ITPA) gene single-nucleotide polymorphisms, pooled ribavirin-containing arms.