To investigate associations between inosine triphosphatase (ITPA) gene polymorphisms and long-term outcomes among chronic hepatitis C (CHC) patients in Northeast China treated with Peg-interferon (IFN)/ribavirin (RBV). CHC patients who received Peg-IFN-2a/RBV treatment during between 2011 and 2013 at 5 hepatitis centers in Northeast China were enrolled. ITPA single nucleotide polymorphisms rs1127354 and rs7270101 from all patients were detected and their associations with 5-year outcomes were analyzed. A total of 635 patients, including 421 infected with hepatitis C virus (HCV) genotype 1 and 214 infected with non-genotype 1 were included. No significant differences were observed in the distribution frequencies of ITPA rs1127354 variants and ITPase activity between patients with HCV genotype 1 and non-genotype 1. In patients who received more than 80% of the planned RBV dose, the 5-year virological response rate and the improvement in liver fibrosis were higher in those with ITPA rs1127354 non-CC with ITPase activity <25% compared with these outcomes in patients with ITPA rs1127354 CC with 100% ITPase activity. Multiple regression analysis revealed that HCV genotype non-1, low baseline HCV ribose nucleic acid (RNA) levels (≤4 × 105 IU/mL), interleukin-28B rs12979860 CC genotype, low baseline liver fibrosis (Fibroscan 0-2), and ITPA rs1127354 non-CC genotype were independent predictors for a high long-term virological response rate, whereas interleukin-28B rs12979860 CC genotype, ITPA rs1127354 non-CC genotype, and low baseline liver fibrosis were independent predictors for improvement of liver fibrosis. ITPA rs1127354 polymorphisms is predictors of long-term outcomes in CHC patients treated with Peg-IFN/RBV.

BACKGROUND: We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV-HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC).
METHODS: Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctrough on anaemia was also studied.
RESULTS: Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0-W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctrough was associated with Hb decrease both at W4 and W8 and an RBV Ctrough cutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough (P=0.012). ITPA deficiency, W4 RBV Ctrough and gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response.
CONCLUSIONS: ITPA deficiency and RBV Ctrough are still predictive of RBV-induced anaemia in HIV-HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.

OBJECTIVE: The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to the pegylated interferon (PEG-IFN) α and ribavirin combination regimen (triple therapy) has dramatically improved treatment outcome. Unfortunately, anemia remains a common adverse effect. This study was done to compare the development of severe anemia during simeprevir- or telaprevir-based triple therapy.
METHODS: This retrospective multicenter study consisted of 837 consecutive Japanese HCV genotype 1 patients treated in a real-world clinical setting, 811 of whom were enrolled (simeprevir 281, telaprevir 530). The inosine triphosphate pyrophosphatase (ITPA) genotype at rs1127354 was determined for all studied patients. Logistic regression was done after propensity score matching to assess the risk of development of severe anemia.
RESULTS: Propensity score matching of the entire study population yielded 266 matched pairs. Severe anemia (nadir hemoglobin < 9.0 g/dL) was developed during the treatment period by 81 (30.5%) and 144 (54.1%) patients treated with simeprevir and telaprevir, respectively. Treatment with simeprevir was independently associated with a lower risk of severe anemia (odds ratio 0.25, 95% confidence interval 0.16-0.38, P < 0.0001). Moreover, ITPA genotype, age, hemoglobin level, and estimated glomerular filtration rate at baseline were also independent factors associated with the development of severe anemia.
CONCLUSIONS: Patients treated with simeprevir-based triple therapy have a lower risk of the development of severe anemia than those treated with telaprevir. Moreover, ITPA genotype and age may be useful for individualizing treatment to reduce the risk of anemia-related adverse effects.

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BACKGROUND: Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance.
METHODS: We analyzed data from a 6-month prospective study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured.
RESULTS: Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C > A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes . h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C > A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C > A mutant allele carrier status.
CONCLUSIONS: Patients with ITPA 94C > A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.

Inositol 1,4,5-trisphosphate (InsP3) is an intracellular messenger generated from the hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C in response to Ca(2+)-mobilizing stimuli. InsP3 interacts with a specific receptor responsible for the release of sequestered Ca2+ from an intracellular store. The purpose of the present study was to evaluate the relative affinities of the naturally occurring D-isomer of InsP3 and that of its L-stereoisomer for the InsP3 receptor and the InsP3 metabolizing enzymes from bovine adrenal cortex. The InsP3 receptor recognized D- and L-isomers with respective affinities of 4.8 nM and 7.3 microM. This high degree of selectivity was also reflected in the capacity of both isomers to mobilize Ca2+ from the microsomal preparation. The partially purified InsP3 kinase preparation was also able to discriminate between the two stereoisomers. The activity of the kinase was half-maximally inhibited in the presence of 11 microM L-InsP3, a value much higher than the Km of the kinase for D-InsP3 (0.4 microM). Both stereoisomers exhibited equipotent affinities (around 17 microM) for the particulate preparation of InsP3 phosphatase. The enzyme, however, appeared to hydrolyze L-InsP3 at a much slower rate. These results demonstrated that the different recognition sites for InsP3 were expressing distinct levels of stereoselectivity. This property, which is an important aspect of ligand-receptor interaction, could be exploited for the design of new selective drugs interfering with InsP3 action and metabolism.