Ai Nakagawa

Serum 25(OH)D3 levels affect treatment outcomes for telaprevir/peg-interferon/ribavirin combination therapy in genotype 1b chronic hepatitis C

BACKGROUND Close relationships between chronic hepatitis C and vitamin D levels have been reported. For genotype 1b infection, the current standard of care is pegylated interferon/ribavirin therapy combined with a protease inhibitor. The present study analyzed the relationship between outcomes of triple therapy and serum 25(OH)D3 levels. METHODS Factors contributing to sustained virological response were investigated in 177 patients with chronic hepatitis C who received telaprevir-based triple therapy in this prospective study. RESULTS The sustained virological response rate was 86.9% in patients with 25(OH)D3 levels of >18 ng/ml; this was higher than the 66.7% in patients with 25(OH)D3 levels of ≤ 18 ng/ml (P=0.003). 25(OH)D3 levels and IL28B genotype were identified as significantly independent factors contributing to sustained virological response. The sustained virological response rate did not differ according to 25(OH)D3 levels in patients with the IL28B major genotype. The sustained virological response rate was 64.9% in patients with the IL28B minor genotype and 25(OH)D3 levels of >18 ng/ml, and was 38.5% in those with decreased 25(OH)D3 levels (P=0.045). CONCLUSIONS In triple therapy, 25(OH)D3 levels were an independent factor contributing to sustained virological response. Of particular note, the sustained virological response rate was significantly lower in patients with the IL28B minor genotype.

Serum 25-hydroxyvitamin D3 levels affect treatment outcome in pegylated interferon/ribavirin combination therapy for compensated cirrhotic patients with hepatitis C virus genotype 1b and high viral load

Much is unknown about the effect of 25‐hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus‐related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25‐hydroxyvitamin D3, that contribute to a sustained virological response (SVR) in patients with cirrhosis.

EFFICACY OF ALFACALCIDOL ON PEG-IFN/ RIBAVIRIN COMBINATION THERAPY FOR ELDERLY PATIENTS WITH CHRONIC HEPATITIS C: A PILOT STUDY

Background Serum vitamin D concentration is reported to show a decrease in older age. Patients with chronic hepatitis C (CHC) in Japan are older on average than those in Western countries. Moreover, the outcome of pegylated-interferon (PEG-IFN)/ ribavirin therapy combined with vitamin D in elderly patients is unclear. Objectives This pilot study explored the efficacy and safety of alfacalcidol as vitamin D source in PEG-IFN/ ribavirin combination therapy for elderly CHC patients infected with hepatitis C virus genotype 1b. Patients and Methods Consecutive twenty CHC patients aged ≥ 65 years were enrolled in this pilot study. Fifteen patients met the inclusion criteria and received PEG-IFN/ ribavirin therapy combined with alfacalcidol. Four-week lead-in of oral alfacalcidol was conducted, and it was subsequently and concurrently administered in PEG-IFN/ ribavirin combination therapy (vitamin D group). Age, gender, and IL28B genotype-matched patients, who received PEG-IFN/ ribavirin alone, were saved as control group (n = 15) to compare the treatment outcome with the vitamin D group. Results Subjects consisted of 14 males and 16 females, with a median age of 70 years (65-78). The serum 25 (OH) D3 concentration in females (20 ng/ml, 11-37) was significantly lower than males (27 ng/mL, 13-49) (P = 0.004). Sustained virological response (SVR) rates were 33.3% (5/15) in the control group and 80.0% (12/15) in the vitamin D group, respectively (P = 0.025). While no significant difference was shown in the (SVR) rate between the two groups among males (P = 0.592), in females the SVR rate was significantly higher in the vitamin D group (87.5%, 7/8) than the control group (25.0%, 2/8) (P = 0.041). The relapse rates in the groups with and without alfacalcidol were 7.7% (1/13) and 61.5% (8/13), respectively (P = 0.011). Interestingly, in females, the relapse in the control group was shown in 5 of 7 (71.4%), whereas in the vitamin D group the relapse rate was decreased (1/8, 12.5%) (P = 0.041). No specific adverse events were observed in the vitamin D group. Conclusions PEG-IFN/ ribavirin combined with alfacalcidol may be effective and safe in elderly CHC patients. In particular, concomitant administration of alfacalcidol may lead to a reduced relapse rate, and consequently improving the SVR rate in elderly females.

Usefulness of portal vein pressure for predicting the effects of tolvaptan in cirrhotic patients

AIM To elucidate influencing factors of treatment response, then tolvaptan has been approved in Japan for liquid retention. METHODS We herein conducted this study to clarify the influencing factors in 40 patients with decompensated liver cirrhosis complicated by liquid retention. Tolvaptan was administered at a dosage of 7.5 mg once a day for patients with conventional diuretic-resistant hepatic edema for 7 d. At the initiation of tolvaptan, the estimated hepatic venous pressure gradient (HVPG) value which was estimated portal vein pressure was measured using hepatic venous catheterization. We analyzed the effects of tolvaptan and influencing factors associated with treatment response. RESULTS Subjects comprised patients with a median age of 65 (range, 40-82) years. According to the Child-Pugh classification, class A was 3 patients, class B was 19, and class C was 18. Changes from the baseline in body weight were -1.0 kg (P = 2.04 × 10(-6)) and -1.3 kg (P = 1.83 × 10(-5)), respectively. The median HVPG value was 240 (range, 105-580) mmH2O. HVPG was only significant influencing factor of the weight loss effect. When patients with body weight loss of 2 kg or greater from the baseline was defined as responders, receiver operating characteristic curve analysis showed that the optimal HVPG cutoff value was 190 mmH2O in predicting treatment response. The response rate was 87.5% (7/8) in patients with HVPG of 190 mmH2O or less, whereas it was only 12.5% (2/16) in those with HVPG of greater than 190 mmH2O (P = 7.46 × 10(-4)). We compared each characteristics factors between responders and non-responders. As a result, HVPG (P = 0.045) and serum hyaluronic acid (P = 0.017) were detected as useful factors. CONCLUSION The present study suggests that tolvaptan in the treatment of liquid retention could be more effective for patients with lower portal vein pressure.

Vitamin D-related gene polymorphisms do not influence the outcome and serum vitamin D level in pegylated interferon/ribavirin therapy combined with protease inhibitor for patients with genotype 1b chronic hepatitis C

Although several vitamin D‐related gene polymorphisms were reported to affect the outcome of pegylated interferon/ribavirin (PR) therapy in chronic hepatitis C patients, there are no reports on the impact of the vitamin D‐related gene polymorphisms in PR therapy combined with protease inhibitor (PI). Vitamin D‐related gene polymorphisms were determined in 177 genotype 1b‐infected chronic hepatitis C patients who received 12 weeks of PR therapy with telaprevir, a first‐generation PI, followed by 12 weeks of PR therapy. The sustained virologic response (SVR) rate was 83.1% (147 of 177 patients). The frequencies of vitamin D‐related gene polymorphisms were: 83 non‐TT and 94 TT genotypes for GC, 97 non‐AA and 80 AA genotypes for DHCR7, 151 non‐AA and 26 AA genotypes for CYP2R1, 162 non‐GG and 15 GG genotypes for CYP27B1, and 105 non‐GG and 72 GG genotypes for VDR gene. Multivariate analysis extracted IL28B TT genotype (P = 2.05×10−6) and serum 25(OH) D3 level (P = 0.024) as independent factors contributing to the achieving of SVR. The SVR rate in IL28B TT genotype patients with serum 25(OH) D3 level of <25 ng/ml was significantly low compared to other patients. None of the vitamin D‐related gene polymorphisms affected the treatment outcome and serum 25(OH) D3 level. In conclusions, the IL28B polymorphism and serum 25(OH) D3 level contributed significantly and independently to SVR in PR combined with PI for genotype 1b‐infected chronic hepatitis C patients. However, none of vitamin D‐related gene polymorphisms had an impact on the treatment outcome and serum 25(OH) D3 level. J. Med. Virol. 87:1904–1912, 2015.

Effect of fluvastatin on 24-week telaprevir-based combination therapy for hepatitis C virus genotype 1b-infected chronic hepatitis C.

Objectives The addition of fluvastatin significantly improves sustained virological response (SVR) in pegylated interferon and ribavirin (peg-IFN/RBV) combination therapy for patients infected with the hepatitis C virus. However, the add-on effect on telaprevir-based triple combination therapy remains unknown. The aim of this study was to investigate the effect of fluvastatin on telaprevir-based combination therapy by conducting a prospective, open-label, randomized, controlled trial. Patients and methods Among 124 genotype 1b-infected chronic hepatitis C patients recruited, 116 eligible patients were allocated randomly to two study arms; they received 12 weeks of telaprevir/peg-IFN/RBV, followed by 12 weeks of peg-IFN/RBV with or without 24 weeks of fluvastatin (fluvastatin group and control group, respectively). Treatment outcomes and adverse effects were compared between the two groups. Results There were 56 men and 60 women, median age 60 years (range, 28–71 years). Rapid virological response and end of treatment response rates were 87.9% (51/58) and 96.6% (56/58) in the control group and 75.9% (44/58) and 98.3% (57/58) in the fluvastatin group, respectively. SVR rates in the control group and the fluvastatin group were 84.5% (49/58) and 81.0% (47/58), respectively; there was no significant difference (P=0.806). Stratified analysis showed that no factors associated with the SVR rate were found between the two groups. No adverse events were associated with fluvastatin. Conclusion In this trial, administration of fluvastatin with telaprevir/peg-IFN/RBV was a safe combination. However, fluvastatin had no add-on effect on 24-week telaprevir-based combination therapy for chronic hepatitis C genotype 1b-infected patients.

Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants: Vitamin D and resistance-associated variants

Although interferon‐free therapy with direct‐acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance‐associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non‐structure 5A (NS5A) region and serum vitamin D level has not yet been examined.

Association between vitamin D deficiency and pre‐existing resistance‐associated hepatitis C virus NS5A variants

Although interferon‐free therapy with direct‐acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance‐associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non‐structure 5A (NS5A) region and serum vitamin D level has not yet been examined.

Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein more reliably distinguishes liver fibrosis stages in non-alcoholic fatty liver disease than serum Mac-2 binding protein: WFA + -M2BP vs M2BP in NAFLD

Serum Mac‐2 binding protein (M2BP) and Wisteria floribunda agglutinin‐positive Mac‐2 binding protein (WFA+‐M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head‐to‐head studies have been carried out to compare the two biomarkers in non‐alcoholic fatty liver disease (NAFLD).

Association between vitamin D deficiency and preexisting resistance-associated HCV NS5A variants

Although interferon‐free therapy with direct‐acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance‐associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non‐structure 5A (NS5A) region and serum vitamin D level has not yet been examined.