Kai Yoshizawa

Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo

BackgroundThis study was carried out to clarify the carcinogenic factors associated with nonviral hepatocellular carcinoma (HCC).MethodsA total of 320 HCC patients diagnosed and treated from January 2000 to December 2006 were enrolled. The clinical characteristics of non-B non-C HCC patients were examined to determine possible carcinogenic factors.ResultsOf 320 HCC patients, 64 were classified as having non-B non-C HCC. The proportion of non-B non-C HCC increased from 17.8% in 2000 to 28.6% in 2006. Non-B non-C HCC patients had a significantly higher rate of early stage cirrhosis (Child-Pugh classification) than viral HCC patients. Significantly fewer non-B non-C HCC patients had periodic intensive medical assessments than viral HCC patients. Forty-five non-B non-C HCC patients were habitual alcohol drinkers, ten had nonalcoholic fatty liver disease (NAFLD), and seven had no apparent etiology. In habitual drinkers, the stage of underlying liver disease varied widely, while most NAFLD patients had early stage cirrhosis. On the other hand, more than half of the patients with HCC of undetermined etiology had noncirrhotic liver disease. Among habitual drinkers, the underlying liver disease was more progressive, and the T stage was more advanced in those with high daily alcohol intake than in those with low daily alcohol intake. Periodic intensive medical assessments were crucial for detecting early stage HCC.ConclusionsAlcohol consumption and NAFLD may be important etiological factors in non-B non-C HCC. Periodic medical assessments for all patients with non-B non-C cirrhosis are crucial for early diagnosis and curative therapy.

Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients.

Standard‐dose ribavirin is crucial for the standard‐of‐care treatment of chronic hepatitis C virus (HCV) infection. Equilibrative nucleoside transporter 1 (ENT1), encoded by SLC29A1 gene, is the main transporter that imports ribavirin into human hepatocytes. Aims:

Expansion of CD4^+CD25^+FoxP3^+ regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma

Aim:  Regulatory T (Treg) cells may play a pivotal role in the persistence of hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC). Therefore, we examined their frequency in peripheral blood from patients with HCV‐positive chronic hepatitis (CH), cirrhosis (LC) and HCC.

Several factors including ITPA polymorphism influence ribavirin-induced anemia in chronic hepatitis C

AIM To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C. METHODS Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors. RESULTS Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10(-17), odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10(-4), OR = 0.962 (mL/min/1.73 m(2))], rs1127354 (P = 5.75 × 10(-4), OR = 10.94) and baseline hemoglobin [P = 7.86 × 10(-4), OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia. CONCLUSION Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.

New Proposal for Response-Guided Peg-Interferon- Plus-Ribavirin Combination Therapy for Chronic Hepatitis C Virus Genotype 2 Infection

This study aimed to determine the most suitable duration of pegylated‐interferon (Peg‐IFN)‐plus‐ribavirin combination therapy in patients infected with hepatitis C virus (HCV) genotype 2 who had not achieved rapid virological response (serum HCV RNA disappearance after 4 weeks of therapy). HCV genotype 2 patients (n = 182) with a high viral load received >80% of the standard Peg‐IFN‐plus‐ribavirin dose for at least 24 weeks, and their final virological responses were studied. Patients were classified into “rapid virological response” and “non‐rapid virological response” groups. The non‐rapid virological response group was further divided into a “virological response at 8 weeks” (serum HCV RNA disappearance after 8 weeks of therapy) and a “non‐virological response at 8 weeks” group. Factors related to rapid virological response and optimal therapy duration in the non‐rapid virological response group were evaluated. Multivariate logistic regression analysis showed that subtype HCV genotype 2a (P = 0.0015) and low concentration of pretreatment serum HCV RNA (P = 0.0058) were independent factors in a rapid virological response. In the virological response at 8 weeks group, the sustained virological response rate after 24 weeks of therapy was significantly lower than after 36 weeks (P = 0.044) or after 48 weeks (P = 0.006), and was similar for 36‐ and 48‐weeks. The cost for achieving (CAS) one sustained virological response was lowest with 36‐week therapy. Prolongation of Peg‐IFN‐plus‐ribavirin combination therapy to 36 weeks is suitable for achieving virological response at 8 weeks, given the high, sustained virological response rate and cost benefit. J. Med. Virol. 85:1523–1533, 2013.

Serum Apolipoprotein B-100 Concentration Predicts the Virological Response to Pegylated Interferon Plus Ribavirin Combination Therapy in Patients Infected With Chronic Hepatitis C Virus Genotype 1b

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg‐IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity‐determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg‐IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b‐infected patients to investigate whether the response to Peg‐IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B‐100 (apoB‐100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB‐100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046–2.456), alpha‐fetoprotein (OR, 0.764; 95% CI, 0.610–0.958), non‐wild‐type ISDR (OR, 5.617; 95% CI, 1.274–24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225–114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3‐log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB‐100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB‐100 concentrations could predict virological response to Peg‐IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype. J. Med. Virol. 85:1180–1190, 2013.

Daclatasvir and asunaprevir for genotype 1b chronic hepatitis C patients with chronic kidney disease

To evaluate the efficacy and safety of daclatasvir and asunaprevir combined therapy in genotype 1b chronic hepatitis C patients with non‐dialysis chronic kidney disease (CKD).

Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin

Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non‐TT. Among such treatment‐refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non‐TT.

A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study.

The sustained virological response (SVR) rate of non‐responders to peginterferon and ribavirin therapy (PR) is low for 24‐week telaprevir‐based triple combination therapy (T12PR24), compared to that of treatment‐naïve patients or previous‐treatment relapsers. This study investigated which characteristics of non‐responders were associated with a better SVR rate to 48‐week therapy (T12PR48).

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.