Journal of Gastroenterology

, Volume 48, Issue 1, pp 1–12 | Cite as

Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines

  • Kazuaki ChayamaEmail author
  • C. Nelson Hayes
  • Waka Ohishi
  • Yoshiiku Kawakami
Open Access


Hepatitis C virus (HCV) infection is a serious health problem leading to cirrhosis, liver failure and hepatocellular carcinoma. The recent introduction of telaprevir, which was approved in November 2011, in combination with peg-interferon and ribavirin is expected to markedly improve the eradication rate of the virus. However, side effects of triple therapy may be severe. In a phase three III clinical trial, 2250 mg of telaprevir, which is the same dosage used in clinical trials in Western countries, was given to Japanese patients. As this dosage is considered to be relatively high for Japanese patients, who typically have lower weight than patients in Western countries, reduction of telaprevir is recommended in the 2012 revision of the guidelines established by the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis published by the Ministry of Health, Labour and Welfare of Japan. Other protease inhibitors with fewer side effects are now in clinical trials in Japan. Alternatively, treatment of patients with combination of direct acting antivirals without interferon has been reported. In this review we summarize current treatment options in Japan and discuss how we treat patients with chronic HCV infection.


Telaprevir Triple therapy Antiviral resistance Anemia Dose reduction 



Hepatitis C virus


Direct acting anti-virals


Sustained virological response


Rapid virological response


At least 1.5 million people in Japan and more than 200 million people worldwide are chronically infected with the hepatitis C virus [1, 2]. Due to an aging patient population, the health burden of chronic HCV infection in Japan is expected to increase over the next several decades [3]. Chronic infection develops in 60–80 % of symptomatic patients, leading to higher risk of cirrhosis, hepatocellular carcinoma, and end-stage liver disease. Chronic HCV infection is also one of the primary indications for liver transplantation [3], and ultimately 5–7 % of patients die from complications related to HCV infection [4, 5, 6, 7].

The goal of HCV therapy is successful eradication of the virus and resolution of liver disease. Success is defined as the absence of detectable virus 24 weeks following the end of treatment. In some patients, the virus becomes undetectable by the end of treatment (end of treatment response) but then rebounds in the absence of therapy (relapse or transient response). Viral breakthrough occurs when the virus rebounds during the course of therapy. In non-responders, the virus remains detectable throughout therapy.

Therapy for chronic HCV infection

Hepatitis C virus genotypes vary by region and susceptibility to interferon treatment [8]. Genotype 1 is the most common genotype worldwide and in Japan [8]. Weekly injections of pegylated interferon (peg-interferon) and daily oral administration of ribavirin constitute the standard therapy for genotype 1 chronic HCV [9]. However, combination therapy is costly and poorly tolerated, requires long-term treatment (48 weeks), and is successful in only 42–52 % of patients [10, 11, 12].

The success rate of HCV therapy in Japan is expected to improve greatly following the November 2011 approval of telaprevir (VX-950/MP-424; Incivek; Vertex Pharmaceuticals, Inc., Cambridge, MA, USA), the first in a class of new direct acting antiviral (DAA) drugs. Teleprevir and a related drug, boceprevir (Victrelis), were also recently approved for treatment of genotype 1 in the US, Canada, and the European Union. While boceprevir is not approved for use in Japan, a meta-analysis found no difference in outcomes between the two drugs, except for slightly higher efficacy among prior relapsers using telaprevir [13].

Telaprevir and direct acting antiviral drugs

DAAs act by specifically inhibiting essential viral targets. Telaprevir is an NS3/4 serine protease inhibitor that mimics the carboxy-terminal region of the NS3 protease and binds slowly and tightly to the protease [14]. The NS3-4A protein is also an attractive target due to its additional role in degrading immune signaling molecules [15]. Consequently, targeting NS3-4A may not only disrupt viral replication but may also help to restore innate antiviral responses [16, 17]. However, treatment with telaprevir alone often results in a rapid decline in viral load followed by viral breakthrough due to rapid selection for resistance mutations [18, 19]. Triple therapy with peg-interferon, ribavirin, and telaprevir appears to be required to suppress viral breakthrough and achieve SVR [20].

Telaprevir clinical trials outside of Japan

Phase II studies

Several phase II and III clinical trials have established the safety and efficacy of telaprevir in the treatment of HCV genotype 1 (Table 1). The PROVE I [20] and PROVE II [21] phase II studies showed SVR rates significantly higher for triple therapy compared to the standard of care (61 vs. 41 %, 69 vs. 46 %, respectively) after 12 weeks of triple therapy followed by another 12 weeks of peg-interferon plus ribavirin combination therapy. Both studies found that reducing the length of peg-interferon and ribavirin to 12 weeks erased the advantage of triple therapy over standard therapy, and PROVE II revealed that ribavirin is required to suppress viral breakthrough [20, 21]. PROVE III examined the efficacy of triple therapy in patients who failed to achieve SVR during prior interferon therapy and reported improved SVR rates among patients with prior nonresponse (39 %), relapse (69 %), or viral breakthrough (57 %) [22].
Table 1

Summary of telaprevir clinical trials





 McHutchison et al. [20]

Phase II; N = 233

T12PR24: 12 week TVR + 24 week PR

T12P48: 12 week TVR + 24 week PR

PR48: 12 week placebo + 48 week PR


 PR: 41 %

 T12PR24: 61 %

 T12P48: 67 %


 Hezode et al. [21]

Phase II; N = 334

T12PR24: 12 week TVR + 24 week PR

PR48: 12 week placebo + 48 week PR


 PR48: 46 %

 T12PR24: 69 %


 McHutchison et al. [22]

Phase II; N = 465

Patients with prior PR treatment failure

T12PR24: 12 week TVR + 24 week PR

T24PR48: 12 week TVR + 24 week PR

T24P24: 12 week TVR + 24 week PR

PR48: 12 week placebo + 48 week PR


 T12PR24: 51 %

 T24PR48: 53 %

 T24P24: 24 %

 PR48: 14 %


 Jacobson et al. [23]

Phase III double-blind; N = 1088

Treatment-naïve patients

T8PR: 8 week TVR + 24 or 48 week PR RGT

T12PR: 12 week TVR + 24 or 48 week PR RGT

PR: 12 week placebo + 48 week PR


 T8PR: 69 %

 T12PR: 75 %

 PR: 44 %


 Sherman et al. [55]

Phase III open-label; N = 540

Treatment-naïve patients

T12PR24: 12 week TVR + 24 or 48 week PR RTG

T12PR48: 12 week TVR + 48 week PR


 T12PR24: 92 %

 T12PR48: 88 %


 Zeuzem et al. [24]

Phase III; N = 662

Patients with prior PR treatment failure

T12PR48: 8 week TVR + 48 week PR

Lead-in T12PR48: 4 week PR + 8 week TVR + 48 week PR

PR48: 12 week placebo + 48 week PR

SVR by treatment

 T12P48: 64 %

 Lead-in T12P48: 66 %

 PR48: 17 %

SVR by prior history

 Relapsers: 83–88 %

 Partial responders: 54–58 %

 Non-responders: 29–33 %

 Yamada et al. [32]

Phase Ib; N = 10

Treatment-naive Japanese patients

TVR monotherapy: 12 week

ETR: 10 %

 Ozeki et al. [19]

Phase IIa; N = 4; single-arm, open label

Older female Japanese patients with prior PR treatment failure

TVR monotherapy: 24 week + off-study PR

SVR (off-study): 100 %

 Toyota et al. [33]

Phase II; N = 15; single-arm, open-label

Treatment-naive Japanese patients

TVR monotherapy: 24 week

SVR: 7 %

 Kumada et al. [28]

Phase III; N = 189

Treatment-naïve Japanese patients

TR12P24: 12 week TVR + 12 week PR

P48: 48 week PR


 TR12P24: 73 %

 P48: 49 %

 Hayashi et al. [31]

Phase III; N = 141

Patients with prior PR treatment failure

TR12P24: 12 week TVR + 12 week PR

P48: 48 week PR


 Relapsers: 88 %

 PR48: 34 %

TVR telaprevir, PR peg-interferon plus ribavirin combination therapy, RGT response-guided therapy—24 week PR if undetectable HCV RNA at weeks 4 and 12 (eRVR); otherwise 48 week PR, ETR end-of-treatment response

Phase III studies

The phase III ADVANCE study compared duration of telaprevir therapy in treatment-naive patients using three treatment arms, a control peg-interferon plus ribavirin group and 8 and 12 week telaprevir triple therapy groups followed by response-guided peg-interferon plus ribavirin combination therapy [23] (Table 1). SVR rates were 69 % for the 8 week telaprevir treatment and 75 % for the 12 week telaprevir treatment, compared to 44 % for standard peg-interferon plus ribavirin combination therapy. The phase III REALISE study assessed response to triple therapy in patients with prior treatment failure [24]. Prior relapsers, partial responders, and null responders were randomized to a 48 week peg-interferon plus ribavirin control group or to 48 week triple therapy groups with 12 weeks of telaprevir with or without a 4 week peg-interferon plus ribavirin lead-in phase. SVR rates in the triple therapy group were 66 % with the lead-in phase and 64 % without it, compared to only 17 % in the control group. When analyzed by response to prior treatment, prior relapsers showed the strongest improvement in SVR rates, but triple therapy also appears to benefit prior null and partial responders as well [24, 25, 26]. Based on these studies, the U.S. Food and Drug Administration (FDA) approved response-guided therapy (RGT) for prior relapsers who achieved extended rapid virological response (eRVR) [27]. This allows prior relapsers to discontinue all treatment after 24 weeks if HCV RNA is undetectable at weeks 4 and 12. In Japan, duration of triple therapy is 24 weeks without regard for response to prior treatment.

Clinical trials of telaprevir in Japan

Triple therapy in treatment-naive patients

Although Asians are under-represented in the above studies (1–2 %), several phase II and III clinical trials have also been performed in Japan (Table 1). In Kumada et al. [28], 126 patients were randomly assigned to 12 weeks of telaprevir triple therapy followed by 12 weeks of combination therapy, and 63 patients were assigned to 48 weeks of combination therapy. Early viral dynamics varied greatly between the two groups, with more rapid and extensive loss of HCV RNA and a significantly higher rate of SVR in the triple therapy group (73.0 vs. 49.2 %). Rates of viral breakthrough and relapse did not differ between the treatment groups. However, patients who underwent triple therapy experienced a significantly higher incidence of side effects during the telaprevir phase of the treatment. Because HCV patients in Japan tend to be more than 10 years older than patients in Western countries and include a higher proportion of women, ribavirin-induced anemia is of particular concern [29]. Moderate or severe anemia developed in 38.1 % of patients in the triple therapy group compared to 17.5 % in the combination therapy group [30]. The ribavirin dose was adjusted accordingly, resulting in a lower total ribavirin dose in the triple therapy group. However, ribavirin dose reduction did not significantly impact treatment efficacy. Skin disorders were about twice as common in triple therapy patients (46.8 vs. 23.8 %), and severe skin lesions were only observed in this group. Due to the higher SVR rate and shorter duration of triple therapy, the study authors recommend triple therapy over combination therapy for treatment of HCV genotype 1 in Japan but stress the need for careful monitoring of hemoglobin levels and close coordination with a dermatologist.

Triple therapy in patients with prior treatment failure

In a second phase III clinical trial in Japan, Hayashi et al. [31] examined the safety and efficacy of triple therapy for difficult-to-treat patients who either relapsed (109) or failed to respond to prior interferon therapy (32). As in the previous studies, patients were treated to 12 weeks of triple therapy followed by 12 weeks of combination therapy. SVR rates were 88.1 % for prior relapsers and 34.4 % for prior non-responders. Adverse events were common but moderate. 82 % of patients experienced rash or other skin disorders, mainly during the telaprevir phase, and nearly all (98.6 %) patients required ribavirin dose reduction for anemia, although ribavirin dose reduction had no effect on SVR rate down to about 20 % of the planned dose. Telaprevir was discontinued in 21.3 % of patients, and all drugs were discontinued in 16.3 % of patients. SVR rates in prior relapsers were significantly higher among men than women (93.9 vs. 79.1 %), but there was no difference among prior non-responders. Rates of viral breakthrough (18.8 %) and relapse (40.6 %) were significantly higher among prior non-responders and were more common after completion of the telaprevir phase, suggesting that extension of telaprevir therapy past 12 weeks or continuation of combination therapy past 24 weeks may improve response for prior non-responders. The study authors recommend weekly hemoglobin monitoring and note that even sharp reductions in ribavirin dose my allow therapy to continue without adversely affecting outcome.

Side effects of telaprevir in clinical trials in Japan

An early phase Ib study was conducted in Japan to examine the safety, tolerability, and antiviral profile of telaprevir monotherapy over 12 weeks in 10 treatment-naive patients with high viral loads of genotype 1b [32]. Telaprevir was well tolerated and no serious adverse events occurred, but 80 % of patients developed a rash and 70 % experienced anemia. Telaprevir monotherapy demonstrated potent antiviral activity, with HCV RNA levels decreasing by 2.3 log10 by 16 h and by 5.2 log10 after 2 weeks. HCV RNA dropped to the limit of detection or became undetectable in all patients during the course of therapy, but only one patient achieved an end-of-treatment response. Viral breakthrough occurred in 8 patients, mainly due to Ala156 mutation. However, resistance mutants reverted to wild type during the 24 week follow-up period.

Another study examined safety and efficacy of telaprevir monotherapy over a longer duration of 24 weeks with a larger number of patients and a greater range of viral loads [33]. The only patient who achieved SVR also had the lowest baseline viral load (3.55 log10 IU/ml), but three other patients were able to achieve an end-of-treatment response. HCV RNA levels decreased rapidly (average −5 log10 IU/ml), and HCV RNA became undetectable in 5 patients within 8 weeks. 10 out of 15 patients (66 %) discontinued the drug due to viral breakthrough, adverse events, or other causes. Incidence of adverse events was high (14/15 patients) and 7 out of 15 patients (47 %) developed anemia, but most incidences were mild to moderate, and anemia did not lead to discontinuation of therapy. T54A and A156V variants were the most common and were not detectable at earlier time points. Secondary substitutions at V158I and I132L were also observed.

SVR rates tend to be lower among women than men over 50 in Japan (53 vs. 22 %), and dose reductions and discontinuation of treatment in standard therapy are high in this group [34]. Ozeki et al. [19] examined 24 weeks of telaprevir monotherapy in a group of four older female patients predicted to be difficult to treat due to age, sex, and Core70 and ISDR substitutions. All patients required telaprevir dose reduction due to anemia but did not require discontinuation. Resistance variants were detected in three patients, and two patients experienced viral breakthrough. Additional substitutions and variants emerged as therapy progressed. However, at the end of the telaprevir administration, all four patients were given at least 48 weeks of standard therapy, and all patients were able to achieve SVR. Although this approach results in longer duration of therapy, it avoids the need for simultaneous administration of the three drugs and takes advantage of the fact that resistance mutants selected during telaprevir therapy often have reduced fitness compared to the wild type and are more susceptible to standard therapy.

Telaprevir antiviral resistance

Pre-existence of resistance mutations and selection for resistance may be an inevitable consequence of DAA therapy [35]. The high replication rate of HCV high (1012 viruses per day) coupled with the low fidelity of HCV polymerase results in a high mutation rate (10−3–10−5 per day) and the presence of viral quasispecies. Single and double substitutions from the consensus sequence are expected to exist at low frequency prior to therapy. The relative proportion of these variants increases rapidly in the viral population as the wild-type virus is eradicated. De novo mutations appear to play only a minor role in the emergence of resistance mutations, suggesting that a genetic barrier of three to four mutations might be sufficient to reduce selection based on pre-existing mutants. At the same time, mutations conferring resistance often have reduced fitness and may require compensatory mutations in order to compete with wild-type viruses. Nonetheless, HCV sub-genotypes vary substantially in sequence, and some are likely to have a reduced genetic barrier against certain DAAs. For example, viral genotypes 1a and 1b already have different genetic barriers to telaprevir resistance; amino acid substitution of amino acid 155 requires only one nucleotide change in genotype 1a, whereas genotype 1b requires two nucleotide substitutions [36, 37]. Resistance substitutions at six major sites within the NS3 HCV protease have been reported, including at amino acids 36, 54, 155, 156, 168, and 170, and some substitutions are known to act synergistically [35]. At least 50 direct-acting antiviral drugs are at some stage of development, but these belong to a small number of distinct drug classes, increasing the risk of cross-resistance. Although wild-type strains are typically restored following removal of the drug due to viral breakthrough, prior treatment experience with DAAs, especially in high-risk subpopulations such as injection drug users, may increase the risk of transferring partially resistant strains during new infections.

Patient selection and predictive factors for triple therapy

Telaprevir triple therapy is an extension of peg-interferon plus ribavirin combination therapy. Therefore, factors that predict the outcome of combination therapy might also help to predict outcome of triple therapy. Age, fibrosis, obesity, hepatic steatosis [38], LDL cholesterol, gamma-GTP [39], insulin resistance [40], baseline viral titer [38, 41], and IL28B SNP genotype [42, 43, 44] are known to affect response to combination therapy. HCV genotype [41] and genetic variants within the viral genome, including amino acid substitutions at positions 70 (Core70) and 91 (Core91) of the HCV core protein and substitutions within the NS5A interferon sensitivity determining region (ISDR) [45, 46], are also thought to influence response to combination therapy. Akuta et al. [47] reported that Core70 substitution and partial response to prior therapy were significant predictors of SVR for triple therapy, and partial response and alpha-fetoprotein levels were significant predictors of end-of-treatment response. Chayama et al. [26] reported that IL28B SNP genotype, rapid virological response (RVR), and response to prior therapy were predictive of outcome of triple therapy. Prior relapsers achieved high levels of SVR (93 %), whereas patients who failed to respond to combination therapy were also less likely to respond to triple therapy. ITPA SNP genotype did not influence outcome of therapy, but patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than patients with other genotypes. Predictive factors for SVR identified during the ADVANCE phase III clinical trial include race, viral load, IL28B, RVR, and stage of fibrosis [48]. IL28B and on-treatment factors such as RVR appear to remain important predictors for response to triple therapy and may aid in patient selection and determination of treatment duration [48].

2012 guidelines for treatment of patients with chronic hepatitis C

Two guidelines for treatment of chronic HCV are available in Japan, both providing recommendations for patient selection for telaprevir triple therapy. Triple therapy in Japan consists of 12 weeks of telaprevir (Telavic) in combination with 24 weeks of dual peg-interferon α 2b (Peg-Intron) and 24 weeks of ribavirin (Rebetol).

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: 2012 Guideline on Therapy for Chronic Hepatitis C

The following are the most recent guidelines from the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis published by the Ministry of Health, Labour and Welfare of Japan (Tables 2, 3, 4, 5, 6). The recommended course of treatment differs depending on HCV genotype, viral titer, and prior history of interferon treatment. Patients with high viral load (>5.0 log IU/ml) of genotype 1 are considered difficult to treat and are recommended for triple therapy in both interferon treatment-naive and treatment-experienced patients (Tables 2, 3). In this group of patients, IL28B SNP genotype, HCV Core70 and ISDR substitutions are strong predictors of treatment outcome and may be used to determine the starting therapy. Patients with rs8099917 TT genotype are recommended for triple therapy. If telaprevir is contraindicated due to age, gender, or hemoglobin levels, peg-interferon plus ribavirin may be used instead (Table 4). However, combination therapy alone without telaprevir is not recommended for patients with rs8099917 TG/GG genotype, Core70 mutant, and wild type ISDR (0–1 substitutions) due to poor response to combination therapy in these patients (Table 4). For treatment-naive patients with low viral loads of either genotype 1 or genotype 2, the recommended treatment is 24–48 weeks of peg-interferon α 2a (Pegasys) (Table 1). Recommended treatment for patients with high viral load of genotype 2 is 24 weeks of dual therapy with ribavirin and either peg-interferon α 2b or interferon β (Feron). In the case of adverse drug reactions, such as depression, or in the case of increased risk of adverse drug reactions due to age, interferon β plus ribavirin should be considered for patients, regardless of genotype 1 or 2. Previously treated patients with genotype 1 should be treated with triple therapy, consisting of 12 weeks of telaprevir and 24 weeks of peg-interferon α 2b and ribavirin regardless of viral load (Table 3). Patients with genotype 2 should be given 36 weeks of dual therapy with ribavirin and either peg-interferon α 2a/b or interferon β (Table 3).
Table 2

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: 2012 guidelines for chronic hepatitis C therapy for treatment-naive patients


Genotype 1

Genotype 2

High viral load

Peg-IFN α 2b: Peg-Intron (24 weeks)

Peg-IFN α 2b: Peg-Intron

 ≥5.0 log IU/mL

+Ribavirin: Rebetol (24 weeks)

+Ribavirin: Rebetol (24 weeks)

 ≥300 fmol/L

+Telaprevir: Telavic (12 weeks)

IFN β: Feron

 ≥1 Meq/mL


+Ribavirin: Rebetol (24 weeks)

Low viral load

IFN (24 weeks)

IFN (8–24 weeks)

 <5.0 log IU/mL

Peg-IFN α 2a: Pegasys (24–48 weeks)

Peg-IFN α 2a: Pegasys (24–48 weeks)

 <300 fmol/L


 <1 Meq/mL

Table 3

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: 2012 guidelines for chronic hepatitis C therapy for previously treated patients


Genotype 1

Genotype 2

High viral load

 ≥5.0 Log IU/mL


 ≥300 fmol/L

Peg-IFN α 2b + Ribavirin (24 weeks)

Peg-IFN α 2b + Ribavirin (36 weeks)


  ≥1 Meq/mL

+Telaprevir (12 weeks) combined therapy

Peg-IFN α 2a + Ribavirin (36 weeks)


Low viral load


IFN β + Ribavirin (36 weeks)

 <5.0 log IU/mL


 <300 fmol/L


 <1 Meq/mL

Table 4

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: pretreatment indicators for triple therapy

Indications for therapy involving a host factor (IL28B) and two viral factors (ISDR and Core70) at the start of triple combined therapy including telaprevir in the initial therapy for the treatment-naive patients with high viral load of genotype 1

1. Telaprevir triple therapy is recommended in patients homozygous for the favorable IL28B SNP allele (e.g., rs8099917 T/T genotype) because the anticipated effect of the therapy is high. If telaprevir therapy is likely to be difficult in consideration of the patient’s age, gender, hemoglobin level, or other factor, then peg-interferon α or interferon β plus ribavirin combination therapy should be chosen instead

2. Telaprevir triple therapy may be preferred over interferon plus ribavirin combination therapy in patients with an unfavorable IL28B SNP genotype (rs8099917 T/G or G/G), wild-type ISDR (0–1 substitutions), and a Core70 mutation, because the effect of interferon plus ribavirin combination therapy is low in these patients

Table 5

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: guidelines for ribavirin and telaprevir dose reduction based on baseline hemoglobin levels

Baseline hemoglobin (g/dl)




Conventional dose

Conventional dose (2250 mg)


Decrease by 200 mg (females only)

Decrease to 1500 mg (females only)


Decrease by 200 mg

Decrease to 1500 mg


Triple therapy unsafe


Initial ribavirin and telaprevir dosages relative to hemoglobin levels are estimated based on the results of clinical trials. Initial dosages should be determined by a specialist based on the patient’s age, weight, etc

Table 6

Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis: precautions for triple therapy with peg-interferon α 2b, ribavirin, and telaprevir in case of high viral load of genotype 1

1. Severe anemia occurs more frequently in peg-interferon α 2b plus ribavirin plus telaprevir triple therapy compared to interferon plus ribavirin combination therapy. Care should be taken to monitor hemoglobin levels, and in case of anemia, ribavirin dosage should be adjusted based on consideration of both the absolute value of hemoglobin as well as the amount of hemoglobin reduction. Because the risk of anemia increases with age, peg-interferon α or interferon β plus ribavirin combination therapy is the preferred initial therapy for older female patients or patients with low hemoglobin levels and high viral loads of genotype 1

2. Peg-interferon α 2b plus ribavirin plus telaprevir triple therapy should be conducted in coordination with a dermatologist because serious skin problems such as Stevens–Johnson syndrome and drug-induced hypersensitivity syndrome are likely to occur. In the event of severe skin problems, use of all three drugs should be immediately ceased. If cutaneous symptoms are expressed, adequate treatment should begin at an early date. Course of treatment should be decided in cooperation with a dermatologist in view of the respective risks and benefits, and administration of oral steroids should be considered if necessary

3. Some patients experience an increase in uric acid and creatinine levels rise during the first week of peg-interferon α 2b plus ribavirin plus telaprevir triple therapy. If uric acid levels become aberrant, early administration of a therapeutic agent for hyperuricemia is required

Telaprevir triple therapy is associated with an increased risk of anemia, skin lesions, and other side effects compared to peg-interferon plus ribavirin dual therapy, especially among females and older patients [20, 26]. Initial dosages should be determined based on the patient’s age, weight, and expected tolerability. However, for female patients with baseline hemoglobin levels between 13 and 14 g/dl or male patients with baseline hemoglobin levels between 12 and 13 g/dl, ribavirin dosage should be reduced by 200 mg and telaprevir dosage should be reduced to 1500 mg (Table 5). Triple therapy is unsafe in patients with baseline hemoglobin levels <12 g/dl. Hemoglobin levels should be closely monitored, and in the case of anemia ribavirin, dosage should be reduced based on both the absolute value of the hemoglobin levels as well as the amount of the reduction (Table 6). Triple therapy should be conducted in cooperation with a dermatologist to manage the high risk of potentially serious skin problems, including Stevens–Johnson syndrome and drug-induced hypersensitivity syndrome. Use of all three drugs should immediately cease in the event of serious skin problems. In the event of cutaneous symptoms, adequate treatment should begin early in consultation with a dermatologist. Benefits and risks of administration of oral steroids or other drugs should be considered, if necessary. Some patients may also experience a rapid increase in uric acid levels at the start of therapy (1–7 days), in which case a therapeutic agent should be administered early to reduce hyperuricemia.

Japan Society of Hepatology: 2012 guidelines for treatment of chronic HCV

The 2012 guidelines supported by the Japan Society of Hepatology ( provide more specific recommendations for patients with high viral load of HCV genotype 1 based on factors including patient age, IL28B SNP genotype, Core70 and ISDR substitutions, prior treatment history, and stage of fibrosis. The English version of this guideline will be published soon in Hepatology Research (2012). Treatment-naive patients with rs8099917 TT genotype should be given triple therapy, if possible, but combination therapy may be substituted if telaprevir is contraindicated (Fig. 1a). Interferon β plus ribavirin may also be substituted in case of depression. Therapy should also be postponed in patients with both the unfavorable IL28B SNP genotype (TG/GG) and Core70 mutation due to the poor expected outcome of therapy. When IL28B and Core70 data are not available, patients should be treated with triple therapy or combination therapy, depending on tolerability and fibrosis stage (Fig. 1b). Therapy may be postponed in nonelderly patients (≤65) with mild fibrosis.
Fig. 1

Japan Society of Hepatology: 2012 treatment guidelines for treatment-naive chronic HCV patients with high viral load of genotype 1. a Patients with the favorable IL28B SNP genotype (rs8099917 TT) and/or wild type viral core protein amino acid 70 (Core70) should be treated with triple or combination therapy, if possible, depending on age and fibrosis stage. Patients with both the unfavorable IL28B SNP genotype (TG/GG) and Core70 substitution should postpone therapy due to poor expected outcome. b When IL28B SNP genotype and Core70 substitutions are unavailable, treatment is determined based on patient age and stage of fibrosis

Triple therapy provides a retreatment opportunity for patients who were unable to eradicate the virus during prior therapy. However, not all patients show an improved response, and a patient’s response to the prior therapy should be used as a guide for treatment selection, if available. Patients who experienced relapse or partial response are expected to respond well to therapy and should be administered triple therapy or combination therapy depending on age and stage of fibrosis (Fig. 2a). On the other hand, patients who experienced null response during prior therapy should be administered triple therapy, if possible; otherwise, treatment should be postponed, as combination therapy alone is unlikely to be successful. When treatment history is unknown but IL28B SNP and Core70 data are available, guidelines for treatment-naive patients should be followed (Fig. 2a). In the absence of both treatment history and IL28B/Core70 data, patients should be treated with triple therapy or combination therapy, depending on tolerability and fibrosis stage (Fig. 2b).
Fig. 2

Japan Society of Hepatology: 2012 treatment guidelines for re-treatment of previously treated chronic HCV patients with high viral load of genotype 1. a Patients who experienced relapse or partial response during prior interferon therapy should be treated with triple therapy or combination therapy, if possible, depending on age. Triple therapy is recommended for patients who experienced null response to prior therapy, but if triple therapy is not possible, therapy should be postponed due to poor expected response to combination therapy in these patients. b When prior treatment history is unavailable but IL28B SNP and core amino acid 70 (Core70) information is available, guidelines for treatment-naive patients should be followed (Fig. 1a). When both prior treatment history and IL28B SNP and Core70 information are unavailable, triple therapy is recommended for older patients as well as for younger patients with advanced fibrosis. If fibrosis is mild, triple therapy for younger patients should be postponed

Future therapies

The development, clinical testing, and approval of telaprevir triple therapy is the culmination of a decades-long process [49]. At the same time, however, the introduction of telaprevir and boceprevir represents the first success in a much broader direct antiviral strategy targeting multiple facets of the viral life cycle. Future clinical trials involving triple therapy are likely to lead to further improvements in SVR rate, shorter duration of therapy, and improved management of side effects, especially among specific patient subgroups. Future research will also identify new predictive factors associated with response to DAA therapy, including risk of viral breakthrough and adverse events.

A major goal of future clinical research, however, is to move beyond interferon-based therapy in favor of interferon-free DAA combination therapies. A number of novel DAAs are currently undergoing clinical testing (Table 7), and DAAs are being evaluated in combination with interferon as well as other DAAs (Table 8). Many other drugs and vaccines are currently in some stage of clinical testing ( Telaprevir and other DAAs under development are not intended for use in monotherapy due to the low genetic barrier to resistance. However, combinations of DAAs with different viral targets and mechanisms of action should have a higher genetic barrier. For example, in a chimeric mouse model a protease inhibitor (telaprevir) in combination with an RNA polymerase inhibitor (MK-0608) resulted in rapid clearance of HCV RNA without emergence of resistance mutants [50].
Table 7

Direct-acting antiviral (DAA) drugs in clinical testing


Phase I

Phase II

Phase III

Phase IV

Protease inhibitor





















Polymerase inhibitor




























NS5A inhibitor













NS4B inhibitor



Entry inhibitor


Table 8

Direct-acting antiviral (DAA) combination therapies in clinical testing


Phase II

Phase III

Phase IV

DAA combinations

ABT-450 + ABT-072

BMS-790052 + BMS-650032a

ABT-450/r + ABT-267a


ABT-450 + ABT-333


BI201335 + BI207127


BMS-790052 + GS-7977


BMS-790052 + TMC435


Boceprevir + mericitabine


GS-9256 + GS-9190


GS-7977 + TMC435


RG7128 + RG7227


Telaprevir + VX-222




Peg + RBV + BI201335

Peg + RBV + telaprevirb

Peg + RBV + BMS-790052


Peg + RBV + GS-7977


Peg + RBV + TMC435b


Peg + RBV + MK-7009b


IFN λ + RBV + BMS-790052a


IFN λ + RBV + BMS-650032a


DAA combinations, interferon-free combination therapies involving two or more DAAs; DAA + IFN, therapies based on interferon plus ribavirin combination with one or more DAAs; Peg, pegylated interferon, RBV, ribavirin; IFN, interferon; IFN λ, interferon-lambda (type III interferon)

aCurrently in clinical trials in Japan

bCompleted clinical trials in Japan

Several DAA combination therapies have entered phase II clinical trials in humans. Safety and efficacy of dual therapy with daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) was examined in two phase II clinical trials in the US and Japan for difficult-to-treat genotype 1 patients with null response to prior interferon therapy [51, 52, 53]. The studies differed notably with respect to sub-genotype; 81 % of patients in the US study had genotype 1a, whereas all patients in the Japanese study had genotype 1b. In the Japanese study, 77 % of patients achieved SVR (90 % in the sentinel cohort) [52, 53], whereas in the dual DAA therapy arm of the US study (group A), only 36 % of patients achieved SVR, while the other patients either relapsed or had viral breakthrough [51]. In the latter study, the two patients with genotype 1b both achieved SVR. All patients in group B, in which all patients received peg-interferon plus ribavirin in addition to daclatasvir and asunaprevir, achieved SVR at 12 weeks after treatment. These discrepancies may reflect differences between genotypes 1a and 1b in the genetic barrier for resistance to this drug combination [51] and suggest that such treatments may be more amenable in Japan where genotype 1b is common.

In another phase II dual DAA therapy study, treatment-naive genotype 1 patients were administered GS-9256, an NS3 serine protease inhibitor, and tegobuvir (GS-9190), a non-nucleoside NS5B polymerase inhibitor, with or without peg-interferon and ribavirin, followed by standard therapy with peg-interferon plus ribavirin [54]. Only 7 % of patients receiving dual DAA therapy alone achieved RVR, whereas RVR rates increased to between 67 and 100 % among patients who also received peg-interferon and/or ribavirin. Although promising, these studies suggest that interferon and ribavirin will continue to be used in future DAA combination therapies to control viral breakthrough.

Future perspective and conclusion

Although SVR rates still fall far short of 100 %, the recent introduction of telaprevir to standard peg-interferon plus ribavirin therapy greatly increases the chance that a patient with chronic HCV infection will be able to successfully clear the virus, and it offers a promising retreatment opportunity for patients who were unable to clear the virus in previous therapy attempts. Despite the higher SVR rate, however, triple therapy also further limits patient eligibility and increases the burden on patients. This issue is of particular concern in Japan where patients tend to be older than in Western countries and at greater risk for HCC, as well as more likely to face complications or treatment discontinuation due to adverse events.



This work was supported in part by Grants-in-Aid for scientific research and development from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labor and Welfare, Government of Japan.

Conflict of interest

The author declares that he has nothing to disclose regarding funding or conflict of interest with respect to this manuscript.


  1. 1.
    Okamoto H, Mishiro S. Genetic heterogeneity of hepatitis C virus. Intervirology. 1994;37:68–76.PubMedGoogle Scholar
  2. 2.
    Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(Suppl 1):74–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of chronic hepatitis C in the United States. Liver Transpl. 2003;9:331–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Alter MJ. Epidemiology of hepatitis C in the West. Semin Liver Dis. 1995;15:5–14.PubMedCrossRefGoogle Scholar
  5. 5.
    Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–67.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002;36:S35–46.PubMedCrossRefGoogle Scholar
  8. 8.
    Chayama K, Hayes CN. Hepatitis C virus: how genetic variability affects pathobiology of disease. J Gastroenterol Hepatol. 2011;26:83–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan. Hepatol Res. 2010;40:8–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346–55.PubMedGoogle Scholar
  11. 11.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  12. 12.
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Schmitz S, O’Leary A, Walsh C, Bergin C, Norris S. The relative efficacy of boceprevir and telaprevir in the treatment of HCV Genotype 1. Clin Infect Dis. 2012. doi: 10.1093/cid/cis880
  14. 14.
    Perni RB, Almquist SJ, Byrn RA, et al. Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. Antimicrob Agents Chemother. 2006;50:899–909.PubMedCrossRefGoogle Scholar
  15. 15.
    Foy E, Li K, Wang C, et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science. 2003;300:1145–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997–1002.PubMedCrossRefGoogle Scholar
  17. 17.
    Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767–77.PubMedCrossRefGoogle Scholar
  18. 18.
    Hiraga N, Imamura M, Abe H, et al. Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo. Hepatology. 2011;54:781–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Ozeki I, Akaike J, Karino Y, et al. Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients. J Gastroenterol. 2011;46:929–37.PubMedCrossRefGoogle Scholar
  20. 20.
    McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.PubMedCrossRefGoogle Scholar
  21. 21.
    Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839–50.PubMedCrossRefGoogle Scholar
  22. 22.
    McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med. 2010;362:1292–303.PubMedCrossRefGoogle Scholar
  23. 23.
    Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. New Engl J Med. 2011;364:2417–28.PubMedCrossRefGoogle Scholar
  25. 25.
    Ramachandran P, Fraser A, Agarwal K, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther. 2012;35:647–62.PubMedCrossRefGoogle Scholar
  26. 26.
    Chayama K, Hayes CN, Abe H, et al. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis. 2011;204:84–93.PubMedCrossRefGoogle Scholar
  27. 27.
    Liu J, Jadhav PR, Amur S, et al. Response guided telaprevir therapy in prior relapsers?: the role of bridging data from treatment-naive and experienced subjects. Hepatol. 2012. doi: 10.1002/hep.25764
  28. 28.
    Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Chayama K, Hayes CN, Yoshioka K, et al. Accumulation of refractory factors for pegylated interferon plus ribavirin therapy in older female patients with chronic hepatitis C. Hepatol Res. 2010;40:1155–67.PubMedCrossRefGoogle Scholar
  30. 30.
    Yoshizawa H, Tanaka J, Miyakawa Y. National prevention of hepatocellular carcinoma in Japan based on epidemiology of hepatitis C virus infection in the general population. Intervirology. 2006;49:7–17.PubMedCrossRefGoogle Scholar
  31. 31.
    Hayashi N, Okanoue T, Tsubouchi H, Toyota J, Chayama K, Kumada H. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19:e134–42.PubMedCrossRefGoogle Scholar
  32. 32.
    Yamada I, Suzuki F, Kamiya N, et al. Safety, pharmacokinetics and resistant variants of telaprevir alone for 12 weeks in hepatitis C virus genotype 1b infection. J Viral Hepat. 2012;19:e112–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Toyota J, Ozeki I, Karino Y, et al. Virological response and safety of 24-week telaprevir alone in Japanese patients infected with hepatitis C virus subtype 1b. J Viral Hepat. 2012.Google Scholar
  34. 34.
    Sezaki H, Suzuki F, Kawamura Y, et al. Poor response to pegylated interferon and ribavirin in older women infected with hepatitis C virus of genotype 1b in high viral loads. Dig Dis Sci. 2009;54:1317–24.PubMedCrossRefGoogle Scholar
  35. 35.
    Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol. 2011;55:192–206.PubMedCrossRefGoogle Scholar
  36. 36.
    Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology. 2007;46:631–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology. 2008;48:1769–78.PubMedCrossRefGoogle Scholar
  38. 38.
    Dienstag JL, McHutchison JG. American Gastroenterological Association technical review on the management of hepatitis C. Gastroenterology. 2006;130:231–64 (quiz 214–7).Google Scholar
  39. 39.
    Akuta N, Suzuki F, Kawamura Y, et al. Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol. 2007;46:403–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Romero-Gómez M, Del Mar Viloria M, Andrade R, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Zeuzem S, Franke A, Lee JH, Herrmann G, Ruster B, Roth WK. Phylogenetic analysis of hepatitis C virus isolates and their correlation to viremia, liver function tests, and histology. Hepatology. 1996;24:1003–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Ge DL, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRefGoogle Scholar
  43. 43.
    Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009; 41:1100–4.Google Scholar
  44. 44.
    Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801.PubMedCrossRefGoogle Scholar
  45. 45.
    Akuta N, Suzuki F, Sezaki H, et al. Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology. 2005;48:372–80.PubMedCrossRefGoogle Scholar
  46. 46.
    Enomoto N, Sakuma I, Asahina Y, et al. Comparison of full-length sequences of interferon-sensitive and resistant hepatitis-C virus 1b—sensitivity to interferon is conferred by amino-acid substitutions in the NS5A region. J Clin Invest. 1995;96:224–30.PubMedCrossRefGoogle Scholar
  47. 47.
    Akuta N, Suzuki F, Seko Y, et al. Determinants of response to triple therapy of telaprevir, peginterferon, and ribavirin in previous non-responders infected with HCV genotype 1. J Med Virol. 2012;84:1097–105.PubMedCrossRefGoogle Scholar
  48. 48.
    Kwo PY. Phase III results in genotype 1 naive patients: predictors of response with boceprevir and telaprevir combined with pegylated interferon and ribavirin. Liver Int. 2012;32(Suppl 1):39–43.PubMedCrossRefGoogle Scholar
  49. 49.
    Kwong AD, Kauffman RS, Hurter P, Mueller P. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol. 2011;29:993–1003.PubMedCrossRefGoogle Scholar
  50. 50.
    Ohara E, Hiraga N, Imamura M, et al. Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice. J Hepatol. 2011;54:872–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216–24.PubMedCrossRefGoogle Scholar
  52. 52.
    Chayama K, Takahashi S, Toyota J, et al. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55:742–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Suzuki F, Ikeda K, Toyota J, et al. Dual oral therapy with the NS5A inhibitor daclatasvir (BMS-790052) and NS3 protease inhibitor asunaprevir (BMS-650032) in HCV genotype 1b-infected null responders or ineligible/intolerant to peginterferon. In: 47th annual meeting of the European Association for the study of the liver (EASL 2012). Barcelona, 2012; Abstract 14.Google Scholar
  54. 54.
    Zeuzem S, Buggisch P, Agarwal K, et al. The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C. Hepatology. 2012;55:749–58.PubMedCrossRefGoogle Scholar
  55. 55.
    Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-24.Google Scholar

Copyright information

© Springer Japan 2012

Authors and Affiliations

  • Kazuaki Chayama
    • 1
    • 2
    • 4
    Email author
  • C. Nelson Hayes
    • 1
    • 2
    • 4
  • Waka Ohishi
    • 2
    • 3
  • Yoshiiku Kawakami
    • 2
    • 4
  1. 1.Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKENHiroshimaJapan
  2. 2.Liver Research Project CenterHiroshima UniversityHiroshimaJapan
  3. 3.Department of Clinical StudiesRadiation Effects Research FoundationHiroshimaJapan
  4. 4.Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan

Personalised recommendations