Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update

The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology (JSH) drafted the first version of the clinical practice guidelines for the management of hepatitis C virus (HCV) infection in 2012. Since then, we have been publishing updates as new drugs for hepatitis C become available and new indications for existing drugs are added. The new approval of sofosbuvir/velpatasvir prompted us to publish the seventh version of the guidelines in Japanese in March 2019. We also published the first English‐language version of the JSH guidelines in 2013 and English versions of updates made to the Japanese‐language guidelines in 2014 and 2016. In 2020, the Committee has decided to publish a new English version, covering general information about treatment for hepatitis C, drugs used, recommended treatments for chronic hepatitis and cirrhosis, and special populations, such as patients who have renal impairment, are on dialysis, or have developed recurrence of hepatitis C after liver transplantation. Furthermore, the Committee has released a separate publication covering the protective effect of antiviral therapy against hepatocarcinogenesis.     

Comparison of acknowledged hepatocellular carcinoma risk scores in high-risk hepatitis C patients with sustained virological response

Hepatitis C patients with advanced fibrosis or cirrhosis are at high risk of developing hepatocellular carcinoma (HCC) even after sustained virological response (SVR). Several HCC risk scores have been developed but which one is most suitable for this population is unclear. In this study, we compared the prediction ability of the aMAP model, THRI model, PAGE-B model and Models of HCV in a prospective hepatitis C cohort in order to propose better model(s) to clinical practice. Adult hepatitis C patients with baseline advanced fibrosis (141 cases), compensated cirrhosis (330 cases) and decompensated cirrhosis (80 cases) were included and followed up every 6 months for about 7 years or until HCC development. Demographic data, medical history and laboratory results were recorded. HCCs were diagnosed by radiography, AFP or liver histology. The median follow-up period was 69.93(60.99–74.93) months, during which 53 (9.62%) patients developed HCC. The areas under the receiver operating characteristic curve of aMAP, THRI, PAGE-B and Models of HCV scores were 0.74, 0.72, 0.70 and 0.63 respectively. The predictive power of the aMAP model score was comparable to that of THRI, PAGE-Band higher than that of Models of HCV (p < 0.05). Dividing patients into non-high-risk and high-risk groups, the cumulative incidence rates of HCC based on aMAP, THRI, PAGE-B and Models of HCV was 5.57% vs. 24.17%, 1.10% vs. 13.90%, 5.80% vs. 15.90% and 6.41% vs. 13.81% (all p < 0.05). The AUC of the four models were all below 0.7 in male while all were higher than 0.7 in female. The performance of all the models was not influenced by fibrosis stage. aMAP, THRI model and PAGE-B model were all performed well while THRI model and PAGE-B model were easier to calculate. There was no need to select score according to fibrosis stage but should be caution when explain the results in male patients.     

Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders

Summary. This study was undertaken to investigate the effect of interferon (IFN) monotherapy on the risk of hepatocellular carcinoma (HCC) in aged‐patients with chronic hepatitis C. Seven hundred and twenty‐five patients with histologically proven chronic hepatitis C were enrolled in this retrospective cohort study; 531 received IFN monotherapy for 6 months between 1992 and 1995, and 157 were collected as a historical control. The effect of IFN therapy on the development of HCC was compared between the patients with chronic hepatitis C under 60 years old (non‐aged group, n = 531) and those 60 and over (aged group, n = 194). A stepwise Cox proportional‐hazards regression analysis in the non‐aged group revealed that IFN therapy (risk ratio 0.52, 95% CI 0.33–0.81, P = 0.004), older age (P = 0.001), and higher histological stage (P < 0.001) were independent factors associated with the development of HCC. In the aged‐group, only higher histological stage (P = 0.002) and male gender (P = 0.011), but not IFN therapy (risk ratio 0.77, 95% CI 0.42–1.40, P = 0.386), were identified as independent risk factors for HCC, although HCC was significantly reduced when sustained virological response (SVR) was obtained (risk ratio 0.23, 95% CI 0.08–0.64, P = 0.005). In conclusion, inhibitory effect of IFN on development of HCC in the patients with chronic hepatitis C aged 60 and over was limited to the patients achieving SVR when treated with 6 months‐IFN monotherapy.     

Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy

BACKGROUND AND AIM: Hepatitis C virus (HCV)-infected patients who responded to interferon (IFN) treatment with clearance of serum HCV RNA may rarely develop hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the risk factors for liver carcinogenesis among such patients. METHODS: In total, 126 patients with chronic hepatitis C (CHC) who achieved a sustained virological response (SVR) to IFN monotherapy, which was defined as the absence of detectable HCV RNA in the serum at 6 months after completion of treatment, were enrolled and possible risk factors for HCC were analyzed. RESULTS: During the observation period of 66 +/- 36 months after cessation of IFN treatment, five (4.0%) of the 126 patients developed HCC. The cumulative incidence of HCC at 3, 5 and 10 years was estimated to be 0.9, 4.7 and 7.5%, respectively. The cumulative incidence of HCC was significantly higher among patients with severe fibrosis (F3 or F4) than among patients with no or mild fibrosis (F0 to F2) in the liver before treatment (P = 0.007); among patients with alcohol intake of > or = 27 g/day than among patients with that of < 27 g/day (P = 0.015); and among patients who were > or = 65 years old than among patients who were < 65 years old at the start of treatment (P = 0.026). CONCLUSIONS: Patients with CHC who had severe fibrosis, who had regularly taken moderate amounts of alcohol, or who were > or = 65 years at the start of IFN treatment should be carefully followed to detect small and controllable HCC, even after eradication of HCV.     

Clinical features of hepatocellular carcinoma that occur after sustained virological response to interferon for chronic hepatitis C

Background and Aim: This study investigated the clinical features of hepatocellular carcinoma in patients with sustained virological response to interferon for hepatitis C viral (HCV) infection. Methods: A total of 7715 patients with HCV infection were treated with interferon and followed up for more than 1 year after withdrawal of interferon in 64 Japanese hospitals and clinics between July 1988 and August 2001. Sustained virological response was obtained in 2515 (32.6%) patients. Of these 2515 patients, clinical data were collected for 38 patients in whom hepatocellular carcinoma developed. Sustained virological response was defined as HCV RNA negativity more than 6 months after the termination of interferon. Results: All patients were HCV RNA negative at the time of diagnosis of hepatocellular carcinoma. The median period until the detection of hepatocellular carcinoma was 4.7 years (range 1.4–9.0 years). There were significant improvements in hepatic function including serum albumin, aspartate aminotransferase, alanine aminotransferase, indocyanine green test, platelet count and histological activity grade in comparison with those before interferon therapy and at the onset of hepatocellular carcinoma. The maximum tumor size in patients without medical follow‐up for 1 year or more (median: 60 mm) was significantly larger than in patients who were periodically followed up for 6 months or less (median: 25 mm) (P = 0.002). Conclusions: The present findings emphasize the importance of regular medical follow up of patients with HCV infection, as even patients showing a sustained virological response to interferon and in whom hepatic function has improved have the potential to develop hepatocellular carcinoma.     

Development of hepatocellular carcinoma in patients with chronic hepatitis C who had a sustained virological response to interferon therapy: a multicenter, retrospective cohort study of 1124 patients.

BACKGROUND: Interferon (IFN) improves hepatic inflammation/fibrosis and reduces the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CH-C). However, HCC develops in some patients who have a sustained virological response (SVR) to IFN therapy. We designed this study to establish a follow-up protocol for patients with CH-C who have SVR to IFN therapy. METHODS: We retrospectively studied 1124 patients with CH-C who received IFN. RESULTS: HCC developed in 3.5% of patients with SVR to IFN. As compared with SVR patients without HCC, SVR patients with HCC were predominantly male (P=0.003), older at the initiation of IFN therapy (P=0.002), and at a more advanced histologic stage of disease (P<0.001). However, three of the 13 SVR HCC patients had mild fibrosis. The mean interval from IFN therapy to the detection of HCC in SVR HCC patients was 5.8 years and did not differ significantly from that in non-SVR HCC patients (P=0.304). Although most patients with HCC received curative therapy, the prognosis of some SVR HCC patients was poor, probably because of insufficient follow-up, resulting in delayed detection of HCC. CONCLUSIONS: SVR patients with CH-C who are elderly, male, or have an advanced histologic stage are at a high risk for the development of HCC after IFN therapy. We recommend that SVR patients should be observed carefully for more than 10 years after the completion of IFN therapy, even if they only have early fibrosis.     

持续病毒学应答对HCV感染相关原发性肝癌发生的影响

HCV感染是世界范围内慢性肝病的主要原因之一,且HCV感染也是肝细胞癌发生的重要原因。以干扰素或聚乙二醇干扰素为基础的抗病毒治疗在过去20余年间使大量HCV感染患者达到了清除病毒的治疗目的,即持续病毒学应答。近年来随着直接抗病毒药的应用,患者中持续病毒学应答的比例得到了进一步提高,且因直接抗病毒药较低的不良反应率使得更多患者能够得到治疗。本文对慢性HCV感染者应用不同的抗病毒治疗方案获得持续病毒学应答后对原发性肝癌的发生率的影响进行综述。     

Hepatocellular carcinoma in long-term sustained virological responders following antiviral combination therapy for chronic hepatitis C

Summary.  Antiviral treatment results in a sustained virologic response (SVR) in 50–75% of patients with chronic hepatitis C. Long-term follow up studies have observed ongoing SVR in the overwhelming majority of them. Thus chronic hepatitis C is considered 'cured' if an SVR is achieved. Consequently, it is expected that in sustained virologic responders long-term complications of hepatatic C virus (HCV) related chronic liver disease including hepatocellular carcinoma are eliminated or have a decreased incidence. We report on five patients (three from Austria, two from USA) who developed hepatocellular carcinoma during follow up (3–6 years) after achieving SVR. During follow up and at diagnosis all were HCV-RNA neg. None of the patients had other liver diseases. One patient presented with bilateral adrenal metastasis, the remaining four with large hepatic tumours. Three patients were noncirrhotic at the start of treatment at the time of tumour diagnosis. Successful antiviral treatment in HCV patients does not prevent development of hepatocellular carcinoma even in non-cirrhotic livers. Long-term follow up of patients with SVR is mandatory and should include surveillance for hepatocellular carcinoma.     

Predictors of a sustained virological response in patients with genotype 4 chronic hepatitis C

Objectives: To determine the clinical, biological, virological and histological predictive factors associated with a sustained virological response (SVR) to combined interferon therapy among Egyptian patients infected by genotype 4 hepatitis C virus (HCV). Patients and Methods: Individual data from 250 patients with genotype 4 chronic hepatitis C, treated with different regimens of combined interferon, were analysed. The primary end point was SVR defined as undetectable HCV RNA by polymerase chain reaction (PCR) 24 weeks after the end of treatment. Multivariate logistic regression analysis was performed to select the independent prognostic parameters associated with SVR. Results: A sustained virological response was achieved among 137/250 (54.8%) patients. Baseline factors independently and negatively associated with SVR were serum α‐fetoprotein (AFP) level (above 0.3 upper limit of normal) [odds ratio (OR)=0.5, 95% confidence interval (CI): 0.2–0.8], severe fibrosis (Metavir score >F2) (OR=0.4, 95% CI: 0.2–0.8), presence of steatosis (OR=0.5, 95% CI: 0.3–0.97) and standard interferon treatment (OR=0.4, 95% CI: 0.2–0.8). Conclusions: Among genotype 4 chronic hepatitis C patients, severe fibrosis, severe steatosis, treatment with standard interferon and a high serum AFP level were all negatively associated with SVR. Pretreatment serum AFP level should be considered in the routine assessment of factors predictive of a treatment response.     

Estimating the likelihood of sustained virological response in chronic hepatitis C therapy

Summary. The likelihood of a sustained virological response (SVR) is the most important factor for physicians and patients in the decision to initiate and continue therapy for chronic hepatitis C (CHC) infection. This study identified predictive factors for SVR with peginterferon plus ribavirin (RBV) in patients with CHC treated under ‘real‐life’ conditions. The study cohort consisted of patients from a large, retrospective German multicentre, observational study who had been treated with peginterferon alfa‐2a plus RBV or peginterferon alfa‐2b plus RBV between the years 2000 and 2007. To ensure comparability regarding peginterferon therapies, patients were analysed in pairs matched by several baseline variables. Univariate and multivariate logistic regression analyses were used to determine the effect of nonmatched baseline variables and treatment modality on SVR. Among 2378 patients (1189 matched pairs), SVR rates were 57.9% overall, 46.5% in HCV genotype 1/4‐infected patients and 77.3% in genotype 2/3‐infected patients. In multivariate logistic regression analysis, positive predictors of SVR were HCV genotype 2 infection, HCV genotype 3 infection, low baseline viral load and treatment with peginterferon alfa‐2a. Negative predictors of SVR were higher age (≥40 years), elevated baseline gamma‐glutamyl transpeptidase (GGT) and low baseline platelet count (<150 000/μL). Among patients treated with peginterferon plus RBV in routine clinical practice, genotype, baseline viral load, age, GGT level and platelet levels all predict the likelihood of treatment success. In patients matched by baseline characteristics, treatment with peginterferon alfa‐2a may be a positive predictor of SVR when compared to peginterferon alfa‐2b.     

Adipocytokine involvement in hepatocellular carcinoma after sustained response to interferon for chronic hepatitis C

Aim: Interferon (IFN) dramatically reduces the risk of hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to chronic hepatitis C (CH‐C). However, HCC still develops in some patients after SVR. To evaluate metabolic factors in patients with HCC occurring after SVR and to determine whether insulin resistance and adipocytokines were involved in this etiology. Methods: We examined clinical and biochemical features, histological findings and serum levels of adipocytokine prior to IFN therapy and at the detection of HCC in nine patients who were diagnosed with HCC. As controls, 27 patients were included who showed SVR but had not been diagnosed with HCC for at least 5 years after SVR. Results: Three of four patients who developed HCC within 5 years after SVR showed liver cirrhosis when HCC was diagnosed. Prior to IFN therapy, four of nine HCC patients were diagnosed as having type 2 diabetes mellitus. Serum levels of leptin and insulin, Homeostatic Model of Assessment of Insulin Resistance and body mass index (BMI) were significantly higher and serum adiponectin was significantly lower in HCC patients at the time of HCC detection than in control patients more than 5 years after SVR. Six HCC patients had increased BMI and one HCC patient had a decreased BMI during the observation period. Conclusion: Hepatic fibrosis may be tightly related to the emergence of HCC after SVR. Insulin resistance and adipocytokine disorders may be implicated in hepatocarcinogenesis after SVR, in part by promoting hepatic fibrosis.     

The homeostasis model assessment of the insulin resistance score is not predictive of a sustained virological response in chronic hepatitis C patients

Objectives: To investigate the independent association between the homeostasis model assessment of the insulin resistance (HOMA‐IR) score and rapid virological response (RVR) and sustained virological response (SVR) in chronic hepatitis C (CHC). Methods: Observational prospective cohort study of 412 CHC patients [59% males; mean age 45 years; genotype 1 (44%), 2 (32%), 3 (19%) and 4 (5%)] treated with pegylated interferon α plus ribavirin. Results: A HOMA‐IR ≥2.0 was present in 49% and a metabolic syndrome in 4% of patients. By multivariate analysis, independent predictors of SVR were the lack of advanced fibrosis (≥F3) in genotype 1 and a lower body mass index in genotype 3 patients. In the subgroup of patients in whom HCV‐RNA was evaluated at week 4 (n=281), independent predictors of RVR were HCV‐RNA <700 000 IU/ml, age <40 years and lower aspartate aminotransferase:alanine aminotransferase ratio in genotype 1 and baseline HOMA‐IR ≤2 in genotype 3 patients. No predictive factor of RVR was identified among genotype 2 patients. RVR was the strongest predictor of SVR among genotype 1 or 3 patients. Conclusions: In this series of treatment‐naïve, Caucasian CHC patients at a low risk for the metabolic syndrome, HOMA‐IR is not a predictor of SVR, irrespective of the HCV genotype, although it may predict RVR in genotype 3 infection.     

Lipid profiling of pre-treatment liver biopsy tissue predicts sustained virological response in patients with chronic hepatitis C

Aim: Hepatic lipid is important in the pathogenesis and progression of hepatitis C‐related liver disease. Polyunsaturated fatty acids have been shown to reduce viral replication in cell culture. Proton magic angle spinning magnetic resonance spectroscopy (¹H MAS MRS) enables metabolic analysis of intact tissue. The aim was to examine the relationship between hepatic lipid composition by metabolic profiling of liver tissue at baseline and treatment response to pegylated‐Interferon alfa2 and Ribavirin. Methods: Baseline liver biopsy samples from 31 patients with chronic hepatitis C were analyzed histologically and by ¹H MAS MRS. Indices of lipid composition were derived and partial least squares discriminant analysis with cross‐validation was used to predict treatment outcome. Results: Of 31 patients, 14 achieved sustained virological response (SVR). Lipid polyunsaturation (median (IQR)) was higher in SVR (3.41% (2.31)) than in treatment failure (TF) (2.15% (1.51)), P = 0.02. Lipid saturation was lower in SVR (85.9% (3.39)) than TF (86.7% (2.17)), P = 0.04. The total lipid content was lower in SVR (1.54% (0.81)) than TF (2.72% (3.47)), P = 0.004. Total choline to lipid ratio was higher in SVR (11.51% (9.99)) than TF (7.5% (6.82)), P = 0.007. Cross‐validation correctly predicted the SVR group in 13 of 14 samples with 1 sample misclassified, and the TF group in all 17 samples. Conclusions: Lipid polyunsaturation was greater and total lipid lower in those with SVR, compared with TF. Metabolic profiling of intact liver biopsy samples predicted SVR with high accuracy. Hepatic lipid composition may impact on treatment success.     

Differences in molecular alterations of hepatocellular carcinoma between patients with a sustained virological response and those with hepatitis C virus infection

Background/Aims: The mechanism of hepatocarcinogenesis remains unclear in patients in whom hepatitis C virus (HCV) disappears after interferon (IFN) therapy. We compared molecular alterations in hepatocellular carcinoma (HCC) between patients with a sustained virological response (SVR) to IFN and patients with HCV. Methods: The study group comprised 44 patients with HCV and 13 patients with SVR. One patient in the SVR group had two tumour nodules, both of which were examined. Mitochondrial DNA (mtDNA) mutations in displacement‐loop lesions were directly sequenced. Mutation of the TP53 gene was examined by direct sequencing. The methylation status of p16, p15, p14, RB and PTEN genes was evaluated by a methylation‐specific polymerase chain reaction. Results: The average number of mtDNA mutations was 4.2 in 44 HCCs with HCV and 2.0 in 14 HCCs with SVR (P=0.0021). mtDNA mutation was less frequently detected in HCCs from patients with SVR than in patients with HCV. TP53 mutations were detected in 12 (27%) of 44 HCCs with HCV and 2 (14%) of 14 SVR‐HCCs. Hypermethylation of the p16, p15, p14, RB and PTEN promoters was, respectively, detected in 34, 13, 8, 12 and 11 of 44 HCCs from patients with HCV and 14, 0, 0, 2 and 2 of 14 HCCs from patients with SVR (P=0.049, 0.021, 0.085, 0.322 and 0.402). Hypermethylation of p16 was one of the most important alterations in SVR‐HCC. Conclusions: Molecular alterations in hepatocarcinogenesis of patients with SVR‐HCC were different from those of patients with continuous HCV infection.     

Community‐based real‐world treatment outcomes of sofosbuvir/ledipasvir in Asians with chronic hepatitis C virus genotype 6 in the United States

Sofosbuvir/ledipasvir (SOF/LDV) is the first all‐oral ribavirin‐free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real‐world outcomes of this regimen are lacking. We aim to evaluate real‐world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community‐based real‐world cohort of Asian chronic HCV genotype 6 patients treated with all‐oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.