Guidelines for the Management of Hepatitis C Virus Infection

THE JAPAN SOCIETY of Hepatology (JSH) has, until now, produced “A Management Guide for Chronic Hepatitis and Liver Cirrhosis”, “A Management Guide for NASH and NAFLD”, and “A Treatment Manual for Hepatocellular Carcinoma”. The only official guidelines produced by the Society have been the “Clinical Practice Guidelines for Hepatocellular Carcinoma Based on Scientific Evidence”, however, and we had not yet developed guidelines for hepatitis. As a scientific body that promotes hepatology research, we considered it necessary to publish our official position on the diagnosis and treatment of hepatitis. The regular JSH board meeting on 19 October 2011 approved the establishment of the Drafting Committee for Hepatitis Management Guidelines. The Committee decided that our first priority was the production of guidelines for the management of hepatitis C, most urgently needed by Society members, so we began with the production of these “Guidelines for the Management of Hepatitis C Virus Infection (First Edition)”. We hope and anticipate that these guidelines will be used throughout Japan in the management of hepatitis C. This is a field that changes rapidly with the accumulation of new evidence, accompanied by changes in the level of evidence, so we have elected not to show evidence levels. We plan to revise these guidelines at appropriate intervals, as new evidence comes to hand. Reproduction of these guidelines is forbidden without authorization. May 2012 Kazuhiko Koike Director General, The Japan Society of Hepatology Hajime Takikawa Chairman, Drafting Committee for Hepatitis Management Guidelines FOLLOWING THE IDENTIFICATION of the hepatitis C virus (HCV) by Choo et al. in the USA in 1989,1 it became clear that over 90% of patients previously diagnosed with non-A non-B hepatitis, and over 50% of those diagnosed with alcoholic hepatitis, in fact suffered from liver disease caused by HCV. Currently, there are an estimated 170 million carriers worldwide, and 1.5–2 million in Japan. Even in healthy adults, once an HCV infection occurs, only approximately 30% resolve completely in the acute phase. HCV infection is prolonged in approximately 70% of cases, causing chronic hepatitis. Once an HCV infection has become chronic, spontaneous elimination of the virus is rare (0.2% annual rate), and persistent inflammation can induce fibrosis, progressing to cirrhosis or hepatocellular carcinoma (HCC).2 Interferon (IFN) therapy commenced in 1986, when Hoofnagle et al. administered human recombinant IFN-α to patients with non-A non-B hepatitis, confirming normalization of transaminase levels.3 IFN therapy has been used in the general clinical setting in Western countries since 1991, and in Japan since 1992. Since that time, with the development of the polymerase chain reaction (PCR) method, a revolutionary new technology for viral detection, quiescence of hepatitis has been confirmed in patients in whom HCV RNA was eradicated by IFN therapy;4 furthermore, inhibition of progression of liver disease and hepatocellular carcinogenesis has been demonstrated in these patients.5-8 The aim of treatment of chronic hepatitis C is to improve the long-term prognosis of chronic liver disease (CLD) associated with persistent HCV infection; in other words, to prevent mortality associated with HCC and CLD. Sustained virological response (SVR) rates have improved with the standard therapy combining pegylated interferon (Peg-IFN) and ribavirin. SVR rates are no better than 40–50% in patients with genotype 1 infection who have high viral loads, however, so HCV cannot be eliminated in around half of these patients. In recent years, a number of new antiviral agents have been developed with the aims of increased therapeutic efficacy and decreased adverse reactions. In November 2011, the first generation protease inhibitor telaprevir became available for clinical use in patients with HCV genotype 1 infection and high viral loads. Triple therapy with telaprevir, Peg-IFN-α-2b and ribavirin has shown an increased antiviral effect, improving initial SVR rates to around 70% in treatment-naive cases, but adverse reactions are also increased, including severe anemia and serious skin rashes.9-13 In Japan, trials are underway with triple therapy comprising a second generation protease inhibitor (TMC435,14 MK700915 or BI-201335), Peg-IFN and ribavirin, as well as IFN-free oral antiviral therapy comprising a protease inhibitor and an NS5A inhibitor.16 Much is anticipated from the next generation direct antiviral agents (DAA), reported to have considerably fewer adverse reactions, and even greater antiviral effects, with SVR rates exceeding 80% in treatment-naive cases. Therapeutic guidelines for chronic hepatitis C should be formulated with the above-mentioned background in mind, with careful consideration of the appropriateness of the presently available antiviral therapies for each individual patient. In general, in patients with chronic hepatitis C, liver disease progresses gradually in association with elevation of alanine aminotransferase (ALT) levels, and the risk of developing cancer increases with the progression of fibrosis.8 Conversely, cancers are rarely seen arising from a normal liver with no inflammation or fibrosis. Accordingly, in general, antiviral therapy is indicated in all chronic hepatitis C patients with elevated ALT levels (ALT >30 IU/L), indicating hepatic inflammation, or a decreased platelet count (platelet count <150 000/μL), reflecting the degree of liver fibrosis. The indication for antiviral therapy should be individualized for patients with ALT ≤30 IU/L and a platelet count ≥150 000/μL, considering the risk of developing HCC is low. Early viral eradication is required in the group at high risk of developing cancer. In patients with HCV infection, three factors have been identified as independent risk factors for hepatocellular carcinogenesis: (i) advanced age; (ii) advanced fibrosis; and (iii) male sex.5-7 Accordingly, the risk of developing cancer is particularly high in patients with multiple risk factors, and early introduction of antiviral therapy should be considered in this group. In developing these guidelines, we formulated separate treatment plans according to the risk of developing cancer in different subgroups of patients with chronic hepatitis C, for elderly and non-elderly patients, and those with advanced fibrosis and mild fibrosis. Analyses of hepatocellular carcinogenesis in older patients with chronic hepatitis C show that the risk of cancer increases with increasing age, although the definition of “older age” varies, considered by some to be greater than 55, 60 or 65 years. In these guidelines, we have defined “elderly” as ≥66 years old, based on Japanese clinical trials of telaprevir conducted with subjects aged ≤65 years,11 and the increased risk of HCC over the age of 65 years.17 Furthermore, although we have defined “advanced fibrosis” as a METAVIR score ≥F2, or platelet count of <150 000/μL, it should be kept in mind that the risk of cancer is particularly high in the patient group with a METAVIR score ≥F3, or platelet count of <120 000/μL. For the group at high risk of developing HCC (elderly and advanced fibrosis), antiviral therapy should be commenced as soon as possible with due consideration to tolerability. Early commencement of antiviral therapy is also desirable in the medium-risk group (elderly or advanced fibrosis). However, some in the particularly high-risk group, elderly and/or with advanced fibrosis, are non-responders, so in order to avoid adverse reactions and the development of drug-resistant mutations, the treatment discontinuation criteria should be kept in mind during antiviral therapy. On the other hand, in the low-risk group comprising non-elderly patients without advanced fibrosis, early introduction of antiviral therapy is not always necessary. In some patients, it may be possible to await the introduction of the new generation antiviral agents, so the present indication for antiviral therapy should be decided after consideration of anticipated therapeutic effect, adverse reactions and the risk of HCC. In any patient group, in case it is difficult with any presently available antiviral regimens to ensure viral eradication, and ALT levels are elevated (≥30 IU/L), patients should be administered long-term low-dose Peg-IFN or supportive therapy, for example, stronger neo-minophagen C (SNMC), ursodeoxycholic acid (UDCA). If an adequate therapeutic effect is not achieved, and iron overload is suspected, then the addition of, or changeover to, therapeutic phlebotomy should be considered. The aim of these therapies is to keep the ALT level ≤30 IU/L, maintaining it as low as possible. Strict control of the ALT level is particularly necessary in the group at high risk of developing HCC. Low-dose Peg-IFN therapy should be discontinued if no improvement is seen within 6 months in the ALT level (to ≤40 IU/L) or the α-fetoprotein (AFP) level (to ≤10 ng/mL).18, 19 THE α- AND β-types of IFN have been approved for use in the treatment of chronic hepatitis C. IFN-α preparations come in non-pegylated and pegylated forms, depending on whether polyethylene glycol (PEG) has been attached. The former comes in the form of natural human IFN-α and recombinant IFN-α-2b, and the latter as Peg-IFN-α-2a and Peg-IFN-α-2b. IFN-β preparations comprise natural non-pegylated-IFN-β. Standard non-pegylated-IFN-α is unstable, with a plasma half-life of 3–8 h, and becomes undetectable after 24 h.20 Administration at least three times per week is therefore required when treating chronic hepatitis C. Adverse reactions, including fever, chills and headache, are common with non-pegylated-IFN due to repeated rises and falls in the plasma levels. Of the non-pegylated IFNs, natural human IFN-α is approved for self-injection, and patients only need to attend hospital once every 2 weeks. Furthermore, patients can self-inject at night before retiring, better taking advantage of diurnal variations in plasma cortisol levels, and minimizing fever and other adverse reactions.21-23 PEG is a water-soluble neutral molecule with no toxicity of itself. The number of ethylene oxide subunits determines the molecular weight. The aims of pegylating IFN are twofold: (i) to alter its in vivo pharmacodynamic properties; and (ii) protect the IFN molecule from recognition and elimination by the host immune defenses. Peg-IFN-α used in the treatment of chronic hepatitis C comes in the form of Peg-IFN-α-2a, with a 40-kD PEG branch chain covalently attached to IFN-α-2a, and Peg-IFN-α-2b, with a 12-kD PEG branch chain attached via a urethane bond to IFN-α-2b. They reach a maximum concentration (Cmax) at 72–96 and 15–44 h after administration, respectively, and after a single dose maintain plasma levels within the therapeutic range for approximately 168 and 80 h, respectively.24 As the molecular weight of PEG attached to IFN in this way increases, the intracorporeal retention time also increases, although the pharmacological effect decreases in inverse proportion. The IFN activity of Peg-IFN-α-2a is 7% that of non-pegylated-IFN-α-2a, whereas the IFN activity of Peg-IFN-α-2b is 28% that of non-pegylated-IFN-α-2b, with the latter more active. Accordingly, the actual antiviral effect is determined in a complex fashion by the balance between intracorporeal retention time and IFN activity, as well as the patient's body type and weight. Peg-IFN-α-2a is approved as monotherapy and in combination with ribavirin for national medical insurance coverage, whereas Peg-IFN-α-2b is approved in combination with ribavirin with or without telaprevir. The two forms of Peg-IFN-α have different standard doses. The standard dosage regimen for Peg-IFN-α-2a is fixed at 180 μg/week, and the dose of Peg-IFN-α-2b varies according to the patient's weight, the standard dosage regimen being 1.5 μg/kg per week. Interferon-β is a natural IFN that can be used in a non-pegylated form, and is approved as monotherapy and in combination with ribavirin for medical insurance coverage. It is administered at least three times per week as an i.v. injection or i.v. infusion. Although IFN-β binds to the same type I IFN receptor as IFN-α, and has a similar antiviral effect to IFN-α, their adverse reaction profiles differ. A retrospective study of natural human IFN-β + ribavirin combination therapy in the treatment of 40 cases with genotype 1b HCV infections reported fewer discontinuations due to adverse reactions, and only mild decreases in platelet counts.25 Even patients with a history of discontinuing IFN-α therapy due to depression tolerated IFN-β + ribavirin combination therapy well in terms of depressive symptoms and other adverse reactions.26-28 IFN therapy with natural human IFN-β is therefore recommended in patients in whom IFN-α therapy is not tolerated, for example, those with a history of depression. Anti-IFN-α neutralizing antibodies were detected in 15% of non-responders to Peg-IFN-α + ribavirin therapy in one study.29 Anti-IFN-α neutralizing antibodies do not block IFN-β activity, so a changeover to natural human IFN-β should be considered in cases of non-response to Peg-IFN-α + ribavirin due to these neutralizing antibodies. Natural human IFN-β can be administered twice daily in divided doses, providing a more potent antiviral effect than once daily dosing as measured by the HCV dynamics.30 Divided dosing IFN-β induction prior to Peg-IFN-α + ribavirin therapy has been trialed.31 IFN acts through binding to type I IFN receptors on the target cell membrane. Type I IFN receptors are common to IFN-α and IFN-β, and binding of either IFN type to the receptor causes activation of the tyrosine-protein kinase, Janus kinase 1 (JAK1). This induces phosphorylation of tyrosine residues in the intracellular domain of the receptor, resulting in phosphorylation and formation of dimer complexes of signal transducer and activator of transcription 1 (STAT1), which transmit signal to the cell nucleus. This in turn induces and upregulates expression of IFN-stimulated genes (ISG). The family of ISG includes a wide variety of antiviral and immunoregulatory genes, and the antiviral effects of IFN are thought to derive from proteins induced by ISG. Adverse reactions to IFN therapy are experienced by almost all patients. The most common are influenza-like symptoms, such as general malaise, fever, headache and aching joints, and are reported by 60–95% of patients. Most influenza-like syndrome can be controlled with anti-inflammatory analgesic medication. Blood tests show leukopenia, with white blood cell counts <1000/mm3 seen in approximately 60% of patients. Serious infections associated with neutropenia are, however, considered rare.35 White blood cell, neutrophil and platelet counts tend to decrease for the first 4 weeks of IFN therapy, then often remain stable without further decline. Neuropsychiatric symptoms such as depression and insomnia occur in 5–10% of patients, and are more common in those with pre-existent neuropsychiatric symptoms or a history of depression.36 Neuropsychiatric symptoms are classified into depression-specific symptoms and depression-related autonomic nervous symptoms, with selective serotonin re-uptake inhibitors (SSRI) reported to be useful in treating the former.37-39 IFN can also trigger or aggravate autoimmune diseases such as chronic thyroiditis, so the utmost caution is required when administrating IFN to patients with autoimmune diseases. Interstitial pneumonia, another reported adverse reaction to IFN therapy, can be serious and even life-threatening. It usually occurs after 2 months of therapy, or in the later stages of treatment. A rapid and appropriate management is required following the onset of respiratory symptoms such as a dry cough or dyspnea, including an immediate chest CT scan. Determination of serum KL-6 levels is also useful in the diagnosis of interstitial pneumonia. Other reported adverse reactions to IFN therapy include cardiomyopathy and fundal hemorrhage. The adverse reaction profile of Peg-IFN differs somewhat to that of non-pegylated-IFN. In a Japanese clinical trial of Peg-IFN-α-2a monotherapy, the adverse reactions with a higher reported frequency than non-pegylated-IFN-α-2a were skin reactions such as erythema at the injection site and hematological reactions such as decreases in the white blood cell counts or platelet counts. On the other hand, mild to moderate adverse reactions such as influenza-like syndrome, including fever and joint pains, or malaise and loss of appetite, were milder than with standard non-pegylated-IFN-α-2a.40 In Japan at present, two Peg-IFN formulations are available for use in Peg-IFN + ribavirin therapy, Peg-IFN-α-2a and Peg-IFN-α-2b. McHutchison et al. conducted a large multi-center study comparing the efficacy of these two agents. In this randomized controlled trail (RCT) conducted at 118 institutions, with 3070 patients with IFN-naive genotype 1 HCV infection, the SVR rate in the Peg-IFN-α-2a 180-μg group was 40.9% and that in the Peg-IFN-α-2b group 39.8%, with no difference seen between groups, and no significant difference was seen between groups in terms of tolerability.41 On the other hand, two Italian single-center studies with 441 and 320 patients with IFN-naive genotype 1–4 HCV infection, respectively, found no significant difference between groups in the incidence of adverse events, but reported significantly higher SVR rates in the Peg-IFN-α-2a group than in the Peg-IFN-α-2b group.42, 43 A recent systematic review examining 12 RCT of the efficacy and safety of these two agents found no difference between them in terms of adverse events causing discontinuation. The overall SVR rates based on 8 RCT were 47% for the Peg-IFN-α-2a group and 41% for the Peg-IFN-α-2b group, significantly higher in the former (risk ratio, 1.11; 95% confidence interval [CI], 1.04–1.19; P = 0.004).44 However, a conclusion has not been reached to recommend either agent, due to heterogeneity of the patient populations in HCV genotype, race and Peg-IFN-α-2b dosage in the different RCT, as well as problems with the quality of the RCT in terms of subject numbers and and only adverse In Japan, studies have been conducted comparing agents, but the have yet to be Accordingly, at present, Peg-IFN-α-2a and Peg-IFN-α-2b are considered similar from the of efficacy and adverse reactions, and there is no evidence a of either in clinical improve therapeutic efficacy more will be of the dosage and of treatment with other agents, such ribavirin, for each individual as well as of a treatment plan with consideration of factors that therapeutic efficacy for each and control of adverse reactions. have from Japan inhibition of hepatocellular carcinogenesis by IFN therapy. et a retrospective of hepatocellular carcinogenesis rates in patients with chronic hepatitis C who IFN monotherapy as initial for therapeutic The hepatocellular carcinogenesis rate was in the group = in the IFN group, with no SVR and ALT levels = and in the SVR group = significantly in the Even in the response group, with no SVR but normalization of ALT levels = the hepatocellular carcinogenesis rate was indicating of et and et have reported similar with IFN therapy hepatocellular carcinogenesis in the ALT group. Furthermore, et conducted a retrospective study with patients, that IFN therapy and SVR the risk of developing including patients in whom ALT levels improved to within two times the of They further reported that the rate of progression of hepatic fibrosis was in IFN indicating of hepatic fibrosis associated with viral and even in patients who to to the rate of progression of indicated inhibition of progression of hepatic fibrosis.8 et al. also reported effect on development of HCC on the degree of progression of hepatic fibrosis, and of fibrosis with IFN et al. conducted a study with patients with HCV eradication or prolonged normalization of ALT levels by IFN therapy significantly the risk of HCC and liver et al. conducted the Hepatitis C Treatment a randomized controlled study of whether low-dose Peg-IFN-α therapy can the rate of liver events, including in non-responders to Peg-IFN-α + ribavirin therapy. They a of patients with fibrosis or cirrhosis who had not had an SVR to therapy with Peg-IFN-α + ribavirin therapy, and them to a group administered Peg-IFN-α-2a for years or an control group. They during the of including the development of development of hepatic and of fibrosis. years of in groups, patients reached one of the of the treatment group and of the control group, with no significant difference seen between groups 95% They also the risk of hepatocellular carcinogenesis in this with patients developing HCC during the The HCC rate was in the treatment group and in the control group, with no significant difference seen between groups = The conclusion was at this low-dose Peg-IFN-α-2a therapy not the rate of liver events, including in non-responders to Peg-IFN-α + ribavirin therapy. were in a study However, et al. the of an of the the the to a years reported HCC in patients patients with and without the HCC rate was in the treatment group and in the control group, with no significant difference seen between groups 95% P = no clear inhibition of hepatocellular carcinogenesis by IFN therapy. If we the to patients with however, the HCC rate was in the treatment group and in the control group, a significant in the risk of HCC with low-dose Peg-IFN-α-2a therapy 95% P = However, this effect was not significant in patients without as the HCC rate was in the treatment group and in the control group, to be higher in the group administered Peg-IFN-α 95% P = of hepatocellular carcinogenesis by low-dose Peg-IFN-α-2a monotherapy was also in Japan in a The subjects were patients administered Peg-IFN-α-2a monotherapy and a control group comprising patients for age, degree of fibrosis, platelet counts and serum levels. They reported a significantly HCC rate in the Peg-IFN-α-2a monotherapy group = with a risk of The in risk of HCC was particularly in patients with advanced fibrosis P = Even in patients who to HCV the HCC rate was significantly in those who either an ALT level IU/L or at treatment week in ALT and levels with Peg-IFN-α-2a monotherapy has been reported in other Japanese We can that with of the the of the trial that low-dose Peg-IFN-α therapy the risk of HCC in patients with The effect was on of the in patients without however, and the that in the risk of HCC not until after at least 4 years of low-dose Peg-IFN-α therapy. On the other hand, the above-mentioned Japanese studies confirmed that IFN therapy significantly the incidence of HCC in patients with normalization of ALT levels, even if SVR was not In the above-mentioned trial of Peg-IFN-α-2a monotherapy, a significant in the HCC was even when patients without cirrhosis were and with In this the of the trial do not with Japanese for this may include the fact that the age of the was years, than the age of Japanese patients with chronic hepatitis C, and the low overall incidence of HCC. et al. reported that in Japanese patients with chronic hepatitis C, even with the same degree of fibrosis the risk of HCC is considerably higher in older patients, whereas in patients with there is no significant difference in the risk of HCC associated with We cannot therefore the that between Japan and the USA in the of patients with chronic hepatitis C and the risk of HCC the of the trial for patients without Furthermore, there were a number of and liver events in the the of which were significantly different between patients on low-dose Peg-IFN therapy and control groups patients without and liver events to in of the risk of HCC. the a degree of caution is needed in the of the As Japanese patients with chronic hepatitis C are older than their Western and the risk of developing HCC is higher in elderly patients, even after for other risk Although the risk of HCC is significantly with even in elderly patients, in with patients are more to to and to treatment due to adverse these of therapeutic efficacy and adverse reactions in mind, in Japan, long-term IFN monotherapy is used in elderly patients, the aim of treatment being inhibition of hepatocellular carcinogenesis by inflammation than viral et the in hepatocellular carcinogenesis by IFN therapy in a study with subjects aged years with either chronic hepatitis C or liver They were with natural IFN-α three times for an of years, and with an and control group not administered IFN comprising As a the HCC rate was in the IFN group and in the control group, with an of levels decreased significantly in the IFN group than in the control group, and the incidence of HCC was particularly low in patients with levels et al. also conducted a study with patients with genotype 1 HCV infection aged years. They were with natural IFN three times for years, and with a control group not administered for age, and hepatic comprising They reported a significantly rate of HCC in the IFN only is IFN administered with the aim of hepatocellular carcinogenesis in patients with chronic hepatitis C and cirrhosis who have not yet developed it is also to patients who have or of HCC with the aims of and improving et patients who had of HCC to a group administered IFN for weeks and an control group, comparing rates and They reported no significant difference between groups in the rate of first however, the rates of second and were significantly in the IFN group, as were indicated the of IFN therapy following et and et administered low-dose long-term or therapy to patients with HCC who had with an control group for age and platelet count a significant in after the first and a significant improvement in the for being study of IFN + ribavirin therapy following hepatic or