丙肝病毒防治指南

Special Report Guidelines for the Management of Hepatitis C Virus Infection First edition, May 2012, The Japan Society of Hepatology Editors of the Drafting Committee for Hepatitis Management Guidelines: The Japan Society of Hepatology*,** 1. INTRODUCTION THE JAPAN SOCIETY of Hepatology (JSH) has, untilnow, 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 offi- cial 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 hepa- titis 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 accumu- lation of new evidence, accompanied by changes in the level of evidence, so we have elected not to show evi- dence levels. We plan to revise these guidelines at appro- priate 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 2. GENERAL STRATEGY AGAINTS HEPATITIS C VIRUS INFECTION FOLLOWING THE IDENTIFICATION of the hepati-tis C virus (HCV) by Choo et al. in the USA in 1989,1 it became clear that over 90% of patients previ- ously 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 *Drafting Committee for Hepatitis Management Guidelines (in alphabetical order): Yasuhiro Asahina, Department of Gastroenterology and Hepatology, Department for Hepatitis Control, Tokyo Medical and Dental University; Norio Hayashi, Kansai Rosai Hospital; Naoki Hiramatsu, Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine; Namiki Izumi, Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital; ‡Kazuhiko Koike, Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Hiromitsu Kumada, Department of Hepatology, Toranomon Hospital; Makoto Oketani, Digestive and Life-style Diseases, Kagoshima University Graduate School of Medical and Dental Sciences; Fumitaka Suzuki, Department of Hepatology, Toranomon Hospital; †Hajime Takikawa, Department of Medicine, Teikyo University School of Medicine; Atsushi Tanaka, Department of Medicine, Teikyo University School of Medicine; Hirohito Tsubouchi, Digestive and Life-style Diseases, Kagoshima University Graduate School of Medical and Dental Sciences; Hiroshi Yotsuyanagi, Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo (†Chairman, ‡Special Committee Member). ** Correspondence: Atsushi Tanaka, Department of Medicine, Teikyo University School of Medicine 2-11-1, Kaga, Itabashi-ku, Tokyo, Japan. Email: a-tanaka@med.teikyo-u.ac.jp bs_bs_banner Hepatology Research 2013; 43: 1–34 doi: 10.1111/hepr.12020 © 2013 The Japan Society of Hepatology 1 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 hepato- cellular carcinoma (HCC).2 Interferon (IFN) therapy commenced in 1986, when Hoofnagle et al. adminis- tered human recombinant IFN-a 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 effi- cacy 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-a-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 pro- tease 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 genera- tion 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 appropriate- ness of the presently available antiviral therapies for each individual patient. Indications for antiviral therapy for HCV infection In general, in patients with chronic hepatitis C, liver disease progresses gradually in association with eleva- tion 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/mL), reflecting the degree of liver fibrosis. The indication for antiviral therapy should be individualized for patients with ALT 230 IU/L and a platelet count 3150 000/mL, 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 indepen- dent risk factors for hepatocellular carcinogenesis: (i) advanced age; (ii) advanced fibrosis; and (iii) male sex.5–7 Accordingly, the risk of developing cancer is par- ticularly high in patients with multiple risk factors, and early introduction of antiviral therapy should be consid- ered in this group. Basic guidelines for treatment of chronic hepatitis C 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. Analy- ses 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 366 years old, based on Japanese clinical trials of telaprevir conducted with subjects aged 265 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 3F2, or plate- let count of <150 000/mL, it should be kept in mind that the risk of cancer is particularly high in the 2 Guidelines for chronic hepatitis C Hepatology Research 2013; 43: 1–34 © 2013 The Japan Society of Hepatology patient group with a METAVIR score 3F3, or platelet count of <120 000/mL. For the group at high risk of developing HCC (elderly and advanced fibrosis), antiviral therapy should be com- menced 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 reac- tions 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 antici- pated 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 (330 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 addi- tion of, or changeover to, therapeutic phlebotomy should be considered. The aim of these therapies is to keep the ALT level 230 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 240 IU/L) or the a-fetoprotein (AFP) level (to 210 ng/mL).18,19 Recommendations: 1 In general, antiviral therapy is indicated in all chronic hepatitis C patients with elevated ALT levels (>30 IU/L) or a decreased platelet count (<150 000/mL). 2 The indication for antiviral therapy should be individu- alized for patients with ALT levels 230 IU/L and a platelet count 3150 000/mL, considering the risk of developing HCC is low. 3 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. 4 Following commencement of antiviral therapy in patients either elderly or with advanced fibrosis, in order to avoid adverse reactions and the development of drug-resistant mutations, the treatment discontinua- tion criteria, used for the early detection of non- responders, should be kept in mind during antiviral therapy. 5 In the low-risk group (non-elderly, non-advanced fibro- sis), the present indication for antiviral therapy should be decided after consideration of anticipated therapeu- tic effect, adverse reactions and the risk of HCC. 6 If viral eradication is not achieved, long-term low-dose Peg-IFN or supportive therapy (SNMC or UDCA) should be administered with the aim of preventing progression of liver disease and preventing hepatocellu- lar carcinogenesis. 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. 7 Low-dose Peg-IFN therapy should be discontinued if no improvement is seen within 6 months in the ALT level (to 240 IU/L) or the AFP level (to 210 ng/mL). 3. INTERFERON THERAPY 3.1 Interferon THE a- AND b-types of IFN have been approved foruse in the treatment of chronic hepatitis C. IFN-a 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-a and recombinant IFN-a-2b, and the latter as Peg-IFN-a-2a and Peg-IFN-a-2b. IFN-b preparations comprise natural non-pegylated-IFN-b. IFN-a Standard non-pegylated-IFN-a 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-a 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 Hepatology Research 2013; 43: 1–34 Guidelines for chronic hepatitis C 3 © 2013 The Japan Society of Hepatology Peg-IFN-a PEG is a water-soluble neutral molecule with no toxicity of itself. The number of ethylene oxide subunits deter- mines 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 rec- ognition and elimination by the host immune defenses. Peg-IFN-a used in the treatment of chronic hepatitis C comes in the form of Peg-IFN-a-2a, with a 40-kD PEG branch chain covalently attached to IFN-a-2a, and Peg- IFN-a-2b, with a 12-kD PEG branch chain attached via a urethane bond to IFN-a-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-a-2a is 7% that of non-pegylated-IFN-a-2a, whereas the IFN activity of Peg-IFN-a-2b is 28% that of non-pegylated- IFN-a-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-a-2a is approved as monotherapy and in combination with ribavirin for national medical insurance coverage, whereas Peg-IFN-a-2b is approved in combination with ribavirin with or without telaprevir. The two forms of Peg-IFN-a have different standard doses. The standard dosage regimen for Peg-IFN-a-2a is fixed at 180 mg/week, and the dose of Peg-IFN-a-2b varies according to the patient’s weight, the standard dosage regimen being 1.5 mg/kg per week. IFN-b Interferon-b 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 cov- erage. It is administered at least three times per week as an i.v. injection or i.v. infusion. Although IFN-b binds to the same type I IFN receptor as IFN-a, and has a similar antiviral effect to IFN-a, their adverse reaction profiles differ. A retrospective study of natural human IFN- b + 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-a therapy due to depression tolerated IFN-b + ribavirin combination therapy well in terms of depressive symptoms and other adverse reactions.26–28 IFN therapy with natural human IFN-b is therefore recommended in patients in whom IFN-a therapy is not tolerated, for example, those with a history of depression. Anti-IFN-a neutralizing antibodies were detected in 15% of non-responders to Peg-IFN-a + ribavirin therapy in one study.29 Anti-IFN-a neutralizing antibodies do not block IFN-b activity, so a changeover to natural human IFN-b should be considered in cases of non- response to Peg-IFN-a + ribavirin due to these neutral- izing antibodies. Natural human IFN-b 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-b induction prior to Peg-IFN-a + ribavirin therapy has been trialed.31 Antiviral effects of IFN32–34 IFN acts through binding to type I IFN receptors on the target cell membrane. Type I IFN receptors are common to IFN-a and IFN-b, and binding of either IFN type to the receptor causes activation of the tyrosine-protein kinase, Janus kinase 1 (JAK1). This induces phosphory- lation of tyrosine residues in the intracellular domain of the receptor, resulting in phosphorylation and forma- tion of dimer complexes of signal transducer and acti- vator 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 immuno- regulatory genes, and the antiviral effects of IFN are thought to derive from proteins induced by ISG. Adverse reactions 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 4 Guidelines for chronic hepatitis C Hepatology Research 2013; 43: 1–34 © 2013 The Japan Society of Hepatology common in those with pre-existent neuropsychiatric symptoms or a history of depression.36 Neuropsychiatric symptoms are classified into depression-specific symp- toms and depression-related autonomic nervous symp- toms, 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 fol- lowing the onset of