A Special Report on Hepatology in Asia Akira Hayasaka A Special Report on Hepatology in Asia -Standardized treatment of hepatitis B and C according to the annually revised guidelines in Japan-Akira Hayasaka, MDThe President of Hayasaka ClinicCorrespondence address:4-6-17 Hatazawaminami,Kisarazu, Chiba,JAPAN #email@example.comAbstractHepatitis B and C virus infections cause chronic inflammation in the liver,chronic hepatitis. These inflammatory diseases damage the liver and resultin cirrhosis, chronic liver failure and hepatocellular carcinoma. As anexample of “hepatology in Asia”, the excerpts are reported on theguidelines for the treatment of chronic hepatitis B and C in Japan. One ofthe characteristic features of the criteria for the treatment eligibility inJapan to patients with chronic hepatitis B is slightly elevated serumaminotransferase level (higher than 31 IU/L) than in the guidelines of thedifferent areas. Long-term interferon and the sequential treatment(entecavir followed by interferon) are recommended for patients youngerthan 35 years old to gain a “drug-free status”. Entecavir is also used as thesecond choice, but for patients 35 years or older, entecavir is the firstchoice for the treatment. Long-term interferon and the sequential treatmentare the second choice. The combination of peginterferon and ribavirin isrecommended for the treatment of patients with hepatitis C with a highviral load. Interferon monotherapy (either standard interferon orpeginterferon) is indicated for the patients with a low viral load. Antiviraltreatment is also recommended for hepatitis C virus carriers with normalserum aminotransferase if they have the fibrotic liver based on plateletcounts. This article will further discuss treatments specific within theJapanese medical practice for hepatitis B and C.Keyword: Hepatitis B, hepatitis C, guideline, interferon, ribavirin, entecavir, adefovir, lamivudine,Japan Article word count (excluding references): 2350Disclosure: The author has no conflicts of interest to declare 1
A Special Report on Hepatology in Asia Akira HayasakaIntroduction“Hepatology in Asia” is an interesting title given to me for a new section of“Special Reports” in US Gastroenterology and Hepatology Review,particularly to readers of the western hemisphere. Asia is the largest, mostpopulous and arguably the most diverse continent. “Hepatology” in thisarea has been studied by a large number of basic and clinical researchers ineach country throughout Asia. Recently, a scan of hepatology research inAsia pacific regions is presented by the Asian Pacific Association of theStudy of Liver Diseases (1). Based on the title and the contents of the abstracts from various countries,the control of viral hepatitis, especially hepatitis B (CHB) and hepatitis C(CHC), must be the most urgent and important clinical issue in Asiabecause these infections are highly prevalent in this area and lead to thedevelopment of hepatocellular carcinoma (HCC) and chronic liver failure,ultimately fatal to these patients. The importance is not only in Asia but allover the world because these viruses constitute a major global health riskwith around 350 million people being chronically infected with hepatitis Band around 170 million people being chronically infected with hepatitis C,according to the World Health Organization (WHO) report (2). Reported in this article, as an example of “hepatology in Asia”, there areexcerpts on the latest guidelines for the treatment of CHB and CHC by“The Study Group for the Standardization of Treatment of Viral HepatitisIncluding Cirrhosis” (3), under the auspice of the Ministry of Health, Laborand Welfare of Japan. The guidelines are revised annually by the memberof the study expert group. The guidelines are widely accepted by practicinghepatologists who are treating patients with both hepatitis B and C in Japan.The latest guidelines are seen on the web site of The Japan Society ofHepatology (JSH) (3). The older one has been published recently byKumada et.al. (4,5).CHRONIC HEPATITIS BThe importance of treatment of CHB in JapanApproximately 1.5 million people are infected with the hepatitis B virus(HBV) in Japan (6).Those that are infected could eventually develop HCC 2
A Special Report on Hepatology in Asia Akira Hayasakaand cirrhosis leading to chronic liver failure. Treatment of patients withchronic hepatitis B (CHB) is important because successful treatment resultsin the suppression of the HBVDNA quantity, stabilizes or improves theliver inflammation, cirrhosis, chronic liver failure, and some regression ofliver fibrosis and reduces the incidence of the development of HCC. Takenall together, patients can live longer with a good quality of life.The goals of the treatment of CHB in JapanThe present goal is to normalize serum levels of alanine aminotransferase(ALT) by reducing the viral load through the various treatments. Theultimate goal for the treatment of CHB is to prevent the progression of thedisease and the development of HCC by eliminating HBV from thepatients.The available drugs for the treatment of CHB in JapanInterferon (IFN) (standard interferon [α and β] and peginterferon α2a andα2b) and nucleotide analogs (such as lamivudine, adefovir,entecavir, telbivudine, and tenofovir) are the major drugs use for thetreatment of CHB. Currently, standard interferon (α and β) and three kindsof nucleotide analogs (lamivudine, adefovir and entecavir) are approved inJapan under the National Health Insurance system for the treatment ofpatients with CHB. Peginterferon and tenofovir have not been approved forthe treatment of CHB by the Ministry of Health, Labor and Welfare ofJapan.The newly approved diagnostic tests for the treatment of CHBIt is well known that HBV genotypes are closely related to the clinicalcourse and the response efficacy to the anti-viral therapy to HBV. Thus, it isbetter to know the genotype of each patient to be treated beforedetermining the most effective treatment. The diagnostic test for thegenotypes was approved by the Ministry in Japan last May. Guidelines for the treatment of patients with CHB separately by theages of the patients (Table 1)In Japan, the guidelines for treatment were constructed separately for 3
A Special Report on Hepatology in Asia Akira Hayasakapatients younger than 35 years old and over 35 years old. These guidelineswere constructed separately for these two groups because younger patientshave the possibility to stabilize the disease activity in their natural course asseen in Table 1 (4). Criteria for treatment eligibility are patients infected with HBV and haveserum aminotransferase (ALT) levels higher than 31 IU/L because thoseinfected patients are considered to have CHB. In the guidelines of othercountries/areas, treatments will be recommended in patients with the higherlevels of serum ALT. In addition, patients are selected for the treatment ifthe HBV DNA titers are 5 log copies of more in HBeAg-positive patients, 4log copies or more in HBeAg-negative patients and 3 log copies/mL ormore in the patients with cirrhosis due to HBV.Guidelines for the treatment of patients younger than 35 years Long-term interferon (IFN) and the sequential treatment (entecavirfollowed by interferon) are recommended for patients younger than 35years to gain a “drug-free status”. However, even for these young patients,starting entecavir treatment is recommended if they are HBe antigennegative and with platelet counts less than 150000/μL or with advancedliver disease of stage F2 or higher. Details are described about “sequentialtherapy” at the Japanese Society of Hepatology website (3).Guidelines for the treatment of patients 35 years or olderFor patients 35 years or older, entecavir is suggested as a first choice fortreatment. There are some differences in the recommendation for thetreatments depending on the extent of the viral load and HBe antigen status(3).Guidelines for the treatment with nucleoside analogs of patients withCHB who are receiving lamivudine (Table 2)Lamivudine is the first nucleotide analogs introduced to the treatment ofHBV infection in Japan. This drug has rapid and potent virus suppressioneffects and has been used for many patients. The main disadvantage of thedrug is the high rate of drug resistance to the HBV mutant. Compared withlamivudine, entecavir has potent antiviral activity and low rate of drugresistance to the HBV mutant. Tenofovir is known to have much lower drugresistance than entecavir, but, as noted above, this drug has not been 4
A Special Report on Hepatology in Asia Akira Hayasakaapproved in Japan. The basic rule is to switch lamivudine to entecavir toreduce the emerging drug-resistant HBV mutants in patients treated withlamivudine.Guidelines for the patients with HBV DNA titers < 2.1 copies/mLAs patients with HBV DNA titers less than 2.1 copies/mL possessentecavir-resistant mutants in low frequencies, they are recommended toswitch to entecavir as soon as possible shown in the upper part of Table 2.Guidelines for the patients with HBV DNA titers ≧2.1 copies/mLFor patients with drug-resistant mutants and with virological breakthroughs,adefovir add-on lamivudine is started for the purpose of stabilizing liverfunction. Otherwise these patients with the high viral load may be switchedto entecavir as indicated in the lower part of Table 2. Supplements to the guidelines for the treatment of CHBTen important supplementary comments are described additionally in thelatest guidelines (3). The following are two of the ten supplementarycomments; 1) the treatment should be chosen based on HBV genotypes(Even in patients 35 years or older, IFN is recommended as the firsttreatment if they have the genotype A or B because of the high responseefficacy of the genotypes to interferon) and 2) self-injection of IFN at homeis recommended to eligible patients, so as to improve their quality of life.The other comments will be translated to English by the expert team whomade the guidelines.HEPATITIS CThe importance of the treatment of CHC in JapanAs with the HBV infection, hepatitis C virus (HCV) infection is a majorpublic health problem. The infection, if not treated progressively worsensover the course of many years and can ultimately result in cirrhosis andHCC. More than 30,000 patients die from these resultant diseases in Japan(8).The goals of the treatment of CHCThe main goal of treatment for patients with CCH is to eradicate HCVvirus. The second goal, if eradication is not possible, is to prevent theprogressions of liver fibrosis and of the development of HCC. 5
A Special Report on Hepatology in Asia Akira HayasakaThe available drugs for the treatment of CHC in Japan At present, standard interferon (α, β), peginterferon (α2a, α2b) andribavirin can be used for the anti-viral treatment of patients with CHC inJapan. Telaprevir, a potent protease inhibitor, has not yet been approved inJapan, however, it will be used in the near future.The predictors of a treatment response to patients with CHCSome of the important predictors of a treatment response include: HCVgenotype (genotypes 2 and 3 are more responsive to treatment thangenotypes 1 and 4), baseline viral load (more responsive in <5.0 LogIU/mL than more than 5.0 Log IU/mL) and host genetic factors (eg, IL28Bpolymorphisms, ISDR mutations and Core aa70 mutations). There are sixmajor genotypes of HCV in the world, but genotype 1 (about 70%) andgenotype 2 (about 30%) are the major genotypes of HCV in Japan (8). Theother types are extremely rare in this country. Therefore, in the guidelinesthere are discussions only about genotype 1 and genotype 2. The TaqManHCV test (Roche Molecular Systems) is available for highly sensitivedetection and reliable quantification of HCV in our clinical practice. IL28Bgene polymorphisms, the interferon sensitivity-determining region (ISDR)mutations and Core aa70 mutations tests are not covered with the NationalHealth Insurance system. Hopefully, these tests will be approval in the nearfuture.Guidelines for patients of CHC Guidelines for the primary treatment of patients with CHC (Table 3) As shown in Table 3, the guidelines are constructed based on thedifference in the genotypes of HCV and the levels of HCV RNA load.Basically, for patients with a high viral load, the combination treatment ofpeginterferon and ribavirin is recommended. The treatment lengths are setfor longer in patients with the genotype 1 (48-72 weeks) than in thegenotype 2 (24 weeks) because of the difference of the response efficiencybetween the two genotypes. In the latest guidelines the combinationtreatment of interferonβ and ribavirin is added for patients with mentalydepressive state. For patients with a low viral load, long-term standard interferon treatmentor peginterferon monotherapy is recommended. Furthermore, the combination treatment with the telaprevir, ribavirin and 6
A Special Report on Hepatology in Asia Akira Hayasakapeginterferon α2b (for 24 weeks) are recommended for the patients of CHCwith the genotype 1 and the high viral load when telaprevir is approved (3). Guidelines for the treatment of patients with normal ALT levelstowards preventing the development of HCC (Table 4)The interpretation of the “normal” upper level of ALT has been changingrecently. As several studies show, patients with the “normal” level of serumALT may have chronic hepatitis with several stages of fibrosis includingcirrhosis. To prevent the development of HCC, the guidelines have beenmade for patients infected with HCV with normal ALT levels. In theseguidelines, patients with CHC with normal ALT levels are divided intofour groups by ALT levels and platelet counts. Patients with platelet countsless than150,000/μL are recommended to receive liver biopsy, if possible,to know the stage of their liver fibrosis.Supplements to the guidelines for the treatment of CHCGuidelines for re-treatment of CCH, for the treatment indication based onthe tests results of IL28B, ISDR and Core aa70 and for the criteria to stopthe treatments are also described in detail at the Japanese Society ofHepatology website (3).DiscussionThis article reports only parts of the guidelines for the treatment of chronichepatitis B and C in Japan. The guidelines are well organized and describedthe needed information in detail. They are accepted and used widely byJapanese practicing hepatologists. In addition, these guidelines are revisedand improved annually, though, usually published only in Japanese with theexception of the fiscal year, 2008 version (4, 5). Because of the languagebarriers, it seems to be a little difficult to discuss them with non-Japanesehepatologists right now. Since academic research from Japan is publishedmainly in English now, this barrier will be resolved soon in clinicalpractical work as well. Through this article-written in a commonlanguage-such as English, “hepatology in Asia” is more known to thewestern hepatologists. 7
A Special Report on Hepatology in Asia Akira HayasakaReferences1 Special Chapter: A Scan of Hepatology in Asia Pacific Region, Hepatology Int.2010 ;4 (Suppl 1):S94-S101.2 The website of the World Health Organization :( http://www.who.int/mediacentre/events/annual/world_hepatitis_day/en/index.html)3 The website of the Japanese Society of Hepatology:http://www.jsh.or.jp/medical/index.html [in Japanese]4 Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronichepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan.Hepatology Research 2010; 40:1-7.5 Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronichepatitis and cirrhosis due to hepatitis C virus infection for the fiscal year 2008 in Japan.Hepatology Research 2010; 40:8-13.6 Yokosuka O, Kurosaki M, Imazeki F, et al. Management of hepatitis B:Consensus of the Japan Society of Hepatology 2009. Hepatology Research 2011;41:1-21.7 Namiki I, Nishiguchi S, Hino K, et al. Management of hepatitis C; Report ofthe Consensus Meeting at the 45th Annual Meeting of the Japan Society ofHepatology (2009). Hepatology Research 2010; 40:347-368. 8
A Special Report on Hepatology in Asia Akira HayasakaAuthor biographyAkira Hayasaka, MD, the President and CEO of the Hayasaka Clinic, is a CertifiedMedical Doctor, and a liver disease expert in Japan. Akira’s mission is to helppatients recover from liver diseases, not only in Japan, but all over the world. Withmore than 30 years of experience in the medical field, Akira is a Board CertifiedHepatologist of the Japan Society of Hepatology, a Board CertifiedGastroenterologist in Japan, and Board Certified Member of the Japanese Societyof Internal Medicine. He is also a Board Councilor of The Japan Society ofHepatology, The Japanese Society of Gastroenterology and former Clinicalassociated professor of medicine at Chiba University School of Medicine.For more information, go to http://akirahayasaka.com 9
Table 1 Guideline for treatment of patients with chronic hepatitis B in Japan 2011 (modified from 4)This guideline is used for patients with HBV infection who has ALT≧31IU/L and HBVDNA≧5 log copies/mL in HBeAg(+) status HBVDNA≧4 log copies/mL in HBeAg(-) status HBVDNA≧3 log copies/mL in cirrhosisPatients Age < 35 years old ≧35 years oldHBV DNA ≧7 log copies/mL < 7 log copies/mL ≧7 log copies/mL < 7 log copies/mL ① IFN (24w-48w) ① Entecavir HBeAg(+) ② Entecavir ② Entecavir followed by IFN* ① Entecavir ② IFN (24w-48w) ① Entecavir followed by IFN* ① Follow-up or Entecavir HBeAg(-) ② Entecavir ② IFN (24w) Entecavir Entecavir: PLT<150,000/μL or ≧F2 in liver biopsyHBV, hepatitis B virus; HBeAg, hepatitis B e-antigen; IFN, interferon; PLT, platlet;.*Sequential therapy with entecavir followed by interferon.
Table 2 Guideline for nucleos(t)ide analogues selection in patients with chronichepatitis B taking lamivudine in Japan 2011 (modified from 4) HBV DNA Recommended Treatment Constantly Change to Entecavir< 2.1 log copies/mL Viral breakthrough (-) Changable to Entecavir≧ 2.1 log copies/mL Viral breakthrough (+) Add AdefovirHBV, hepatitis B virus.
Table 3 Guideline of treatment of naïve patients with chronic hepatitis C in Japan 2011 (modified from 4) HCVRNA Genotype 1 Genotype 2 Peg-IFNα2b + Ribavirin (48-72w) Peg-IFNα2b + Ribavirin (24w) ≧ 5.0 Log IU/mL Peg-IFNα2a + Ribavirin (48-72w) IFNβ + Ribavirin (48-72w) IFNβ + Ribavirin (24w) IFN (24w) IFN (8-24w) < 5.0nLog IU/mL Peg-IFNα2a (24-48w) Peg-IFNα2a (24-48w)
Table 4 Guideline of anti-viral treatment of patients with chronic hepatitis C with "normal" ALT levels in Japan 2011 ( for theeradication of hepatitis C virus and/or the prevention of development of hepatocellular carcinoma) (modified from 4) Platlet Count ≧150,000/μL ＜ 150,000/μL Followup of ALT is needed every 2-4 month. Liver biopsy is recommended. When ALT is elevated, consider anti-viral ① Consider anti-viral treatment: if the biopsy treatment with the careful evaluation of the shows ≧F2A2. hepatitis condition. ② Without liver biopsy, followup of ALT is ALT ≦ 30IU/L needed every 2-4 month. When ALT is elevated, consider anti-viral treatment . Consider anti-viral treatment Consider anti-viral treatment ALT: 31-40IU/L ≦65 years old according to the guideline shown according to the guideline shown in Table 3 in Table 3