JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2

This is the authors' abstract. We don't add key points for this paper.

The Japan Society of Hepatology and Drafting Committee for Hepatitis Management Guidelines produced the first clinical practice guidelines for the management of hepatitis C virus (HCV) infection in 2012, followed by frequent updates. As English versions, we published JSH guidelines in 2013,1 and a 2014 update for genotype 1 in 2014.2 Thereafter several interferon-free regimens with direct acting antivirals (DAAs) have been launched in the clinical setting both for genotype 1 and 2 and treatment recommendations have been greatly changed with these progresses. In this year 2016, the Drafting Committee for Hepatitis Management Guidelines lauched a 2016 update for genotype 1 and 2. These JSH guidelines are intended to assist physicians and other healthcare providers to assist their decision making in the clinical process. The Committee defenitely hope these guideline help patients infected with HCV, their families and other interested individuals to overcome HCV infection and improve the outcome and quality of life with assistance of physicians and other healthcare providers. In these updated version, we focused on newly-available IFN-free DAAs and the current treatment recommendations. Please refer to the previous versions1, 2 when IFN, ribavirin, and other IFN-based DAAs (telaprevir, simeprevir) are of interst. Hepatitis C virus (HCV) was discovered by Choo et al. in the United States of America in 1989,3 and it has become clear that at least 90% of patients who were diagnosed as non-A, non-B hepatitis and at least half of all patients who were diagnosed as alcoholic liver diseases have liver damages caused by HCV. It is estimated that 170 million persons around the world and between 1.5 and 2 million persons in Japan are HCV carriers. When healthy persons are infected with HCV, around 30% have an acute course and then recover, and in around 70% the HCV infection persists and progresses to chronic hepatitis. If the infection becomes chronic, the incidence of spontaneous clearance of the virus is extremely low – 0.2% annually – and hepatic fibrosis results from inflammation caused by the infection, and the disease progresses to cirrhosis and/or hepatocellular carcinoma.4 The goal of hepatitis C therapy is to improve the long-term prognosis for chronic liver disease caused by persistent HCV infection – specifically, to prevent hepatocarcinogenesis and death associated with liver disease. To reach this goal, antiviral therapies are administered to achieve HCV clearance. Inflammation has in fact been shown to subside in patients who have achieved complete elimination of HCV RNA through interferon (IFN) therapy,5 and it has also been shown that progression to cirrhosis and hepatocarcinogenesis are prevented in such patients.6, 7 However, even in patients achieving a sustained virological response (SVR) with IFN therapy, the clearance of HCV does not by itself prevent hepatocarcinogenesis and, as described below, of patients with a mean observation period of 3.3 to 8.0 years.9-16 Furthermore, it is not at present clear whether or not the clearance of HCV through the use of IFN-free DAAs (direct-acting antivirals), which were introduced to clinical practice in 2014, will afford the same level of hepatocarcinogenesis prevention efficacy as IFN therapy. Therefore, follow-up for hepatocarcinogenesis needs to be performed to improve the long-term prognosis even after HCV clearance has been achieved through the use of IFN or DAAs. Patients who are elderly and have advanced fibrosis and are therefore at high risk for carcinogenesis need to be monitored particularly carefully. IFN therapy started to be used for hepatitis C in the clinical setting in the West in 1991 and in Japan in 1992 following confirmation by Hoofnagle et al. in 1986 that the administration of human recombinant IFN-alfa in non-A, non-B hepatitis resulted in the normalization of transaminases.17 IFN monotherapy gave way to the use of IFN in combination with ribavirin (RBV), and Peg-ylated IFN (Peg-IFN) and RBV combination therapy ended up becoming the standard antiviral therapy, and resulted in an increase in the percentage of patients achieving an SVR. However, among HCV genotype 1 and high viral load patients, who are difficult to treat, the percentage achieving SVR on this same therapy is 40% to 50%, and about half of these patients do not achieve HCV clearance. In recent years, a number of novel antiviral drugs have been developed with the aim of improving treatment efficacy or reducing the adverse reactions, and in November 2011, it became possible to use telaprevir, a first-generation protease inhibitor, in the clinical setting in genotype 1 and high viral load patients. Telaprevir + Peg-IFN + RBV combination therapy results in a higher SVR rate – 70% – in treatment-naïve patients. This therapy therefore affords better antiviral efficacy, but adverse events including the progression of severe anemia, the emergence of serious skin esions, and decreased renal function have been observed.18-22 Then, in November 2013, insurance coverage was approved for the use of simeprevir,23-25 a second-generation protease inhibitor, in genotype 1 and high viral load patients. In a Japanese clinical study of simeprevir + Peg-IFN + RBV combination therapy, the percentage of treatment-naïve patients achieving SVR rose to about 90%, and the adverse reactions were nearly identical to those seen in the placebo group.23 Then, in July 2014, IFN-free DAA combination therapy with a protease inhibitor (asunaprevir) and an NS5A inhibitor (daclatasvir) was approved, and it became possible to treat IFN-ineligible and non-responded patients, who had been difficult to treat with conventional antiviral therapies; the SVR rate in Japanese clinical studies was 80% to 90%.26 Furthermore, in a Japanese clinical study of combination therapy with an NS5B inhibitor (sofosbuvir) and an NS5A inhibitor (ledipasvir), which are second-generation IFN-free DAAs, the SVR rate was 90%, and none of the patients in the sofosbuvir plus ledipasvir combination therapy group discontinued from the study because of adverse reactions and no serious adverse reactions occurred. Furthermore, in September 2015, combination therapy with a protease inhibitor (paritaprevir), NS5A inhibitor (ombitasvir) and ritonavir, which has no antiviral effect but is added for anticipating booster effect (increasing plasma concentration and prolongation of half-life of patritaprevir) was approved, and the SVR rate in Japanese clinical trials was excellent as well, more than 95%. In genotype 2 patients, although the SVR rate on Peg-IFN + RBV combination therapy had normally been about 80%, in September 2014 is became possible to use telaprevir +Peg-IFN + RBV combination therapy in patients for whom Peg-IFN plus RBV combination therapy is not particularly effective. Then, in March 2015, the use of the IFN-free combination therapy sofosbuvir plus RBV was approved for use in genotype 2 patients as well; the SVR rate in Japanese clinical studies was 97%. Generally, the liver diseases of patients with persistent HCV infections progress gradually, accompanied by ALT increases, and the risk of carcinogenesis increases along with the progression of fibrosis.9 Conversely, carcinogenesis from a normal liver with no inflammation or fibrosis is almost never seen. Therefore, although all HCV infected patients, except for decompensated cirrhosis patients, are eligible for antiviral therapy, patients with increased ALT levels that are indicative of liver inflammation (ALT > 30 U/l) and patients with decreased platelet counts that are indicative of liver fibrosis (platelet count < 150,000/μl) are good candidates for antiviral therapy for HCV. In addition, patients with poor prognoses because of concurrent illnesses other than liver diseases should not be targeted for antiviral therapy. Although it needs to be kept in mind when determining the suitability of antiviral therapy that patients with ALT < 30 U/l and platelet count ≥ 150,000/μl are at low risk of hepatocarcinogenesis, it should also be kept in mind that the risk of carcinogenesis is not low in the elderly, even in elderly patients with ALT < 30 U/l and platelet count ≥ 150,000/μl. In addition, the patients that are believed to need rapid viral clearance are patients that are at high risk for carcinogenesis. It has become clear that in hepatitis C, the three factors "advanced age," "advanced fibrosis," and "male sex" are independent risk factors for hepatocarcinogenesis.6-8 Because patients with more than one of these factors are at particularly high risk for oncogenesis, early antiviral therapy induction should be considered. In analyses of hepatocarcinogenesis in hepatitis C, although the definition of who is an elderly person is not uniform, with the cutoff sometimes being 55 years, or 60 years, or 65 years, even among elderly persons the risk of carcinogenesis increases as age increases. In this guideline, elderly persons are defined as persons with "age ≥ 66 years" based on, for example, the fact that the incidence of hepatocarcinogenesis increases after age 65.10 In addition, although advanced fibrosis is defined as "hepatic fibrosis ≥ F2 or platelet count < 150,000/μl," it is necessary to keep in mind that the risk of carcinogenesis is particularly high in those patients with "hepatic fibrosis ≥ F3 or platelet count < 120,000/μl." In patients at high risk for carcinogenesis (patients who are both elderly and have advanced fibrosis), antiviral therapy should be initiated as soon as possible, provided the treatment is judged to be tolerable, and patients who are either elderly or have advanced fibrosis should also be started on antiviral therapy early on. However, in patients who are neither elderly nor have advanced fibrosis, who are at low risk for carcinogenesis, the suitability of antiviral therapy should be determined taking into account therapeutic efficacy and adverse reactions as well as the risk of carcinogenesis. In addition, in both groups, it is at present difficult to achieve viral clearance with antiviral therapy, and liver supporting therapies with ursodeoxycholic acid and glycyrrhizin should be administered in patients with abnormal ALT levels (< 30 U/l). Moreover, the long-term use of low doses of Peg-IFN to bring inflammation under control is another option. If such therapies fail to afford adequate efficacy, and iron overload is suspected, then switching to phlebotomy therapy or adding phlebotomy therapy as a concomitant therapy should be considered. The goal of these therapies is to maintain the ALT level at no higher than 30 U/l and to keep the ALT level as low as possible. Strict ALT control is particularly necessary in patients at high risk for carcinogenesis. Furthermore, low-dose Peg-IFN therapy should be discontinued if an improvement in ALT levels (≤40 U/l) or an improvement in AFT levels (≤10 ng/ml) is not achieved within 6 months.27, 28 SVR is defined as a negative result for HCV RNA at 24 weeks after the end of antiviral therapy. Patients who achieve SVR following IFN therapy normally remain HCV RNA negative, and the percentage of subjects achieving SVR on IFN + RBV combination therapy who remain negative has been reported to be between 99% and 100% (mean course observation period of 5.6 years; range: 1 year to 8.3 years).29, 30 In studies conducted before the year 2000, however, the percentage of patients remaining HCV RNA negative was reported to be somewhat lower: 96% to 98%.31-35 This is attributed to the fact that, in these studies, IFN monotherapy was the principal therapy administered, and to the fact that at that time HCV RNA detection sensitivity was low, and false positive results were obtained when assessing SVR. When SVR is achieved through IFN therapy, the patients remain negative for HCV RNA, and the risk of carcinogenesis developing from hepatitis C is significantly decreased.7-9, 12, 36 However, liver cancer has been reported during course observation even in patients who have achieved SVR. There are many reports in Japan of hepatocarcinogenesis following achievement of SVR,9-16 with the reported incidence of carcinogenesis ranging from 0.9% to 4.2% over a mean observation period of 3.3 years to 8.0 years. Reported risk factors for carcinogenesis include advanced age, male sex, advanced fibrosis, alcohol use, fatty liver, and insulin resistance. The time from SVR achievement to carcinogenesis is most often less than 10 years, although there have been scattered reports of carcinogenesis occurring after more than 10 years. Therefore, although no definitive conclusions have been reached about what hepatocarcinogenesis screening period is required following the achievement of SVR through IFN therapy, it appears that screening for liver cancer should be continued for 5 to 10 years after achievement of SVR. In addition, at present there is little evidence regarding whether or not a level of hepatocarcinogenesis prevention efficacy equivalent to that obtained with IFN-induced SVR is obtained when SVR is achieved with the IFN-free DAA therapies that are not being introduced to the clinical setting. Therefore, once HCV clearance is achieved through DAA therapy, patients need to be screened more closely for hepatocarcinogenesis. Careful follow-up is particularly recommended for patients at high risk of hepatocarcinogenesis (patients who are both elderly and have advanced fibrosis). The positive stranded RNA genome of the hepatitis C virus has approximately 9,600 base pairs; the non-structural region that is not incorporated into the viral particles comprises NS2 through NS5B proteins. The current targets of DAAs are the NS3/4A, NS5A, and NS5B proteins, which have, respectively, protease activity, virus genome replication complex formation, and RNA-dependent RNA polymerase activity. As of now, December 2015, five NS3/4A protease inhibitors (telaprevir, simeprevir, asunaprevir, vaniprevir and paritaprevir), two NS5A replication complex inhibitors (daclatasvir, ledipasvir and ombitasvir), and one NS5B inhibitor (sofosbuvir) have been approved and are used in daily practice (Fig. 1). Among them, combinations of NS3/4A and NS5A (daclatasvir/asunaprevir and paritaprevir/ombitasvir) and NS5A and NS5B (sofosbuvir/ledipasvir) are currently used as interferon-free DAA regimens. Daclatasvir was the first NS5A inhibitor that was developed and approved for use in the clinical setting (Fig. 1).37 The HCV nonstructural protein region NS5A is a region that codes for a phosphorylation protein comprising 447 amino acid residues. This region contains an IFN sensitivity determining region (ISDR; aa2209-2248) that correlates to the efficacy of IFN therapy and an IFN/RBV resistance-determining region (IRRDR; aa2334-2379) that correlates to the efficacy of IFN + RBV therapy. Although the functions of NS5A have not been thoroughly elucidated, NS5A is believed to play an important role in virus RNA replication; specifically, it is inferred that the NS5A protein and the core protein interact in HCV particle formation. NS5A inhibitors are low-molecular-weight inhibitors that are expected to have significant virus replication inhibition efficacy. Daclatasvir is a first-in-class, picomolar, highly selective NS5A replication complex inhibitor that exhibits effects in various genotypes. It has been reported, on the basis of investigation of its antiviral efficacy in HCV infected patients, that the HCV RNA load is markedly decreased by the oral administration of daclatasvir 10 mg and above.37 The adult dose is 60 mg as oral daclatasvir once a day. Asunaprevir, on the other hand, is similar to telaprevir and simeprevir in that it is a protease inhibitor that targets the NS3-4A region (Fig. 1).38 The HCV nonstructural protein 3-4A (NS3-4A) is a noncovalent bond complex that comprises NS3 and the cofactor thereof, NS4A. NS3 is a 70 kDa multifunctional protein with a serine protease region in the N-terminal one-third of the protein (amino acids [aa]1-180). The serine protease is a proteolytic enzyme that cleaves the NS3-5 protein. Protease inhibitors, by directly inhibiting this serine protease, inhibit the production of the virus proteins needed for virus genome replication and viral particle formation, and thus strongly inhibit virus replication. Asunaprevir, which is a second-generation protease inhibitor, possesses strong antiviral effects against genotype 1a, 1b, and 4 HCV because it possesses a mechanism of action such as that described above. The adult dose is 100 mg as oral asunaprevir twice a day. In Japan, clinical trials of daclatasvir + asunaprevir combination therapy have been conducted in IFN-ineligible or intolerant patients and in IFN-non responders, and based on the results of these studies, in July 2014 daclatasvir + asunaprevir combination therapy received health insurance coverage for use in IFN-ineligible/intolerant or non-responded patients. Another clinical trial was then conducted in treatment-naïve and relapsed patients, and based on the results of this trial the limitations on health insurance coverage for this therapy were completely lifted in March 2015, and daclatasvir +asunaprevir combination therapy is now covered by health insurance for use in all genotype 1 chronic hepatitis/compensated cirrhosis patients. This therapy is an IFN-free antiviral therapy, which makes it possible to avoid the various adverse reactions that are experienced with IFN, but which also has problematic adverse reactions of its own including elevation of liver enzymes as well as producing drug-resistance associated variants (RAVs), and which therefore needs to be administered by a physician with sufficient knowledge of and experience with the treatment of viral liver disease who has confirmed that the patient is a suitable candidate for said therapy. Similar to other DAAs, asunaprevir and daclatasvir are used together in a two-drug combination therapy because they are insufficiently effective alone. Lok et al. has reported the results of a comparison conducted in the United States in 21 genotype 1 patients who were null responders to Peg-IFN + RBV combination therapy in which 11 patients received daclatasvir + asunaprevir combination therapy (group A) and 10 patients received Peg-IFN + RBV in addition to daclatasvir and asunaprevir (group B).39 The treatment period was 24 weeks for both groups. In group A, 4 of the 11 patients achieved SVR. By genotype, the SVR rate in genotype 1a patients was 22.2% (2 of 9 patients), and all two genotype 1b patients achieved SVR. In group B, however, 9 of the 10 patients achieved SVR. These results show that daclatasvir + asunaprevir combination therapy is more effective in genotype 1b patients than in genotype 1a patients. In Japan, a phase 3 study of daclatasvir + asunaprevir combination therapy was conducted in IFN-ineligible or intolerant patients, and non-responded patients.26 Table 1 shows the backgrounds of the patients enrolled. There were 87 non-responders and 135 IFN-intolerant or ineligible patients. The median ages in these two groups were 60 years and 64 years, respectively, the sex ratios (males/females) were 39/48 and 39/97, respectively, the IL28B genotype (rs12979860) ratios (CC/CT, TT) were 16/71 and 94/41, and the median HCV RNA loads (Log IU/mL) were 6.8 and 6.6. Twenty-two patients with Child-Pugh Grade A compensated cirrhosis were included in this study. However, no studies have been performed in patients with decompensated cirrhosis. Looking at the antiviral efficacy in the study population overall, the HCV RNA virological response rate after treatment initiation was 75.2% (RVR) at week 4, 91.0% (cEVR) at week 12, and 92.3% at week 24 or at the end of treatment (EOT). The percentage of patients with HCV RNA below the limit of quantitation after EOT was 88.7% at week 4 (SVR) and 85.1% at week 12 after EOT (SVR12); the SVR24 rate in the study population overall was 84.7% (188 of 222 patients). The SVR24 rates in non-responders and IFN (+ RBV)-intolerant/ineligible patients were, respectively, 80.5% (70 of 87 patients) and 87.4% (118 of 135 patients), and 90.9% (20 of 22 patients) in the compensated cirrhosis patients (Fig. 2). Efficacy was therefore confirmed in compensated cirrhosis as well. Looking at the results of treatment by background factor, by IL28B genotype, which has a substantial effect on the therapeutic efficacy of IFN, the SVR24 rates in the TT and TG/GG groups were, respectively, 84.8% and 84.3%, so there was no difference in therapeutic efficacy between these two groups. In addition, therapeutic efficacy remained the same for the other background factors as well, such as age, sex, and HCV RNA load at initiation (Fig. 3). The number of patients who experienced relapse after EOT was 6 (7.9%) in the non-responders group and 11 (8.5%) in the IFN (+ RBV)-intolerant/ineligible group. The number of patients who experienced viral during treatment was 10 in the non-responders and 4 in the IFN (+ RBV)-intolerant/ineligible and the of patients in these groups who were HCV RNA positive at EOT were, respectively, 1 and 2. A phase 3 study of daclatasvir + asunaprevir combination therapy was conducted in treatment-naïve and relapsed This study was conducted based on a that for daclatasvir + asunaprevir combination therapy to telaprevir + Peg-IFN + RBV combination therapy in treatment-naïve patients, and for daclatasvir + asunaprevir combination therapy in relapsed patients. The backgrounds of the patients are shown in Table there were treatment-naïve patients and 22 relapsed patients. Because the treatment-naïve patients were based on a comparison telaprevir + Peg-IFN + RBV combination therapy, these patients were with a median age of years; none were over 70 years of In addition, patients with compensated cirrhosis for 6 of the patients. The results of treatment in this study were the rate in the treatment-naïve patients was to in the telaprevir therapy and in the relapsed patients (Fig. As in the clinical study in non-responders and IFN-ineligible/intolerant patients, no significant were in the treatment results by sex, age, HCV RNA load at treatment or IL28B In a phase 3 study in IFN-ineligible/intolerant and serious adverse events in patients The most adverse events included and The most was of The study was performed a that that liver be performed 2 weeks 12 weeks after treatment and then 4 weeks and that treatment should be discontinued if Grade 4 of ALT was Grade of ALT or ≥ 5 and 10 Grade > 10 in of patients patients) and of patients patients), patients discontinued study The median time to of ALT elevation was 10 weeks after treatment the time to was 4 and the was no was However, in most of the patients who experienced Grade 4 ALT the time it from when the ALT started to increase it reached Grade 4 was less than 28 with the time being 5 of the patients who discontinued from study treatment improvement in their ALT and of the 10 patients who discontinued achieved SVR. In addition, in a phase 3 study in treatment-naïve patients and relapsed patients, as well, Grade ALT or elevation in patients and 6 patients respectively, in the treatment-naïve patients, and in 1 patient and 1 patient respectively, in relapsed patients. Although there were 5 patients in the treatment-naïve group and 1 patient in the relapsed group who discontinued from study treatment because of all 6 of these patients achieved SVR. In addition, although no significant were in between compensated cirrhosis patients and other patients, decompensated cirrhosis patients were not in clinical studies, and the in such patients has therefore not been Therefore, daclatasvir + asunaprevir combination therapy should not be administered to decompensated cirrhosis patients. Daclatasvir is a and asunaprevir is a and and In addition, daclatasvir has an inhibitor effect on and and asunaprevir has an effect on and and to Because the concomitant use with daclatasvir and asunaprevir of the or inhibitors, inhibitors, or with a therapeutic result in or increases of the levels of asunaprevir, or the the concomitant use of these drugs is that when either daclatasvir or asunaprevir or be by said should be with The of that is to be be before The following are that significantly the therapeutic efficacy of for asunaprevir, which is a protease inhibitor, the NS3-4A amino acid variants and, for the NS5A region and amino acid variants and Because HCV is a virus that has in its base there are patients who have these to DAA In a Japanese phase 3 study of daclatasvir + asunaprevir in IFN-ineligible/intolerant patients and patients, of patients in whom an of HCV was performed before treatment initiation a direct 30 patients had and patients had before treatment and show the treatment results by the or of NS5A before In the IFN (+ groups, of the patients who not have before treatment achieved SVR. Therefore, when the population was to those patients the SVR rate was a good However, of the 21 patients who had 10 achieved SVR (Fig. In the the SVR rate in patients before treatment initiation was of patients), to a rate of of 9 patients) in patients with before treatment the patients achieved SVR. In patients with of which there were of the 6 patients with such 1 achieved SVR (Fig. In addition, in an phase 3 study patients had before treatment and the SVR rate in these patients was of and patients had before treatment and the SVR rate in these patients was of In a phase 3 study in treatment-naïve and relapsed patients, as well, the treatment results are significantly by the before treatment of NS5A of patients for whom NS5A were by a direct had and 6 had and had either one or both of the patients who not have achieved This is in to the rate of of patients) in patients with either one or both of (Fig. Furthermore, in combination therapy null responders, the emergence of that are to both drugs has been when were after or relapse in patients who had NS5A or before therapy, were to have not in the NS5A but also at NS3 In the phase 3 in in and NS3 in of null responders, and NS5A and NS3 in of null these NS5A and NS3 the NS5A were to for at least 1 In an in virus variants NS5A that had both and were more to NS5A inhibitors than or and the emergence of a that was a with a high level of and high replication was also reported 3). In patients with no of treatment with NS5A inhibitors, it is expected that and will be in no more than of patients and that NS5A will be extremely However, in combination therapy null responders, and are and NS5A thus to be present in a high of such Because there are currently no therapies that are effective against such it is of the to prevent the emergence of such RNA-dependent RNA which is necessary for virus is