JSH G uidelines for the M anagement of H epatitis C V irus I nfection: A 2014 Update for G enotype 1
2014; Wiley; Volume: 44; Issue: S1 Linguagem: Inglês
10.1111/hepr.12272
ISSN1872-034X
Tópico(s)Hepatitis B Virus Studies
ResumoHepatology ResearchVolume 44, Issue S1 p. 59-70 Special ReportFree Access JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2014 Update for Genotype 1 Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology, Corresponding Author Drafting Committee for Hepatitis Management Guidelines, the Japan Society of HepatologyDrafting 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; Masayuki Kurosaki, Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital; Makoto Oketani, Digestive and Lifestyle-related 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; Eiji Tanaka, Department of Medicine, Shinshu University School of Medicine; Yasuhito Tanaka, Department of Clinical Molecular Informative Medicine, Nagoya City University Medical School Graduate School of Sciences; Hirohito Tsubouchi, Kagoshima City Hospital; 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 173-8605, Japan. Email: [email protected]Search for more papers by this author Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology, Corresponding Author Drafting Committee for Hepatitis Management Guidelines, the Japan Society of HepatologyDrafting 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; Masayuki Kurosaki, Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital; Makoto Oketani, Digestive and Lifestyle-related 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; Eiji Tanaka, Department of Medicine, Shinshu University School of Medicine; Yasuhito Tanaka, Department of Clinical Molecular Informative Medicine, Nagoya City University Medical School Graduate School of Sciences; Hirohito Tsubouchi, Kagoshima City Hospital; 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 173-8605, Japan. Email: [email protected]Search for more papers by this author First published: 07 January 2014 https://doi.org/10.1111/hepr.12272Citations: 48 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL 1. Introduction Recently, the management of chronic hepatitis C virus (HCV) has been greatly advanced with introduction of direct-acting antiviral agents (DAAs) in clinical setting. In Japan, the first DAA, telaprevir (TVR), was approved for patients with chronic hepatitis C in 2011. Along with this, the Japan Society of Hepatology (JSH) produced the first clinical practice guideline for the management of HCV infection, "Guidelines for the Management of Hepatitis C Virus Infection" in May 2012 (English version, 20131). It is our great pleasure that these Guidelines were welcomed and utilized by physicians and other health care providers in daily clinical practices in Japan. Meanwhile, in September 2013, a second-generation DAA, simeprevir (SMV), was approved for use in Japan. According to Phase III trials in Japan and overseas, SMV has a robust therapeutic effect with better safety profiles compared to TVR. As a result, we have decided to update the clinical guidelines for HCV with launch of this new DAA. SMV has now been approved for use in patients with chronic hepatitis C with genotype 1 and high viral load, and therefore these current Guidelines are updated for patients in this group. As stated in the previous Guidelines, this is a field that changes rapidly with the accumulation of new evidence, and evidence levels are not shown in the recommendations. At present, several other therapeutic agents are expected to be approved for daily use and we plan to revise these guidelines at appropriate intervals, as new evidence comes to hand. 2. Simeprevir (SMV) Inhibitors of hepatitis C virus (HCV) NS3-4A protease are classified into 2 groups on the basis of their molecular structures, linear inhibitors with no branches and macrocyclic inhibitors containing macrocycles. Macrocyclic small molecule compounds show superior affinity and selectivity for therapeutic target proteins.2 Whereas TVR is a first-generation protease inhibitor with linear structure, SMV is a second-generation protease inhibitor with macrocyclic structure discovered during the optimization process for early protease inhibitors.3 In vitro resistance testing has yielded different drug resistance profiles, due to their different structures, with cross resistance to SMV seen in TVR resistant mutations at amino acids 155 and 156, whereas mutations at amino acids 36, 54 and 170 were sensitive to SMV, and mutations at amino acids 80 and 168 resistant to SMV alone.4 Pharmacokinetic studies have shown that once daily administration of SMV provides effective plasma levels 24 h post-dose.5 SMV shows inhibitory activity against HCV genotypes 1, 2, 4, 5 and 6, with particularly strong anti-proliferative action against genotypes 1a and 1b. In September 2013, the use of SMV in clinical setting was approved in combination with Peg-IFN + RBV in patients with chronic hepatitis C with genotype 1 and a high viral load (≥5.0 log IU/mL). Therapeutic results Phase II trials of SMV + Peg-IFN + RBV combination therapy for genotype 1 chronic hepatitis C include the Japanese DRAGON study (treatment-naïve patients),6 and the overseas PILLAR study (treatment-naïve patients)7 and the ASPIRE trial (relapsers following previous treatment and non-responders to previous treatment).8 Based on the results of these studies, the SMV dosage was set at 100 mg once daily for clinical phase III studies in Japan, and 150 mg once daily for overseas studies. Published Japanese clinical phase III studies comprise the CONCERTO-1 (treatment-naïve patients),9 CONCERTO-2 (non-responders to previous treatment),10 CONCERTO-3 (relapsers following previous treatment),10 and CONCERTO-4 (treatment-naïve patients, non-responders, and relapsers) trials.11 Published overseas clinical phase III studies comprise the QUEST-1 (treatment-naïve patients),12 QUEST-2 (treatment-naïve patients),13 and PROMISE (relapsers) studies.14 The subjects for the Japanese clinical trials were patients with chronic hepatitis C (excluding cirrhosis) with genotype 1 and a high viral load (≥5.0 log IU/mL), aged 20–70 years (Table 1). Table 1A. Characteristics of patients enrolled in CONCERTO-1/2/3 Treatment-naïve Non-responders Relapsers SMV 12W PBO SMV 12W SMV 24W SMV 12W (n = 123) (n = 60) (n = 53) (n = 53) (n = 49) male, % 31.7 40.0 50.9 49.1 40.8 age * 56 (23–69) 54.5 (30–69) 60 (30–70) 60 (24–70) 61 (22–70) ≥65, % 17.9 16.7 26.4 22.6 24.5 BMI, kg/m2 * 22.0 (16.9–32.9) 22.5 (17.3–33.2) 22.3 (16.8–29.5) 21.9 (19.2–33.4) 22.3 (17.9–32.2) IL28B SNP (rs8099917), % TT 61.7 70 15.1 11.3 71.4 TG 31.7 28.3 83 86.8 28.6 GG 1.6 1.7 1.9 1.9 0 HCV genotype 1b, % 98.4 98.3 100 94.3 98 HCV RNA at baseline, LogIU/mL * 6.3 (4.5–7.2) 6.4 (3.3–7.4) 6.4 (4.6–7.3) 6.4 (5.1–7.0) 6.5 (5.0–7.0) previous IFN Tx IFN mono 7.5 3.8 4.1 IFN+RBV 7.5 7.5 8.2 Peg-IFN mono 0 1.9 4.1 Peg-IFN+RBV 84.9 86.8 83.7 * expressed as median (range). Table 1B. Characteristics of patients enrolled in CONCERTO-4 Treatment-naïve Non-responders Relapsers SMV 12W SMV 12W SMV 12W, PR 48W (n = 24) (n = 29) (n = 26) male, % 33.3 55.2 50 age * 60 (37–68) 60 (38–70) 53 (45–69) ≥65, % 20.8 31 15.4 BMI, kg/m2 * 23.0 (18.1–30.2) 22.5 (18.1–31.9) 22.4 (16.9–34.3) IL28B SNP (rs8099917), % TT 66.7 89.7 7.7 TG 33.3 10.3 80.8 GG 0 0 11.5 HCV genotype 1b, % 100 100 96.2 HCV RNA at baseline, LogIU/mL * 6.6 (5.4–7.0) 6.6 (4.9–7.4) 6.5 (5.1–7.4) previous IFN Tx IFN mono 3.4 0 IFN+RBV 0 11.5 Peg-IFN mono 0 0 Peg-IFN+RBV 96.6 88.5 * expressed as median (range). 2.1.1 Treatment-naïve patients The protocol for the Japanese CONCERTO-1 trial,9 conducted with IFN-naïve subjects, administered SMV 100 mg once daily + Peg-IFNα-2a + RBV triple therapy for the first 12 weeks, then Peg-IFNα-2a + RBV dual therapy for 12 or 36 weeks according to the response-guided therapy (RGT). Using this RGT, subjects with HCV RNA < 1.2 log IU/mL or undetectable after 4 weeks' treatment, and undetectable after 12 weeks, were administered Peg-IFNα-2a + RBV for 12 weeks (total treatment duration 24 weeks), and all other subjects for 36 weeks (total treatment duration 48 weeks). As a result, 99% of subjects met the response-guided criteria, and underwent 24 weeks of treatment. The SVR24 rate was 89% (109/123) for the triple therapy group, significantly higher than that of 57% (34/60) in the control group (Fig. 1). Figure 1Open in figure viewerPowerPoint Therapeutic results for SMV + Peg-IFNα-2a + RBV triple therapy for treatment-naïve patients (from CONCERTO-1 trial9). , SMV + Peg-IFNα-2a + RBV; , Peg-IFNα-2a + RBV. Peg-IFNα-2b was used in the CONCERTO-4 trial,11 conducted with IFN-naïve subjects, the same response-guided criteria were set, all subjects met the criteria and underwent 24 weeks of treatment, yielding an SVR24 rate of 92% (22/24) (Fig. 2). Figure 2Open in figure viewerPowerPoint Therapeutic results for SMV + Peg-IFNα-2b + RBV triple therapy for treatment-naïve patients, non-responders, and relapsers (from CONCERTO-4 trial11). , treatment-naïve cases; , relapsers; , non-responders. Total treatment duration was 24W for treatment-naive and relapsers, and 48W for non-responders. In the overseas QUEST-1 study,12 subjects were administered SMV 150 mg once daily + Peg-IFNα-2a + RBV triple therapy for the first 12 weeks, then response-guided criteria were set as for the CONCERTO-1 trial, with 85% of subjects meeting the criteria and undergoing 24 weeks of treatment. The overall SVR12 rate was 80%; 71% (105/147) in genotype 1a and 90% (105/117) in genotype 1b. The QUEST-2 study13 set two groups, with either Peg-IFNα-2a or Peg-IFNα-2b, otherwise following the same protocol as the QUEST-1 study for treatment durations. As a result, 91% of subjects met the criteria and underwent 24 weeks of treatment. The overall SVR12 rate was 81%; 80% (86/107) and 82% (123/150) in genotype 1a and 1b, respectively. The SVR12 rate for Peg-IFNα-2a and Peg-IFNα-2b was 88% and 78%, respectively. In both these studies, triple therapy including SMV yielded significantly higher SVR rates than for 48 weeks of Peg-IFN + RBV dual therapy. In this way, clinical trials of SMV-based triple therapy regimens were conducted using a response-guided protocol that set a treatment duration of 24 or 48 weeks, with almost all subjects meeting the criteria for the shorter duration. The SVR rate for IFN-naïve subjects in the Japanese studies was 89–92%, and in the overseas studies it was 82–90% for genotype 1b, significantly higher than the SVR rate in the control groups administered 48 weeks of Peg-IFN + RBV dual therapy. 2.1.2 Relapsers following previous treatment The Japanese CONCERTO-3 trial,10 conducted with subjects who relapsed following previous IFN therapy, was conducted using a similar protocol to the CONCERTO-1 trial.9 All subjects met the response-guided criteria and underwent 24 weeks of treatment, yielding an SVR24 rate of 90% (44/49) (Fig. 3). Similarly, the CONCERTO-4 trial,11 conducted with relapsers, followed a similar therapeutic protocol to the CONCERTO-3 trial,10 using Peg-IFNα-2b. All subjects met the response-guided criteria and underwent 24 weeks of treatment, yielding an SVR24 rate of 97% (28/29) (Fig. 2). Figure 3Open in figure viewerPowerPoint Therapeutic results for SMV + Peg-IFNα-2a + RBV triple therapy for non-responders and relapsers (from CONCERTO-2 and CONCERTO-3 trials10). , relapsers; , non-responders (SMV for 12 wks); , non-responders (SMV for 24 wks). The overseas PROMISE study,14 conducted with relapsers, was performed using a similar protocol to the QUEST-1 study. As a result, 93% of subjects met the response-guided criteria and underwent 24 weeks of treatment. The overall SVR12 rate was 79%; 70% (78/111) in genotype 1a and 86% (128/149) in genotype 1b. In this way, in clinical trials of SMV-based triple therapy regimens with relapsers following previous IFN therapy, majority of subjects met the response-guided criteria and underwent 24 weeks of treatment. The SVR rate for the Japanese studies was 90–97%, and in the overseas studies it was 86% for genotype 1b, significantly higher than the SVR rate in the control groups administered 48 weeks of Peg-IFN + RBV dual therapy. 2.1.3 Non-responders to previous treatment In the Japanese CONCERTO-2 trial,10 non-responders to previous IFN therapy were administered SMV + Peg-IFNα-2a + RBV triple therapy for 12 weeks (SMV 12W group) or 24 weeks (SMV 24W group). The total treatment duration for both groups was set using response-guided criteria similar to those for the CONCERTO-1 trial,9 with 96% and 98% of subjects, who completed 24 weeks of treatment respectively, meeting the criteria and finishing the treatment at 24 weeks. The SVR24 rate was 51% (27/53) for the SMV 12W group, and 36% (19/53) for the SMV 24W group (Fig. 3). In the CONCERTO-4 trial,11 non-responders were administered SMV + Peg-IFNα-2b + RBV triple therapy for 12 weeks, followed by Peg-IFNα-2b + RBV dual therapy for 36 weeks, for a total treatment duration of 48 weeks. The SVR24 rate was 38% (10/26) (Fig. 2). Although the Japanese CONCERTO-210 and CONCERTO-411 trials were conducted with non-responders, they did not conduct any further analyses subdividing non-responders into partial responders, with a decrease in the HCV RNA level by ≥2 log IU/mL at week 12 of the previous treatment, and null responders, with a decrease < 2 log IU/mL. On the other hand, the overseas phase II ASPIRE trial,8 conducted with relapsers and non-responders, reported therapeutic results separately for partial responders and null responders. This trial assigned subjects to one of 3 groups, all with a total treatment period of 48 weeks. They were administered SMV + Peg-IFNα-2a + RBV triple therapy for 12 weeks or 24 weeks, followed by Peg-IFNα-2a + RBV dual therapy for the remaining time, or triple therapy for the entire 48 weeks. SMV was administered in a daily dosage of either 100 mg or 150 mg. The SVR rate for the SMV 12, 24 and 48 week groups was 70%, 66% and 61%, respectively, at the 100 mg dosage, and 67%, 72% and 80% at the 150 mg dosage, with no difference seen between groups due to treatment duration. The SVR rate in relapsers was 85% for both the 100 mg and 150 mg dosages. On the other hand, the SVR rate for partial responders and null responders was 57% and 46%, respectively, at the 100 mg dosage of SMV, and 75% and 51% at the 150 mg dosage. This indicates that within the non-responders, a higher SVR rate is achieved in partial responders than in null responders. In particular, if we confine the analysis to genotype 1b, common in Japanese patients, the SVR rate for partial responders and null responders was 68% and 56%, respectively, at the 100 mg dosage of SMV, and 88% and 58% at the 150 mg dosage. In genotype 1a, the SVR rate for partial/null responders was 56%/33% at 100 mg and 42%/33% at 150 mg.8 Table 2. Drugs contraindicated for co-administration with SMV (reproduced from16) Generic name Trade name Efavirenz Stocrin Rifampicin Rifadin Rifabutin Mycobutin Recommendations The SVR rate in IFN-naïve subjects was significantly higher for SMV + Peg-IFN + RBV triple therapy than for Peg-IFN + RBV dual therapy for 48 weeks. A high SVR rate of 90–97% was achieved with SMV + Peg-IFN + RBV triple therapy in relapsers following previous IFN therapy. An SVR rate of 36–51% was achieved with SMV + Peg-IFN + RBV triple therapy in non-responders to previous IFN therapy. In an overseas trial, subanalysis of non-responders to previous IFN therapy showed a higher SVR rate in partial responders than in null responders, although there is no data available regarding Japanese subjects. Adverse reactions In the CONCERT-1 trial,9 the treatment completion rate was 92.7%. Only 4.9% of subjects in the triple therapy group discontinued treatment due to adverse events, as against 8.3% of subjects in the Peg-IFNα-2a + RBV dual therapy group, with no significant difference between groups. Elevated bilirubin levels were seen in 40.7% of subjects administered SMV, but these were mild, transient increases not associated with elevated AST or ALT levels. Bilirubin levels in grade 1 (1.1–1.5 mg/dL) were seen in 25.2%, grade 2 (1.6–2.5 mg/dL) in 14.6%, and grade 3 (2.6–5.0 mg/dL) in 0.8%, with no cases of grade 4 (> 5.0 mg/dL). Elevated bilirubin levels are reported to be caused by inhibition of hepatic transporter activity by SMV.15 The type and incidence of adverse reactions, including anemia, skin conditions, renal dysfunction, hyperuricemia, malaise, and gastrointestinal symptoms, were similar for SMV + Peg-IFN + RBV triple therapy and for Peg-IFN + RBV dual therapy. The incidence and degree of anemia was similar for both treatment groups; for the SMV-based triple therapy group, the lowest hemoglobin level was ≥10.6 g/dL in 29.3% of subjects, grade 1 anemia (Hb 9.5–10.5 g/dL) in 41.5%, grade 2 anemia (8.0–9.4 g/dL) in 29.3%, and no cases of grade 3 anemia ( 30 U/L or platelet count <150 000/μL), irrespective of IL28B SNP status. In some patients, however, in whom adverse reactions are a concern, and the risk of carcinogenesis is considered low, it may be possible to await the introduction of the new agents with more favorable safety profiles. Selection of antiviral therapy in treatment-naïve patients (Fig. 5) Figure 5Open in figure viewerPowerPoint Treatment flow chart for treatment-naïve patients. Use IL28B testing as a reference if available. Follow therapy protocol for treatment-naïve patients if previous therapy was Peg-IFN (IFN) monotherapy or details of previous therapy with Peg-IFN (IFN) and RBV are unknown. Consider IFNβ + RBV combination if depressive symptoms present. *1 TVR + Peg-IFN + RBV triple therapy is another option (TVR should be commenced at a reduced dosage of 1500 mg/day in the elderly). *2 Protective therapy or low dose Peg-IFN(IFN) therapy if abnormal ALT levels. 3.2.1 Elderly patients In this patient group at high risk of hepatocellular carcinogenesis, the best possible antiviral therapy should be promptly commenced. However, the possibility of adver
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