TITLE: Re-treatment with Direct Acting Antivirals for Chronic Hepatitis C Genotype 1: Emerging Evidence of Clinical Effectiveness and Safety An Update

Transcription

1 TITLE: Re-treatment with Direct Acting Antivirals for Chronic Hepatitis C Genotype 1: Emerging Evidence of Clinical Effectiveness and Safety An Update DATE: 02 January 2015 RESEARCH QUESTION What is the clinical effectiveness and safety of telaprevir, boceprevir, simeprevir or sofosbuvir and peginterferon + ribavirin (PR) combination treatments in patients with chronic hepatitis C genotype 1 who have had an inadequate response to prior direct acting antiviral (DAA) plus (PR) therapy or PR therapy alone? KEY FINDINGS Four relevant conference abstracts of randomized controlled trials were identified regarding the clinical effectiveness and safety of triple therapy in patients with chronic hepatitis C genotype 1 who have had an inadequate response to prior direct acting antiviral (DAA) plus (PR) therapy or PR therapy alone. METHODS A limited literature search was conducted on key resources including PubMed, EMBASE, The Cochrane Library (2014, Issue 12), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2014 and December 15, Internet links were provided, where available. Selection was limited to conference abstracts to capture emerging evidence regarding the retreatment of patients with chronic hepatitis C genotype 1 who have had an inadequate response to prior DAA plus PR therapy or PR therapy alone. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material and may contain material in which a third party owns copyright. This report may be used for the purposes of research or private study only. It may not be copied, posted on a web site, redistributed by or stored on an electronic system without the prior written permission of CADTH or applicable copyright owner. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 SELECTION CRITERIA One reviewer screened citations and selected studies based on the inclusion criteria presented in Table 1. Table 1: Selection Criteria Population Adult patients with CHC genotype 1 infection who have an inadequate response to DAA+PR therapy (due to virologic failure or intolerance) Intervention Telaprevir in combination with PR Boceprevir in combination with PR Simeprevir in combination with PR Sofosbuvir in combination with PR Comparator Comparisons between dual therapy (PR) vs. triple therapy (PR + DAA) Comparisons between DAA triple therapy options Outcomes SVR, treatment completion, histological changes, relapse, quality of life, liver failure, hepatocellular carcinoma, liver transplants, and mortality (allcause and liver related). Serious adverse events, adverse events, withdrawals due to adverse events, rash, fatigue, anemia, pruritus, anorectal discomfort, neutropenia, depression, suicidal ideation, and flu-like symptoms. Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies CHC = chronic hepatitis C; DAA = direct acting antiviral; PR = peginterferon + ribavirin; SVR = sustained virological response. RESULTS Four relevant conference abstracts of randomized controlled trials were identified regarding the clinical effectiveness and safety of triple therapy in patients with chronic hepatitis C genotype 1 who have had an inadequate response to prior direct acting antiviral (DAA) plus (PR) therapy or PR therapy alone.no relevant conference abstracts of health technology assessments or systematic reviews were identified. OVERALL SUMMARY OF FINDINGS One abstract 1 was identified regarding a randomized controlled trial (RCT) that examined the safety and efficacy of boceprevir (BOC) in combination with peginterferon and ribavirin (PR) versus PR alone in patients in the Asia-Pacific region who had previously failed treatment for hepatitis C. At treatment week eight, hepatitis C virus was undetectable in 83.1% of patients in the BOC + PR group versus 47.2% in the PR group. The authors concluded that the safety of BOC + PR was similar for Korean patients as that reported in the North American studies. Three abstracts 2-4 were identified describing the ATTAIN trial which examined the safety and efficacy of simeprevir versus telaprevir, each in combination with PR for patients with hepatitis C who were partial or non-responders to previous PR therapy. Patients were stratified by genotype 1 subtype and by prior treatment response before randomization. 2 Mean patientreported outcomes (PRO) questionnaire scores worsened in both treatment groups by treatment week When examining the results of PRO questionnaires, no statistically significant difference in Fatigue Severity Scale (FSS) scores were reported between groups. 3 Based on the statistical analysis plan, the other patient-reported outcome endpoints were not examined due to the lack of significance for FSS. 3 The authors reported that the differences in FSS, depressive symptoms, skin symptoms, and quality of life were clinically meaningful in favor of simeprevir. 4 Re-treatment with DAAs for Hepatitis C Patients - Update 2

3 Fewer adverse events were reported in the simeprevir group. 3,4 The results of this trial will be published in the January 2015 issue of The Lancet Infectious Diseases. REFERENCES SUMMARIZED Health Technology Assessments No conference abstracts identified. Systematic Reviews and Meta-analyses No conference abstracts identified. Randomized Controlled Trials 1. Han KH, Helmond FA, Paik SW, Han SY, Heo J, Tak WY, et al. Boceprevir plus peginterferon alfa and ribavirin for Korean patients with chronic hepatitis C virus genotype 1 infection and previous treatment failure [abstract]. Hepatology International Conference: 23rd Conference of the Asian Pacific Association for the Study of the Liver, APASL 2014 Brisbane, QLD Australia Conference Start: Conference End: Conference Publication: (var pagings) 8 (1 Suppl (Presented at ; Conference Publication: (var.pagings). 8 (1 Suppl 1) ()(pp S222-S223), Date of Publication: March 2014.). OVID EMBASE Entry Week Summary: Addition of boceprevir (BOC) to peginterferon plus ribavirin (PR) significantly increased sustained virologic response (SVR) rates in patients from the Americas and Europe with hepatitis C virus (HCV) genotype (G)1 infection and previous treatment failure (PTF). The aim of this study is to explore the efficacy and safety of BOC + PR among patients in the Asia-Pacific region. Patients with HCV G1 infection and PTF were randomized to BOC + PR or PR. Patients randomized to BOC + PR received PR for 4 weeks then BOC + PR for 32 weeks. Patients with detectable HCV RNA at treatment week (TW)8 received a further 12 weeks of PR therapy. Patients randomized to PR received PR for 4 weeks then placebo + PR for 44 weeks. Patients with detectable HCV RNA at TW12 were discontinued. An interim analysis to assess TW8 response included patients from South Korea who reached TW12 or were discontinued before that time. In total, 107 Korean patients were enrolled. Most patients had previous relapse to PR with fewer prior null responders and prior partial responders. Undetectable HCV RNA at TW8 was higher among patients receiving BOC + PR compared with PR (83.1 vs 47.2 %) and this trend was consistent across prior response categories. Among patients receiving BOC + PR, TW8 response rates were slightly higher in noncirrhotic versus cirrhotic patients (85 vs 79 %); and in those with the IL28B CC genotype versus non-cc (90 vs 65 %). Approximately 83 % of patients receiving BOC + PR had undetectable HCV RNA at TW8, and would be eligible for short-duration response-guided therapy. Anemia, neutropenia, and adverse events leading to discontinuation or dose modification were more common in the boceprevir treatment arm. There were no deaths. In Korean patients with HCV G1 infection and PTF with PR, TW8 response rates are higher when retreated with BOC + PR versus PR. The safety profile of BOC + PR in Korean patients is consistent with the known safety profile of BOC + PR in Western patients. Background/aims: In the phase III RESPOND-2 study, addition of boceprevir (BOC) to peginterferon plus ribavirin (PR) significantly increased sustained virologic response (SVR) rates in patients from the Americas and Europe with hepatitis C Re-treatment with DAAs for Hepatitis C Patients - Update 3

4 virus (HCV) genotype (G)1 infection and previous treatment failure (PTF). Boceprevir response-guided therapy permits a shortened treatment duration of 36 weeks for PTF patients with undetectable HCV RNA at treatment week (TW)8. The aim of this study is to explore the efficacy and safety of BOC + PR among patients in the Asia-Pacific region. Methods: Patients in South Korea, Taiwan, and India with HCV G1 infection and PTF (PR for > 12 weeks) were randomized 2:1 to BOC + PR or PR. Patients randomized to BOC + PR received PR for 4 weeks then BOC + PR for 32 weeks. Patients with detectable HCV RNA at TW8 received a further 12 weeks of PR therapy. Patients randomized to PR received PR for 4 weeks then placebo + PR for 44 weeks. Patients with detectable HCV RNA at TW12 were discontinued. An interim analysis to assess TW8 response included patients from South Korea who reached TW12 or were discontinued before that time. Results from Korean patients are presented here. Results: In total, 107 Korean patients were enrolled (male, 63 %; IL28B CC, 71 %; baseline viral load < 800,000 IU/mL, 29 %; HCV G1b, 99 %; cirrhotic, 25 %). Most patients had previous relapse to PR (76 vs 14 % with prior null response and 9 % with prior partial response). Undetectable HCV RNA at TW8 was higher among patients receiving BOC + PR compared with PR (83.1 vs 47.2 %; between-group difference = 29 %, 95 % confidence interval = %) and this trend was consistent across prior response categories (Table). Among patients receiving BOC + PR, TW8 response rates were slightly higher in noncirrhotic versus cirrhotic patients (85 [44/52] vs 79 % [15/19]); and in those with the IL28B CC genotype versus non-cc (90 % [46/51] vs 65 % [13/20]). Approximately 83 % of patients receiving BOC + PR had undetectable HCV RNA at TW8 (59/71) and would be eligible for short-duration responseguided therapy. SVR24 data will be presented at the meeting. Safety summaries are based on a mean observation period of approximately 25 weeks/person in both arms (Table). There were no deaths. Conclusions: In Korean patients with HCV G1 infection and PTF with PR, TW8 response rates are higher when retreated with BOC + PR versus PR. The safety profile of BOC + PR in Korean patients is consistent with the known safety profile of BOC + PR in Western patients. (Table Presented). ATTAIN Study 2. Reddy KR, Zeuzem S, Zoulim F, Weiland O, Horban A, Stanciu C, et al. A Phase III randomised, double-blind study to evaluate the efficacy, safety and tolerability of simeprevir vs telaprevir in combination with pegylated interferon and ribavirin in chronic hepatitis C virus genotype 1 treatment-experienced patients: the ATTAIN study [abstract]. Hepatology International Conference: 23rd Conference of the Asian Pacific Association for the Study of the Liver, APASL 2014 Brisbane, QLD Australia Conference Start: Conference End: Conference Publication: (var pagings) 8 (1 Suppl (Presented at ; Conference Publication: (var.pagings). 8 (1 Suppl 1) ()(pp S397), Date of Publication: March 2014.). OVID EMBASE Entry Week Introduction: Simeprevir (SMV, TMC435) is a one-pill, once-daily (QD), oral, hepatitis C virus (HCV) NS3/4A protease inhibitor (PI), with anti-viral activity against HCV genotypes 1, 2, 4, 5 and 6. SMV has been approved in Canada, Japan and the USA and is under regulatory review in Europe. The safety and efficacy of SMV (150 mg QD) has been evaluated in several multicentre Phase IIB/III studies in treatment-naive and -experienced patients with chronic HCV genotype 1 infection and compensated liver disease. Telaprevir (TVR) is an oral, twice- (BID) or three-times daily (TID) HCV NS3/4A PI with efficacy against HCV genotype 1 when used in combination with pegylated interferon plus ribavirin Re-treatment with DAAs for Hepatitis C Patients - Update 4

5 (PR). ATTAIN (NCT ) aimed to demonstrate the non-inferiority of SMV versus TVR when used in a triple-therapy regimen of a direct-acting antiviral agent plus PR. Materials and methods: Adults (N = 744) with chronic HCV genotype 1 infection and compensated liver disease who were partial or null responders to prior PR therapy were enrolled in this Phase III randomised, double-blind study. Patients were stratified by HCV genotype 1 subtype (1a, 1b, other) and prior treatment response (null or partial response) and were randomised (1:1) to treatment with either SMV 150 mg QD + PR or TVR 750 mg TID + PR for 12 weeks, followed by 36 weeks of PR alone. The primary efficacy endpoint was sustained virologic response 12 weeks after the planned end of treatment (SVR12). Secondary endpoints included SVR24, ontreatment failure, viral breakthrough or viral relapse. Quality of life was assessed using validated, patient-reported outcome questionnaires for fatigue (FSS), productivity (WPAI-Hepatitis C), depression (CESD) and health status (EQ-5D). Safety outcomes included adverse events (AEs) including AEs of clinical interest, serious AEs, and laboratory abnormalities. Results: Results from this head-to-head study are due in early 2014, and will be presented at the meeting. Conclusion: This is the first Phase III, randomised, doubleblind study to directly compare the efficacy, safety and tolerability of SMV versus TVR both in combination with PR in prior non-responder patients chronically infected with HCV genotype 1 and compensated liver disease. This study was funded by Janssen Pharmaceuticals. 3. Scott J, Cerri K, Sbarigia U, Corbett C, Fu M, Jessner W. Simeprevir with PegIFN/ribavirin for chronic HCV infection shortens time with patientreported symptoms and impairment in QoL: ATTAIN study results [abstract]. Journal of Viral Hepatitis Conference: Viral Hepatitis Congress 2014 Frankfurt Germany Conference Start: Conference End: Conference Publication: (var pagings) 21 ()(pp 25), 2014 Date of Publication: October (Presented at ; Conference Publication: (var.pagings). 21 ()(pp 25), Date of Publication: October 2014). OVID EMBASE Entry Week BACKGROUND: Fatigue, skin and depressive symptoms are common in chronic hepatitis C virus (HCV)-infected patients, and can impair functioning and quality of life (QoL). ATTAIN, a Phase III, randomised, double-blind study compared simeprevir (SMV) plus peginterferon/ribavirin (PR) versus telaprevir (TVR) plus PR in HCV genotype 1-infected patients with compensated liver disease who were null- or partialresponders to prior PR. Patientreported outcomes (PRO) provide the patient's perspective on HCV therapy. METHODS: Patients received SMV (150 mg once-daily) or TVR (750 mg three-times-daily) plus PR for 12 weeks, then PR alone for 36 weeks. Patients completed PRO questionnaires to rate severity of fatigue [Fatigue Severity Scale (FSS)], skin symptoms (Skindex-16), depressive symptoms [Center for Epidemiologic Studies Depression (CES-D)], work productivity and daily activity impairment (hepatitis C-specific version of Work Productivity and Activity Impairment score, WPAI) and QoL (EuroQoL 5 Dimension, EQ-5D) at baseline (BL) and throughout the study. PRO data analyses compared areaunder- the-curve (BL towk60, AUC 60 ; BL towk12, AUC 12 ). RESULTS: Mean scores for all PRO scores (763 patients, SMV = 379, TVR = 384) worsened in both groups from BL to Wk12, were generally stable from Wk16 to Wk48 and returned close to BL values from Wk60 onwards. As AUC60 analyses did not show a statistically significant difference between groups in FSS, treatment comparisons for other PRO endpoints were not analysed statistically in keeping with the hierarchical testing procedure specified in the statistical analysis Re-treatment with DAAs for Hepatitis C Patients - Update 5

6 plan. Post-hoc AUC 12 analyses significantly favoured SMV versus TVR for FSS (p = 0.003, clinically meaningful difference), WPAI Daily Activity Impairment (p = 0.022), EQ- 5D VAS (p < 0.001), and maximum Skindex-16 score (p = ). Trends for lower CES- D and WPAI Work Impairment scores were observed for AUC 12. There were fewer serious adverse events (AEs), treatment-related AEs, AEs leading to permanent stop and anaemia AEs (grade 3 and serious AEs) reported with SMV versus TVR. CONCLUSIONS: During the initial 12-Wk triple treatment period, patients on SMV/PR reported significantly less fatigue and skin symptoms, and less impairment in daily activities and QoL versus TVR/PR patients, consistent with the better safety profile of SMV versus TVR. Significant differences in AUC 12 in favour of SMV were not replicated in AUC 60 analyses due to longer PR therapy duration, which dominated the overall results. 4. Scott J, Corbett C, Gilles L, Wan G, Sbarigia U, Jessner W. Impact of simeprevir versus telaprevir triple therapy for chronic HCV infection on patient-reported outcomes in prior non-responders to peginterferon/ribavirin results from the phase III attain study [abstract]. Value in Health Conference: ISPOR 17th Annual European Congress Amsterdam Netherlands Conference Start: Conference End: Conference Publication: (var pagings) 17 (7) ()(pp A682), 2014 Date of Publication: November (Presented at ; Conference Publication: (var.pagings). 17 (7) ()(pp A682), Date of Publication: November 2014.). OVID EMBASE Entry Week Objectives: In ATTAIN, a Phase III, randomised, head-to-head comparison study of simeprevir versus telaprevir, both with peginterferon/ribavirin (PR), in HCV genotype 1- infected prior null or partial PR responders, simeprevir exhibited better safety and tolerability. In this analysis, the impact on patient-reported outcomes (PRO) was analysed. Methods: Patients received simeprevir (150mg QD) or telaprevir (750mg TID, 7-9hrs apart) +PR for 12wks followed by PR alone (36wks) in a double-blind, double-dummy design. PRO questionnaires, completed at baseline, throughout treatment and at follow-up, rated fatigue severity (FSS), depressive symptoms (CES-D), work and daily activities impairment (WPAI: Hepatitis-C), health-related quality of life (EQ-5D visual analogue scale), and skin symptoms (Skindex-16). During simeprevir/telaprevir treatment, between-treatment meanvalue differences were calculated using area-under-the curve to Wk12 (AUC12) for all measures except Skindex- 16 where maximum (worst) scores during the first 12 wks were used. Subgroup analyses evaluated the impact of SVR12, age, fibrosis and treatment completion. Results: Compared with normative studies, baseline PRO scores indicated greater fatigue, depressive symptoms and daily activities impairment. Mean PRO scores in both groups worsened during the first 12 weeks of treatment, remained stable through Week 48 and returned to values close to baseline at end of treatment. Clinically relevant between-treatment differences in FSS, CES-D, Skindex-16 and EQ-5D scores indicated less impairment with simeprevir than telaprevir. AUC12 betweentreatment differences significantly favoured simeprevir for FSS (p= 0.003), WPAI Activity Impairment (p= 0.022), and EQ-5D (p< 0.001). Mean Skindex-16 maximum total (p= ) and subscale scores were significantly lower for simeprevir. Subgroup analyses showed less impairment with simeprevir versus telaprevir on most PRO scores in patients who failed treatment, were > 45 years old or had advanced fibrosis. Conclusions: Simeprevir/PR resulted in less fatigue, depressive and skin-related symptoms and less impairment in daily activities than telaprevir/pr. These findings Re-treatment with DAAs for Hepatitis C Patients - Update 6

7 provide valuable information on the tolerability of these regimens from the patient perspective. Non-Randomized Studies No conference abstracts identified. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Re-treatment with DAAs for Hepatitis C Patients - Update 7