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Emerging Oral, Combination, Interferon-Free Regimens for the Treatment of Chronic Hepatitis C Genotype 1

Published on: November 20, 2014
Project Number: EH0015
Issue: 140
Result type: Report

Summary

  • All-oral, interferon-free regimens for the treatment of chronic hepatitis C genotype 1 are alternatives to the combination of direct-acting antivirals with pegylated interferon and ribavirin.
  • These regimens include multiple direct-acting antiviral agents with different mechanisms of action. Of the regimens, only the combinations of ledipasvir and sofosbuvir (Harvoni) and omibitasvir/ paritaprevir/ritonavir and dasabuvir (Holkira) are approved for use in Canada. Other regimens are currently under review by Health Canada and could potentially receive market access in 2015.
  • The regimens and findings from phase 2 and 3 clinical trials are summarized in Table 1. While several regimens have been approved for use, others remain in the development stage and, as such, it is uncertain whether they will be marketed in Canada in the future.

The Technology

Oral, interferon-free regimens for the management of genotype 1 chronic hepatitis C (CHC) currently under development consist of combinations of direct-acting antiviral agents (DAAs) that differ in their mechanisms of action, which may reduce the potential for resistance and improve efficacy. The first DAAs approved for the treatment of CHC were boceprevir and telaprevir, both first-generation NS3/4A protease inhibitors (PIs).1 Boceprevir and telaprevir are used in combination with pegylated interferon and ribavirin (PR), as rapid emergence of resistance can occur with either when used as monotherapy.2 However, additive adverse effects and poor tolerability are concerns with these triple-therapy regimens.2 Moreover, cure rates with the first-generation PIs combined with PR remained suboptimal in important subgroups of patients (i.e., those with genotype 1a CHC or cirrhosis, or previous null responders to PR), with sustained virologic response (SVR) rates of 30% to 40%.2 Telaprevir had been discontinued in Canada, and both boceprevir and telaprevir had been discontinued in the United States.3,4 Thus, the need for more efficacious, better-tolerated regimens for the management of genotype 1 CHC remained. Initially, the second-generation PI, simeprevir, and first polymerase inhibitor, sofosbuvir, offered some improvement over the first-generation PIs in terms of treatment duration, ease of dosing, and adverse effect profile, but the required co-administration with interferon still presented a burden for patients in terms of tolerability. However, simeprevir and sofosbuvir in combination are now approved for the treatment of CHC genotype 1 without requiring the co-administration of interferon. There are newer DAAs that have recently been approved in Canada, those that are currently under review by Health Canada and others that are under development, that target proteins involved with the replication of the chronic hepatitis C virus (HCV) and include NS5B nucleotide polymerase inhibitors, NS5B non-nucleoside polymerase inhibitors, and NS5A replication complex inhibitors.2

Multi-drug, interferon-free, oral regimens of DAAs are currently in various stages of development; some have reached phase 2 and phase 3 clinical trials (Table 2) and a few have reached the stage of regulatory approval. Some combination regimens include ribavirin; however, some are also ribavirin-free.

An optimal treatment regimen for CHC would be pan-genotypic, and have a high efficacy and barrier to resistance while being simple and convenient from the patient perspective. The ideal regimen would also have a favourable adverse effect profile and few drug interactions (for example, with treatments for HIV and tuberculosis, methadone, buprenorphine, statins, hormonal contraception, and psychotropic medications).5 In addition, characteristics that improve adherence to treatment — including all-oral administration without regard to food, low pill burden, once-daily administration, and an abbreviated treatment duration (preferably 12 weeks or fewer) — are important.5,6 Furthermore, the regimen ideally would not require pre-treatment testing (interleukin [IL]-28B genotyping, viral subtyping, and drug resistance) or extensive, ongoing monitoring for safety and efficacy.5

Regulatory Status

The anticipated timeline for submission and regulatory approval for the majority of regimens outlined in Table 1 could not be determined at the time of writing of this Bulletin.

Ledipasvir 90 mg/sofosbuvir 400 mg (LDV/SOF) — The fixed-dose combination of ledipasvir 90 mg/sofosbuvir 400 mg (LDV/ SOF), marketed under the brand name Harvoni, received a Notice of Compliance from Health Canada in October 2014 for the treatment of genotype 1 CHC in adults as a single, oncedaily, fixed-dose tablet.13 Although studied with and without ribavirin, its Health Canada–approved indication does not require treatment in combination with ribavirin.14

Sofosbuvir — Sofosbuvir is also available in Canada as a 400 mg tablet (Sovaldi) and approved for the management of genotype 1 CHC in combination with PR or ribavirin alone (see Table 2).15 Sovaldi is also indicated in the treatment of genotype 4 CHC infection in combination with PR and for the treatment of genotype 2 and genotype 3 CHC infection in combination with ribavirin alone.16

AbbVie 3D combination — The combination of ombitasvir (ABT- 267)/paritaprevir (ABT-450)/ritonavir (150 mg/100 mg) once daily co-packaged with 25 mg, dosed once daily, and dasabuvir (ABT-333) 250 mg, dosed twice daily (a regimen referred to as “3D”), was recently approved for use in Canada under the brand name Holkira for patients with genotype 1 CHC as a 12-week regimen for most indications.17

Daclatasvir combinations — The combination of daclatasvir with sofosbuvir is approved for use in Europe for genotype 1 CHC.18 In addition, daclatasvir is currently approved for use in Japan in combination with the protease inhibitor asunaprevir. The approval of daclatasvir is also expected to be pursued in other countries with the exception of the United States, where plans to pursue the regulatory approval of this combination were abandoned.19 However, the combination of asunaprevir, daclatasvir, and beclabuvir continues to be developed.20-23

Simeprevir and sofosbuvir — The combination of simeprevir and sofosbuvir was recently added as an approved indication to the labelling of simeprevir in both Canada and the US.24 In Canada, simeprevir was issued a Health Canada Notice of Compliance with conditions in January 2015 for use in combination with sofosbuvir for the treatment of genotype 1 CHC in adults with compensated liver disease.12 Simeprevir is also approved for use in Europe for genotype 1 CHC in combination with sofosbuvir with or without ribavirin.25 Simeprevir is marketed in Canada as a 150 mg capsule under the brand name Galexos and is also approved for the treatment of genotype 1 CHC in combination with PR.26

Table 1: Summary of Oral, Interferon-Free Treatment Regimens for the Treatment of Chronic

Regimen and Manufacturer (Brand Name) Regulatory Status in Canada Phase (Number of Included RCTs) Treatment Durationa SVR12
Ledipasvir/sofosbuvir without ribavirin Gilead (Harvoni) Approved for use Phase 3 (3)
Phase 2 (2)
8 to 24 weeksb 93% to 100%
Sofosbuvir with ribavirin Gilead Approved for usec Phase 2 (1) 24 weeks 48% to 68%d
Sofosbuvir/GS-9669
Gilead
Not yet approved Phase 2 (1) 6 to 12 weeks 68% to 100%
Sofosbuvir/ledipasvir/GS-9669
Gilead
Not yet approved Phase 2 (1) 8 weeks 82% to 91%
Sofosbuvir/simeprevir Janssen Approved for usee No studies met the inclusion criteria for the review 12 to 24 weeksf 93%f
Sofosbuvir/daclatasvir with or without ribavirin
BMS
Not yet approved Phase 2 (1) 12 to 24 weeks 95% to 100%
Sofosbuvir/GS-5816 with or without
ribavirin Gilead
Not yet approved Phase 2 (2) 8 to 24 weeks 81% to 100%
Ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin
AbbVie (Holkira Pak)
Approved for use Phase 3 (4)
Phase 2 (1)
12 to 24 weeksg 90% to 100%h
Ombitasvir/paritaprevir/ritonavir AbbVie Not yet approved Phase 2 (1) 12 to 24 weeks 89% to 100%
Daclatasvir/asunaprevir BMS Not yet approved Phase 3 (1) 24 weeks 82% to 90%

Daclatasvir, asunaprevir, and beclabuvir with or without ribavirin
BMS

Not yet approved

Phase 3 (1)

12 weeks

87% to 98%

Grazoprevir/elbasvir with or without
ribavirin Merck

Not yet approved

Phase 2 (1)

8 to 12 weeks

80% to 98%

Daclatasvir and simeprevir with or without ribavirin
Janssen BMS

Not yet approved

Phase 2 (1)

12 to 24 weeks

0% to 95%

IU = international unit; RCT = randomized controlled trial; RNA = ribonucleic acid; SVR = sustained virologic response at 12 weeks.
a Duration of treatment in the studies included in this Bulletin.
b The treatment duration according to Health Canada approval. Eight weeks can be considered in treatment-naive patients who have a hepatitis C RNA < 6 million IU/mL.
c Sofosbuvir in combination with ribavirin for 24 weeks can be considered as a therapeutic option for treatment-naive and non-cirrhotic treatment-experienced chronic hepatitis C patients with genotype 1 infection who are ineligible to receive an interferon-based regimen.7
d SVR at 24 weeks.
e Simeprevir was issued a Health Canada Notice of Compliance with conditions in January 2015 for use in combination with sofosbuvir for the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease.

Patient Group

It is estimated that more than 250,000 Canadians have CHC infection, affecting approximately 1% of the population.27,28 The prevalence of CHC peaks in young to middle-aged adults (those aged 30 to 59 years).28 There are six main genotypes of HCV, of which the most prevalent in Canada is genotype 1 (approximately 65% of the HCV-infected patient population). There are two subtypes of genotype 1 (1a and 1b), with 1a being more prevalent.28 Approximately 60% of HCV cases are attributable to current or former use of injection drugs, while approximately 11% of cases are attributable to contaminated blood products.29

Acute infection with HCV is most frequently asymptomatic.30 Following acute infection with HCV, the risk of developing CHC is high, with approximately 50% to 85% of individuals remaining positive for HCV ribonucleic acid (RNA).30 As with acute infection, CHC is often asymptomatic or is associated with mild, non-specific symptoms. For those with symptoms, fatigue is most common, but less frequent manifestations include nausea, anorexia, myalgia, arthralgia, weakness, and weight loss.30 Approximately 15% to 20% of individuals with CHC will develop end-stage liver disease over 20 years of infection.31 All-oral interferon-free regimens may be more efficacious, better tolerated, and more convenient for treatment-naive and treatment-experienced patients and will provide an additional treatment alternative for these patients.

Table 2: Oral Interferon-Free Regimens for Genotype 1 Chronic Hepatitis C in Phase 2 or Phase 3 Clinical Trials

Manufacturer Combination of Agents
  NS3/4 Protease Inhibitor NS5B Nucleotide Polymerase Inhibitor NS5B Non- Nucleoside Polymerase Inhibitor NS5A Replication Complex Inhibitor Ribavirin Included Phase of Development
Gilead   sofosbuvir   GS-5816 Without Phase 3
  sofosbuvir     With Phase 2
  sofosbuvir GS-9669   Without Phase 2
  sofosbuvir GS-9669 ledipasvir Without Phase 2
  sofosbuvir   ledipasvir Without Phase 3a
AbbVie paritaprevirb/ ritonavir   dasabuvir ombitasvir With or without Phase 3a
paritaprevirb/ ritonavir   dasabuvir ABT-530 (for
first 3 days) ombitasvir
With Phase 2
ABT-493
paritaprevir/ ritonavirb
  dasabuvir ombitasvir With Phase 3
ABT-493     ABT-530   Phase 2
Merck grazoprevirc sofosbuvir   elbasvird With Phase 2
grazoprevirc     elbasvird With or without Phase 2
Merck BMS grazoprevirc     daclatasvir Without Phase 2
Achillion sovaprevir     ACH-3102 Without Phase 2
Janssen
Idenix Pharmaceuticals
simeprevir     samatasvire With or without Phase 2
Janssen
BMS
simeprevir     daclatasvir With or without Phase 2
BMS asunaprevir     daclatasvir Without Phase 3
asunaprevir   beclabuvirf daclatasvir With or without Phase 3
  sofosbuvir   daclatasvir Without Phase 3
Janssen simeprevir sofosbuvir     With or
withoutg
Phase 3
simeprevir sofosbuvir   daclatasvir Without Phase 2

a Combinations have received Health Canada Notice of Compliance.
b  Formerly ABT-450. c Formerly MK-5172.
d Formerly MK-8742. e Formerly IDX719.
f  Formerly BMS-791325.
g Simeprevir was issued a Health Canada Notice of Compliance with conditions in January 2015 for use in combination with sofosbuvir for the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease.12

Current Practice

According to the most recent update (2015) of consensus guidelines from the Canadian Association for the Study of the Liver (CASL),32 all patients with CHC should be considered candidates for antiviral therapy, particularly those with evidence of liver fibrosis.32 The decision to initiate treatment is based on patient preference and potential risks and benefits of treatment. The goal of antiviral therapy is complete eradication of the virus, as measured by an SVR at least 24 weeks after the end of treatment.29 The treatment choice for patients with genotype 1 CHC may take into consideration expected efficacy, duration of the regimen, and the adverse effect profile. In addition, the potential for drug interactions, contraindications, comorbid medical conditions, the patient’s experience with previous treatment, and the stage of fibrosis are considerations.33

The 2015 update to the CASL guidelines recommends the use of all-oral interferon-free regimens as first-line therapy for treatment-naive and treatment-experienced patients with genotype 1 CHC.32 This includes the combination of ledipasvir 90 mg/sofosbuvir 400 mg (Harvoni) and the AbbVie 3D combination (Holkira Pak). At the same time, the guidelines recognize that access to such regimens may not be universal across Canada and that other factors, such as the patient’s wishes, the severity of liver disease, and the potential to tolerate PR, are also considerations.32 Recent Canadian guidelines for the treatment of HIV/HCV coinfection34 recommend the combinations of simeprevir and sofosbuvir and sofosbuvir with ribavirin as alternatives for treatment-naive patients with genotype 1 CHC without cirrhosis. For treatment-naive patients with cirrhosis, simeprevir and sofosbuvir is also recommended as an alternative.

Methods

Literature Search

A peer-reviewed literature search was conducted using the following bibliographic databases: MEDLINE, PubMed, and Embase. Grey literature was identified by selectively searching relevant sections of the Grey Matters checklist (http://www.cadth.ca/resources/grey-matters). No filters were applied to limit the retrieval by study type. The search was limited to English-language documents published between January 1, 2012 and September 15, 2014. Regular alerts were established to update the search until February 23, 2015.

Study Selection

Phase 2 or 3 randomized controlled clinical trials, published in full or as conference abstracts, that compared interferonfree oral regimens with placebo or an active comparator (consisting of PR alone or in combination with a DAA) in adults with genotype 1 CHC were selected for inclusion. Open-label extension trials were not included, nor were interim reports of phase 2 or phase 3 randomized controlled trials (RCTs), studies in which patients received treatment for less than one week, or studies that compared only the identical regimen with a different duration of treatment (as per Table 3). The proof-ofconcept phase 2a studies were excluded. However, those phase 2 studies that did not specify whether the trial phase was 2a or 2b were included.

The Evidence

Efficacy

Phase 2 and phase 3 RCTs of all-oral, interferon-free regimens for genotype 1 CHC are summarized in Appendix A, including study design, patient populations, treatment regimens, SVR at 12 and 24 weeks (where reported), and a summary of the key limitations. The key limitations were similar for the included studies (Appendix A) and were mainly related to the generalizability of the findings, the open-label designs, and the use of historical controls. Some studies excluded patients with HIV or hepatitis B coinfection and cirrhosis; thus, the SVR that was achieved may not be applicable to those populations. Exclusion of patients based on previous adverse reactions may also affect the generalizability of a few studies,35-37 as this may have led to the selection of patients less likely to experience an adverse reaction. In some studies, particularly those with multiple treatment arms, the number of participants in each arm was relatively small, which could limit their study power in identifying rare adverse events. While the outcome of SVR may be objective, reporting of adverse events could potentially be influenced by knowledge of treatment, as could patient-reported outcomes (reported in only one study38). In some studies, participants were first randomized to a blinded placebo arm, then treated with the active drug so that the adverse events associated with the investigational product could be evaluated against those of the untreated condition. The use of the historical control has some important limitations. Comparison with a historical control is not equivalent to randomizing participants to a treatment or control group and then making a statistical comparison between the groups. Further, given that the characteristics of the historical controls were not reported, it is unclear how similar the historical control patients and study participants would be, thereby decreasing confidence in the findings. Moreover, it is not clear that the treatment received by the historical control aligns with current practice. Thus, the relevance of a comparison with these treatment regimens is unclear.

Table 3: Selection Criteria for Phase 2 and Phase 3 Studies of Oral, Interferon-Free Regimens for Genotype 1 Chronic Hepatitis C

Populations Adult patients with genotype 1 CHC
Mixed populations of multiple genotypes; provided data for genotype 1 CHC were reported separately
Interventions Interferon-free regimens in phase 2b or 3 clinical stage development
Comparators Placebo
Active comparators (e.g., PR or PR + DAA)
Outcomes SVR, adverse effects
Study Design Inclusion: Phase 2b or 3 randomized controlled clinical trials, published in full or as conference
abstracts
Exclusion: Open-label extension trials, interim reports of results, proof-of-concept studies of limited duration (e.g., fewer than 7 days of treatment)

CHC = chronic hepatitis C; DAA = direct-acting antiviral; PR = pegylated interferon and ribavirin; SVR = sustained virologic response.

Ledipasvir/Sofosbuvir With and Without Ribavirin (Harvoni)

Four phase 2 or 3, open-label RCTs35,36,38,39 (ION-1, ION-2, ION-3, and LONESTAR) and one double-blind RCT40 met the selection criteria in which a fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) was evaluated with and without ribavirin (see Appendix A). Across the five studies, the combination was assessed in treatment-naive and treatment experienced populations, with study outcomes assessed and analyzed separately for these groups. The studies were conducted in the US,35,36,38,39 Europe,38 and France.40 Durations of treatment ranged from eight weeks to 24 weeks, with the SVR evaluated at 12 weeks (SVR12) in most studies. The SVR12 ranged from 93% to 100% and was numerically similar between eight-, 12-, and 24-week durations of treatment. The SVR was similar between treatment arms that did and did not receive ribavirin.

Sofosbuvir With Ribavirin

One phase 2 open-label RCT compared sofosbuvir in combination with two different regimens of ribavirin (standard and low-dose).41 The study was conducted in the US and included only treatment-naive patients who were seronegative for HIV and hepatitis B. The duration of treatment was 24 weeks. The SVR12 was 68% with standard dosing of ribavirin and 48% with low-dose ribavirin (see Appendix A).

Sofosbuvir and GS-9669 Compared With Ledipasvir/ Sofosbuvir

The combination of sofosbuvir and GS-9669 was compared with LDV/SOF in treatment-naive and treatment-experienced patients with genotype 1 CHC, in a phase 2, open-label RCT (ELECTRON) conducted in New Zealand.42 The duration of treatment was 12 weeks. All LDV/SOF and GS-9669 plus SOF groups received ribavirin as part of the regimen, with the exception of one group of treatment-experienced patients with cirrhosis, who were treated with LDV/SOF alone for 12 weeks. In addition, one treatment-naive arm received LDV/SOF with ribavirin for six weeks, rather than 12 weeks. In treatment-naive and treatment-experienced patients, the SVR12 was 100% both in the LDV/SOF group and the SOF plus GS-9669 group. The SVR12 was 68% (95% confidence interval [CI], 47% to 85%) with six weeks of LDV/SOF in the treatment-naive population. In treatment-experienced patients, LDV/SOF with ribavirin was compared with LDV/SOF alone, and it was found that the SVR12 was lower in the absence of ribavirin (70% with LDV/SOF alone versus 100% for LDV/SOF with ribavirin).

Ledipasvir/Sofosbuvir with GS-9669 Compared With Ledipasvir/Sofosbuvir and Ribavirin

The combination of SOF, GS-9669 (250 mg or 500 mg), and LDV (two arms) was compared with LDV/SOF and ribavirin (one arm) in a US-based phase 2 open-label RCT that included patients with genotype 1 CHC and compensated cirrhosis.43 Patients in all arms were treated for eight weeks. The SVR12 was 82% in the sofosbuvir, GS-9669 500 mg, and LDV arm; 89% in the LDV/SOF with ribavirin (RBV) arm; and 91% in the arm received sofosbuvir, GS-9669 250 mg, and LDV (see Appendix A).

Sofosbuvir and Daclatasvir With or Without Ribavirin

In a US-based phase 2, open-label RCT that included treatmentnaive and treatment-experienced patients with genotype 1 CHC, combinations of sofosbuvir and daclatasvir (SOF/DCV) with and without ribavirin were compared (see Appendix A).37 Treatment regimens with durations of 12 and 24 weeks were assessed. The SVR12 ranged from 95% to 100% and was similar in groups that did and did not receive ribavirin, and in treatment-naive and treatment-experienced patients. The SVR24 was reported for treatment-experienced patients and ranged from 93% (SOF/DCV with ribavirin for 12 weeks) to 100% (SOF/DCV with and without ribavirin for 24 weeks).

Sofosbuvir and GS-5816 With or Without Ribavirin

Multiple dosages of GS-5816 in combination with sofosbuvir (with or without ribavirin) were compared in treatment-naive patients without cirrhosis for eight- and 12-week durations in two open-label phase 2 RCTs (see Appendix A).44,45 For the eight-week regimens,44 the SVR12 ranged from 81% to 90%, while the SVR12 ranged from 96% (SOF/GS-5816 25 mg without ribavirin) to 100% (SOF/GS-5816 100 mg without ribavirin) with 12 weeks of treatment.

Ombitasvir/Paritaprevir (ABT-450)/Ritonavir

The combination of paritaprevir/ritonavir with ombitasvir was evaluated in one open-label phase 2 study conducted in Japan (see Appendix A).46 The study included treatmentexperienced, non-cirrhotic patients with genotype 1b CHC. Four treatment regimens were assessed that differed in the dosage of paritaprevir (100 mg versus 150 mg) and duration of treatment (12 weeks versus 24 weeks). In the treatment arms that received ombitasvir with paritaprevir/ritonavir 100 mg/ 100 mg for 12 weeks and 24 weeks, the SVR12 was 100%. In the treatment arms that received ombitasvir with paritaprevir/ ritonavir 150 mg/100 mg, the SVR12 was 89% with 12 weeks’ duration of therapy, but 100% with 24 weeks’ duration.

Ombitasvir/Paritaprevir (ABT-450)/Ritonavir and Dasabuvir (Holkira Pak) With or Without Ribavirin

The combination of paritaprevir/ritonavir, dasabuvir, and ombitasvir (referred to as “3D” and marketed in Canada under the brand name Holkira Pak) has been evaluated in one phase 2b47 (AVIATOR) and three phase 3, non-inferiority, open-label (PEARL-II) and double-blind (PEARL-III, and PEARL-IV) RCTs,8,9 as well as two randomized, double-blind placebo-controlled trials10,11 (SAPPHIRE-I and SAPPHIRE-II) conducted in Canada, the US, Europe, and the United Kingdom (see Appendix A). The studies included both treatment-experienced and treatmentnaive non-cirrhotic patients with genotype 1 CHC. Treatment regimens of 12 weeks were evaluated in all studies, with the 3D combination being assessed alone or with ribavirin. In one study, eight- and 24-week regimens were also evaluated (AVIATOR).47 SVR12 rates ranged from 90% to 100%. SVR24 rates ranged from 83% to 100% in the phase 2b study (AVIATOR).47 Three studies that assessed the non-inferiority of the 3D combination alone compared with the 3D combination with ribavirin found that 3D alone was non-inferior.8,9

Daclatasvir and Asunaprevir

The HALLMARK DUAL study48 was an international phase 3 study that included four treatment arms in total. Treatmentnaive patients with genotype 1b CHC were randomized in a 2:1 ratio to receive daclatasvir and asunaprevir or placebo; however, no results were reported for the placebo group. The other two treatment arms (non-responders and patients ineligible for or intolerant to PR) received open-label daclatasvir and asunaprevir, with no comparator. The SVR12 in both of these groups was 82% (95% CI, 77% to 87%). In treatment-naive patients, the SVR12 was 90% (95% CI, 85% to 94%).

Daclatasvir, Asunaprevir, and Beclabuvir With or Without Ribavirin

The UNITY-2 study was an international phase 3 RCT that compared daclatasvir, asunaprevir, beclabuvir, and RBV with daclatasvir, asunaprevir, beclabuvir, and placebo in treatmentnaive and treatment-experienced patients with genotype 1 CHC and compensated cirrhosis (see Appendix A).20 Patients in all arms received 12 weeks of treatment. In treatment-naive patients, the SVR12 was 93% in the arm without ribavirin and 98% in the ribavirin arm, while in treatment-experienced patients, the SVR12 was 87% in the arm without ribavirin and 93% in the ribavirin arm.

Grazoprevir/Elbasvir With or Without Ribavirin

An open-label phase 2 study (C-WORTHY Part B) assessed the efficacy of the combination of grazoprevir/elbasvir with or without ribavirin in four different groups of patients with genotype 1 CHC: treatment-naive patients with HIV; treatment-naive patients without HIV; treatment-naive patients with cirrhosis; and null responders with or without cirrhosis.49,50 Results were published in two different reports (see Appendix A).49,50 For the first two treatment arms, eight- and 12-week regimens were assessed in the monoinfected population, while the HIV-coinfected population was treated for 12 weeks only.49 The SVR12 ranged from 80% (in the eight-week regimen) up to 98% in the other treatment arms. Treatment regimens of 12 and 18 weeks were also assessed in treatment-naive patients with cirrhosis and in null responders with or without cirrhosis.50 In previously treated patients with cirrhosis, the SVR12 ranged from 90% to 94%, while in null responders with or without cirrhosis, the SVR12 ranged from 91% to 100%.50

Daclatasvir and Simeprevir With or Without Ribavirin

The efficacy of the combination of daclatasvir and simeprevir (SMV) with or without ribavirin was assessed in treatmentnaive and treatment-experienced patients (null responders) in a phase 2, open-label RCT (LEAGUE-I).51 The duration of treatment was for 12 or 24 weeks (see Appendix A). The results were presented in an abstract in which it was unclear whether the outcomes reported were for 12- or 24-week treatment regimens. In treatment-naive patients, the SVR12 ranged from 75% to 85%, with the lower SVR being for the combination with ribavirin. No explanation was provided for this finding. For null responders, the SVR12 was 0% for genotype 1a (treated with DCV and SMV and RBV), 65% for genotype 1b treated with DCV plus SMV, and 95% for genotype 1b treated with DCV plus SMV and RBV. It should be noted that the dose of DCV used in the LEAGUE-1 study was 30 mg, due to a drug interaction with SMV, which was expected to increase DCV exposure two-fold. However, ongoing trials of DCV plus SMV are using a 60 mg dose, as the increase in DCV exposure related to the drug interaction was not as large as originally anticipated.52

Adverse Effects

The most frequently observed adverse effects reported in clinical trials of oral interferon-free regimens for genotype 1 CHC are summarized in Table 4. Overall, headache, fatigue, and nausea were the most frequently observed.

Administration and Cost

The antiviral regimens included in this Bulletin were all administered orally, requiring once- or twice-daily dosing. The pill burden would be expected to differ to some extent across regimens, although co-formulated tablets that include two or three different drugs have been used in trials, which simplifies the regimens somewhat. The combination of LDV/SOF (Harvoni) is administered as a once-daily, single tablet, whereas Holkira (3D regimen) is administered as two tablets (ombitasvir/ paritaprevir/ritonavir co-formulation) taken once daily and one tablet (dasabuvir) twice daily. However, for many regimens, the number of tablets or dosing times required for each regimen was unclear from the study descriptions. In addition, it is possible that later in the development of the all-oral interferonfree regimens, co-formulations will be introduced to reduce the pill burden. Thus, comparison of pill burden across regimens is premature at present. For those regimens that have not yet been approved by Health Canada, the cost of the regimens has not yet been determined. The cost of Harvoni in Canada is approximately $798 per tablet, and $44,667 and $67,000 for the eight-week and 12-week regimens, respectively.55 The cost of Sovaldi (sofosbuvir alone) is $655 per tablet55 and Galexos (simeprevir) is $435 per capsule.55 This would make the cost of a 12-week course of the combination simeprevir/sofosbuvir $91,560. The cost of Holkira Pak in Canada is $665 per daily pack and $58,653 to 117,306 for the annual cost of therapy.56

Concurrent Developments

In addition to the regimens listed in Table 2, other all-oral regimens for the CHC virus that are in development are listed in Appendix B. Appendix B also lists ongoing studies for several of the regimens from Table 2 that do not have trial results reported.

Rate of Technology Diffusion

Compared with the current standard regimens that include PR, all-oral, interferon-free regimens have advantages in terms of convenience, potential for improved adherence related to oral administration, shorter duration of treatment, and favourable adverse effect profiles, and these advantages may contribute to rapid uptake of these regimens. There is also no need for interferon, which is attractive given interferon’s unfavourable impact in terms of adverse effects and quality of life. In addition, there may be a clinical advantage of increased rates of SVR 12 to 24 weeks after treatment, based on clinical trial evidence. There may be a potential for off-label use of DAAs that are active against other genotypes of HCV, in addition to genotype 1. The majority of included phase 2 and phase 3 RCTs excluded certain populations, such as HIV- or hepatitis B–coinfected patients or patients with cirrhosis. However, data from the HIV-coinfected population in the C-WORTHY study suggest SVR rates and adverse events that are similar to monoinfected patients.49 Further, in the TURQUOISE-II study, which included only patients with genotype 1 CHC and cirrhosis, ombitasvir/ paritaprevir/ritonavir and dasabuvir (3D regimen) demonstrated SVR rates superior to a historical control and infrequent discontinuations due to adverse effects.57 Despite limited RCT evidence, it is possible that oral agents will be used in these populations. Studies for some all-oral, interferon-free regimens are ongoing in more specific populations, such as those with cirrhosis and HIV coinfection (see Appendix B). Observational or non-randomized studies or RCTs assessing the safety and efficacy in these excluded populations are currently ongoing, so adoption in populations outside of the scope of the trials included in this Bulletin remains a possibility.

Table 4: Most Frequently Observed Adverse Effects Reported in Clinical Trials of Oral Interferon-Free Regimens for Genotype 1 Chronic Hepatitis C

Ledipasvir/sofosbuvir with and without ribavirin ION-153
Headache (25%), fatigue (23%), and nausea (12%)

ION-235
Headache (26% to 32%), fatigue (21% to 45%), and nausea (6% to 23%)

ION-339
Headache (14% to 25%), fatigue (21% to 35%), and nausea (7% to 18%)

LONESTAR36
Headache (5% to 14%), nausea (0% to 10%), and decreased appetite (0% to 10%)

Sofosbuvir with ribavirin Osinusi41
Headache (28%), anemia (16% to 32%), fatigue (16% to 24%), and nausea
(16% to 24%)
Sofosbuvir and GS-9669 ELECTRON42
Headache (22% to 67%), fatigue (10% to 78%), and nausea (0% to 44%)
Sofosbuvir/ledipasvir and GS-9669 Headache, diarrhea, and nausea (data not reported)
Sofosbuvir and daclatasvir with or without ribavirin Sulkowski37
Fatigue (29% to 50%), headache (16% to 38%), and nausea (0% to 32%)
Sofosbuvir and GS-5816 with or without ribavirin Tran 201444
Fatigue, headache, and nausea (> 10%)

Pianko 201445
Fatigue, headache, nausea, and insomnia (> 10%)

Ombitasvir/paritaprevir/ritonavir Chayama46
Headache (6% to 16%), back pain (11% to 17%), diarrhea (0% to 17%), vomiting
(0% to 17%)
Ombitasvir/paritaprevir/ ritonavir and dasabuvir with or without ribavirin PEARL-II8
Fatigue (16% to 32%), headache (23% to 24%), and nausea (6% to 29%)

PEARL-III and PEARL-IV9
Headache (23% to 28%), nausea (4% to 21%), fatigue (21% to 46%), pruritus (5% to
12%), and insomnia (3% to 17%)

SAPPHIRE-I10
Fatigue (29% to 35%), headache (27% to 33%), and nausea (13% to 24%)

SAPPHIRE-II11
Fatigue (23% to 33%), headache (35% to 36%), and nausea (18% to 20%)

AVIATOR47
Fatigue (21% to 36%), headache (19% to 35%), and nausea (13% to 25%)

Daclatasvir and asunaprevir without ribavirin HALLMARK DUAL48
Headache (20% to 25%), fatigue (17% to 22%), diarrhea (11% to 22%), and nausea
(11% to 12%)
Daclatasvir, asunaprevir, and beclabuvir with or without ribavirin UNITY-220
Fatigue, headache, nausea, diarrhea, insomnia, and pruritus (> 10% of patients)
Grazoprevir, elbasvir with or without ribavirin C-WORTHY49,50
Fatigue (7% to 47%), headache (3% to 35%), and nausea (0% to 27%)
Daclatasvir and simeprevir with or without ribavirin LEAGUE-154
Most common adverse effects not reported.

The cost of the all-oral, interferon-free regimens may potentially be a barrier to treatment for many patients in the absence of reimbursement by third-party payers. It is conceivable that manufacturers may establish programs to facilitate financial access to these regimens for treatment-eligible patients who require such assistance. Gilead, the manufacturer of Harvoni, is currently offering such a program.13

Implementation Issues

The availability of treatment options for genotype 1 CHC is changing quickly. With numerous oral, interferon-free regimens either already on the Canadian market or in development, there is the potential for multiple treatment options to be available. Due to the rapidly changing landscape, treatment guidelines for regimen selection, sequence, and individualization of therapy based on response may lag behind clinical practice for the foreseeable future. Care will have to be provided by a highly knowledgeable team, and frequent monitoring and follow-up will be needed to optimize treatment. It is possible that there will be regional, knowledge, and infrastructure gaps. The guidelines from CASL state that all patients should be considered as candidates for antiviral therapy.32 However, high drug cost remains a barrier for treatment access. In addition, accessibility to accurate, non-invasive means of liver fibrosis assessment across jurisdictions has been identified in the guidelines as critical to the treatment of CHC.32 Current gaps in the evidence include the safety and efficacy of the all-oral interferon-free regimens in subgroups, such as those with HIV or hepatitis B coinfection, and salvage treatment options for patients who do not achieve an SVR following all-oral interferon-free therapy.

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Author: Ron Pohar

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Cite as: Emerging oral, combination, interferon-free regimens for the treatment of chronic hepatitis C. Ottawa: CADTH; 2015 Oct. (CADTH issues in emerging health
technologies; issue 140)

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ISSN: 1488-6324