Drugs for Chronic Hepatitis C Infection

1. Drugs for Chronic
Hepatitis C Infection
MAY 6, 2017
Shannon Kelly, MSc, PhD (in progress)
University of Ottawa Heart Institute

2. Authorship
Presentation authors:
Shannon Kelly, MSc, PhD (in progress)
University of Ottawa Heart Institute
Presentation based on:
George Wells, Shannon Kelly, Bechara Farah, Sumeet Singh, William Wong,
Murray Drahn, Karen Lee, Li Chen, Shuching Hsieh, David Kaunelis.
Drugs for chronic hepatitis C infection: clinical review, cost analysis, and
recommendations report. Ottawa: CADTH; 2016. Available from:
www.cadth.ca/drugs-chronic-hepatitis-c-infection
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CADTH adheres to the authorship and contribution guidelines established by the
International Committee of Medical Journal Editors (ICMJE).

3. Disclosure
• Funded by federal, provincial, and territorial ministries of
health.
• Application fees for three programs:
• CADTH Common Drug Review (CDR)
• CADTH pan-Canadian Oncology Drug Review (pCODR)
• CADTH Scientific Advice
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4. Outline
• Background
• CADTH Therapeutic Review of Hepatitis C therapies
• Methods (brief!)
• Overview of Efficacy and Safety Results
• Overview of Cost Effectiveness Results
• CDEC Recommendations
• Newer developments
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5. The Hepatitis C Virus
• Infects the liver
• Spread by blood contact (e.g., sharing needles, razors)
• No vaccine
• ~25% of infected people clear
the virus spontaneously;
remainder will develop chronic
infection
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6. Background
Chronic Hepatitis C (CHC) Infection:
• 242,000 infected individuals in Canada, ~7,900 new
infections each year, many may be undiagnosed.
• Genotype 1 is the most common (55% to 65%), followed
by genotypes 2 (14%) and 3 (20%); Genotypes 4 – 6
account for less than 5% of HCV cases.
• 15% to 25% of patients develop hepatocellular carcinoma
or progressive liver disease within 20 years of infection.
• Goal of therapy: prevent morbidity and mortality by
achieving sustained virological response (SVR).
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7. Background
Dramatic and ongoing shifts in CHC treatment:
• For many years, standard therapy for CHC infection
consisted of PEG-IFN-ribavirin (PR)
• In 2011, the first direct-acting antiviral (DAA) agents,
boceprevir and telaprevir, were approved in Canada — ↑
SVR in G1, still PR-based
• Continued developments have resulted in all-oral IFN-free
and even ribavirin-free regimens, some of which also have
activity beyond G1
• In 2015 alone, HARVONI (ledipasvir/sofosbuvir); HOLKIRA
PAK (paritaprevir/ritonavir/ombitasvir + dasabuvir); and
DAKLINZA (daclatasvir) were approved
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8. High costs
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Drug / Comparator Strength Dosage Form Duration
Cost for 1
course of
therapy ($)
Interferon-Free Regimens
HOLKIRA PAK
75/ 50/12.5 mg
250 mg Tab 12 to 24 weeksa
55,860 to 111,720
400 mg
600 mg
3,045 to 7,308
HARVONI 90/400 mg Tab 8 to 24 weeksd
44,667
(8 weeks)
67,000 to 134,000
(12 to 24 weeks)
Combination Peginterferon alpha plus Ribavirin Therapy
PegIFN alfa-2a plus RBV
(Pegasys RBV)
180 mcg /200mg
Vial or syringe/ 28,
35 or 42 Tabs
24 to 48 weeks 9,500 to 19,000
PegIFN alfa-2b plus RBV
(Pegetron)
50 mcg/200 mg 2 Vials + 56 Caps
24 to 48 weeks
9,437 to 18,873
150 mcg/200 mg
2 Vials + 84 or 98
Caps
10,428 to 20,855
80 mcg/200 mg
100 mcg/200 mg
120 mcg/200 mg
150 mcg/200 mg
2 Pens / 56 to 98
Caps
9,437 to 20,855

9. Background
CADTH has completed considerable work on CHC
treatments since 2011:
• Therapeutic Review with recommendations in October
2014 for CHC regimens available for G1 infection at the
time (PR, boceprevir, telaprevir, simeprevir, sofosbuvir)
• Rapid Response reports
• Common Drug Review listing recommendations
In 2015, CADTH updated its Therapeutic Review to
capture all-oral regimens and to expand scope to
genotypes 1 through 6.
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10. Research Questions
1. What is the comparative efficacy, safety, and cost
effectiveness of treatment regimens for patients with CHC
infection (treatment naïve, treatment experienced)?
2. Do comparative efficacy, safety, and cost-effectiveness
of treatment regimens vary across subgroups, e.g., by
fibrosis stage, HIV co-infection, by baseline viral load,
patients with liver transplant?
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11. Methods – Clinical Review
Systematic review of PUBLISHED evidence:
• Included all approved regimens, unapproved regimens
recommended by Canadian Association for Study of the
Liver (CASL) guidelines, and promising emerging
regimens (based on information available in early 2015).
Network meta-analysis (NMA):
• Used to generate indirect estimates of between-treatment
differences in efficacy (i.e., SVR) and for key adverse
events (rash, depression, anemia).
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12. Methods – Cost Effectiveness
• Cost-utility analysis, Markov model
• Primary outcome: number of Quality Adjusted Life Years
(QALYs), with treatments compared by incremental cost per
QALY (incremental cost-utility ratio (ICUR))
• Perspective: Ministry of Health in Canada
• Time Horizon: Lifetime
• Discount rate of 5%
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13. RESULTS
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14. 13
Genotype Health Canada
Approved Regimens
Guideline-recommended
Unapproved Regimens
1 HARVONI 12 weeks
(24 weeks for tx-exp pts with cirrhosis)
HOLKIRA PAK+/-RIBAVIRIN 12 weeks
DAKLINZA-SOVALDI 12 weeks
(24 weeks for pts with cirrhosis)
2 SOVALDI-RIBAVIRIN 12 weeks
DAKLINZA-SOVALDI 24 weeks
SOVALDI-PEGIFN-RIBAVIRIN 12 weeks
3 SOVALDI-RIBAVIRIN 24 weeks
DAKLINZA-SOVALDI 12 weeks
(24 weeks for pts with cirrhosis)
SOVALDI-PEGIFN-RIBAVIRIN 12 weeks
4 SOVALDI-PEGIFN-RIBAVIRIN 12 weeks SOVALDI-RIBAVIRIN 24 weeks
Key Regimens
HARVONI = ledipasvir/sofosbuvir; HOLKIRA PAK= ombitasvir/paritaprevir/ritonavir/dasabuvir;
SOVALDI=sofosbuvir; DAKLINZA=daclatasvir; PEGIFN = peginterferon alfa-2a/b

15. Results – Quantity of Evidence
Total of 77 studies included in systematic review
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Genotype Studies Reporting (n)
Single Genotype Studies
1 40
2 1
3 1
4 2
5 0
6 0
Mixed Genotype Studies
1 to 3 3
1 or 4 1
1,4,6 1
1,4 to 6 2
2, 3 5
Additional Studies (Outcomes not Reported by Genotype)
Mixed Genotype 8

16. Results – Genotype 1
Evidence Network for
Genotype 1, treatment-
naive
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17. Results for SVR – Genotype 1
For treatment-naïve and experienced patients:
• HARVONI, HOLKIRA PAK, DAKLINZA-based regimens were
superior to PR-based treatments.
• In pair-wise comparisons, generally no significant differences
across these three regimens.
• Results generally consistent across the various subgroups,
but HARVONI and HOLKIRA PAK were statistically superior
to DAKLINZA-based regimens in some subgroups.
• In particular, HOLKIRA PAK was better for genotype 1b
and for tx-exp patients without cirrhosis.
• There was less evidence for patients with cirrhosis.
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18. Results for SVR – Genotype 2
Treatment-naïve: SOVALDI-RIBAVIRIN 12 weeks significantly
improved SVR rates over PEGIFN-RIBAVIRIN 24 weeks in
treatment-naive patients.
Treatment-experienced: SOVALDI-RIBAVIRIN-PEGIFN 12
weeks was not significantly different from SOVALDI-
RIBAVIRIN 12 weeks.
No data for DAKLINZA-SOVALDI 24 weeks (HC approved
label) that could be analyzed in NMA.
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19. Results for SVR – Genotype 3
SOVALDI-RIBAVIRIN 24 weeks
SOVALDI-PEGIFN-RIBAVIRIN 12 weeks
DAKLINZA-SOVALDI 12 weeks
All significantly improved SVR compared with PEGIFN-
ribavirin 48 weeks regardless of treatment experience.
No significant differences between these three regimens.
No data for DAKLINZA-SOVALDI in patients with cirrhosis.
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20. Results for SVR – Genotype 4
Treatment naïve: SOVALDI-RIBAVIRIN 24 weeks and
SOVALDI-PEGIFN 12 weeks significantly improved SVR
compared with PEGIFN-ribavirin 48 weeks. No significant
differences between the two SOVALDI regimens.
Treatment experienced: DAKLINZA-PEGIFN 24 weeks
significantly improved SVR relative to SOVALDI-RIBAVIRIN
12 weeks.
No data available for analysis of SOVALDI-PEGIFN-
RIBAVIRIN 12 weeks, the only HC-approved regimen for
genotype 4.
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21. Results for SVR – Genotypes 5 & 6
Only one study (NEUTRINO) evaluated a regimen for
genotypes 5 and 6 infection that is currently on the market in
Canada (SOVALDI-PEGIFN-RIBAVIRIN 12 weeks).
In this study, all six patients with genotype 6 infection and the
single patient with genotype 5 infection who received this
regimen achieved SVR12.
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22. Results for SVR – Patients
previously treated with DAA
Evidence only in genotype 1
• HARVONI +/- RIBAVIRIN for 12 or 24 weeks
• SVR 96-100%: patients without cirrhosis
• SVR 85-100%: patients with cirrhosis, higher SVR in the
24-week arms
• SOVALDI-PEGIFN-RIBAVIRIN 12 weeks: SVR 79%
Only data for patients failing prior all-oral therapy was
from 14 patients treated with HARVONI 12 weeks: 100%
SVR
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23. Results – Safety
Rash and anemia:
• HARVONI, HOLKIRA PAK, DAKLINZA associated with
significantly lower risks than PR-based treatments
• HOLKIRA PAK + RIBAVIRIN less favourable for rash than
the other regimens and HOLKIRA PAK without ribavirin
• HOLKIRA PAK +/- RIBAVIRIN was less favorable than
HARVONI for anemia
Depression:
• HARVONI and DAKLINZA associated with significantly
less depression compared to PR-based treatments, but
not HOLKIRA PAK
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24. Cost effectiveness results
Genotype 1: HOLKIRA PAK and HARVONI were the most
cost effective treatments versus PEGIFN-ribavirin
• E.g., ICURs ~$30,000 per QALY in treatment-naïve,
somewhat less for treatment-experienced
• Very small incremental differences in QALYs between
HARVONI and HOLKIRA PAK
• Treatment with all-oral therapy cost-effective across full
range of fibrosis scores (F0-F4)
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25. Cost effectiveness results
Genotypes 2, 3, and 4:
• Newer regimens generally not cost-effective compared with
PEGIFN-RIBAVIRIN for treatment-naïve patients without
cirrhosis
• Cost effectiveness improves in patients with cirrhosis
• Also likely to be cost-effective in treatment-experienced
patients versus no therapy
Genotypes 5, 6:
• Insufficient evidence to model cost effectiveness
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26. CDEC RECOMMENDATIONS
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27. Members of the CADTH Canadian
Drug Expert Committee (CDEC)
Dr. Lindsay Nicolle (Chair) Dr. Peter Jamieson
Dr. James Silvius (Vice-Chair) Dr. Anatoly Langer
Dr. Silvia Alessi-Severini Mr. Allen Lefebvre
Dr. Ahmed Bayoumi Dr. Kerry Mansell
Dr. Bruce Carleton Dr. Irvin Mayers
Mr. Frank Gavin Dr. Yvonne Shevchuck
Dr. Adil Verani Dr. Harindra Wijeysundera
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Two external clinical experts in hepatology attended the August 2015
CDEC meeting and participated in discussions but did not vote on the
draft recommendations.

28. CDEC Recommendations
Recommendation 1:
CDEC recommends that all patients with CHC infection should be
considered for treatment, regardless of fibrosis score. Given the
potential impact on health system sustainability of treating all patients with
CHC infection on a first-come basis, priority for treatment should be
given to patients with more severe disease.
Recommendation 2:
CDEC recommends that HARVONI and HOLKIRA PAK ± RIBAVIRIN are
preferred regimens for treatment-naïve and treatment-experienced
patients with CHC genotype 1 infection, regardless of cirrhosis status.
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29. CDEC Recommendations
Recommendation 3:
CDEC recommends the following as preferred regimens for patients with
CHC infection genotypes 2 through 4:
• Genotype 2: SOVALDI-RIBAVIRIN for 12 weeks
• Genotype 3, without cirrhosis: DAKLINZA-SOVALDI for 12 weeks
• Genotype 3, with cirrhosis: SOVALDI-RIBAVIRIN for 24 weeks
• Genotype 4, treatment-naïve without cirrhosis: SOVALDI-PEGIFN-
RIBAVIRIN for 12 weeks
• Genotype 4, treatment-experienced or with cirrhosis: insufficient
evidence to make a recommendation.
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30. CDEC Recommendations
Recommendation 4:
CDEC considered there to be insufficient evidence to make a
recommendation for patients with Genotype 5 or 6 infection.
Recommendation 5:
CDEC recommends HARVONI as the preferred regimen for patients with
genotype 1 previously treated with a DAA-PEG-RBV regimen.
Insufficient evidence to make a recommendation for:
• patients previously treated with an all-oral DAA regimen.
• patients with non-genotype 1 CHC infection previously treated with
a DAA-based regimen.
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31. Who should manage treatment?
• With all-oral regimens, treatment may be increasingly
available outside of specialized centres.
• CDEC recommends therapy should be managed by
medical specialists with experience in the treatment of
CHC infection
• The physician managing treatment requires specialized
knowledge on monitoring therapy and ensuring adherence
with therapy.
• Telehealth or Direct Observed Therapy (DOT) programs
exist or are being developed.
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32. NEW DEVELOPMENTS
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33. New Developments: More DAAs
• Elbasvir/grazoprevir (ZEPATIER)
• Genotype 1, 3, and 4
• Ombitasvir/paritaprevir/ritonavir (TECHNIVIE)
• Genotype 4
• Sofosbuvir/velpatasvir (EPCLUSA)
• Pan-genotypic: no genotype specified in the indication
• One tablet once-daily for 12 weeks for nearly all populations plus
indication for decompensated cirrhosis (in combination with ribavirin)
• Implications: possibility of wider prescribing beyond liver
specialists?
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34. New Developments: Safety
• Post-marketing safety information (FDA MedWatch) has
revealed rare but potentially serious adverse effects:
• March 2015: Serious and life-threatening bradycardia among patients
using amiodarone with HARVONI or SOFOSBUVIR taken with another
DAA.
• October 2015: Serious liver injury with HOLKIRA PAK, TECHNIVIE in
patients with underlying advanced liver disease.
• October 2016: Re-activation of Hep B in individuals with current or
previous co-infection with B/C that were treated with DAAs.
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35. New Developments: Real World Data
• CADTH Symposium 2017: Kevin Wilson, Executive Director
- Drug Plan and Extended Benefits, SK MoH
• Are patients achieving the same SVR rates in the real
world setting as they did in clinical studies?
• Preliminary results for 88 pts followed so far:
• 92.3% achieved SVR
• Most of non-responders were F4
• HIV co-infection (n=5) all responded
• Promising given P/T expansion of coverage to less-severe
pts.
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36. Visit Our Evidence Bundle:
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www.cadth.ca/hepatitisc

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