Drugs for Chronic

Hepatitis C Infection MAY 6, 2017

Shannon Kelly, MSc, PhD (in progress)

University of Ottawa Heart Institute

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).

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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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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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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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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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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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

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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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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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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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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RESULTS

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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

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

Results – Genotype 1

Evidence Network for

Genotype 1, treatment-

naive

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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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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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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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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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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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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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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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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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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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CDEC RECOMMENDATIONS

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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.

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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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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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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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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NEW DEVELOPMENTS

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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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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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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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Visit Our Evidence Bundle:

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www.cadth.ca/hepatitisc

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