Hepatitis C Clinical Update

18th Australian an New Zealand Conference on Bleeding Disorders

Assoc. Prof. Joe Sasadeusz Royal Melbourne and Alfred Hospitals

Disclosures

Research grants: Gilead, Abbvie

Advisory boards: Gilead, Abbvie, BMS, Merck

Speaker: Gilead, BMS

“Perfectovir”

Hepatitis C is a Curable Disease Sustained Virological Response (SVR) = Neg HCV PCR 12 weeks post Rx

» usually considered as ‘cure’ of HCV » Associated with reduced morbidity and mortality

Pawlotsky JM. J Hepatol 2006;44:S10–3; Siliciano JD, et al. J Antimicrob Chemother 2004;54:6–9; Lucas GM. J Antimicrob Chemother 2005;55:413–6; van der Meer AJ, et al. JAMA 2014;312:1927–8; Burki T. Lancet Infect Dis 2014;14:452–3

cccDNA: covalently closed circular DNA; SVR: sustained virological response

Lifelong suppression

HBV HIV HCV

Treatment Treatment Treatment

Lifelong suppression HCV clearance

Cure

Host cell

Nucleus cccDNA

Host DNA

Proviral DNA

Viral RNA

“This is the first chronic viral illness that we’ve

been able to cure”

Michael

Houghton, (jointly

discovered HCV in 1989)

SVR24 with Pegylated IFN and Ribavirin

0

25

50

75

100

G1 G2/3

Monoinfection

APRICOT ACTG RIBAVIC Laguno et al. PRESCO

14–38%

44–73%

Genotype

SV

R (

%)

Adapted from: Fried et al, NEJM 2002;347:975-982, Torriani et al, NEJM 2004;351:438-50, Chung R, et al, NEJM 2004;351:451-9

Carrat F, et al, JAMA 2004;292:2839-42, Laguno et al, AIDS 2004;18:F27-F36, Nunez et al, JAIDS 2007;45:439-44

50%

80%

6

HCV Therapy: Adverse Events

Frequency

Peg-IFN

Ribavirin

Common Flu-like Symptoms Mood disturbance

Cytopaenias Thinning hair Weight loss Insomnia

Cough Rash Gout

Mild haemolyisis

Serious

Depression/psychosis Thyroid dysfunction

Exacerbation of psoriasis Seizures

Diabetes mellitus Retinopathy

Severe haemolysis Teratogenic

3’UTR 5’UTR Core E1 E2 NS2 NS3 NS5A NS5B P7

Polymerase

Daclatasvir (DCV) Elbasvir (EBR)

Ledipasvir (LDV) Ombitasvir (OBV) Velpatasvir (VEL)

Pibrentasvir (PIB)*

Sofosbuvir (SOF)

Dasabuvir (DSV)

NS5B NUC

Inhibitors

NS5A Replication

Complex Inhibitors

NS5B Non-NUC Inhibitors

Grazoprevir (GZR) Paritaprevir/Ritonavir

(PTV/RTV) Simeprevir (SMV)

Voxilaprevir (VOX)* Glecaprevir (GLE)*

NS3 Protease Inhibitors

Protease

Approved DAAs From Multiple Classes

Structural Domain

4A NS4B

Nonstructural Domain

*Possible approval in 2017.

NS5A

HARVONI for adult GT 1 patients: One tablet, once daily1

• Ledipasvir (LDV) – Picomolar potency against multiple

HCV genotypes in vitro1,2

– Once daily, oral, 90 mg1

• Sofosbuvir (SOF)

‒ Potent pangenotypic antiviral activity against HCV GT 1–63

‒ High barrier to resistance3

‒ Once daily, oral, 400 mg tablet3

• LDV/SOF – HARVONI

‒ Once-daily, oral, fixed-dose (90/400 mg) combination tablet, RBV-free1

‒ Minimal DDIs, no food effect1

1. HARVONI Product Information, May 2015;

2. Lawitz E et al. EASL 2011; Poster #1219; 3. SOVALDI Product Information, March 2015;

DDI: drug–drug interaction; GT: genotype; HCV: hepatitis C virus; LDV: ledipasvir; RBV:

ribavirin; SOF: sofosbuvir.

LDV NS5A inhibitor1

SOF – NS5B nucleotide polymerase inhibitor1

LDV NS5A inhibitor1

SOF – NS5B nucleotide polymerase inhibitor1

High SVR12 in GT 1 patients with IFN-free, HARVONI

1. Afdhal N, et al. N Engl J Med 2014;370:1889–98; 2. Kowdley KV, et al. N Engl J Med 2014;370:1879–88; 3. Afdhal N, et al. N Engl J Med 2014;370:1483–93

*HARVONI + RBV is not a recommended treatment regimen in Australia; †Excluding one subject with GT 4 infection

99 97 98 99

0

20

40

60

80

100

LDV/SOF LDV/SOF+ RBV*

LDV/SOF LDV/SOF+ RBV*

94 93 95

LDV/SOF LDV/SOF+ RBV*

LDV/SOF

Treatment-naïve (16% cirrhotic)

12 weeks

210/ 213†

212/ 217

24 weeks

94 96 99 99

LDV/SOF LDV/SOF+ RBV*

LDV/SOF LDV/SOF+ RBV*

Treatment-experienced (20% cirrhotic)

Treatment-naïve non-cirrhotic

ION-11 ION-23 ION-32

12 weeks 24 weeks 12 weeks 8 weeks

211/ 217

215/ 217

102/ 109

108/ 109

107/ 111

110/ 111

202/ 215

206/ 216

201/ 216

SVR

12 (%

) SVR in 97% (1884/1951)1–4

Relapse in 1.8% (36/1951)1–4

100

80

60

40

20

0 8 12 24 12 24

Terrault N, et al. AASLD 2015. Abstract 94. Reproduced with permission.

SVR

12 (%

) HCV-TARGET: SVR12 With 8-, 12-, or

24-Wk Ledipasvir/Sofosbuvir ± Ribavirin

Only 131 out of 323 pts who qualified for 8-wk treatment (treatment naive, no cirrhosis, and baseline HCV RNA ≤ 6 million IU/mL) received 8-wk regimen Tx Outcome in

Pts Qualifying for 8-Wk Regimen

LDV/SOF 8 Wks

(n = 131)

LDV/SOF 12 Wks

(n = 192) SVR12, % 97 97

Failure, % 3 3

SVR12 according to Wk 4 HCV RNA, % (n/N) (n = 99) (n = 133)

Below limit of quantification

97 (89/92)

97 (114/117)

Quantifiable 100 (7/7)

94 (15/16)

97 97 95 97 92

150/ 154

607/ 627

153/ 161

86/ 89

12/ 13

n/N =

LDV/SOF LDV/SOF + RBV

Wks of Treatment

HARVONI for 12 weeks in HCV/HIV co-infected patients: Phase 3 study (ION-4): SVR12

Naggie S et al. N Engl J Med 2015;373:705–13. HCV: hepatitis C virus; HIV: human immunodeficiency virus; LDV: ledipasvir; SOF: sofosbuvir; SVR: sustained virological response.

SVR

12 (%

)

96

0

20

40

60

80

100

LDV/SOF 12 Weeks

322/335

95 97

0

20

40

60

80

100

Experienced Naïve

Naïve vs Experienced

142/150 179/185

96 94

0

20

40

60

80

100

No Cirrhosis Cirrhosis

Cirrhosis status

63/67 258/268

Overall

SVR rates in HCV/HIV co-infected patients were similar to those seen in the Phase 3 registration trials for this regimen in HCV-monoinfected patients1

Harvoni in GT 1 HIV-HCV Coinfection Clinical Trial Vs Real World Data

Naggei et.al. AASLD , 2016

Sofosbuvir + Daclatasvir: SVR12 in HCV GT 3 Patients with and without Cirrhosis

96 97 94

63 58 69

0

20

40

60

80

100

SVR

12, %

Present Absent Present Absent Present Absent

Treatment-naive

Treatment-experienced

Overall

Cirrhosis

Nelson DR, et al. Hepatology. 2015;61:1127-1135.

Interim Analysis of French CUP in GT 3 Cirrhosis: SVR12 by Child-Pugh Score

Hezode C, et al. AASLD 2015. Abstract 206. Reproduced with permission.

DCV + SOF ± RBV 12 Wks

DCV + SOF 24 Wks

Child-Pugh A Child-Pugh B or C

SVR

12 (%

)

DCV + SOF + RBV 24 Wks

100

80

60

40

20

0

80

33

90

71

85

70

28/ 33

7/ 10

90/ 100

12/ 17

24/ 30

2/ 6

Agarwal, EASL 2016, Poster SAT-195

15

SVR

12 (%

)

98 99 95 100 97 100

0

20

40

60

80

100 98

Total

1015 1035

323 328

264 277

116 116

34 35

41 41

237 238

GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

2 relapse 2 LTFU 1 D/C 1 D/C

11 relapse 2 D/C 1 death

Sofosbuvir + velpatasvir = Epclusa 12 wks Pangenotypc Regimen

Sofosbuvir (SOF)/Velpatasvir (VEL) SOF: Nucleotide polymerase inhibitor with

activity against HCV GT 1–6

VEL: Potent pangenotypic NS5A inhibitor

VEL NS5A inhibitor

SOF Nucleotide polymerase

inhibitor

*As reported in the PI

DAAs were well tolerated in clinical trials

Gilead Sciences Pty Ltd. SOVALDI (sofosbuvir), PI, March 2015; Gilead Sciences Pty Ltd. HARVONI (ledipasvir/sofosbuvir), PI, May 2015; Bristol-Myers Squibb Australia Pty Ltd. DAKLINZA (daclatasvir), PI, June 2015; AbbVie Pty Ltd. VIEKIRA PAK (ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin), PI, July 2015.

SOF + RBV LDV/SOF SOF + DCV

± RBV OMV/PTV/RTV + DSV + RBV

Fatigue 30–38% 13–18% 27–30% 27–39% Headache 24–30% 11–17% 23–25% <5% Nausea 13–22% 6–9% 15–16% 8–22% Diarrhoea 9–12% 3–7% 8–9% <5% Insomnia 15–16% 3–6% 6–8% 5–17%

• Majority of adverse events for DAAs were mild to moderate • Discontinuation due to adverse events from IFN-free

regimens occurred in ≤3% patients

Most common adverse events reported in clinical trials of DAAs*

17

Australia one of the first countries to make “access for all” public health policy

December 2015: $AUD1 billion for HCV treatment over 5 years (2016-2020) “a watershed moment”

Health Minister: Sussan Ley

Interferon-free Drug Availability in Australia • Drugs Listed under PBS (first March 1st 2016):

– Sovaldi (Sofosbuvir)

– Harvoni (Sofosbuvir + Ledipasvir)

– Daclinza (Daclatasvir)

– Ibavyr (Ribavirin)

– Abbvie 3D (Veikira Pak)

– Zepatier (elbasvir +grazoprevir)

– Epclusa (Sofosbuvir + Velpatasvir)

• S 85 listing

• Cost: $38.30 for general patients and $6.20 for concessional

Key features of Australian DAA Access

• No restrictions based on liver disease stage or drug

and alcohol use

• No cap on number of patients treated per year

• Risk-sharing arrangement with pharma, with capped annual expenditure

• Broad practitioner base: including GPs and community pharmacy (S85) dispensing

• Retreatment (including for reinfections) allowed

Royal Melbourne Hospital Hepatitis Clinic March 1st 2016

© ASHM 2017

Annual HCV Treatment Uptake, 1997-2016

The Kirby Institute. Monitoring hepatitis C treatment uptake in Australia (Issue 7). The Kirby Institute, UNSW Sydney, Sydney, Australia, July 2017

No Free Lunch

Polypharmacy for co-morbidities in HCV patients is typical – potential for DDIs

Vutien P, et al. AASLD 2014; Poster #1481.

Depression

Cirrhosis

Portal hypertension

Substance misuse

Dysglycaemia

Renal disease

Cognitive impairment

Psychosis

Respiratory disease

Dyslipidaemia

Cardiovascular disease

Transplant

HIV co-infection

• 92% HCV patients had co-

morbidities

• 40% had 5 or more

Watch out for potential DDI Summary of drug-drug interactions with Ledipasvir/Sofosbuvir

25

No restrictions Immunosuppressants: cyclosporin, tacrolimus • Antiretrovirals: abacavir, atazanavir/ritonavir, darunavir/ritonavir, emtricitabine, efavirenz, lamivudine, raltegravir, rilpivirine • Calcium channel blockers: verapamil • Oral contraceptives • Opioids: methadone • Antacids • H2-receptor antagonists • Proton pump inhibitors • HMG-CoA reductase inhibitors: pravastatin

Contraindicated or Not Recommended

Antiarrhythmics: amiodarone × Anticonvulsants: carbamazepine, phenytoin, phenobarbital, oxcarbazepine × Antimycobacterials: rifampicin, rifapentine, rifabutin × Antiretrovirals: tipranavir/ritonavir × Herbal supplements: St John’s wort × HCV Products: simeprevir × HMG-CoA reductase inhibitors: rosuvastatin

Caution and/or dose adjustments

HMG-CoA reductase inhibitors: pravastatin Antiarrhythmics: digoxin Antiretrovirals: tenofovir disoproxil fumarate Direct thrombin inhibitor: dabigatran

DAAs and Recreational Drugs

EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol. 2015; 63:199–236.

Cirrhosis and HCV with and without SVR

Kanwal et.al. Gastroentology 2017

Conclusions

New Interferon –free regimens are highly effective, including in traditionally difficult to treat populations:

» HIV-HCV coinfected patients

» Cirrhosis

We now have one size fits all pangenotypic regimens

Extremely well tolerated

Challenge is management of drug-drug interactions, both ART and other medications, but these are manageable

Conclusions

Aim for eradication in bleeding disorder community

Plea to health care providers and affected individuals to come forward for treatment if haven’t done so yet

“Perfectovir” is here !

Thank You

Aim of treatment

SVR Cure

SVR 12 : HCV PCR negative 12 weeks post end of therapy

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding and endocytosis

Fusion and

uncoating

Transport and release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virion assembly

Membranous web

ER lumen

LD

LD ER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors • Nucleoside/nucleotide • Nonnucleoside

NS5A* inhibitors

Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir

Daclatasvir Ledipasvir Ombitasvir Elbasvir Velpatasvir

Sofosbuvir

Dasabuvir

HCV polyprotein translation & processing:

NS3/4a protease

Fusion and

uncoating

Virion assembly

RNA replication: NS5B polymerase

NS5A protein

Direct Acting Antivirals (DAAs) Target HCV Life Cycle

paritaprevir grazoprevir

NS3/4A Protease Inhibitors

NI - sofosbuvir

NNI - dasabuvir

NS5B Inhibitors ledipasvir

daclatasvir ombitasvir

elbasvir velpatasvir

NS5A Inhibitors

Receptor binding and endocytosis

Transport and release

IFN 6 months

IFN 12 months

IFN/RBV 6 months

IFN/RBV 12 months

PEG-IFN 12 months

PEG-IFN + RBV

12 months

PI + PEG-IFN + RBV 6–12

months

SOF + PEG-IFN + RBV

3 months

63–79

54–56

39 42 34

16 6

90

1986 1998 2002 2001 2011 2013

SVR

(%)

SMV + PEG-IFN + RBV 6–12

months

81

Progress of HCV Therapy

Adapted from Strader DB, et al. Hepatology 2004;39:1147–71; Janssen-Cilag Pty Ltd. INCIVO (telaprevir), PI, September 2014; Merck, Sharpe and Dohme Pty Ltd. VICTRELIS (boceprevir), PI, October 2014; Manns M, et al. Lancet 2014;384:414–26; Lawitz E, et al. N Engl J Med 2013;368:1878–87; Gilead Sciences Pty Ltd. HARVONI (ledipasvir/sofosbuvir), PI, May 2015; AbbVie Pty Ltd. VIEKIRA PAK (ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin), PI, July 2015.

2014

90–100

IFN-free 8–24 weeks

2015

Cross-study comparison of clinical trials in GT 1 patients

Current all-oral therapies highly effective, simple, well tolerated

IFN 6 Mos

PegIFN/RBV

12 Mos

IFN 12 Mos

IFN/RBV

12 Mos

PegIFN 12 Mos

2001

1998

2011

Standard Interferon

(IFN)

Ribavirin (RBV)

Peginterferon (pegIFN)

1991

PegIFN/ RBV + DAA

IFN/RBV 6 Mos

6 16

34 42 39

55

70+

0

20

40

60

80

100

DAA + RBV ± PegIFN

90+ 2013

All–Oral DAA±

RBV

Current 95+

All-Oral Therapy

Direct-Acting

Antivirals (DAAs)

Liverpool Hep iChart

• These drugs should not be co-administered

• No clinically significant interaction expected

• Potential interaction – May require monitoring or dosage change