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Hepatitis C

DR TOM SCH UL Z

INF ECTIOUS D ISEASES AND G E NE R AL PH YS IC IAN

TodayBackground

Epidemiology

Testing

Fibrosis Assessment

Treatment

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Learning Objectives Outline the mechanism of action and potential side effects of hepatitis C direct acting antivirals (DAAs).

Apply the University of Liverpool’s hepatitis drug interaction tool to identify potential interactions.

Identify suitable treatment regimens for people with hepatitis C based on their genotype.

List common risk factors for hepatitis C transmission

What is it?A virus

A virus that gets into the blood

A virus that then infects the liver

A virus that causes problems in the liver◦ Cirrhosis

◦ Liver failure

◦ Liver Cancer

Envelope glycoprotein 2

RNA genome

Envelope glycoprotein 1Lipid Envelope

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Who has it?

Low prevalence overall (1% / 230000) but higher risk groups

IVDU – 70% prevalence if >3yrs of use

Transfusion/blood products prior to 1991 (haemophiliacs)

People who have been in prison

Tattoos (Home done and overseas)

HIV positive (MSM) – sexual transmission

Acquired overseas

HCV modelling - prevalence

Of those with chronic HCV:

◦ 82% - though IVDU

◦ 10.9% - from countries of high HCV prevalence

◦ 6.8% - through blood or blood product or other exposure routes (eg tattooing)

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4

HCV genotypes in Australia

Data from >10,000 patients at VIDRL in Melbourne

Author’s own data; Victorian Infectious Diseases Reference Laboratory (data on file). GT: genotype; VIDRL: Victorian Infectious Diseases Reference Laboratory

54%

5%

37%

2% 0 2%

GT 1

GT 2

GT 3

GT 4

GT 5

GT 6

GT 1 24%GT 1a 39%GT 1a/b 8%GT 1b 29%

HCV burden in Australia, 20131

1. Sievert W et al. J Gastroenterol Hepatol 2014;29(Suppl 1):1–9 HCC: hepatocellular carcinoma; HCV: hepatitis C virus.

Deaths

F4 13,850 (6%)

F3 29,770 (13%)

F2 32,840 (14%)

F0/1 154,700 (66%)

1430 (0.6%)

530 (0.2%)

590 (0.2%)

Decompensated

HCC

People living with HCV in 2013

total 233,490

≥80% F2 or below

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Serologic Pattern of Acute HCV Infection Serologic Pattern of Acute HCV Infection Serologic Pattern of Acute HCV Infection Serologic Pattern of Acute HCV Infection with Recoverywith Recoverywith Recoverywith Recovery

Symptoms +/-

Time after Exposure

Titer

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

YearsMonths

HCV RNA

Serologic Pattern of Acute HCV Infection with Serologic Pattern of Acute HCV Infection with Serologic Pattern of Acute HCV Infection with Serologic Pattern of Acute HCV Infection with Progression to Chronic InfectionProgression to Chronic InfectionProgression to Chronic InfectionProgression to Chronic Infection

Symptoms +/-

Time after Exposure

Titer

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

YearsMonths

HCV RNA

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Disease progression

If untreated:

20%-30% may

develop cirrhosis

4%-6% hepatocellular

carcinoma

Significant personal

and economic impact

Who to

test?

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ALT may be normal in chronic HCV infection

*Patients with ≥4 serum ALT level measurements during 25 months of follow-up (n=1042)

Inglesby TV, et al. Hepatology. 1999; 29: 590

42 43

15

0

20

40

60

80

100

Persistently

Normal ALT

Intermittently

Elevated ALT

Persistently

Elevated ALT

Pa

tie

nts

* W

ith

HC

V in

fect

ion

(%

)

Testing• HCV serology –––– false positives do occur, stays positive

• HCV RNA PCR

◦ Qualitative –––– presence of HCV (+ve or –ve)

◦ Quantitative – viral load, prognostic information, used during treatment*

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What to do if someone is positiveProvide Information

◦ How you got it

◦ How to not give it to someone else

◦ What is the prognosis

◦ 25% of people will clear without treatment

◦ Dispel myths

Consider treatment

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Disclosure and hepatitis C

Generally speaking, you don’t have to tell anyone you have hepatitis C except:

• If donating blood

• If you are a health care or dental worker involved in exposure-prone procedures (EPP)

• If you are in the Australian Defence Force

• On insurance applications, especially life insurance

Hepatitis C is a notifiable disease, so the Health Department is confidentially informed of any diagnosis

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Assess Liver Status?

Liver

fibrosis

Time

Need biopsy

or fibroscan

to quantify

More rapid

•Alcohol excess

•Male

•Co-infection

•Obesity

Slower

•Female

•Young

•Normal LFTs

Fibrosis

Cirrhosis

Normal

Assessing FibrosisClinical exam

Blood tests

◦ FBC

◦ INR

◦ LFT’s

◦ Other scoring systems eg APRI

Ultrasound

Fibroscan

Biopsy

◦ Ouch!!

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Non Invasive assessment of fibrosis

What is FibroScan?®

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Results from FibroScan®

2.5 75 kPa7.0 9.5 12.5

Absent or mild fibrosis

(Metavir F0-F1)

Significant Fibrosis

(F2)

Severe Fibrosis

(F3)

Cirrhosis

(F4)

Castera et al. J Hepatol 2008

• Report should include

– Number of valid readings– Minimum of 10

– Should be at least 60% of the total

– Median score

– IQR (Should be ≤ 30% of the median)

General Management

Lifestyle issues

•Minimal alcohol intake (< 70 g/week)

•Dietary recommendations as per general population

Harm reduction advice

•NSPs

•Methadone programs

•Vaccinations (Hep B, A)

Other BBV’s

• HIV

• Hep B

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Alcohol use and liver fibrosis in patients with chronic HCV

More advanced fibrosis (stages 2

through 4)

29% no alcohol intake,

34% minimal intake,

38% mild intake,

67% moderate drinkers.

Hézode et al. 2003

Cascade of Care in Australia

75% diagnosis rate

but only

1.7% / year treatment

rate

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26000 scripts in first 5 monthsKirby Institute 2016

Aim of treatment

SVR Cure

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

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1. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 2. van der Meer AJ. Expert Rev Gastroenterol Hepatol.

2015;9:559-566. 3. Younossi Z, et al. Clin Gastroenterol Hepatol. 2014;12:1349-1359.

Benefits of SVR (Cure)

�Advanced fibrosis

– Multicenter study[1]

– 5 hospitals (Europe, Canada)

– 530 pts with HCV

– IFN regimens 1990-2003

– Advanced fibrosis or cirrhosis

– Median follow-up: 8.4 yrs

�Early-stage disease

– Health-related quality of life[3]

– Decreased infectivity

– Extra-hepatic manifestations[2]

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20

10

All cause mortality

Liver-related mortality or transplant

HCC

10-Yr Cumulative Incidence[1]

0

26

8.9

1.9

27.

4

5.1

21.

8

SVR No SVR

Pe

rce

nt

Treatment of Hepatitis C in 2016

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HCV Life Cycle and DAA Targets –Drugs

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

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation andpolyproteinprocessing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4

protease

inhibitors

NS5B polymerase inhibitors

• Nucleoside/nucleotide• Nonnucleoside

NS5A* inhibitors

TelaprevirBoceprevirSimeprevirParitaprevirAsunaprevirGrazoprevir

Daclatasvir

Ledipasvir

OmbitasvirElbasvirVelpatasvir

Sofosbuvir

DasabuvirBeclabuvir

IFN6 months

IFN12 months

IFN/RBV6 months

IFN/RBV12 months

PEG-IFN12 months

PEG-IFN + RBV

12 months

PI +PEG-IFN

+ RBV6–12

months

SOF + PEG-IFN

+ RBV3 months

63–79

54–56

3942

34

16

6

90

1986 1998 20022001 2011 2013

SV

R (

%)

SMV + PEG-IFN

+ RBV6–12

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

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Interferon-free Drug Availability in Australia

• Listed from March 1st 2016

• Drugs:

– Sovaldi (Sofosbuvir)

– Harvoni (Sofosbuvir + Ledipasvir)

– Daclinza (Daclatasvir)

– Ibavyr (Ribavirin)

– Viekera Pak (Parataprevir/Ritonavir/Ombitasvir/Dasabuvir)

• S 85 listing

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

Genotype 1

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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

Genotype 1

Non-cirrhotic patients

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HARVONI in GT 1 TN non-cirrhotic

patients (ION-3): Study design1,2

Kowdley KV et al. N Engl J Med 2014;370:1879–88;

LDV/SOF

n=215

LDV/SOF + RBV*

n=216

HCV GT 1

TN

Non-cirrhotic

N=647

LDV/SOF

n=216

Primary endpoint:SVR12

Week 0 Week 8 Week

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Efficacy of 8 or 12 week LDV/SOF

regimen in naïve, non-cirrhotic GT 1

patients (ION-3)

Gilead Sciences Pty Ltd. HARVONI (ledipasvir/sofosbuvir), PI, May 2015;

Kowdley KV, et al. N Engl J Med 2014;370:1879–88;

Jacobson I, et al. AASLD 2014; Poster #1945. *LDV/SOF + RBV is not a TGA-recommended treatment regimen.

93 95

0

20

40

60

80

100

LDV/SOF

8 weeks

LDV/SOF + RBV

8 weeks*

LDV/SOF

12 weeks

Relapse rates <6 M 2% (2/123) 2% (3/137) 2% (2/131)

Relapse rates >6 M 10% (9/92) 8% (6/77) 1% (1/85)

SV

R1

2 (

%)

119/123 133/138 126/131

94

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Genotype 1

Compensated cirrhotic

patients

HARVONI in GT1 TE cirrhotic or

non-cirrhotic patients (ION-2): Study

design1,2

Afdhal N et al. N Engl J Med 2014;370:1483–93;

LDV/SOF

n=109

LDV/SOF + RBV*

n=111HCV GT 1

TE

N=440 LDV/SOF

n=109

LDV/SOF + RBV*

n=111

Primary endpoint:SVR12

Week 0 Week

12

Week

24

20

Relapsers(n)

ION-2: SVR12 according to

cirrhotic status1-3

95 100 99 99 86 82

100 100

0

20

40

60

80

100

LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV

Afdhal N et al. N Engl J Med 2014;370:1483–93 and supplementaryappendix. Afdhal N et al. EASL 2014; Oral #109.

12 weeks 24 weeks

SV

R12 (

%)

Non-cirrhotic Cirrhotic

7 00

83/87 19/22 88/88 18/22 85/86 22/22 88/89 22/22

4

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Genotype 1 Recommendations

Australian recommendations for the management of hepatitis virus infection: A consensus statement 2016

Genotype 3

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ALLY-3: Study Design

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• Eligible patients

– Age ≥ 18 years with chronic GT 3 infection and HCV RNA ≥ 10,000 IU/mL

– Treatment-naive or -experienced (prior treatment failures), including patients with cirrhosis

Follow-upDCV 60 mg +SOF 400 mg QD

Day 1 Week 24 Week 36

DCV 60 mg +SOF 400 mg QD

Week 12

Treatment-naiveN = 101

Treatment-experiencedN = 51

SVR12Primary end point

GT 3

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

Ally 3: SVR12: Primary Endpoint

90 86

0

20

40

60

80

100

Treatment-naive

SV

R12,

%a

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

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Ally 3: SVR12 in Patients With

Cirrhosis

96 97 94

63 58

69

0

20

40

60

80

100

SV

R12,

%

PresentAbsent PresentAbsent PresentAbsent

Treatment-

naive

Treatment-

experiencedOverall

Cirrhosis

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

Interim Analysis of French CUP in

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

SV

R12 (

%)

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

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Genotype 3 Recommendations

Australian recommendations for the management of hepatitis virus infection: A consensus statement 2016

Other Genotypes

• Only listing on PBS for genotype 1, 2

and 3

• Genotype 2 – Sofosbuvir and Ribavirin for 12 weeks

• Genotype 4 – Elbasvir with Grazoprevir for 12 weeks (special

access)

• Genotype 5 and 6– Peg Interferon and Ribavirin

– (Harvoni or Sofosbuvir/Velpatasvir in future)

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Monitoring during and post

treatment

Australian recommendations for the management of hepatitis virus infection: A consensus statement 2016

*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*

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Polypharmacy for co-morbidities in HCV

patients is typical – potential for DDIs

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

Depression

CirrhosisPortal

hypertension

Substance

misuse

Dysglycaemia

Renal disease

Cognitive

impairmentPsychosis

Respiratory

disease

Dyslipidaemia

Cardiovascular

disease

TransplantHIV

co-infection

92% HCV patients

had co-morbidities

40% had 5 or more

The potential for DDIs varies

between DAAs

• Numerous and complex DDIs are possible with DAAs

EASL. J Hepatol 2015;63:199–236;

University of Liverpool Drug Interaction Charts.

Available at: http://www.hep-druginteractions.org/Interactions.aspx (accessed July 2015).

NNRTI: non-nucleoside reverse-transcriptase inhibitor;

NRTI: nucleoside reverse-transcriptase inhibitor

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Evaluation of Drug-Drug Interactions

Conclusions

• Interferon free therapy is here

• It is highly effective with cure rates of 85-100%

• Treatment depends on genotype

• Treatment duration depends on cirrhosis and

prior treatment

• Side effects are minimal

• Drug-drug interactions need to be considered

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Thankyou