HCV Management in the New Age of Direct-Acting Antivirals

Dr Jess HowellGastroenterologist and Hepatologist

St Vincent’s Hospital MelbourneNHMRC Post Doctoral Research Fellow

Centre for Population HealthBurnet Institute

1. Identify patients at risk of HCV and ensure they are regularly screened

2. Interpret test results and diagnose HCV correctly3. Manage and monitor people with HCV including:

– Assess severity of liver disease– Lifestyle modifications to reduce liver disease– Perform related health assessments (eg screen for

complications of liver disease, BBVs/STIs, HCC)

5. Advise patients about new DAAs and support them to make treatment decisions

6. Link people with HCV to care and start treatment

Learning Objectives

Epidemiology of Hepatitis C

HCV- A Global Problem

• Global prevalence 2-3%• 130-170 million chronically infected• 3-4 million new infections/ year• 350,000 deaths annually due to HCV-

related cirrhosis and liver cancer• Greatest burden in low-middle

income countries

ASHM, 2016

230,000

HCV genotype 1

HCV genotype 3

Other

Australians live with chronic HCV infection

Epidemiology of HCV in Australia

ASHM, 2016

230,000Australians live with chronic HCV infection

Fibrosis Stage F0/1

Fibrosis Stage F2

Fibrosis Stage F3

Fibrosis Stage F4

Epidemiology of HCV in Australia

Risks for HCV transmission

• Blood borne

– Injecting drug use/ intranasal drug use

– Tattoos/ scarification/ other procedures

– Iatrogenic (esp endemic countries)

– Blood transfusions, dialysis prior to 1992

• Sexual* (MSM, multiple partners, violence)

• Vertical (3%)/ Early horizontal

Risks for HCV TransmissionRisks for HCV Transmission

Why treat HCV?

• HCV is now curable

• Halt progression of liver disease

• Prevent liver-related morbidity and mortality

• Prevent liver cancer

• Improve symptoms, QOL

• Reduce transmission

• Reduce stigma

Why treat HCV?

Di Bisceglie AM. Hepatology. 2000;31(4):1014-1018. 2. Bialek SR, Terrault NA. Clin Liver Dis. 2006;10(4):697-715. 3. John-Baptiste A et al J Hepatol 2010; 53: 245-51; AASLD Guidelines. http://www.hcvguidelines.org.

Natural History of Hepatitis C Infection

HCC = hepatocellular carcinoma ESLD = end stage liver disease

15% 85%

80% 25%

75%

6%/yr

4%/yr

3-4%/yr

10 yr 20 yr 30 yr

Determinants of liver disease progression

Host

Modifiable

Alcohol consumption

NAFLD

Obesity

Insulin resistance

Non-modifiable

Fibrosis stage

Inflammation grade

Older age

Male sex

Viral

Genotype 3

Co-infection with HBV or HIV

Natural history of HCV infection

Benefits of HCV Cure

Non-cirrhotic patients

Reduce

Progression to cirrhosis

Extra-hepatic manifestations (NHL, IR/ diabetes, cryoglobulinaemia)

Improve

Neuro-cognitive function Fatigue

Health-related QOL

Overall survival

Cirrhotic compensated patients

Reduce

Clinical decompensationVariceal bleeding

HCC incidence*

Improve

Cirrhosis regression

Liver-related survival

Cirrhotic decompensated

patients

Reduce

Need for liver transplant (LT)

HCV Recurrence post-LT

Improve

Cirrhosis regression

Liver-related survival

Post LT outcomes

Aghemo A et al, J Hepatol 2012;57:1326-35; Ghany MG, et al. Hepatology. 2009;49(4):1335-1374; Hill A et al, AASLD 2014

Benefits of HCV Cure

What does cure mean?

• Sustained virological response (SVR) at week 12 (or 24*) of treatment

• Undetectable HCV RNA 12 weeks after completion of HCV antiviral therapy

• Durable

• Cure means the virus is gone, but the liver disease is still present– BUT will improve over time in absence of other

liver cofactors (eg: alcohol, obesity)

What does cure mean?

Testing for HCV infection

Diagnosis of HCV

• HCV Antibody test= Screening test• HCV RNA test= Confirm active infection

Infected with HCV NOW

RNA

+Ab

+

Infected with HCV in the PAST

Ab

+RNA

-

NEVER infected with HCV

Ab

-RNA

-

Ab Antibody test EVER

come into contact

with HCV

RNAInfected with the

virus NOW

Diagnosis of HCV

Natural history of Acute HCV

1 in 4 with new infection clear HCV

3 in 4 will develop

chronic HCV

Natural history of Acute HCV

Who should be tested for HCV?

Risk behaviours Risk exposures Other

Injecting drug use (current or ever, including those who injected once)

Intranasal illicit drug use

Long term haemodialysis (ever)

Tattoos

Health care, emergency medical, and public health safety workers after needlesticks, sharps, or mucosal exposures to HCV-infected blood

Prior recipients of transfusion of blood or clotting factor concentrates or organ transplant prior to 1992, or where blood safety is inadequate

History of incarceration

HIV or HBV infection

Unexplained chronic liver disease and chronic hepatitis including elevated ALT levels

Aborigines & Torres Strait Islanders

Maternal transmission (5-6%)

Sex workers

Persons born in endemic countries (Pakistan, Egypt, Mediterranean, Eastern Europe, Asia & Africa )

Solid organ donors (deceased or living)

• Persons should be screened for risk factors for HCV infection, and 1-time testing should be performed for all persons with behaviours, exposures, and conditions associated with an increased risk of HCV infection.

Australian Concensus Statement 2016 at http://www.hepcguidelines.org.au; Centre for Disease Control at http://www.cdc.gov/; AASLD/IDSA Treatment Guidelines 2016 at http://www.hcvguidelines.org; Edlin, BR & Winkelstein ER. Antiviral Research 2014;110:79-93; Coffin PO et al. Clin Infect Dis 2012;54(9):1259-1271

Who should be tested for HCV?

Assessment of the patient with HCV infection

Patient Assessment

1. Assess severity of underlying liver disease

2. Identify and manage other liver disease cofactors

3. Exclude other causes chronic hepatitis

4. Screen for related BBVs +/- STIs +/- other diseases and factors that may affect adherence

5. Provide adequate information and support to make decisions about treatment

Patient Assessment

Staging Liver Disease: Diagnosing Cirrhosis

Serum BiomarkersProprietaryCommon testsMarkers of hepatic function or matrix production or degradation

Liver biopsyPercutaneousTransjugularLaparoscopic

Transient elastography:Fibroscan(ARFI)

Imaging: US (CT, MRI) Insensitive for advanced fibrosis / early cirrhosis Cirrhotic liver, splenomegaly, ascites, varices

Clinical signsJaundice, ascites, varices, encephalopathyLab: low platelet, low albumin, high bilirubin, high INR

• Formal evaluation for cirrhosis with a non-invasive test is recommended for all individuals with chronic HCV (APRI, Fib-4 or transient elastography)

• It is a PBS requirement that you know whether or not your HCV-infected patient has cirrhosis

• BUT liver histology is not required for accessing antiviral therapy

Staging of Liver Disease

Serum biomarkersAPRI (AST Platelet Ratio Index) Score

AST Level

AST (Upper Limit of Normal)

Platelet count (109/L)x 100APRI =

*Other scores:Modified APRI Score:[Age (y) x (AST/upper limit of normal] / [Serum albumin (g/dl) x platelet count (expressed as platelets × 109/L) × 100]

FIB-4:Age (y) × AST (IU/l) /platelet count (×109/litre) ×√ALT (IU/l))

Serum Biomarkers

Source: Shaheen AA, et al. Hepatology 2007;46:912-921

APRI (AST Platelet Ratio Index) Score: meta-analysis

APRI Score >1.0 for cirrhosis determination

Chronic HCV: cirrhosis determination

Negative predictive

value

Specificity

76%

Sensitivity

71% 91%

Chronic HCV: Diagnosis of cirrhosis

Transient Elastography• Ultrasonic transducer sends a vibration wave into the liver• Velocity of the wave correlates with tissue stiffness• Accurate for F0/1 stage fibrosis and cirrhosis• Poor discriminatory ability for intermediate stage fibrosis• Affected by steatosis, liver inflammation, cardiac failure/

fluid overload• Mostly accessed through tertiary centres, also specialist

community hepatitis clinics (nurse or doctor)• More accurate than serum biomarkers (ie APRI)• Should consider in all patients with APRI > 1.0

Caster aL et al. Hepatology 2008;48:835-847

Transient Elastography

Identify and manage liver cofactors

• Screen for HBV, HIV +/- other BBVs/ STIs if relevant

• Vaccinate HAV, HBV (*PBS rebate if CLD)

• Alcohol

• Obesity and the metabolic syndrome

• Smoking* (inc marijuana)

• Diet and lifestyle advice

Identify and Manage Liver Cofactors

Patients with advanced fibrosis/ cirrhosis

• Screen for liver cancer

– 6 monthly ultrasound

• Screen for osteopaenia/ osteoporosis

– Annual DEXA scan

• Screen for portal hypertension

– Gastroscopy 1-2 yearly (or directed by specialist)

• Refer for assessment by a liver specialist

• Dietician review (liver disease experienced)

Patients with advanced fibrosis/ cirrhosis

• BBVs/ STIs (eg HIV, syphilis)

• Mental illness

• Drug dependence, related risk behaviours

• Homelessness

• Socio-economic

• Violence (past and present)

• All these factors affect treatment adherence and require maximisation pre-treatment

• *Consider treat-a-friend strategy

Screen for related disorders

Interferon-free HCV treatment:Direct Acting Antivirals (DAAs)

Australian Recommendations for the Management of HCV Infection: A Consensus Statement 2016

Choosing the Most Appropriate HCV Regimen

?When

to start

treatment?

Which

drugs

to use?

How long

to treat?

Considerations:

• HCV genotype (& subtype for GT 1)

• Presence / absence of cirrhosis

• Prior treatment experience (failed PR, PI or DAAs)

• HCV viral load (only for GT 1)

• Comorbidities

• Drug interactions

• Resistance

ALL people living with HCV should be considered for treatmentExcept limited life expectancy (<12mths)

Choosing the best HCV DAA regimen

Currently available DAAs in Australia

Drug Name Dose of each tablet Method of action

Daclatasvir Daklinza 60 mg NS5A polymerase inhibitor

Sofosbuvir Sovaldi 400 mg NS5B polymerase nucleotide analogue inhibitor

Ledipasvir / Sofosbuvir Harvoni 90 mg / 400mg NS5A and NS5B polymerase inhibitor

Ribavirin Ibavyr 400 mg or 600 mg Guanosine analogue

Ombitasvir / Paritaprevir / Ritonavir

Viekira Pak 12.5mg/75mg/50mgcoformulated250mg

NS5A inhibitor/ NS3-4A protease inhibitor

Dasabuvir Viekira Pak-RBV Includes Ribavirin 200mg or 400mg or 1000mg or 1200mg

NS5A inhibitor/ NS3-4A protease inhibitor/ guanosine analogue

Coming soon………

Elbasvir/ Grazoprevir Zepatier ?December 2016 NS5A inhibitor/ NS3-4A protease inhibitor

Currently available DAAs in Australia

Common DAA Regimens• Geno 1

– No cirrhosis: Harvoni 12 wks– Compensated cirrhosis: Harvoni 12wks– Geno 1b (irrespective cirrhosis): Viekera Pak 12 wks

• Geno 2– Sofosbuvir + Ribavirin 12 wks

• Geno 3– No cirrhosis: Sofosbuvir + Daclatasvir 12wks– Compensated cirrhosis: Sofosbuvir + Daclatasvir 24 wks– Previous treatment: Sof/ Dac 24 wks

• Geno 4/5/6• REFER (Trials; Elbasvir/ Grazepravir *dependent PBS listing)

• Renal impairment?– <30ml/min Viekera Pak (Zepatier)

Common DAA regimens

Side Effects

• Generally very well tolerated• Nausea, Fatigue• Headaches• Pruritis, gastrointestinal disturbance less common• *Effects of altered metabolism of other medications• SEs more pronounced with cirrhosis

• **Unclear safety profile of DAAs in pregnancy• Recommend double contraception for duration of

treatment • **Ribavirin- TERATOGENIC• Recommend double contraception during Rx and 6/12 post

Side effects

Information on drug interactions with new DAAs

HEP Drug Interactions websitewww.hep-druginteractions.org

HEP iChart appApp store | Google Play

Information on drug interactions

PBS Requirements

• Patients > 18 years• Was only in consultation with experienced

gastroenterologist, hepatologist or ID physician BUT now you can treat without support IF you have *experience* in HCV management

• Info required:– Genotype– Cirrhosis (Yes/ No)– Intended duration treatment

• Must document in patient history:– HCV antibody and RNA positive – HCV genotype test performed

PBS Requirements

S100: Public hospital pharmacy dispensing(Phone or written authority; no streamlined authority, co-payment: Nil)

• Gastrohepatology/ID Specialists in public hospitals.

• Gastrohepatology/ID Specialist in prisons

S85: Community pharmacy dispensing (Phone or written authority; no streamlined authority, co-payment: $7/38 per month)

• Gastrohepatology/ID specialists with private practice rights in public hospitals.

• Gastrohepatology/ID specialist in private hospitals/rooms

• Other registered medical practitioners following “consultation” with HCV treatment experienced gastroenterologists, hepatologists, ID physicians

Key HCV milestones during treatmentKey HCV Milestones during treatment

• Routine on-treatment HCV RNA testing is considered where there is concern about non-compliance with treatment, especially in people with cirrhosis

• Closer monitoring for patients on PEG / RBV containing regimens and patients with cirrhosis especially decompensated cirrhosis

Frequency and type of contact based on need for sufficient safety assessments and treatment response

Australian Recommendations for the Management of HCV Infection: A Consensus Statement 2016

On-Treatment Monitoring

ASHM 2016

1. Explain lab results

2. Review medication adherence

– Reinforce goal of 100% adherence

– Review timing of daily dosing schedule, food intake

– Reinforce timely refill request s85

– Ensure adequate supply of drug if traveling or hospitalized

3. Query regarding any new drugs or supplements and drug–drug interactions

4. Assess for new adverse events

5. Address contraceptive practices

6. Review alcohol, illicit drug use behaviours, and reinfection risk

7. Reinforce healthy liver habits: diet, exercise, smoking cessation

8. Provide lab and clinic appointment reminders

Checklist for Each Patient Clinic VisitChecklist for each patient visit

Who do I refer to a specialist?

1. Patients with advanced fibrosis or cirrhosis

2. Patients with extrahepatic manifestations

3. Patients with complex co-morbidities

4. Patients with renal impairment

5. Patients with HIV/HCV or HBV/HIV coinfection

6. Patients who failed first line DAA

• BUT

• Tertiary centres will continue to provide treatment for patients of all disease stages

Who do I refer to a specialist?

Phase III trials

1) Feld, J.J. N Engl J Med 2014. 2) Puoti, M. AASLD 2014. 3) Lalezari, J. J Hepatol 2015. 4) Grebely CID 2016. 5) Grebely CID 2016. 6) Zeuzem, S. Ann Intern Med 2015. 7) Dore, G.J. Ann Intern Med 2016.

Are results the same for HCV patients on OST for IFN-free DAAs? YES!

ASHM 2016; Bruggmann P & Litwin AH. Clin Infect Dis 2013;57(S2): S80–S89

Linkage to Care For HCV-Infected Persons Can Occur in a Variety of Settings

One size does not fit all

HCV Linkage to Care

University of Liverpool (Hep iChart)

Potential drug-drug interactions

DAA treatment for people on OST

Regimen Methadone Buprenorphine

Sofosbuvir/Ledipasvir Not studied; no DDI anticipatedNot studied; levels possibly

increased

Sofosbuvir/Daclatasvir

Studied (DCV); increased

levels (7-8%), not significant

Studied (SOF); no effect

Studied (DCV); increased

levels (20-30%); not

significant

Not studied (SOF); no DDI

anticipated

Paritaprevir/r/Dasabavir/

Ombitasvir +/- RBVStudied; no effect

Studied; conc. increased 2-3

fold; no dose modification;

monitor

Elbasvir/Grazoprevir Studied; no effect Studied; no effect

Drug interactions with OST

EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016),

DDIs: illicit recreational drugs

DCV SOFSOF/

LDVViekera

GZR/

EBR

SOF/

VEL

Amphetamine ● ● ● ● ● ●Cannabis ● ● ● ● ● ●Cocaine ● ● ● ● ● ●Diamorphine ● ● ● ● ● ●Diazepam ● ● ● ● ● ●Gamma-

hydroxybutyrate ● ● ● ● ● ●

Ketamine ● ● ● ● ● ●MDMA (ecstasy) ● ● ● ● ● ●Methamphetamine ● ● ● ● ● ●Phencyclidine (PHP) ● ● ● ● ● ●Temazepam ● ● ● ● ● ●

DAA treatment for people on OST DDIs- Illicit drugs

Post-Treatment Follow Up

DDIs: illicit recreational drugsDAA treatment for people on OST

Post-Treatment Follow Up

• HCV RNA test 12 weeks post Rx (SVR12)

• Annual HCV RNA test if ongoing risks– Eg: PWID, HIV, MSM

• Repeat HCV genotype if detectable VL

• If cirrhosis:– HCC surveillance (6 monthly US)

– Bone health (Annual DEXA)

– Portal Hypertension (Gastroscopy 1-2 yearly)

– Dietician review

DDIs: illicit recreational drugsDAA treatment for people on OST Post Treatment Follow Up

El-Serag H et al. AASLD 2015 Abstract 90

Incidence and Predictors of Hepatocellular Carcinoma Following SVRPost-Treatment Follow UpDDIs: illicit recreational drugsDAA treatment for people on OST

Incidence and risks for HCC post SVR

Source: Simmons B et al. CID 2016

HCV reinfection meta-analysis

1%

10%

15%

0

2

4

6

8

10

12

14

16

Low risk PWID / prisoner HIV co-infected

% H

CV

re

infe

ctio

ns a

t 5

ye

ars

10%

43 studiesn=7,969

Avg. FU=3.9 years

14 studiesn=771

Avg. FU=2.8 years

4 studiesn=309

Avg. FU=3.3 years

DDIs: illicit recreational drugsDAA treatment for people on OST HCV Reinfection Meta-Analysis

Safety and tolerability• Decreased adverse effects and

discontinuation• Minimal drug-drug interaction

Towards Elimination in Australia:Why Eliminating HCV is Possible With the DAAs

Efficacy• Increased SVR rates• High barrier to resistance• Pangenotypic regimens coming

(one size fits all)

Broader population• PWID, prisoners• Interferon-ineligible/-intolerant• Advanced liver disease • Comorbidities and elderly

Convenience • Shorter duration• Less pill burden• “Treat-A-Friend” strategies more

acceptable• Less intensive monitoring

HCV reinfection meta-analysis DDIs: illicit recreational drugsDAA treatment for people on OST Towards HCV Elimination in Australia

More information?• Australian recommendations for the management of hepatitis

C virus infection: a consensus statement (MJA, GESA)

• GESA/ ALA website

• ASHM website, ASID website

• EASL (EU), AASLD (USA) websites

• Burnet Institute- Eliminate C

• Community: Hepatitis Victoria, Hepatitis Australia

Towards Elimination in Australia:Why Eliminating HCV is Possible With the DAAsHCV reinfection meta-analysis DDIs: illicit recreational drugsDAA treatment for people on OST More Information?