hcv management in the new age of direct-acting …hcv management in the new age of direct-acting...
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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?