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Hepatitis C Update
Mohamed Kaif, MDAssistant Professor of MedicineDigestive Disease and NutritionUniversity of South Florida
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Disclosures
None
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Personal Introduction
From Pinellas County University of Miami Miller SOM University of Texas Southwestern
IM Residency University of Alabama Birmingham
GI/Hepatology Fellowship USF Assistant Professor
– Focus on non-transplant hepatology• Treatment of hepatitis C
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Aim
Reflect on epidemiology and advances in treatment over 25 years Delineate assessment of patients for
treatment Review treatment options Discuss special cases
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Epidemiology and Healthcare
Buckley GJ, Strom BL, 2016
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Natural History
Recovery & Clearanceof HCV (20)
Chronic Hepatitis
Mild (24) Moderate (32)
End-Stage LiverDisease
HepatocellularCA
Cirrhosis
Severe (24)
Chronic Infection(80)
Acute HCV Infection (100)
Thomas DL, Seeff LB, 2005
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Prevalence by Age GroupIn
divi
dual
s, (n
)
Birth Year Group
0
1,600,0001,400,0001,200,0001,000,000
800,000600,000400,000200,000
1990+1980-1989
1970-1979
1960-1969
1950-1959
1940-1949
1930-1939
1920-1929
<1920
Pyenson B et al, 2009
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Decompensated Cirrhosis and HCC
1950 1960 1970 1980 1990 2000 2010 2020 2030Year
Num
ber o
f cas
es
160,000
0
140,000120,000100,00080,00060,00040,00020,000
Decompensated cirrhosis
Hepatocellular cancer
Ghany MG et al, 2009
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Brief History of Treatment
IFN
IFN + RBV
Peg-IFN + RBV
PI + PegIFN+ RBV
IFN-free Combos
1989 1998 2001 2011 2014
Webster DP et al, 2015
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Advances in Standard of Care
Webster DP et al, 2015
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Patient Assessment
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Patient Case
A 62 year-old asymptomatic female presents to you with recent diagnosis of hepatitis C, inquiring about treatment– Denies history of IV drug abuse– On routine screening, found to have positive
HCV Ab
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Testing for HCV
All persons born between 1945 and 1965, regardless of risk factors– Why?
• Retrospective review of >100,000 patients
• Only 27% would be screened with risk-based criteria
• 68% would have been tested by meeting the 1945-1965 birth cohort criteria
Mahajan R et al, 2013
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Testing for HCV
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Population to consider
All patients
Except those with severely limited life expectancy
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History
Factors associated with accelerated disease progression and compliance– Alcohol use– Drug abuse– Metabolic complications related to fatty liver
Complications that would suggest underlying cirrhosis Concurrent medication use
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Physical Exam
Stigmata of advanced liver disease Signs of extrahepatic manifestations of
HCV infection
Retamozo S et al, 2013
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Physical Exam
Stigmata of advanced liver disease Signs of extrahepatic manifestations of
HCV infection
White G, 2013 and UsatineRP, Tinitigan M, 2011
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Lab Evaluation
Basic Laboratory Testing– CBC, CMP, INR, lipid panel, U/A, pregnancy
test HIV, HBV, HAV HCV RNA HCV genotype Assessment of fibrosis stage
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Genotype
Messina JP et al, 2015
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Assessment of Fibrosis
Necessary in every patient May affect
– Length of therapy– Success of therapy– Surveillance– Insurance approval
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Laboratory Assessment of Fibrosis
Indirect– AST/ALT ratio– APRI score– FIB-4
Direct– Biomarkers
• Fibrosure
Teshale E et al, 2014
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Imaging Assessment of Fibrosis
Transient elastography
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Assessment of Fibrosis
ALL markers of fibrosis are imperfect (even biopsy)None alone have adequate sensitivityA combination approach is preferred to assess concordance
– Direct• Imaging is preferred (i.e. transient elastography)• Biomarkers have limitations
– Expensive, not universally covered– Some no more sensitive than indirect tests
– Indirect• APRI or FIB-4
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Management
AASLD/ISDA GuidelinesHcvguidelines.org
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When to refer
USF GI is accepting referrals for patients with HCV – Patients without cirrhosis or with compensated
cirrhosis– Previously treated patients– Patients with renal failure– Fine print
• Patients with decompensated cirrhosis or OLT often better served by TGMG transplant hepatology
• Patients with concurrent HIV better served by Infectious Disease
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DAA Drug Classes
Protease inhibitors– NS 3/4 inhibitors
NS5a inhibitors
Polymerase inhibitors– NS5b inhibitors
• Nucleoside• Non-nucleoside
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Suffixes
“-previr”– Protease inhibitors– Metabolized in the liver
• Avoid in decompensated liver disease “-asvir”
– NS5a inhibitors– Pangenotypic
“-buvir”– NS5b inhibitors– Pangenotypic
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Which combinations are which??
Harvoni = Sofosbuvir/Ledipasvir Epclusa = Sofosbuvir/Velpatasvir Zepatier = Elbasvir/Grazoprevir Viekira pak:
– Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir
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NOT Recommended Treatments
General– Monotherapy with Peg-IFN, Ribavirin, or DAA– PegIFN + Ribavirin– Sofosbuvir + Ribavirin
Decompensated cirrhosis– Protease-inhibitor-based treatments
• Paritaprevir• Simeprevir• Grazoprevir
Pregnancy– Ribavirin
AASLD/ISDA 2016
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Current Treatment Recommendations
Treatment Naive
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Of Note
Efficacy of proposed regimens exceeds 90% Only the most effective recommended
regimens will be discussed
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Gen 1 – Non-cirrhotic
Sofosbuvir/Velpatasvir Sofosbuvir/Ledipasvir Elbasvir/Grazoprevir* Paritaprevir/Ritonavir/Ombitasvir +
Dasabuvir +/- Ribavirin** Sofosbuvir + Daclatasvir Sofosbuir + Simeprevir
AASLD/IDSA 2016
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Gen 1 – Cirrhotic
Sofosbuvir/Velpatasvir Sofosbuvir/Ledipasvir Elbasvir/Grazoprevir Paritaprevir/Ritonavir/Ombitasvir +
Dasabuvir (Gen 1b) Sofosbuvir + Daclatasvir Sofosbuir + Simeprevir
AASLD/IDSA 2016
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Harvoni
Nkuize et al, 2016
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Gen 2
Sofosbuvir/Velpatasvir
AASLD/IDSA 2016
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Epclusa – ASTRAL1
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Analysis of SOF/VEL x 12 weeks
Patients, n (%) GT1n=328
GT2n=238
GT3n=277
GT4n=116
GT5n=35
GT6n=41
TotalN=1035
Cirrhosis 73 (22) 29 (12) 80 (29) 27 (23) 5 (14) 6 (15) 220 (21)
Platelets <100 x 103/µL 21 (6) 4 (2) 25 (9) 8 (7) 1 (3) 3 (7) 62 (6)
Albumin <3.5 mg/dL 6 (2) 1 (<1) 8 (3) 6 (5) 0 0 21 (2)
Fibroscan ≥15 kPa 30 (16) 9 (7) 40 (20) 17 (19) 4 (17) 5 (19) 105 (16)
HCV RNA ≥800,000 IU/mL 255 (78) 186 (78) 191 (69) 74 (64) 26 (74) 31 (76) 763 (74)
Treatment experienced 110 (34) 44 (18) 71 (26) 52 (45) 11 (31) 3 (7) 291 (28)
Black race 25 (8) 19 (8) 3 (1) 14 (12) 0 0 61 (6)
Age ≥65 years 36 (11) 53 (22) 7 (3) 11 (10) 16 (46) 0 123 (12)
BMI ≥35 kg/m2 20 (6) 18 (8) 21 (8) 8 (7) 3 (9) 0 70 (7)
HbA1c ≥6.5% 21 (6) 9 (4) 13 (5) 10 (9) 3 (9) 4 (10) 60 (6)
NS5A RAVs (15% cut off) 50 (15) 146 (61) 31 (11) 69 (59) 3 (9) 19 (46) 318 (31)
The ASTRAL-1, -2, and -3 studies enrolled patients with baseline characteristics historically associated with poor response
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Integrated Efficacy - ASTRALSV
R12
(%)
98 99 95 100 97 100
0
20
40
60
80
100 98
Total
10151035
323328
264277
116116
3435
4141
237238
GT 1 GT 2 GT 3 GT 4 GT 5 GT 6
2 relapse2 LTFU1 D/C 1 D/C
11 relapse2 D/C 1 death
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Gen 3
Sofosbuvir/Velpatasvir Sofosbuvir + Daclatasvir (if cirrhotic, 24
weeks)
AASLD/IDSA 2016
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Gen 4
Sofosbuvir/Velpatasvir Sofosbuvir/Ledipasvir Elbasvir/Grazoprevir Paritaprevir/Ritonavir/Ombitasvir +
Dasaburvir +/- Ribavirin
AASLD/IDSA 2016
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Current Treatment Recommendations
Treatment Experienced
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Treatment Experienced
Prior peg-IFN/Ribavirin– Same as treatment for naïve patients
AASLD/IDSA 2016
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Treatment Experienced
Gen 1, prior NS5A Inibitor or SOF/SIM– Non-cirrhotic and no urgent reason for
treatment• Defer treatment pending availability of data
– Cirrhotic or urgent reason for treatment• Test for RAVs to NS3/NS5A inhibitors
AASLD/IDSA 2016
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Treatment Experienced
Test for RAVs
None
SOF/LDVor SOF/VEL
x 24wk
NS5A RAVs
SOF/SIM + RBV x 24wk
NS3 & NS5A RAV
?
AASLD/IDSA 2016
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SOF/VEL + Voxilaprevir (GS-9857)
Lawitz E et al, 2016
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Special Considerations
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Medication Interactions
80% 85% 90% 95% 100%
PPI Drug NameDexlansproprazole (n=10)
Esomeprazole (n=48)
Lansoprazole (n=26)
Omeprazole (n=228)
Pantoprazole (n=77)
Rabeprazole (n=5)
Low (n=282)
High (n=172)
Once Daily (n=420)
Twice Daily (n=34)
PPI Dose
PPI Frequency
p=0.030
p=0.965
p=0.799
97%
Discontinue PPI OR
Take 20mg >2 hours after
DAA
Afdhal N et al, 2016
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Medication Interactions
Avoid amiodarone with sofosbuvir– Risk of symptomatic bradycardia
Caution with inducers of P-glycoprotein– Rifampin– St. John’s Wort– Carbemazepine– Phenytoin
– Statins– Digoxin
Hep-druginteractions.org
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Renal Failure
Gen 1 and 4: Elbasvir/Grazoprevir– 224pts, CKD 4/5, 75% on HD: SVR12 99%
Gen 1b: Paritaprevir/Ritonavir/Ombitasvir + Dasabuvir* Gen 2, 3, 5, or 6: Peg-IFN and Ribavirin*
In the works: Glecaprevir/Pibrentasvir(ABT-493/ABT-530): 98% SVR across GT 1-6
AASLD/IDSA 2016 and Gane E et al, 2016
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Side Effects
DAA side effects similar to placebo– Nausea– Headache– Fatigue
Ribavirin– Anemia– Rash/pruritus– Irritability, insomnia, anxiety, depression– Teratogenic
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Cost
Rosenthal E and Graham CS, 2016
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Public Health
“In the US, HCV has all the attributes of an eradicable disease except sufficient public investment. Delivering care effectively, safely, and broadly to all patient populations in an economically acceptable fashion must be our goal.”– Dr. Nezam Afdhal
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Key Points
Hepatitis C is a curable viral illness Estimating fibrosis is necessary Every patient should be considered for
treatment irrespective of fibrosis New therapies are safe, simple, and
effective Cost is currently a primary barrier to
treatment
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Acknowledgements
Dr. Philip Henderson Dr. Brendan McGuire Dr. Omar Massoud Dr. John Jacobs Dr. Joel Richter
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References
1. Wise M, et al. Changing trends in hepatitis C-related mortality in the United States, 1995-2004. Hepatology. 2008 Apr;47(4):1128-35.
2. Buckley GJ, Strom BL. Eliminating the Public Health Problem of Hepatitis B and C in the United States: Phase One Report. Washington, D.C. The National Academies of Sciences; 2016.
3. Thomas DL, Seeff LB. Natural History of Hepatitis C. Clin Liver Dis. 2005 Aug;9(3):383-98.
4. Pyenson B, et al. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. New York, NY: Milliman, Inc; 2009.
5. Ghany MG, et al. Diagnosis, management, and treatment of Hepatitis C: an update. Hepatology. 2009 Apr;59(4):1335-74.
6. Webster DP, et al. Hepatitis C. Lancet. 2015 Mar 21;385(9973):1124-35.
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7. Mahajan R, et al. Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004-2010. Am J Public Health. 2013 Aug;103(8):1445-9.
8. Retamozo S, et al. Cryoglobulinemic Disease. Oncology. 2013 Nov.9. White G. Porphyria Cutanea Tarda. Courtesy of regionalderm.com10. Usatine RP, Tinitigan M. Diagnosis and treatment of lichen planus.
Am Fam Physician. 2011 Jul 1;84(1):53-60.11. Messina JP, et al. Global distribution and prevalence of hepatitis C
virus genotypes. Hepatology. 2015 Jan;61(1):77-87.12. Teshale E, et al. APRI and FIB-4 are Good Predictors of the Stage
of Liver Fibrosis in Chronic Hepatitis B. The Chronic Hepatitis Cohort Study (CHeCS). J Viral Hepat. 2014;21(12):917-920.
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13. Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases and Infections Diseases Society of America. 2016 Jul. www.hcvguidelines.org.
14. Nkuize M, et al. Combination ledipasvir-sofosbuvir for the treatment of chronic hepatitis C virus infection: a review and clinical perspective. Therapeutics and Clinical Risk Management 2016:12;861-872.
15. Lawitz E, et al. High Efficacy of Sofosbuvir/Velpatasvir Plus GS-9857 for 12 Weeks in Treatment-Experienced Genotypes 1-6 HCV-Infected Patients, Including Those Previously Treated with Direct-Acting Antivirals. EASL 2016, Barcelona.
16. Afdhal N, et al. No Effect of Proton Pump Inhibitor (PPI) Use on SVR with Ledipasvir/Sofosbuvir (LDV/SOF): Real World Data from 2034 Genotype 1 Patients in the Trio Network. EASL 2016, Barcelona.
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17. Gane E, et al. Expedition-4: Efficacy and Safety of Glecaprevir/Pibrentasvir (ABT-493/ABT-530) in Patients with Renal Impairment and Chronic Hepatitis C Virus Genotype 1-6 Infection. AASLD 2016, Boston.
18. Rosenthal ES, Graham CS. Price and affordability of direct-acting antiviral regimens for hepatitis C virus in the United States. Infect Agent Cancer. 2016 May 16;11:24.
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Thank You