approach to hcv treatment in patients with...
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Jorge L. Herrera, MD, MACG
Approach to HCV Treatment in Patients with HCCJORGE L. HERRERA, MD, MACGU N I V E RS I T Y O F S O U T H A L A BA MA C O L L EG E O F M E DI C I N E
Worldwide Causes of HCC
54%
31%
15%
0%
10%
20%
30%
40%
50%
60%
Hepatitis B Hepatitis C Other
EASL-EORTC Clinical Practice Guidelines. Management of HCC. J Hepatol 2012;56:908-943
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Jorge L. Herrera, MD, MACG
Seroprevalence of HCV and HBV in Patients with HCC - USA
Before the year 2000After the year 2000
De Martel C, et al. Hepatology 2015;62:1190-1200
Age-adjusted incidence of HCC and intrahepatic bile duct cancer 2008-2012
Ryerson AB et al. Cancer 2016;122:1312-37
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Jorge L. Herrera, MD, MACG
U.S. Adjusted Rates of Liver/Biliary Cancer
El-Serag HB, Kanwal F. Hepatology 2014;1767-1775
Liver Cancer Mortality 2003-2012 – United StatesDeath rates declined for all cancers combined◦ Decrease of 1.5% per year
Deaths from liver cancers increased at the highest rate of all cancer sites◦ Men 2x incidence compared to women◦ Highest risk for persons born after 1947
Ryerson AB et al. Cancer 2016;122:1312-37
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
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Jorge L. Herrera, MD, MACG
Age-specific incidence of liver and intrahepatic bile duct cancer from 2008-2012 – U.S.
Ryerson AB et al. Cancer 2016;122:1312-37
HCV and HCC ConnectionHCV Infection◦ 15x – 20x increased risk for HCC vs. uninfected individuals◦ HCC cumulative risk of 1% to 3% over 25 years◦ After cirrhosis: HCC annual risk 1% to 8%, average 3.5%
Risk factors for HCC in HCV cirrhosis◦ Male sex◦ Coinfection with HBV or HIV◦ Alcohol use◦ Obesity ◦ Diabetes◦ Genotype
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Jorge L. Herrera, MD, MACG
HCC in HCV and DiabetesTaiwan National Health Insurance Research Database (>99% of the population)
Patients with chronic HCV who developed new onset diabetes
Adjusted Relative Risks for HCC
Study population: 1.9 (CI: 1.1-3.3)
Age 40-59: 3.09 (CI: 1.04-9.11)
Huang YW, et al. Aliment Pharmacol Ther 2015;42:902-911
Increased Risk of HCC in Genotype 3 Infection
0 0.5 1 1.5 2
HCC
Liver-relatedhospitalization
Decompensatedcirrhosis
CirrhosisGT1GT2GT3Other
10
(n=123,988)
(n=128,055)
(n=128,769)
(n=128,481)
(reference point; n=102,191)(n=15,113)
(n=9851)
(n=1614)
• Observational cohort study of 128,769 HCV patients from the VA HCV Clinical Registry, which compiled electronic medical records data from 1999 to 2010
McCombs J, et al. JAMA Intern Med. 2014;17:204-212.
Hazard Ratio
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Jorge L. Herrera, MD, MACG
Incidence of HCC According to Genotype
Kanwal F, et al. Hepatology 2014;60:98-105
VA HCV Clinical Case Registry 2000-2009. 110,484 HCV patients, 8,337 genotype 3 infection
G3 patients were younger
Adjusted HR for HCC: 1.8 (compared to G1)
Independent of:AgeDiabetesBMI
Fibrosis and Risk of HCC in HCVHCC develops in the setting of advanced fibrosis in HCV
HALT-C Study (n=1,005) Stage 3 or 4 fibrosis Median Follow up 4.6 years Cumulative 5y incidence
of HCC: 5.2%√ Cirrhosis: 7.0%√ Bridging fibrosis: 4.1%
Lok AS, et al. Gastroenterology 2009;136:138-148
EASL Clinical guidelines recommend HCC screening
for F-3 fibrosis in HCV
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Jorge L. Herrera, MD, MACG
Other Factors Predictive of HCCADVANCED LIVER DISEASE PLATELET COUNT
Lok AS, et al. Gastroenterology 2009;136:138-148
Identifying Patients at RiskTake Home MessagesRisk restricted to advanced fibrosis (F3-F4)Risk is highest in◦ Cirrhosis◦ Males◦ Genotype 3 infection◦ Advanced liver disease
Screening for HCC in F0-2 is not recommended
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Jorge L. Herrera, MD, MACG
How to ScreenWho to screen◦ Cirrhosis (F4 fibrosis)1
◦ Bridging fibrosis (F3 fibrosis)2
Current guidelines:◦ Ultrasound exam every 6 months
Alpha-fetoprotein is not recommended◦ Lacks sensitivity and specificity◦ Frequent false positive results◦ Normal levels in up to 40% of documented HCC
1. AASLD & EASL guidelines 2. EASL guidelines
If you are using AFP…AFP cannot be used as the only screening testMany HCV cirrhosis patients will have elevated AFPThe trend is more important than the actual value
AFP usually rises as ALT risesA normal AFP should not dissuade you from evaluating a possible abnormality on ultrasound
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Jorge L. Herrera, MD, MACG
Why Screening FailsOnly 40% of HCC patients are diagnosed at an early stage
1,005 patients with F3/4 fibrosis, mean follow-up 6.1 years (HALT-C)◦ 69% (692) had consistent surveillance◦ 83 patients had HCC◦ 28% (n=23) were detected beyond Milan Criteria◦ 3/23 had absence of screening◦ 4/23 absence of follow up◦ 16/23 absence of detection
Singal AG et al. Am J Gastroenterol 2013;108:425-432
Ultrasound is far from a perfect test!
What to do with Screening Results
Bruix J, Sherman M. Hepatology 2011;53:1020-1022
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Jorge L. Herrera, MD, MACG
Effects of HCV Therapy on HCCALL STAGES OF FIBROSIS
HR OF HCC AFTER THERAPYADVANCED FIBROSIS
HR OF HCC AFTER THERAPY
Morgan RL, et al. Ann Intern Med 2013;158:329-337
Meta-analysis of observational studies
HCV Cure Does Not Eliminate Risk
n=530, advanced fibrosis; 8.4 year follow up post SVR. Europe and Canada
Van der Meer AJ, et al. JAMA 2012;308(24):2584-2593
n=124, biopsy proven cirrhosis; 8-year follow up post SVR. Italy
Ascione A, et al. Hepatology 2007;45:579-587
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Jorge L. Herrera, MD, MACG
Management of HCV after HCC DiagnosisEradicate the virus prior to or after the transplant?Factors to consider◦ Severity of liver disease◦ CP-C lower SVR, better served by a transplant
◦ Type of donor◦ Pre-transplant strategy works best for living donors
◦ Availability of HCV (-) livers◦ Treating HCV pre-transplant eliminates the possibility of an HCV (+)
organ◦ Wait time until transplant◦ The longer the patient is negative pre-transplant, the better
Sofosbuvir + Ribavirin Pre OLT61 patients CP-A patients with HCC waiting for OLT
Treated with sofosbuvir + ribavirin for up to 48 weeks prior to OLT
49% achieved a cure post-OLT
43 patients RNA (-) Pre-OLT◦ SVR post OLT: 70%◦ SVR was inversely related to number of days of undetectable RNA◦ 30 days seems to be the cut-off
Curry MP et al. Gastroenterology 2015;148:100-107
Sofosbuvir + ribavirin is now considered suboptimal therapy for G1
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Jorge L. Herrera, MD, MACG
HCV Recurrence vs. Time Undetectable HCV-RNA
Curry MP et al. Gastroenterology 2015;148:100-107
Sofosbuvir + ribavirin for up to 48 weeks prior to OLT
Post Liver Transplantation96% 98%
0%10%20%30%40%50%60%70%80%90%
100%
No Cirrhosis
Sofosbuvir + Ledipasvir + Ribavirin
12 wks 24 wks
53/55 55/56
Charlton M, et al. Gastroenterology 2015;149:649-659
AASLD 2015: Ribavirin probably not necessary in post OLT non-cirrhotic patients
ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology
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Jorge L. Herrera, MD, MACG
HCC in HCVTake Home Points
1. Hepatitis C markedly increases risk of HCC◦ Risk increased in F3 and F4 fibrosis
2. F3 and F4 HCV patients should undergo appropriate HCC screening
3. Cure of HCV markedly reduces risk of HCC in all patients
4. After cure, F3 and F4 patients remain at risk of HCC
5. Timing of treatment of HCV after HCC diagnosis is evolving
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