Approach to HCV Treatment in Patients with...

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

ACG 2016 Washington, DC, Hepatitis School Copyright 2016 American College of Gastroenterology

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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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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



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Age-specific incidence of liver and intrahepatic bile duct cancer from 2008-2012 – U.S.


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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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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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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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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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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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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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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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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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


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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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