Update on Hepatitis C virus

infection

24th Annual Southwestern

Conference on Medicine

April 2015

Ester C. Little, MD, FACP

Banner University Medical Center

Phoenix Campus

Disclosures:

Advisory board for Gilead

Speaker for Abbvie

Hepatitis C Virus :

• Structure of the virus

• Historical facts

• Prevalence

• Diagnosis

• Clinical manifestations

• Natural history

• Treatment

Nucleic Acid: 9.6 kb ssRNA

Classification: Flaviviridae, Hepacivirus

Genotypes: 1 to 9

Enveloped

In vitro model: primary hepatocyte and T cell cultures; replicon system

In vivo replication: in cytoplasm, hepatocyte and lymphocyte; human and other primates

40-60 nm

Hepatitis C Virus

Hepatitis C Virus: Morphology and Characteristics

Hepatitis C Virus

5’ UTR 3’ UTR

C E1 E2 NS2 NS3

NS4A

NS4B NS5A NS5B

C E1 E2 NS2 NS3 A NS4 NS5A NS5BB

P7

Core

Envelope

Protease

Serine protease

Protease Cofactor

RNA polymerase

Structural protein coding region

Nonstructural protein coding region

Serine ProteaseHost signal peptidase

Helicase

Genome and Gene Products

Hepatitis C Virus: Genome and Gene Products, pt.5

HCV historical facts:• 1970-80’s a chronic type of hepatitis associated

with transfusion was recognized

• 1989 the HCV virus was identified

• 1990 blood banks start screening but tests were not perfected until 1992

• 1991 FDA approved first Interferon alpha

• 1998 FDA approved Interferon plus Ribavirin

• 2001 FDA approved Pegylated Interferon

• 2011 FDA approved first direct anti viral agent for HCV

Prevalence

HCV - Epidemiology

United States

Anti-HCV positive 3.9 million (1.8%)

HCV RNA positive 2.7 million (1.4%)

Worldwide 170 million ( 3%)

Alter MJ et al., New Engl J Med 1999; 341:556

Lavanchy D & McMahon B, In: Liang TJ & Hoofnagle JH (eds.)

Hepatitis C. New York: Academic Press, 2000:185

Prevalence

HCV - Epidemiology

Heintges, T., Hepatology 1997; 26:521

10 to 205 to 102 to 51 to 20 to 1

HCV Ab pos (%)

Worldwide Prevalence

Worldwide Prevalence

By 2007 hepatitis C-associated deaths had overtaken HIV as a cause of mortality in the United States. To achieve declines in mortality similar to those seen with HIV will require new policy directions and commitment to detect and link infected persons to care and successful treatment.

Mortality Rates of HBV, HCV and HIV: 1999-20071

Morbidity and MortalityPredictions2

DCC, decompensated cirrhosis1. Adapted from Ly KN et al. Ann Intern Med. 2012;156:271-278. 2. Adapted from Rein DB et al. Dig Liver Dis. 2011;43:66-72.

United States: Increased Morbidity and Mortality Due to

HCV Now and in the Future

Holmberg SD et al. New Engl J Med. 2013;368:1859-1861.

Most Americans With Chronic HCV Have Not Been Diagnosed

and Few Have Been Treated

• Limited response to treatment with Interferon• Severe side effect profile• Multiple contra indications

HCV - Epidemiology

Risk Factorsfor Hepatitis C Injection

Drug Use

Multiple

Sexual Partners

Clotting Factor

Treatment Prior

to 1987Long-Term

Hemodialysis

Blood

Transfusion

or Organ Transplant

Prior to 1992

Birth from

Infected Mother

Mass Injections

and Traditional

Practices

Risk Factors for Hepatitis C

Baby boomers

Who should be tested for

hepatitis C

Test for HCVantibody

Riskfactors for HCV

ElevatedALT

Extra-hepatic

HCV Antibody

test

If positive,

test HCV RNA

HCVRNA negative=

False positive or past

infection

HCV RNA positive =

current HCV infection

If negative

No HCV infection

Diagnostic Tests for HCV

Diagnostic Tests

• Hepatitis C antibody test: screening

• Qualitative HCV RNA test: confirmatory

• Quantitative HCV RNA test: monitor treatment

• Genotype: how to treat and for how long

• Liver biopsy: when to treat*

HCV - Diagnosis

Diagnostic Tests

Hoofnagle JH, Hepatology 1997; 26:15S

HCV - Diagnosis

Acute HCV Infection

Time After Exposure

0

400

600

800

1000

ALT(IU/L)

0 2 4 6 8 10 12 24 1 2 3 4 5 6

Anti-HCV

Symptoms

Weeks Months

HCV RNA positive

200

7

Normal

ALT

Acute hepatitis C infection

Acute hepatitis C• Signs and symptoms:

• Asymptomatic ( 79% of cases)

• Anorexia, right upper quadrant abdominal pain, with or without jaundice, arthralgia, myalgia, fatigue, weight loss, skin rash and fever.

• Laboratory tests: • CMP: increased AST, ALT up to thousands, mild

increase in ALK phosphatase and GGT, variable increase in bilirubin, decreased albumin

• Coagulation: prolonged prothrombin time in severe cases.

• Natural history: 55 to 85% of the patients will progress to chronic HCV

Chronic hepatitis C

• Signs and symptoms:• Asymptomatic

• Fatigue, join pain, dull right upper quadrant abdominal pain, anorexia, nausea, pruritus, memory loss

• Laboratory tests:• 1/3 of patients have normal ALT/AST.

• Mildly increased AST/ALT ( 50-low hundreds), with typical fluctuation over time.

• Increased PT and bilirubin, low albumin is seen as the disease progresses to cirrhosis.

• Natural history:• Remain as chronic hepatitis

• Progress to cirrhosis and liver failure

• Patients may develop liver cancer.

Extra hepatic DisordersAssociated with Chronic HCV

Hematological Essential mixed cryoglobulinemia

Non-Hodgkin’s lymphoma

Renal Membranoproliferative glomerulonephritis

Membranous nephropathy

Dermatological Porphyria cutanea tarda

Leukocytoclastic vasculitis

Lichen planus

Autoimmune Diabetes mellitus *

Idiopathic thrombocytopenic purpura

Gumber SC and Chopra S., Ann Intern Med 1995;126

Cacoub P, et al., Medicine 2000; 79:47

Extrahepatic Disorders Associated with Chronic HCV

Photo

Skin Lesion in PCT

HCV - Natural History

Outcome Following Hepatitis C InfectionAcute hepatitis C

Chronic infection

Chronic hepatitis

Cirrhosis

Time(yr)

55 - 85%

70%

20%

10 20 30

Decompensation

HCC1 - 4%/yr

4 - 5%/yr

Outcome Following Hepatitis C Infection

Stages of Fibrosis In Chronic

Hepatitis

HCV - Natural History

Portal Periportal

Septal Cirrhosis

1 2

3 4

Stages of Fibrosis In Chronic Hepatitis

HCV - Diagnosis

Liver biopsy or image modalities

• Degree of fibrosis is most important

predictor of prognosis

• Useful in determining need for

anti-viral therapy

• Advanced cirrhosis is associated with

reduced response to treatment

Liver biopsy in chronic hepatitis C

Liver Biopsy

X

X

X

X

HCV - Natural History

Poynard T, et al., Lancet 1997; 349:825

Duration of infection

Alcohol > 50 gm per day

Age > 40 years at infection

Male gender

Factors Associated With Fibrosis

Factors Associated With Fibrosis

HCV - Diagnosis

HCV Genotypes• Six major genotypes found throughout the

world ( 1 to 6).

• In Europe and U.S., 60-70% of patients

have genotype 1 infection, followed by

genotypes 2 and 3.

• Treatment is different for G 1 and G 2 and 3.

Genotype in hepatitis C

HCV - Treatment

Goals of Hepatitis C Treatment

Goals of Hepatitis C

Treatment Primary

Eradicate the virus

Secondary

Prevent progression to cirrhosis

Reduce incidence of HCC

Reduce need for transplantation

Enhance survival

HCV - Natural History

Outcome Following Hepatitis C InfectionAcute hepatitis C

Chronic infection

Chronic hepatitis

Cirrhosis

Time(yr)

55 - 85%

70%

20%

10 20 30

Decompensation

HCC1 - 4%/yr

4 - 5%/yr

Outcome Following Hepatitis C Infection

HCV - Treatment

Patterns of response to treatment in hepatitis C

HCV RNANegative

SustainedResponder

Nonresponder

Baseline Treatment

Time

HCV RNA

Relapser

Patterns of Response to Hepatitis C

Treatment

Current HCV therapy Genotype 1:

• Sofosbuvir and Ledipasvir for 12 weeks or 24 weeks if patients is treatment experienced with cirrhosis.

• Sofosbuvir and Simeprevir combination for 12 weeks if treatment naïve, for 24 weeks if treatment experienced

• Ombitasvir/Paritaprevir/Ritonavir without Ribavirin for Genotype 1b and with Ribavirin for Genotype 1a. Treat for 12 weeks if treatment naïve and 24 if treatment experienced

HCV therapy for Genotypes 2 and 3:

• Sofosbuvir and Ribavirin for 12 weeks (Genotype 2)

• Sofosbuvir and Ribavirin for 24 weeks (Genotype 3)

HCV treatment special

populations:

• HIV co-infected patients (pts) can be treated with similar response rate

• Pts with GFR no less than 30 can be treated safely

• Post liver and post kidney transplant pts can be treated with excellent response rate

• On going trials for treatment of pts on dialysis

• DAA awaiting FDA approval for pts on dialysis

Current HCV therapy:

• Response rate is similar regardless of genotype

• Response rate is similar regardless of the presence of cirrhosis

• Response rate is similar in different ethnic groups

• Overall response rates are 70 to 90 %

• Interferon free regimens are well tolerated with mild adverse effects (headache, nausea, diarrhea and anemia)

•

Resources for DDIs

• AASLD treatment guidelines with regular updates

• Outstanding – University of Liverpool (David Back, Editorial Board, EASL reps); sponsored by Janssen, MSD, Roche, Vertex:– http://www.hep-druginteractions.org

• FDA:– http://www.fda.gov/Drugs/DrugSafety/

• Other Online Resources –– http://www.drugs.com/drug-interactions/html

– http://www.merckmedicus.com/pp/us/hep

– Epocrates

– Micromedex, Lexicomp and Others

What is in the pipeline?

• Even more effective direct anti-viral agents

• Shorter duration of therapy

• Therapy for pts on HD

HCV summary• HCV infection is common and can be silent

• In addition to the classic risk factors all baby boomers MUST be tested

• Normal AST and ALT does not exclude HCV

• Untreated HCV may progress to cirrhosis and HCC

• Treatment is no simpler, better tolerated and shorter duration

• Response to therapy is seen in 70 to 90% of the treated patients

Thank you!