Hepatitis C in 2015: Where do we

stand?

Janak Koirala, MD MPH

Professor & Division Chief

Division of Infectious Diseases

Case Discussion:

55 year old female…

Asymptomatic, on antihypertensive and cholesterol lowering drugs

underwent routine blood test including liver function test

LABS:Bili (total) 1.2 mg/dL

ALT 74 U/L

AST 85 U/L

Alk Phos 120 U/L

Albumin 3.6 g/dL

Case Discussion:

55 year old female…

she had tried intravenous drugs a few times when in college

used to drink alcohol, quit a few years ago

sees a psychiatrist for depression and takes antidepressants

Labs: Hepatitis A Total Ab negative

Hepatitis B suface Ag negative

Hepatitis B suface Ab negative

Hepatitis C Ab positive

Hepatitis C virus

(Electron micrograph source: Kaito et al, J Gen Virol. 1994)

Hepatitis C : Global Annual rates

New Infections 3-4 million

Living with Chronic Infection 150 million

Deaths from chronic liver disease 0.5 million

(Source: WHO)

(Source: CDC)

Hepatitis C in the US (Source: CDC)

(Source: CDC)

The New York TimesFeb 27, 2012

Hepatitis C Death Rate Creeps Past AIDSBy NICHOLAS BAKALAR

More people in the United States now die from hepatitis C each year than from AIDS , according to a new report from Centers for Disease Control and Prevention. More than 3.2 million people are currently infected with hepatitis C.

Using data on more than 22 million deaths and their causes, researchers found that hepatitis C death rates increased to almost 5 per 100,000 people in 2007 from fewer than 3 per 100,000 in 1999. Over the same period, the HIV death rate declined to a little more than 4 per 100,000 from more than 6 per 100,000.

Date of download:

10/14/2013

Copyright © The American College of Physicians.

All rights reserved.

Increasing Burden of Mortality From Viral Hepatitis in the United States

Between 1999 and 2007 (Ann Intern Med. 2012;156(4):271-278)

Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the United States

between 1999 and 2007.

Because a decedent can have multiple causes of death, a record listing more than 1 type of infection was counted for each type of infection.

Figure Legend:

Hepatitis C: Transmission

• Injection Drug use (IVDU)- currently most common

• Receipt of blood, blood products, and organs - transfusion-associated cases occurred prior to blood donor

screening (1992) - now occurs in <1 per 2 million transfused units of blood

• Perinatal transmission- risk is about 4%

• Occupational exposure• Sexual- inefficient transmission

• Sharing personal items: razors or toothbrushes

contaminated with blood (inefficient transmission)

Features of HCV Infection

Incubation period 4-12 weeks(Range 2-26 wks)

Acute illness (jaundice) 20-30%Chronic hepatitis 70%Cirrhosis 5%-20%Mortality from chr liver dis. 1%-5%

Acute Hepatitis C

Clinical Features

• Acute symptoms may occur in 20-30%Usually mild Fever, FatigueLoss of appetite Nausea, VomitingJaundice Dark urine, Clay-colored stoolAbdominal pain Joint pain

Chronic Hepatitis C

Clinical Features

• Most patients asymptomatic• Usually found incidentally

- abnormal liver enzymes (ALT, AST) - at blood donation

• Sometimes symptoms may occur- fatigue, abdominal discomfort, joint pain

• Extrahepatic manifestationsMixed cryoglobulinemia, vasculitis, MPGNPorphyria cutanea tardaLichen PlanusArthralgia, Arthritis

Online published on 25 June 2013

HCV Testing Routinely Recommended

All adults born between 1945 and 1965

Persons at high risk for infection Any injected drug use or intranasal drug use

Received clotting factors made before 1987

Received blood/organs before July 1992

Long-term hemodialysis

Children born to HCV-positive mother (>18 months)

HIV infected persons

Incarceration

Tattoo (unregulated), other percutaneous exposure

Evidence of liver disease

Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood

(Source: CDC and Annals of Int Med, 2013)

HCV Testing

Dennis trying to catch hepatitis C

HCV: Diagnosis

Screening: Anti-HCV antibody in blood

Traditional HCV antibody test done in lab

Rapid HCV test (OraQuick HCV test)

Confirmatory Tests:

HCV RNA PCR Qualitative Assay

RIBA (Recombinant Immunosorbent Assay): discontinued

HCV: Post-test counseling

HCV Ab positive, but HCV RNA not detected. Should be informed that they do not have HCV infection

Positive HCV Ab and HCV RNA Tests

1. Refer to a specialist - Infectious Disease or Hepatology medical evaluation of chronic liver disease

evaluation for coinfection with HIV or HBV

advice on possible treatment options and strategies

2. Protect the liver from further harm by- Hepatitis A and B vaccination, if susceptible

reducing or discontinuing alcohol consumption

avoiding new medicines, including OTC and herbal agents , without first checking with their health-care provider; and

obtaining HIV risk assessment and testing.

HCV: Post-test counseling

3. For persons who are overweight (BMI ≥25kg/m2) or obese (BMI ≥30kg/m2)-

consider weight management or losing weight

follow a healthy diet and stay physically active

4. To minimize the risk for transmission to others

do not donate blood, tissue, or semen

do not share needles

do not share appliances that might come into contact with blood, such as toothbrushes, dental appliances, razors, and nail clippers

In case of contamination with blood, clean surfaces with household bleach (1:10 dilution)

HCV: Further work up

HCV RNA PCR Quantitative Assay

Plasma viral load measurement

HCV Genotyping

6 major genotypes (designated 1-6)

many subtypes (designated a, b, c, etc.)

in USA, Genotype 1 is more common than 2 and 3

important for therapeutic decision

HCV: Liver staging

Liver Biopsy

to stage liver fibrosis and to grade inflammation

to exclude other causes of hepatitis/ liver disease

Noninvasive Fibrosis Staging

Imaging: Fibroscan (ultrasound based technique)

USG, MRI, CT scan

Biomarker Indices: APRI (AST/Platelet Ratio Index), Fibrotest , ACTI, Forns Index, FIB4

(Cox-North, Hepatitis C online, 2014)

Liver staging

Chronic Hepatitis C

Factors Promoting Progression or Severity

Increased alcohol intake

Age > 40 years at time of infection

HIV co-infection

Other Male gender Chronic HBV co-infection

Case Discussion:

55 year old female …(Continued)

Anti-HCV Antibody : Positive

HCV RNA PCR (Qualitative Assay): Positive

HCV RNA Quantitative PCR (Viral Load): 106 IU/ml

HCV Genotype : 1b

Liver Biopsy : stage 3 of 4 fibrosis

grade 2-3 of 4 inflammation

Case Discussion:

55 year old female …(Continued)

Patient was counseled for:

taking precautions to avoid transmission to others

avoiding alcohol and hepatotoxic drugs

Available treatment options were discussed

For depression, patient was advised to work with her psychiatrist to make sure her depression was stable during therapy

Treatment

Interferons: Pegylated interferon alpha (2a or 2b)

Ribavirin

Directly Acting Agents

Timeline for Treatment of Chronic HCV infection(1989 – 2010)

Year Treatment

1989 Success reported with IFN- monotherapy

1991 FDA approval of first IFN-

1998 IFN- PLUS Ribavirin (FDA approval)

2001 PEG-IFN- (2b) PLUS Ribavirin (FDA approval)

2002 PEG-IFN- (2a) PLUS Ribavirin (FDA approval)

2011 First DAAs approved (Boceprevir, Telaprevir)

1. Lauer and Walker, NEJM, 2001; 2. Franciscus A, HCV Advocate, 2010;

3. Sjogren, et al. Dig Dis Sci, 2005.

Response to Treatment with Dual Therapy

42%

52%

80%84%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Peg-IFN-alfa 2b + RBV Peg-IFN-alfa 2a + RBV

Genotype 1

Genotype 2/3

(Manns, et al. Lancet. 2001; Hadziyannis, Ann Intern Med. 2004)

Genotype 1- standard dose regimens for 48 weeks ;

Genotype 2/3- Peg-IFN alfa plus low dose ribavirin for 24 weeks

24-weeks SVR

Contraindications for interferon-based therapy

Pregnancy

Age less than 3 years

Solid organ transplants- lungs, heart, kidney

Mental Disorder – major depression, psychosis

Autoimmune hepatitis, other autoimmune disorder

Untreated hyperthyroidism

Other severe concurrent illness (DM, CHF, CAD)

Active alcoholism

Cytopenias - anemia, ANC <1500, thrombocytopenia

First Directly Acting Agents (DAA)

NS3/4A serine protease inhibitors

first available DAAs approved in May 2011

Drugs: Boceprevir, Telaprevir

NS3/4A serine protease is required for RNA replication and virion assembly (NS= Nonstructural protein)

Used only for HCV genotype 1 infection

Always used in combination with PEG-IFN- and Ribavirin

HCV Genome and Polyproteins

(Laur and Walker, NEJM, 2001)

Combination of Boceprevir with PEG-IFN- and Ribavirin in Previously Untreated Patients (SPRINT-2)

(Poordad et al, NEJM 2011)

Protease Inhibitor Toxicities

Adverse Event Boceprevir1,4 Telaprevir2,3 PEG-IFN/RIB

Fatigue 53% 57% 57%

Rash 17% 37% 24%

Pruritus - 50% 36%

Nausea 48% 43% 31%

Diarrhea 25% 28% 22%

Dysgeusia 37% 10% 18%

Headache 46% 41% 39%

Pyrexia 33% 26% 24%

Alopecia 27% 21% 11%

Anorectal AEs - 26% 5%

Discontinuation 12% 10% 7-16%

(Ref: 1. Poordad et al, NEJM 2011; 2. Jacobson et al, NEJM, 2011;

3. Hézode C, Liver Int, 2012; 4. Boceprevir package insert, 5/2011)

SIU Cohort (V Jogi, J Koirala, et al; ID Week 2012)

Triple regimen Group (BPR/TPR) 25 pts, Double regimen group (PR) 54 pts

7 discontinued triple therapy for hematological side effects: severe anemia needing blood transfusions (5 pts), febrile neutropenia (1 pt), and thrombocytopenia with vaginal bleeding needing hysterectomy (1 pt)

PI Based Triple Combination Regimen: Remarks

The 2 new PI containing regimens improved overall viral response rates (60-80%)

PI containing regimens also have higher rates of adverse events and contraindications

Resistance to PI can occur in patients while on treatment

Other Direct Acting Agents

(Laur and Walker, NEJM, 2001)

FDA Approved Direct Acting Agents

NS3/4A protease inhibitors• Simeprevir• Paritaprevir• Boceprevir , Telaprevir (not recommended anymore)

NS5A inhibitors• Ledipasvir• Ombitasvir

NS5B Polymerase Inhibitors• Sofosbuvir• Dasabuvir

AASLD-IDSA Treatment Recommendations

American Association for the Study of Liver Diseases (AASLD)

Infectious Diseases Society of America (IDSA)

Available at: http://hcvguidelines.org/

Treatment Naïve Patients: HCV genotype 1a (AASLD-IDSA Guideline)

Drug Regimens Combo names Duration

Ledipasvir (90 mg daily)

Sofosbuvir (400 mg daily) Harvoni 12 weeks

Paritaprevir (150 mg daily)

Ritonavir (100 mg daily)

Ombitasvir (25 mg daily)

Dasabuvir (250 mg BID)

Ribavirin (weight-based)

Viekira Pak12 weeks

(24 weeks for cirrhosis)

Sofosbuvir (400 mg daily)

Simeprevir* (150 mg daily)

± Ribavirin (weight-based)

12 weeks(24 weeks for

cirrhosis)

* baseline Q80K testing recommended for simeprevir

Treatment Naïve Patients: HCV genotype 1b(AASLD-IDSA Guideline)

Drug Regimens Combo names Duration

Ledipasvir (90 mg daily)

Sofosbuvir (400 mg daily) Harvoni 12 weeks

Paritaprevir (150 mg daily)

Ritonavir (100 mg daily)

Ombitasvir (25 mg daily)

Dasabuvir (250 mg BID)

+ Ribavirin (for cirrhosis)

Viekira Pak12 weeks(includingcirrhosis)

Sofosbuvir (400 mg daily)

Simeprevir (150 mg daily)

12 weeks(24 weeks for

cirrhosis)

Treatment Naïve Patients: HCV genotypes 2 and 3(AASLD-IDSA Guideline)

Genotype Drug Regimens Duration

Genotype 2 Sofosbuvir (400 mg daily)

Ribavirin (weight-based) 12 weeks(16 weeks for

cirrhosis)

Genotype 3 Sofosbuvir (400 mg daily)

Ribavirin (weight-based)

Alternative Regimen:Sofosbuvir (400 mg daily)

Ribavirin (weight-based)

Peg-IFN

24 weeks

12 weeks

Adverse Events : Ledipasvir-Sofosbuvir (ION-3 Study)

(Kowdleyet al, NEJM, May 2014 )

Source: Feld JJ, et al. N Engl J Med. 2014;370:1594-1603.

Adverse Events : SAPPHIRE-I StudyOmbitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin in GT1

EventGroup A = 3D + RBV

(N=473)Group B = Placebo

(N=158)

Any adverse event (%) 87.5 73.4

Any adverse event leading to discontinuation of study drug (%)

0.6 0.6

Any serious adverse event (%) 2.1 0

Grade 3 or 4 lab abnormality (%)

Alanine aminotransferase 0.9 4.4

Aspartate aminotransferase 0.6 1.9

Alkaline phosphatase 0 0

Total bilirubin 2.8 0

Hemoglobin 0 0

3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = Ribavirin

Recommendations for when and whom to treat

Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatichepatitis C complications are given high priority

A pretreatment assessment of the degree of hepatic fibrosis, using noninvasive testing or liver biopsy, is recommended. (Rating: I, A)

If therapy is deferred, an ongoing assessment of liver disease is recommended. (Rating: I, C)

(AASLD-IDSA Guideline)

Recommendations for when and whom to treat

Highest priority patients:

advanced fibrosis (Metavir F3)

compensated cirrhosis (Metavir F4)

liver transplant recipients

patients with severe extrahepatic hepatitis C

type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg, vasculitis)

proteinuria, nephrotic syndrome, or MPGN (membranoproliferative glomerulonephritis)

(AASLD-IDSA Guideline)

Recommendations for when and whom to treat

High priority:

Fibrosis (Metavir F2)

HIV-1 coinfection

HBV coinfection

Other coexistent liver disease (eg, NASH)

Debilitating fatigue

Type 2 Diabetes mellitus (insulin resistant)

Porphyria cutanea tarda

(AASLD-IDSA Guideline)

Recommendations for when and whom to treat

High HCV Transmission Risk

MSM with high-risk sexual practices

Active injection drug users

Incarcerated persons

Persons on long-term hemodialysis

HCV-infected women wishing to get pregnant

HCV-infected health care workers who perform exposure-prone procedures

(AASLD-IDSA Guideline)

Contraindications and Major Drug Interactions

Sofosbuvir/Ledipasvir P-gp inducers (eg. rifampin, St. John’s Wort) Amiodarone (FDA warning) Other drugs: anticonvulsants, antiretrovirals

Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir Decompensated cirrhosis Drugs- strong hepatic enzyme inducers or inhibitors

Drugs Interactions: Ombitasvir-Paritaprevir-Ritonavir + Dasabuvir

Drug Class Individual Drugs

Alpha1- antagonist Alfuzosin HCL

Anticonvulsants Carbamazepine, phenytoin, phenobarbital

Antihyperlipidemic agent Gemfibrozil

Antimycobacterial Rifampin

Ergot derivatives Ergotamine, dihydroergotamine, ergonovine, methylergonovine

Ethinyl estradiol-containing products

Ethinyl estradiol-containing medications such as combined oral contraceptives

Herbal Product St. John’s Wort (Hypericum perforatum)

HMG-CoA Reductase Lovastatin, simvastatin

Neuroleptics Pimozide

HIV NNRTI Efavirenz

PDE5 inhibitor Sildenafil when dosed as Revatio for pulmonary arterial hypertension (PAH)

Sedatives/hypnotics Triazolam; Oral midazolam

Source: Viekira Pak Prescribing Information. AbbVie Inc

Case Discussion:

55 year old female …(Continued)

Patient was cleared by her psychiatrist

Received complete series of HAV + HBV vaccines

Treatment for 12 weeks total with a standard regimen

Case Discussion:

55 year old female …(Continued)

Follow up:

During treatment:

at 4 and 12 weeks- HCV viral load <20 IU/ml,

LFTs- normal

After completion of treatment:

12 weeks after treatment- HCV viral load <20 IU/ml

LFTs- normal

6 months after completion- HCV viral load <20 IU/ml, LFTs- normal

=> sustained viral response (SVR)

Goals of treatment

To achieve virologic cure as evidenced by an SVR (sustained viral response)

To reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma

70% reduction in the risk of liver cancer (hepatocellular carcinoma)

90% reduction in the risk of liver-related mortality and liver transplantation

(AASLD-IDSA Guideline)

Other Direct Acting Agents in the Pipeline

NS3/4A protease inhibitors

• Asunaprevir, Danoprevir, Faldaprevir, Grazoprevir

NS5A inhibitors

• Elbasvir, Daclatasvir, ACH-3102

NS5B Polymerase Inhibitors

• nucleoside analogue: Mericitabine

• non-nucleoside inhibitors: Tegobuvir, BI 207127, VX222

Other Classes of Drugs in Pipeline

Cyclophilin inhibitor: Alisporivir, BC 556

Alisporivir trial on hold- 3 patients had pancreatitis (1 fatal)

Interferons: Interferon-λ (IL-29)

Albinterferon -2b (albIFN)

miRNA-122 antagonist: Miraversen

Management of Acute HCV Infection

Preexposure or postexposure prophylaxis with antivirals is NOT recommended

Check HCV antibody and HCV RNA

Monitor HCV RNA, eg, every 4-8 weeks, for 6-12 months

Monitor ALT level until normalizes

Counseling: to avoid hepatotoxic drugs and alcohol

to reduce risk of HCV transmission to others

Referral to an addiction specialist for IV drug users

Treatment Decisions: Monitor HCV RNA for at least 12-16 weeks to allow for

spontaneous clearance before starting treatment Use same regimens as recommended for chronic HCV

infection

HCV Prevention & Control

Advocacy and raising awareness

Risk reduction :

Blood safety strategies

Infection control precautions in health care and community

Safe injection practices

Safer sex practices: minimizing number of partners

using barrier protective measures

Harm reduction practices for injecting drug users

Occupational safety measures to prevent transmission

Early identification through screening

Early treatment strategies

Conclusions

Hepatitis C has become a major cause of chronic infection leading to high rates of morbidity and mortality

Directly acting agents (DAA) have made a significant impact in the treatment of chronic hepatitis C infection

• Cost has been a major factor in limiting access to treatment

All eligible patients should be tested for hepatitis C

• Adults born between 1945 – 1965

• High risk persons

In the absence of an effective vaccine, most important prevention strategies include risk reduction, early identification and treatment