Hepatitis C Primer for HIV Care Providers

Adeel A. Butt, MD Assistant Professor of Medicine Division of Infectious Diseases University of Pittsburgh Director, Pittsburgh VAMC ID-HIV Clinics Center for Health Equity Research and Promotion

Overview

Prevalence of HCV A word of virology Risk Factors Natural History of HCV Treatment of HCV

Treatment Indications and Goals

HCV-HIV Co-infection

Treatment of HCV-HIV co-infection

Adeel A. Butt, MD

HCV - Epidemiology

Epidemiology:

1.8% of the U.S. population ~ 4 million infected persons in the U.S. 8,000 10,000 deaths per year Global prevalence 170 million 5 X more prevalent than HIV

Lauer, NEJM 2001;345:41-52

Adeel A. Butt, MD

HCV Global Prevalence

WHO Region Africa Americas
Eastern Mediterranean

Total Population (Millions) 602 785 466 858 1 500 1 600 5 811

Hepatitis C prevalence Rate % 5.3 1.7 4.6 1.03 2.15 3.9 3.1

Infected Population (Millions) 31.9 13.1 21.3 8.9 32.3 62.2 169.7

Number-of countries by WHO Region where data are not available

12 7 7 19 3 11
Adeel A. Butt, MD

Europe
South-East Asia Western Pacific

Total

57

HCV - Virology

The Virus

Single stranded, positive sense, RNA Falviviridae family Spherical, enveloped ~ 50 nm Discovered in 1989

Choo, Science 1989;244:359-62

Adeel A. Butt, MD

HCV - Genetics

Six genotypes, 1 through 6 Multiple subtypes, a, b, c, etc.

Further divided into quasispecies, varying in RNA sequence by 1-9%

RNA sequence may vary by 35% between genotype Great genetic diversity

Farci, Semin Liver Dis 2000;20:103-26

Adeel A. Butt, MD

HCV Genotype Distribution

Genotype/Subtype

Geographic Distribution
America, Europe, Japan North America, Western Europe Japan Indonesia (20% of total) Worldwide distribution Northern Italy
Younger population in Western countries, especially IDUs

1
1a 1b 1c 2 2c 3 3a 3b 3c 4

Predominant genotype in Pakistan Japan, Nepal, Thailand, Indonesia Nepal Africa Egypt South Africa Asia
Adeel A. Butt, MD

4a
5 6

HCV Risk factors

Transfusion

Dependent on prevalence in general population Screening methods and diligence in screening

In the US, it dropped from 25% to 0.1% after initiation of screening

1996 risk in the US was 1 in 103,000 units (for HIV this risk was 1 in 493,000 units) HCV 1 in 1,600,000 units HIV 1 in 1,800,000 units HBV 1 in 220,000 units

Current risks:

Adeel A. Butt, MD

Decline in transfusion transmitted viral infections

Adeel A. Butt, MD

Blood Supply Screening

Antibody based Antigen based Nucleic acid technology (NAT)

Introduced in 1998 Reduces window period

For HCV: from 70 days to 10 days For HIV: from 22 days (antibody) to 11 days

Potential reasons for transmission

Window period Immunovariant strains Persistently antibody negative carriers Testing errors
Adeel A. Butt, MD

HCV Risk Factors (contd.)

Sexual Transmission

Inefficient route of transmission ?risk 1-3% 1 of 85 long term sexual partners1 2 of 42 index cases (one had independent risk factors)2 Probably enhanced by HIV co-infection3

1 2 3

Conry-Cantilena NEJM 1996;334:1691-6 Feldman, STD 2001;27:338-42 Bonacini, Arch Int Med 2000,160:3365-73
Adeel A. Butt, MD

HCV Risk factors (contd.)

Other risk factors and routes of transmission:

Tattoos Person-to-person in hemodialysis units Person-to-person by HCW Nosocomial outbreaks reported Organ and tissue transplant

Adeel A. Butt, MD

HCV Transmission

Pregnancy and Vertical Transmission

Prevalence in pregnant women 0.3-4.4% Over 40% in IDU from NY Overall vertical transmission rate ~ 6% HIV co-infection increases transmission rates Role of HCV VL and mode of delivery unclear No known transmission from breast milk
Adeel A. Butt, MD

HCV and Health Care Workers

600,000-800,000 needlestick injuries occur each year Prevalence in Public Safety workers 1.3-3.2% Prevalence in Scottish HCW 0.28%
Risk of HCV from a needlestick estimated to be 2.7-6%

Multiple reported cases of transmission from HCW to patients Risk of HCV+ surgeon transmitting it a patient estimated at 1 in 1,750-16,000 procedures
Adeel A. Butt, MD

HCV Natural History

Acute HCV-100 patients Resolved - 25 Stable 45-55 Chronic - 75 Cirrhosis 20-30 20 30 years
Accelerated by:

alcohol
HIV

Stable 15-25 Decompensation 5-8 HCC 1-3 per year

Adeel A. Butt, MD

Goals of Treatment
Eradicate HCV replication Delay fibrosis Prevent liver failure Prevent hepatocellular carcinoma Prevent death Enhance quality of life
Butt, Singh. Hepatitis C: Prevention, Therapy and Role of Transplantation. In Wenzel (ed) Prevention and Control of Nosocomial Infections. Fourth Edition. Lippincott, Adeel A. Butt, MD Williams and Wilkins.

HCV - Treatment

Indications for treatment

Not recommended

Recommended
Detectable HCV RNA Persistently elevated ALT Abnormal liver biopsy showing portal or bridging fibrosis, or at least moderate inflammation

Unclear Compensated cirrhosis Elevated ALT but normal liver histology

Persistently normal ALT Advanced or decompensated cirrhosis Excessive alcohol use Active drug use Contraindications to treatment

Adeel A. Butt, MD

HCV Pretreatment Workup

History and Physical Exam Psychiatric history/evaluation Blood counts Chemistry panel Liver panel, including PT TFTs HCV genotype HCV RNA AFP; ?liver imaging Liver biopsy
Adeel A. Butt, MD

HCV - Treatment
Drugs approved for the treatment of HCV infection

Therapy
Interferon alfa-2b

Trade name (manufacturer)

Intron A (Schering-Plough)

Interferon alfa-2a
Interferon alfacon-1
Interferon alfa-2b plus Ribavirin

Roferon (Roche)
Infergen (?Amgen)

Rebetron (Schering-Plough)
Pegasys (Roche)
Adeel A. Butt, MD PEG-Intron (Schering-Plough)

Pegylated Interferon alfa-2a

Pegylated Interferon alfa-2b

HCV Treatment (non-HIV Patients)

Sustained Virologic Response Rates
60 50 41 39 54

40
30 20 10 0 IFN 24 wks IFN 48 wks IFN/RBV 24 wks IFN/RBV PEG-IFN PEG/RBV 48 wks 6 16 24

Source: Multiple randomized controlled trails

Adeel A. Butt, MD

Treatment Patterns in HCV Infected Patients

Demographics of patients with HCV (N=237) Age (mean) 48 years Gender (%) Male Female Race (%) Caucasian African-American Other
Estimated duration of HCV infection (years)

98 2 72.5 26.6 <1 23 1 to 36

155 (65)
Adeel A. Butt, MD

Mean Range Number of patients who did not receive treatment for HCV (%)

Reasons for non-treatment in HCV only infected patients

Ten most common reasons for non-treatment of HCV in 155 patients. (excludes the unknown category) n (%)
Non compliance with follow up visits

37 (24) 15 (10) 15 (10) 12 (8) 12 (8)

Current drug or alcohol use Normal liver enzymes Undetectable HCV RNA Psychiatric problems

Concurrent medical problems

Patient refused treatment Referred for transplant evaluation End stage liver disease
Deferred while waiting for approval

11 (7)
9 (6) 7 (4) 5 (3) 3 (2)
Adeel A. Butt, MD

Treatment Patterns in HCV-HIV Co-infected Patients (VACS-3 Cohort)

881 Patients 181 (20.5%, 20.5%) Not Tested 700 (79.5%, 79.5%) Tested 400 (57.1%, 45.4%) Hepatitis C Negative 300 (42.9%, 34.1%) Hepatitis C Postive

210 (70.0%, 23.8%) without GI Referral 67 (31.9%, 7.6%) with No Indication 143 (68.1%, 16.2%) with Indications

90 (30.0%, 10.2%) with GI Referral 26 (28.9%, 3.0%) with No Indication 64 (71.1%, 7.3%) with Indications

38 (26.6%, 4.3%) Eligible for Treatment

27 (42.2%, 3.1%) Eligible for Treatment

12 (44.4%, 1.4%) Underwent Liver Biopsy

2 (16.7%, 0.2%) Received Interferon

Adeel A. Butt, MD

HCV - Treatment

Predictors of a Favorable Response

Genotype 2 or 3 Low HCV Viral Load (<2 million) No or only portal fibrosis Female gender Age < 40 years Role of gender not an independent factor if controlled for body weight

Poynard, Hepatlogy 2000;31:211-8

Manns, Lancet 2001;358:958-65

Adeel A. Butt, MD

Functional Characteristics of PEGylated Proteins

Protected from proteolytic degradation Restricted distribution Reduced renal clearance Enhanced solubility PEG-moiety is biocompatible and nontoxic
Harris JM, Poly (Ethylene Glycol) Chemistry. 1992. Katre NV. Adv Drug Delivery Rev. 1993.
Adeel A. Butt, MD

The Inherent Qualities of PEG-alfa 2a

30

Mon

Tue

Wed

Thu

Fri

Sat

Sun

Concentration (ng/mL)

25 20 15 10 5 0 0 24 48 72 96 120 144 168 192

Time (hours)

PEGASYS (PEG-IFN) 180 mcg SC qw in patients with CHC* (Week 48)

*CHC=chronic hepatitis C

Roche, data on file, Phase II trial.

Adeel A. Butt, MD