Hepatitis C Primer for HIV Care Providers

Adeel A. Butt, MDAssistant Professor of MedicineDivision of Infectious DiseasesUniversity of PittsburghDirector, Pittsburgh VAMC ID-HIV ClinicsCenter for Health Equity Research and Promotion

Adeel A. Butt, MD

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

57169.73.15 811Total

1162.23.91 600Western Pacific

332.32.151 500South-East Asia

198.91.03858Europe

721.34.6 466Eastern Mediterranean

713.11.7785Americas

1231.95.3602Africa

Number-of countries by

WHO Region where data are not available

Infected Population(Millions)

Hepatitis C prevalence

Rate %

Total Population(Millions)

WHO Region

Adeel A. Butt, MD

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

Asia6

South Africa5

Africa Egypt

4 4a

Younger population in Western countries, especially IDUs

Predominant genotype in Pakistan Japan, Nepal, Thailand, Indonesia Nepal

3 3a 3b 3c

Worldwide distribution Northern Italy

2 2c

America, Europe, Japan North America, Western Europe Japan Indonesia (20% of total)

1 1a 1b 1c

Geographic DistributionGenotype/Subtype

Adeel A. Butt, MD

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)

Current risks: HCV – 1 in 1,600,000 units HIV – 1 in 1,800,000 units HBV – 1 in 220,000 units

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 Conry-Cantilena NEJM 1996;334:1691-6

2 Feldman, STD 2001;27:338-42

3 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 Chronic - 75

Stable – 45-55 Cirrhosis – 20-30

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

20 – 30 yearsAccelerated by:

alcohol

HIV

Adeel A. Butt, MD

Goals of Treatment

Eradicate HCV replicationDelay fibrosisPrevent liver failurePrevent hepatocellular carcinomaPrevent deathEnhance 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, Williams and Wilkins.

Adeel A. Butt, MD

HCV - Treatment

Indications for treatment

Recommended Not recommended Unclear

Detectable HCV RNAPersistently elevated ALTAbnormal liver biopsy showing portal or bridging fibrosis, or at least moderate inflammation

Persistently normal ALTAdvanced or decompensated cirrhosisExcessive alcohol useActive drug useContraindications to treatment

Compensated cirrhosisElevated ALT but normal liver histology

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

Therapy Trade name (manufacturer)

Interferon alfa-2b Intron A (Schering-Plough)

Interferon alfa-2a Roferon (Roche)

Interferon alfacon-1 Infergen (?Amgen)

Interferon alfa-2b plus Ribavirin Rebetron (Schering-Plough)

Pegylated Interferon alfa-2a Pegasys (Roche)

Pegylated Interferon alfa-2b PEG-Intron (Schering-Plough)

Drugs approved for the treatment of HCV infection

Adeel A. Butt, MD

HCV – Treatment (non-HIV Patients)

Sustained Virologic Response Rates

Source: Multiple randomized controlled trails

6

1624

41 39

54

0

10

20

30

40

50

60

IFN 24wks

IFN 48wks

IFN/RBV24 wks

IFN/RBV48 wks

PEG-IFN PEG/RBV

Adeel A. Butt, MD

Treatment Patterns in HCV Infected Patients

155 (65)Number of patients who did not receive treatment for HCV (%)

231 to 36

Estimated duration of HCV infection (years) Mean Range

72.526.6< 1

Race (%) Caucasian African-American Other

982

Gender (%) Male Female

48 yearsAge (mean)

Demographics of patients with HCV (N=237)

Adeel A. Butt, MD

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)

3 (2)Deferred while waiting for approval for pegylated interferon

5 (3)End stage liver disease

7 (4)Referred for transplant evaluation

9 (6)Patient refused treatment

11 (7)Concurrent medical problems

12 (8)Psychiatric problems

12 (8)Undetectable HCV RNA

15 (10)Normal liver enzymes

15 (10)Current drug or alcohol use

37 (24)Non compliance with follow up visits

n (%) 

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

38 (26.6%, 4.3%) Eligible for Treatment

90 (30.0%, 10.2%) with GI Referral

26 (28.9%, 3.0%) with No Indication

64 (71.1%, 7.3%) with Indications

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 weightPoynard, 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, MDRoche, data on file, Phase

II trial.

0

5

10

15

20

25

30

0 24 48 72 96 120 144 168 192

Time (hours)

Con

cen

trati

on

(n

g/m

L) Tue Wed Thu Fri Sat SunMon

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

The Inherent Qualities of PEG-alfa 2a

*CHC=chronic hepatitis C