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Hepatitis C Primer for HIVCare Providers

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

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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

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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

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HCV Global Prevalence

57169.73.15 811Total

1162.23.91 600Western Pacific

332.32.151 500South-East Asia

198.91.03858Europe

721.34.6466EasternMediterranean

713.11.7785Americas1231.95.3602Africa

Number-ofcountries by

WHO Region

where data are

not available

InfectedPopulation

(Millions)

Hepatitis Cprevalence

Rate %

TotalPopulation

(Millions)

WHORegion

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HCV - Virology

The Virus

Single stranded, positive sense, RNA

Falviviridae family

Spherical, enveloped

~ 50 nm

Discovered in 1989

Choo, Science 1989;244:359-62

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HCV - Genetics

Six genotypes, 1 through 6

Multiple subtypes, a, b, c, etc.

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

RNA sequence may vary by 35%between genotype

Great genetic diversity

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

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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

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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

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Decline in transfusion transmitted viral infections

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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

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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 independentrisk 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

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HCV Risk factors (contd.)

Other risk factors and routes oftransmission:

Tattoos Person-to-person in hemodialysis units

Person-to-person by HCW

Nosocomial outbreaks reported

Organ and tissue transplant

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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 transmissionrates

Role of HCV VL and mode of delivery unclear

No known transmission from breast milk

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HCV and Health Care Workers

600,000-800,000 needlestick injuries occur eachyear

Prevalence in Public Safety workers 1.3-3.2%

Prevalence in Scottish HCW 0.28%

Risk of HCV from a needlestick estimated to be2.7-6%

Multiple reported cases of transmission from HCWto patients

Risk of HCV+ surgeon transmitting it a patientestimated at 1 in 1,750-16,000 procedures

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HCV Natural History

Acute HCV-100 patients

Resolved - 25 Chronic - 75

Stable 45-55 Cirrhosis 20-30

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

20 30 years

Accelerated by:

alcohol

HIV

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Goals of Treatment

Eradicate HCV replication

Delay fibrosis

Prevent liver failure

Prevent hepatocellularcarcinoma

Prevent death

Enhance quality of life

Butt, Singh. Hepatitis C: Prevention, Therapy and Role ofTransplantation. In Wenzel (ed) Prevention

and Control of Nosocomial Infections. Fourth Edition. Lippincott,Williams and Wilkins.

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HCV - Treatment

Indications for treatment

Recommended Not recommended Unclear

Detectable HCV RNAPersistently elevated

ALT

Abnormal liver

biopsy showing portal

or bridging fibrosis, orat least moderate

inflammation

Persistently normalALT

Advanced or

decompensated

cirrhosis

Excessive alcohol useActive drug use

Contraindications to

treatment

Compensated

cirrhosis

Elevated ALT

but normal liverhistology

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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

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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

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HCV Treatment (non-HIV Patients)

Sustained Virologic Response Rates

Source: Multiple randomized controlled trails

6

16

24

41 39

54

0

10

20

30

40

50

60

IFN 24wks

IFN 48wks

IFN/RBV24 wks

IFN/RBV48 wks

PEG-IFN PEG/RBV

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Treatment Patterns in HCV Infected Patients

155 (65)Number of patients who did notreceive treatment for HCV (%)

23

1 to 36

Estimated duration of HCV

infection (years)

Mean

Range

72.5

26.6

< 1

Race (%)

Caucasian

African-American

Other

98

2

Gender (%)

Male

Female

48 yearsAge (mean)Demographics of patients with HCV (N=237)

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Reasons for non-treatment inHCV 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

5 (3)End stage liver disease

7 (4)Referred for transplant evaluation

9 (6)Patient refused treatment11 (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 (%)

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Treatment Patterns in HCV-HIVCo-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

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HCV - Treatment

Predictors of a Favorable Response Genotype 2 or 3

Low HCV Viral Load (

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Functional Characteristics ofPEGylated 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.

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Roche, data on file, Phase II trial.

0

5

10

15

20

25

30

0 24 48 72 96 120 144 168 192Time (hours)

C

naonmL

Tue Wed Thu Fr i Sat Sunon

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

The Inherent Qualities of PEG-alfa 2a