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 Treatment of HCV-HIV co-infection
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 1 1a 1b 1c
2
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
2c 3 3a 3b 3c
4 4a 5 6
Predominant genotype in Pakistan Japan, Nepal, Thailand, Indonesia Nepal
Africa Egypt South Africa Asia
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) 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 Window period Immunovariant strains Persistently antibody negative carriers Testing errors
Adeel A. Butt, MD
Potential reasons for transmission
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
NEJM 1996;334:1691-6
1 Conry-Cantilena 2 3
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
Stable – 15-25
Chronic - 75
Cirrhosis – 20-30
20 – 30 years
Accelerated by: alcohol
HIV
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
Interferon alfa-2a
Trade name (manufacturer) Intron A (Schering-Plough)
Roferon (Roche)
Interferon alfacon-1
Interferon alfa-2b plus Ribavirin
Infergen (?Amgen)
Rebetron (Schering-Plough)
Pegylated Interferon alfa-2a Pegylated Interferon alfa-2b
Pegasys (Roche)
Adeel A. Butt, PEG-Intron (Schering-Plough) MD
HCV – Treatment (non-HIV Patients)
Sustained Virologic Response Rates
60
50 40
54 41 39
30 20
10 0 6 16
24
IFN 24 wks
IFN 48 wks
IFN/RBV 24 wks
IFN/RBV 48 wks
PEG-IFN PEG/RBV
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)
Current drug or alcohol use
Normal liver enzymes Undetectable HCV RNA Psychiatric problems
Concurrent medical problems Patient refused treatment
15 (10) 12 (8) 12 (8)
11 (7) 9 (6)
Referred for transplant evaluation End stage liver disease
Deferred while waiting for approval
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