Hepatitis C Primer for HIV Care Providers - University of ...

  • 332 views
Uploaded on

 

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
332
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
8
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • Kane, Bull WHO 1999;77:801-7
  • There are geographic differences in the predominant genotypes as can be seen in this table. Farci, Semin Liver Dis 2000;20:103-26 Wasley, Semin Liver Dis 2000;20:1-16
  • Before the screening of the donated blood for HCV was mandated, the most common route of acquisition of HCV was blood transfusion. Currently transfusion related HCV is rare in the US, though not in certain resource poor countries. Al-Sheyyab, J Trop Ped 2001;47:239-42 Schreiber, NEJM 1996;334:1685-90 Busch, JAMA 2003;289:959-962
  • Busch, JAMA 2003;289:959-962
  • Sexual route is a rather inefficient mode of transmission. The risk of infection in discordant monogamous couples is low, but not zero, and may be enhanced by factors like HIV co-infection.
  • Read from slide
  • Vertical transmission occurs in about 6% of cases. Again, HIV co-infection appears to enhance transmission, but the role of maternal HCV viral load and the mode of delivery is less clear than in HIV. Yeung, Hepatology 2001;34:223-9 Polywka, Clin Infect Dis 1999;29:1327-9
  • A tricky and difficult situation is the risk to a HCW after accidental exposure. CDC reports that 600,000 to 800,000 needlestick injuries occur in HCW each year. However, the prevalence of HCV in public safety workers is low at 1.3-2.2% and in one study in Scotland, the prevalence in HCW was 0.28%. Read rest from slide. Kiyosawa, Ann Int Med 1991;115:367-9 Ross, Arch Int Med 2000;160:2313-6
  • Before we begin treatment, we should know what we are aiming for and what our limitations are. Here is what I would want to achieve in a patient I put on treatment. (read from slide)
  • Okay, lets get to what we are here for today: treatment! Here I have listed scenarios where treatment is recommended. (read from slide) 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.
  • And to achieve these goals, here is our armamentarium. Tonight, I will present data on the efficacy, safety and adverse event profile of pegylated Interferon alpha 2a and ribavirin combination.
  • But before I go onto that, let me walk through the evolution of HCV treatment in HCV mono-infected patients over the last decade. We started with Interferon monotherapy for 24 weeks, which resulted in sustained viral eradication in only about 6% of patients. Increasing the duration of treatment to 48 weeks increased that response rate to 16%. Addition of ribavirin more than doubled the response rates if you treated these patients for 48 weeks. Enter pegylated IFN and it alone achieves that the standard IFN plus ribavirin were able to do together. The next obvious step was to try Peg plus RBV which achieves sustained viral eradication in over half the patients – beating the 50% psychological barrier of 50% for the first time. Makes me wish my stocks would perform like that!
  • Butt AA et al. 40th Annual Meeting of the Infectious Diseases Society of America. Chicago, IL. October 24 - 27, 2002.
  • Butt AA et al. 40th Annual Meeting of the Infectious Diseases Society of America. Chicago, IL. October 24 - 27, 2002.
  • Fultz, Justice, Butt et al. Clinical Infectious Diseases 2003.
  • The response rates are not uniform for all patients. A favorable response can be expected in patients with genotype 2 and 3, possibly those with a lower viral load, women, those under the age of 40, and those who have a favorable histology to begin with. The role of gender becomes insignificant if you control for the body weight, meaning that it may be a matter of getting the correct dose to the patient.
  • The PEG molecule does many things, most important of which, from our stand point are, to protect the degradation of IFN, decrease its renal clearance and increase its half life.
  • And this slide shows the plasma levels after an injection of Pegasys. For me the most important thing is that the levels are sustained at a relatively constant level rather than the fluctuations we saw with the standard IFN.

Transcript

  • 1. 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 Member of Academic Research Council A non-profit organization dedicated to improving medical education and fostering research
  • 2. 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
  • 3. 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
  • 4. HCV – Global Prevalence 57 169.7 3.1 5 811 Total 11 62.2 3.9 1 600 Western Pacific 3 32.3 2.15 1 500 South-East Asia 19 8.9 1.03 858 Europe 7 21.3 4.6   466 Eastern Mediterranean 7 13.1 1.7 785 Americas 12 31.9 5.3 602 Africa Number-of countries by WHO Region where data are not available Infected Population (Millions) Hepatitis C prevalence Rate % Total Population (Millions) WHO Region
  • 5. HCV - Virology
    • The Virus
      • Single stranded, positive sense, RNA
      • Falviviridae family
      • Spherical, enveloped
      • ~ 50 nm
      • Discovered in 1989
    Choo, Science 1989;244:359-62
  • 6. 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
  • 7. HCV Genotype Distribution Asia 6 South Africa 5 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 Distribution Genotype/Subtype
  • 8. 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
  • 9. Decline in transfusion transmitted viral infections
  • 10. 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
  • 11. HCV – Risk Factors (contd.)
    • Sexual Transmission
        • Inefficient route of transmission
        • ?risk 1-3%
        • 1 of 85 long term sexual partners 1
        • 2 of 42 index cases (one had independent risk factors) 2
        • Probably enhanced by HIV co-infection 3
    1 Conry-Cantilena NEJM 1996;334:1691-6 2 Feldman, STD 2001;27:338-42 3 Bonacini, Arch Int Med 2000,160:3365-73
  • 12. 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
  • 13. 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
  • 14. 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
  • 15. 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
  • 16. Goals of Treatment 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.
    • Eradicate HCV replication
    • Delay fibrosis
    • Prevent liver failure
    • Prevent hepatocellular carcinoma
    • Prevent death
    • Enhance quality of life
  • 17. HCV - Treatment
    • Indications for treatment
    • Compensated cirrhosis
    • Elevated ALT but normal liver histology
    • Persistently normal ALT
    • Advanced or decompensated cirrhosis
    • Excessive alcohol use
    • Active drug use
    • Contraindications to treatment
    • Detectable HCV RNA
    • Persistently elevated ALT
    • Abnormal liver biopsy showing portal or bridging fibrosis, or at least moderate inflammation
    Unclear Not recommended Recommended
  • 18. 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
  • 19. HCV - Treatment Drugs approved for the treatment of HCV infection
    • PEG-Intron (Schering-Plough)
    • Pegylated Interferon alfa-2b
    • Pegasys (Roche)
    • Pegylated Interferon alfa-2a
    • Rebetron (Schering-Plough)
    • Interferon alfa-2b plus Ribavirin
    • Infergen (?Amgen)
    • Interferon alfacon-1
    • Roferon (Roche)
    • Interferon alfa-2a
    • Intron A (Schering-Plough)
    • Interferon alfa-2b
    Trade name (manufacturer) Therapy
  • 20. 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 24 wks IFN 48 wks IFN/RBV 24 wks IFN/RBV 48 wks PEG-IFN PEG/RBV
  • 21. Treatment Patterns in HCV Infected Patients 155 (65) Number of patients who did not receive 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 years Age (mean) Demographics of patients with HCV (N=237)
  • 22. 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 (%)  
  • 23. 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
  • 24. 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
  • 25. 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.
  • 26. The Inherent Qualities of PEG-alfa 2a Roche, data on file, Phase II trial. 0 5 10 15 20 25 30 0 24 48 72 96 120 144 168 192 Time (hours) Concentration (ng/mL) Tue Wed Thu Fri Sat Sun Mon PEGASYS (PEG-IFN) 180 mcg SC qw in patients with CHC* (Week 48) *CHC=chronic hepatitis C