Hepatitis C and HIV/HCV Co-infection

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Hepatitis C and HIV/HCV Co-infection

• Mary Van Bronkhorst, PA
• Christopher Behrens, MD
• Northwest AIDS Education Training Center
• University of Washington

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Hepatitis definition

• Inflammation of the liver caused by many
  different agents, including
• Viruses (A through E)
• Alcohol
• Drugs/prescriptions
• Herbs
• Genetic disorders
• Obesity (NASH)

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Major Hepatitis Viruses
Virus Means of transmission
Hepatitis A Fecal-oral Contaminated food or water
Hepatitis B Sexual, mother-to-child, blood exposure (transfusion, IDU, tattoo)
Hepatitis C Blood exposure (transfusion, IDU, tattoo) sexual, mother-to-child less common
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Hepatitis C A Global Health Problem
170-200 Million (M) Carriers Worldwide
Far East Asia 60 M
Eastern Europe 10 M
Western Europe 5 M
United States 3-4 M
Southeast Asia 30-35 M
Africa 30-40 M
Americas 12-15 M
Australia 0.2 M
World Health Organization. Weekly epidemiological
record. 199974421-428.
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Hepatitis C United States

• 3.7 million infected in U.S. (1.8 of population)
• 25,000-35,000 new infections per year
• Sixty percent due to injection drug use (IDU)
• A leading cause of cirrhosis and liver cancer and
  the most common reason for liver transplantation
  in the United States
• 8,000-10,000 deaths from HCV annually
• HCV-related deaths and transplants projected to
  triple in next decade

CDC. MMWR. 1998 47(No. RR-19)1-39.
NIH Consensus Development Conference Panel
Statement Management of Hepatitis C, 2002
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Prevalence of HCV infection in selected subgroups
in the U.S.

• Injection drug users 52-90
• Hemophiliacs 60-85
• HIV infected individuals 9-40
• incarcerated HIV 50
• MSM 4-8

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Risk factors for Hepatitis C infection
IVDU
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Cocaine
Exposure to infected sex partner or multiple
partners
10
20
Occupational, hemodialysis, household, perinatal
55
5
No recognized source
http//www.cdc.gov/ncidod/diseases/hepatitis/c_tra
ining/edu/transmission modes 2000
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Natural History of Hepatitis C
Most patients with chronic HCV infection are
asymptomatic
Acute Hepatitis C
10-20 years
Chronic Hepatitis 75-85
Cirrhosis 20
Hoofnagle JH Hepatology. 199726 (suppl 1)
15S-20S Di Bisceglie, Hepatology, 2000
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Hepatitis C Pathophysiology

• Hepatitis C virus (HCV) replicates in liver cells
  (hepatocytes)
• Immune system responds with inflammation
• Inflammation leads to fibrosis and eventually, in
  some cases, cirrhosis (scarring)

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Complications of Cirrhosis

• Dangerous impairment of liver function
• Inability to clear toxins from the circulation gt
  jaundice hepatic encephalopathy
• Inability to synthesize key proteins (albumin,
  clotting factors)
• Cancer (hepatocellular carcinoma)
• Blockage of portal vein blood flow through the
  liver, leading to ascites
• Bacterial peritonitis (infection of the ascites)
• Esophageal varices

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Edema
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Ascites
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Massive ascites due to hepatocellular carcinoma,
with collateral venous dilation
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Other Extrahepatic Manifestations of Hepatitis C

• Hematologic
• Cryoglobulinemia
• lymphoma
• Rheumatologic rheumatoid arthritis
• Renal Glomerulonephritis
• Dermatologic
• Porphyria cutanea tarda
• Cutaneous necrotizing vasculitis
• Lichen planus
• CNS depression
• Systemic fatigue

Management of Hepatitis C. NIH Consensus
Statement, 2002.
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Testing

• It is important to test people who have risk
  factors even if they have no symptoms.
• Consider asking about drug experimentation when
  doing routine physicals.

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Community Clinic Pt. 1

• 48yo. man presents for a routine physical. Labs
  reveal mildly elevated ALT liver enzyme. Further
  tests reveal that he is HCV antibody positive.
• PCR confirmatory test is positive.
• New element of social history obtained he
  experimented with injection drugs as a teenager.

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Diagnostic Approach Elevated ALT Levels with
Risk Factors for HCV
Elevated ALT levels risk factors for hepatitis
Anti-HCV (EIA) testing
Negative
Positive
lt5 chance of hepatitis C
Diagnosis of hepatitis
Cgt95 certain
Refer to specialist for evaluation and treatment
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Hepatitis C Diagnosis

• Antibody test (EIA)
• Indicates past or active infection
• Unlike hepatitis B, presence of antibodies does
  not confer immunity
• HCV RNA test (PCR)
• Confirms active infection, infectivity to others
• Quantitative or qualitative RNA tests exist the
  former is more often used because it provides a
  potentially useful viral load measurement

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Predictors of Advanced Disease

• Person infected 20-40 years
• Person with long history of moderate to high
  alcohol consumption
• Lab values that suggest cirrhosis low
  platelets, low albumin, high bilirubin, AST level
  higher than ALT level

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Liver Biopsy

• Provides information regarding
• Degree of inflammation
• Stage of fibrosis or scarring
• Presence/absence of cirrhosis
• Helps determine
• Prognosis
• Cause of liver disease
• Need for treatment

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Histologic Staging
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Progression of Fibrosis on Biopsy
Stage 4 Fibrous expansion of portal areas with
marked bridging (portal to portal and portal to
central)
No Fibrosis
Stage 1 Fibrous expansion of some portal areas
Stage 5,6 Cirrhosis, probable or defined
Stage 3 Fibrous expansion of most portal areas
with occasional portal to portal bridging
Cirrhotic liver Gross anatomy of cadaver
Courtesy of Gregory Everson, MD.
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Treatment is there a cure?

• Yes, for many but not all.

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Combination Therapy

• Pegylated interferon
• Ribavirin

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Hepatitis CPEGYLATED INTERFERON

• Pegylated interferon
• Complexed w/polyethylene glycol (PEG)
• More stable blood levels, thus more effective
• Weekly injection
• Better compliance? ( regular interferon was
  dosed 3x per week!)
• Side effects similar

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Treatment Goals

• Prevent progression of scarring
• Eradicate virus
• Prevent complications of end stage liver disease

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Sustained Response
56
60
n 453
45
40
n 444
30
Patients
n 224
20
0
PEG-IFN
IFN RBV
PEG-IFN RBV
Fried MW et al. DDW. 2001.
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Types of Hep C

• Hepatitis C has six major types called genotypes
• Genotype 1 needs one year of treatment, by far
  the most common type in the US.
• Genotype 2 or 3 needs six months of treatment

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Sustained ResponseAccording to Genotype

80
76
70
61
60
of Patients
46
45
50
n 140
37
40
n 298
n 145
30
n 69
21
n 285
20
n 145
10
0
Genotype 1
Genotype 2, 3
PEG-IFN RBV
PEG-IFN IFN RBV
Fried MW et al. DDW. 2001.
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Predictors of Virologic Response
Viral Factors
Host Factors

• Age
• Cirrhosis
• Race
• Gender
• Weight

• Genotype
• Viral Load

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Side Effects of Interferon

• Flu-like symptoms
• Headache
• Fatigue or asthenia
• Myalgia, arthralgia
• Fever, chills
• Neuropsychiatric disorders
• Depression
• Mood lability
• Brain Fog

• Alopecia
• Thyroiditis
• Nausea
• Diarrhea
• Injection-site reaction
• Lab alterations
• Neutropenia
• Anemia
• Thrombocytopenia

PEGASYS (peginterferon alfa-2a) package
insert. Nutley, NJ Hoffmann-La Roche 2002.
PEG-Intron (peginterferon alfa-2b) package
insert. Kenilworth, NJ Schering Corporation
2001.
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Side Effects of Ribavirin

• Hemolytic anemia
• Teratogenicity
• Cough and dyspnea
• Rash and pruritus
• Insomnia
• Anorexia

COPEGUS (ribavirin, USP) package insert.
Nutley, NJ Hoffmann-La Roche 2002.
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Hepatitis CINTERFERON AND RIBAVIRIN

• Serious, less common side effects
• Bacterial infections
• Thyroid disease
• Severe depression, suicide
• Seizures
• Vision or hearing loss
• Kidney or heart failure
• Fetal abnormalities/fetal loss

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Hepatitis CINTERFERON AND RIBAVIRIN

• Requirements of treated patients
• 6-12 month course
• Monitoring
• For side effects visits and blood tests at 2 and
  4 wks, then every 1-3 months
• For effectiveness recheck viral level at 6 and
  12 months

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Monitoring the Patient

• Anemia
• Bone marrow toxicity
• Pulmonary disorders
• Pancreatitis
• Psychiatric

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Side Effect Management

• Aggressive management of side effects increases
  compliance and treatment success.
• Anti-depressants, anti-nausea and insomnia
  meds are helpful.
• Growth factors erythropoetin and filgastim
  are helpful. (off label use)

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Management of Fatigue

• Conduct baseline assessment
• Check hydration status and diet
• Advise patients to
• Avoid strenuous activities, incorporate relaxing
  activities in daily regimen
• Plan lighter activities for days after interferon
  dosing

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Management of Depression

• Assess before starting treatment
• Stabilize on antidepressant before treatment
• Establish care with counselor, psychiatrist,
  primary care giver before treatment
• Immediate evaluation if suicidal. May need to
  discontinue treatment.

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Management of Cough

• Assess for pneumonia
• Rule out other causes (eg, allergies, bronchial
  infections)
• Advise patients to
• Increase daily fluid intake, use humidifier, use
  cough drops or nonsedating cough medications

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Management of Skin Rashes

• Topical hydrocortisone, increase strength as
  needed
• Oral antihistamines
• Avoid tanning and sun exposure
• Hydrate, moisturize

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Vaccinations

• Test all HIV and Hepatitis C patients for
  antibodies to hepatitis A and B
• Vaccinate as needed

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Antibody Testing

• Hepatitis A order only IgG unless the patient is
  acutely ill
• Hepatitis B
• HBV surface antibody IgG
• HBV core antibody IgG
• HBV surface Antigen

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Hepatitis B

• Vaccinate if surface antibody is less than 10
  units and core antibody is absent
• Vaccinate if HBV core and surface IgG antibody
  negative
• Patients who have had HBV infection in the
  distant past will often have no surface
  antibodies but will have immunity because they
  have core antibodies.

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Treatment Outcomes

• EVR early viral response, undetectable at 12
  weeks
• ETR end of treatment response undetectable at
  end of treatment
• SVR undetectable 6 months after tx. complete

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Hepatitis CTreatment Decisions

• Who to treat?
• People w/bridging fibrosis or cirrhosis
• People with symptoms
• ? Acute hepatitis
• Decreased rate of developing chronic infection in
  2 small studies

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Hepatitis CTreatment Decisions

• Do not treat patients with
• Advanced cirrhosis
• Severe depression/psychiatric disorder
• Low blood counts
• Thyroid disease, untreated
• Autoimmune diseases
• Alcohol/drug dependency
• Pregnancy

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Case Study 2

• A 54 year old woman with HCV presents with COPD,
  depression, is a smoker, distant use of heroin.
• What do you need to know?
• Do you think that she is a treatment candidate?

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Case Study 2

• Need to know
• Oxygen dependent?
• Taking anti-depressant?
• Suicidal?
• How important is it to treat in terms of her
  liver disease?

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Patient Evaluation

• Does the patient need treatment?
• Is the patient ready for treatment?
• Is it safe to treat this person?
• Will the benefits outweigh the risks?

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Pt. readiness

• Stable mood
• Alcohol free
• Stable housing
• Right time
• Chronic health conditions well managed

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Case Study 3

• A 24 year old homeless man presents with a
  positive antibody test. He is anxious to begin
  treatment. He has been talking with friends who
  have been through tx and thinks it would be OK.

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Case 3

• Assess health, psychiatric issues, stability
  issues, HIV status, HCV status.

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Case Study 4

• A 32 year old man presents with HIV and Hep C
  infection. He is a student at a local community
  college. He states that he has mostly stopped
  using drugs (heroin and crystal meth). He is
  currently attending an out pt. support group to
  assist with recovery.

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Case Study 4

• He has recently separated from a partner of 3
  years and is feeling a bit down.
• What do you want to know ?

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Patient Education

• Transmission
• Alcohol use
• Depression/Antidepressants
• Treatment Choices

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Role of Alcohol

• Alcohol can damage the liver
• Alcohol plus the Hep C virus causes more fibrosis
  and faster development of cirrhosis
• Recommendation for persons with Hep.C there is
  no safe level of alcohol consumption

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Hepatitis C/HIV
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Hep C and HIV Topics

• Interactions of viruses
• Treatment decisions
• Drug interactions

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Hepatitis CHIV/HCV COINFECTION

• 10-30 w/ HIV also have HCV
• Rate of HCV depends on risk factor
• Hemophiliacs gt90
• IDUs 70-90
• MSM 5-10

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HCV/HIV Coinfection

• HIV accelerates Hep C liver disease (may cut
  time to cirrhosis in half!)
• Hep C may impair immune reconstitution after
  HAART
• HCC may occur at an earlier age with coinfection

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Hepatitis CHIV/HCV COINFECTION

• HCV liver disease is more severe in HIV
• HCV liver disease is now more important
• HIV deaths are decreasing
• Deaths related to liver disease are increasing
• Effect of HCV infection on HIV/AIDS progression
  is not known

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Hepatitis CHIV/HCV COINFECTION

• HIV treatments can cause liver problems/liver
  enzyme elevations
• In some studies these liver problems are
  increased in those w/HCV
• Some report worsening of HCV liver disease after
  HIV treatment is started

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HIV/HCV Treatment

• Predictors of success in achieving a sustained
  viral response
• CD4 count greater than 500
• HIV RNA levels below 10,000 copies
• No alcohol consumption

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Drug interactions in Co-infection

• ddI and d4T plus interferon/ribavirin appear to
  cause mitochondrial toxicity
• result lactic acidosis, peripheral neuropathy
• Avoid starting these drugs if plan to treat HCV
  later

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Drug interactions

• Clinical manifestations pancreatitis,
  hepatitis, myopathy, peripheral neuropathy and
  lactic acidosis

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Drug interactions

• Monitor serum lactate and amylase monthly
• Consider changing HAART before starting
  combination therapy
• Discontinue all meds immediately if lactate rising

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Treatment Decisions

• Treat Hep. C first ? (if HIV stable, if CD4 count
  good)
• Treat HIV first? (if immune compromised)

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Murky Middle Ground

• What to do if CD4 count is 300-500? Which to
  treat first?

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HIV/HCV Co-infection Study
AIDS PEGASYS Ribavirin International CO-Infection
Trial
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Key Inclusion Criteria

• HCV criteria
• Naive to IFN and ribavirin
• HCV antibody positive
• Quantifiable HCV RNA (Amplicor MONITOR)
• Elevated serum ALT
• Liver biopsy (?15 months) consistent with HCV
  infection
• Non-cirrhotic or cirrhotic
• If cirrhotic, Child-Pugh Grade A

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Key Inclusion Criteria

• HIV criteria
• HIV antibody or quantifiable HIV RNA
• CD4 cell count
• ?200/µL or
• ?100/µL to ?200/µL with ?5000 copies/mL HIV RNA
• Stable HIV disease with or without antiretroviral
  treatment

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Sustained Virologic Response
IFN alfa-2a RBV
PEGASYS(40 kDa) Placebo
PEGASYS(40 kDa) COPEGUS
Defined as lt50 IU/mL HCV RNA at week 72 ITT
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Summary

• SVR was significantly higher for PEGASYS (40 kDa)
  COPEGUS compared to conventional combination
  therapy
• Overall 40 vs 12 P lt0.0001
• Genotype 1 29 vs 7
• Genotype 2/3 62 vs 20
• Adverse event profile of PEGASYS (40kDa)
  COPEGUS is generally similar to IFN RBV therapy
• Only 15 of patients discontinued for adverse
  events or laboratory abnormalities

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Conclusion

• APRICOT is the largest and the only international
  registration study in HIV/HCV co-infection
• HCV therapy did not negatively impact control of
  HIV
• 40 SVR is the highest of any reported study in
  HIV/HCV co-infection

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Hepatitis C/HIVSUMMARY

• HIV persons have worse liver disease
• Treatment should be considered
• Expect greater side effects, possible
  interactions with HIV medications

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Primary Care Role

• HCV antibody testing/ ?PCR testing
• Hepatitis A and B testing and vaccination
• Patient education
• HIV testing
• Referral for liver evaluation
• Referral for drug and alcohol treatment

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Specialist Role

• Special tests abdominal ultrasounds/EGD/Liver
  biopsy
• Combination therapy management
• Vaccinations HAV, HBV, pneumovax?
• Education

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Team Work

• Physician/PA/NP providers
• Nurses
• Nutritionists
• Social workers
• Mental health psychiatrist/counselors
• Pharmacists
• Advocates

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Helpful Resources

• Hepatitis Education Project website
  www.hepeducation.org
• Drug company websites and patient support
  programs Roche 1-877-PEGASYS, Schering
  Commitment to Care 1-800-521-7157
• Support groups

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Investigational Drugs

• Protease inhibitors
• Helicase inhibitors
• Anti-fibrotic agents

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Independent Factors Associated with SVR PEG IFN
Alfa-2a RBV
180
160
Multiple Logistic Regression Model, N 1737
140
120
100
Wald Chi-Square
80
60
40
20
0
FDA Antiviral Drugs Advisory Committee
Proceedings. Peginterferon alfa-2a. November
14, 2002.
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Virologic Response End of Treatment vs End of
Follow-up (Genotype 1)
Response
IFN alfa-2a RBV
PEGASYS(40 kDa) Placebo
PEGASYS(40 kDa) COPEGUS
Defined as lt50 IU/mL HCV RNA
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Virologic Response End of Treatment vs End of
Follow-up (Genotype 2 and 3)
Response
IFN alfa-2a RBV
PEGASYS(40 kDa) Placebo
PEGASYS(40 kDa) COPEGUS
Defined as lt50 IU/mL HCV RNA
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Extra slides