Download Hepatitis C and HIV/HCV Co-infection

Hepatitis C and
HIV/HCV Co-infection
Mary Van Bronkhorst, PA
Christopher Behrens, MD
Northwest AIDS Education & Training Center
University of Washington
Hepatitis: definition
• Inflammation of the liver caused by many
different agents, including:
–
–
–
–
–
–
Viruses (A through E)
Alcohol
Drugs/prescriptions
Herbs
Genetic disorders
Obesity (NASH)
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
Hepatitis C: A Global Health Problem
170-200 Million (M) Carriers Worldwide
United
States
3-4 M
Americas
12-15 M
Western
Europe
5M
Eastern
Europe
10 M
Far East Asia
60 M
Southeast Asia
30-35 M
Africa
30-40 M
Australia
0.2 M
World Health Organization. Weekly epidemiological record. 1999;74:421-428.
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
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%
Risk factors for Hepatitis C infection
10%
10%
20%
55%
5%
IVDU
Cocaine
Exposure to infected
sex partner or
multiple partners
Occupational,
hemodialysis,
household,
perinatal
No recognized source
http://www.cdc.gov/ncidod/diseases/hepatitis/c_training/edu/transmission modes; 2000
Natural History of Hepatitis C
Most patients with chronic HCV infection are asymptomatic
10-20 years
Acute Hepatitis C
Chronic Hepatitis
75%-85 %
Cirrhosis 20 %
Hoofnagle JH Hepatology. 1997;26 (suppl 1): 15S-20S
Di Bisceglie, Hepatology, 2000
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)
Complications of Cirrhosis
• Dangerous impairment of liver function
– Inability to clear toxins from the circulation => 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
Edema
Ascites
Massive ascites due to hepatocellular carcinoma, with collateral venous dilation
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.
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.
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.
Diagnostic Approach: Elevated ALT Levels
with Risk Factors for HCV
Elevated ALT levels + risk
factors for hepatitis
Anti-HCV (EIA) testing
Negative
<5% chance of
hepatitis C
Positive
Diagnosis of
hepatitis C>95% certain
Refer to specialist for evaluation
and treatment
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
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
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
Histologic Staging
Stage 0
Stage 1
No Fibrosis
Stage 2
Few septa
Portal Fibrosis
Stage 3
Numerous septa
Stage 4
Cirrhosis
Progression of Fibrosis on Biopsy
No Fibrosis
Stage 1: Fibrous
expansion of
some portal areas
Stage 3: Fibrous
expansion of
most portal areas
with occasional
portal to portal
bridging
Courtesy of Gregory Everson, MD.
Stage 4: Fibrous
expansion of portal
areas with marked
bridging (portal to
portal and portal to
central)
Stage 5,6: Cirrhosis,
probable or defined
Cirrhotic liver:
Gross anatomy
of cadaver
Treatment: is there a cure?
Yes, for many but not all.
Combination Therapy
• Pegylated interferon
• Ribavirin
Hepatitis C
PEGYLATED 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
Treatment Goals
• Prevent progression of scarring
• Eradicate virus
• Prevent complications of end stage liver
disease
Sustained Response
56%
60%
% Patients
45%
40%
n = 453
30%
20%
n = 444
n = 224
0%
PEG-IFN
IFN + RBV
PEG-IFN + RBV
Fried MW et al. DDW. 2001.
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
% of Patients
Sustained Response
According to Genotype
80
70
60
50
40
30
20
10
0
76%
61%
46%
37%
21%
45%
n = 140
n = 298
n = 285
n = 145
n = 69
n = 145
Genotype 1
PEG-IFN
IFN + RBV
Genotype 2, 3
PEG-IFN + RBV
Fried MW et al. DDW. 2001.
Predictors of Virologic Response
Viral Factors
• Genotype
• Viral Load
Host Factors
• Age
• Cirrhosis
• Race
• Gender
• Weight
Side Effects of Interferon
• Flu-like symptoms
–
–
–
–
Headache
Fatigue or asthenia
Myalgia, arthralgia
Fever, chills
• Alopecia
• Thyroiditis
• Nausea
• Diarrhea
• Neuropsychiatric disorders• Injection-site reaction
– Depression
– Mood lability
– “Brain Fog”
• 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.
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.
Hepatitis C
INTERFERON 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
Hepatitis C
INTERFERON 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
Monitoring the Patient
• Anemia
• Bone marrow toxicity
• Pulmonary disorders
• Pancreatitis
• Psychiatric
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)
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
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.
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
Management of Skin Rashes
• Topical hydrocortisone, increase strength as
needed
• Oral antihistamines
• Avoid tanning and sun exposure
• Hydrate, moisturize
Vaccinations
• Test all HIV+ and Hepatitis C patients for
antibodies to hepatitis A and B
• Vaccinate as needed
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
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.
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
Hepatitis C
Treatment 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
Hepatitis C
Treatment Decisions
• Do not treat patients with
–
–
–
–
–
–
–
Advanced cirrhosis
Severe depression/psychiatric disorder
Low blood counts
Thyroid disease, untreated
Autoimmune diseases
Alcohol/drug dependency
Pregnancy
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?
Case Study #2
Need to know:
Oxygen dependent?
Taking anti-depressant?
Suicidal?
How important is it to treat in terms of her liver
disease?
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?
Pt. readiness
• Stable mood
• Alcohol free
• Stable housing
• “Right time”
• Chronic health conditions well managed
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.
Case # 3
Assess: health, psychiatric issues, stability
issues, HIV status, HCV status.
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.
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 ?
Patient Education
• Transmission
• Alcohol use
• Depression/Antidepressants
• Treatment Choices
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
Hepatitis C/HIV
Hep C and HIV Topics
• Interactions of viruses
• Treatment decisions
• Drug interactions
Hepatitis C
HIV/HCV COINFECTION
• 10%-30% w/ HIV also have HCV
• Rate of HCV depends on risk factor
– Hemophiliacs – >90%
– IDUs – 70%-90%
– MSM – 5%-10%
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
Hepatitis C
HIV/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
Hepatitis C
HIV/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
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
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
Drug interactions
• Clinical manifestations: pancreatitis, hepatitis,
myopathy, peripheral neuropathy and lactic
acidosis
Drug interactions
• Monitor serum lactate and amylase monthly
• Consider changing HAART before starting
combination therapy
• Discontinue all meds immediately if lactate
rising
Treatment Decisions
• Treat Hep. C first ? (if HIV stable, if CD4
count good)
• Treat HIV first? (if immune compromised)
Murky Middle Ground
• What to do if CD4 count is 300-500? Which to
treat first?
HIV/HCV Co-infection Study
AIDS
PEGASYS®
Ribavirin
International
CO-Infection
Trial
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
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
Sustained Virologic Response*
60%
P 0.0001
P 0.0001
50%
% Response
40%
40%
P = 0.0084
30%
20%
20%
12%
10%
0%
n = 285
n = 286
n = 289
IFN alfa-2a + RBV
PEGASYS
(40 kDa) + Placebo
PEGASYS
(40 kDa) + COPEGUS
* Defined as <50 IU/mL HCV RNA at week 72; ITT
Summary
• SVR was significantly higher for PEGASYS (40
kDa) + COPEGUS compared to conventional
combination therapy
– Overall: 40% vs 12%; P <0.0001
– 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
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
Hepatitis C/HIV
SUMMARY
• HIV+ persons have worse liver disease
– Treatment should be considered
– Expect greater side effects, possible interactions
with HIV medications
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
Specialist Role
• Special tests: abdominal
ultrasounds/EGD/Liver biopsy
• Combination therapy management
• Vaccinations: HAV, HBV, pneumovax?
• Education
Team Work
•
•
•
•
•
•
•
Physician/PA/NP providers
Nurses
Nutritionists
Social workers
Mental health: psychiatrist/counselors
Pharmacists
Advocates
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
Investigational Drugs
• Protease inhibitors
• Helicase inhibitors
• Anti-fibrotic agents
Independent Factors Associated with SVR
PEG IFN Alfa-2a + RBV
180
Wald Chi-Square
160
140
Multiple Logistic Regression Model, N= 1737
120
100
80
60
40
20
0
FDA Antiviral Drugs Advisory Committee Proceedings. Peginterferon alfa-2a. November 14, 2002.
Virologic Response* – End of Treatment
vs End of Follow-up (Genotype 1)
End of treatment
End of follow-up
60%
% Response
50%
38%
40%
29%
30%
21%
20%
10%
14%
8%
7%
0%
IFN alfa-2a + RBV
* Defined as <50 IU/mL HCV RNA
PEGASYS
(40 kDa) + Placebo
PEGASYS
(40 kDa) + COPEGUS
Virologic Response* – End of Treatment
vs End of Follow-up (Genotype 2 and 3)
End of treatment
End of follow-up
70%
64%
57%
% Response
60%
62%
50%
36%
40%
30%
27%
20%
20%
10%
0%
IFN alfa-2a + RBV
* Defined as <50 IU/mL HCV RNA
PEGASYS
(40 kDa) + Placebo
PEGASYS
(40 kDa) + COPEGUS
Extra slides