Transcript Hepatitis B/HIV Coinfection

Management of Hepatitis
B & HIV Co-infection in
the Incarcerated Patient:
A Clinical Update
Douglas G. Fish, MD
Head, Division of HIV Medicine
Albany Medical College
April 10, 2006
National Commission on Correctional Health Care
Updated August 15, 2006
AMC is a Local Performance
Site of the NY/NJ AETC
Objectives
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Epidemiology & transmission
Review serologic evaluation of hepatitis
Review the work-up for chronic
hepatitis B
Treatment of hepatitis B in patients
with HIV
Prevention
Hepatitis B: A Global
Healthcare Challenge
350 million chronic
HBsAg carriers worldwide
Remainder
Asia Pacific
75%
1.25 million in US with
chronic HBV
25-40% will die due to
hepatitis B, or HBV
related complications
Up to 2 million die each
year from HBV infection,
making it the 9th leading
cause of death
Lok A et al. Hepatology 2004;39(3).
Geographic Distribution
of Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
CDC
HBV Modes of Transmission
• Sexual
• Parenteral
• Perinatal
CDC
Risk Factors for Hepatitis B
Transfusion recipients
Individuals with
multiple
sexual partners
Healthcare
workers
Newborns of chronic
carriers
Intravenous drug
users
Prisoners and other
institutionalized people
Risk Factors Associated with
Reported Hepatitis B, 1990-2000,
United States
Other*
Injection drug use
14%
15%
Sexual contact with
hepatitis B patient
13%
Household contact of
hepatitis B patient
2%
Men who have
sex with men 6%
Unknown 32%
Blood transfusion
0%
Medical
Employee 1%
Multiple sex partners
Hemodialysis 0%
17%
*Other: Surgery, dental surgery, acupuncture, tattoo, other percutaneous injury
Source: NNDSS/VHSP
CDC
Concentration of HBV
in Various Body Fluids
High
blood
serum
wound exudates
CDC
Moderate
semen
vaginal fluid
saliva
Low/Not
Detectable
urine
feces
sweat
tears
breast milk
Hepatitis B Virus
CDC
Hepatitis B Virus
Large Surface antigen
Middle Surface
antigen
Genomic DNA
Nucleocapsid
or Core
DNA
polymerase
Envelope
Small Surface
antigen
RNA primer
Hepatitis B

Acute and chronic forms
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
Asymptomatic or symptomatic
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CDC
Clinical illness <5 yrs of age: <10%
(jaundice)
>5 yrs of age: 30%-50%
Incubation: 45 – 180 days
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2-10% develop chronic disease over 5 years
of age
Average 60-90 days
Most common cause of cirrhosis and
hepatocellular carcinoma worldwide
Risk of Chronic Disease if
Untreated/Unvaccinated
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Neonates
90-100% HBsAg +
Children
20- 40% HBsAg +
Adults
<5% HBsAg +
Nearly 40% of children with chronic
hepatitis B will develop end-stage
liver disease in 20-30 years

Peters M 9th CROI Seattle, 2002
Patient
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52 yo male with AIDS 1995 seen 12/02
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CD4 126 (10%)
VL < 50 copies/ml on d4T, 3TC, abacavir
Cryptococcal meningitis
Thrombocytopenia 100,000/cmm
Coronary artery disease & hypertension
Chronic hepatitis B
Serologic Evaluation
of HBV
Hepatitis B Serologies

HBsAg
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HBsAb:
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acute disease or
chronic carrier
past infection or
vaccinated
Hbcore Ab (HBcAb) IgM: acute infection
HBcore Ab total: past infection
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Combined IgM & IgG serology
Hepatitis B(e) Serologies
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HBe Ag: more infectious
HBe Ab: less infectious
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Marker of treatment response
Acute Hepatitis B Virus
Infection: RECOVERY
Symptoms
HBe Ab
HBeAg
Core Total Ab
Titer
HBs Ag
0
4
8
HBs Ab
Core IgM
12 16 20 24 28 32 36
Weeks after
Exposure
52
100
CDC
Chronic Hepatitis B Virus
Infection
Acute
(6 months)
Chronic
(Years)
HBeAg
anti-HBe
HBsAg
Core Total Ab
Titer
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36
Weeks after Exposure
52
Years
CDC
Only Hbcore Ab Positive
(Total IgG + IgM)
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HBs antigen and HBs antibody negative
Common with HIV co-infection
IgM component negative with chronic
disease
May be carrier (chronically infected),
despite negative HBsAg
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Can distinguish by hepatitis B DNA PCR
Chronic Hepatitis B Virus Infection
without Persistent HBsAg
Symptoms
HBe Ab
HBeAg
Core Total Ab
Titer
HBs Ag
0
4
8
Core IgM
12 16 20 24 28 32 36
Weeks after
Exposure
52
100
CDC
Patient’s Hepatitis
Serologies
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Hepatitis B sAg positive
Hepatitis B coreAb total positive
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IgM component negative
Hepatitis
Hepatitis
Hepatitis
Hepatitis

B
B
C
A
sAb negative
eAg positive, eAb negative
Ab negative
Ab (total) positive
IgM component negative
Chronic Hepatitis B
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10-20% will develop cirrhosis
25% of these will develop decompensated
liver disease
6-15% of those with chronic disease will
develop hepatocellular carcinoma
HBV not directly cytopathic to hepatocytes
The host immune response causes much of
the damage
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Peters M 9th CROI Seattle, 2002
HBeAg and Risk of
Hepatocellular Carcinoma
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11,893 men in
Taiwan
1991-92 enrolled
HBeAg, HBsAg
testing
HCC by link with
cancer registry
Yang HI et al. NEJM 2002;347:168-174.
1400
1200
1000
HCC
per 800
100K
600
PY
400
200
0
HBeAg
HBsAg
+
+
+
-
HIV Co-infection Increases
the Risk of ESLD due to HBV
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MACS, 4,967 men
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HIV, 47%
HBV, 6% (n=326)
HIV/HBV, 4.3% (n=213)
Liver Mortaility by HIV
and HBV Status
HIV/HBV: 17-fold higher
risk of liver death
compared to HBV alone
10
Alcohol
Low CD4
Increased risk after 1996
0
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Thio C et al. Lancet 2002;360:9349.
14.1
15
5
0
0.8
1.7
No
HIV or
HBV
HBV
only
HIV
only
HIV
and
HBV
Hepatitis B and HIV
Co-infection
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Higher HBV DNA viral loads than with HBV
alone
Higher mortality with HIV co-infection
Less hepatic damage with uncontrolled
HIV
Immune reconstitution increases hepatic
injury due to inflammatory response
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Peters M 9th CROI Seattle, 2002
Work-up of Chronic
Hepatitis B
Chronic Hepatitis B Work-up
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Liver enzymes
Viral load for HBV DNA by PCR
Alpha fetoprotein monitoring
Hepatic imaging – US or CT scan
Liver biopsy
Patient’s Hepatitis
Work-up
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AST 61 IU/L, ALT 57, bilirubin 1.5 mg/dl,
albumin 3.5 gm/dl at baseline
HBV viral load (DNA PCR)
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Alpha fetoprotein
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750 million copies/ml
2.3 ng/ml (normal)
Abdominal ultrasound - splenomegaly
Treatment of Chronic
Hepatitis B
Criteria for Treatment
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American Association for the Study of
Liver Diseases
AST/ALT > 2 times ULN
HBV DNA PCR > 100,000 c/ml
Liver histology showing moderate or
severe hepatitis
Lok A et al. Hepatology 2004;39,(3).
Chronic Hepatitis B
Treatment: FDA-approved
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Alfa interferon; pegylated interferon
Lamivudine (Epivir HB)
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Adefovir (Hepsera) - active against
lamivudine-resistant HBV; pilot study
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HBV rebound possible if lamivudine stopped
N = 35; 5.15 log10 decrease in viral load
Mean CD4+ 423 cells/cmm
Benhamou Lancet 2001:358
Entecavir (Baraclude)
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Active against lamivudine-resistant HBV
Dual Hepatitis B/HIV
Co-infection Therapies
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Lamivudine (Epivir)
Off-label uses
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Emtricitabine (Emtriva)
Tenofovir DF (Viread) – active against
lamivudine-resistant HBV
Truvada (emtricitabine/tenofovir)
Rebound Hepatitis
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
Associated with removal of hepatitis B
therapy
Could occur inadvertently with change
in HIV therapy for virologic failure

Consider maintaining HIV therapy with
activity against HBV when changing ART
Important Safety
Information

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Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of
nucleoside analogs alone or in combination with other
antiretrovirals1-3
TRUVADA, EMTRIVA, and VIREAD are not indicated for the
treatment of chronic hepatitis B virus (HBV) infection and the
safety and efficacy of TRUVADA, EMTRIVA, and VIREAD have
not been established in patients coinfected with HBV and HIV.
Severe acute exacerbations of hepatitis B have been reported in
patients who have discontinued EMTRIVA or VIREAD. Hepatic
function should be monitored closely with both clinical and
laboratory follow-up for at least several months in patients who
discontinue TRUVADA, EMTRIVA, or VIREAD and are coinfected
with HIV and HBV. If appropriate, initiation of anti-hepatitis B
therapy may be warranted1-3
1. TRUVADA® (emtricitabine/tenofovir disoproxil fumarate) Prescribing Information.
2. EMTRIVA® (emtricitabine) Prescribing Information.
3. VIREAD® (tenofovir disoproxil fumarate) Prescribing Information.
Interferon for Chronic
Hepatitis B




Immune modulator and antiviral activity
Subcutaneous injection of 30-35 million
units/week for 16 weeks1
Lasting response (HBeAg loss) in about
20-40% of patients treated
Poorer response in Asians, long-term
infection, more advanced disease2
1. Intron A. Physicians’ Desk Reference.® Montvale, NJ: Medical Economics;1998:2637-2645.
2. Wong DK, et al. Ann Intern Med. 1993;119:312-323.
Lamivudine Antiviral Effect in Chronic HBV
Patients: Serum HBV DNA Over Time vs.
Lamivudine Dose
(NUCA2004, U.S. 3-mo. dosing study)
100
Serum HBV DNA
(median % change 80
from baseline) 60
40
20
0
-20
-40
-60
-80
-100
Treatment
period
0
4
8
25 mg
100 mg
300 mg
12
16
20
24
Time (weeks)
NUCA2004; Dienstag, New Engl J Med. 1995
28
32
36
Incidence of LAM Resistance in
HBV and HBV/HIV Patients
HIV negative
HIV positive
100%
90%
80%
67%
60%
38%
40%
47%
49%
20%
20%
0%
1
2
Benhamou et al., Hepatology, 1999)
3
4
Adefovir for Hepatitis B e
Antigen-Negative Chronic HBV
Median Change of Serum HBV DNA from Baseline to 48 wks
Hidziyannis SJ et al. New Engl J Med. 2003; 348:800-7.
Adefovir for Hepatitis B e
Antigen-Positive Chronic HBV
Median Change of Serum HBV DNA from Baseline to 48 wks
Marcellin P et al.
New Engl J Med. 2003; 348:808-16.
Treatment of HIV-infected, HBeAg+,
LAM-experienced Patients

HBV resistance to 3TC (YMDD mutation) develops in >75%
of patients treated for 3 years with monotherapy1
Adefovir (10 mg QD)2 and TDF (300 mg QD)3 are safe and
effective even if HBV is 3TC resistant
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
Placebo n =
TDF
n=
Placebo
60
50
Placebo
TDF
40
ALT (U/L)

TDF
30
20
10
0
-10
-20
Weeks on study
-30
Weeks
BL
Baseline
2
12
12
24
36
48
2
12
2
12
0
10
0
8
2
4
8
12
16
2 2 2 2 2
2
12 10 12 12 11 12
20
24
28
32
36
2 2
12 12 10 10
1. Ghany M. 52nd AASLD, #606; 2. Benhamou Y. XIV Int AIDS Conference, Barcelona, 2002, #7528;
3. Cooper D. ibid, #6015
40
9
44
8
48
8
9
Study 907: Mean HBV DNA Change
from Baseline with Tenofovir in Coinfected Patients by Lamivudine
Resistance Status
Baseline VL log10
CD4+ cells/cmm
Week 24
Wild-type
N=4
Lamivudine
Resistant
N=6
9.65
497
8.50
603
-5.39
-4.58
ALT normalized in 2
Hepatitis B e antigen converted to e Ab in one
Cooper D, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 124.
TDF + LMV May be More Efficacious than LMV
Alone in Anti-retroviral Naïve Patients
Study design: TDF vs. stavudine with efavirenz and lamviudine.
Substudy Of GS 903 – naïve to HBV therapy
Week 48
TDF+LMV
N=5
LMV
N=6
ΔHBV DNA (log10
copies/ml), mean
-4.70
-2.95
HBV DNA <1000
4
1
0/1
4/5
1
1
-55
-22
YMDD
Anti-HBe+
ΔALT, mean
Cooper D et al. 10th CROI, Boston 2003 Abstract 825
TDF vs ADV for HIV/HBV
Co-infection (AACTG 5127)
TDF 300 mg qd
96 weeks
ADV placebo
HIV/HBV
Co-infection
+/- Lamresistant
HBV
(N = 60)
Randomized
1:1
Stratification by:
• Compensated and decompensated
liver function
(Child-Pugh-Turcotte Score ≥ or < 7)
• CD4 count  or < 200 cells/mm³
ADV 10 mg qd
TDF placebo
Peters M et al. 12th CROI; 2005, Boston. #124.
96 weeks
‡
Child-Pugh Scores
Measure
1 point
2 points
3 points
Units
Bilirubin (total)
<34
(<2)
34-50 (2-3)
>50 (>3)
Umol/l
(mg/dL)
Serum albumin
>35
28-35
<28
Mg/L
INR
<1.7
1.71-2.20
>2.20
No unit
Ascites
None
Suppressed with
medication
Refractory
No unit
None
Grade I-II (or
supressed with
medication)
Grade III-IV
(for refractory)
No unit
Hepatic
Encephalopathy
Baseline Demographic
Characteristics
Median age (years)
Male
Caucasian
Black
Hispanic
Asian
IDU
Median CD4 cells/mm3
HIV RNA < 400 c/mL
* p=0.001;
#
p=0.10
ADV
(n=25)
TDF
(n=27)
47
96 %
56 %
32 %
4%
4%
4%
486
80%
40*
89 %
56 %
33 %
11 %
0%
22 %#
422
70%
Peters M et al. 12th CROI; 2005, Boston. #124.
‡
Baseline HBV and HIV
Disease Characteristics
Mean HBV DNA log10 c/mL
CPT < 7
ALT ≤ ULN
Mean ALT (IU/L)
HBeAg positive
3TC/ LAM experienced
*Normal CBC, creatinine, albumin, bilirubin (88%)
Peters M et al. 12th CROI; 2005, Boston. #124.
ADV*
TDF*
8.8 ± 1.9
100%
60%
66 ± 33
82%
80%
9.5 ± 1.1
96%
67%
70 ± 92
92%
74%
‡
Serum HBV DNA DAVG 48
(log10 c/mL)*
(n)
ADV
TDF
Diff
lower CI
52
-3.12
-4.03
0.91
-0.498
Modified ITT 47
-3.35
-4.46
1.11
-0.090
As treated
-3.48
-4.76
1.28
0.180
ITT
41
ITT: DAVG48 for all 52 subjects
Modified ITT: all subjects with 2 post baseline tests
As treated: as above with at least 36 week follow up
DAVG: time-weighted average change from baseline
*Roche Cobas Amplicor, LLQ 200 copies/mL
Peters M et al. 12th CROI; 2005, Boston. #124.
‡
0
‡
Mean Change from
Baseline in HBV DNA
HBV DNA (log10 c/mL)*
-1
ADV
TDF
-2
-3
-4
-5
-6
-7
0
ADV 25
TDF 27
24
12
23
24
20
36
18
48
17
26
23
18
17
18
*Roche Cobas Amplicor, LLQ 200 copies/mL
Peters M et al. 12th CROI; 2005, Boston. #124.
Week
‡
Adverse Events
2 deaths:
one HCC at week 49 on ADV
one TDF at 57 weeks cause unknown
Lab Abnormality
Chemistry
Liver
amylase/ lipase
Pancreatitis
Abnormal Protime
Creatinine grade 2
Peters M et al. 12th CROI; 2005, Boston. #124.
ADV
8/25
14/25
4/25
2/25
(ddI)
0/25
0/25
TDF
8/27
13/27
8/27
1/27
(AZT/3TC/NVP)
1/27
0/27
Entecavir (Baraclude)





Potent selective inhibitor of HBV
polymerase
No anti-HIV activity
No mitochondrial toxicity
No impact on cytochrome P450
Oral therapy

0.5 mg and 1 mg doses
Pessoa M. et al. 45th ICAAC, Washington DC 2005, #H-415





Double-blind, placebocontrolled trial in HIV/HBV
coinfection; n=68
Entry criteria: >24 weeks
prior 3TC or evidence of
resistance (YMDD)
Randomized to placebo
(n=17) or ETV (n=51)
No DC due to AE up to
Week 48
42/51 (82%) at Week 48
in the ETV arm had HBV
DNA <300 c/mL
HBV DNA level by PCR
(log10 c/mL)
Entecavir (ETV) in HIV/HBV
Co-infection: 48-week results
Double-blind
phase
10
9
8
7
6
5
4
All patients on
ETV 1.0 mg
9.19 (+0.11)
5.56 (–3.66)
0
n(ETV) 51
n(PBO) 17
12
24
Weeks
36
48
16
Initial treatment regimen:
5.63 (–3.56)
4.79 (–4.20)
48
43
17
ETV
Pessoa M. et al. 45th ICAAC, Washington DC 2005, #H-415
PBO
Patient’s Hepatitis B
Treatment


Tenofovir added to d4T, 3TC, abacavir
5 month post-therapy viral load



12 month post-therapy viral load




HBV 120,000 c/ml
AST 161 IU/L, ALT 148 bilirubin 2.1 mg/dl
HBV 3,400 c/ml (5 log10 decrease)
AST 55 IU/L, ALT 44, bilirubin 1.9 mg/dl
CD4 269 cells/cmm; VL < 50 c/ml
Released 2005
Hepatitis Delta (D)






Defective RNA virus that uses HBsAg for
its structural protein shell
Most common in IVDU, hemophiliacs
Incubation: 30 – 180 days
High prevalence in Amazon basin, Central
Africa, southern Italy, and Middle East
Simultaneous coinfection – concomitant with
acute HBV
Superinfection – in patients with chronic HBV
Hepatitis Delta (D)

Simultaneous coinfection



<5% result in chronic infection
HDV is cleared as HBsAg is cleared
Severe illness, with 2 - 20% mortality
Hepatitis Delta (D)

Superinfection




> 70% result in chronic infection, as
HBsAg is persisting
Worse than HBV or HCV alone
High titers of anti-HDV (>1:100)
Progression to cirrhosis in 10 - 15 years
Hepatitis B Prevention
Hepatitis B Vaccination





MSM or multiple sexual partners
Chronic hepatitis/liver disease (nonHBV)
Injection drug users
Inmates/staff; staff for mentally
disabled
Health care workers, including
laboratory staff
Hepatitis B Vaccination



Household contacts of carriers
Hemophiliacs; dialysis patients
Infants/children
Transmission Risk: Percutaneous
Exposure to Susceptible Host




HIV
HCV
HBV
HBV
0.3% risk
2 - 3%
20 - 30%, if source HBeAg +
1 - 6%, if source HBeAg -
Post-exposure Prophylaxis

Hepatitis B Immune Globulin



Best if administered in 1st 24 hours, but
can be given up to 7 days after
percutaneous or permucosal exposure
Within 14 days for post-sexual exposure
Hepatitis B vaccine series
The Future for HBV Therapy





More data coming with HIV-infected
population
Chronic therapy beyond 1-2 years
Combination therapies for HBV
Investigational agents
Liver transplantation for advanced
cirrhosis
Summary –
Chronic Hepatitis B




Check serologies for hepatitis A, B & C
for all HIV-infected patients
Vaccinate for A & B if non-immune
Options exist for simultaneous
treatment of HIV and HBV
If HIV does not need treated, select
agent without anti-HIV activity
Web Addresses/ Phone
Numbers





www.aidsetc.org
www.HIVguidelines.org
www.hivandhepatitis.com
www.aidsinfo.nih.gov
www.cdc.gov