Management of Hepatitis B

1
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
2
Objectives

• Epidemiology transmission
• Review serologic evaluation of hepatitis
• Review the work-up for chronic hepatitis B
• Treatment of hepatitis B in patients with HIV
• Prevention

3
Hepatitis B A Global Healthcare Challenge

• 350 million chronic HBsAg carriers worldwide
• 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

Remainder
Asia Pacific75
Lok A et al. Hepatology 200439(3).
4
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
³8 - High
2-7 - Intermediate
lt2 - Low
CDC
5
HBV Modes of Transmission

• Sexual
• Parenteral
• Perinatal

CDC
6
Risk Factors for Hepatitis B
Newborns of chronic carriers
Transfusion recipients
Individuals with multiple sexual partners
Intravenous drug users
Healthcare workers
Prisoners and other institutionalized people
7
Risk Factors Associated with Reported Hepatitis
B, 1990-2000, United States
CDC
Other Surgery, dental surgery, acupuncture,
tattoo, other percutaneous injury
Source NNDSS/VHSP
8
Concentration of HBV in Various Body Fluids

CDC
9
Hepatitis B Virus
CDC
10
Hepatitis B Virus
11
Hepatitis B

• Acute and chronic forms
• 2-10 develop chronic disease over 5 years of age
• Asymptomatic or symptomatic
• Clinical illness lt5 yrs of age lt10(jaundice)
  gt5 yrs of age 30-50
• Incubation 45 180 days
• Average 60-90 days
• Most common cause of cirrhosis and
  hepatocellular carcinoma worldwide

CDC
12
Risk of Chronic Disease if Untreated/Unvaccinated

• Neonates 90-100 HBsAg
• Children 20- 40 HBsAg
• Adults lt5 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

13
Patient

• 52 yo male with AIDS 1995 seen 12/02
• CD4 126 (10)
• VL lt 50 copies/ml on d4T, 3TC, abacavir
• Cryptococcal meningitis
• Thrombocytopenia 100,000/cmm
• Coronary artery disease hypertension
• Chronic hepatitis B

14
Serologic Evaluation of HBV
15
Hepatitis B Serologies

• HBsAg
• acute disease or
• chronic carrier
• HBsAb
• past infection or
• vaccinated
• Hbcore Ab (HBcAb) IgM acute infection
• HBcore Ab total past infection
• Combined IgM IgG serology

16
Hepatitis B(e) Serologies

• HBe Ag more infectious
• HBe Ab less infectious
• Marker of treatment response

17
Acute Hepatitis B Virus Infection RECOVERY
Symptoms
HBeAg
HBe Ab
Core Total Ab
HBs Ab
Core IgM
CDC
18
Chronic Hepatitis B Virus Infection
Acute (6 months)
Chronic (Years)
HBeAg
anti-HBe
HBsAg
Core Total Ab
Titer
IgM anti-HBc
Years
0
4
8
12
16
20
24
28
32
36
52
CDC
Weeks after Exposure
19
Only Hbcore Ab Positive (Total IgG IgM)

• 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
• Can distinguish by hepatitis B DNA PCR

20
Chronic Hepatitis B Virus Infection without
Persistent HBsAg
Symptoms
HBeAg
HBe Ab
Core Total Ab
Core IgM
CDC
21
Patients Hepatitis Serologies

• Hepatitis B sAg positive
• Hepatitis B coreAb total positive
• IgM component negative
• Hepatitis B sAb negative
• Hepatitis B eAg positive, eAb negative
• Hepatitis C Ab negative
• Hepatitis A Ab (total) positive
• IgM component negative

22
Chronic Hepatitis B

• 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
• Peters M 9th CROI Seattle, 2002

23
HBeAg and Risk of Hepatocellular Carcinoma

• 11,893 men in Taiwan
• 1991-92 enrolled
• HBeAg, HBsAg testing
• HCC by link with cancer registry

HBeAg - -
HBsAg -
Yang HI et al. NEJM 2002347168-174.
24
HIV Co-infection Increases the Risk of ESLD due
to HBV

• MACS, 4,967 men
• HIV, 47
• HBV, 6 (n326)
• HIV/HBV, 4.3 (n213)
• HIV/HBV 17-fold higher risk of liver death
  compared to HBV alone
• Alcohol
• Low CD4
• Increased risk after 1996

Thio C et al. Lancet 20023609349.
25
Hepatitis B and HIV Co-infection

• 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
• Peters M 9th CROI Seattle, 2002

26
Work-up of Chronic Hepatitis B
27
Chronic Hepatitis B Work-up

• Liver enzymes
• Viral load for HBV DNA by PCR
• Alpha fetoprotein monitoring
• Hepatic imaging US or CT scan
• Liver biopsy

28
Patients Hepatitis Work-up

• AST 61 IU/L, ALT 57, bilirubin 1.5 mg/dl,
  albumin 3.5 gm/dl at baseline
• HBV viral load (DNA PCR)
• 750 million copies/ml
• Alpha fetoprotein
• 2.3 ng/ml (normal)
• Abdominal ultrasound - splenomegaly

29
Treatment of Chronic Hepatitis B
30
Criteria for Treatment

• American Association for the Study of Liver
  Diseases
• AST/ALT gt 2 times ULN
• HBV DNA PCR gt 100,000 c/ml
• Liver histology showing moderate or severe
  hepatitis

Lok A et al. Hepatology 200439,(3).
31
Chronic Hepatitis B Treatment FDA-approved

• Alfa interferon pegylated interferon
• Lamivudine (Epivir HB)
• HBV rebound possible if lamivudine stopped
• Adefovir (Hepsera) - active against
  lamivudine-resistant HBV pilot study
• N 35 5.15 log10 decrease in viral load
• Mean CD4 423 cells/cmm
• Benhamou Lancet 2001358
• Entecavir (Baraclude)
• Active against lamivudine-resistant HBV

32
Dual Hepatitis B/HIV Co-infection Therapies

• Lamivudine (Epivir)
• Off-label uses
• Emtricitabine (Emtriva)
• Tenofovir DF (Viread) active against
  lamivudine-resistant HBV
• Truvada (emtricitabine/tenofovir)

33
Rebound Hepatitis

• 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

34
Important Safety Information

• 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.
35
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 Economics19982637-2645.
• 2. Wong DK, et al. Ann Intern Med.
  1993119312-323.

36
Lamivudine Antiviral Effect in Chronic HBV
Patients Serum HBV DNA Over Time vs.
Lamivudine Dose (NUCA2004, U.S. 3-mo.
dosing study)
100
80
60
40
20
0
-20
-40
-60
-80
-100
Time (weeks)
37
Incidence of LAM Resistance in HBV and HBV/HIV
Patients
Benhamou et al., Hepatology, 1999)
38
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
348800-7.
39
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
348808-16.
40
Treatment of HIV-infected, HBeAg,
LAM-experienced Patients

• HBV resistance to 3TC (YMDD mutation) develops in
  gt75 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

Placebo
Mean change in HBV DNA (log10 c/mL)
TDF
Weeks
Baseline
12
24
36
48
Placebo n 2 2 2 0 0 2 2 2 2 2
2 2 2 TDF n 12 12 12 10 8 12
10 12 12 11 12 12 12 10 10 9
8 8 9
1. Ghany M. 52nd AASLD, 606 2. Benhamou Y. XIV
Int AIDS Conference, Barcelona, 2002, 7528 3.
Cooper D. ibid, 6015
41
Study 907 Mean HBV DNA Change from Baseline with
Tenofovir in Co-infected Patients by Lamivudine
Resistance Status
Lamivudine Wild-type Resistant N 4 N 6
Baseline VL log10 9.65 8.50 CD4 cells/cmm
497 603 Week
24 -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.
42
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 TDFLMV N5 LMV N6
?HBV DNA (log10 copies/ml), mean -4.70 -2.95
HBV DNA lt1000 4 1
YMDD 0/1 4/5
Anti-HBe 1 1
?ALT, mean -55 -22

• Cooper D et al. 10th CROI, Boston 2003 Abstract
  825

43
TDF vs ADV for HIV/HBV Co-infection (AACTG 5127)

96 weeks
TDF 300 mg qd
ADV placebo
HIV/HBV Co-infection /-
Lam-resistant HBV (N 60) Randomized 11

• Stratification by
• Compensated and decompensated liver function
  
  (Child-Pugh-Turcotte Score or lt 7)
• CD4 count ? or lt 200 cells/mm³

ADV 10 mg qd
TDF placebo
96 weeks
Peters M et al. 12th CROI 2005, Boston. 124.
44
Child-Pugh Scores
Measure 1 point 2 points 3 points Units
Bilirubin (total) lt34 (lt2) 34-50 (2-3) gt50 (gt3) Umol/l (mg/dL)
Serum albumin gt35 28-35 lt28 Mg/L
INR lt1.7 1.71-2.20 gt2.20 No unit
Ascites None Suppressed with medication Refractory No unit
Hepatic Encephalopathy None Grade I-II (or supressed with medication) Grade III-IV (for refractory) No unit
45
Child-Pugh Interpretation
Points Class Life Expectancy Perioperative Mortality
5-6 A 15-20 10
7-9 B Candidate for transplant 30
10-15 C 1-3 months 82
46
Baseline Demographic Characteristics

• ADV TDF
• 
  (n25) (n27)
• Median age (years) 47 40
• Male 96 89
• Caucasian 56 56
• Black 32 33
• Hispanic 4 11
• Asian 4 0
• IDU 4 22
• Median CD4 cells/mm3 486 422
• HIV RNA lt 400 c/mL 80 70
• p0.001 p0.10

Peters M et al. 12th CROI 2005, Boston. 124.
47
Baseline HBV and HIV Disease Characteristics

• ADV TDF
• Mean HBV DNA log10 c/mL 8.8 1.9 9.5
  1.1
• CPT lt 7 100 96
• ALT ULN 60 67
• Mean ALT (IU/L) 66 33 70 92
• HBeAg positive 82 92
• 3TC/ LAM experienced 80 74

Normal CBC, creatinine, albumin, bilirubin (88)
Peters M et al. 12th CROI 2005, Boston. 124.
48
Serum HBV DNA DAVG 48 (log10 c/mL)

• (n) ADV TDF Diff lower CI
• ITT 52 -3.12 -4.03 0.91 -0.498
• Modified ITT 47 -3.35 -4.46 1.11
  -0.090
• As treated 41 -3.48 -4.76 1.28 0.180
• 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.
49
Mean Change from Baseline in HBV DNA

Week
Roche Cobas Amplicor, LLQ 200 copies/mL
Peters M et al. 12th CROI 2005, Boston. 124.
50
Adverse Events

• 2 deaths one HCC at week 49 on ADV
• one TDF at 57 weeks cause unknown
• Lab Abnormality ADV TDF
• Chemistry 8/25 8/27
• Liver 14/25 13/27
• ?amylase/ lipase 4/25 8/27
• Pancreatitis 2/25 1/27
• (ddI) (AZT/3TC/NVP)
• Abnormal Protime 0/25 1/27
• Creatinine ?grade 2 0/25 0/27

Peters M et al. 12th CROI 2005, Boston. 124.
51
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
52
Entecavir (ETV) in HIV/HBV Co-infection 48-week
results

• Double-blind, placebo-controlled trial in HIV/HBV
  coinfection n68
• Entry criteria gt24 weeks prior 3TC or evidence
  of resistance (YMDD)
• Randomized to placebo (n17) or ETV (n51)
• No DC due to AE up to Week 48
• 42/51 (82) at Week 48 in the ETV arm had HBV DNA
  lt300 c/mL

Pessoa M. et al. 45th ICAAC, Washington DC 2005,
H-415
53
Patients Hepatitis B Treatment

• Tenofovir added to d4T, 3TC, abacavir
• 5 month post-therapy viral load
• HBV 120,000 c/ml
• AST 161 IU/L, ALT 148 bilirubin 2.1 mg/dl
• 12 month post-therapy viral load
• HBV 3,400 c/ml (5 log10 decrease)
• AST 55 IU/L, ALT 44, bilirubin 1.9 mg/dl
• CD4 269 cells/cmm VL lt 50 c/ml
• Released 2005

54
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

55
Hepatitis Delta (D)

• Simultaneous coinfection
• lt5 result in chronic infection
• HDV is cleared as HBsAg is cleared
• Severe illness, with 2 - 20 mortality

56
Hepatitis Delta (D)

• Superinfection
• gt 70 result in chronic infection, as HBsAg is
  persisting
• Worse than HBV or HCV alone
• High titers of anti-HDV (gt1100)
• Progression to cirrhosis in 10 - 15 years

57
Hepatitis B Prevention
58
Hepatitis B Vaccination

• MSM or multiple sexual partners
• Chronic hepatitis/liver disease (non- HBV)
• Injection drug users
• Inmates/staff staff for mentally disabled
• Health care workers, including laboratory staff

59
Hepatitis B Vaccination

• Household contacts of carriers
• Hemophiliacs dialysis patients
• Infants/children

60
Transmission Risk Percutaneous Exposure to
Susceptible Host

• HIV 0.3 risk
• HCV 2 - 3
• HBV 20 - 30, if source HBeAg
• HBV 1 - 6, if source HBeAg -

61
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

62
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

63
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

64
Web Addresses/ Phone Numbers

• www.aidsetc.org
• www.HIVguidelines.org
• www.hivandhepatitis.com
• www.aidsinfo.nih.gov
• www.cdc.gov