Management of Hepatitis B & HIV Co-infection in the Incarcerated Patient:

A Clinical UpdateDouglas G. Fish, MDHead, Division of HIV

MedicineAlbany Medical College

April 10, 2006National Commission on Correctional Health

CareUpdated August 15, 2006

AMC is a Local Performance Site of the

NY/NJ AETC

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

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 complicationsUp 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 2004;39(3).

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low

Geographic Distribution of Chronic HBV Infection

CDC

• Sexual

• Parenteral

• Perinatal

HBV Modes of Transmission

CDC

Risk Factors for Hepatitis B

Transfusion recipientsTransfusion recipients

Individuals with Individuals with multiple multiple

sexual partnerssexual partners

HealthcareHealthcareworkersworkers

Newborns of chronic Newborns of chronic carrierscarriers

Intravenous drug Intravenous drug usersusers

Prisoners and other Prisoners and other institutionaliinstitutionalizzed people ed people

Blood transfusion 0%

Other* 15%

Unknown 32%

Hemodialysis 0%Multiple sex partners 17%

Injection drug use 14%

Men who have sex with men 6%

Sexual contact with hepatitis B patient 13%

Medical Employee 1%

Household contact of hepatitis B patient 2%

Risk Factors Associated with Reported Hepatitis B, 1990-2000,

United States

Source: NNDSS/VHSP*Other: Surgery, dental surgery, acupuncture, tattoo, other percutaneous injury

CDC

Low/Not

High Moderate Detectable

semenserum vaginal fluidblood

wound exudates saliva

urinefecessweat

tearsbreast milk

Concentration of HBV in Various Body Fluids

CDC

Hepatitis B Virus

CDC

Middle Surfaceantigen

Nucleocapsidor Core

DNApolymerase

Envelope

Small Surfaceantigen

Large Surface antigen

Genomic DNA

RNA primer

Hepatitis B VirusHepatitis B Virus

Hepatitis B Acute and chronic forms

2-10% develop chronic disease over 5 years of age

Asymptomatic or symptomatic Clinical illness <5 yrs of age: <10%

(jaundice) >5 yrs of age: 30%-50% Incubation: 45 – 180 days

Average 60-90 days Most common cause of cirrhosis and

hepatocellular carcinoma worldwideCDC

Risk of Chronic Disease if Untreated/Unvaccinated

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

52 yo male with AIDS 1995 seen 12/02 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

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

Hepatitis B(e) Serologies HBe Ag: more infectious HBe Ab: less infectious

Marker of treatment response

Symptoms

HBeAg HBe Ab

Core Total Ab

Core IgM HBs AbHBs Ag

Weeks after ExposureWeeks after Exposure

TiterTiter

0 4 8 12 16 20 24 28 32 36 52 100

Acute Hepatitis B Virus Infection: RECOVERY

CDC

Weeks after ExposureWeeks after Exposure

TiterTiter

IgM anti-HBc

Core Total Ab

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Chronic Hepatitis B Virus Infection

CDC

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

Symptoms

HBeAg HBe Ab

Core Total Ab

Core IgMHBs Ag

Weeks after ExposureWeeks after Exposure

TiterTiter

0 4 8 12 16 20 24 28 32 36 52 100

Chronic Hepatitis B Virus Infection without Persistent

HBsAg

CDC

Patient’s 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

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

HBeAg and Risk of Hepatocellular Carcinoma

11,893 men in Taiwan

1991-92 enrolled HBeAg, HBsAg

testing HCC by link with

cancer registry 0

200

400

600

800

1000

1200

1400

HCC per

100K PY

HBeAg + - -

HBsAg + + -Yang HI et al. NEJM 2002;347:168-174.

HIV Co-infection Increases the Risk of ESLD due to HBV

MACS, 4,967 men HIV, 47% HBV, 6% (n=326) HIV/HBV, 4.3% (n=213)

HIV/HBV: 17-fold higher risk of liver death compared to HBV alone

Alcohol Low CD4 Increased risk after

1996

Liver Mortaility by HIV and HBV Status

0 0.8 1.7

14.1

0

5

10

15

NoHIV orHBV

HBVonly

HIVonly

HIVandHBV

Thio C et al. Lancet 2002;360:9349.

Hepatitis B and HIV Co-infection

Higher HBV DNA viral loads than withHBV 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

Work-up of Chronic

Hepatitis B

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

Patient’s 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

Treatment of Chronic Hepatitis B

Criteria for Treatment 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 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 2001:358

Entecavir (Baraclude) Active against lamivudine-resistant HBV

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)

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

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.

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. 1. Intron A. Physicians’ Desk Reference.® Physicians’ Desk Reference.® Montvale, NJ: Medical Economics;1998:2637-2645.Montvale, NJ: Medical Economics;1998:2637-2645.2. Wong DK, et al. 2. Wong DK, et al. Ann Intern Med.Ann Intern Med. 1993;119:312-323. 1993;119:312-323.

NUCA2004; Dienstag, New Engl J Med. 1995

Treatmentperiod

Time (weeks)

-100-80-60-40-20

020406080

100

0 4 8 12 16 20 24 28 32 36

25 mg100 mg300 mg

Serum HBV DNA(median % change

from baseline)

Lamivudine Antiviral Effect in Chronic HBV Patients: Serum HBV DNA Over Time vs.

Lamivudine Dose

(NUCA2004, U.S. 3-mo. dosing study)

Incidence of LAM Incidence of LAM Resistance in HBV and Resistance in HBV and HBV/HIV PatientsHBV/HIV Patients

20%

49%47%

67%

38%

90%

0%

20%

40%

60%

80%

100%

1 2 3 4

HIV negative HIV positive

Benhamou et al., Hepatology, 1999)

Adefovir for Hepatitis B e Antigen-Negative Chronic HBV

Hidziyannis SJ et al. New Engl J Med. 2003; 348:800-7.

Median Change of Serum HBV DNA from Baseline to 48 wks

Adefovir for Hepatitis B e Antigen-Positive Chronic HBV

Marcellin P et al. New Engl J Med. 2003; 348:808-16.

Median Change of Serum HBV DNA from Baseline to 48 wks

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

Treatment of HIV-infected, HBeAg+, LAM-experienced Patients

1. Ghany M. 52nd AASLD, #606; 2. Benhamou Y. XIV Int AIDS Conference, Barcelona, 2002, #7528; 3. Cooper D. ibid, #6015

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

-7-6-5-4-3-2-10123

12 24 36 48Baseline

Placebo

TDF

Me

an

ch

an

ge

in

H

BV

DN

A (

log

10 c

/mL

)

Weeks -30

-20

-10

0

10

20

30

40

50

60

BL 2 4 8 12 16 20 24 28 32 36 40 44 48

Weeks on study

AL

T (

U/L

)

Placebo

TDF

Study 907: Mean HBV DNA Change from Baseline with Tenofovir in Co-infected Patients by Lamivudine

Resistance StatusLamivudine

Wild-type ResistantN = 4 N = 6

Cooper D, et al. Presented at: 9th CROI; 2002; Seattle, Wash. Abstract 124.

Baseline VL log10 9.65 8.50CD4+ cells/cmm 497 603

Week 24 -5.39 -4.58

ALT normalized in 2Hepatitis B e antigen converted to e Ab in one

TDF + LMV May be More Efficacious than LMV Alone in Anti-retroviral Naïve Patients

Week 48 TDF+LMVN=5

LMVN=6

ΔHBV DNA (log10

copies/ml), mean

-4.70 -2.95

HBV DNA <1000 4 1

YMDD 0/1 4/5

Anti-HBe+ 1 1

ΔALT, mean -55 -22

Study design: TDF vs. stavudine with efavirenz and lamviudine.

Substudy Of GS 903 – naïve to HBV therapy

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

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

TDF 300 mg qd

ADV placebo

ADV 10 mg qd

TDF placebo

HIV/HBV Co-infection

+/- Lam-resistant

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

96 weeks

96 weeks

Peters M et al. 12th CROI; 2005, Boston. #124.

‡

Child-Pugh Scores

Measure1

point2 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 NoneSuppressed

with medication

Refractory No unit

Hepatic Encephalopathy

NoneGrade I-II (or

supressed with medication)

Grade III-IV (for

refractory)No unit

ADV TDF (n=25) (n=27)

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 422HIV RNA < 400 c/mL 80% 70%

* p=0.001; # p=0.10

Baseline Demographic Characteristics

Peters M et al. 12th CROI; 2005, Boston. #124.

‡

Baseline HBV and HIV Disease Characteristics

ADV* TDF*

Mean HBV DNA log10 c/mL 8.8 ± 1.9 9.5 ± 1.1

CPT < 7 100% 96%ALT ≤ ULN 60% 67%Mean ALT (IU/L) 66 ± 33 70 ± 92HBeAg positive 82% 92% 3TC/ LAM experienced 80% 74%

*Normal CBC, creatinine, albumin, bilirubin (88%)

Peters M et al. 12th CROI; 2005, Boston. #124.

‡

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 subjectsModified ITT: all subjects with 2 post baseline testsAs treated: as above with at least 36 week follow upDAVG: time-weighted average change from baselinePeters M et al. 12th CROI; 2005, Boston. #124.*Roche Cobas Amplicor, LLQ 200 copies/mL

‡

Mean Change from Baseline in HBV DNA

Week*Roche Cobas Amplicor, LLQ 200 copies/mL

-7

-6

-5

-4

-3

-2

-1

0

0 12 24 36 48

ADVTDF

HB

V D

NA

(lo

g 10

c/m

L)*

ADV 25 24 23 20 18 17

TDF 27 26 23 18 17 18

Peters M et al. 12th CROI; 2005, Boston. #124.

‡

Adverse Events

2 deaths: one HCC at week 49 on ADV one TDF at 57 weeks cause unknown

Lab Abnormality ADV TDFChemistry 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 1/27Creatinine grade 2 0/25 0/27

Peters M et al. 12th CROI; 2005, Boston. #124.

‡

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

Entecavir (ETV) in HIV/HBV Co-infection: 48-week results

Double-blind, placebo-controlled 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

Pessoa M. et al. 45th ICAAC, Washington DC 2005, #H-415

Initial treatment regimen: ETV PBO

0 12 24 36 48

10987

65

4

HB

V D

NA

lev

el b

y P

CR

(lo

g1

0 c

/mL

)

Double-blindphase

All patients onETV 1.0 mg

5.63 (–3.56)4.79 (–4.20)

5.56 (–3.66)

9.19 (+0.11)

Weeks

4816

4317

n(ETV)n(PBO)

5117

Patient’s 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 < 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

(non- HBV) 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 0.3% risk HCV 2 - 3% HBV 20 - 30%, if source HBeAg

+ HBV 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