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 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 complications Up to 2 million die each year from HBV infection, making it the 9th leading cause of death Remainder Asia Pacific 75% Lok A et al. Hepatology 2004;39(3).

Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ³8% - High 2-7% - Intermediate <2% - Low CDC 36

HBV Modes of Transmission Sexual Parenteral Perinatal CDC 2 2 2

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

Risk Factors Associated with Reported Hepatitis B, 1990-2000, United States [Slide 8] Risk Factors Associated with Reported Hepatitis B, 1990-2000, United States Of persons with acute hepatitis B reported in the National Notifiable Diseases Surveillance System and the Viral Hepatitis Surveillance Program from 1990‑2000, 36% had a sexual risk factor (>1 sex partner during the previous 6 months, sex contact with a person with hepatitis, or men who have sex with men), 14% reported injecting drug use, and 18% had other risk factors (e.g., household contact with a hepatitis patient, health care employment). No risk factor could be identified for 32% of reported cases. CDC *Other: Surgery, dental surgery, acupuncture, tattoo, other percutaneous injury Source: NNDSS/VHSP

Concentration of HBV in Various Body Fluids Low/Not High Moderate Detectable semen serum vaginal fluid blood wound exudates saliva urine feces sweat tears breast milk CDC 1 1 1

Hepatitis B Virus CDC 28

Hepatitis B Virus Middle Surface antigen Nucleocapsid or Core DNA polymerase Envelope Small Surface Large Surface antigen Genomic DNA RNA primer

Hepatitis B Acute and chronic forms Asymptomatic or symptomatic 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 worldwide CDC

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 Cryptococcal meningitis 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

Acute Hepatitis B Virus Infection: RECOVERY Weeks after Exposure Titer 4 8 12 16 20 24 28 32 36 52 100 Symptoms HBeAg HBe Ab Core Total Ab HBs Ag Core IgM HBs Ab CDC 30

Chronic Hepatitis B Virus Infection Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Core Total Ab Titer IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 Years CDC Weeks after Exposure 31

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

Chronic Hepatitis B Virus Infection without Persistent HBsAg Weeks after Exposure Titer 4 8 12 16 20 24 28 32 36 52 100 Symptoms HBeAg HBe Ab Core Total Ab HBs Ag Core IgM CDC 30

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

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

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

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. 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 from baseline) Treatment period 80 25 mg 100 mg 300 mg 60 40 20 -20 -40 -60 -80 -100 4 8 12 16 20 24 28 32 36 Time (weeks) NUCA2004; Dienstag, New Engl J Med. 1995

Incidence of LAM Resistance in HBV and HBV/HIV Patients Benhamou et al., Hepatology, 1999)

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 -7 -6 -5 -4 -3 -2 -1 1 2 3 Placebo HBV DNA (log10 c/mL) Mean change in 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

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.

TDF + LMV May be More Efficacious than LMV 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 YMDD 0/1 4/5 Anti-HBe+ ΔALT, mean -55 -22 Cooper D et al. 10th CROI, Boston 2003 Abstract 825

TDF vs ADV for HIV/HBV Co-infection (AACTG 5127) ‡ 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 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 96 weeks Peters M et al. 12th CROI; 2005, Boston. #124.

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 Hepatic Encephalopathy Grade I-II (or supressed with medication) Grade III-IV (for refractory)

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%

Baseline Demographic Characteristics ‡ Baseline Demographic Characteristics 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 486 422 HIV RNA < 400 c/mL 80% 70% * p=0.001; # p=0.10 Peters M et al. 12th CROI; 2005, Boston. #124.

Baseline HBV and HIV Disease Characteristics ‡ 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 ± 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.

Serum HBV DNA DAVG 48 (log10 c/mL)* ‡ 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.

Mean Change from Baseline in HBV DNA ‡ Mean Change from Baseline in HBV DNA ADV TDF HBV DNA (log10 c/mL)* ADV 25 24 23 20 18 17 TDF 27 26 23 18 17 18 *Roche Cobas Amplicor, LLQ 200 copies/mL Week Peters M et al. 12th CROI; 2005, Boston. #124.

Adverse Events 2 deaths: one HCC at week 49 on ADV ‡ 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.

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 12 24 36 48 10 9 8 7 6 5 4 HBV DNA level by PCR (log10 c/mL) Double-blind phase All patients on ETV 1.0 mg 5.63 (–3.56) 4.79 (–4.20) 5.56 (–3.66) 9.19 (+0.11) Weeks 16 43 17 n(ETV) n(PBO) 51 24-week results published at 12th CROI (Pessoa M, et al. 12thCROI, Boston 2005, # 123) Initial treatment regimen: ETV PBO Pessoa M. et al. 45th ICAAC, Washington DC 2005, #H-415

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