# Presentation: 236089

## Overview

**Review chronic hepatitis B infection and interpretation of hepatitis B blood tests**
**Discuss patient selection criteria and medications to treat chronic hepatitis B**
**Review patient case studies including the management of lamivudine resistance**

## Hepatitis A and E

| Type | Source | Transmission | Chronic | Prevention |
| --- | --- | --- | --- | --- |
| A | Feces | Fecal-oral | No | Immunization |
| E | Feces | Fecal-oral | No | Ensure safe drinking water |

## Hepatitis B, C and D

| Type | Source | Transmission | Chronic | Prevention |
| --- | --- | --- | --- | --- |
| B | Blood/ body fluids | Percutaneous permucosal | Yes | Immunization |
| C | Blood/ body fluids | Percutaneous permucosal
 | Yes | Blood donor screening, risk behavior modification |
| D | Blood/ body fluids | Percutaneous permucosal | Yes | Immunization risk behavior modification |

## Geographic Distribution of Chronic HBV

**HBsAg Prevalence**

**≥********8% - High **

**   ****2 - 7%- Intermediate **

**Geographic Distribution of Chronic HBV**
**350 million chronic carriers**

- World Health Organization / Centers for Disease Control and Prevention

## Natural History of Chronic Hepatitis B 

**15 - 40% of patients progress to cirrhosis or hepatocellular carcinoma**
**520,000 deaths/year related to HBV complications**
**Liver cancer is the fifth most common cause of cancer deaths worldwide**

- Maddrey WC. J Med Virol 2000; 61: 362

## Chronic HBV Infection, US

**1.25 million ****chronic carriers**
**0.3% of adult population**
**4–5,000 deaths/year related to HBV complications**
**Immigration ****from endemic areas, including Asia, impacts the US pattern of disease**

## Acquisition of Hepatitis B, US 

**Mother to baby ****(vertical)**
**Close contact (horizontal) **
**Blood or sexual exposure**
**Intravenous drug use**
**Transfusion**** ****(blood, blood products)**
**Organ**** & ****tissue transplantation**

## Acute Hepatitis B Infections, US

- MMWR 2002: 51; 549-552,563        MMWR 2004: 53;1015-1018

**Vaccine **
**licensed**

**HBsAg screening of pregnant women**
**recommended**

**Adolescent Immunization recommended**

**Infant Immunization**
**recommended**

**Acute Hepatitis B Infections, US**

## Risk of Chronic Hepatitis B InfectionDecreases with Age of Acquisition

- Lok AS et al. Hepatology 2004;39:857-861
- Ganem D and Prince AM.  N Engl J Med 2004;350:1118-29

## Natural History of Hepatitis B

**90% neonates**

**Natural History of Hepatitis B**

**Acute HBV infection**

**<10% adults**

**Progressive chronic hepatitis**

**Cirrhosis**

**HCC**

**Death**

**Inactive****carrier state**

- Lok AS and McMahon BJ. Hepatology 2007;45:507-39

**Chronic infection**

## Hepatitis B Blood Tests

| Markers	 | Definition/Diagnostic Use |
| --- | --- |
| HBsAg: Hepatitis B surface antigen | General marker of infection
Persistence for > 6 months = chronic infection |
| HBeAg: Hepatitis B e antigen | Indicates active replication of virus  |
| HBV DNA | Indicates actual level of virus in the blood |

## Hepatitis B Blood Tests: Antibodies

| Markers	 | Definition/Diagnostic Use |
| --- | --- |
| Anti-HBs: Antibody to hepatitis B s antigen | Documents recovery and/or immunity to HBV
Detectable after successful hepatitis B vaccination |
| Anti-HBc: Antibody to hepatitis B core antigen | Documents past or present infection with HBV |
| Anti-HBe: Antibody to hepatitis B e antigen | Indicates lower level of viral replication |

## Hepatitis B Disease States

**HBsAg + **
**HBeAg –**
**Anti-HBe +/-**
**Normal**** ALT**
**HBV DNA - / low**
**(< 20,000 IU/mL, < ****10****5**** c/mL****)**

**Antiviral Therapy**

**Inactive HBsAg**
**Carrier**

**Active Chronic **
**Hepatitis**

**HBsAg + **
**HBeAg +**
**Elevated ALT**** **
**HBV DNA +**
**( ******** ****20,000 IU/mL,      ******** ****10****5**** c/mL****)**

**HBsAg-**
**HBcAb+**
**HBsAb+**

**Immune to Hepatitis B**

**Chronic HBV**
**Infection**

## Liver Biopsy: Stages of Fibrosis

**Cirrhosis (F4)**

**Severe fibrosis (F3)**

**Normal Liver (F0)**

**Mild fibrosis (F1-2)**

## AASLD Guidelines on Chronic HBV: Whom to Treat with Antiviral Therapy 

**Elevated HBV DNA levels **
****** ****20,000 IU/mL or ******** ****10****5**** copies/mL**
**AND**
**Persistently elevated ALT levels **
**>2 x ULN (normal ALT: 30 IU/mL for men, 19 IU/mL for women)**
**OR**
**Moderate/advanced liver disease on biopsy **
**Stage 2, 3 or 4 fibrosis**

-  Lok AS and McMahon BJ. Hepatology 2007;45:507-39

## Goals for Treatment-Naïve Chronic HBV Patients

**Normalization of liver function tests**
**Undetectable HBV DNA**
**HBeAg seroconversion (if originally HBeAg+)**
**HBeAg neg & HBeAb pos**
**Reduce fibrosis progression & risk of HCC**

## Pharmacologic Treatment Options for Chronic Hepatitis B

**First-line oral antiviral agents**
**Adefovir (Hepsera****®****) 10 mg daily****	**
**Entecavir (Baraclude****®****) 0.5 -1 mg daily**
**Second-line oral antiviral agents**
**Lamivudine (Epivir-HBV****®****) 100 mg daily**
**Telbivudine (Tyzeka****) 600 mg daily**

## Pharmacologic Treatment Options for Chronic Hepatitis B

**Interferon-based preparation in select patients (injectable)**
**Peginterferon alfa-2a (Pegasys********)**
**    ****180 mcg SQ q week x 48 weeks**

## Algorithm in Treatment-Naïve Chronic HBV

**No Antiviral Treatment:**
**Monitor every 6-12 months**

**HBV DNA**
**(PCR)**

**HBV DNA**
**<20,000 IU/mL, **
**<10****5 ****c/mL**

**Algorithm in Treatment-Naïve Chronic HBV**

## Algorithm in Treatment-Naïve Chronic HBV

**ALT**

**Consider liver biopsy and treat with an antiviral agent if there is fibrosis.  **

**First-line options: Adefovir, Entecavir or Peginterferon**
**Second-line options: Lamivudine, or Telbivudine**

**HBV DNA**
**(PCR)**

**HBV DNA**
**≥****20,000 IU/mL, **
**≥****10****5 ****c/mL**

**Normal**

**Elevated**

**Algorithm in Treatment-Naïve Chronic HBV**

## Case 1

**43 year old Asian male with chronic HBV**
**HBsAg positive, HBeAg positive **
**AST 25 (nl 5-35), ALT 28 (nl 7-56), Cr 0.8**
**HBV DNA 1,800 copies/mL (~330 IU/mL)**
** ****Hepatitis A, total antibody negative**
**Mode of HBV acquisition**
**Mother is chronic hepatitis B carrier **
**Patient likely acquired HBV at birth or early   in life  **

## Case 1

**Habits: does not use alcohol, tobacco, or illicit drugs**
**Allergies: NKDA**
**Current Meds: none **
**VS: 118/68   P 72   T 98 F   Wt 150 lbs**
**Physical Exam: no evidence of chronic liver disease**

## Patient Education

**Prevent further liver damage**
**Avoid alcohol **
**Avoid hepatotoxins including acetaminophen >2 grams/day**
**Reduce risk of transmission**
**Do not share needles, toothbrushes, razors**
**Cover open cuts & sores**
**Adopt safe sex practices**
**Check immunity of household members & sexual partners, vaccinate if needed**

- http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5516a1.htm?s_cid=rr5516a1_e

## Routine Care: Chronic Hepatitis B

**Vaccinate against hepatitis A if not immune**
**Screen for HIV, HCV & HDV**
**Evaluate LFT’s & HBV DNA levels**
**Discuss screening for hepatocellular carcinoma (HCC)**
**Evaluate the need for antiviral therapy**

## AASLD Guidelines on Chronic HBV: Whom to Treat with Antiviral Therapy 

**Elevated HBV DNA levels **
******20,000 IU/mL or ********10****5**** copies/mL**
**AND**
**Persistently elevated ALT levels >2 x ULN**
**OR**
**Moderate/advanced liver disease on biopsy **
**Stage 2, 3 or 4 fibrosis**

-  Lok AS and McMahon BJ. Hepatology 2007;45:507-39

## Case 1: 6 and 9 Month Follow-up Visits

**43 year old Asian male with chronic HBV and HBeAg positive**
**Physical Exam: Unchanged**
**HIV, HCV and HDV negative**
**AST 120 - 150 , ALT 300 - 350 at consecutive follow-up visits**
**HBV DNA >10****8**** copies/mL (2 x 10****7**** IU/mL) **
**CT liver: no masses,  AFP 2.5 (nl 0-8.9)**

## AASLD Guidelines on Chronic HBV: Whom to Treat with Antiviral Therapy 

**Elevated HBV DNA levels **
******20,000 IU/mL or ********10****5**** copies/mL**
**AND**
**Persistently elevated ALT levels >2 x ULN**
**OR**
**Moderate/advanced liver disease on biopsy **
**Stage 2, 3 or 4 fibrosis**

-  Lok AS and McMahon BJ. Hepatology 2007;45:507-39

## Case 1: Which Medication Would You Choose?

**a. Lamivudine**
**b. Adefovir **
**c. Entecavir**
**d. Telbivudine**
**e. Peginterferon alfa**

## Considerations in Antiviral Agent Selection

**Resistance profile **
**Highest risk with lamivudine**
**Low risk with adefovir, very low risk with entecavir**
**No resistance issues with peginterferon alfa**
**Anticipated HBV DNA reduction (log****10****) **
**Adefovir: 3-4**
**Entecavir: 5-7**
**Lamivudine: 5.5**
**Telbivudine: 6 **
**Peginterferon alfa-2a: 3-4 **

## Tolerability
Oral antiviral agents well tolerated 
Significant adverse effects with injectable peginterferon alfa
Cost
Lamivudine is least expensive
Peginterferon alfa 
Most costly treatment but duration is finite

**Oral antiviral agents well tolerated **
**Significant adverse effects with injectable peginterferon alfa**
**Cost**
**Lamivudine is least expensive**
**Peginterferon alfa **
**Most costly treatment but duration is finite**

**Considerations in Antiviral Agent Selection**

## Case 1

**Start adefovir 10 mg po daily OR entecavir 0.5 mg po daily**
**Adjust dose for renal dysfunction**
**Monitor creatinine, LFT’s, HBV DNA levels every 3-6 months**
**If <2 log HBV DNA reduction on adefovir at Month 6 **
**Assess patient compliance**
**Switch to entecavir or add lamivudine**

## Case 1

**Treatment duration**
**Non-cirrhotics: Indefinite unless patient loses HBeAg and develops HBeAb, which is maintained for 6-12 months**
**Cirrhotics: Indefinite**
**Continue HCC screening every 6-12 months**
**US or CT liver**
**AFP**

## Case 2

**50 year old Caucasian male with chronic HBV on lamivudine 100 mg po daily x 3 yrs**
**HIV, HCV, and HDV negative**
**Pt reports medication compliance**
**CT liver: no masses, AFP 5.6 (nl 0-8.9)**
**Liver biopsy (4 yrs ago): Stage 2 fibrosis**
**Habits: does not use tobacco, alcohol, or illicit drugs**
**VS: 110/68   P 72   T 98 F   Wt 175 lbs**
**Physical examination is unremarkable**

## Case 2

| 
Pertinent Labs | Baseline – Three Yrs Ago (Prior to Lamivudine) | Last Visit 
6 Months ago   | Today’s Visit    |
| --- | --- | --- | --- |
| HBsAg | pos | pos | pos |
| HBeAg | neg | --- | ---  |
| HBV DNA (c/mL)
                  (IU/mL) | 5.1 x 107
9.1 x 106 | <500
<89 | 6,990
1,248 |
| AST (U/L), (nl 5-35) | 180 | 47 | 60 |
| ALT (U/L), (nl 7-56) | 390 | 26 | 118 |
| Cr (mg/dL) | 0.9 | 0.8 | 0.9 |

## Case 2:  ALT During Lamivudine Treatment

**Case 2:  ALT During Lamivudine Treatment**

**Months of Lamivudine** **Therapy**

**HBV DNA **
**5.1 x 10****7 ****c/mL**

**HBV DNA <500**

**HBV DNA**
**6,990 c/mL **

**ALT (U/L)**

**HBV DNA <500**

## Lamivudine Resistance Over Time

**Lamivudine Resistance Over Time**

- Lai CL et al. Clin Infect Dis 2003; 36:687-96
- Lok AS et al. Gastroenterology 2003; 125:1714-22

**49%**

**24%**

** ****67%**

** ****38%**

**0%**

**20%**

**40%**

**60%**

**80%**

**1**

**2**

**3**

**4**

**Percent**** ****of**** ****Patients**

**Years of Lamivudine Therapy**

** ****69%**

**5**

## Identification of Antiviral Treatment Resistance

**≥****1 log increase in HBV DNA from nadir**
**LFT elevations**
**Assess patient compliance**

## Goals for Antiviral Treatment of Resistant Hepatitis B

**Normalization of LFT’s**
**Undetectable HBV DNA**
**Avoid liver enzyme flares and decompensation if cirrhotic**
**HBeAg seroconversion (if originally HBeAg+)**
**Reduce fibrosis progression & risk of HCC**

## Case 2: What Would You Do for this Patient?

**Continue lamivudine monotherapy**
**Add adefovir**
**Switch to adefovir**
**Add entecavir**
**Switch to telbivudine**

## Considerations in Treatment of Lamivudine Resistance

**Continue lamivudine monotherapy**
**HBV DNA will continue to be detectable**
**Risk hepatic flare**
**Add adefovir **
**Adefovir resistance reduced with combination therapy compared to switching to adefovir monotherapy**

## Considerations in Treatment of Lamivudine Resistance

**Add or switch to telbivudine or entecavir**
**May select for future antiviral resistance **
**Cross resistance with lamivudine, telbivudine, entecavir**

## Case 2

**Combination therapy for lamivudine-resistant HBV**
**Add adefovir 10 mg po daily**
**Monitor creatinine, LFT’s, HBV DNA levels **
**Indefinite treatment duration**
**Continue HCC screening every 6-12 months**

## VANTS Calls

**October 17, 2007**
**November 29, 2007**
**1:00 PM Eastern**
**1-800-767-1750**
**Access code: 90166#**

## Appendix 1: Recommended Hepatitis A & B Vaccination Schedule 

**Appendix 1: Recommended Hepatitis A & B Vaccination Schedule**

## Appendix 2: Recommended References 

**Lok AS and McMahon BJ. AASLD Practice Guidelines. Chronic Hepatitis B. Hepatology 2007; 45:507-39.**
**EASL International Consensus Conference on Hepatitis B. J Hepatol 2003; 38: 533-40.**