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Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians. Primary Care Specialist Screening Diagnostic testing Identification of treatment candidates Initiation of treatment On-treatment monitoring Long-term follow-up for

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Optimal management of hbv a partnership between primary care and specialty physicians l.jpg

Optimal Management of HBV: A Partnership Between Primary Care and Specialty Physicians


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Primary Care Specialist

Screening

Diagnostic testing

Identification of treatment candidates

Initiation of treatment

On-treatment monitoring

Long-term follow-up for

disease activation

HCC screening

Vaccination


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Hepatitis B: An Important Disease for Primary Care and Specialty Physicians


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Why Is HBV Relevant in Primary Care?

  • High global impact

    • High prevalence in specific risk groups

    • Risk of death/cancer

  • Effective prevention

  • Effective treatment

    • Improve liver disease outcomes

    • Decrease progression to cirrhosis or HCC and improve survival


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Global Impact of HBVA Significant Cause of Worldwide Morbidity and Mortality

  • >2 billion have been infected1

  • 4 million acute cases per year1

  • 1 million deaths per year1

  • 350 million chronic carriers1

    • 25% of carriers die from chronic active hepatitis, cirrhosis, or liver cancer1

    • Nearly 75% of chronic carriers are Asian2

  • 2nd most important carcinogen behind tobacco3

  • Causes 60%–80% of all primary liver cancer1

  • HBV is 100 times more contagious than HIV4

1. WHO. Hepatitis B. 2002. 2. Maynard JE, et al. In: Viral Hepatitis and Liver Disease. New York: Alan R. Liss, Inc. 1988. 3. CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed. 4. CDC. MMWR. 2001;50:RR-11.


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HBVA Global Health Problem

HBsAg Prevalence (%)1

<8: High

2–8: Intermediate

<2: Low

1. WHO. Hepatitis B. 2002. 2. Custer B. et al. J Clin Gastroenterol. 2004;38(10 suppl):S158. 3. WHO/WPRO data.


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HBV Disease Progression

Liver Cancer (HCC)

Death

Liver Transplantation

Chronic

Infection

Cirrhosis

Liver Failure

Torresi J, et al. Gastroenterology. 2000;118:S83. Fattovich G, et al. Hepatology. 1995;21:77.

Perrillo RP, et al. Hepatology. 2001;33:424.


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Burden of HBV Infection in the United States

73,000

1,250,000

New Acute Infections

per Year1

Chronic Infections1

5000

3100

230

Deaths per

Year1

HCC per

Year2

Liver Transplants

per Year3

1. CDC. HBV Disease Burden. 2005. 2. El-Serag HB, et al. Arch Intern Med. 2000;160:3227. 3. UNOS/OPTN.


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Poor Survival inHBV-Related Cirrhosis

100

80

Cirrhosis1(n = 130)

60

55%

Patients Surviving (%)

40

Decompensated Cirrhosis2

(n = 21)

20

14%

0

0

1

2

3

4

5

Years

1. Weissberg JI, et al. Ann Intern Med. 1984;101:613. 2. De Jongh FE, et al. Gastroenterology. 1992;103:1630.



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Clinical-Epidemiologic Correlations

Age of Mode of ESLD HCC

Endemicity Location Infection Transmission Chronicity Risk Risk

Low N. America Early Percutaneous Rare Low Low W. Europe Adulthood Sexual

High Sub-Sahara Birth Perinatal Likely High High Far East Toddler Horizontal


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HBV VaccineIndications

  • Routine vaccination of infants

    • Regardless of mother’s HBsAg status

    • With HBIG for HBsAg positive mothers

  • Catch-up vaccination of children and adolescents

  • Vaccination of adults with risk factors for infection

    • High-risk sexual activity

    • Illegal injection drug use

    • Occupational exposure

    • Hemodialysis patients

    • Household contacts of infected persons

HBIG = hepatitis B immune globulin.

CDC. MMWR. 1991;40(RR-13):1.


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US Incidence of Viral Hepatitis Infection Over Time

Incidence of Hepatitis A, US

180

Incidence of Acute Hepatitis B, US

Incidence of Acute Hepatitis C, US

160

140

Estimated Number of Cases

(Thousands)

120

100

80

60

40

20

0

1990

1992

1994

1996

1998

2000

2002

1991

1993

1995

1997

1999

2001

2003

Year

CDC. Disease burden from viral hepatitis A, B, and C in the United States. 2003.


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HBV VaccinationEffect on HCC Incidence and Mortality*

Incidence

Mortality

1

1

0.80

0.8

0.8

0.70

Per 100,000 Children (6–14 Years)

0.58

0.57

Per 100,000 Children(6–14 Years)

0.6

0.6

0.36

0.34

0.4

0.4

0.2

0.2

0

0

1981–86

1986–90

1990–94

1981–86

1986–90

1990–94

*Nationwide vaccination in Taiwan, implemented 7/84

Chang M-H, et al. N Engl J Med. 1997;336:1855.


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Screening for HBV and Evaluating Infected Patients


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Who Should Be Screened?

  • Patients with abnormal ALT

  • Patients engaged in high-risk sexual behaviors

  • Injection drug users

  • Immigrants, refugees, or adoptees from areas of high endemicity

  • Immunocompromised patients

  • Dialysis patients

  • Recipients of organ/tissue transplants or blood transfusion

  • Household members or sexual partners of known HBV carriers

  • Occupational exposure (healthcare workers, police, EMTs)

  • Inmates in long-term correctional facilities or residents in institutions for the developmentally disabled

  • Pregnant women

  • Individuals infected with HCV or HIV

Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases. “The Pink Book.” 8th ed, 2005. Lok ASF, et al. Hepatology. 2001;34:1225.


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Prevalence of HBV Serologic Markers in Population Groups Who Should Be Tested for HBV Infection

Prevalence of HBV Serologic Markers (%)

Population HBsAg Any Marker

Persons born in high endemic areas* 13 70–85

Men who have sex with men 6 35–80

Injection drug users 7 60–80

Dialysis patients 3–10 20–80

HIV infected patients 8–11 89–90

Pregnant females (USA) 0.4–1.5

Family/household and sexual contacts 3–6 30–60

*Africa; Southeast Asia, including China, Korea, Indonesia, and the Philippines; the Middle East, except Israel; South and Western Pacific Islands; the interior Amazon River basin; and certain parts of the Caribbean (Haiti and the Dominican Republic)

Lok ASF, et al. Hepatology. 2001;34:1225. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.


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Screening Tests

  • HBsAg

    • If positive, indicates infection

  • Anti-HBc

    • If positive, indicates HBV exposure

  • Anti-HBs

    • If positive, indicates immunity


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History and Physical Evaluation

  • Risk factors for coinfection

  • Alcohol use

  • Family history of HBV infection and HCC

  • Physical findings of advanced disease

    • Jaundice

    • Abdominal swelling

    • Upper GI bleeding

Lok ASF, et al. Hepatology. 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71.


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Assessment ofLiver Disease Severity

  • Liver disease activity, biochemical

    • ALT

    • AST

  • Liver function/synthetic testing

    • Albumin

    • Bilirubin

    • Prothrombin time (INR)

  • Ultrasonography: morphologic assessment

    • Liver size, contour, and echogenicity

    • Splenomegaly

Lok ASF, et al. Hepatology 2001;34:1225. Tsai NCS, et al. Semin Liver Dis. 2004;24(suppl 1):71. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2004;2:87.


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2nd-Phase Testing in HBsAg+ Patients

  • Anti-HBc

    • IgG: if positive, indicates HBV exposure

    • IgM: if positive, indicates acute HBV

  • HBeAg

    • If positive, indicates active HBV replication

    • If negative

      • If HBV DNA negative, suggests HBV replication is suppressed

      • If HBV DNA positive, most likely has precore mutation

  • Anti-HBe

  • HBV DNA quantification

    • Quantitative level correlates with level of HBV replication


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Further Testing for HBsAg+ Patients

  • HCV antibody in at-risk individuals

  • HIV antibody or RNA quantification in at-risk individuals

  • Consider screening for hepatitis delta virus (HDV) if adult-acquired HBV

    • Anti-HDV

    • Delta antigen

    • Delta RNA if any HDV testing is available


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Hepatitis Delta Virus (HDV)

Clinical Scenario

Outcome

Acute HDV/acute HBV

 Risk of acute liver disease

Acute HDV/chronic HBV

 Risk of progressive liver disease

Chronic HDV/chronic HBV

 Risk of cirrhosis and cancer



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Natural History of HBV Infection

Immune Tolerance

Early Childhood

>95%

Adulthood

<5%

HBeAg-

Chronic

Hepatitis B

HBeAg+

Chronic

Hepatitis B

Cirrhosis

Inactive Carrier

Courtesy of W. Ray Kim, MD

Chen DS, et al . J. Gastroenterol Hep. 1993:8(5):470.Seeff L, et al. N Engl J Med. 1987;316(16):965.


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Phases of Chronic HBV Infection

Immune Inactive HBeAg HBeAg Tolerant HBsAg Positive Negative Phase Carrier CHB CHB*

HBsAg + + + +

HBeAg + – + –

Anti-HBe – + – +

ALT Normal Normal 

HBV DNA >105 >104 <105 >104† copies/mL copies/mL copies/mL copies/mL

Histology Normal/Mild Inactive Active Active

*Precore mutant

†Expert opinions vary as to this value

1IU = ~5 copies/mL

Lai CL, et al. Lancet. 2003:362:2089. Lok AS, et al. Gastroenterology. 2001;120:1828.


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HBV Disease Progression

Liver

Cancer (HCC)

5%–10%1

6% in 5 yr2

Liver Transplantation

Death

Chronic

Infection

30%1

Cirrhosis

23% in 5 yr2

Acute Flare

Liver Failure

Chronic HBV is the 6th leading indication of liver transplantation in the US3~5%

  • Torresi J, et al. Gastroenterology. 2000;118:S83. 2. Fattovich G, et al. Hepatology. 1995;21:77.

  • 3. Perrillo RP, et al. Hepatology. 2001;33:424.


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HBeAg Negative Patients

  • HBeAg positive patients may develop antibodies (anti-HBe)

  • When HBeAg is lost, 2 possible scenarios

    • Inactive carrier (normal ALT, low or negative HBV DNA level)

    • Precore mutant chronic HBV (moderate to high HBV DNA, elevated ALT)


Inactive carriers l.jpg
Inactive Carriers

  • HBeAg negative, normal ALT, low/negative HBV DNA

  • “Healthy carriers” = oxymoron

  • All patients who are HBsAg positive need ongoing monitoring as part of management

    • Monitor for increased ALT or HBV DNA every 6 months

    • Monitor for HCC in at-risk groups

Sherman M. Semin Liver Dis. 2005;25:143.


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Precore Mutant (HBeAg Negative) Chronic HBV

  • HBeAg negative, elevated ALT, moderate to high HBV DNA

  • Usually result of mutation in precore or basal core promoter regions of HBV

  • Potentially more severe and progressive chronic disease

  • Longer, more aggressive (suppression of HBV DNA) treatment needed

  • 29% risk of adefovir resistance at 5 years of therapy1

  • Seen predominantly in genotypes B,C, and D

1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.


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HBV DNA and Prognosis

High viral load predicts

  • Progression of liver disease1

  • Cirrhosis1

  • Cirrhosis-related complications2

  • HCC1,3

    • Independent of HBeAg, ALT, and cirrhosis3

1. Chen G, et al. Abstract 996. Presented at: AASLD 2004. 2. Yuan JH, et al. J Viral Hepat. 2005;12:373. 3. Chen C-J, et al. JAMA. 2006;295:65.


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Baseline HBV DNA Level and Cumulative Incidence of HCCEntire Cohort

16

14.89

14

12.17

12

N = 3653, 13-year follow-up

10

Cumulative Incidence of HCC (%)

8

6

3.57

4

1.37

1.3

2

0

300–<104

104–<105

105–<106

≥106

<300

HBV DNA (Copies/mL)

1IU = ~5 copies/mL

Chen C-J, et al. JAMA. 2006;295:65.


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Baseline HBV DNA Level and Cumulative Incidence of HCCSubgroup of Noncirrhotic HBeAg– Patients with Normal ALT

16

13.50

14

12

N = 2925

10

Cumulative Incidence of HCC (%)

7.96

8

6

4

3.15

0.89

2

0.74

0

300–<104

104–<105

105–<106

≥106

<300

HBV DNA (Copies/mL)

Chen C-J, et al. JAMA. 2006;295:65.


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Baseline HBV DNA Level and Relative Risk of Cirrhosis

Adjusted for gender, age, smoking, alcohol consumption

9.8

10

N = 3582, 11-year follow-up

9

8

7

5.9

6

Relative Risk

5

4

2.5

3

1.4

2

1

1

0

300–9.9x103

1.0–9.9x104

1.0–9.9x105

>105

<300

HBV DNA (Copies/mL)

Iloeje UH, et al, Gastroenterology. 2006;130:678.


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HBV DNA and Prognosis Caveat

Low HBV DNA does not rule out risk

  • In HBeAg positive patients, HBV DNA 20,000 IU (<105 copies/mL) predicted better histology

    • But 14.3% of patients withHBV DNA 20,000 IU (<105 copies/mL) still had fibrosis1

  • In patients with cirrhosis, viral load was the best predictor of complications

    • But even with HBV DNA 20,000 IU (<104 copies/mL) complications continued to develop2

1. Yuen MF, et al. Am J Gastroenterol. 2004;99:2031. 2. Yuan HJ, et al. J Viral Hepat. 2005;12:373.


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Candidacy for anti-HBV TreatmentPrinciple

In general, a patient with chronic HBV is a treatment candidate if there is evidence of

  • Liver disease (abnormal ALT) and

  • HBV replication (HBV DNA+)


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When Do You Initiate anti-HBV Therapy?

  • Parameters

    • HBV DNA levels >104-5 copies/mL

    • ALT levels >1–2 x ULN

  • Factors

    • HBeAg positive vs HBeAg negative

    • Cirrhosis vs no cirrhosis

    • Compensated vs decompensated disease


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Which Patients Should Be Treated?AASLD Guidelines1

HBV DNA

HBeAg (Copies/mL) ALT Management

+ >105 ≤2 x ULN Follow

+ >105 >2 x ULN Treat

– >105 >2 x ULN Treat

– – ≤2 x ULN Follow

+/– >105 Cirrhosis If compensated, treat; if decompensated*, refer for liver transplant

+/– – Cirrhosis If compensated, observe; if decompensated*, refer for liver transplant

*Do not use interferon or peginterferon if the patient has decompensated cirrhosis.2,3 Specific treatment recommendations are made elsewhere in this activity.

1. Lok ASF, et al. Hepatology. 2004;39:857. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. 2. INTRON® A (interferon alfa-2b) Product Information. Kenllworth, NJ: Schering Corporation: 2004. 3. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.


Us treatment algorithm update hbeag positive compensated disease l.jpg
US Treatment Algorithm UpdateHBeAg Positive Compensated Disease

HBeAg Positive

HBV DNA

<105 c/mL

HBV DNA

≥105 c/mL

ALT Normal

ALT Elevated

  • No treatment

  • Monitor every 6–12 mo

  • Monitor every 3–12 mo (immune tolerant)

  • Consider biopsy, if age >35–40 y, and treat if significant disease

Treat

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.


Us treatment algorithm update hbeag negative compensated disease l.jpg
US Treatment Algorithm UpdateHBeAg Negative Compensated Disease

HBeAg Negative

HBV DNA

<104 c/mL

HBV DNA

≥104 c/mL

ALT Normal

ALT Elevated

  • No treatment

  • Monitor every 6–12 mo

  • Monitor ALT, or

  • Consider biopsy, since ALT often fluctuates, and treat if significant disease

  • Long-term treatment required

  • Treat

  • Long-termtreatment required

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.


Us treatment algorithm update compensated cirrhosis l.jpg
US Treatment Algorithm UpdateCompensated Cirrhosis

HBV DNA

(PCR)

HBV DNA

≥104 c/mL

HBV DNA

<104 c/mL

May Choose to Treat or Observe

Treat

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.


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US Treatment Algorithm UpdateDecompensated Cirrhosis

HBV DNA Detectable by PCR?

No

Yes

  • Observe

  • Wait list for transplant

  • Treat

  • Wait list for transplant

Courtesy of Emmet Keeffe, MD. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.


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Who May Not Need Referral to a Specialist?

Noncirrhotic patients with persistently normal ALT

  • Inactive carrier

    • HBeAg negative

    • DNA <104

    • Persistently normal ALT

  • Immune tolerant

    • HBeAg positive

    • Persistently normal ALT


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Who Is Likely to Benefit from Referral to a Specialist?

  • HBeAg positive chronic hepatitis B

    • Abnormal ALT

    • DNA >105

  • HBeAg negative chronic hepatitis B

    • Abnormal ALT

    • HBV DNA may be variable

  • Cirrhosis

    • Regardless of HBeAg, DNA or ALT status


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Management of Chronic HBV Infection

ALT <17–25* U/L ALT >17–25* U/L

DNA<2000 IU/mL Observe† Biopsy‡<10,0000 c/mL

DNA

>2000 IU/mL Biopsy Treat:>10,000 c/mL and treat if eAg (+): >6 mo post Ag seroC active HBV eAg (–): prolonged Rx (at least 24 mo) beyond NAT negative§ (Consider biopsy or use noninvasive testing to stage disease)

*Upper limits of normal for a person with normal BMI, 17 for women and 25 for men;†Treat any patient with cirrhosis who is NAT positive, refer to specialist; ‡Rule out fatty liver and other causes of CLD; §Consider 3–5 years. NAT = nucleic acid testing, such as PCR, bDNA or TMA.

Reprinted from Gish R. Clin Liver Dis. 2005;9:541, with permission from Elsevier.


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Monitoring for Patients Not Considered for Treatment

  • Check ALT every 3–6 months

    • If ALT is persistently elevated, reevaluate for treatment

  • HCC surveillance in relevant population

Lok ASF, et al. Hepatology. 2001;34:1225. Lok ASF, et al. Hepatology. 2004;39:857.


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HCC Surveillance Is Recommended for the Following Groups of Patients (Level III)

Hepatitis B Carriers

Asian males ≥40 years

Asian females ≥50 years

All cirrhotic hepatitis B carriers

Family history of HCC

Africans over age 20

For noncirrhotic hepatitis B carriers not listed above, the risk of HCC varies depending on the severity of the underlying liver disease and current and past hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for HCC.

Nonhepatitis B Cirrhosis

Hepatitis C

Alcoholic cirrhosis

Genetic hemochromatosis

Primary biliary cirrhosis

Although the following groups have an increased risk of HCC, no recommendations for or against surveillance can be made because a lack of data precludes an assessment of whether surveillance would be beneficial.

Alpha1-antitrypsin deficiency

Nonalcoholic steatohepatitis

Autoimmune hepatitis

Bruix J, Sherman M. Hepatology. 2005;42:1208. Reprinted with permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc.


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Counseling of HBV-Infected Patients

  • Limit use of alcohol1-3

  • Prevent transmission1,4

  • Screen and vaccinate sexual and household contacts1,4

  • Vaccinate against hepatitis A1

1. Lok ASF, et al. Hepatology. 2001;34:1225. 2. Chevillotte G, et al. Gastroenterology. 1983;85:141.

3. Villa E, et al. Lancet. 1982;2:1243. 4. CDC. “The Pink Book.” 8th ed, 2005.


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Treatment of Hepatitis B


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Primary Goal of anti-HBV Therapy

Preventing Cirrhosis, HCC, and Death

Durable Suppressionof HBV Replication


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Treatment Goal (Endpoints)

  • Remission of liver disease

  • Suppression of HBV

  • HBeAg positive HBV

    • Seroconversion

  • HBeAg negative HBV

    • Sustained suppression of HBV DNA


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Initial Therapy: What Are the Therapeutic Options and Considerations?

  • First-line therapy

    • Adefovir

    • Entecavir

    • Peginterferon alfa-2a

  • Lamivudine no longer considered first-line therapy due to high rate of resistance, except in specific settings

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006: In press.


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Peginterferon Considerations?

  • Pegylated recombinant interferon alfa protein/immune modulator

  • Subcutaneous injection, but less frequent than standard interferon

  • Dual immunomodulatory and antiviral mode of action

  • Defined, finite treatment interval

  • High rate of HBeAg seroconversion in wild-type infection

  • High rate of HBV DNA suppression in precore mutant variant

  • High rate of HBsAg seroconversion

  • No reports of resistance mutations

  • Significant adverse events

    • Better than or similar to that when used to treat HCV infection


Peginterferon considerations for use l.jpg
Peginterferon Considerations?Considerations for Use

  • HBeAg positive

    • Response in genotype A better than B = C, better than D1,2

    • ALT >80 IU/mL2

    • HBV DNA <108 copies/mL2

    • Compensated liver disease guidelines3-6

    • Monoinfected

    • No psychiatric or medical contraindications

  • HBeAg negative

    • No specific genotype populations that benefit over others7

    • Modest number of patients negative by PCR (20%) long term7

  • Consider PEG IFN before nucleos(t)ide therapy due to defined treatment intervals and high HBeAg seroconversion rates

  • Should not be used in decompensated cirrhosis8

1. Janssen HL, et al. Lancet. 2005;365:123. 2. Lau G, et al. N Engl J Med. 2005;352:2682. 3. Liaw YF, et al. J Gastroenterol Hepatol. 2003;18:239. 4. De Franchis R, et al. J Hepatol. 2003;39:S3. 5. Lok AS, et al. Gastroenterology. 2001;120:1828. 6. Lok ASF, et al. Hepatology. 2004;39:957. 7. Marcellin P, et al. Hepatology. 2005;42:580A.8. PEGASYS® (peginterferon alfa-2a) Product Information. Nutley, NJ: Hoffmann-La Roche Inc.: 2004.


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Lamivudine Considerations?

  • First oral nucleoside approved for treatment of HBV

  • Cytidine nucleoside analog: inhibits 1st-strand DNA synthesis

  • Extensive database and publications

    • Half of patients who are HBeAg positive undergo seroconversion by 5 years1

  • Safety profile excellent except for resistance

  • Risk of resistance is high (70%) at 4 years of therapy2

    • Associated with flares and decompensation

    • No longer a first-choice therapy due to high rate of resistance3

1. Guan R, et al. J Gastroenterol Hepatol. 2001;16(suppl):A60. 2. Lai CL, et al. Clin Infect Dis. 2003;36:687. 3. Keeffe EB, et al. Clin Gatroenterol Hepatol. 2006: In press.


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70% Considerations?

53%

42%

24%

n = 426

n = 74

n = 58

n = 58

Year 3

Year 1

Year 2

Year 4

Lamivudine in CHBIncidence of YMDD Mutants Over Time—Integrated Phase 3 Data

100

80

60

YMDD (%)

40

20

0

Lai C-L, et al. Clin Infect Dis. 2003;36:687.


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Adefovir Considerations?

  • Adenosine nucleotide analog

  • First oral medication and first nucleotide approved by regulatory authorities for the treatment of HBV

  • Inhibits HBV DNA polymerase

  • Oral bioavailability not affected by food

  • No significant drug-drug interactions

  • Rare events of nephrotoxicity (overall risk – low)

  • Effective against lamivudine-resistant mutants

  • Long/indefinite duration

HEPSERA® Product Insert.


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Resistance is 29% at 5 years of use in HBeAg negative patients1

Resistance is more likely if patients are lamivudine resistant and switched to adefovir2

Renal safety

Infrequent (3%) increases in creatinine ≥0.5 mg/dL

Maximum value 1.5 mg/dL

Maximum increase 0.8 mg/dL

Safety of Adefovir Dipivoxil Over 4–5 Years

1. Borroto-Esoda K, et al. J Hepatol. 2006;44(Suppl 2):179.

2. Lee YS, et al. Hepatology. 2006;43:1385.

3. Hadziyannis S, et al. J Hepatol. 2006;44(Suppl 2):283.


Entecavir l.jpg
Entecavir patients

  • Oral deoxyguanine nucleoside analog

  • Inhibits priming of HBV DNA polymerase, reverse transcription of negative DNA strand from pregenomic RNA, and synthesis of positive DNA strand

  • Superior efficacy to lamivudine1-3

  • Comparable safety profiles except fewer ALT flares compared with lamivudine1-3

  • ETV-associated resistancemutations were not observed in nucleoside-naive, HBeAg positive, or negative studies4

  • ETV-associated resistance mutations with rebound were seen in 9% of patients with previous lamivudine resistance during second year of therapy4

ETV = entecavir.

1. Chang TT, et al. Hepatology. 2004;40:193A. 2. Sherman M, et al. Hepatology. 2004;40:664A. 3. Shouval D, et al. Hepatology. 2004;40:728A. 4. Colonno RJ, et al. 56th AASLD. November 11–15, 2005. Poster 962.


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Entecavir Phase 3 Studies patientsHistologic Endpoints–Primary Efficacy Endpoint

Primary analysis: only patients with evaluable baseline biopsy included; missing/inadequate week-48 biopsy counted as failures.

*Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders. ETV = entecavir; LVD = lamivudine.

FDA. Entecavir briefing document. February 10, 2005.


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Entecavir Phase 3 Studies patientsSelected Secondary Efficacy Endpoints

*Treatment for 52 weeks up to 96 weeks for partial responders. †Treatment for 48 weeks for up to 96 weeks for partial responders. ETV = entecavir; LVD = lamivudine.

FDA. Entecavir briefing document. February 10, 2005.


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Current FDA-Approved Nucleoside and Nucleotide Treatment Options(Not Head-to-Head Studies)

Lamivudine Adefovir Entecavir

Resistance ~20% ~3% ~0% Naive;

9% Lam-R

E antigen seroconversion ~17% ~12% ~22%

Flares Moderate Low Low

Viral suppression 4.5–5.5 3.5–5.5 5.2–7 (log reduction)

DNA negativity 32%–78% 21%–51% 69%–91%

Availability of long-term data 5 year 5 year 2 year

AEs Rare Rare Rare

Lam-R = lamivudine resistance

Slide Courtesy of Robert G. Gish, MD.


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Results Following Suppression Optionsof Viral Replication

Virologic ResponseReduction in:

  • HBV DNA

  • cccDNA

Histologic Improvement

Prevention of Death, Cirrhosis, and HCC

  • Biochemical and Liver Synthetic Test Improvement

  • ALT

  • Bilirubin, INR,

  • Albumin

  • SerologicResponse

  • HBeAg loss

  • HBeAg seroconversion

  • HBsAg loss and seroconversion


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Summary Options

  • HBV infection is a worldwide epidemiologic and clinical challenge

  • Screening at-risk individuals identifies those with HBV infection

  • Pretreatment evaluation includes history, physical exam, and additional diagnostic testing

  • Candidates for anti-HBV treatment include patients with active liver disease and high levels of HBV replication

  • Refer HBsAg positive patients for treatment with entecavir, adefovir, or peginterferon


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