HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B Norah Terrault, MD, MPH...

HBV Core Curriculum:Epidemiology, Prevention and Treatment of Hepatitis B

Norah Terrault, MD, MPH

Adjunct Assistant Professor, Medicine/GastroenterologyUniversity of California, San Francisco

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Epidemiology, Prevention, and Treatment of Hepatitis B

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Global Burden of HBV

2 billion current or past infections

300-400 million with chronic HBV disease

– 1.25 million in the US

25%-40% of persons with chronic HBV disease die from cirrhosis or HCC

– Over 300,000 cases/year of HBV-related HCC

– HBV is second most important carcinogen behind tobacco

World Health Organization. Fact sheet. Available at: http://www.who.int. Accessed January 31, 2006. Centers for Disease Control. Fact sheet. Available at: http://www.cdc.gov. Accessed January 31, 2006. Lai CL, et al. Lancet. 2003;362:2089-2094.



Hepatitis B Disease Burden in the United States

Percent ever infected 4.9%

New infections 78,000/year

Highest rate of disease 20-49 year olds

Greatest decline in disease

Children and adolescents

Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2996.



Prevalence of Chronic Hepatitis B

HBsAg Prevalence

> 8% - High 2-8% - Intermediate< 2% - Low

Immigration numbers summed by continent from 1996-2002

~ 2 million Asians

~ 400,000South Americans

~ 350,000 Africans

~ 930, 000 Europeans

Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.



HBV Seroprevalence Among Asian Americans

Guan R, et al. AASLD 2004. Abstract 1269.

5 large US cities (2001-2004)

– Chinese

– Korean

– Vietnamese

Median age

– 43 yrs (12-80)

HBsAg+, overall

– 558/5341 (10.4%)

11%

14%

10%

11%

15%

11%

10.4%

0% 4% 8% 12% 16%

Philadelphia

San Francisco

Boston

Chicago

NY(1)

NY(2)

Overall

Proportion of Individuals HBsAg+



Clinical Consequences of HBV Acquisition Acute Infection

– Major risk of death related to development of fulminant liver failure (rare)

Chronic Infection

– Progressive liver disease

– Risk of cirrhosis, liver failure, hepatocellular carcinoma (HCC)

– Rarely extrahepatic manifestations



Reducing the Burden of Chronic HBV Disease

Prevention of infection

– Vaccination!

Prevention of liver-related complications

– Modify lifestyle: weight control, limit alcohol

– Anti-HBV therapies: interferon, lamivudine, adefovir, entecavir

– HCC surveillance



Incidence of Acute Hepatitis B:United States, 1978-1995

Vaccinelicensed HBsAg screening

of pregnant women

Infantimmunization

Adolescent immunization

80

70

60

50

40

30

20

10

078 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95

Cas

es/1

00,0

00

Safer Injection and Sexual Practices

Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/b/. Accessed February 5, 2006.

Year

http://www.cdc.gov/ncidod/diseases/hepatitis/b/



Hepatitis B Vaccine

Vaccine licensed in 1982– Plasma-derived recombinant vaccine – 3-dose series, high efficacy, no boosters, safe

Since licensing, adolescents and adults at high risk recommended to receive vaccine

Comprehensive strategy to eliminate HBV transmission implemented in 1991– 1991: universal infant vaccination recommended– 1995: expansion to include vaccination of all adolescents

ages 11-12 yrs– 1998: vaccination of all persons age 0-18 yrs not

previously vaccinated



Achievements With HBV Vaccination

Decline in acute HBV in past decade by 67%

– Reflects effects of routine infant and childhood vaccination

– Vaccination rates high in this population but decline to ~ 60% in adolescents

– Slowest rate of decline in adults

– Some adult subgroups showing increase in incidence (men ≥ 19 yrs, women ≥ 40 yrs)

Decline in risk of serious complications of chronic HBV

– Reduced rates of childhood HCC in countries of high endemnicity

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.



Annual Incidence of Liver Cancer in Children Aged 6-15 Years

Age at Diagnosis

Before Program Cohort(1974-1984),

Incidence per 100,000

After Program Cohort (1984-1986),

Incidence per 100,000 6 0.46 0.00

7 0.53 0.15

8 0.48 0.31

9 0.61 0.00

Total 0.52 0.13*

Chang MH, et al. N Engl J Med. 1997;336:1855-1859.

*P < .001 for comparison between birth cohort.Vaccination program in effect since July 1984



Issues Related to HBV Vaccination

Poor or nonresponse to vaccination

– Strategies to maximize likelihood of response

Durability of vaccine response

– Need for booster vaccinations?

Missed opportunities for vaccination

– Especially among adults at risk

– During 1983-2000: ~ 110,000 adults acquired chronic HBV infection due to lack of adult hepatitis B immunization

Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.



Factors Associated with Reduced Vaccine ResponsesPatient-Related

Older age (> 50 years)

Male gender

Smoking

Obesity

Immune deficiency

– HIV

– Transplant recipients

– Dialysis

Compliance

Vaccine-Related

Schedule (accelerated vs 0, 1, 2, 6 months)

Double vs single dose

Use of “adjuvants”

– GCSF, levamisole

IM versus ID



HBV Vaccination Durability of Response Durable immunity 15-18 years

– 84% of Alaskan natives at 15 years[1]

– 85% of MSM (some HIV+) at 7 years[2]

– > 50% of Chinese children at 15 years[3]

Immunity preserved in anti-HBs-negative persons

– Amnestic response with booster dose

– Preserved T cell responses in PBMCs in vitro1. McMahon BJ, et al. Ann Intern Med. 2005;142:333-341. 2. Hadler SC, et al. N Engl J Med. 1986;315:209-214. 3. Ni YH, et al. Ann Intern Med. 2001;135:796-800.



HBV Vaccination: Durability of Response

Predictors of decline in anti-HBs titers over 15 yrs

– Low initial antibody response

– Female gender

– Younger age (0-4 yrs greatest decline)

Vaccines With Specific Anti-HBs Titers

McMahon B, et al. Ann Intern Med. 2005;143:333-341.

0

10

20

30

40

< 2IU/L ≥ 2 IU/L ≥ 10 IU/L ≥ 100 IU/L

1618

38

28

Per

cen

tag

e o

f P

atie

nts



Hepatitis B Vaccination in Adults:Missed Opportunities Of all individuals with reported acute hepatitis B

infection

– 56% have been treated for an STD and/or were incarcerated prior to their illness

– 89% are IDUs

– 35% are MSM

– 70% are persons with multiple sexual partners

Overlapping risks: IDU and sexual activities

Goldstein ST, et.al. JID. 2002;185:713-719. Khan A, et al. Antiviral Therapy. 2000:5(suppl 1):21.



Prevention of HBV InfectionSummary Vaccine is highly effective – HBV incidence is declining

– Infants and children vaccination rates high

– In countries endemic for HBV, infant vaccination has reduced rates of liver complications

Missed opportunities among adults

– If sexually active, IDU at risk

HBV-related HCC is vaccine-preventable cancer



Outcomes of Acute HBV Infection

Recover

Subclinical Hepatitis

Fulminant Hepatitis

Acute Hepatitis

ACUTE INFECTION

Chronic InfectionDEATH

< 1% 0.1-2.7%

5-20%

Risk is Related to Age at Infection

Outcome Neonates, % Children, % Adults, %

Chronic carrier 90 20 < 5

Recover 10 80 > 95

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.



Clinical-Epidemiologic Correlations

HBV Endemicity Location Age of Infection

Mode of Transmission Chronicity HCC Risk

High 10-15% AsiaSub-Sahara Africa

BirthToddler

PerinatalHorizontal Likely High

Low < 2%N. AmericaW. Europe

Scandinavia

EarlyAdulthood

PercutaneousSexual Rare Low

Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.

http://www.who.int/mediacentre/factsheets/fs204/en/



Natural History of Chronic HBV Infection

0 10 20 30 40 50 60 70

Years

SerologyHBeAg Anti-HBe

ALT level

HBV DNA level

(viremia)

DiseaseChronic active

hepatitisCirrhosis/HCC

Immune tolerant (phase I)

Immune Active (phase II)

Non-Replicative (phase III)

Chronicity Stage

Minimal inflammation

Resolved

Normal to cirrhosis/HCC

HBsAg Anti-HBs



Possible Outcomes of HBeAg+ Chronic HBV Infection

24% HBeAg-negative CHB

with detectable HBV DNA

5% Undetermined causes

67% Sustained remission

Spontaneous seroconversion

(n = 283)

33% ALT elevation

(> 2 x ULN)

4% HBeAg reversion

Hsu YS, et al. Hepatology. 2002;35:1522-1527.



Possible Outcomes of HBeAg+ Chronic HBV Infection

Patient Populations in Chronic Hepatitis B

Marker ImmuneTolerant HBeAg+ CHB Inactive HBsAg

CarrierHBeAg– CHB

(Precore Mutant)

HBsAg + + + +

HBeAg + + – –

Anti-HBe – – + +

ALT Normal Normal

HBV DNA (copies/mL) > 105 > 105 < 103 > 104

Histology Normal/Mild Active Normal Active

Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853.



Natural Clearance of HBsAg

Occurs in ~ 0.5% of HBsAg carriers/year

Duration of infection is primary determinant of HBsAg loss

~ 50% of carriers who clear HBsAg have HBV DNA present in sera in low titer (1–2 logs)

McMahon BJ, et al. Ann Intern Med. 2001;135:759-768.



Annual Risk of HBV Progression

HBeAg+ chronic hepatitis B

HBeAg-Neg chronic hepatitis B

Cirrhosis

Decompensation HCC

5.0%

1.0%-2.0%

3.0% 2.0%

All HBsAg +individuals

0.4%

Factors linked with progression

– Duration of “active”disease– Heavy alcohol use– Immune suppression (HIV)

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25.



Initial Evaluation of HBsAg+ Patient

History and PE

Assess risk factors (coinfection)

Alcohol use

Family history of HBV and HCC

Physical findings of cirrhosis

Lok AS, et al. Hepatology 2001;34:1225-1241.Tsai NC. Sem Liver Dis. 2004;24(suppl 1):71-76.

Investigations

Liver disease activity

Serologic and virologic markers

Screening for HCC (AFP and ultrasound)



Categorization of Disease

HBeAg positive or negative

Replication high or low (HBV DNA)

ALT elevated or normal

Liver histology



Role of Baseline Liver Biopsy

Confirm diagnosis of chronic hepatitis B

Establish baseline severity

– Grade: severity of necroinflammation

– Stage: amount of fibrosis

Clarify diagnosis when ALT and HBV DNA levels are discordant

Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease)

Guide decision regarding initiation of treatment

Ferrell L, et al. in McSween, et al, editors. Pathology of the liver, 4th ed. London:Churchill Livingstone; 2002:313-362. Buckley A ,et al. Can J Gastroenterol 2000;14:481-82. Park A , et al. Minerva Gastroenterol Dietol. 2004;50:289-303.



Indications for Treatment ofChronic HBV

Patients with active liver disease:

– Abnormal liver function tests (AST, ALT)

– HBeAg positive and > 105 HBV DNA

– HBeAg negative and > 104 HBV DNA

– Biopsy if HBV DNA < 104 with ALT

– Treat if active hepatitis (biochemical or histologic)

Lok AS, et al. Hepatology. 2001;34:1225-1241.



2 Distinct Patient Populations With Chronic HBV

HBeAg+ (wild-type), HBV DNA+

– HBeAg loss

– Seroconversion to anti-HBe

– Durability of response ~ 80%

HBeAg-/anti-HBe+/HBV DNA+ (precore mutant)

– HBeAg seroconversion not an endpoint

– Long-term therapy the rule



Endpoints of Treatment

Sustained suppression of HBV DNA replication

HBeAg seroconversion

Improvement in liver histology

Reduced rates of liver complications



Histologic Improvement in Cirrhosis: 3 Years of Lamivudine Therapy

Pre-Rx Post-Rx

Wild-Type HBV



Pat

ien

ts,

%

Placebo (n = 215)

Lamivudine (n = 436)

Liaw et al. N Engl J Med. 2004;351:1521-1531.

All P values ≤ .05

18%

9%7%8%

3% 4%

0

10

20

30

Overall DiseaseProgression

CPT Increase

HCC

Long-Term Benefit of Lamivudine in Compensated Cirrhosis



Screening for Liver Cancer:Lack of ConsensusAt what age should HCC screening be initiated?

1) Among HBV-infected individuals, HCC can occur at any age, including childhood

2) Optimal age for initiation of screening unknown1

3) Patients ≥ 35 yrs are at much higher risk for HCC than those

< 35 years2

1. Lok AS, and McMahon BJ. Hepatology. 2001; 34:1225-1241.2. Liaw YF, et al. Gastroenterology. 1986;90:263-267.



Screening for Liver Cancer: Alpha-fetoprotein (AFP)

Up to 1/3 of patients with HCC have normal AFP

AFP may be elevated in 1/3 of patients with cirrhosis without HCC

Very high level of AFP (> 1000 ng/mL) diagnostic of HCC, with few exceptions

Persistently rising AFP levels highly suggestive of HCC but not often seen



Screening for Liver Cancer:Patients With Chronic HBV Cancer screening strategies:

High Risk- AFP + U/S every 6 months

– Cirrhosis

– Family history HCC

Medium Risk- AFP + U/S every year

– Age ≥ 30-40

– Active disease (ALT)

If rising AFP or high AFP > 20 ng/mL, spiral CT or MRI at least once



Chronic HBV Infection:Recent Advances

4 antiviral drugs now available

Longer term benefits of treatment known

Resistance emerging as issue with oral antivirals

Combination therapy under study

Several new nucleos/tides in development

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HBV Core Curriculum: Epidemiology, Prevention and Treatment of Hepatitis B Norah Terrault, MD, MPH...

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