Viral Hepatitis

Dr Melissa HainesGastroenterologist

Waikato Hospital

Viral Hepatitis

HAV HBV HCV HDV HEV Other viral: CMV, EBV, HSV Unknown

Hepatitis AHepatitis A

Hepatitis A

Transmitted via the faecal-oral route Faecally contaminated food or water

Worldwide distribution

Most common cause of viral hepatitis

Causes acute infection only Asymptomatic fulminant hepatitis

Hepatitis A Diagnosis

Prodromal symptoms Jaundice Abdominal tenderness and liver enlargement ALT elevated HAV IgM antibody positive

Symptoms resolve in majority after 2 months

Prevention Public and personal health measures Vaccination

Hepatitis BHepatitis B

Hepatitis B virus (HBV) is one of the world’s most common infectious agents

Serious global public health problem

One third of world’s population (~2 billion) have been infected with HBV

Estimated 350 million people (~5% of world’s population) have chronic HBV infection

25-40% (75-160 million) die of cirrhosis or liver cancer

WHO 2003

Global Importance of Hepatitis B Virus

Worldwide Prevalence of HBV and Incidence of HCC

World prevalence of HBV carriers

HBsAg carriers-prevalence<2%2–7%>8%Poorly documented

Annual incidence of primary HCC

Cases/100,000 population1–33–1010–150Poorly documented

WHO 2003

Impact of HBV in NZ

Asia-Pacific

Maori, 625000

Pacific295000

Asian, 395,000

European2.7million

1.2millio

n

1.2millio

n

Estimated 90,000 HBsAg+living in New Zealand in 2006

http://www.stats.govt.nz/products-and-services/Articles/pop-proj-Jun04.htm

National HBV Screening Programme

7.7%5.8% 6.2%6.5% 1%

45%

9%

59%59%54%

0%

25%

50%

75%

100%

Overall Maori Pacifican Asian European

HBV

Stat

us

HBsAg(-)/anti-HBs(-)= HBV naïve

anti-HBs(+) = immune to HBV

HBsAg+ = chronic HBV

177,292 Screened 177,292 Screened (July 1999 (July 1999 -- July 2002)July 2002) 11,300 HBsAg+ identified11,300 HBsAg+ identified

EndEnd--Stage Liver Disease in New ZealandStage Liver Disease in New ZealandLiverLiver--Related MortalityRelated Mortality

HCV30%

HBV5%

other15%

HCV5%

HBV50%

other5%

USAUSA25,000 deaths per annum25,000 deaths per annum

New ZealandNew Zealand300 deaths per annum300 deaths per annum

Alcohol 50%

Alcohol 40%

Alcohol31%

Other4%

HBV63%

HCV8%

LiverLiver--related Mortalityrelated Mortality19991999

Weir,2002Weir,2002

HCV26%

Alcohol8%

Biliary12%

Acute6%

HBV30%

Liver TransplantLiver Transplant19981998--20062006

(n=290)(n=290)

NZLTU,2006NZLTU,2006

Alcohol7% Other

9%

HBV75%

HCV9%

Hepatoma Clinic Hepatoma Clinic 20002000--20062006

(n=544)(n=544)

Gane,2006Gane,2006

Impact of HBV Infection

9090--100 cases 100 cases per annumper annum

15 cases per 15 cases per annumannum

200+ cases 200+ cases per annumper annum

Transfusion and transplant recipients

Sexual partners of known chronic

carrier

Healthcareworkers

Newborns of long- term carriers

Intravenousdrug users

Prisoners and other institutionalised people

Transmission of Hepatitis B Infection

Outcomes of Acute HBV Infection

Recover

Subclinical Hepatitis

Fulminant Hepatitis

Acute Hepatitis

ACUTE INFECTION

Chronic InfectionDEATH

< 1% 0.1-2.7%

5-20%

> 958010Recover< 52090Chronic carrier

Adults, %Children, %Neonates, %OutcomeRisk is Related to Age at Infection

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

They are all healthy carriers!

Chronic hepatitis B has serious long-term consequences

HBsAg-positiveChronic Hepatitis B

Cirrhosis

Liver Failure

DeathHepatocellularcarcinoma (HCC)

Lok et al 2002

30%

Natural History of Chronic HBV Infection

0 10 20 30 40 50 60 70Years

SerologyHBeAg Anti-HBe

ALT level

HBV DNA level

(viremia)

Disease Chronic activehepatitis

Cirrhosis/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

Initial Evaluation of HBV Carriers (HBsAg+)

History and examination 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 Liver fibrosis/cirrhosis INR, albumin, bilirubin

Serologic and virologic markers

Screening for HCC (AFP and ultrasound)

Is HBV Serology Confusing??

HBV Serology

sAg determines carrier status eAg determines replication and infectivity

cAb confirms natural infection sAb confirms immunity

HBV DNA (viral load) measures infectivity and replication

7 Taiwanese townships Individuals aged 30–65 years eligible

(n = 89,293)

Baseline HBV DNA(n = 3851)

Baseline HBsAg+(n=9800)

1991-1992: recruitment

June 2004: 43,993 PYs follow-up

Follow-up analysisFor Cirrhosis/HCC

(n = 3774)

Chen CJ ,Chen CJ , JAMA JAMA 20062006

Risk Evaluation of Viremia Elevation & Associated Liver Disease prospective, multicenter, observational cohort study (REVEAL)

Viral Load predicts Disease Progression

Iloeje UH et al. Gastroenterology 2006; 130: 678–86.

Higher viral loads are associated with increased rate of cirrhosis

≥106cpm

Year of follow-up

Cum

ulat

ive

inci

denc

eof

live

r cirr

hosi

s

36.2%36.2%

4.5%4.5%

RR=9.6RR=9.6

0

.01

.02

.04

.03

0 21 3 4 5 6 7 8 9 10 11 12 13

105-106cpm

<300 cpm

104-105cpm300-104cpm

>10>1066cpmcpm

101055--101066cpm cpm

101044--101055cpm cpm 300300--101044cpm cpm < 300cpm < 300cpm

Higher viral loads are associated with increased rate of hepatoma

1515%%

1.3%1.3%

RR=11RR=11

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11 12 13Year of follow-up

Cum

ulat

ive

inci

denc

e of

HC

C %

Year of follow-up

Yang et al. J Hepatol 2005: 42(suppl 2); 195.

Cum

ulat

ive ra

te o

f live

r fail

ure

≥105 cpm

104-105 cpm<104 cpm

00

21 3 4 5 6 7 8 9 10 11 12

5%

10%

15%

20%

25%

30%

Higher viral loads associated with increased rate of liver failure

1.00

0.96

0.92

0.88

0.84

0.800 1 2 3 4 5 6 7 8 9 10 11 12

Cum

ulat

iev

Surv

ival

Survival Time (Years)

HBV DNA 3-5 logsRR=1.5 (0.2–11.8)

HBV DNA (-)

HBV DNA >5 logsRR=15.2 (2.1–110)

Higher viral loads associated with increased liver-related mortality

Chen G et al., Am J Gastro, 2006

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.

Viral suppression Reduction or loss of serum HBV DNA

Immune system activation Development of antibodies against HBV

Reduction/cessation of liver injury Normalisation of liver function Improvement in liver histology

Prevention of complications Cirrhosis, liver failure, hepatoma

Improve survival

Objectives of TreatmentObjectives of Treatment

Anti-viral agents Lamivudine Adefovir dipivoxil*

Immunomodulators Interferon-

Current approaches to treatment of Current approaches to treatment of chronic hepatitis Bchronic hepatitis B

Drug typesDrug types Continuous long term

Finite course

Undefined: dependant on response

Treatment durationTreatment duration

Vaccination for Hepatitis B

Reducing the Burden of Chronic HBV

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

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

0.000.6190.13*0.52Total

0.310.4880.150.537

After Program Cohort

(1984-1986),Incidence per

100,000

Before Program Cohort

(1974-1984),Incidence per

100,000

Age at Diagnosis

0.000.466

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

Babies who end up as carriers have a 1 out of 4 chance of dying from liver problems.

Up to 9 out of 10 babies born to infected mothers will end up being carriers for the rest of their lives, if they do not get the shots.

19 out of 20 babies who get the shots will be protected for life!

Infants who do not receive vaccination

6 months oldHepatitis B

Vaccine

Baby Shots for Hepatitis Bif the mother has Hepatitis B

1 - 2 months old

Hepatitis BVaccine

+Birth

H-BIGHepatitis B

Vaccine

Infants who receive all 3 shots, plus H-BIG, have a 95% chance of being cured from hepatitis B for life.

If you have never had hepatitis B,you can get 3 shots . . .

. . . and get long lasting protection.

321

Hepatitis B can be prevented!

• Since hepatitis B virus can be passed to them, they should be tested to see if they have this virus in their bodies.

• If they do not have the hepatitis B virus, they should get the shots to protect themselves.

Should relatives/partners be tested for HBV?

Issues Related to HBV Vaccination

• Poor or non-response 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

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

Hepatitis CHepatitis C

25,000 New Zealanders have HCV infection Most are young, ex-IDU 9% are cirrhotic at presentation referrals to Hepatitis Clinics

detectionawareness of risk factors

demand for treatmentmore effective therapies

HBV still main cause of end-stage liver disease in NZ BUT HCV-ESLD over next decade

HCV infection

Intravenous drug use

74%

Blood products

13%

HCV+ partner2%

Tattoo1%

Other2%

None8%

Risk factors for HCV exposure

Natural History of Hepatitis C

Acute HCV infection

70-80% chronic HCV 20-30% spontaneous clearance

Chronic hepatitis:Minimal-severe

inflammation & fibrosisBridging fibrosis

Hepatocellularcarcinoma

Cirrhosis develops in 10-15% over 20-30yrs

Liver transplantation

Liver Failure Death

Management Diagnosis HCV IgG antibody positive HCV RNA positive

Determine genotype 1 & 4 ‘hard to treat’: 12 months, 55% cure rate 2 & 3 ‘easy to treat’: 6 months, 80% cure rate

Treatment Pegylated interferon +ribavirin

Conclusion

HBV and HCV are New Zealand problems

Refer patients Surveillance for HCC is necessary

Treatment is available Prevents disease progression

HBV vaccine is highly effective Reduces incidence HBV Reduces rates of liver complications