Viral Hep 2007

Viral Hepatitis Medicine Student Lecture

David R Nelson, M.D. Associate Professor of Medicine Director, Hepatology and Liver Transplantation University of Florida

Case 1: 29 y/o female came to your clinic with: • Jaundice, Abdominal pain, Nausea / Vomiting • AST-2,000 ALT- 2,500, Total bili 1.8 • She denies IVDA or any recent drug/medicine exposure, but had unprotected sex about 6 weeks ago • Ultrasound shows normal appearing liver and blood flow • Her diagnosis is……

Causes of Acute Hepatitis Acute Hepatitis

Viral Hepatitis

Drugs

A, B/D, C, E EBV CMV & HSV

Ethanol Tylenol Halothane

Toxins

Vascular

Jamaica Bush Tea Mushrooms

Hypotension Budd-Chiari

Autoimmune Hepatitis

Metabolic Wilson's Disease A1AT

Case: • 38 y/o male with past medical history of abnormal ALT for past 4 years. He had a blood tx as a child due to MVA. Patient came to your clinic with: – ALT 150, AST 100 – HBsAb +, HBcAb + – HCV Ab + – HAV IgG + • What is your dx?

Causes of Chronic Hepatitis Chronic Hepatitis

Viral Hepatitis Hep B Hep C

Drugs MTX INH Amiodarone

Alcohol

NAFLD

Autoimmune AIH PBC PSC

Metabolic A1AT HHC Wilson's

Abbreviations: NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosis PSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis

Acute Viral Hepatitis by Type, USA: 1982-1993

34% 47%

16% 3%

Source: CDC Sentinel Counties Study on Viral Hepatitis

Hepatitis A Hepatitis B Hepatitis C Hepatitis Non-ABC

Hepatitis A Virus • Transmission route: fecal-oral 27 nm

Nucleic Acid: 7.5 kb ssRNA

• Clinical presentation - Jaundice: Adults- 30%, Children- <5% - Fulminant: <1% • Diagnostic tests - Acute infection: IgM anti-HAV - Chronic infection: Not applicable • Immunity: IgG anti-HAV • Case-fatality rate: 0.1 – 2.7% • Chronic infection: None

Global Prevalence of Hepatitis A Infection

HAV Prevalence High Intermediate Low Very Low

Hepatitis A Virus Infection Typical Serologic Course

Symptoms

Total anti-HAV

Titer

ALT

Fecal HAV

0

1

IgM anti-HAV

2

3

4

5

6

Months after Exposure

12

24

Hepatitis A Prevention - Immune Globulin Preexposure • Travelers to high HAV-prevalence regions Postexposure (within 14 days) • Routine • Household and other intimate contacts • Selected situations • Institutions (e.g. daycare centers) • Common source exposure (e.g. food prepared by infected food handler)

Hepatitis A: Pre-exposure Vaccination Persons at increased risk or danger of infection • Travelers to intermediate and high HAV prevalence areas • Men having sex with men • Injecting drug users • Persons with chronic liver disease Communities with high rates of hepatitis A (e.g., Alaskan Natives, Native-Americans) Routine pre-school childhood vaccination

ACIP Recommendations MMWR 1999; 48(RR12):1

Hepatitis E Virus

32 nm

Nucleic Acid: 7.5 kb ssRNA

• Fecal-oral transmission (human to human) • Contaminated water supplies in tropical or subtropical developing countries • Mainly young adults • Can infect primates, swine, sheep, rats • Swine may be reservoir of infection in North America • Maternal-infant transmission occurs and is often fatal

Hepatitis E

Clinical Characteristics • Similar to hepatitis A • Dx: IgG anti-HEV (seroconversion) • Can cause severe acute hepatitis • Subclinical infection is common • Attenuated virus from animal reservoirs • Low-dose infections often asymptomatic • No chronic infection • Up to 20% mortality among pregnant women (esp. third trimester)

Hepatitis B Virus HBsAg

42 nm

HBcAg

HBV DNA

• Hepadnaviridae member that primarily infects liver cells • 50 to 100 times more infective than HIV • Multiple genotypes exist (A-H) • DNA virus found in blood and body fluids – Able to survive in dried blood for longer than 1 week

> 350 million carriers (HBsAg + > 6 months)

Geographic Distribution of Chronic HBV Infection

10th cause of death (1 million / year)

Cirrhosis in 20% (75 - 100 million)

HCC in 5 - 10% (20 - 40 million)

HBsAg Prevalence ≥8% - High 2-7% - Intermediate <2% - Low

Hepatitis B Prevalence • Overall U.S. prevalence: 0.3% • Asian Americans: ~10-13% Laotians Vietnamese Korean Japanese Filipino Chinese 0%

Son D, Asian Am Pac Isl J Health 2001 Slide courtesy of Robert Gish, MD

2%

4%

6%

8%

10%

12%

14%

HBV Sources of Infection Household, 3% MSM, 23% Other, 23% Sex contact, 23%

Multiple sex partners, 24%

IDU, 20%

Many patients do not reveal IDU as source of infection Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology & Prevention of Vaccine-Preventable Diseases. 8th ed Washington DC: Public Health Foundation; 2005:191-212.

Signs and Symptoms of Acute Hepatitis B • About 30% of persons have no signs or symptoms • If symptoms are present, generally nonspecific including: • • • •

Jaundice Fatigue Abdominal Pain Loss of Appetite

• • • •

Nausea, vomiting Joint pain Dark Urine Clay-colored bowel movements

Hepatitis B - Clinical Features Incubation period

Average: 60 – 90 days Range: 45 – 180 days

Clinical illness (jaundice)

< 5 yrs of age: <10% ≥ 5 yrs of age: 30 – 50%

Acute case-fatality rate

0.5 – 1%

Chronic infection

< 5 yrs of age: 30 – 90% ≥ 5 yrs of age: 2 – 10%

Mortality from chronic liver disease

15 – 25%

Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course Acute (6 months)

Chronic (Years) HBeAg

anti-HBe HBsAg Total anti-HBc

Titer

HBV DNA

IgM anti-HBc

0

4

8 12 16 20 24 28 32 36

52

Weeks after Exposure

Years

Interpretation of Serologic Markers Acute hepatitis B HBsAg

 (may clear)

Anti-HBs

Chronic HBeAg + disease

Chronic HBeAG – disease







Anti-HBc IgM



Anti-HBc



HBeAg





 (may be only marker during window period)

Successful Vaccination

Resistance to antiviral agents







  (in some cases)

Anti-HBe

DNA (PCR if required)

Recovery from acute hepatitis B







 (sequence pol region)

Hepatitis B: Disease Progression Liver Cancer (HCC) 5%-10% 1 2-6% Acute Infection

Chronic Infection

90% in perinatal 30-90% in children<5yrs old 5% in healthy adults Higher in HIV, immune suppressed

Cirrhosis 10-30% 1

Liver Failure (Decompensation) 23% within 5 years

1. 2. 3. 4.

Torresi J et al. Gastroenterology. 2000. Fattovich G et al. Hepatology. 1995. Moyer LA et al. Am J Prev Med. 1994. Perrillo R et al. Hepatology. 2001.

Liver Transplantation

Death

Chronic HBV is the 6th leading cause of liver transplantation in the US4

Targeted Surveillance for HCC Hepatitis B Carriers • • • • • •

Asian males > age 40 Asian females > age 50 All cirrhotic HBV carriers Family history of HCC Africans > age 20 High HBV DNA



Non-hepatitis B Cirrhosis • • • • •

Hepatitis C Alcoholic cirrhosis Genetic hemochromatosis Primary biliary cirrhosis Other (? efficacy) • A1AT deficiency • NAFLD • Autoimmune hepatitis

Surveillance for HCC should be with ultrasound at 6 to 12 month intervals; AFP is not adequate

Bruix J and Sherman M. Hepatology 2005;42:1208

Prevention of Transmission of Hepatitis B Vaccination 1. Vaccinate Sexual and household contacts 2. Newborns of HBV-infected mothers • HBIG and • hepatitis B vaccine at delivery 3. Test for response to vaccination • infants of HBsAg-positive mothers (9 to 15 months ) • health care workers, • dialysis patients, and 1-2 months • sexual partners 4. Follow-up testing of vaccine responders • Annually for chronic hemodialysis patients

Goals of Treatment in HBV • Reduce the risk of disease progression • Reduce the risk of hepatocellular carcinoma • Loss of HBeAg, HBeAg  HBeAb • Undetectable HBV-DNA • (<105 copies/ml = 20,000IU/mL) • Normalization of ALT • Histologic Response • HBsAg  HBsAb

Virologic Response

Approved Treatments

Lok AND McMahon. .Hepatology, Vol. 45, No. 2, 2007

Hepatitis D Virus: Morphology and Characteristics • Nucleic Acid: 1.7 kb ssRNA • Classification: unclassified, related to viroids; deltavirus • Transmission: sex, IVDA

35-37nm

• Clinical features - Fulminant: 2 – 7.5% - Chronic infection Superinfection: 80% Coinfection: < 5% • Diagnostic tests -Acute infection: IgM anti-HDV -Chronic infection:IgG anti-HDV, HBsAg +

Modes of HDV infection

Coinfection

B

D Superinfection

B D

HCV Life-Cycle and Pathogenesis

Cell Binding and Infection

Immune Recognition

Replication

HCV

Immune Response

Effector

CD4 CD8 NK DC

Cytokines HSC Viral Packaging and Release

Fibrosis

Course of Acute HCV Infection HCV RNA positive Anti-HCV Symptoms

1000

ALT (IU/L)

800 600 400 200

Normal ALT

0

0

2

4

6 8 10 12 24 1 2 3 4 5 Weeks Months Time After Exposure

Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis. 2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.

6

7

Symptoms, or Lack of, in Chronic HCV Infection Symptomatic 37% Patients (%)

Cirrhosis 7%

100 80 60 40 20 0

56% Asymptomatic

80

Fatigue

Patients* With HCV infection (%)

ALT Elevations Are Not Indicative of Chronic HCV Infection 100 80 60 42

43

40 15

20 0 Persistently Normal ALT

Inglesby TV, et al. Hepatology. 1999;29:590-596.

Intermittently Elevated ALT

Persistently Elevated ALT

Diagnostic Tests for HCV Infection Specifications Mode of detection Sensitivity Specificity Detection postexposure Use

Diagnostic Test Type Serologic Virologic Antibodies Virus > 95% > 98% Variable > 98% 2-6 mos 2-6 wks Screening Confirmation

CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.

Molecular Virologic Assays Qualitative assays

Quantitative assays

High sensitivity (≤ 50 IU/mL)

Detection cutoff > qualitative

How much HCV is present? Is HCV present?

Genotype assays

What type of HCV is present?

Clinical Significance of HCV Genotypes • Great genetic diversity: 2 genotypes (1 through 6) • Multiple subtypes: a, b, c, etc • Genotype is best pretreatment predictor of response • Genotype 1: least responsive to therapy • Determines dose and duration of therapy • Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200 mg • Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg • All patients should have genotype determined prior to initiating therapy Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355.

Prevalence of HCV Dependant on Risk Factors • • • • • • • •

Hemophilia IVDA Prison HIV Blood transfusion prior to 90 Infants to HCV+ Mothers Sexual Partner General Population

Adapted from MMWR.1998;47:5.

74-90% 72-89% 40% 30-40% 5-9% 5% 0.5-3% 1.8%

Prevalence of HCV Infection: United States 7

Mexican American 3.5%

Anti-HCV+ (%)

6

African American 3.2%

5 4 3

Caucasian 1.1%

2 1 0

6–11

12–19

20–29

40–49 30–39 Age (yr)

Alter et al. N Engl J Med. 1999;341:556-562.

50–59

60–69

70+

HCV: Disease Progression Time: 20-30 years

HCV infection 60-85%1

Chronic HCV

Cirrhosis 20%-50%2

Hepatic Failure ~ 20%3

~20%4

Liver Cancer 1. NIH Consensus Development Conference Statement; March 24-26, 1997. 2. Davis GL et al. Gastroenterol Clin North Am. 1994;23:603-613. 3. Koretz RL et al. Ann Intern Med. 1993;119:110-115. 4. Takahashi M et al. Am J Gastroenterol. 1993;88:240-243.

Liver Transplant Candidates

Histologic Progression of HCV Monitored by Liver Biopsy Inflammation Grade • Measure of severity and ongoing disease activity • 0-4 (METAVIR) • Inflammation leads to scarring/fibrosis

No fibrosis

Fibrosis Stage • Amount of fibrous scar tissue • 0-4 (METAVIR) • Stage 4 = cirrhosis • Indicates long-term disease progression

Brunt EM. Hepatology. 2000;31:241-246.

Cirrhosis

Common Schedule and Type of HCV Testing

Decision to Treat

Identification Identification and Planning and Planning

Treatment

Stage

Diagnosis

Prognosis

Treatment Duration

Assess Response and Resistance

• Liver biopsy

• Genotyping • Quant HCV RNA

• Quant HCV RNA

Assay

• Serological • Qual HCV RNA

Improvements in Therapy of HCV

Sustained Virologic Response (%)

100

1991

1998

2001

2002

80 54-56%

60 42% 40

34%

39%

16%

20 6% 0 IFN 6m Strader DB et al. Hepatology 2004;39:1147-1171

IFN 12m

IFN/RBV 6m

IFN/RBV 12m

Peg-IFN 12m

Peg-IFN/ RBV 12m

Current standard treatment duration is 48 or 24 weeks according to genotype HCV genotyping HCV-1 (4,5,6) Quantitative HCV RNA

HCV-2,3

Peg-IFN+ RBV 1000/1200 mg/day

Peg-IFN + RBV 800 mg/day for 24 weeks

Quantitative HCV RNA at week 12

<2 log decline

Stop or re-evaluate therapy

≥ 2 log decline or HCV RNA (–)

48 weeks

The Burden of Liver Disease Associated with HCV is Increasing An estimated 5 million Americans have been infected with HCV, of whom 4 million are chronically infected Approximately 30,000 people in the US are infected with hepatitis C each year Hepatitis C is the leading causes of liver disease and cirrhosis in US 12,000 - 15,000 people die of hepatitis C each year in the US The CDC estimate that the number of annual deaths from hepatitis C will triple in the next 10 - 20 years The estimated medical and work loss costs per year of hepatitis C is over $600 million

Source: American Liver Foundation