Hepatitis A-E Viruses Enock Anassi MD, PharmD

Viral Hepatitis - Historical Perspectives Enterically transmitted “Infectious” A E Viral hepatitis NANB Parenterally transmitted “Serum” B D C F, G, TTV ? other 2

Type of Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces virus blood-derived blood-derived blood-derived body fluids body fluids body fluids Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral transmission permucosal permucosal permucosal Chronic no yes yes yes no infection Prevention pre/post- pre/post- blood donor pre/post- ensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification 3

Hepatitis A Virus 6

HEPATITIS A: signs and symptoms Nausea and vomiting, anorexia, jaundice Self limited No chronic disease Stool excretion 2 weeks before and 1 week after appearance

Hepatitis A - Clinical Features Incubation period: Average 30 days Range 15-50 days Jaundice by <6 yrs, <10% age group: 6-14 yrs, 40%-50% >14 yrs, 70%-80% Complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis Chronic sequelae: None 7

Hepatitis A Infection Typical Serological Course Total anti-HAV Titre Symptoms Titre ALT Fecal HAV IgM anti-HAV 1 2 3 4 5 6 12 24 Months after exposure 9

Hepatitis A Virus Transmission Close personal contact (e.g., household contact, sex contact, child day care centers) Contaminated food, water (e.g., infected food handlers, raw shellfish) Blood exposure (rare) (e.g., injecting drug use, transfusion) 11

Global Patterns of Hepatitis A Virus Transmission Disease Peak Age Endemicity Rate of Infection Transmission Patterns High Low to Early Person to person; High childhood outbreaks uncommon Moderate High Late Person to person; childhood/ food and waterborne young adults outbreaks Low Low Young adults Person to person; food and waterborne outbreaks Very low Very low Adults Travelers; outbreaks uncommon 15

Laboratory Diagnosis Acute infection is diagnosed by the detection of HAV-IgM in serum by EIA. Past Infection i.e. immunity is determined by the detection of HAV-IgG by EIA.

Hepatitis A Vaccination Strategies Epidemiologic Considerations Many cases occur in community-wide outbreaks no risk factor identified for most cases highest attack rates in 5-14 year olds children serve as reservoir of infection Persons at increased risk of infection travelers homosexual men injecting drug users 18

Hepatitis A Prevention - Immune Globulin Pre-exposure travelers to intermediate and high HAV-endemic regions Post-exposure (within 14 days) Routine household and other intimate contacts Selected situations institutions (e.g., day care centers) common source exposure (e.g., food prepared by infected food handler) 27

VIRAL HEPATITIS HEPATITIS B

Hepatitis B Virus 28

Hepatitis B - Clinical Features Incubation period: Average 60-90 days Range 45-180 days Clinical illness (jaundice): <5 yrs, <10% 5 yrs, 30%-50% Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90% immunocompetent 5 yrs, 1%-5% Premature mortality from chronic liver disease: 15%-25% 29

Spectrum of Chronic Hepatitis B Diseases 1Chronic Persistent Hepatitis - asymptomatic 2. Chronic Active Hepatitis - symptomatic exacerbations of hepatitis 3. Cirrhosis of Liver 4. Hepatocellular Carcinoma

Hepatitis B ACUTE CHRONIC- 5-10% <6 months (infection >6months) Every year 1 to 2 million people die due to an infection by this virus complications of chronic hepatitis

Endemicity

Global Patterns of Chronic HBV Infection High (>8%): 45% of global population lifetime risk of infection >60% early childhood infections common Intermediate (2%-7%): 43% of global population lifetime risk of infection 20%-60% infections occur in all age groups Low (<2%): 12% of global population lifetime risk of infection <20% most infections occur in adult risk groups 35

Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course Symptoms HBeAg anti-HBe Total anti-HBc Titre anti-HBs HBsAg IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure 30

Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course Acute (< 6 months) Chronic (>6 months) HBeAg anti-HBe HBsAg Total anti-HBc Titre IgM anti-HBc 4 8 12 16 20 24 28 32 36 52 Years Weeks after Exposure 31

Outcome of Hepatitis B Virus Infection by Age at Infection 100 100 80 Chronic Infection (%) 80 60 60 Chronic Infection Symptomatic Infection (%) 40 Chronic Infection (%) 40 20 20 Symptomatic Infection Birth 1-6 months 7-12 months 1-4 years Older Children and Adults Age at Infection 34

Interpretation of Serologic Tests in Hepatitis B +

Viral Hepatitis and Serology Type of Viral Hepatitis Positive Virology Acute HBV HBsAg, HBeAg, HBcAb IgM Acute HBV, windows period HBcAb IgM Chronic active HBV HBsAg, HBeAg, HBcAb IgG Recovery HBV HBsAb IgG, HBcAb IgG, Normal ALT Immunized HBV HBsAb IgG

Serological Marker Hep B 1) HBsAg (Hepatitis B surface antigen): if positive, person is infectious Sensitivity = 0.15 ng/ml Specificity = 99.5% 2) Anti-HBs (Antibody to HBV surface antigen): indicates immunity to HBV and protection from disease Protective level is >10 IU/ml

Serological Markers Hep B 3) Anti - HBc (Antibody to HBV core antigen): Total - indicates past or active infection; present whether person is immune or chronic carrier Specificity = 99.8% to 99.9% IgM - early indicator of acute infection No antigen test

Serological Marker Hep B 4) HBeAg (Hepatitis Be antigen): indicates person is highly infectious Selecting patients for therapy 5) Anti-HBe (Antibody to HBVe antigen): prognostic for resolution of infection; less infectious; spontaneous seroconversion in 10 to 20% of healthy adults per year

Serologic markers – caveats: Precore or HBeAg negative mutants: Due to mutation in precore (abolishes HBeAg production) or core promoter region (down-regulates HBeAg production) No effect on viral replication (may be enhanced) More difficult to treat; greater risk of cirrhosis Co-infection with HCV may suppress both HBeAg and HBsAg

Serologic markers – caveats: Persistent HBsAg for >6 mos = chronic infection HBsAg and anti-HBs may co-exist in up to 24% of chronically infected individuals; likely due to mutations in the “a” determinant of the S gene Surface antigen escape mutants described in infants infected with HBV after HBIG + vaccination and in Liver transplants after prolonged HBIG Anti-HBc IgM may persist for up to 2 years in 20%; chronically infected individuals may have low titres which rise during acute flares

Hepatitis B – Laboratory Tests Serologic markers – caveats: Isolated HBcAb may be due to: Remote infection (immune or chronic carrier) “Window” period between HBsAg and HBsAb Co-infection with HCV False positive test result – HBcAb is marker most prone to false positives HBV DNA may help sort this out

Concentration of Hepatitis B Virus in Various Body Fluids Low/Not High Moderate Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk 1 1 1

Hepatitis B Virus Modes of Transmission Sexual - sex workers and homosexuals are particular at risk. Parenteral - IVDA, Health Workers are at increased risk. Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations. 2 2 2

Diagnosis A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection. HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection. anti-HBcIgG - past or chronic infection. HBeAg - indicates active replication of virus and therefore infectiveness. Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV. HBV-DNA - indicates active replication of virus, more accurate than HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

Treatment Interferon (PEGinterferon-2α) , - for HBeAg +ve carriers with chronic active hepatitis. Response rate is 30 to 40%. Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance. Entecavir and Adefovir Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

Prevention Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries. Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive. Other measures - screening of blood donors, blood and body fluid precautions.

Complications Arthritis Glomerulonephritis Polyarteritis nodosa Hepatocellular carcinoma

Hepatitis D Transmission: parenteral (intravenous drug use mostly) Subviral satellite because it can propagate only in the presence of hepatitis B coinfection superinfection Transmission: parenteral (intravenous drug use mostly) > 60% develop cirrhosis

Hepatitis D (Delta) Virus  antigen HBsAg RNA 19 19 19

Hepatitis D Anti-HDV Total (IgG & IgM) available Incubation time – similar to Hepatitis B High titires of HDV antibodies indicate ongoing chronic infection Treatment same as HBV If acquired as superainfection in chronic HBV there is in severity of infection i.e fulminant hepatitis, chronic hepatitis with rapid progression to cirhosis

HBV - HDV Superinfection Typical Serologic Course Jaundice Symptoms Total anti-HDV ALT Titre HDV RNA HBsAg IgM anti-HDV Time after Exposure 23 23 23

Hepatitis D - Prevention HBV-HDV Coinfection Pre or postexposure prophylaxis to prevent HBV infection. HBV-HDV Superinfection Education to reduce risk behaviors among persons with chronic HBV infection. 25 25 25

Hepatitis C Affects each person differently No vaccine available Many people have the virus and do not even know it By blood transfusion and IV drug abuse Intranasal cocaine use, piercing Type 1 (most resistant) type II and III

Hepatitis C - Clinical Features Incubation period: Average 6-7 wks Range 2-26 wks Clinical illness (jaundice): 30-40% (20-30%) Chronic hepatitis: 70% Persistent infection: 85-100% Immunity: No protective antibody response identified 8 8 8

Chronic Hepatitis C Infection The spectrum of chronic hepatitis C infection is essentially the same as chronic hepatitis B infection. All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Waxing and waning aminotransferases (ALT/AST)

Hepatitis C Virus Infection Waxing and Waning ALT/AST anti-HCV Symptoms Titre ALT Normal 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure 10 10 10

Risk Factors Associated with Transmission of HCV Transfusion or transplant from infected donor Injecting drug use Hemodialysis (yrs on treatment) Accidental injuries with needles/sharps Sexual/household exposure to anti-HCV-positive contact Multiple sex partners Birth to HCV-infected mother 11 11 11

Hepatitis C Dispelling Myths Hepatitis C is not spread by: Casual contact Hugging/kissing Sharing eating utensils and drinking glasses Sneezing/coughing Shaking hands Sitting on a toilet seat

Prevention Never share drug equipment Straws, bills, needles, syringes, water, filter, cooker, pipes etc… Never share tooth brushes/razors or any personal hygiene articles that have blood on them (even tiny amounts). Practice safer sex

Prevention Always make sure new & sterilized equipment is being used for tattooing & piercing Make sure ink for tattooing is not being shared Do not touch dirty needles without proper equipment or following proper procedures

14 14 14

Laboratory Diagnosis HCV antibody - generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears. HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy. HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

Treatment Types 1 II and III Type I is resistant than II and III Acute HCV –alfa- interferon for 6 months also type II and III Chronic HCV –alfa interferon+ ribavirin or peginterferon +ribavirin Type I use alfa interferon +Ribavirin for 1 year, Telaprevir, Betapravir HAV and HBV vaccination.

Prevention of Hepatitis C Screening of blood, organ, tissue donors High-risk behavior modification Blood and body fluid precautions 15 15 15

Complications Cryoglobulinemia Membranoproliferative glomerulonephritis Hepatocellular Carcinoma Cirrhosis Alfa interferon is contraindicated with major depression and organ transplant Ribavirin contraindicated in pregnancy, avoid for 6 months after therapy

Treatment Alcoholics should stop for 1 month before starting treatment Screen for hepatocellular carcinoma every 6 months Inteferon S/E: flu like syndrome (malasia, HA, fever, myalgia) depression, myelosuppression (neutropenia, anemia) Ribavirin S/E HA, fatigue, hemolysis

Hepatitis E Virus 26 26 26

Hepatitis E - Clinical Features Incubation period: Average 40 days Range 15-60 days Case-fatality rate: Overall, 1%-3% Pregnant women, 15%-25% Illness severity: Increased with age Chronic sequelae: None identified 27 27 27

Hepatitis E Virus Infection Typical Serologic Course Symptoms ALT IgG anti-HEV Titer IgM anti-HEV Virus in stool 1 2 3 4 5 6 7 8 9 10 11 12 13 Weeks after Exposure 28 28 28

Epidemiologic Features Hepatitis E - Epidemiologic Features Most outbreaks associated with faecally contaminated drinking water. Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico. In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown. Minimal person-to-person transmission. 29 29 29

Prevention and Control Measures for Travelers to HEV-Endemic Regions Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler. IG prepared from donors in Western countries does not prevent infection. Unknown efficacy of IG prepared from donors in endemic areas. Vaccine? 31 31 31

Hepatitis Virus – Molecular Tests Molecular assays available as follows: Commercial assays for HBV DNA and HCV RNA In-house assays for HAV RNA & HDV RNA No molecular assay for HEV RNA HCV RNA & HBV DNA, plasma or serum must be separated from cells within 6 hrs and plasma can be stored at 4oC for several days or -70oC for long-term No licensed tests for diagnostic purposes; all tests are for monitoring or donor screening HCV RNA will be done in HIV or other immunocompromised patients if requested

Nucleic Acid Amplification Tests (NAAT) for Detection of RNA/DNA Quantitation of RNA or DNA may be reported as copies/ml or IU/ml Conversion factor for copies/ml to IU/ml is not the same for different assays measuring the same target or different targets HBV DNA: 5.82 copies/IU HCV RNA: PCR - 2.4 copies/IU; bDNA: 5.2 copies/IU Coefficient of variation (COV) may range from 15 to 50%

HBV DNA in Clinical Practice Routine monitoring on therapy to assess response to treatment Every 3 months X years on oral agents Every 1 month X 6-12 on PEG/IFN Routine monitoring off therapy to estimate prognosis and to evaluate need for treatment Every 6 –12 months normally Diagnosis of occult HBV infection