Hepatitis B Diagrammatic representation of the hepatitis B virion and the surface antigen components EM of Hepatitis B viron –Hepadnaviridae family –DNA virus –Double-shelled particles –Outer lipoprotein envelope (surface Ag) –Inner viral nucleocapsid (core) –seven genotypes –four major subtypes. –All HBV subtypes share one common antigenic determinant - "a.“ –Thus, antibodies to the "a" determinant confer protection to all HBV subtypes
Hep B epidemiology 1/3 of world’s population has been infected 350 million with chronic disease 15-25% of these die due to liver related diseases 1 million deaths annually United States 1.25 million chronic carriers 5000 deaths annually Hep B surface Ag prevalence, 2002 Source: CDC website
Hepatitis B transmission Dominant mode of transmission related to prevalence Low prevalence (.1 to <2%) –adults unprotected sexual intercourse intravenous drug use Moderate (3-5%) - children Horizontal transmission High prevalence (>10-20%) - infants Maternal infant Percutaneous Other Occupational exposure Blood transfusions Increasingly rare
Hepatitis B primary infection Symptoms Malaise, fatigue, anorexia, nausea, low grade fever after day incubation Can be asymptomatic More common in children Usually self limited – in adults Viral clearance from blood and liver Lasting immunity Can result in fulminate hepatic failure
HBsAg 4-10 wks Anti-HBc antibody follows +/- HBeAg Viral load very high 10 9 to Highly contagious at this time Hepatitis B primary infection
Decrease in HBsAg correlates with onset of T-cell mediated immune response Also, when present, correlates with onset of elevated liver enzymes Traditionally, conversion to anti-HBs antibodies signals cure Viral DNA may persist for years to lifetime Significance unknown Hepatitis B primary infection
Hep B - Persistent Infection Definition: Persistence of HBsAg for greater than 6 months
Hepatitis B persistent infection Persistent viral load that declines over time HBeAg declines overtime, converting eventually to anti-HBe antibody Seroconversion correlates with rise in LFTs and 5 order of magnitude decline in viral load. Classically, to Anti-HBe antibody = no viral DNA circulating, which is incorrect 0.5% clear HBsAg annually
Persistent Hepatitis B Two clinical patterns Chronic liver disease Elevated LFTS Abnormal hepatic histology 20% develop cirrhosis Asymptomatic carrier Normal LFTs Asymptomatic Near normal liver histology Both risk development of Hepatocellular Carcinoma
Persistent Hepatitis B HBV replication extensive and continuous in chronic carriers Replication is not cytotoxic Host immune response to viral antigens expressed on infected hepatocytes
Hepatocellular carcinoma 100 times the risk in persistently infected patients Risk is greater if HBeAg positive Twice a year screening is recommended in persistent carriers Alpha fetoprotein and/or hepatic U/S When to start screening is unclear
Who gets chronic disease? Rule of thumb, the younger the age, the more likely to become chronic Neonates – 95% chronic, most asymptomatic Infant to 6 yo – 30% chronic Older children to adults 3-5% chronic
Hepatitis B - Serology Surface Antigen (HBsAg) Hep B surface antigen Outer surface lipoprotein, appears early Hallmark of infection Surface antigen antibody (anti-HBs) signifies cure Hep B core antigen (HBcAg) intracellular antigen expressed in infected hepatocytes not detectable in serum Core antibody appear early in infection (Anti-HBc) Predominately IGM early in infection detection of IgM anti-HBc usually regarded as an indication of acute HBV infection Traditionally, the sole marker of HBV infection during the window period between the disappearance of HBsAg and the appearance of anti-HBs
secretory protein that is processed from the precore protein Elevated early in infection and usually coverts to antibody early on. Traditionally used as a marker for viral load as viral load was undetectable with early assays when Ag was absent. However, certain variants of the Hep B virus do not create the HBeAg as it has no known function. When present, it does correlate with elevated viral load and seroconversion the antibody usually correlates with a decrease in viral load by a magnitude of 4-5. Hep B – e antigen
Acute infection HBsAg positive and anti-HBcAg IGM Rarely, IgM anti-HBc only marker Usually seen in acute fulminate Hep B Chronic infection HBsAg positive and anti-HBcAg Previous Infection HBsAg negative anti-HBs positive IgG anti-HBc positive Hep B – serology interpretation
Screening – Who? Who Persons born in hyperendemic areas Men who have sex with men Injection drug users Patients on dialysis HIV infected patients Pregnant women Family and household contacts and sexual contacts of HBV-infected persons. Testing should be performed by obtaining an HBsAg and anti-HBs.
Hepatitis B Treatments Prevention Neonates Vaccine Prophylaxis Possible exposure Chronic infection
Prevention In 1991, US started routine vaccination Since then incidence of acute HBV infection has declined by 67% However, incidence has continued to increase in adults Offer vaccine to high risk individuals
Prophylaxis Hepatitis B immune globulin (HBIG) and vaccine Indications Patients with no history of vaccine and Percutaneous exposure (needle sticks) Household contacts exposed to blood Perinatal exposure – prevents transmission in 95% of mothers HBsAg positive when given within 12 hours of birth Breast feeding ok if baby received prophylaxis
Treatment of persistent infection- Who to treat? Treat: HBeAg positive with persistent infection No treatment: HBeAg negative and carrier (nl LFTs, viral load less than 10 5 and asymptomatic) Probably treat: HBeAg negative with chronic infection (high viral load, abnormal LFTs) HBeAg PosNeg Chronic dz Carrier treat Probably not treat Probably treat
Treatment options FDA approved Interferon Alfa Lamivudine – reverse transcriptase inhibitor Adefovir – nucleotide analogue that inhibits viral polymerase Investigational Tenofovir – adenine nucleotide analogue Approved for HIV Entecavir – guanosine analogue, highly selective for the HBV polymerase
Interferon alfa Had been mainstay for therapy Subcutaneous injection three times per week for 3 months or longer 30% of patients who could tolerated regime had a successful response Seroconverted to HBe antibodies Normalization of LFTs Multiple side effects Fever, myalgia, thrombocytopenia, depression
Interferon alfa Contraindicated in very advanced liver disease ‘Flairs’ or bump in LFTs occur at time of seroconversion to anti-Hbe due to increased immune response may precipiate overt liver failure
Lamivudine Oral medication Usually given for year or longer Found to inhibit HIV reverse transcriptase. Noted that patients with both HIV and chronic Hep B had large declines in Hep B viral load This phenomenon was then noted in patients with only chronic Hep B By itself, results in a 3 to 4 log decrease serum viral load Increased rate of seroconversion to HBe- antibodies and normalization of LFTs
Lamivudine Those who respond best are those with elevated LFTs >5 times normal -> 65% response rate 2-5 times normal -> 26% response 5% response Remember, liver damage is caused by immune response So higher LFTs likely correlates to a most robust host immune response By inhibiting viral reproduction, the immune system is able to clear the virus more effectively.
Lamivudine Use limited by resistance At one year of treatment 15-20% of patients develop resistance 40% at two years 67% at four years However, the resistant virus is less hearty than the native virus resulting is lower replication rates than pretreatment Resistant variants also convert to anti- HBe antibodies at higher rates.
Lamivudine Resistance No clear evidence regarding continuation of treatment Prior to new meds, many continued. Discontinuing medication is associated with flairs Overlapping with another medication recommended
Adefovir Initially, devoloped for HIV Nucleotide analogue Prodrug phosphorylated intracellularly to yield active drug Inhibits viral polymerase Has been evaluated for primary monotherapy and in patients with resistance to Lamivudine
Adefovir Efficacy Reduces viral load by 3 to 4 log Enhances HBeAg seroconversion Results in histological improvement of liver Improved LFTs Effective even in Lamivudine resistant patients Much lower rate of resistance than Lamivudine
Approach to treatment Unfortunately, studies are lacking to define what is the best approach Presently, alpa interferon, Adefovir and Lamivudine are all considered first line therapy Considerations Adefovir – less resistance, possibly nephrotoxic Lamivudine – good side effect profile Interferon – difficult course All provided about the same results Unknown if benefit to using combination therapy.
Hepatitis B/C Alternative Therapy: What your patient might read about on the internet MTH-68/B. vaccine strain of Newcastle disease, virus that causes a bird infection Controlled study - conventional tx’ment vs vaccine in acute phase n=42, showed more progressed to chronic infection with conventional tx’mt. Case reports of benefit to pts given this vaccines after progressing to decompensated liver failure. Both studies investigated the use in both Hepatitis B and C.
Hepatitis B and Herbs – Cochrane review Asymptomatic carries Very few quality studies Three randomised clinical trials of carriers (307 patients) three months or more of follow identified. The methodological quality was poor overall, only one significant trial 'Jianpi Wenshen recipe' significant effects on viral markers compared to interferon serum: HBsAg,HBeAg, and seroconversion of HBeAg to anti-HBe. Poor long term f/u Chronic carriers Fuzheng Jiedu Tang (compound of herbs) positive effects on clearance of serum HBsAg, HBeAg, and HBV DNA Polyporus umbellatus polysaccharide vs interferon Positive effects on serum HBeAg and HBV DNA Phyllanthus amarus vs interferon Improvement in serum HBeAg
Hepatitis B Alternative Therapies One small retrospective study showed patients in fulminent hepatic failure who took dietary or herbal supplements often did worse than those who did not. Arch Surg Aug;138(8): Thought to be due to heptotoxic effects of componds in these supplements. Basically – No firm evidence supporting medicinal herbs follow-up randomized trials seem justified for some Would not recommend due to potential hepatotoxic effects
Images: Am J Gastroenterol Mar;98(3): Arch Surg Aug;138(8):852-8 N Engl J Med Mar 11,2004; Pediatrics in Review, Vol 24, No.12 Dec 2003 References