HEAPTITIS

DEFINITION
Hepatitis is an inflammation of the liver characterized by diffuse or patchy necrosis [1]
Chronic hepatitis is characterized by the presence of hepatic inflammation on liver biopsy and elevation of serum liver enzymes, especially transaminases, generally defined as disease that has lasted for 6 months or longer [2]

APPROACH TO A PATIENT WITH JAUNDICE [3, 4]

• If patient has jaundice, the classic definition of jaundice is a serum bilirubin level greater than 2.5 to 3 mg per dL (42.8 to 51.3 µmol per L) in conjunction with a clinical picture of yellow skin and sclera
• Patient with jaundice may present with no symptoms at all (i.e., the condition is found accidentally), or they may present with a life-threatening condition. The wide range of possibilities is based on the variety of underlying causes and whether disease onset is quick or slow moving.
• If patient with jaundice has acute illness, which is frequently caused by infection, may seek medical care because of fever, chills, abdominal pain, and flu-like symptoms. For these patients, the change in skin color may not be their greatest concern
• Patients with noninfectious jaundice may complain of weight loss or pruritus.
• Abdominal pain is the most common presenting symptom in patients with pancreatic or biliary tract cancers.
• Even something as nonspecific as depression may be a presenting complaint in patients with chronic infectious hepatitis and in those with a history of alcoholism
• Patients may present with jaundice and some extrahepatic manifestations of liver disease. Examples include patients with chronic hepatitis and pyoderma gangrenosum, and patients with acute hepatitis B or C and polyarthralgias
• Jaundice can reflect a medical emergency in a few select situations. These include massive hemolysis (eg, due to Clostridium perfringens sepsis or falciparum malaria), ascending cholangitis and unconjugated hyperbilirubinemia in the neonatal period (which can lead to kernicterus), and fulminant hepatic failure.
• The physical examination should focus primarily on signs of liver disease other than jaundice, including bruising, spider angiomas, gynecomastia, testicular atrophy, and palmar erythema. An abdominal examination to assess liver size and tenderness is important. The presence or absence of ascites also should be noted.
• If patient has jaundice, the initial work-up of the patient with jaundice depends on whether the hyperbilirubinemia is conjugated (direct) or unconjugated (indirect).
• A urinalysis that is positive for bilirubin indicates the presence of conjugated bilirubinemia. Conjugated bilirubin is water soluble and therefore able to be excreted in urine.
• The findings of urinalysis should be confirmed by measurements of the serum total and direct bilirubin levels
• If patient appearing to have jaundice has normal bilirubin and liver enzymes, patient has pseudo jaundice which may be due to high vegetable intake. Unlike true jaundice, carotenemia does not result in scleral icterus or elevation of the bilirubin level
• If patient has unconjugated hyperbilirubinemia in which urine is negative for bilirubin, increased total and normal cojugated bilirubin look for hemolysis, drug toxicity, genetic syndrome(Gilbert's and Crigler-Najjar syndrome) and hematoma
• If urine is positive for bilirubin, increased total and cojugated bilirubin patient has conjugated hyperbilirubinemia, obtain Liver function tests( AST,ALT, AP, GGT) and CBC
• If patient has jaundice, a CBC is useful in detecting hemolysis, which is indicated by the presence of fractured red blood cells (schistocytes) and increased reticulocytes on the smear.
• If patient has jaundice, AST and ALT are markers of hepatocellular injury.
• They can be less helpful in patients with chronic liver disease, because levels can be normal or only slightly elevated when there is little liver parenchyma left to damage.
• Acute viral hepatitis may cause the levels of ALT to raise several thousand units per liter. Levels greater than 10,000 U per L usually occur in patients with acute injury to the liver from another source (e.g., drugs [acetaminophen] or ischemia)
• If patients have acute alcoholic hepatitis, they have AST and ALT levels that rise to several hundred units per liter. With alcohol-induced damage, the ratio of AST to ALT is usually greater than 1, whereas infectious causes of hepatitis typically cause greater elevation in ALT than in AST
• Alkaline phosphatase and gamma-glutamyltransferase are markers for cholestasis. As bile obstruction progresses, the levels of these two markers rise several times above normal
• The disorders associated with isolated conjugated hyperbilirubinemia and normal liver enzymes are Rotor and Dubin-Johnson syndrome.
• If still no cause is apparent obtain viral serology for hepatitis A, B and C
• If patient has jaundice, the second-line serum investigations may include tests for hepatitis A IgM antibody, hepatitis B surface antigen and core antibody, hepatitis C antibody
• If still no cause is appearent screen for autoimmune disorders (ANA, antiLKM and anti-smooth muscle antibodies)
• If patient with jaundice has an elevated amylase level would corroborate the presence of pancreatitis when this condition is suspected based on the history or physical examination.
• Other tests to be carried out include serum levels of iron, transferrin, and ferritin (for hemochromatosis), serum levels of ceruloplasmin (for Wilson's disease) and measurement of alpha-1-antitrypsin activity (for alpha-1-antitrypsin deficiency).
• If no diagnosis is appearent than go for imaging studies like ultrasonography and CT scan to rule out intra and extra hepatic causes of jaundice
• Ultrasonography is typically the first test ordered, because of its lower cost, wide availability, and lack of radiation exposure, which may be particularly important in pregnant patients.
• While ultrasonography is the most sensitive imaging technique for detecting biliary stones, CT scanning can provide more information about liver and pancreatic parenchymal disease. Neither modality is good at delineating intraductal stones
• Further imaging that may be done by a gastroenterologist or interventional radiologist includes endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography
• If patient has jaundice, a liver biopsy provides information on the architecture of the liver and is used mostly for determining prognosis.
• It also may be useful for diagnosis if serum and imaging studies do not lead to a firm diagnosis.
• Liver biopsy can be particularly helpful in diagnosing autoimmune hepatitis or biliary tract disorders (e.g., primary biliary cirrhosis, primary sclerosing cholangitis).

MILD CHRONIC ELEVATION IN SERUM AMINOTRANSFERASES [4]
The laboratory evaluation of patients with chronic (defined as six months or greater), mild elevation (defined as less than 250 U/L) of one or both of the aminotransferases is best achieved in a stepwise fashion to eliminate unnecessary testing.
• Review possible link to medications, herbal therapies or recreational drugs
• Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1)
• Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab)
• Screen for hemochromatosis (FE/TIBC >45 percent)
• Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)
• If the above is unrevealing confirm that source is hepatic by following:
Exclude muscle disorders (obtain creatinine kinase or aldolase)
Obtain thyroid function tests (TSH if hypothyroidism is suspected otherwise obtain a full set of thyroid function tests)
Consider celiac disease (especially in patients with a history of diarrhea or unexplained iron deficiency - serum anti endomysial IgA or anti tissue transglutaminase IgA antibodies are reasonable screening tests)
Consider adrenal insufficiency

• Consider less common causes of liver disease if now it is confirmed that source is of liver origin :
• Consider autoimmune hepatitis particularly in women and those with a history of other autoimmune disorders (check serum protein electrophoresis, obtain ANA and ASMA if positive)
• Consider Wilson's disease in those <40 (check ceruloplasmin, evaluate for Kayser Fletcher rings)
• Consider alpha-1-antitrypsin deficiency especially in patients with a history of emphysema out of proportion to their age or smoking history (obtain alpha-1-antitrypsin phenotype)
• Observe if ALT and AST are less than two-fold elevated
• Otherwise consider a liver biopsy

ISOLATED ELEVATION OF THE ALKALINE PHOSPHATASE AND/OR GAMMA GLUTAMYL TRANSPEPTIDASE [4]
• The first step in the evaluation of an elevated alkaline phosphatase is to identify its source
• Physiological causes of alkaline phosphatase should be ruled out like pregnancy and after eating a fatty meal. Test should be repeated in a fasting state.
• If gel electrophoresis is not available which is the most specific test, either a 5'-nucleotidase or GGT should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders.
• An elevated serum alkaline phosphatase with a normal 5'-nucleotidase or GGT should prompt an evaluation for bone diseases.
• The most common causes to be considered in patients of elevated alkaline phosphatase include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile ductopenia, and certain drugs such as androgenic steroids and phenytoin.
• Initial testing should include a right upper quadrant ultrasound (which can assess the hepatic parenchyma and bile ducts) and an antimitochondrial antibody (AMA), which is highly suggestive of PBC.
• The presence of biliary dilatation suggests obstruction of the biliary tree.
• In patients with biliary dilatation or choledocholithiasis, an endoscopic retrograde cholangiopancreatogram (ERCP) should be done to identify the cause of obstruction and to allow for an intervention such as stone removal or stent placement.
• Patients with a positive AMA should have a liver biopsy to verify the diagnosis of PBC.
• Suggest a liver biopsy and either an ERCP or magnetic resonance cholangiopancreatogram (MRCP) if the AMA and ultrasound are both negative and the alkaline phosphatase is persistently more than 50 percent above normal for more than six months.
• If the alkaline phosphatase is less than 50 percent above normal, all of the other liver tests are normal, and the patient is asymptomatic, we suggest observation alone

CAUSES OF HEPATITIS [3, 4]
ACUTE HEPATITIS
• Infectious viral hepatitis such as hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E.
• Other viral diseases such as: mononucleosis and cytomegalovirus.
• Severe bacterial infections.
• Amoebic infections.
• Medicines, eg paracetamol poisoning and halothane (an anaesthetic).
• Toxins: alcohol and fungal toxins, eg toadstool poisoning
CHRONIC HEPATITIS

Chronic hepatitis also has a number of different causes.
• Contagious viral hepatitis such as hepatitis B, hepatitis C and hepatitis D.
• Medicines.
• Toxins such as alcohol.
• Autoimmune hepatitis. This is a disease in which a number of liver cells are destroyed by the patient's own immune system. Autoimmune hepatitis can also sometimes occur as acute hepatitis. The cause is unknown.
• Inborn metabolic disorders, such as Wilson's disease (disorder of the body's copper metabolism) and haemochromatosis (disorder of the body's iron metabolism).

HEPATITIS A
DEFINITION:
Hepatitis A is acute inflammation of liver caused due to RNA virus, causing epidemics or sporadic cases of hepatitis, transmitted by the fecal-oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus [5].

DIAGNOSTIC CONSIDERATIONS
Prodrome of anorexia, nausea, vomiting, malaise, aversion to smoking.
Fever, enlarged and tender liver, jaundice.
Normal to low white cell count; abnormal liver tests, especially markedly elevated aminotransferases early in the course.
Evidence of transmission by the fecal-oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus, but in approximately 40 percent of reported cases of hepatitis A, the source of infection cannot be identified.
Hepatitis A IgM is positive
Hepatitis never goes into chronic stage.
Incubation period is 14 -21 days
Liver biopsy may show hepatocellular necrosis and mononuclear infiltrate but is very rarely indicated.


EPIDIMEOLOGY
Worldwide, four major patterns of HAV infection can be described based on the age-specific prevalence of antibodies to HAV. These range from high endemicity, such as in Africa and parts of Asia and Latin America, where the majority of infections occur in early childhood, to low and very low endemicity, such as in North America and Western Europe, where few persons are infected in childhood, and the majority of the population remains susceptible throughout adulthood [6]
In 2003 in US, the incidence of Hepatitis A was 2.6 per 100,000 which has declined due to introduction of vaccine against it
Persons aged 5-14 years are most likely to acquire acute HAV infection. Over the last 40 years, the average age of infected persons has steadily increased [6]
Over last 20 years, shifting patterns in the prevalence of antibodies to HAV (anti-HAV) are seen throughout South-East Asia and China. In general in the late 1970s and early 1980s, 85-95% of the population of developing countries like the Philippines, Korea, China and Thailand were anti-HAV-positive by age 10-15 years, compared with only about 50% in the more affluent countries like Malaysia and Singapore. In the early 1990s, 85-95% of the population was immune by age 30-40 years in the Philippines, Korea, China and Thailand and by 50 years of age and above in Malaysia and Singapore. Similar trends were noted in Hong Kong, Taiwan and Japan [7].
Race: Immigrants from countries of high endemicity to countries of low endemicity may be responsible for some of the periodicity observed with outbreaks of infection. In this setting, affected individuals tend to be infants born since the last outbreak or susceptible adults who moved to the area.
Sex: Except for persons in high-risk populations (eg, sewage workers, childcare workers, aid workers, male homosexuals), no sexual predilection is apparent.
Age: With increasing age of acquisition, both symptomatic disease and adverse sequelae increase [8]
TRANSMISSION
• Hepatitis A virus is transmitted by the fecal–oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus.
• Contaminated food is identified as the source of transmission for less than 5 percent of cases reported in the United States [9]. Spread is favored by crowding and poor sanitation
• It can spread by [6]
1. Person to person contact
2. Homosexual contact
3. Contact with contaminated food or water
4. Raw or undercooked shellfish (oysters, clams, mussels)
5. Foods contaminated by infected food handlers
6. Persons in daycare centers
7. Persons in institutions
8. Military personnel
9. Through blood transfusions
10. Via intravenous drug use
11. No identifiable risk factor


CLINICAL FEATURES
• HAV infection usually results in an acute, self-limited illness and only rarely leads to fulminant hepatic failure.
• Fulminant hepatic failure occurs more commonly in patients with underlying liver disease, particularly chronic hepatitis C virus infection
• The manifestations of Hepatitis A infection vary with age.
• HAV infection is usually silent or subclinical in children. In contrast, infection in adults can vary in severity from a mild flu-like illness to fulminant hepatitis.

SYMPTOMS
• The incubation period averages 30 days (range 15 to 49 days).
• After incubation period the illness begins in symptomatic patients with the abrupt onset of prodromal symptoms including, fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper quadrant pain [11].
• Within a few days to one week, these patients enter icteric phase and note dark urine, acholic stool (light-colored stools lacking bilirubin pigment), jaundice, and pruritus. The prodromal symptoms usually diminish when jaundice appears; jaundice typically peaks within two weeks [12]
• In convalescent phase, there is an increasing sense of well-being, return of appetite, and disappearance of jaundice, abdominal pain and tenderness, and fatigability.
• Three atypical clinical manifestations of acute infection are recognized: prolonged cholestasis, relapsing hepatitis, and extra hepatic disease associated with acute infection [13].
• A relapsing form of hepatitis is observed in 3 to 20 percent of patients with HAV infection. The clinical course is usually preceded by an apparent full clinical recovery with near normalization of the serum aminotransferases lasting 4 to 15 weeks, followed by biochemical and, in some cases, clinical relapse, which is often milder than the initial episode.
• Variety of extrahepatic manifestations of hepatitis A virus has been described [13]
• Evanescent rash and arthralgias are the most common, occurring in approximately 11 and 14 percent of patients, respectively [13]
• Extra hepatic manifestations also include toxic epidermal necrolysis, myocarditis, optic neuritis, transverse myelitis, thrombocytopenia, aplastic anemia and red cell aplasia [13]
• Acute renal failure, interstitial nephritis, pancreatitis, transient heart block, Guillain-Barré syndrome, lupuslike syndrome, and Sjögren syndrome have been reported in association with HAV infection. These complications are all rare



SIGNS:
The two most common physical examination findings are jaundice and hepatomegaly, which occur in 70 and 80 percent of symptomatic patients, respectively [18].
Less common findings include splenomegaly, cervical lymphadenopathy, evanescent rash, arthritis, and, rarely, a leukocytoclastic vasculitis.


DIFFRENTIAL DIAGNOSIS [14]
Hepatitis A should be differentiated from other causes of acute hepatitis:
Acute Viral Hepatitis like hepatitis B, C , E
Acute drug-induced liver injury (e.g., Paracetamol, ecstasy)
Acute HIV infection
Drug-induced hypersensitivity reactions (e.g., sulfasalazine hypersensitivity)
Viral hepatitis (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV])
Budd Chiari syndrome

INVESTIGATIONS

• Hepatitis A infection is confirmed by a positive serum hepatitis A virus-specific immunoglobulin M (HAV-IgM) which remains positive for 6 months or more.
• Hepatitis A virus-immunoglobulin G (HAV-IgG) does not distinguish between current or past infection and may remain positive for life.
• If patient has hepatitis A, serum/plasma aminotransferases (AST/ALT) can range from 500 to 10,000 IU/L.
• Bilirubin can be up to 500 micromoles/L.
• Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection
• Alkaline phosphatase levels are usually <2x the upper limit of normal, but higher if there is cholestasis
• Modest falls in serum albumin level may accompany the illness
• If in a patient of Hepatitis A, prothrombin time (PT) is prolonged by more than 5 seconds, suggest developing hepatic decompensation
• If patient has Hepatitis A, advise CBC. Blood picture may show mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection. Indices of low-grade hemolysis are not uncommon
• An ultrasound scan may be required when alternative diagnoses warrant exclusion and should assess vessel patency and evaluate any evidence supporting unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with fulminant hepatic failure.
• Blood urea and serum creatinine should be obtained at baseline.
• Screen for other sexually transmitted infections in cases of sexually-acquired hepatitis or if otherwise appropriate.

TREATMENT
If patient has Hepatitis A, he/she should be advised against handling food, keeping cleanliness, avoiding unprotected intercourse. Treat the patient symptomatically and maintain oral rehydration. If patient develops fulmanent hepatic failure admit the patient. Contacts should be given immunoglobulins and vaccination and other people vaccinated.

NON PHARMACOLOGICAL TREATMENT
• Patients should be advised to avoid food handling and unprotected sexual intercourse until they have become non-infectious [15].
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s). This should be reinforced by giving them clear and accurate written information.
• Hepatitis A is a notifiable disease [15].
• Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary
Bed rest during the acute illness may be important, although data to support this practice are lacking. Restricting transmission is important, especially in the early phases of the illness. Returning to work should probably be delayed for 10 days after the onset of jaundice [15]
PHARMACOLOGICAL TREATMENT
Acute Icteric Hepatitis [15]

Mild/moderate (80%), manage as an outpatient emphasising rest and oral hydration.
Nausea and vomiting are treated with antiemetics
Paracetamol may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/d in adults
Severe attack with vomiting, dehydration, or signs of hepatic decompensation (change in conscious level or personality), admit to hospital.
If patient has cholestatic type of hepatitis, cholestyramine should be administered if the pruritus is bothersome.
Pregnancy and Breast Feeding [15]

• Pregnant women should be advised of the increased risk of miscarriage/premature labor and the need to seek medical advice if this happens.
• Breast-feeding can be continued but consider giving human normal immunoglobulin (HNIG) 125 mg intramuscularly (i.m.) to the baby, although most children will have mild or asymptomatic infection.
Sexual and Other Contacts [15]
• Partner notification should be performed for at-risk homosexual contacts (oro/anal, digital/rectal, and penetrative anal sex) within the period 2 weeks before to 1 week after the onset of jaundice. This to be documented and the outcome documented at subsequent follow-up.
• Other people thought to be at risk (household contacts, those at risk from food/water contamination) to be contacted via the public health authorities.
• Hepatitis A vaccine may be given up to 7 days after exposure providing exposure was within the infectious period of the source case (during the prodromal illness or first week of jaundice).
• HNIG, 250 to 500 mg intramuscularly, should be considered for patients at higher risk of complication (concurrent chronic hepatitis B or C, chronic liver disease, or age >50 yr) or if there has been a delay of more than 7 days after exposure.
• HNIG works best if given in the first few days after first contact, with an efficacy of 90%, and is unlikely to give any protection more than 2 weeks after first exposure, but may reduce disease severity if given up to 28 days after exposure
• Patients are most infectious for 2 weeks before the jaundice (i.e., before the illness is recognized).
• Hepatitis A vaccine 3 scheduled doses provide 95% protection for at least 5 years. Current advice is to revaccinate after 10 years; however there is increasing evidence that vaccine-induced immunity may be >20 years and possibly lifelong, so no further booster doses may be needed after the primary course in immunocompetent patients.
• Human immunodeficiency virus (HIV)-positive patients respond (antibody production) in 73 to 88%, but titers are lower than in HIV-negative individuals.
• If patients with a low CD4 count (<300 cells/mm3) are vaccinated, they should be revaccinated if the CD4 count rises above 500/mm3 as a result of highly active antiretroviral therapy (HAART).
• There is a combined hepatitis A+B vaccine given on the same schedule as the hepatitis B vaccine and has similar efficacy to the individual vaccines although early immunity to hepatitis B may be impaired
• If an outbreak is suspected or if the index case is a food handler, notify the local public health department.

• Relapsing HAV infection
o This complication occurs in 3-20% of patients with acute HAV infection and uncommonly takes the form of multiple relapses.
o Following a typical acute course of HAV infection, a remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. The initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually <3 wk) and mimics the initially presentation, although it usually is clinically milder.
A tendency to greater cholestasis exists in these patients. Vasculitic skin rashes and nephritis may be additional clinical clues to this syndrome.
During relapses, shedding of virus can be detected. IgM antibody test findings are positive.
The clinical course is toward resolution, with lengthening periods between flares. The total duration is 3-9 months.
Liver transplantation has been performed in patients with this condition when signs of significant decompensation have occurred. Corticosteroid treatment has been shown to improve the clinical course, although the course is generally benign without treatment.

Follow-up
• See at 1 or 2 weekly intervals until aminotransferase levels are normal (usually 4-12 weeks) [15].
• Immunity is lifelong [15].

Primary Prevention
• Health/sex education should stress the routes of transmission and the higher incidence in developing countries [15]
• Clinicians should offer the hepatitis A vaccine to patients who are at increased risk of hepatitis A infection [16]:
1. Persons with chronic liver disease (e.g., hepatitis B or C)
2. Men who have sex with men
3. Travelers to countries with high endemicity of infection
4. Persons who live in a community experiencing an outbreak of HAV infection
5. Illicit drug users, particularly injection drug users
6. Persons who have clotting-factor disorders
7. Persons at occupational risk for infection
• The full series should be given (initial dose and a second dose 6 to 12 months later) to ensure maximal antibody response [16].
• Non-immune patients who are at increased risk for both hepatitis A and hepatitis B infection may be given the combined hepatitis A and B vaccine in a total of three doses at 0, 1, and 6 months [16].
• If patient has to be vaccinated against Hepatitis A, different vaccines in use are: formalin-inactivated vaccines with and without aluminum hydroxide as an adjuvant, live attenuated vaccines, and combined hepatitis A and hepatitis B vaccines.
• Clinicians should administer HAV vaccination early in the course of human immunodeficiency virus (HIV) infection [16]
• If a patient's CD4 count is <300 cells/mm3 or the patient has symptomatic HIV disease, it is preferable to defer vaccination until several months after initiation of antiretroviral (ARV) therapy in an attempt to maximize the antibody response to the vaccine [16]
• Routine post-vaccination antibody measurement is not recommended because of the generally high efficacy of the vaccine [16]
RECOMMENDATIONS FOR TRAVELLERS TO ENDEMIC AREAS FROM LOW PREVALENCE AREAS [17]:
• All susceptible persons traveling to or working in countries with intermediate or high HAV endemicity (countries other than the United States, Australia, Canada, Japan, New Zealand, and countries in western Europe and Scandinavia) should be vaccinated with HAV vaccine or receive IG before departure.
• If hepatitis A vaccine has to be given, HAV vaccine at the age-appropriate dose is preferred for persons who plan to travel repeatedly to or reside for long periods in these high-risk areas; IG is recommended for travelers less than two years of age
• If hepatitis A vaccine is given, after receiving the initial dose of the HAV vaccine, persons are considered to be protected after four weeks. A booster dose at 6 to 12 months is required for long-term protection
• If persons who will travel to high-risk areas less than four weeks after the initial vaccine dose, IG (0.02 mL/kg) should be administered simultaneously with the first vaccine dose but at different injection sites.
• If persons are allergic to a vaccine component or otherwise elect not to receive vaccine should receive a single dose of IG (0.02 mL/kg IM) shortly before departure. This approach provides effective protection against HAV for approximately four to six months.
PROGNOSIS

• Prognosis is excellent. Long-term immunity accompanies infection. Recurrence and chronic hepatitis does not usually occur.

• Approximately 85 percent of individuals who are infected with hepatitis A have full clinical and biochemical recovery within three months, and nearly all have complete recovery by six months [14].
• Serum aminotransferase concentrations decrease more rapidly than the serum bilirubin; the latter normalizes in more than 85 percent of individuals by three months.
• Fatalities due to hepatitis A are more common with advancing age and, as noted above, in patients with chronic hepatitis C [18]. Reported case fatality rates are 0.1 percent in infants and children, 0.4 percent between the ages of 15 and 39, and 1.1 percent in those over age 40 [19].

COUNCELLING
Travelers should be educated about good hygiene and clean, safe water supplies. Advice should be provided regarding the benefits of immunization, particularly in high-risk individuals.
Travelers should avoid uncontrolled water sources, raw shellfish, and uncooked food.
Boiling water or adding iodine inactivates the virus. Chlorination and certain disinfecting solutions (household bleach 1:100 dilution) are sufficient to inactivate the virus
All fruit should be washed and peeled.
• People with HAV infection who are treated at home and those around them should follow strict enteric precautions.
• Improved sanitary conditions, adherence to sanitary practices such as hand washing, heating foods appropriately, and avoidance of water and foods from endemic areas should be practiced strictly.
• Handwashing is highly effective in preventing the transmission of the virus since hepatitis A virus may survive for up to four hours on the fingertips
• If patient develops Hepatitis A, advise to drink plenty of clear fluids to prevent dehydration.
• Avoid medicines and substances that can cause harm to the liver.
• Avoid alcoholic beverages, as these can worsen the effects of HAV on the liver.
• Avoid prolonged, vigorous exercise until symptoms start to improve.
• Take complete rest at least 10 days after appearance of jaundice




HEPATITIS B
DEFINITION
Acute Hepatitis B
Acute hepatitis B is hepatitis due to Hepatitis B virus lasting < 6 months [20]
Chronic hepatitis B
Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus for > 6 months. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B [21].
Inactive HBsAg carrier state
Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease [21]
Resolved hepatitis B
Previous HBV infection without further virological, biochemical or histological evidence of active virus infection or disease [21]
Acute exacerbation or flare of hepatitis B
Intermittent elevations of aminotransferase activity to more than 10 times the upper limit of normal and more than twice the baseline value [21]
Reactivation of hepatitis B
Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B [21]
HBeAg clearance
Loss of HBeAg in a person who was previously HBeAg positive [21]
HBeAg seroconversion
Loss of HBeAg and detection of anti-HBe [21]
HBeAg reversion
Reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive [21]


DIAGNOSTIC CONSIDERATIONS

• The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease.
• During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis.
• During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations also can occur with both acute and chronic infection.
• Perinatal infection in high prevalence areas [22], horizontal transmission, particularly in early childhood in intermediate prevalence areas, while unprotected sexual intercourse and intravenous drug use in adults are the major routes of spread in low prevalence areas [23]. Also spread by transfusion and needle stick injuries
• Incubation period is 1 to 6 months (average 12–14 weeks)

Diagnostic criteria for various types of Hepatitis B are:
Chronic hepatitis B
1. HBsAg _ _ 6 months
2. Serum HBV DNA _20,000 IU/ml (105copies/ml), lower values 2,000-
20,000 IU/ml (104-105 copies/ml) are often seen in HBeAg-negative chronic hepatitis B
3. Persistent or intermittent elevation in ALT/AST levels
4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation

Inactive HBsAg carrier state
1. HBsAg_ _ 6 months
2. HBeAg-, anti-HBe_
3. Serum HBV DNA _2,000 IU/ml
4. Persistently normal ALT/AST levels
5. Liver biopsy confirms absence of significant hepatitis

Resolved hepatitis B
1. Previous known history of acute or chronic hepatitis B or the presence of anti-HBc +/- anti-HBs
2. HBsAg negative
3. Undetectable serum HBV DNA
4. Normal ALT levels

EPIDEMIOLOGY
• The prevalence of HBV carriers varies from 0.1 percent to 2 percent in low prevalence areas (United States and Canada, Western Europe, Australia and New Zealand), to 3 to 5 percent in intermediate prevalence areas (Mediterranean countries, Japan, Central Asia, Middle East, and Latin and South America), to 10 to 20 percent in high prevalence areas (southeast Asia, China, sub-Saharan Africa) [23]
• An estimated 350 million persons worldwide are chronically infected with HBV [26].
• The 10th leading cause of death worldwide, HBV infections result in 500 000 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last accounts for 320,000 deaths per year[24,25, 27]
Race:
African Americans have a higher prevalence of the disease than persons of Hispanic origin or white persons.
Sex:
More cases occur in males than in females.
Age:
The earlier the disease is acquired, the greater the chance of developing chronic infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and persons who are elderly have an approximately 20-30% chance of developing chronic disease.

TRANSMISSION
• Perinatal transmission
• Horizontal transmission
• Transfusion
• Sexual transmission
• Percutaneous inoculation
• Nosocomial infection
• Organ transplantation


CLINICAL FEATURES

The spectrum of the symptoms varies from subclinical hepatitis to icteric hepatitis to fulmanant hepatitis during the acute phase and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.
• Acute phase [28]
o The incubation period is 1-6 months.
o Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic about 70%.
o Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis.
o Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.
o Icteric hepatitis is associated with the prodromal period, during which a serum sickness–like syndrome can occur. The symptoms are more constitutional and includes the following:
 Anorexia
 Nausea
 Vomiting
 Low-grade fever
 Myalgia
 Fatigability
 Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
 Right upper quadrant and epigastric pain (intermittent, mild to moderate)
 Extrahepatic manifestations of acute hepatitis may be heralded by a serum sickness-like syndrome manifested as fever, skin rashes, arthralgia and arthritis, which usually subside with the onset of jaundice. The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease [30, 31].
o Fulminant hepatic failure is unusual, occurring in approximately 0.1 to 0.5 percent of patients. They can present with [29]:
 Hepatic encephalopathy
 Somnolence
 Deepening jaundice
 Mental confusion
 Coma
• Chronic phase
o Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.
o Patients with chronic active hepatitis, especially during the replicative state, may complain of symptoms such as the following:
 Symptoms similar to those of acute hepatitis
 Fatigue
 Anorexia
 Nausea
 Mild upper quadrant pain or discomfort
 Hepatic decompensation

SIGNS
The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease [28].
• Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
Low-grade fever
o Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)
o Hepatomegaly (mildly enlarged soft liver)
Splenomegaly (5-15%)
o Palmar erythema (rarely)
Spider nevi (rarely)
• The physical examination of patients with chronic hepatitis B can reveal stigmata of chronic liver disease such as the following:
o Hepatomegaly
o Palmar erythema
o Spider angioma
• Patients with cirrhosis may have the following symptoms:
o Ascites
o Jaundice
o History of variceal bleeding
o Peripheral edema
o Gynecomastia
o Testicular atrophy
o Abdominal collateral veins (caput medusa)
COMPLICATIONS
1. Hepatocellular carcinoma [33]
• Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with HBV infection and cirrhosis
• HCV along with HBV increases the risk of HCC
2. HDV Super / Co infection
The prevalence of hepatitis D virus (HDV) co-infection among patients infected with HBV worldwide is 0-20%.
2. Glomerulonephritis [34]
• The most common type of glomerulonephritis (GN) described is membranous GN (MGN), mainly in children.
• However, membranoproliferative GN (MPGN) and, even more rarely, immunoglobulin A (IgA) nephropathy, have been identified.
• The prevalence rate of GN among patients with chronic HBV infection is not well known, although observations have been made in children that suggest a range of 11-56.2% but lower in US.
4. Polyarteritis nodosa [35]
• An association between HBV and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN).
• The clinical manifestations of the disease include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), gastrointestinal (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurological (eg, mononeuritis), and dermatological (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), gastrointestinal involvement, cardiomyopathy, and CNS involvement are associated with increased mortality.
5. Skin manifestations
o A variety of cutaneous manifestations are recognized, among which are hives and fleeting maculopapular rash, during the early course of viral hepatitis. Women are more prone to developing cutaneous manifestations.
o The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.
o Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.
6. Cardiopulmonary manifestations
o Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis.
o Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis.
7. Joint and neurologic manifestations
o Guillain-Barré syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis.
o Arthralgias and arthritis (serum sickness) subcutaneous nodules also may occur but are rare.
8. Hematologic and gastrointestinal tract manifestations
o Patients may develop pancreatitis.
o Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon.
o Diffuse intravascular coagulation may occur in patients with fulminant hepatitis.


DIFFRENTIAL DIAGNOSIS [36]
If patient has Hepatitis due to HBV, consider following differential diagnosis:

Alcoholic Hepatitis
Autoimmune Hepatitis
Cholangitis
Cirrhosis
Hemochromatosis
Hepatic Carcinoma, Primary
Hepatitis A
Hepatitis C
Hepatitis D
Hepatitis E
Hepatitis, Viral
Primary Sclerosing Cholangitis
Wilson Disease
Drug hepatotoxicity
Congestive heart failure
INVESTIGATIONS
Acute Hepatitis B [15]
• If patient has acute hepatitis B in early stages surface antigen(HBsAg), e antigen(HBeAg), IgM and IgG anticore antibodies and Hepatitis B viral DNA(HBV DNA) will be positive but Anti Hbe and Anti HBs will be negative
• If patient has acute resolving Hepatitis B HBsAg and IgM and IgG anti core antibodies will be positive, Anti Hbe may or may not be positive and HBV DNA and Anti HBs will be negative
• If patient has hepatitis B, serum/plasma aminotransferases (AST/ALT) can range from 500 to 10,000 IU/L.
• Bilirubin can be upto 500 micromoles/L.
• Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HBV infection
• Alkaline phosphatase levels are usually <2x the upper limit of normal, but higher if there is cholestasis
• Modest falls in serum albumin level may accompany the illness
• If in a patient of acute Hepatitis B, prothrombin time (PT) is prolonged by more than 5 seconds, suggest developing hepatic decompensation
• If patient has Hepatitis B, advise CBC. Blood picture may show mild lymphocytosis is not uncommon. Indices of low-grade hemolysis are not uncommon
• An ultrasound scan may be required when alternative diagnoses warrant exclusion and should assess vessel patency and evaluate any evidence supporting unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with fulminant hepatic failure.
• Blood urea and serum creatinine should be obtained at baseline.
• Screen for other sexually transmitted infections in cases of sexually-acquired hepatitis or if otherwise appropriate

Chronic Hepatitis B [15]

• In most cases the only abnormality to be found will be mildly abnormal aminotransferase levels (usually <100 IU/L) and in many the liver function tests will be normal. Only in severe late stage liver disease do the liver function tests become grossly abnormal
• If patient has chronic Hepatitis B having high infectivity HBsAg, IgG anticore antibody and HBV DNA will be present in blood, HBeAg may or may not be positive and IgM anti core antibody, Anti Hbe and Anti HBs will be negative.
• If patient has chronic Hepatitis B having low infectivity HBsAg and IgG anticore antibody will be positive, Anti HBe may or may not be positive and HBeAg, IgM anticore antibody, HBV DNA and Anti HBs are negative
• If patient had Hepatitis B which has now resolved IgG anticore antibodies will be present, Anti Hbe and Anti HBs may or may not be present and HBsAg, HBeAg, IgM anti core antibodies and HBV DNA will not be present
• If person is successfully vaccinated against Hepatitis B only Anti HBs will be present but all other markers of HBV will be negative
• If patient has Hepatitis B other tests like liver biopsy (for assessment of chronic disease) should be performed only by specialists in this field
• If patient has Hepatitis B, liver biopsy should be considered in HBeAg negative patients who have serum HBV DNA levels of 10(4) to 10(5) copies/mL and normal or mildly elevated ALT to determine if treatment is warranted.


TREATMENT
If patient has Hepatitis B he/ she should be given detailed education about their disease, modes of spread and things to be avoided. If patient has acute hepatitis B treatment is symptomatic with oral hydration, rest and admission if patient is severely ill. If patient has chronic hepatitis B treatment is with alpha interferon. Other promising treatments, alone or in combination with interferon, include lamivudine, famciclovir, thymosine alpha, adefovir and ribavarin
NON PHARMACOLOGICAL TREATMENT
• Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and oro-genital contact, until they have become non-infectious or their partners have been successfully vaccinated [15].
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s) and routes of transmission of infection and advised not to donate blood
• Hepatitis B is a notifiable disease.
• Patient should avoid alcohol
• Patient should avoid hepatotoxic drugs

PHARMACOLOGICAL TREATMENT

Acute Icteric Hepatitis [15]

• Mild/moderate (80%), manage as an outpatient emphasizing rest and oral hydration.
• Nausea and vomiting are treated with antiemetics
• Paracetamol may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/d in adults
• Severe attack with vomiting, dehydration, or signs of hepatic decompensation (change in conscious level or personality), admit to hospital.
• Specific Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B.
• Lamivudine, telbivudine or entecavir is preferred.
a. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation.
b. IFN-alpha is contraindicated.

Chronic Hepatitis B

• All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart [21].
• Treatment options include interferon, lamuvidine, adefovir and other new drugs.

EVALUATION FOR TREATMENT
Patients Not Initially Considered for Treatment [21]
HBeAg positive, HBV DNA _> 20,000 IU/ml and normal ALT
● ALT every 3-6 months, more often if ALT becomes elevated
● If ALT levels are between 1-2 times ULN, recheck ALT 1-3 months; consider liver biopsy if age >40, ALT borderline or mildly elevated on serial tests.
Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis
● If ALT _> 2 times ULN for 3-6 months and HBeAg_positive, HBV DNA >_ 20,000 IU/ml,
consider liver biopsy and treatment.
● Consider screening for HCC in relevant population
Inactive HBsAg carrier state (HBeAg-negative, anti-HBe Positive Patients with
Normal ALT Levels and HBV DNA <2,000IU/ml)
● ALT every 3 months for 1 year, if persistently normal, ALT every 6-12 months
● If ALT > 1-2 times ULN, check serum HBV DNA level and exclude other causes of liver disease.
Consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently >20,000 IU/ml.
Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis
● Consider screening for HCC in relevant population

Recommendations for Monitoring Patients with Chronic HBV Infection [21]
• HBeAg-positive and HBeAg-negative patients who meet criteria for chronic hepatitis B should be evaluated for treatment.
HBeAg-positive patients:
• HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals.
• ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months.
• Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/ml after a 3-6 month period of elevated ALT levels between 1-2 times ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/ml and are>40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy showsmoderate/severe inflammation or significant fibrosis.
• Patients who remain HBeAg positive with HBV DNA levels >20,000
IU/ml after a 3-6 month period of elevated ALT levels >2 times ULN should be considered for treatment.
• HBeAg-negative patients:
● HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml should be tested for ALT every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every
6-12 months.
● Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit.

AIMS OF TREATMENT [21]

• The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC.
• Parameters used to assess treatment response include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology.
Treating chronic hepatitis B [21]:
Currently, six therapeutic agents have been approved for the treatment of adults with chronic hepatitis B.
For HBeAg-positive patients, viral suppression with currently approved treatments can be sustained in 50%-90% patients if treatment is stopped after HBeAg seroconversion is achieved.
For HBeAg-negative patients, relapse is frequent even when HBV DNA has been suppressed to undetectable levels by PCR assays for more than a year; thus, the endpoint for stopping treatment is unclear.
While IFNs are administered for predefined durations, NAs are usually administered until specific endpoints are achieved.
patients with minimal disease and those who are unlikely to achieve sustained response should not be treated with NA, particularly if they are young (<30 years).

Interferon
Interferons (IFNs) have antiviral, antiproliferative, and immunomodulatory effects. IFN- alfa has been shown to be effective in suppressing HBV replication and in inducing remission of liver disease. However, its efficacy is limited to a small percentage of highly selected patients.
Efficacy in Various Categories of Patients.
1. HBeAg-positive chronic hepatitis B with the following
a. Persistent or intermittent elevation in ALT.
Significantly higher percentage of IFN alfa treated patients has a virologic response compared with untreated controls. High pretreatment ALT (greater than twice the upper limit of normal) and lower levels of serum HBV DNA are the most important predictors of a response to IFN alfa therapy.
b. Normal ALT.
HBeAg seroconversion occurs in less than 10% of these patients.

c. Asian patients.
Trials in Asian patients with HBeAg positive chronic hepatitis B found that the response in patients with normal ALT was poor, but the response in patients with elevated ALT was similar to that in Caucasian patients.
d. Children.
The efficacy of IFN-alpha is similar to that in adults.

2. HBeAg-negative chronic hepatitis B

End-of-treatment response ranges from 38% to 90% in treated patients compared with only 0% to 37% of controls. However, approximately half of the responders relapse when therapy is discontinued, and relapses can occur up to 5 years post-therapy. Longer duration of treatment, 24 months verses 6-12 months, may increase the rate of sustained response

3. Nonresponders to IFN-alpha treatment
Retreatment of IFN-alpha nonresponders with IFN-alpha alone is associated with a very low rate of response. Limited data suggest that 20%-30% HBeAg-negative patients who relapsed or had no response during previous IFN- alpha treatment had a sustained response after a second course of IFN-alpha

4. Decompensated cirrhosis
Approximately 20% to 40% of patients with HBeAg positive chronic hepatitis B develop a flare in their ALT values during IFN-alpha treatment. In patients with cirrhosis, the flare may precipitate hepatic decompensation.

Durability of Response and Long-term Outcome of IFN-alpha treated Patients.
• IFN-alpha induced HBeAg clearance has been reported to be durable in 80% to 90% of patients after a follow-up period of 4 to 8 years.
• Studies in Europe and the United States reported that delayed clearance of HBsAg occurred in 12% to 65% of patients within 5 years of HBeAg loss, but delayed HBsAg clearance was not observed in studies on Chinese patients.
• Studies comparing the outcome of responders versus nonresponders found that patients who cleared HBeAg had better overall survival and survival free of hepatic decompensation; the benefit was most apparent in patients with cirrhosis.

• Contrary to HBeAg-positive patients, relapse after cessation of IFN- alpha treatment is frequent in HBeAg-negative patients, with sustained response rates of only 15%-30%.

• Among the long-term responders, approximately 20% cleared HBsAg after 5 years of follow-up, and the risks of progression to cirrhosis, HCC, and liver-related deaths were reduced

Dose Regimen.
• IFN-alpha is administered as subcutaneous injections.
• The recommended dose for adults is 5MU daily or 10 MU thrice weekly and for children 6 MU/m2 thrice weekly with a maximum of 10 MU.
• The recommended duration of treatment for patients with HBeAg positive chronic hepatitis B is 16 to 24 weeks.
• Current data suggest that patients with HBeAg-negative chronic hepatitis B should be treated for at least 12 months, and one study suggested that 24 months treatment may increase the rate of sustained response

Pegylated Interferon alfa (pegIFN-alpha)
• PegIFN-alpha has the advantages of more convenient administration and more sustained viral suppression.
• Clinical trials suggest that the efficacy of pegIFN-alpha is similar to or slightly better than standard IFN alpha

Dose Regimen.
• PegIFN-alpha 2a is the only pegylated interferon approved for the treatment of chronic hepatitis B
• The recommended dose is 180 mcg weekly for 48 weeks.
• Whether longer duration of treatment (>48 week) will result in higher rates of sustained response in HBeAg negative patients remains to be determined.
Predictors of Response to Standard and PegIFN-alpha.
• In HBeAg-positive patients, the strongest predictor of HBeAg seroconversion to standard and pegIFN-alpha is the pretreatment ALT level.
• Other factors include high histologic activity index, low HBV DNA level, and more recently some studies have suggested that persons infected with HBV genotypes A and B respond better than those with genotypes C and D.

Adverse Events.
Standard IFN-alpha and pegIFN-alpha have similar side effect profiles.
• The most common side effect is an initial influenza-like illness: fever, chills, headache, malaise and myalgia.
• Other common side effects include fatigue, anorexia, weight loss and mild increase in hair loss.
• IFN-alpha has myelosuppressive effects but significant neutropenia (<1000/mm3) or thrombocytopenia (<50,000/mm3) are uncommon except in patients who have decreased cell counts prior to treatment.
• IFN-alpha treatment is accompanied by a flare in ALT in 30%-40% of patients.
• Hepatitis flares are considered to be an indicator of a favorable response but they can lead to hepatic decompensation, especially in patients with underlying cirrhosis.
• The most troublesome side effect of IFN-alpha is emotional lability: anxiety, irritability, depression and even suicidal tendency.
• IFN-alpha has been reported to induce the development of a variety of autoantibodies.
• Both hyper- and hypo-thyroidism that require treatment have been reported.
• Rarely, retinal changes and even impaired vision have been reported.

Lamivudine
Efficacy in Various Categories of Patients.
• Lamivudine monotherapy is effective in suppressing HBV replication and in ameliorating liver disease.
• HBeAg seroconversion after a 1-year course of lamivudine treatment is similar to that of a 16-week course of standard IFN-alpha but lower than that of a 1-year course of pegIFN- alpha.
1. HBeAg-positive chronic hepatitis B with the following

a. Persistent or intermittent elevation in ALT.
• HBeAg seroconversion occurred in 16% to 18% of patients compared with 4% to 6% of untreated controls.
• HBeAg seroconversion rates increased with the duration of treatment to 50% after 5 years of continued treatment.
b. Normal ALT levels.
• In patients with pretreatment ALT levels less than 2 times normal, the HBeAg seroconversion rate is less than 10% after 1 year and 19% after 3 years of treatment.
c. Asian patients.
• Asians respond similarly to lamivudine as Caucasian patients.
d. Children.
• In children HBeAg seroconversion is observed in about 22% of the lamivudine-treated children versus 13% placebo controls (P = 0.06).
• HBeAg seroconversion is increased to 34% after 2 years of continuous treatment.
• Lamivudine resistant HBV mutation is detected in 19%, 49% and 64% of patients after 1, 2 and 3 years of treatment, respectively.
• These data indicate that lamivudine is safe and effective in children but the benefit must be carefully balanced against the risk of selecting drug resistant mutants.

2. HBeAg-negative chronic hepatitis B
• Lamivudine has been shown to benefit patients with HBeAg-negative chronic hepatitis B.
• Several studies have reported that serum HBV DNA is suppressed to undetectable levels by PCR assays in 60% to 70% patients after 1 year of treatment.
• However, the vast majority (90%) of patients relapsed when treatment was stopped.
• Extending the duration of treatment resulted in a progressively lower rate of response due to the selection of lamivudine-resistant mutants.
• In one study of 201 patients, virologic remission (undetectable HBV DNAby PCR assay) decreased from 73% at 12 months to 34% at 48 months while biochemical remission decreased from 84% to 36%.

3. Nonresponders to IFN-alpha treatment
• A multicenter trial in IFN-alpha nonresponders found that patients had a similar HBeAg seroconversion rate to lamivudine alone (18%), a combination of lamivudine and IFN-alpha (12%) or placebo (13%) indicating that response of IFN-alpha nonresponders to lamivudine is similar to treatment-naive patients, and that retreatment with combination of IFN-alpha and lamivudine did not confer any added benefit compared with retreatment with lamivudine monotherapy.
4. Bridging Fibrosis and Compensated Cirrhosis

• Antiviral therapy can improve clinical outcomes in patients with advanced fibrosis who have maintained viral suppression.

5. Decompensated cirrhosis

• Lamivudine treatment is well tolerated and can stabilize or improve liver function in patients with decompensated cirrhosis thereby obviating or delaying the need for liver transplant.
• However, these studies showed that clinical benefit takes 3-6 months, and that HCC can occur even among patients with clinical improvement.
• Thus, prompt initiation of treatment and continued HCC surveillance are warranted.

Durability of Response
• Several factors have been found to be associated with increased durability of lamivudine-induced HBeAg seroconversion including longer duration of consolidation treatment—defined as duration of treatment beyond the time after HBeAg seroconversion, younger age, lower HBV DNA level at the time treatment was stopped, and genotype B vs. C.
• Although there are no good direct comparison data, it appears that the durability of lamivudine-induced HBeAg seroconversion is less than that for IFN-alpha.

• Among HBeAg-negative patients, the durability of viral suppression after 1-year of lamivudine treatment is less than 10%.

• One small study reported that the durability of virologic response was improved to 50% in patients who had completed 2 years of treatment and had persistently undetectable HBV DNA by PCR assay during year 2

Lamivudine Resistance.
• Selection of lamivudine-resistant mutations is the main concern with lamivudine treatment.
• Genotypic resistance can be detected in 14% to 32% after 1 year of lamivudine treatment and increases with the duration of treatment to 60% to 70% after 5 years of treatment
• Factors associated with an increase rate of lamivudine resistance include long duration of treatment, high pretreatment serum HBV DNA level, and a high level of residual virus after initiation of treatment
• Lamivudine resistance is significantly higher in patients whose serum HBV DNA level exceeded 200 IU/ml (1,000 copies/ml) after 6 months of treatment compared to those with lower HBV DNA levels (63% vs. 13%).
• Virologic breakthrough is usually followed by biochemical breakthrough (increase in ALT after initial normalization), and in some patients may be associated with acute exacerbations of liver disease and rarely hepatic decompensation and death
• Hepatitis flares may also occur after withdrawal of treatment due to rapid outgrowth of wild type virus, but two studies in Asia found that the occurrence of hepatitis flares and hepatic decompensation were similar among patients with lamivudine breakthrough who stopped or continued lamivudine treatment.
Long-term Outcome of Lamivudine-treated Patients.
• Follow-up of patients receiving continued lamivudine treatment showed that the rates of maintained virologic and biochemical response decreased with time due to selection of drug-resistant mutants.
Dose Regimen.
• The recommended dose of lamivudine for adults with normal renal function (creatinine clearance >50 ml/min) and no HIV co infection is 100 mg orally daily.
• The recommended dose for children is 3 mg/kg/d with a maximum dose of 100 mg/d. Dose reduction is necessary for patients with renal insufficiency
• The end point of treatment for HBeAg-positive patients is HBeAg seroconversion.
• Liver chemistries should be monitored every 3 months and HBV DNA levels every 3-6 months while on therapy, and HBeAg and anti-HBe tested at the end of 1 year of treatment and every 3-6 months thereafter.
• Treatment may be discontinued in patients who have confirmed HBeAg seroconversion (HBeAg loss and anti-HBe detection on 2 occasions 1-3 months apart) and have completed at least 6 months of consolidation therapy after the appearance of anti-HBe.
• The durability of response after cessation of treatment is expected to be 70% to 90%
• All patients should be closely monitored after treatment is discontinued (every 1-3 months for the first 6 months, and every 3-6 months thereafter)
• Reinstitution of lamivudine treatment is usually effective in patients who have not developed resistance.
• Treatment may be continued in patients who have not achieved HBeAg seroconversion and have no evidence of breakthrough infection as HBeAg seroconversion may occur with continued treatment.
• With the availability of newer therapies with lower risk of drug resistance, a switch to an alternative treatment may be considered particularly in patients who have received lamivudine for more than 2 years.
• In patients who have breakthrough infection, testing for lamivudine-resistant mutants should be performed when possible.
• Patients whose ALT and HBV DNA levels remain significantly lower than pretreatment values may be maintained on lamivudine temporarily without resorting to rescue therapy but it must be recognized that compensatory mutations will be selected during continued treatment leading to subsequent viral rebound and possibly hepatitis flares.
• The end point of treatment for HBeAg-negative chronic hepatitis B is unknown.
• Post-treatment relapse can occur even in patients with persistently undetectable serum HBV DNA by PCR assay.
• Because of the need for long durations of treatment, lamivudine is not an optimal first-line treatment for HBeAg-negative chronic hepatitis B.
Adverse Events.
In general, lamivudine is very well tolerated. Various adverse events including a mild (2- to 3-fold) increase in ALT level have been reported in patients receiving lamivudine, but these events occurred in the same frequency among the controls.

Adefovir Dipivoxil
Efficacy in Various Categories of Patients.
1. HBeAg positive chronic hepatitis B
• Adefovir for 1-year is beneficial in patients with HBeAg-positive chronic hepatitis and that the 10-mg dose has a more favorable risk benefit profile.
• Cumulative HBeAg seroconversion rates appeared to increase during the second and third years but the exact number of patients who achieved HBeAg seroconversion was unclear.
• Some studies have reported that 20%-50% of patients receiving the 10 mg dose of adefovir have primary nonresponse indicating that the approved dose of adefovir may be suboptimal.

2. HBeAg negative chronic hepatitis
Patients who are HBeAg negative histologic response is 64% versus 33%; normalization of ALT 72% versus 29% ; and undetectable serum HBV DNA by PCR assay, 51% versus 0% at 48 weeks while still increased after 3- 5 years


3. Children
Clinical trials of adefovir in children are ongoing.
4. Decompensated cirrhosis
Adefovir has not been evaluated as a primary treatment for patients with decompensated cirrhosis.
5. Lamivudine-resistant hepatitis B
a. Decompensated cirrhosis and liver transplant recipients
• Among the patients who complets 48 weeks of treatment, 81% of the pre- and 34% of the post-transplant patients have undetectable HBV DNA by PCR assay, and 76% and 49%, respectively have normalization of ALT.
• Child-Turcotte-Pugh score improves in more than 90% of the pre-transplant patients, and 1-year survival is 84% for the pre- and 93% for the post-transplant patients.
b. Compensated liver disease
Study in patients with compensated chronic hepatitis B and lamivudine resistance found no differences in HBV DNA suppression and ALT normalization in persons treated with the combination of lamivudine and adefovir compared to those receiving adefovir alone,204 patients who discontinued lamivudine were more likely to develop ALT flares during the first 12 weeks of adefovir monotherapy.
c. HIV and HBV coinfection
Adefovir when added to existing HIV treatment regimens which included lamivudine 150 mg bid has also been shown to be effective in decreasing serum HBV DNA levels in patients with HIV and HBV coinfection and lamivudine-resistant HBV.
Adefovir Resistance.
• Resistance occurs at a slower rate during adefovir treatment compared to lamivudine
• Risk factors for adefovir resistance that have been identified include suboptimal viral suppression and sequential monotherapy.
• Sequential treatment with lamivudine followed by adefovir had also been reported to select for dual-resistant HBV mutants.
Dose Regimen.
• The recommended dose of adefovir for adults with normal renal function (creatinine clearance > 50 ml/min) is 10 mg orally daily. The dosing interval should be increased in patients with renal insufficiency.
• Adefovir has not been approved for use in children. Adefovir at the 10 mg dose is ineffective in suppressing HIV replication.
• For patients with HBeAg-positive chronic hepatitis B, treatment may be discontinued for those who have confirmed HBeAg seroconversion and have completed an additional 6 months of consolidation treatment.
• Treatment may be continued in patients who have not achieved HBeAg seroconversion but in whom HBV DNA levels remain suppressed.
• For patients with HBeAg-negative chronic hepatitis B, continued treatment (beyond 1 year) is needed to maintain the response.
• For most patients with lamivudine-resistant mutants, particularly those with decompensated cirrhosis or recurrent hepatitis B post-transplant, long-term treatment will be required.
• Increasing data indicate that lamivudine should be continued indefinitely after the addition of adefovir to reduce the risk of adefovir resistance.
• Approximately 30% of patients who have no prior treatment with NAs have primary nonresponse to adefovir, defined as a <2 log drop in HBV DNA after 6months of treatment.
• Alternative treatments should be considered for these patients.
Adverse Events.
Adefovir in 10 mg doses is well tolerated and has a similar side effect profile as placebo
• Nephrotoxicity has been reported in 3% of patients with compensated liver disease after 4-5 years of continued adefovir therapy, and in 12% of transplant recipients and 28% of patients with decompensated cirrhosis during the first year of therapy.
• Monitoring of serum creatinine every 3 months is necessary for patients with medical conditions that predispose to renal insufficiency and in all patients on adefovir for more than 1 year. More frequent monitoring should be performed in patients with pre-existing renal insufficiency.

Entecavir (Baraclude)

In vitro studies showed that entecavir is more potent than lamivudine and adefovir and is effective against lamivudine-resistant HBV mutants although the activity is lower compared to wild-type HBV.

Efficacy in Various Categories of Patients.
1. HBeAg-positive patients
Serum HBV DNA is undetectable by PCR in 81% vs. 39%, and normalization of ALT occurred in 79% vs. 68% of patients who continue entecavir and lamivudine treatment, respectively for 48 weeks

2 HBeAg-negative patients
At week 48, entecavir resulted in significantly higher rates of histologic (70% vs. 61%), virologic (90% vs. 72%) and biochemical (78% vs. 71%) responses compared to lamivudine.
3. Decompensated cirrhosis / recurrent hepatitis B after
liver transplantation
Studies on the safety and efficacy of entecavir in patients with decompensated cirrhosis are ongoing.
4.Lamivudine-refractory HBV
At week 48, entecavir resulted in significantly higher rates of histologic (55% vs. 28%), virologic (21% vs. 1%) and biochemical (75% vs. 23%) responses compared to lamivudine in a phase 2 trial.
5. Adefovir-resistant HBV
In vitro studies showed that entecavir is effective in suppressing adefovir-resistant HBV mutants.
Entecavir Resistance.
• Virologic breakthrough was rare in nucleoside-naı¨ve patients, and was observed in only 3% of patients by Week 96 of entecavir treatment in the two phase III clinical trials.
• Resistant mutations to lamivudine and entecavir were detected in only two (_1%) patients while resistant mutations to lamivudine only were found in three patients.
• However, virologic breakthrough was detected in 7% of patients after 48 weeks and in 16% after 96 weeks of treatment in the phase III trial of lamivudine refractory patients.
• Lamivudine should be discontinued when patients are switched to entecavir to decrease the risk of entecavir resistance.
• In vitro studies show that entecavir-resistant mutations are susceptible to adefovir, but there are very little clinical data on the efficacy of adefovir in patients with entecavir-resistant HBV
Adverse Events.
Entecavir had a similar safety profile as lamivudine in clinical trials.
Studies in rodents exposed to doses 3-40 times that in humans found an increased incidence of lung adenomas, brain gliomas and HCCs. To date, no difference in the incidence of HCC or other neoplasm has been observed between patients who received entecavir versus lamivudine.

Other Therapies

Other therapies approved for use in chronic hepatitis B include
• L-deoxythymidine (Telbivudine/LdT, Tyzeka)
• Emtricitabine (Emtriva, FTC)
• Clevudine (LFMAU, 2_-fluoro-5-methyl-beta-Larabinofuranosyl uracil)
• Thymosin

Combination Therapies
• Combinition therapies have been proven to be more effective than monotherapy in the treatment of HIV and HCV infections.
• Various combination therapies have been evaluated; to date, none of the combination therapies has been proven to be superior to monotherapy in inducing a higher rate of sustained response.
• Although several combination therapies have been shown to reduce the rate of lamivudine resistance compared to lamivudine monotherapy, there are as yet no data to support that combination therapies will reduce the rate of resistance to antiviral compounds that have a low risk of drug resistance when used alone.
Recommendations for the Treatment of Chronic Hepatitis B:

• Treatment is indicated if the risk of liver-related morbidity and mortality in the near future (5-10 years) and the likelihood of achieving maintained viral suppression during continued treatment are high.
• Treatment is also indicated if the risk of liver-related morbidity and mortality in the foreseeable future (10-20 years) and the likelihood of achieving sustained viral suppression after a defined course of treatment are high.
• Treatment is not indicated if the risk of liver-related morbidity or mortality in the next 20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are low.
• Because of the fluctuating nature of chronic HBV infection, the risk of liver-related morbidity and mortality and the likelihood of response may vary as patient progresses through the course of chronic HBV infection. Thus, continued monitoring is essential for risk assessment.

Recommendations on Whom to Treat and with What Antiviral Agent [21]
Patients with HBeAg-positive chronic hepatitis B
a. ALT greater than 2 times normal or moderate/ severe hepatitis on biopsy, and HBV DNA >20,000 IU/ml.
These patients should be considered for treatment.
● Treatment should be delayed for 3 to 6months in persons with compensated liver disease to determine if spontaneous HBeAg seroconversion occurs.
● Patients with icteric ALT flares should be promptly treated.
● Treatment may be initiated with any of the 6 approved antiviral medications, but pegIFN-alpha, adefovir or entecavir are preferred.
b. ALT persistently normal or minimally elevated (<2 times normal).
These patients generally should not be initiated on treatment. (
● Liver biopsy may be considered in patients with fluctuating or minimally elevated ALT levels especially in those above 40 years of age.
● Treatment may be initiated if there is moderate or severe necroinflammation or significant fibrosis on liver biopsy.
c. Children with elevated ALT greater than 2 times normal.
These patients should be considered for treatment if ALT levels remain elevated at this level for longer than 6 months.
● Treatment may be initiated with IFN-alpha or lamivudine.
Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA >20,000 IU/ml and elevated ALT>2 times normal)
These patients should be considered for treatment.
● Liver biopsy may be considered for HBeAg-negative patients with lower HBV DNA levels (2,000-20,000 IU/ml) and borderline normal or minimally elevated ALT levels.
● Treatment may be initiated if there is moderate/ severe inflammation or significant fibrosis on biopsy.
● Treatment may be initiated with any of the 6 approved antiviral medications but pegIFN-alpha, adefovir or entecavir are preferred in view of the need for long-term treatment
Patients who failed to respond to prior IFN-alpha (standard or pegylated) therapy
May be retreated with nucleoside analogues (NA) if they fulfill the criteria
Patients who failed to achieve primary response as evidenced by <2 log decrease in serum HBV DNA level after at least 6 months of NA therapy
Should be switched to an alternative treatment.
Patients who develop breakthrough infection while receiving NA therapy
● Compliance should be ascertained and treatment resumed in patients who have had long lapses in medications.
● A confirmatory test for antiviral-resistant mutation should be performed if possible to differentiate primary non-response from breakthrough infection and to determine if there is evidence of multi-drug resistance (in patients who have been exposed to more than one NA treatment).
● All patients with virologic breakthrough should be considered for rescue therapy.
● For patients in whom there was no clear indication for hepatitis B treatment and who continue to have compensated liver disease, withdrawal of therapy may be considered but these patients need to be closely monitored and treatment reinitiated if they experience severe hepatitis flares.
Treatment of patients with lamivudine (or telbivudine)- resistant HBV
a. If adefovir is used, lamivudine (or telbivudine) should be continued indefinitely to decrease the risk of hepatitis flares during the transition period and to reduce the risk of subsequent adefovir resistance.
b. If entecavir is used, lamivudine or telbivudine should be stopped as continued presence of lamivudine (or telbivudine)-resistant mutations will increase the risk of entecavir resistance.
Treatment of patients with adefovir-resistant HBV
a. In patients with no prior exposure to other NA, lamivudine or entacavir may be added.
b. In patients with prior lamivudine resistance in whom lamivudine had been stopped when treatment was switched to adefovir, lamivudine may be added but the durability of response is unknown and reemergence of lamivudine-resistant mutations has been reported
Treatment of patients with entecavir-resistant HBV
Adefovir can be used as it has been shown to have activity against entecavir-resistant HBV in in vitro studies, but clinical data are lacking. Patients with compensated cirrhosis
Treatment should be considered for patients with ALT >2 times normal, and for patients with normal or minimally elevated ALT if serum HBV DNA levels are high (>2,000 IU/ml).
a. Patients with compensated cirrhosis are best treated with NAs because of the risk of hepatic decompensation associated with IFN-alpha related flares of hepatitis.
In view of the need for long-term therapy, adefovir or entecavir is preferred.
Patients with decompensated cirrhosis
Treatment should be promptly initiated with a NA that can produce rapid viral suppression with low risk of drug resistance.
a. Lamivudine or adefovir may be used as initial treatment preferably in combination to reduce the risk of drug resistance and to achieve rapid virus suppression.
Telbivudine may be substituted for lamivudine but clinical data documenting its safety and efficacy in patients with decompensated cirrhosis are lacking.
b. Entecavir would be an appropriate treatment in this setting but clinical data documenting its safety and efficacy in patients with decompensated cirrhosis are lacking.
c. Treatment should be coordinated with a transplant center.
d. IFN-alpha /pegIFN alpha should not be used in patients with decompensated cirrhosis.
In patients with inactive HBsAg carrier state
Antiviral treatment is not indicated, but these patients should be monitored
Duration of nucleoside analogue treatment
a. HBeAg-positive chronic hepatitis B — Treatment should be continued until the patient has achieved HBeAg seroconversion and completed at least 6 months of additional treatment after appearance of anti-HBe.
● Close monitoring for relapse is needed after withdrawal of treatment.
b. HBeAg-negative chronic hepatitis B — Treatment should be continued until the patient has achieved HBsAg clearance
c. Compensated cirrhosis — These patients should receive long-term treatment. However, treatment may be stopped in HBeAg-positive patients if they have confirmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy and in HBeAg-negative patients if they have confirmed HBsAg clearance.
● Close monitoring for viral relapse and hepatitis flare is mandatory if treatment is stopped.
d. Decompensated cirrhosis and recurrent hepatitis B post-liver transplantation — Life-long treatment is recommended

Special Populations [21]
Co infection with HBV and HCV
There is scanty information on the treatment of HBV/ HCV coinfection and recommendations on treatment for HBV/HCV coinfection cannot be made at this time.

Coinfection with HBV and HDV

High-dose IFN-alpha (9 MU 3 times a week) or pegIFN-_ for 1 year appears to have long-term beneficial effects in patients with chronic hepatitis D.

Co-Infection with HBV and HIV

Patients who meet criteria for chronic hepatitis B should be treated.
● Liver biopsy should be considered in patients with fluctuating or mildly elevated ALT (1-2 x normal).
Patients who are not on HAART and are not anticipated to require HAART in the near future should be treated with an antiviral therapy that does not target HIV, such as pegIFN-alpha, adefovir or entecavir.
Although telbivudine does not target HIV, it should not be used in this circumstance.
Patients in whom treatment for both HBV and HIV is planned should receive therapies that are effective against both viruses: lamivudine plus tenofovir or emtricitabine plus tenofovir are preferred.
Patients who are already on effective HAART that does not include a drug active against HBV may be treated with pegIFN alpha, adefovir or entecavir. In patients with lamivudine resistance, tenofovir or adefovir should be added.
When HAART regimens are altered, drugs that are effective against HBV should not be discontinued
Recommendations for Treatment of Hepatitis B carriers who require Immunosuppressive or Cytotoxic Therapy [21]
• HBsAg testing should be performed in patients who are at high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy.
• Prophylactic antiviral therapy is recommended for HBV carriers at the onset of cancer chemotherapy or of a finite course of immunosuppressive therapy.
a. Patients with baseline HBV DNA <2,000 IU/ml level should continue treatment for 6 months after completion of chemotherapy or immunosuppressive therapy.
b. Patients with high baseline HBV DNA (>2,000 IU/ml) level should continue treatment until they reach treatment endpoints as in immunocompetent patients.
c. Lamivudine or telbivudine can be used if the anticipated duration of treatment is short (<12 months).
d. Adefovir or entecavir is preferred if longer duration of treatment is anticipated. Entecavir has more rapid onset of action than adefovir and may be more appropriate in this setting.
e. IFN-alpha should be avoided in view of the bone marrow suppressive effect.
Treatment of Hepatitis B in Dialysis Patients


• Treatment is indicated in HBsAg-positive patients with evidence of disease activity, as indicated by viral replication and elevated transaminase levels, preferably corroborated by examination of liver histology.
• A level of 10(5) copies/mL for HBV DNA has been recommended to justify treatment, based upon sensitivity limits of quantitative assays [37].
• With the advent of more sensitive quantitative assays, it remains to be investigated whether a lower cut-off level may be more appropriate. It is important to realize that HBeAg can be negative in patients with precore- or core promotor-mutant infection despite active disease [37].
• In view of the side effects profile, lamivudine given for at least one year appears to be a better choice than interferon-alfa in dialysis patients.
• Available results suggest that the efficacy and the incidence of drug-resistance with lamivudine therapy appear similar to patients without renal failure [37].
• However, the optimal duration of treatment and the management of lamivudine-resistant HBV variants remain to be determined.






Treatment of complications
1. Glumerulonephritis:

INF-a therapy has been successful in treating HBV-related GN. A regimen of 5 million units of IFN-a subcutaneously daily for 4 months has achieved HBsAg seroconversion with improvement of GN. It also has been reported that IFN-a given at a dose of 3 million units 3 times per week led to improvement of proteinuria only in patients with mesangial proliferative GN but not in patients with MPGN. Finally, a single case report described the resolution of this complication after liver transplantation
2. Polyarteritis nodosa
• Although corticosteroids and immunosuppressive agents may be beneficial for treating vasculitis, they potentially may have a deleterious effect on the course of HBV liver disease because of viral reactivation, particularly after the withdrawal of treatment.
• Adenine arabinoside, an antiviral drug, and IFN-a, an immunomodulator and antiviral protein, have been used in conjunction with plasmapheresis and a short course of corticosteroids, with promising results. Because of the fact that this is a rare complication, to date no reports have been published on the use of the newer therapies for HBV that include the nucleoside analogue, lamivudine


Liver transplantation for chronic hepatitis B virus infection
• Despite advances in treatment of chronic hepatitis B (HBV), liver transplantation remains the only hope for many patients with end-stage liver disease due to HBV [38].
• The high rate of HBV reinfection after liver transplantation is probably due to enhanced virus replication resulting from immunosuppression or from direct stimulatory effects of steroid therapy on the glucocorticoid-responsive enhancer region of the HBV genome
• Factors associated with a lower rate of graft reinfection and improved survival include:
1. HBeAg negative
2. Lower levels of serum HBV-DNA negative (by hybridization or other non-PCR-based assays)
3. Fulminant hepatitis B
4. Coexistent hepatitis D virus (HDV) infection
• HBV reinfection is diagnosed by the reappearance of HBsAg in the serum. Most reinfected patients are also HBeAg positive and have high levels of circulating HBV DNA [39]
• Reinfection is almost always accompanied by recurrent liver disease which is often severe and rapidly progressive [40]. If untreated, cirrhosis occurs within one to two years of reinfection.
• Active and passive immunoprophylaxis and antiviral strategies have been tried to prevent or delay graft reinfection.
• Currently, the most effective prophylaxis involves the use of combination prophylaxis of HBIG and lamivudine or adefovir.
• HBIG is usually given intravenously as a 10,000 IU bolus dose during the anhepatic phase followed by daily doses during the first week.
• Subsequent doses are either given monthly or in accordance with anti-HBs titers.
• A trough anti-HBs titer of at least 100 IU/ L is thought to be protective.
• However, some studies have suggested that the rate of reinfection can be reduced further in patients with anti-HBs titers consistently above 500 IU/l [41, 42].
• Active immunization using standard hepatitis B vaccines has been studied to reduce the need for life-long HBIG prophylaxis.
• Combination of HBIG and antiviral therapy has reduced recurrent hepatitis B to less than 10 percent with resultant improvement in patient and graft survival

Pregnancy and Hepatitis B

• Pregnancy is well-tolerated by women who are chronic carriers of hepatitis B. Reactivation of the virus and exacerbation of the disease during or after gestation are uncommon [43]. The placenta forms an excellent barrier against transmission of this large virus, and intrauterine infection with hepatitis B is rare. However, transplacental transmission due to leakage can occur, such as during a threatened abortion [43, 44].
• The major problem for women who are chronic carriers of hepatitis B is the risk of maternal to infant (vertical) transmission at delivery due to exposure to maternal blood in the birth canal.
• Routine prenatal screening of all pregnant women for HBsAg is now the standard of care, as is universal hepatitis B vaccination of all newborns at birth [45].
• Transmission at birth is more likely if the mother is hepatitis B e antigen (HBeAg) positive or has high circulating levels of hepatitis B DNA (HBV DNA) [46,47]. Appropriate immunoprophylaxis of the newborn with both hepatitis B hyperimmune globulin (HBIG) and vaccine interrupts transmission in over 90 percent [48]. Performance of a cesarean section to prevent vertical transmission is not warranted [49].
• There is some evidence that treating the mother in the last month of pregnancy with lamivudine may further reduce the transmission rate if she is highly infectious (HBV-DNA >1.2x109 geq/mL), but this needs to be further substantiated [50].
• Infants born to carriers of the hepatitis B precore mutant (which does not produce HBeAg) are at particular risk for fulminant hepatitis B in the first two to four months following birth [51]. Thus, immunoprophylaxis should be given to infants from all mothers who are HBsAg positive, regardless of HBeAg status.
• Infected mothers should continue to breast feed as there is no additional risk of transmission
FOLLOW UP
Acute infection:
• See at 1 or 2 weekly intervals until aminotransferase levels are normal (usually 4-12 weeks) [15]
• In view of the possibility of chronic infection, serology should be repeated after 6 months even if the liver function tests are normal [15]

Chronic Infection [21]
HBeAg-positive patients:
• HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals.
• ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months.
• Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/ml after a 3-6 month period of elevated ALT levels between 1-2 times ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/ml and are>40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy shows moderate/severe inflammation or significant fibrosis.
• Patients who remain HBeAg positive with HBV DNA levels >20,000
IU/ml after a 3-6 month period of elevated ALT levels >2 times ULN should be considered for treatment.
• HBeAg-negative patients:
● HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml should be tested for ALT every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every
6-12 months.
● Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit.

Patient on treatment of chronic Hepatitis B [21]
• Patients receiving IFN-alpha therapy should have blood counts and liver panel monitored every 4 weeks,
• Patients receiving IFN-alpha therapy should have thyroid stimulating hormone (TSH) and HBV DNA levels every 12 weeks,
• If initially HBeAg-positive, HBeAg/anti- HBe every 24 weeks during treatment.
• Blood counts, liver panel, TSH and HBV DNA, and if initially HBeAg positive, HBeAg/anti-HBe should be tested every 12 weeks during the first 24 weeks post-treatment.
• Patients receiving NA therapy should have liver panel monitored every 12 weeks and HBV DNA levels every 12-24 weeks, and, if initially HBeAg-positive HBeAg/anti-HBe every 24 weeks during treatment.
• In addition serum creatinine should be tested every 12 weeks for patients receiving adefovir or tenofovir.
• HBsAg should be tested every 6-12 months in those who are HBeAg negative with persistently undetectable serum HBV DNA by PCR assay.

Post Vaccination response testing
• Follow-up testing of vaccine responders is recommended annually for chronic hemodialysis patients.


SCREENING AND PRIMARY PREVENTION

• Hepatitis B testing in asymptomatic patients should be considered in [53]
1. Men who have sex with men,
2. Sex workers (of either sex),
3. Intravenous drug users,
4. HIV-positive patients,
5. Sexual assault victims,
6. People from countries where hepatitis B is common (outside of Western Europe, North America, and Australasia),
7. Needle-stick victims
8. Sexual partners of positive or high-risk patients
9. Neonates of HBsAg positive mothers
• If non-immune, consider vaccination
• The simplest initial screening test in someone who is unvaccinated or is of unknown infection status is anti-hepatitis B core antigen (anti-HBc), with the addition of other tests as necessary. Some also screen for hepatitis B surface antigen (HBsAg) initially [15]
• Measure anti-HBs in those who have been vaccinated
• Vaccination should be offered to non-immune patients in most of the above groups . The main exception is people born in countries of high endemicity but not at continuing risk who are being screened primarily to detect chronic carriage [54]
• HIV-positive patients show a reduced response rate to the vaccine (approximately 40%) and become anti-HBs negative more quickly, although double dose vaccine increases the response by 13% . Offer a repeat course of three doses of vaccine, which may be double dose, for HIV-positive vaccine non-responders
• If patient has to be vaccinated against hepatitis B, two recombinant hepatitis B vaccines have been licensed in the United States: Engerix-B and Recombivax HB. Engerix-B is formulated to contain 20 mcg HBsAg/mL while Recombivax HB contains 10 mcg HBsAg/m [55].
• The recommendation for adults is to administer Engerix-B 20 mcg or Recombivax HB 10 mcg in three doses at months 0, 1 to 2, and then 6 to 12 [15].
• In infants, three doses of 0.5 mL vaccine are required to complete the course, the timing of which depends upon the clinical setting [15].
• If patient has to be vaccinated against hepatitis B, longer than recommended intervals between doses do not reduce final antibody concentrations, although protection might not be attained until the recommended number of doses has been administered. Thus, an interruption in the vaccination schedule does not require restarting the entire series of vaccination or adding extra doses [15].
• If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least two months. If only the third dose is delayed, it should be administered when convenient.
• If person is to be vaccinated against hapatitis B using monovalent vaccine or combined A+B one of the regeimn is to give injections at 0, 7, 14 days, 12 months which has advantage of inducing Rapid immunity,Short duration and high antibody titres at 12 and 13 months. It has potential for better uptake while it has disadvantages of being not tested in HIV or other immunocompromised patients, having little published data ,low antibody titres in the first year (but current evidence suggests that protection is still adequate in the immunocompetent [15].
• If vaccine is given at 0, 1, 2 and 12 months the advantages include early immunity, shorter time to early immunity than the 0, 1, 6 course and high antibody titres at 12 and 13 months and the disadvantage is antibody titres lower than the 0, 1, 6 in the first year[15].
• If vaccine is given at 0, 1, 6 months the advantages include higher antibody titres at 7 months than other two regimens, although this may not be clinically important, long established regimen and most researched in HIV and the Disadvantages include poor uptake of the 6 month dose in the clinical setting
• If person is to be vaccinated quickly the new ultra-rapid 0, 7, 14 day regimen offers the advantage of potentially higher uptake of the full course [15].
• If person is vaccinated the test for response (anti-HBs >10 IU/l, ideally >100 IU/l) 4-12 weeks after the last dose
• Persons who remain at risk for HBV infection such as infants of HBsAg-positive mothers, health care workers, dialysis patients, and sexual partners of carriers should be tested for response to vaccination. Postvaccination testing should be performed 3 to 9 months after the last dose in infants of carrier mothers and 1 to 2 months after the last dose in other persons.
• If person is a non- or poor responders usually respond to further doses (up to three injections), ideally as a repeat course with response rates up to 100% [15].
• If person is to be vaccinated with new pre S containing vaccine which are effective and may also be used for conventional-vaccine non-responders
• If person is vaccinated with Hepatitis B Vaccine it is probable that booster doses of vaccine are not required for at least fifteen years in immunocompetent children and adults who have responded to an initial vaccine course
• If person vaccinated is HIV-positive or other immunocompromised patients will still need to be monitored and given boosters when antibody to hepatitis B surface antigen (anti-HBs) levels fall below 100 IU./l [15].
• If vaccine courses are not completed in immunocompetent patients, the outstanding doses can be given four or more years later without the need to restart a three dose course. One or two doses of vaccine may provide immunity in 40% and over 90% of immunocompetent patients respectively [15].
• If person is vaccinated with Hepatitis B Vaccine, the most common adverse reaction is soreness over the site of injection, which occurs in fewer than 25 percent of the vaccinees. Other adverse reactions reported by 1 to 3 percent of vaccinees include low grade fever, malaise, headache, joint pain and myalgia. These adverse reactions are usually mild and do not result in any serious clinical sequelae [15].
• If person is vaccinated with Hepatitis B Vaccine , they have no teratogenic effects and can be administered during pregnancy
• If person is vaccinated with Hepatitis B Vaccine, there are three main groups of vaccine nonresponders: Patients with underlying medical conditions such as chronic renal failure and immunosuppressed states. In patients undergoing hemodialysis, response rate to the standard dose of vaccine is between 50 to 60 percent. This can be augmented to above 70 percent by doubling the dose of the vaccine. The response rate can also be augmented by intradermal administration of the vaccine [55]
POST EXPOSURE PROPHYLAXIS [52]
Contamination incidents include needle stick or sharps injuries, bites, scratches or other incidents such as contamination of the mucous membrane or conjunctivae. Most contamination incidents occur as a result of handling used needles or other sharps. Clinical staff is also at risk from blood borne diseases if minor cuts, abrasions and other open skin lesions are contaminated with blood, serum or other body fluids.
In studies of health care workers who sustained injuries from needles contaminated with blood positive for both HBsAg and HBeAg, the risk of developing clinical hepatitis was 22% - 31% and the risk of serologic evidence of HBV infection was 37% - 62%. In comparison, the risk of developing clinical hepatitis from a needle contaminated with HBsAg-positive, HBeAg-negative blood was 1% - 6%, while the risk of developing serologic evidence of HBV infection was 23% - 37%


ACTION TO BE TAKEN BY STAFF FOLLOWING A CONTAMINATION INCIDENT

1 Wash the site of exposure/injury liberally with soap and warm water but without scrubbing. Exposed mucous membrane or conjunctivae should be irrigated copiously with water. If there is a puncture wound free bleeding should be encouraged but the wound should not be sucked.

2 Bleed the source patient (if known) for HBsAg as soon as possible.

3 Bleed the staff member involved in the incident for 1st storage sample
4 Report the incident
5 The following information should be obtained from the injured person and verified from their medical/occupational health record:
• Dates of hepatitis B immunizations,
• Postimmunization titer, if known
• Previous testing (if available) for HIV, HBV, and HCV
• Tetanus immunization status
• Current medications
• Current or underlying medical conditions that might influence drug selection (eg, pregnancy, breast feeding, renal or hepatic disease)

Significant exposure

A significant exposure includes:
• percutaneous exposure (sharps injury)
• mucocutaneous exposure (contamination of broken skin/mucous membrane exposure/bite)

A percutaneous exposure carries a higher risk than a mucocutaneous exposure. The risk is greater the greater the volume of blood involved. A deep sharps injury carries a higher risk than a superficial one
Non-Significant Exposure

• Small splashes of blood onto intact skin and scratches (unless contaminated by the patient’s blood)
• Exposure to saliva, urine, vomit and faeces (unless blood stained).
• Exposure to uncontaminated sharp objects

Post Exposure Prophylaxis is given as
• If person is unvaccinated and patient to whose secretions is exposed is HBsAg +, start HBIG once at a dose of 0.6 ml/kg; initiate HB vaccine series
• If person has significant exposure and is unvaccinated and source is HBsAg -, start HBV vaccination series
• If person has significant exposure and is unvaccinated and source is HBsAg unknown, start accelerated HBV vaccination series (An accelerated course of vaccine consists of doses spaced at 0, 1 and 2 months. A booster dose may be given at 12 months to those at continuing risk of exposure to HBV.)
• If person has Non-significant exposure consider HBV vaccination only if continued exposure is anticipated like health care workers, but if not anticipated like public, reassure only.
• If exposed person has significant exposure and  1 dose HB vaccine pre-exposure (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) and source is HBsAg +, recommend accelerated course of HB vaccine and one dose HBIG
• If exposed person has significant exposure and  1 dose HB vaccine pre-exposure (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) and source is HBsAg unknown, recommend accelerated course of HB vaccine
• If exposed person has significant exposure and  1 dose HB vaccine pre-exposure (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) and source is HBsAg -, initiate course of HB vaccine
• If exposed person has no significant exposure and  1 dose HB vaccine pre-exposure (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) consider HBV vaccination only if continued exposure is anticipated like health care workers, but if not anticipated like public, reassure only.
• If exposed person has significant exposure and  2 doses HB vaccine pre-exposure (anti-HBs not known) (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) and source is HBsAg +, recommend one dose of HB vaccine followed by second dose one month later
• If exposed person has significant exposure and  2 doses HB vaccine pre-exposure (anti-HBs not known) (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) and source is HBsAg – or unknown, recommend one dose of HB vaccine
• If exposed person has no significant exposure and  2 doses HB vaccine pre-exposure (anti-HBs not known) (HBV status of person exposed – please wait until result is available providing this will be within 48 hours before vaccinating with HBIG or an accelerated HB vaccine) recommend to finish vaccination and reassure
• If exposed person has significant exposure and is a known responder to HBV vaccine (anti-HBs  10 miU/ml), and source of any HBsAg status, consider giving a booster dose
• If exposed person has no significant exposure and is a known responder to HBV vaccine (anti-HBs  10 miU/ml), and is a health care worker consider booster and if not at risk of reexposure no prophylaxis is required.
• If exposed person has significant exposure and is a known non-responder to HB vaccine (anti-HBs  10 miU/ml 2-4 months post-vaccination and source is HBsAg + or unknown, give HBIG once and consider booster dose of HB vaccine
• If exposed person has significant exposure and is a known non-responder to HB vaccine (anti-HBs  10 miU/ml 2-4 months post-vaccination and source is HBsAg -, consider booster of HBV vaccine.
• If exposed person has no significant exposure and is a known non-responder to HB vaccine (anti-HBs  10 miU/ml 2-4 months post-vaccination consider booster of HBV vaccine for person with continued risk E.g. healthcare worker and no prophylaxis is required if no continued risk.
• HBIG should be given as soon as possible after exposure but preferably within 48 hours of the incident. It should not be given later than 7 days following exposure
Pregnancy and Lactation

• Because of the potential risks from exposure to Hepatitis B infection pregnancy is not considered to be a contraindication to the use of HBIG when clearly needed. It is not known whether HBIG can cause foetal harm when administered to pregnant women.

• It is not known if transmission of HBIG to a nursing infant presents any unusual risk. HBIG should be administered with caution to nursing women.