Hepatitis B virus

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Hepatitis B Virus (HBV) Update :

By Haitham Mohammad El-Amir Assisted Lecturer Of Internal Medicine Hepatitis B Virus (HBV) Update

Introduction:

Hepatitis B is a serious and common infectious disease of the liver, affecting millions of people throughout the world. Hepatitis B virus (HBV) infection is a global public health problem. Its prevalence and patterns of transmission vary greatly throughout the world. Furthermore, the consequences of chronic HBV infection represent a burden to health systems as a large proportion of patients develop cirrhosis and hepatocellular carcinoma (HCC). Introduction

Hepatitis B In the World :

Hepatitis B is one of the world’s most common and serious infectious diseases. Globally about one third of the world’s population, has serological evidence of past or present infection with HBV. Of theses about 350- 400 million people are chronic HBV surface antigen (HBs Ag) carriers. Each year, approximately 2.1% will develop cirrhosis, and 3 to 6% will develop hepatocellular carcinoma (HCC). HBV-related end stage liver diseases are responsible for over 0.5–1 million deaths per year and currently represent 5–10% of cases of liver transplantation. Hepatitis B In the World

Hepatitis B In the United States: :

12 million Americans have been infected (1 out of 20 people). More than one million people are chronically infected. Up to 100,000 new people will become infected each year. 5,000 people will die each year from hepatitis B and its complications. Approximately 1 health care worker dies each day from hepatitis B. Hepatitis B In the United States :

:

Hepatitis B in China: The world's largest population of hepatitis B patients with nearly half a million people dieing of the liver disease every year. 120 million Chinese have tested positive for hepatitis B, which has become a severe public health problem in the country. Hepatitis B in Egypt: According to Egyptian studies ,the prevalence of HBsAg in Egypt is of intermediate endemicity, (2–8%). Nearly 2-3 million Egyptians are chronic carriers of HBV.

HBV : Structure:

HBV is a small ( 42nm enveloped virus), circular and partially double-stranded DNA virus that belongs to the family Hepadnaviridae. The virus B is one of a few known non-retroviral viruses which employ reverse transcription as a part of its replication process. The virion composed of ; A Core particle: composed of ; Nucleocapsid: that located in the center: Core antigen ( HBcAg ) e antigen (HBeAg)- an indicator of transmissibility (minor component of the core- antigenically distinct from HBcAg ) HBV : Structure

HBV : Structure:

A Single molecule of partially double-stranded DNA, DNA-dependent polymerase. lipoprotein envelope: The outer surface membrane contains hepatitis B surface antigen (HBsAg), which also circulates in blood as 22-nm Spherical or filamentous particles. HBsAg -containing particles are released into the serum of infected people and outnumber the actual virions. They are immunogenic and were processed into the first commercial vaccine against HBV. HBV : Structure

HBV : Structure:

HBV : Structure

HBV Genotypes:

HBV is classified into four serotypes (adr, adw, ayr and ayw) based on antigenic determinants of the hepatitis B surface antigen (HBsAg), and eight genotypes (A to H) based on its nucleotide sequence. Different HBV genotypes have distinct geographical distributions. Genotype A is found mainly in Northwest Europe, the United States, India. Genotypes B and C are prevail in East Asia, Genotype B is more likely to resolve, less risk of cirrhosis and liver cancer than genotype C. Genotype D is common in the Mediterranean countries . HBV Genotypes

:HBV Genotypes:

Genotype E is only found in Africa . Genotype F is found mainly in Central and South America. The distribution of HBV genotypes G and H mainly in Central America, USA, and Europe. Africa is one of the highly endemic regions of HBV with five genotypes (A-E) identified. HBV genotype D is the prevalent genotype in Egypt . The clinical impact of HBV genotype D has been studied less extensively. However, initial studies have found that it may be associated with lower rates of sustained remission and HBsAg clearance and more severe liver disease compared with genotype A. : HBV Genotypes

:HBV Genotypes:

Recent data suggest that HBV genotypes may play an important role in the progression of HBV-related liver disease as well as response to interferon therapy. Several studies of standard interferon-alpha (IFN-) and one study of pegylated IFN-alpha ( pegIFN -) therapy showed that genotypes A and B were associated with higher rates of HBeAg seroconversion compared to genotypes C and D. : HBV Genotypes

Geographic distribution of hepatitis B virus genotypes :

Genotypes Geographic distribution Tendency of chronicity Clinical outcome A Europe, United States Higher Better B Eastern Asia Lower Better C Eastern Asia Higher Worse D Southern Europe, North Africa , Middle East, Indian Lower Worse E Sub-Saharan Africa - - F South America - - G Europe, United States - - H Central America Geographic distribution of hepatitis B virus genotypes

Hepatitis B Serological markers:

Hepatitis B surface antigen (HBsAg): This is a protein on the surface of the hepatitis B virus. The first marker to appear after HBV infection, preceding clinical disease by weeks, peaking with the onset of symptoms. It is the earliest indicator of acute infection Is also indicative of chronic infection , if its presence persists for more than 6 months. The presence of HBsAg indicates that the person is infectious. HBsAg is the antigen used to make Hepatitis B vaccine and useful for screening of blood. Hepatitis B Serological markers

Hepatitis B Serological markers::

Hepatitis B surface antibody (HBs Ab or anti-HBs): This is the specific antibody to hepatitis B surface antigen. The presence of anti-HBs is generally indicating recovery and immunity from HBV infection. It is detectable 8-10 weeks post infection, is regarded as being protective against re-infection, and persists for life. Is not present in the chronic phase of the disease. Hepatitis B core antigen (HBc Ag): Hepatitis B core antigen is derived from the protein envelope that encloses the viral DNA. It is not detectable in the bloodstream, it is only found when liver tissue (cells ) is examined under a microscope . It is the most accurate index of viral replication. Hepatitis B Serological markers:

Hepatitis B Serological markers::

Total Hepatitis B core antibody (anti- HBc ):  This is the specific antibody to hepatitis B core antigen . The first antibody to appear in the blood (as soon as a few weeks after initial infection ), appears at the onset of symptoms in acute Hepatitis B and persists for life . The core antibody can be found in anyone who has ever been infected with the hepatitis B virus, but does not differentiate carriers and non-carriers. A long-term serologic marker for HBV. The presence of anti- HBc indicates past or ongoing infection. Antibodies to HBc are of two class IgM and IgG . Hepatitis B Serological markers :

Hepatitis B Serological markers::

IgM anti- HBc (IgM HBc Ab ); Present in high titre during acute infection , which rises early–within 2-4 weeks of HBV infection and slowly disappears within 6 months. The best serologic marker for acute HBV infection. ↓ levels of IgM HBcAb indicate resolving infection . IgG anti- HBc ( IgG HBc Ab ); A 'convalescent' antibody that indicates past HBV infection , it rises 4-6 months after infection and persists for life. IgG with no IgM may be present in chronic and resolved infections.   Hepatitis B Serological markers:

Hepatitis B Serological markers::

Hepatitis B e antigen (HBe Ag ): An antigen that rises and falls parallel to HBsAg. Is the second antigen that appears as a result of the virus replication in the body. HBeAg is not incorporated into virions, but it is secreted into the serum, so its presence means that the person’s blood and body fluids are very infectious. Hepatitis B e antigen appearing during 3-6 weeks indicates an acute active infection at its most infectious period, and means that the patient is infectious . Persistence of this virological marker beyond 10 weeks indicates chronic infection and infectiousness . Hepatitis B Serological markers:

Hepatitis B Serological markers::

Hepatitis B e antibody (HBe Ab or anti- HBe): This is the specific antibody to hepatitis B e antigen. Once “e” antibodies are produced, there are usually fewer HBV infecting and damaging the liver. During the acute stage of infection the seroconversion from e antigen to e antibody is prognostic for resolution of infection . Production of “e” antibodies, is one of the goals of most medical treatments for hepatitis B and is a predictor of long-term clearance of HBV in patients undergoing antiviral therapy. HBV DNA: It is found in the bloodstream and is the best indication of how rapidly the virus is replicating in the liver . Hepatitis B Serological markers :

Hepatitis B Serological markers::

HBV DNA : High levels of HBV-DNA, indicate rapid viral replication in the liver and a higher risk of liver damage. Low or undetectable rates indicate low viral replication in the liver. HBV DNA is detectable by hybridization assays or Polymerase chain reaction (PCR) as soon as 1 week after initial infection. Also performed for monitoring of antiviral treatment or to detect mutants that escape detection by current methods . HBV DNA polymerase; Tests for the presence of HBV DNA polymerase, detectable within 1 week of initial infection, are only performed for research purposes. Hepatitis B Serological markers :

The Hepatitis B Panel Tests Results Interpretation :

Tests Results  Interpretation HBsAg anti-HBc anti-HBs negative negative negative     susceptible    HBsAg anti-HBc anti-HBs negative positive positive    Immune due to natural infection     HBsAg anti-HBc anti-HBs negative negative positive Immune due to hepatitis B vaccination HBsAg anti-HBc IgM anti-HBc anti-HBs positive positive positive negative    Acutely infected    HBsAg anti- HBc IgM anti- HBc anti-HBs positive positive negative negative     Chronically infected     HBsAg anti-HBc anti-HBs negative positive negative Four interpretations possible 1. Resolved infection (most common). 2. Recovering from acute HBV infection 3. False positive anti- HBc , thus susceptible 4. “Low level” chronic infection,(carrier). The Hepatitis B Panel Tests Results Interpretation

HBV: Modes of Transmission:

Parenteral - IV drug abusers , h ealth w orkers are at increased risk. Sexual - Sex workers and homosexuals are particular at risk. Perinatal ( Vertical) – Mother ( HBeAg +) → infant . In Egypt, it appears that HBV transmission is a mixture of perinatal and horizontal transmission. However, the majority of HBV infection is acquired by horizontal transmission. HBV: Modes of Transmission

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

:Modes of Transmission:

The risk of transmission is closely related to the rate of viral replication in the infected individual at the time of exposure. HBV is able to remain on any surface it comes into contact with for about a week , e.g. razor blades, blood stains, without losing infectivity. HBV does not cross the skin or the mucous membrane barrier, some break in this barrier, which can be minimal and insignificant, is required for transmission. Without intervention, a mother who is positive for the hepatitis B surface antigen confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for the hepatitis B e antigen. : Modes of Transmission

High-risk groups for HBV infection:

Susceptibility is general. Only people who have been vaccinated successfully or those who have developed anti-HBs antibodies after HBV infection are immune to HBV infection . Who Should Be Tested for HBV Infection? The following groups should be tested for HBV infection: Persons born in high or intermediate endemic areas, Born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity, Persons with chronically elevated amino transferases , High-risk groups for HBV infection

High-risk groups for HBV infection::

Persons needing immunosuppressive therapy, Men who have sex with men, persons with multiple sexual partners or history of sexually transmitted disease, Injecting drug users, Dialysis patients, HIV or HCV-infected individuals, Family members, household members, and sexual contacts of HBV-infected persons. Testing for HBsAg and anti- HBs should be performed, and sero negative persons should be Vaccinated. High-risk groups for HBV infection:

Elimination of HBV Transmission:

Objectives: Prevent chronic HBV Infection, Prevent chronic liver disease, Prevent primary hepatocellular carcinoma, Prevent acute symptomatic HBV infection. Prevention of acute and chronic HBV infection and elimination of HBV transmission in all age groups is most effectively achieved through hepatitis B vaccination . Elimination of HBV Transmission

Hepatitis B Vaccine:

Hepatitis B is a vaccine-preventable disease. Vaccination is the most effective tool in preventing the transmission of HBV and HDV. Hepatitis B vaccine is the first and currently the only vaccine against a major human cancer , and has been available since 1982. Hepatitis B vaccines are composed of the surface antigen of HBV (HBs Ag), and does not contain any of live components. Hepatitis B vaccines are produced by two different methods: plasma derived or recombinant DNA . Hepatitis B vaccines currently available are made using recombinant DNA technology, (yeast-derived or mammalian cell-derived). , Hepatitis B Vaccine

Hepatitis B Vaccine::

The two major yeast-derived hepatitis B vaccines that are licensed in most countries are: Engerix -B ® (SmithKline Beecham, 1992), Recombivax HB® (Merck & Co .). When administered properly, hepatitis B vaccine induces protection in about 95% of recipents . WHO recommends that hepatitis B vaccine be included in routine immunization services in all countries. The primary objective of hepatitis B immunization is to prevent chronic HBV. By preventing chronic HBV infections, the major reservoir for transmission of new infections is also reduced. Hepatitis B Vaccine:

Hepatitis B Vaccine::

Is Hepatitis B Vaccine Safe? Hepatitis B vaccines have been shown to be very safe when given to infants, children, and adults. Most common side effects are pain at the injection site and mild to moderate fever that is not more common than among children receiving other vaccines. How is Hepatitis B Vaccine Given? Hepatitis B is given as a series of three intramuscular doses, 0, 1 and 6 intramuscular injections, (standard practice). The vaccine is to be administered in the anterolateral aspect of the thigh of newborns and infants or the deltoid (arm) muscle of children and adults in order to achieve optimal protection. Hepatitis B Vaccine:

Post-exposure Prophylaxis:

Post exposure immunization should especially be considered for : Neonates born of HBsAg -positive mothers . Such infants are infected commonly, especially when mothers are HBeAg -positive, and the risk of becoming chronic carriers is extremely high (90%). When HBIG is given within the first hours after birth, the risk of infection can be reduced to 20 %. After any percutaneous exposure (e.g., sharing injection) or mucosal exposure (e.g., sexual) to blood, unvaccinated should begin the vaccine series, and the exposure incident should be evaluated to determine if additional post exposure prophylaxis ( i.e HBIG) is required or Strongly recommended. Post-exposure Prophylaxis

Post-exposure Prophylaxis::

Following sexual exposure to an infected person , it is currently recommended to use both HBIG and hepatitis B vaccine. Administration of HBIG more than 7 days after percutaneous or perinatal exposure and 14 days after sexual exposure is unlikely to be effective. No post exposure prophylaxis is indicated for contamination of unbroken skin, for staff members who provide routine care of patients with hepatitis B, or for people who share food. Post-exposure Prophylaxis: HBIG Vaccine Exposure dose ( i.m .) timing dose ( i.m .)° timing (first dose) Perinatal 0.5 ml <12 h of birth 0.5 ml <12 h of birth Sexual 0.06 ml/kg <14 days since last exposure 1.0 ml Concurrent with HBIG (first dose)

Post-vaccination Testing:

After routine vaccination of infants, children, adolescents, or adults post-vaccination testing for adequate antibody response is not necessary. Post-vaccination testing is recommended for persons who remain at risk for HBV infection such as : Immunocompromised (e.g., hemodialysis patients), Received the vaccine in the buttock, Infants born to HBsAg (hepatitis B surface antigen)- positive mothers, Healthcare workers who have contact with blood, Sexual partners of persons with chronic hepatitis B virus infection. Post vaccination testing should be performed at 9 to 15 months of age in infants of carrier mothers and 1-2 months after the last dose in other persons. Post-vaccination Testing

Booster Doses:

Current data show that vaccine-induced hepatitis B surface antibody (anti-HBs) levels may decline over time; however, immune memory (anamnestic anti-HBs response) that develops after exposure to the virus remains intact indefinitely following immunization. The duration of vaccine -induced immunity is uncertain but it is definitely long term (>15 years). An initial anti-HBs titre of >10 IU/l, is regarded as being protective.     For health care workers with normal immune status who have demonstrated an anti-HBs response following vaccination, booster doses of vaccine are not recommended nor is periodic anti-HBs testing. Booster Doses

:Booster Doses:

If your patient is not immune after vaccination: Although uncommon, about 5% of those who complete the hepatitis B vaccine series may not acquire immunity (anti-HBs titre of <10 IU/l). In these cases take theses steps : Administer another 3-shots at the normal schedule. Test again for 1-2 months after completion of the series to confirm protection. 44-100% of these patient will develop immunity. The rare group of people not protected after six doses should take care to avoid HBV transmission. Non responders exposed to HBV infected fluids should get the HBIG shot to prevent chronic infection . : Booster Doses

Counseling and Prevention of Transmission of Hepatitis B from Individuals with Chronic HBV Infection:

Carriers should be counseled regarding prevention of transmission of HBV. Sexual and household contacts of carriers who are negative for HBV sero markers should receive hepatitis B vaccination. Newborns of HBV-infected mothers should receive HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series . 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. Counseling and Prevention of Transmission of Hepatitis B from Individuals with Chronic HBV Infection

Counseling and Prevention of Transmission of Hepatitis B from Individuals with Chronic HBV Infection::

Follow-up testing of vaccine responders recommended annually for chronic hemodialysis patients. Abstinence or only limited use of alcohol is recommended in hepatitis B carriers. Persons who are positive only for anti-HBc and who are from a low endemic area with no risk factors for HBV should be given the full series of hepatitis B vaccine. Counseling and Prevention of Transmission of Hepatitis B from Individuals with Chronic HBV Infection:

Recommendations for Infected Persons Regarding Prevention of Transmission of HBV to Others:

Persons who are HBsAg -positive should: Have sexual contacts vaccinated. Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune. Not share toothbrushes or razors. Cover open cuts and scratches. Not donate blood, organs or sperms . Can participate in all activities including contact sports. Should not be excluded from daycare or school participation and should not be isolated from other children. Can share food or kiss others. Recommendations for Infected Persons Regarding Prevention of Transmission of HBV to Others

Spectrum of liver disease after HBV infection:

What happens when infected with HBV? Primary HBV infection may be associated with: Little or no liver disease , Acute hepatitis, Chronic hepatitis. The infecting dose of virus and the age of the person infected are important factors that correlate with the severity of acute or chronic hepatitis B. Young children rarely develop acute clinical disease, but many of those infected before the age of seven will become chronic carriers . Persistent HBV infection is sometimes associated with histologically normal liver and normal liver function, but about one third of chronic HBV infections are associated with cirrhosis and HCC. Spectrum of liver disease after HBV infection

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Possible Outcomes of HBV Infection Acute hepatitis B infection Chronic HBV infection <10% of adult-acquired infections >90% of infant-acquired infections Cirrhosis Chronic hepatitis 12-25% in 5 years Liver failure Hepatocellular carcinoma Liver transplant 6-15% in 5 years 20-23% in 5 years Death Death

Acute HBV infection:

The incubation period varies usually between 45 and 180 days, with an average of 60 to 90 days. The variation is related to the amount of virus, the mode of transmission and host factors. The larger the virus dose (may occur in transfusions of infectious blood), the shorter the incubation period and the more likely that icteric hepatitis will result. Most cases of acute hepatitis are subclinica l , only a small proportion of acute HBV infections are recognized clinically, and less than 1% of symptomatic cases are fulminant. Acute HBV infection

:Acute hepatitis B:

In patients with clinical illness , the onset is usually insidious with tiredness, anorexia, vague abdominal discomfort, nausea and vomiting, sometimes arthralgia and rash, fever may be absent or mild and often progressing to jaundice. Less than 10% of children and 30-50% of adults with acute HBV infection will have icteric disease. The icteric phase of acute viral hepatitis begins usually within 10 days of the initial symptoms with the appearance of dark urine followed by pale stools and jaundice. Jaundice is accompanied by hepatomegaly and splenomegaly. About 4-12 weeks thereafter, the jaundice disappears and the illness resolves with the development of natural, protective antibodies (anti-HBs), in about 90% of adults. : Acute hepatitis B

Clinical Features:

Incubation period : Average( 60-90) days Range( 45-180 )days Insidious onset of symptoms .. Clinical illness (jaundice) : <5 yrs, <10% ≥ 5 yrs, 30%-50% 1/3 adults-no symptoms Clinical Illness at presentation (10 - 15%0 Acute case-fatality rate: ( 0.5%-1%) Chronic infection : (< 5 yrs, 30%-90%) ( ≥ 5 yrs, 2%-6%) More likely in asymptomatic infections Premature mortality from chronic liver disease : (15%-25% ) Clinical Features

Acute hepatitis B::

Laboratory Diagnosis of acute HBV infection can be made on the basis of the detection of IgM class antibody to hepatitis B core antigen (IgM anti-HBc ) in serum which is generally detectable at the time of clinical onset. The first serologic marker to appear following acute infection is HBsAg, which can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks (30-60 days) after exposure to HBV. The presence of HBeAg in serum correlates with higher titers of HBV and greater infectivity. The hallmark of acute viral hepatitis is the striking elevation in serum transaminase (aminotransferase) activity. Acute hepatitis B:

Acute hepatitis B::

The increase in aminotransferases, especially ALT, during acute hepatitis B varies from a mild/moderate increase of 3- to 10-fold to a striking increase of >100-fold. Values up to 1000 to 2000 IU/L are typically seen during the acute phase with ALT being higher than AST . In patients who recover, normalization of serum aminotransferases usually occurs within one to four months. Acute hepatitis B:

Possible outcomes of acute hepatitis B: :

HBV infection is transient in about 90% of adults and 10% of newborn, Persons with self-limiting infection clear the infection spontaneously within weeks to months. More than 90% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. About10% of adult-onset infection and over 90% of cases of neonatal infection become chronic, and may continue for the life span of the patient A small percentage < 1% of persons die from acute HBV ( fulminant). Although rare, reactivation is seen most often in people with impaired immunity. Possible outcomes of acute hepatitis B :

Acute hepatitis B::

Male patients with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than patients with lower levels. Patients who undergo chemotherapy are at risk for HBV reactivation. The current view is that immunosuppressive drugs favor increased HBV replication while inhibiting cytotoxic T cell function in the liver. Acute hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously . Early antiviral treatment may only be required in fewer than 1% of patients, whose infection takes a very aggressive course (fulminant hepatitis) or who are immunocompromised. Acute hepatitis B:

Chronic HBV Infection:

Global burden of chronic HBV infection : Persistent or chronic HBV infection is among the most common persistent viral infections in humans . An estimated 350- 400 million people worldwide have chronic HBV infection. Each year, approximately 2.1% will develop cirrhosis, and 3% to 6% will develop HCC , and about 1 million deaths are attributed annually to HBV-related complications. Chronic HBV Infection

Global pattern of chronic HBV infection: :

The world can be divided into three areas where the prevalence of chronic HBV infection is: High endemicity areas (> 8%): Include south-east Asia and the Pacific Basin (excluding Japan, Australia, and New Zealand), sub-Saharan Africa, the Amazon Basin, parts of the Middle East, the central Asian Republics, and some countries in eastern Europe . About 70 to 90% of the population becomes HBV-infected before the age of 40. Early childhood infections common. About 8 to 20% of people are HBV carriers . Intermediate endemicity areas (2-7 %): 2 to 7% of a given population being HBV carriers. Infections occur in all age groups. Global pattern of chronic HBV infection :

Chronic hepatitis B::

Low endemicity areas (<2%): Include North America, Western and Northern Europe, Australia, and parts of South America. The carriers rate here is less than 2%. Most infections occur in adult risk groups . Clinically, a history of acute hepatitis is elicited in only a small percentage of patients with chronic HBV infection. Many patients with chronic hepatitis B are asymptomatic, while others have nonspecific symptoms such as fatigue. Some patients experience exacerbations of the infection which may be asymptomatic, mimic acute hepatitis, or manifest as hepatic failure. Chronic hepatitis B :

Chronic hepatitis B::

A serum sickness-like syndrome may develop during the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice and right upper quadrant discomfort. The symptoms and jaundice generally disappear after one to three months, but some patients have prolonged fatigue even after normalization of serum aminotransferase concentrations. Chronic hepatitis B :

Extra hepatic manifestations of HBV infection:

Extra hepatic manifestations of hepatitis B are seen in 10-20% of patients as: Transient serum sickness-like syndrome : Fever (<39°C), skin rash and polyarthritis . Symptoms usually precede the onset of jaundice by a few days to 4 weeks and subside after onset of jaundice and may persist throughout the course of the disease. No recurrent or chronic arthritis occurs after recovery. Acute necrotizing vasculitis ( polyarteritis nodosa) : Highly variable disease with mortality rate of 40% within 3 years unless treated. The diagnosis is established by angiography. Extra hepatic manifestations of HBV infection

Extra hepatic manifestations of HBV infection:

Membranous glomerulonephritis :        Is present in both adults and children. Remission of nephropathy occurs in 85 to 90% of cases over a period of 9 years and is associated with clearance of HBeAg from serum. Papular acro dermatitis of childhood (Gianotti-Crosti syndrome): A distinctive disease of childhood. Skin lesions, (small-sized , flat, erythematous, and papular eruptions localized to the face and extremities), last 15 to 20 days. The disease is accompanied by generalized lymphadenopathy, hepatomegaly, and acute anicteric hepatitis B.    Extra hepatic manifestations of HBV infection

Glossary of Clinical Terms Used in HBV Infection:

The consensus definition and diagnostic criteria for clinical terms relating to HBV infection adopted at the National Institutes of Health (NIH) conferences on Management of Hepatitis B in 2000 and 2006. Chronic hepatitis B : Chronic necro inflammatory disease of the liver caused by persistent infection with HBV. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B. Inactive HBsAg carrier state : Persistent HBV infection of the liver without significant, ongoing necro inflammatory disease. Glossary of Clinical Terms Used in HBV Infection

Clinical Terms Used in HBV Infection::

Resolved hepatitis B; Previous HBV infection without further virologic, biochemical or histological evidence of active virus infection or disease. Diagnostic criteria: Previous known history of acute or chronic hepatitis B or the presence of anti- HBc or anti-HBs , HBsAg negativity. Undetectable serum HBV DNA *,(* Very low levels may be detectable using sensitive PCR assays). Normal ALT levels. Clinical Terms Used in HBV Infection:

Clinical Terms Used in HBV Infection::

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 . Reactivation of hepatitis B: Reappearance of active necro inflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B . HBeAg clearance: Loss of HBeAg in a person who was previously HBeAg positive. HBeAg seroconversion : Loss of HBeAg and detection of anti- HBe in a person who was previously HBeAg positive and anti- HBe negative. HBeAg reversion: Reappearance of HBeAg in a person who was previously HBeAg negative, and anti- HBe positive. Clinical Terms Used in HBV Infection:

Natural History of Chronic HBV Infection:

Chronic HBV infection is a dynamic process. The natural history of chronic HBV infection consists of 4 phases ; which are not necessarily sequential. however, patients may not experience all phases. Phases of the natural course of chronic HBV infection are: Immune-tolerant phase. Immune clearance phase or ‘‘immune reactive HBeAg -positive phase. Inactive HBV carrier state. Reactivation phase or ( “ HBeAg -negative chronic hepatitis B”. Natural History of Chronic HBV Infection

Natural History of Chronic HBV Infection::

The ‘‘immune tolerant’’ phase is characterized by: HBeAg positivity, High levels of HBV replication ( reflected by high levels of serum HBV DNA), Persistently normal or low levels of aminotransferases , No evidence of active liver disease ; mild or no liver necro inflammation and no or slow progression of fibrosis. During this phase, the rate of spontaneous HBeAg loss is very low. This phase is more frequent and more prolonged in subjects infected perinatally or in the first years of life. Because of high levels of viremia, these patients are highly contagious Natural History of Chronic HBV Infection :

Natural History of Chronic HBV Infection::

The immune clearance phase ‘‘ immune reactive HBeAg -positive phase’’ is characterized by: HBeAg positivity, Relatively lower level of replication compared to the immune tolerant phase ( as reflected by lower serum HBV DNA levels ), Increased or fluctuating levels of aminotransferases, Moderate or severe liver necro inflammation and more rapid progression of fibrosis compared to the previous phase. The rate of spontaneous HBeAg loss is enhanced. It may last for several weeks to several years. Natural History of Chronic HBV Infection :

Natural History of Chronic HBV Infection::

This phase may occur after several years of immune tolerance (partial breakdown of tolerance) and is more frequently and/or more rapidly reached in subjects infected during adulthood, paralleling maturation of specific anti-HBV immunity . This phase ends with HBeAg seroconversion resulting in the appearance of antibodies to HBeAg (anti- HBe ) and suppression of viral replication. Most patients then enter the inactive HBV carrier phase. Natural History of Chronic HBV Infection :

Natural History of Chronic HBV Infection::

The inactive HBV carrier state: May follow seroconversion from HBeAg to anti- HBe antibody. It is characterized By: Very low or undetectable serum HBV DNA levels, Normal serum aminotransferases, and No or minimal inflammation on liver biopsy. HBsAg loss and seroconversion to anti-HBs antibody may occur spontaneously in 1–3% of cases per year, usually after several years with persistently undetectable HBV DNA A minimum follow-up of 1 year with alanine aminotransferase (ALT) levels at least every 3–4 months and serum HBV DNA levels is required before classifying a patient as inactive HBV carrier. Natural History of Chronic HBV Infection :

Natural History of Chronic HBV Infection::

ALT levels should remain persistently within the normal range according to traditional cut-off values (approximately 40 IU/ml) and HBV DNA should be below 2000 IU/ml. Some inactive carriers, however, may have HBV DNA levels greater than 2000 IU/ml (usually below 20,000 IU/ml) accompanied by persistently normal ALT levels. Patients with HBV DNA <2000 IU/ml and elevated ALT values should be usually advised to undergo liver biopsy for the evaluation of the cause of liver injury. As a result of immunological control of the infection, the inactive HBV carrier state confers a favorable long-term outcome with a very low risk of cirrhosis or HCC in the majority of patients. Natural History of Chronic HBV Infection :

Natural History of Chronic HBV Infection::

On the other hand, progression to CHB, usually HBeAg -negative, may also occur. Therefore, inactive HBV carriers should be followed up for life with ALT determinations at least every 6 months after the first year and periodical measurement of HBV DNA levels. The reactivation phase , also called ( HBe Ag-negative chronic hepatitis B) : ‘‘HBeAg-negative CHB’’ may follow seroconversion from HBeAg to anti- HBe antibodies during the immune reactive phase or may develop after years or decades of the inactive carrier state. Natural History of Chronic HBV Infection:

Natural History of Chronic HBV Infection::

It represents a later immune reactive phase in the natural history of chronic HBV infection. It is characterized by: HBe Ag-negativity , Periodic reactivation with a pattern of fluctuating levels of HBV DNA and aminotransferases (Intermittent/persistently elevated), and Active hepatitis : Inflammation on liver biopsy. HBeAg -negative CHB is associated with low rates of prolonged spontaneous disease remission . It is important and sometimes difficult to distinguish true inactive HBV carriers from patients with active HBeAg negative CHB in whom phases of spontaneous remission may occur. Natural History of Chronic HBV Infection:

Natural History of Chronic HBV Infection::

The true inactive HBV carriers patient s have a good prognosis with a very low risk of complications , while the active HBeAg negative CHB patients have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and subsequent complications such as decompensated cirrhosis and HCC. In those individuals with chronic hepatitis B, either HBeAg-positive or HBeAg-negative disease, repeated disease flares over time lead to fibrosis, cirrhosis, and carcinogenesis. In those with compensated cirrhosis, mortality rate 5 years is 16% .   Without liver transplantation, mortality rates may range from 65% to 86% in patients with decompensated cirrhosis. Natural History of Chronic HBV Infection:

Natural History of Chronic HBV Infection:

Natural History of Chronic HBV Infection

Factors Associated with Progression of HBV-related Liver Diseases:

Host, viral, and environmental factors influence progression of HBV-related liver disease. Recent studies have focused on the importance of HBV replication as an independent predictor of cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. Host and viral risk factors associated with increased rates of cirrhosis include: Older age (longer duration of infection), HBV genotype C, High levels of HBV DNA, Habitual alcohol consumption, and Concurrent infection with hepatitis C virus (HCV), hepatitis D virus (HDV) o human immunodeficiency virus (HIV). Factors Associated with Progression of HBV-related Liver Diseases

Factors Associated with Progression of HBV-related Liver Diseases::

A number of HBV patients with chronic hepatitis will develop hepatocellular carcinoma . The incidence of HCC varies with geography, race, age, and sex. HCC is responsible for 90% of the primary liver cancer. Up to 60- 80% of liver cancers are due to HBV. Liver cancer is the cause of more than 500,000 deaths annually throughout the world, with a male: female ratio of 4:1. The frequency of HCC follows the same general geographic distribution pattern as that of persistent HBV infection. Factors Associated with Progression of HBV-related Liver Diseases:

Factors Associated with Progression of HBV-related Liver Diseases::

Host and viral risk factors for HCC include: Male gender, Family history of HCC, Older age, History of reversions from anti- HBe to HBeAg, HBV genotype C, and Co-infection with HCV, Presence of cirrhosis, Although cirrhosis is a strong risk factor for HCC, 30% to 50% of HCC associated with HBV occur in the absence of cirrhosis Factors Associated with Progression of HBV-related Liver Diseases:

Factors Associated with Progression of HBV-related Liver Diseases: :

Environmental factors that are associated with an increase risk of cirrhosis or HCC include: Heavy alcohol consumption, Carcinogens such as aflatoxin, and More recently smoking . Co-infection with HCV. Factors Associated with Progression of HBV-related Liver Diseases:

Evaluation of Patients with Chronic HBV Infection :

As a first step, the causal relationship between chronic HBV infection and liver disease has to be established and an assessment of the severity of liver disease needs to be performed. The initial evaluation of patients with chronic HBV infection should include a thorough history and physical examination, with special emphasis on risk factors for co-infection, alcohol use, and family history of HBV infection and liver cancer. In addition, all first degree relatives and sexual partners of patients with chronic HBV infection should be advised to be tested for HBV serological markers (HBsAg, anti-HBc, anti-HBs) and to be vaccinated if they are negative for these markers (A1). Evaluation of Patients with Chronic HBV Infection

Pre-therapeutic assessment of liver disease: :

Not all patients with chronic HBV infection have persistently elevated aminotransferases. Patients in the immune tolerant phase and inactive carriers have persistently normal ALT levels, while a proportion of patients with HBeAg -negative CHB may have intermittently normal ALT levels. Therefore, appropriate longitudinal long-term follow-up is crucial . 1)-The assessment of the severity of the liver should include : Biochemical markers, and hepatic ultrasound (A1). Biochemical markers including aspartate aminotransferase (AST) and ALT, gamma- glutamyl transpeptidase (GGT), alkaline phosphatase, bilirubin, and serum albumin and globulins, blood counts , prothrombin time and (AFP) at baseline . Pre-therapeutic assessment of liver disease:

Pre-therapeutic assessment of liver disease: :

Usually, ALT levels are higher than those of AST. However, when the disease progresses to cirrhosis, the ratio may be reversed. A progressive decline in serum albumin concentrations and/or increase of (gamma )globulins and prolongation of the prothrombin time, often accompanied by declining platelet counts, are characteristically observed after cirrhosis has developed. 2)-HBV DNA detection and HBV DNA level measurement are essential for the diagnosis, decision to treat and subsequent monitoring of patients (A1). Pre-therapeutic assessment of liver disease:

Pre-therapeutic assessment of liver disease: :

Follow-up using real time PCR quantification assays is strongly recommended because of their sensitivity, specificity, accuracy and broad dynamic range. The World Health Organization (WHO) has defined an international standard for normalization of expression of HBV DNA concentrations. Serum HBV DNA levels should be expressed in IU/ml to ensure comparability; the same assay should be used in the same patient to evaluate antiviral efficacy. 3)- Other causes of chronic liver disease should be systematically looked for including co-infections with HDV, HCV and/or HIV (A1) . Pre-therapeutic assessment of liver disease:

Pre-therapeutic assessment of liver disease: :

Patients with chronic HBV infection should be also tested for antibody against hepatitis A virus (anti-HAV ) and should be advised to be vaccinated against HAV if they are anti-HAV negative. Co-morbidities , including alcoholic, autoimmune, metabolic liver disease with steatosis or steato hepatitis should be assessed (A1). 4)-A liver biopsy is often recommended for determining the degree of necro inflammation and fibrosis since hepatic histology can assist the decision to start treatment (A1). Pre-therapeutic assessment of liver disease:

Pre-therapeutic assessment of liver disease: :

The biopsy is also useful for evaluating and rule out other possible causes of liver disease such as fatty liver disease . Although liver biopsy is an invasive procedure, the risk of severe complications is very low (1/4000–10,000). It is important that the size of the needle biopsy specimen is large enough to accurately assess the degree of liver injury, in particular fibrosis (A1). A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis (A1). Pre-therapeutic assessment of liver disease:

Liver biopsy : :

There is growing interest in the use of non-invasive methods , including serum markers and transient elastography, to assess hepatic fibrosis to complement or avoid a liver biopsy. Transient elastography, which is a non-invasive method widely used in Europe, offers high diagnostic accuracy for the detection of cirrhosis, although the results may be confounded by severe inflammation associated with high ALT levels and the optimal cut-off of liver stiffness measurements vary among studies. Recent studies suggest that the upper limits of normal for ALT and AST should be decreased to 30 U/L for men and 19 U/L for women. Liver biopsy :

Role of liver biopsy in chronic hepatitis patients : :

Assess the degree of liver damage (grade and stage liver disease for patients who meet criteria for chronic hepatitis . Rule out other causes of liver disease . Treatment monitoring , ( As liver histology can improve significantly in patients who have sustained response to antiviral therapy or spontaneous HBeAg seroconversion. Liver histology also can worsen rapidly in patients who have recurrent exacerbations or reactivations of hepatitis). Useful in persons who do not meet clear cut guidelines for treatment. Role of liver biopsy in chronic hepatitis patients :

Liver biopsy : :

HBV infected patients with ALT values close to the upper limit of normal may have abnormal histology and can be at increased risk of mortality from liver disease especially those above age 40. Thus, decisions on liver biopsy should take into consideration : Age, The new suggested upper limits of normal for ALT, HBeAg status, HBV DNA levels, and Other clinical features suggestive of chronic liver disease or portal hypertension . Liver biopsy :

Treatment of chronic Hepatitis B:

Chronic HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the HBV genome integrates into the host genome and might favor oncogenesis and the development of HCC. Therefore, current therapeutic options only achieve a functional cure through viral suppression , and are associated with numerous adverse effects. Hence the decision on when to initiate treatment is controversial. Treatment of chronic Hepatitis B

Treatment of chronic Hepatitis B::

Goals of therapy: Sustained suppression of HBV replication: Decrease in serum HBV DNA to <10 5 copies/ml, Seroconversion (HBeAg to HBeAb ). Remission of liver disease: Normalization of serum ALT levels, Decreased necro inflammation in liver. Improvement in clinical outcome: Decreased risks of developing cirrhosis, liver failure and HCC, Increased survival . Treatment of chronic Hepatitis B:

Clinical Practice Guidelines:

The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) have developed clinical practice guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with CHB. Recommendations of the 3 guidelines vary slightly because of differences in timing when the guidelines were issued and also differences in available resources. Clinical Practice Guidelines

Clinical Practice Guidelines::

Because of the high cost and risk of adverse events, as well as drug resistance with long-term treatment, the most important question regarding the management of hepatitis B is: What is the indications of treatment? Who should be treat? Who Can Be Monitored? What is treatment? How should treatment be monitored? When to stop treatment? How should special groups be treated ? Clinical Practice Guidelines:

Indications for Treatment :

Practice guidelines recommend that the treatment decision be made based mainly on the combination of three: Levels of serum HBV DNA, Serum ALT, and The liver histology if available. There is no significant distinction made between HBeAg positive and HBeAg negative infection . Besides HBV replication status, ALT levels, and liver histology, all guidelines recommend that patient age, Health status, family history of HCC, extra hepatic manifestations, occupational requirements, family planning and patient preference should be considered in making treatment decisions. Indications for Treatment

Indications for Treatment: :

Generally patients should be considered for treatment when they have: HBV DNA levels above 2000 IU/ml, Serum ALT levels above the upper limit of normal (ULN) Severity of liver disease assessed by liver biopsy (or non-invasive markers validated in HBV infected patients), showing moderate to severe active necro inflammation and/or at least moderate fibrosis using a standardized scoring system. In patients who fulfill the above criteria for HBV DNA and histological severity of liver disease, treatment may be initiated even if ALT levels are normal. Indications for Treatment :

Indications for Treatment: :

Current guidelines from NICE in the United Kingdom recommend the use of transient elastography as an initial test to assess the severity of liver disease, and need for treatment. For adults with a transient elastography score ≥ 11, there is a high likelihood of hepatic fibrosis, and treatment should be commenced irrespective of viral load to prevent further deterioration of liver function. All patients with a HBV DNA level > 20,000 IU/mL treatment should be initiated due to a strong correlation between high viraemia, cirrhosis, and HCC . Indications for Treatment :

Who Should Be Treated? :

All guidelines recommend starting treatment as soon as possible in patients with life-threatening liver disease: Acute liver failure, Decompensated cirrhosis, or Severe exacerbation of chronic hepatitis B, ( CHB) regardless of HBV DNA and ALT levels . In addition, for patients requiring liver transplantation , viral suppression decreases the risk of HBV recurrence after transplant. Who Should Be Treated?

Non cirrhotic CHB patients:

All guidelines agree that treatment should be initiated in non cirrhotic patients with: Serum HBV DNA levels greater than 20,000 IU/mL, Persistently increased ALT levels and/or Histologic evidence of moderate/severe inflammation or fibrosis. However , cut-off values of HBV DNA and ALT levels and the need for liver biopsy in determining treatment indications vary slightly among the guidelines. The AASLD guideline suggests an arbitrary HBV DNA level of 20,000 IU/mL for initiating treatment . The EASL guideline recommends a cut-off value of 2000 IU/mL irrespective of HBeAg status. Non cirrhotic CHB patients

Non cirrhotic chronic hepatitis B patients ::

The APASL guideline recommends an HBV DNA threshold of 20,000 IU/mL for HBeAg-positive patients and 2000 IU/mL for HBeAg -negative patients. All guidelines agree that serial HBV DNA and ALT level is more important than a single value in making treatment decisions. For patients who fulfill the criteria for HBV DNA, the EASL recommends treating patients with ALT levels greater than the upper limit of normal (ULN ), if the liver biopsy (or noninvasive markers validated in HBV infected patients) shows moderate-severe inflammation and/or at least moderate fibrosis. Non cirrhotic chronic hepatitis B patients :

Non cirrhotic chronic hepatitis B patients ::

The APASL and AASLD recommend treatment for patients with an ALT level greater than 2 times the ULN . The EASL and AASLD guidelines use Traditional cut-off value of 40 U/L, while The AASLD guideline suggested lower values be used to define the ULN for an ALT level of 30 U/L for men and 19 U/L for women . All guidelines recommend 3 to 6 months of observation pre treatment in HBeAg-positive patients and treatment if there is no spontaneous HBeAg seroconversion , but a period of pre treatment observation is not necessary in HBeAg negative patients who meet criteria for treatment . Non cirrhotic chronic hepatitis B patients :

HBV- infected patients with cirrhosis:

In HBV-infected patients with compensated cirrhosis: The AASLD and APASL guidelines recommend antiviral therapy when serum HBV DNA level is ≥ 2000 IU/Ml regardless of ALT level and HBeAg status. For those patients with increased ALT levels , the AASLD guidelines recommend treatment regardless of HBV DNA level. The EASL guideline recommends treatment of patients with any detectable level of serum HBV DNA. HBV- infected patients with cirrhosis

HBV- infected patients with cirrhosis::

There is growing evidence that long-term treatment with nucleos (t)ide analogues (NAs) not only prevents disease progression but also reverses fibrosis and cirrhosis. Observed patients with cirrhosis should undergo laboratory testing every 3-6 months and be screened for complications, such as esophageal varices and HCC. In HBV-infected patients with decompensated cirrhosis: Treatment is universally indicated for hepatitis B patients with decompensated cirrhosis, regardless of HBV DNA level . However, therapy must be coupled with referral for liver transplantation HBV- infected patients with cirrhosis:

Who Can Be Monitored?:

All guidelines agree that treatment is not required in the immune tolerance and inactive carrier phases patients (HBV DNA < 2000 IU/mL, serum ALT normal) because liver injury is mild and the likelihood of response (in particular HBeAg seroconversion) to available treatment is low. Treatment is not required in patients under 30 years of age with a normal liver biopsy..? Whilst nucleos(t)ide therapy accelerates seroconversion, the risk of HBV reactivation is higher after nucleos(t)ide analogue induced seroconversion. Hence close monitoring of young, non-cirrhotic, and compensated HBeAg positive patients may be more appropriate than immediate nucleos(t)ide analogue therapy. Who Can Be Monitored?

Monitoring of Patients With Chronic HBV Infection:

All guidelines recommend that patients who are not indicated for treatment at presentation and those who decide to defer treatment should undergo monitoring. Guidelines recommend monitoring immune tolerant patients at 3-6 month intervals and more frequent monitoring if ALT levels become increased. For HBeAg-negative patients with normal ALT and HBV DNA levels less than 2000 IU/mL , the AASLD guideline recommends testing for ALT level every 3 months during the first year , to confirm that they are truly in the inactive carrier state. Thereafter, patients should be monitored by ALT and HBV DNA levels every 6 to 12 months. Monitoring of Patients With Chronic HBV Infection

Monitoring of Patients With Chronic HBV Infection::

For patients with persistently normal ALT and HBV DNA levels between 2000 and 20,000 IU/mL , the EASL guideline recommends monitoring ALT level every 3 months and HBV DNA level every 6 to 12 months for the first 3 years. Liver biopsy should be considered in patients with persistent borderline normal or slightly increased ALT levels, particularly those older than age 40 (age 30 according to the EASL guidelines), and treatment should be recommended if the biopsy shows moderate/severe inflammation and/or fibrosis. Monitoring of Patients With Chronic HBV Infection:

HCC Surveillance: Who and How? :

HCC Surveillance: Who? The AASLD guideline recommends HCC surveillance for HBV carriers who are: Asian men older than age 40, Asian women older than age 50, Persons with cirrhosis, Persons with a family history of HCC, First generation African Americans older than age 20. Any carrier older than age 40 with persistent or intermittent ALT increases and/or HBV DNA levels greater than 2000 IU/ mL. HCC Surveillance: Who and How?

HCC Surveillance : Who and How? :

HCC Surveillance: How? Surveillance with ultrasonography at 6-months intervals is recommended by the EASL and AASLD guidelines. The APASL recommends a combination of ultrasound and a-fetoprotein (AFP ) testing every 6 months . Although AFP has limited sensitivity and specificity, the reliability of ultrasound in the surveillance of HCC is suboptimal and operator dependent. Studies have shown that AFP and ultrasound are complementary. HCC Surveillance : Who and How?

Comparison of AASLD, APASL, and EASL Guideline Recommendations Regarding Treatment of Hepatitis B. :

AASLD ( 2009 ) APASL ( 2012 ) EASL ( 2012 ) HBV DNA cut-off level, IU/mL HBeAg-positive HBeAg-negative ALT cut-off level, U/L 20,000 2.000-20,000 30 for men, 19 for women 20,000 2,000 Traditional cut-off value of 40 U/L 2,000 2,000 Traditional cut-off value of 40 U/L Comparison of AASLD, APASL, and EASL Guideline Recommendations Regarding Treatment of Hepatitis B .

:

Noncirrhotic patients AASLD ( 2009 ) APASL ( 2012 ) EASL ( 2012 ) H BeAg-positive HBV DNA >20,000IU/ and ALT >2XULN Monitor for 3–6 ms , Treat if no spontaneous HBeAg loss Liver biopsy before treatment is optiona l HBV DNA >20,000 IU/mL, ALT < 2x ULN Monitor every 3–6 m s Consider biopsy in patients >40 y, ALT persistently 1–2 ULN, or with family history of HCC. Treat if biopsy shows moderate/severe inflammation or significant fibrosis HBV DNA >20,000IU/ and ALT >2XULN Monitor for 3–6 ms , Treat if no spontaneous HBeAg loss Liver biopsy before treatment is optiona l HBV DNA >20,000 IU/mL, ALT < 2x ULN Monitor every 3–6 m s Consider biopsy in patients >40 y, ALT persistently 1–2 ULN, or with family history of HCC. Treat if biopsy shows moderate/severe inflammation or significant fibrosis HBV DNA >2000 IU/mL, ALT >ULN Monitor for 3–6 mo Liver biopsy (or noninvasive markers of fibrosis) is recommended Treat if no spontaneous HBeAg loss and biopsy shows moderate-severe inflammation and/or at least moderate fibrosis. HBV DNA >20,000 IU/mL, ALT <ULN Monitor every 3–6 mo Consider biopsy in patients >30 y, ALT persistently 1–2 ULN, or with family history of HCC Treat if biopsy shows moderate-severe inflammation or significant fibrosis .

PowerPoint Presentation:

Noncirrhotic patients AASLD ( 2009 ) APASL ( 2012 ) EASL ( (2012 H BeAg-negative HBV DNA >20,000IU/ and ALT >2XULN Treatment is clearly indicated, liver biopsy is optional HBV DNA 2000–20,000 IU/mL, ALT 1–2 X ULN Consider liver biopsy Treat if liver biopsy shows moderate/severe ninflammation or significant fibrosis. HBV DNA <2000 IU/mL, ALT< ULN Monitor HBV DNA >2000 IU/mL, ALT >2X U LN Treatment is clearly indicated, liver biopsy is optional. HBV DNA >20,000 IU/mL, ALT 1- 2x ULN Monitor ALT and HBV DNA every 1–3 ms. Consider liver biopsy if patient is > 40 y Treat if biopsy shows moderate/severe inflammation or fibrosis HBV DNA < 2000 IU/mL, ALT< ULN Monitor HBV DNA >2000 IU/mL, ALT >2X ULN Treatment is clearly indicated, liver biopsy is optional. HBV DNA >2,000 IU/mL, ALT >ULN Liver biopsy (or noninvasive markers of fibrosis) is recommended Treat if biopsy shows moderate severe inflammation and/or at least moderate Fibrosis. HBV DNA < 2000 IU/mL, ALT< ULN Monitor

PowerPoint Presentation:

: Cirrhosis AASLD ( 2009 ) APASL (2012) EASL (2012) Compensated Decompensated HCC surveillance HBV DNA >2000 IU/mL Treat regardless of ALT level HBV DNA <2000 IU/mL Consider treatment if ALT >ULN Regardless of HBV DNA or ALT level Treat and refer for liver transplantation US every 6 months HBV DNA >2000 IU/mL Treat regardless of ALT level HBV DNA <2000 IU/mL Consider treatment if ALT >ULN Regardless of HBV DNA or ALT level Treat and refer for liver transplantation US and AFP every 6 months HBV DNA detectable Treat regardless of ALT level . Regardless of HBV DNA or ALT level Treat and refer for liver transplantation US every 6 months

Algorithm showing guidelines recommendation for the treatment of patients with HBeAg positive CHB.:

Algorithm showing guidelines recommendation for the treatment of patients with HBeAg positive CHB .

Algorithm showing guidelines recommendation for the treatment of patients with HBeAg negative CHB:

Algorithm showing guidelines recommendation for the treatment of patients with HBeAg negative CHB

What is treatment? :

Currently approved medications for chronic HBV infection include: I mmune Modulators Interferon alfa-2b – (1991)..Standard INF Peg. Interferon alfa-2a – (2005)…Pegylated INF. Nucleos (t)ide Analogs (NA)s: (NA)s for HBV therapy can be classified into Nucleosides Nucleotides Lamivudine – (1998) Adefovir – (2002 ). Entecavir – (2005) Tenofovir – (2008 ). Telbivudine – (2006) What is treatment?

Main advantages and disadvantages of (pegylated) interferon alpha [(PEG-)IFN] and nucleos(t)ide analogues (NA)s) in the treatment of CHB. :

( PEG-)IFN Nucleos (t)ide analogues Advantages Dis advantages Finite duration Absence of resistance Higher rates of anti- HBe and anti –HBs seroconversion with 12 months of therapy Moderate antiviral effect Inferior tolerability Risk of adverse events Subcutaneous injections Potent antiviral effect. Good tolerance. Oral administration. Indefinite duration Risk of resistance Unknown long-term safety Main advantages and disadvantages of ( pegylated ) interferon alpha [(PEG-)IFN] and nucleos(t)ide analogues ( NA)s ) in the treatment of CHB .

What is treatment?:

Interferon/ Pegylated -Interferon ( Pegasys ): IFNs are cytokines which interfere with viral replication in host cells by inhibiting viral DNA synthesis, and enhancing the cellular immune response against HBV-infected hepatocytes , (Antiviral and Immuno modulatory activity). Its half-life and drug efficacy may be improved through pegylation. Advantages , IFN has which may lead to a higher rate of HBeAg and HBsAg loss so more likely to produce a sustained virological response. Pegylated interferon (PEG-IFN) has a finite duration of treatment. INF does not develop drug resistance . As it is not a direct antiviral medication. What is treatment ?

IFN/PEG-IFN::

Disadvantages: The major drawback of interferon-based therapy is: High costs, Subcutaneous mode of administration, Extensive side-effect profile : (depression, paraesthesia, myelosuppression, and other influenza-like symptoms such as fatigue, headaches, and weight loss). Contraindicated in patients with decompensated liver disease, as they can precipitate worsening hepatic function. PEG-IFN is given at a dose of 180 µg through a weekly injection under the skin. I FN/PEG-IFN :

IFN/PEG-IFN based treatment: :

Pretreatment predictors of IFN/PEG-IFN response are”: In HBeAg-positive patients: High serum ALT levels, Low viral load, HBV genotype A and B, and High histologic activity index. In HBeAg-negative patients : Predictive factors for response have not been defined clearly . PEG-IFN has been reported to enable 3% of those treated to clear the virus , (clearing the hepatitis B surface antigen and producing surface antibodies). IFN/PEG-IFN based treatment :

IFN/PEG-IFN based treatment: :

Who should be treated with pegylated interferon include: People who are HBeAg -positive , have elevated ALT levels, and have HBV genotype A or B may benefit from interferon treatment over a 24- to 48-week period. In HBeAg-positive people treated with pegylated interferon, the following results achieved : Undetectable HBV DNA in 25%, HBeAg loss and “ e” antibodies development in 27%, Normal ALT levels in 39%. People who are HBeAg -negative may also benefit from interferon. Studies show that 63% treated with pegylated interferon achieved undetectable HBV DNA, and 38% achieved normal ALT . IFN/PEG-IFN based treatment :

Nucleos(t)ide Analougs(NAs):

Advantages ; NAs have become the mainstay of CHB treatment because: Oral route of administration, less frequent side effects, Effectively suppress HBV DNA levels to cause clinical and histological improvements. Disadvantages: High rate of antiviral drug resistance; however, the new NAs, entecavir and tenofovir, have high barriers to resistance, with rates of antiviral drug resistance reported to be 1.2% and 0% after 5 years of treatment, respectively, long-term treatment is required to maintain virologic control. Nucleos (t)ide Analougs (NAs)

Nucleos(t)ide (NAs)based treatment::

These drugs, interrupt important steps in the virus’s reproduction process by stopping or interfering with the DNA formation or replication. Pretreatment predictors of ( NAs) response are”: In HBeAg-positive patients: High pre treatment ALT level is the most important predictor , Low viral load, High histologic activity index on liver biopsy . In HBeAg -negative patients : Predictive factors for response have not been identified . Contrary to IFN, HBV genotype is not predictive of response to NUC , and NUC treatment results in a minimal decrease in HBsAg. Nucleos(t)ide (NAs)based treatment :

Lamivudine:

The first oral anti-HBV therapy. Lamivudine, received FDA approval in 1998. It is administered at a dose of 100 mg daily. In HBeAg -positive hepatitis, lamivudine is effective in : Reducing HBV DNA levels (undetectable levels) in 44% at 48 weeks, HBe -Ag seroconversion in 16%, and Durable response in only 50% to 80%. In HBeAg -negative patients , lamivudine is effective in: Reducing HBV DNA levels in 63% at 24 weeks, HBeAg seroconversion in 17%, and Durable response is seen in only 20% to 25%. Lamivudine

Lamivudine::

How ever lamivudine is not currently considered first-line therapy for the treatment of hepatitis B why?.. Lamivudine leads to resistance in approximately 20% of patients per year, with a rate as high as 70% after 5 years of therapy in HBeAg-positive patients or after 4 years in HBeAg-negative patients, high rate of resistance, associated with a known mutation in the reverse transcriptase region of the HBV polymerase. Lamivudine:

Entecavir (Baraclude):

Entecavir is a guanosine analogue with potent activity against HBV through inhibition three steps in the viral replication process and reduces viral load and improves liver health faster than older antivirals, such as lamivudine and adefovir. Entecavir, is considered by all guidelines to be a first-line therapeutic agent for the treatment of naïve chronic hepatitis B. Long-term use of entecavir is not associated with any serious adverse effects, however lactic acidosis has been reported in patients with severely impaired liver function. Its rate of viral resistance is quite low – 1.25% after five years Entecavir ( Baraclude )

:Entecavir (Baraclude):

Entecavir Approved in 2005, administered at a dose of 0.5 mg orally once daily . In HBeAg -positive hepatitis: 0.5 mg daily of entecavir resulted in a greater mean reduction in viral load and a higher rate of HBV DNA undetectability than either lamivudine or adefovir.It is effective in : Reducing HBV DNA levels (undetectable levels) in 67% after 48 weeks, HBeAg loss in 22%, ALT normalization in 68%. In HBeAg -negative patients: Entecavir was associated with: HBV DNA loss in 90%, ALT normalization in 78%, and Histologic improvement in 70% to 72%. : Entecavir ( Baraclude )

Telbivudine (Tyzeka):

Telbivudine inhibits second-strand DNA synthesis by the HBV polymerase.   It is administered at a dose of 600 mg daily and, like other nucleoside analogs, has been found to have an excellent safety and adverse-event profile. In HBeAg -positive hepatitis: With 1 year of therapy It has been demonstrated to produce: HBV DNA suppression in 60%, ALT normalization in 77%, and HBeAg seroconversion in 22%. In HBeAg -negative patients: A higher rate of HBV DNA loss was also seen in HBeAg -negative patients for telbivudine , although normalization of serum ALT levels was not significantly. Telbivudine ( Tyzeka )

Telbivudine (Tyzeka):

Telbivudine is limited by its high rate of resistance, second only to lamivudine.   Resistance is less likely to develop in patients who achieve early, rapid suppression of viral replication, as indicated by undetectable HBV DNA levels (< 300 copies/mL) at 24 weeks. Myopathy and neuropathy have been reported in patients treated with telbivudine It i s not currently considered first-line therapy for the treatment of hepatitis B . Telbivudine ( Tyzeka )

Adefovir (Hepsera) :

Adefovir is an acyclic nucleotide analog. It was approved by the FDA in 2002 for the treatment of chronic hepatitis B. Like lamivudine, terminate and inhibit of both reverse transcriptase and DNA polymerase activity . Adefovir is administered at a dose of 10 mg daily. In HBeAg -positive hepatitis: Adefovir has been demonstrated to produce: Serum HBV DNA reduction in 21%,   HBeAg seroconversion in 12%, and A durable response in 91%. In HBeAg-negative patients : Adefovir has been demonstrated to reduce serum HBV DNA in 71%. Adefovir ( Hepsera )

Adefovir (Hepsera): :

Resistance to adefovir develops at a slower rate than with lamivudine, but, typically developing after 1 year of treatment. Adefovir resistance is most likely to occur in patients with a history of lamivudine resistance who are switched to adefovir monotherapy; it develops at a lower rate in those who have had adefovir added to lamivudine . The most notable side effect associated with adefovir is nephrotoxicity and renal tubular dysfunction , which has been reported in 3% of patients with compensated liver disease after 4-5 years   and in 28% of patients with decompensated cirrhosis during the first year of therapy . The drug is not currently considered first-line therapy for the treatment of hepatitis. Adefovir ( Hepsera ) :

Tenofovir (Viread) :

Tenofovir disoproxil fumarate is a nucleotide analog that is structurally related to adefovir but has more potent antiviral activity   and previously approved for the treatment of HIV. Tenofovir gained FDA approval for the treatment of chronic hepatitis B in the third quarter of 2008 Tenofovir 300 mg daily is more effective than adefovir 10 mg daily in the treatment of chronic HBV infection. It is a potent antiviral, and has been found to help a small percentage of people even clear the virus entirely out of the body – something only pegylated interferon has been found to do. Tenofovir ( Viread )

Tenofovir (Viread)::

In HBeAg -positive patients; It resulted in: HBV DNA suppression (< 400 copies/mL < 69 IU/mL) in 76% of those treated for 48 weeks, ALT normalization in 69%, Histologic improvement in 74%, and Complete clearance of the virus (marked by loss of the hepatitis B surface antigen – HBsAg) in 3% of patients, the highest rate seen among oral nucleos (t)ide agents. In HBeAg-negative patients; It resulted in : Undetectable HBV DNA in 93%,and ALT normalization in 77%. Information on clearance of HBsAg is not yet available . Tenofovir ( Viread ) :

Tenofovir (Viread)::

Resistance to tenofovir is so low as no resistance has been reported thus far for tenofovir in data for up to 2 years. On the basis of its greater potency and superior resistance profile, tenofovir has replaced adefovir as a first-line therapeutic agent for treatment patients with HBeAg -positive and HBeAg -negative hepatitis B. Tenofovir ( Viread ) :

Emerging Antiviral Agents:

Emtricitabine : Anucleos (t)ide analogue approved for the treatment of HIV with structural similarity to lamivudine and clinical activity against HBV. It significantly suppresses viral replication and improves liver histology, but is not used as a monotherapy due to high rates of resistance (9 % after 1 year and 13% after 48 weeks). Instead , dual therapy with tenofovir and emtricitabine was found to produce high rates of HBeAg seroconversion , HBsAg loss and improving clinical outcomes for patients with decompensated HBV cirrhosis. Emerging Antiviral Agents

Emerging Antiviral Agents::

However , further studies are needed to establish whether tenofovir plus emtricitabine offers any advantage over tenofovir monotherapy in treatment-naïve patients. It is also the treatment of choice in patients with HIV co-infection . Clevudine : is another nucleos (t)ide analogue which has potent antiviral activity against HBV. Initial studies demonstrated that 24 wks of clevudine at 30 mg once daily achieved statistically significant differences in viral suppression and durability compared to placebo. HBV DNA loss < 300 copies/mL in 59% and ALT normalization in 68.2% of HBeAg-positive patients. Emerging Antiviral Agents :

:Emerging Antiviral Agents:

Among HBeAg-negative patients , HBV DNA loss occurred in 92% and ALT normalization in approximately 75%). Long-term use is further limited by development of drug resistance, and drug-induced toxic myopathy due to depletion of mitochondrial DNA. Clevudine is currently approved for treatment of CHB in South Korea and the Philippines. Clevudine is unlikely to have a role in treatment where entecavir and tenofovir are available. Thus new therapeutic approaches are needed. . : Emerging Antiviral Agents

Which Should Be the First-Line Treatment?:

The first treatment used should quickly lower viral load without causing viral resistance. The choices are complex and highly dependent on: The individual’s gender, Hepatitis B “e” antigen status (HBeAg), Viral load (HBV DNA), HBV genotype or strain, Length of infection. The safety and efficacy of the medication, Risk of drug resistance, Cost of treatment, Patient preference. W hich Should Be the First-Line Treatment?

Which Should Be the First-Line Treatment?:

The main advantages of IFN include a finite duration of treatment and a higher rate of HBeAg and HBsAg loss, particularly in HBeAg-positive patients with genotype A. NAs are well tolerated but most patients require many years or lifelong treatment. Entecavir, telbivudine, and tenofovir have more potent antiviral activity. Entecavir and tenofovir have very low rates of drug resistance . The AASLD, EASL, and APASL guidelines all recommend initial treatment with PEG-IFN, entecavir, or tenofovir as monotherapy . Which Should Be the First-Line Treatment?

Which Should Be the First-Line Treatment?:

Because of cost concerns and the lack of access to tenofovir in some Asian countries, the APASL guideline recommends entecavir, adefovir, telbivudine , or lamivudine as first-line treatment in treatment-naive patients. To avoid hepatic decompensation secondary to ALT flare, APASL recommends NAs and not IFN in patients with an ALT level greater than 5 times the ULN . IFN is not recommended in patients with acute liver failure, decompensated cirrhosis, or severe exacerbations of CHB in all 3 guidelines . All guidelines recommend entecavir or tenofovir as the preferred treatment in patients with decompensated cirrhosis . Which Should Be the First-Line Treatment?

Which Should Be the First-Line Treatment?:

The AASLD guideline states that patients with compensated cirrhosis are best treated with NAs , because of the risk of hepatic decompensation associated with IFN-related hepatitis flares . The EASL and APASL guidelines indicate PEG-IFN can be used with careful monitoring in patients with compensated cirrhosis because IFN has been shown to be safe in carefully selected patients with compensated cirrhosis in clinical trials. Which Should Be the First-Line Treatment?

Monitoring During Treatment and Deciding When to Stop Treatment   :

Guidelines recommend all patients should be monitored closely during treatment to evaluate response, tolerability, and adherence. Patients receiving IFN require frequent clinical and laboratory monitoring. Guidelines recommend monitoring patients receiving IFN/PEG-IFN therapy with blood counts and a liver panel every 4 weeks initially and then every 4 to 12 weeks . The AASLD and EASL also recommend thyroid-stimulating hormone testing every 12 weeks. The AASLD and APASL recommend monitoring HBV DNA levels every 12 weeks, and the EASL recommends HBV DNA testing at weeks 24 and 48. Monitoring During Treatment and Deciding When to Stop Treatment  

Treatment Monitoring:   :

The EASL guideline also recommends monitoring HBsAg levels at week 12. For patients who initially were HBeAg positive , the AASLD and EASL recommend HBeAg and hepatitis B e-antibody (anti-HBe) testing every 24 weeks during Treatment and the APASL recommends testing every 12 weeks. After completion of IFN/PEG-IFN therapy, blood counts, liver panel, HBeAg, and anti-HBe if initially HBeAg-positive should be tested every 12 weeks during the first 24 weeks. Patients receiving NAs should have their renal function checked initially to ensure appropriate dosing. Treatment Monitoring:  

Treatment Monitoring:   :

Patients who are at risk of impaired renal function should have their renal function monitored regularly, particularly if they are receiving adefovir or tenofovi r because of the risk of nephrotoxicity. In the post-treatment period : T he APASL recommends monitoring ALT and HBV DNA levels monthly for the first 3 months and then every 3 months in the first year. The AASLD and EASL recommend HBsAg testing every 6 to 12 months in patients with HBeAg seroconversion and undetectable HBV DNA levels. . Treatment Monitoring:  

When to Stop Treatment?   :

All guidelines recommend administration of PEG-IFN for 48 weeks in both HBeAg-positive and HBeAg-negative patients. The 2012 EASL guideline recommends discontinuation of PEG-IFN in HBeAg-positive patients who fail to achieve serum HBV DNA levels of less than 20,000 IU/mL or who have no decrease in serum HBsAg levels by week 12 because these patients have a low probability of achieving HBeAg seroconversion. For HBeAg-negative patients , particularly those with genotype D , discontinuation of PEG-IFN is recommended if they fail to achieve any decline in serum HBsAg levels and a 2 log decrease or greater in HBV DNA levels by week 12. When to Stop Treatment?  

When to Stop Treatment?   :

Patients who failed to respond to IFN therapy can be treated with NAs with the expectation of a similar response as treatment-naive patients . There is some variation in recommendations regarding when NAs can be stopped . For HBeAg-positive patients with out cirrhosis: All guidelines recommend that in HBeAg-positive patients, NAs can be stopped when the patient has achieved HBeAg seroconversion and undetectable HBV DNA and completed 6 to 12 months of consolidation treatment. In HBeAg-positive patients with cirrhosis Because of the high rate of relapse after withdrawal of NAs and the persistence of HBV replication in some patients despite HBeAg seroconversion , When to Stop Treatment?  

When to Stop Treatment:   :

the EASL recommends continuing NAs until HBsAg loss in patients with severe fibrosis and cirrhosis Given the low rate of NAs-induced HBsAg loss, most of these patients will remain on treatment indefinitely. In HBeAg-negative patients without cirrhosis : Treatment must be administered indefinitely , due to high rates of relapse despite prolonged HBV DNA undetectability. The EASL and AASLD agree that discontinuation of treatment can only be considered if HBsAg clearance is is achieved . However , the APASL recommends considering withdrawal of treatment in HBeAg-negative patients who have been treated for 2 years with undetectable HBV DNA levels documented on 3 separate measurements 6 months apart . When to Stop Treatment:  

When to Stop Treatment:   :

The basis for the APASL recommendation is related mainly to cost. In HBeAg-negative patients with cirrhosis : All guidelines recommend lifelong NAs in patients with cirrhosis before treatment; however, discontinuation of treatment may be considered in patients who had compensated cirrhosis if they achieved HBsAg loss with an undetectable HBV DNA . After withdrawal of treatment, patients need to be monitored closely for relapse so that treatment can be re-instituted promptly if needed.   When to Stop Treatment :  

Treatment Failure   :

Therapy must ensure a degree of virologica l suppression that will then lead to biochemica l remission, histologica l improvement and prevention of complications. The ideal end point is HBsAg loss , which however is infrequently achievable with the currently available anti-HBV agents. A more realistic end point is the induction of sustained or maintained virological remission . Responses can be divided into biochemical, serological, virological and histological . All responses can be estimated at several time points during and after therapy. Treatment Failure  

Definitions of response   :

Time of Assessment On-therapy: During therapy Maintained: Persist throughout the course of treatment End-of-treatment : At the end of a defined course of therapy Off-therapy : After discontinuation of therapy Sustained ( SR-6 or12) : 6 or12 months after discontinuation of therapy. Biochemical response: Is defined as normalisation of ALT levels . It can be evaluated at several time points on-therapy, at the end and after the end of therapy. Definitions of response  

Definitions of response:   :

Virological response: The definitions of virological responses vary according to the timing (on or after therapy) and type of therapy. Is defined as decrease in serum HBV DNA to undetectable levels by PCR assays. Virological relapse : Is defined as an increase in serum HBV DNA of (1 log) IU/mL after discontinuation of treatment in at least two determinations more than 4 weeks apart . Serological response for HBeAg: Applies only to patients with HBeAg-positive CHB and is defined as HBeAg loss and seroconversion to anti- Hbe . Definitions of response:  

Definitions of response:   :

Serological response for HBsAg: Applies to all CHB patients and is defined as HBsAg loss and development of anti-HBs. Histological response: Is defined as a decrease in histology activity index (HAI) by at least 2 points and no worsening of fibrosis score compared to pre-treatment liver biopsy. Complete response: Is defined as sustained off-treatment virological response together with loss of HBsAg , (fulfill criteria of biochemical and virological response and loss of HBsAg ). Primary non-response: Is defined as less than 1 log IU/ml decrease in HBV DNA level from baseline at 12 weeks of therapy. Definitions of response:  

Definitions of response:   :

Virological responses on IFN/PEG-IFN therapy : Primary non-response has not been well established. Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy as well as at 6 and12 months after the end of therapy. Sustained off-treatment virological response ; is defined as HBV DNA levels below 2000 IU/ml for at least 12 months after the end of therapy . Virological responses on NAs therapy: Primary non-response is defined as less than 1 log IU/ml decrease in HBV DNA level from baseline at 3 months of therapy. Definitions of response:  

Virological responses on NAs therapy:   :

Virological response is defined as undetectable HBV DNA by a sensitive PCR assay. It is usually evaluated every 3– 6 months during therapy depending on the severity of liver disease and the type of NAs. Partial virological response is defined as a decrease in HBV DNA of more than 1 log IU/ml but detectable HBV DNA after at least 6 months of therapy in compliant patients. Sustained off-treatment virological response may be defined similarly to the definition used for IFN therapy, which requires HBV DNA values below 2000 IU/ml for at least 12 months after treatment discontinuation. Virological responses on NAs therapy :  

Virological responses on NA(s) therapy :   :

Virological breakthrough : is defined as a confirmed increase in HBV DNA level of more than 1 log (10-fold) above the nadir (lowest value) after achieving virologic response, during continued treatment; it may precede A biochemical breakthrough , which is characterized by an increase in ALT levels after achieving normalization, during continued treatment . The main causes of virological breakthrough on NA therapy are poor adherence to therapy and/or selection of drug-resistant HBV variants (resistance). Virological breakthrough in compliant patients is related to the development of HBV drug resistance Virological responses on NA (s) therapy :  

Virological responses on NAs therapy:   :

Viral rebound : Increase in serum HBV DNA to 20,000 IU/ mL or above pretreatment level after achieving virologic response,during continued treatment. Genotypic resistance: Detection of mutations that have been shown in in vitro studies to confer resistance to the NA that is being administered. Phenotypic resistance: In vitro confirmation that the mutation detected decreases susceptibility ( as demonstrated by increase in inhibitory concentrations ) to the NA(s ) administered . Virological responses on NAs therapy :  

Drug Resistance:

HBV resistance to NA(s ) . is defined by the loss of an initial response to a drug and a rebound in HBV DNA levels, may result in primary non-response or virological breakthrough on therapy. The risk of developing resistance depends not only on the resistance profile and potency of the antiviral agent being used but also on pretreatment HBV DNA levels, duration of treatment, and previous exposure to oral antiviral therapy. The risk of resistance is associated with high baseline HBV DNA levels, a slow decline in HBV DNA and suboptimal previous NA(s ) treatment. Drug Resistance

:Management of Treatment Failure:

Primary non response is very rare with NAs therapy except for adefovir. An inadequate decrease in HBV DNA levels during the first 12 to 24 weeks of NAs that have a low barrier to resistance is associated with a higher chance of subsequent antiviral resistance, prompting the roadmap approach that recommends the addition of a second NAs in patients with an inadequate initial response; however, these data do not apply to NAs with a high barrier to resistance. : Management of Treatment Failure

:Management of Treatment Failure:

Guidelines recommend counseling patients with a virologic breakthrough regarding medication adherence and confirmation of breakthrough by retesting HBV DNA levels after 1 to 3 months. Salvage therapy should be initiated immediately in patients who have decompensated liver disease or severe hepatitis flares, but in other patients it can be deferred until after breakthrough is confirmed to avoid unnecessary changes in medications. The choice of salvage therapy depends on the current and prior treatments and the pattern of drug. : Management of Treatment Failure

Management of Antiviral-Resistant HBV:

Prevention: Avoid unnecessary treatment. Initiate treatment with potent antiviral that has low rate of drug resistance or with combination therapy. Switch to alternative therapy in patients with primary non-response. Monitoring: Test for serum HBV DNA (PCR assay) every 3-6 months during treatment. Check for medication compliance in patients with virologic breakthrough. Confirm antiviral resistance with genotypic testing. Management of Antiviral-Resistant HBV

Management of Antiviral-Resistant HBV::

Lamivudine resistance: The EASL guideline recommends : Switch to tenofovir, Add adefovir if tenofovir is not available. The ASSLD guideline recommends: Add adefovir or tenofovir Stop lamivudine, switch to Truvada (combination pill with emtricitabine 200 mg and tenofovir 300) Adefovir resistance: The EASL guideline recommends : If the patient was NAs naive before adefovir , switch to entecavir or tenofovir. Entecavir may be preferred in such patients with high viraemia . Management of Antiviral-Resistant HBV:

Management of Antiviral-Resistant HBV::

Adefovir resistance: The patient had prior lamivudine resistance , switch to tenofovir and add a nucleoside analogue. The ASSLD guideline recommends: Add lamivudine. Stop adefovir, switch to Truvada . Switch to or add entecavir . Telbivudine resistance : The EASL guideline recommends Switch to or add tenofovir, (Add adefovir If tenofovir is not available) Management of Antiviral-Resistant HBV:

Management of Antiviral-Resistant HBV::

Telbivudine resistance : The ASSLD guideline recommends: Add adefovir or tenofovir Stop telbivudine , switch to Truvada . Entecavir resistance: The EASL guideline recommends: Switch to or add tenofovir (add adefovir if tenofovir is not available ). The ASSLD guideline recommends: Switch to tenofovir or Truvada Management of Antiviral-Resistant HBV:

Management of Antiviral-Resistant HBV::

Tenofovir resistance: Tenofovir resistance has not been detected to date and therefore there is no experience, but it seems reasonable to: Add entecavir, telbivudine , lamivudine or emtricitabine if tenofovir resistance is confirmed A switch to entecavir may be sufficient if the patient has not been treated with lamivudine in the past, While adding entecavir may be the preferred option for patients with prior lamivudine resistance , according to the EASL guideline recommends . Management of Antiviral-Resistant HBV:

AASLD and EASL Recommendations for Salvage Therapy in Patients With Antiviral Drug Resistance :

Drug to which resistance has developed AASLD (2009) EASL (2012) Lamivudine or telbivudine resistance Adefovir resistance Entecavir resistance     Add adefovir or Stop lamivudine, Switch to Truvada Add lamivudine Stop adefovir, switch to Truvada Switch to or add entecavir Switch to tenofovir or Truvada Switch to tenofovir Add adefovir if tenofovir is not available If nucleoside-naive before adefovir then switch to entecavir or tenofovir If the patient has high viremia then switch to entecavir If there is prior lamivudine resistance then switch to tenofovir or add a nucleoside analogue. Switch to or add tenofovir Add adefovir if tenofovir is not available AASLD and EASL Recommendations for Salvage Therapy in Patients With Antiviral Drug Resistance

Treatment in special patient groups:

Treatment Of Acute Hpatitis B: All guide lines recommend treatment in Patients with patients with fulminant hepatitis B. The ASSLD recommends treatment with Lamivudine or telbivudine when the anticipated duration of treatment is short; otherwise, entecavir is preferred The E ASL recommends treatment with entecavir or tenofovir , and those patient must be evaluated for liver transplantation. The duration of treatment is not established. However, continuation of antiviral therapy for at least 3 months after seroconversion to anti-HBs or at least 12 months after anti- HBe seroconversion without HBsAg loss is recommended . Treatment in special patient groups

Treatment Of Acute Hpatitis B::

Indefinite treatment is recommended in those who undergo liver transplantation. IFN- is contraindicated . Sometimes , the distinction between true severe acute hepatitis B and reactivation of CHB may be difficult and may require liver biopsy. However, NAs treatment is the treatment of choice in both cases Treatment Of Acute Hpatitis B:

Pregnancy :

The EASL guideline recommends that in women of childbearing age, the immediacy of their plans to become pregnant should be discussed before deciding to initiate treatment. The EASL and APASL recommends prophylactic antiviral treatment in pregnant women with high levels of viremia. PEG-IFN is contraindicated during pregnancy . Lamivudine, adefovir are listed by the FDA as pregnancy category C drugs , and telbivudine and tenofovir as category B Drugs. The safety of entecavir in pregnancy is not known. Pregnancy

Children :

Chronic hepatitis B runs an asymptomatic course in most children, in whom treatment indications should be very carefully evaluated. The aim of treatment is to stop multiplication of the virus, and if possible, eliminate it from the body. This is necessary to prevent progression from the chronic carrier state to chronic hepatitis, liver cirrhosis, and liver cancer . Only conventional IFN, lamivudine and adefovir have been evaluated for safety and efficacy, which were comparable to adults. These drugs have also been used in combination with each other, and with interferon. If these measures fail, or if cancer develops, one option is liver transplantation . Children

Children: :

None of these drugs or combinations are effective, yielding cure rates of around 40%.  The only good strategy against hepatitis B is to prevent it. Neonates born to mothers who are HBeAg positive should be given a combination of passive and active immunization to provide immediate protection with HBIG in the first 6 hours after delivery , followed by long-term immunity with the vaccine. At the currently recommended doses, HBIG does not interfere with the active immune response of the vaccine. When concurrent administration of HBIG and vaccine are indicated, different sites should be used. Children:

Healthcare workers :

Healthcare workers need special attention, as they may require antiviral therapy even if they do not fulfill the typical indications for treatment to reduce direct transmission during exposure prone procedures to patients. Policies for HBsAg-positive healthcare workers vary among countries. In many countries, healthcare workers, including surgeons, gynecologists and dentists, who are HBsAg-positive with HBV DNA >2000 IU/ml should be treated with a potent antiviral agent with a high barrier to resistance (i.e. entecavir or tenofovir) , to reduce levels of HBV DNA ideally to undetectable or at least to <2000 IU/ml before resuming exposure-prone procedures. Healthcare workers

HDV co-infected patients:

HDV is a satellite virus , which is dependent on HBV for the production of envelope proteins. HBV/ HDV co-infection most commonly occurs in the Mediterranean area and parts of South America. The availability of HBV vaccines and public health education on the prevention of transmission of HBV infection has led to a significant decline in the prevalence of HDV infection in the past decade. HDV infection can occur in two forms: The first form is caused by the co-infection of HBV and HDV, this usually results in a more severe acute hepatitis with a higher mortality rate than is seen with acute hepatitis B alone, but rarely results in chronic infection. HDV co-infected patients

HDV co-infected patients::

A second form is a result of a super infection of HDV in a HBV carrier and can manifest as a severe acute Hepatitis “in previously asymptomatic HBV carriers or as an exacerbation of underlying chronic hepatitis B. Unlike co-infection , HDV super infection in HBV carriers almost always results in chronic infection with both viruses. A higher proportion of persons with chronic HBV/HDV co-infection develop cirrhosis, hepatic decompensation , and HCC compared to those with chronic HBV infection alone . Active co-infection with HDV is confirmed by detectable HDV RNA, immuno-histochemical staining for HDV antigen, or IgM anti-HDV. However , diagnosis of active HDV infection may be difficult, as HDV RNA assays are not standardized and HDV antigen and IgM anti-HDV assays are not widely available HDV co-infected patients:

HDV co-infected patients::

PEG-IFN is the only drug effective against HDV . The efficacy of (PEG-)IFN therapy can be assessed during treatment (after 3–6 months) by measuring HDV RNA levels. More than 1 year of therapy may be necessary, as there may be some benefit from treatment prolongation. However, the optimal duration of therapy is not well defined. Around 25–40% of treated patients have a sustained off-treatment virological response with undetectable HDV RNA and improvement in histology, while some also lose HBsAg. NAs do not impact HDV replication and related disease . Lamivudine has been evaluated in a small number of patients and found to be ineffective in inhibiting HDV replication. HDV co-infected patients:

HCV co-infected patients:

Coexistent HCV infection has been estimated to be present in 10% to 15% of patients with chronic hepatitis B and is more common among injecting drug users. Patients with dual HBV and HCV infection have a higher rate of cirrhosis and HCC development compared to patients infected by either virus alone. Acute co-infection of HCV and HBV, or acute HCV on preexisting chronic HBV have also been reported to increase the risk of severe hepatitis and fulminant hepatic failure. HBV and HCV replicate in the same hepatocyte without interference. A proportion of these patients may have fluctuating serum HBV DNA levels , HCV co-infected patients

:HCV co-infected patients:

thus indicating the need for longitudinal evaluation of viral loads before starting any antiviral therapy in order to clarify the respective pathogenic role of each virus. Nevertheless, HBV DNA level is often low or undetectable and HCV is responsible for the activity of chronic hepatitis in most patients, Thus, patients should usually receive treatment for HCV. There is a potential risk of HBV reactivation during treatment or after clearance of HCV. Therefore, HBV DNA monitoring is necessary. Any HBV reactivation must then be treated with NA(s ). : HCV co-infected patients

HCV co-infected patients::

There is scant information on the treatmentof HBV/HCV co-infection and recommendations on treatment for HBV/HCV co-infection cannot be made at this time. Two studies on standard IFN- and ribavirin showed no difference in sustained virological response to HCV infection in patients with HBV/ HCV co-infection compared to patients with HCV infection only. A third study showed that combination therapy with peg IFN and ribavirin was equally effective in patients with HCV mono infection and in those with HBV/HCV co-infection. HCV co-infected patients:

HIV co-infected patients:

Studies have found that between 6% and 13% of persons infected with HIV are also co-infected with HBV . Individuals with HBV and HIV co-infection tend to have higher levels of HBV DNA, lower rates of spontaneous HBeAg sero conversion, more severe liver disease, and increased rates of liver related mortality. In addition, severe flares of hepatitis can occur in HIV co-infected patients with low CD4 counts after initiation of highly active antiretroviral therapy (HAART) and in certain opportunistic infections such as cytomegalovirus. Patients with HIV infection can have high levels of HBV DNA and hepatic necro inflammation with anti- HBc but not HBsAg, so called “occult HBV”. HIV co-infected patients

HIV co-infected patients::

Therefore it is important to test all HIV infected persons for both HBsAg and anti-HBc and if either is positive, to test for HBV DNA. Persons who are negative for all HBV sero markers should receive hepatitis B vaccine. Hepatitis B vaccine should be given when CD4 cell counts are 200/uL as respose to vaccine is poor below this level. Persons with CD4 counts below 200 should receive HAART first and HBV vaccine when CD4 counts rise above 200/uL. The indications for therapy are the same as in HIV-negative patients, based on HBV DNA levels, serum ALT levels and histological lesions . HIV co-infected patients:

:HIV co-infected patients:

Patients being treated for HIV alone, or who need treatment for both HIV and HBV infection, should be treated with medications that have activity against both viruses. Lamivudine, entecavir and tenofovir have activity against both HIV and HBV and are contraindicated as single agents for hepatitis B in co-infected patients because of the risk of HIV resistance. All HBsAg -positive patients should be screened for HIV before these drugs are used in the treatment of HBV infection. The treatment must include at least 2 agents with activity against HBV . The combination of tenofovir plus emtricitabine is preferred in this setting, although lamivudine plus tenofovir can also be used. : HIV co-infected patients

Treatment algorithm for HIV-HBV co-infection:

Treatment algorithm for HIV-HBV co-infection

Patients undergoing immunosuppressive therapy or chemotherapy :

Reactivation of HBV replication in patients receiving immunosuppressive therapy can lead to severe hepatitis, liver failure, and even death. The EASL and AASLD guidelines recommend testing for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) in patients who will be receiving chemotherapy or immunosuppressive therapy. The APASL guideline recommends screening for HBsAg only, and additional testing for anti-HBc in patients who will be receiving biologic treatment such as rituximab or anti–tumor necrosis factor-a. Patients undergoing immunosuppressive therapy or chemotherapy

Patients undergoing immunosuppressive therapy or chemotherapy: :

Prophylactic antiviral therapy has been shown to decrease the risk of HBV reactivation. All 3 guidelines recommend initiating prophylactic antiviral therapy in HBsAg-positive patients who will be receiving cancer chemotherapy or immunosuppressive therapy and monitoring of HBsAg-negative, anti–HBc-positive patients and initiating antiviral therapy when serum HBV DNA level becomes detectable . The EASL guideline recommends prophylactic antiviral therapy in patients who will receive rituximab or stem cell transplantation. Patients undergoing immunosuppressive therapy or chemotherapy:

Prevention of recurrent hepatitis B after liver transplantation::

In patients who have undergone liver transplantation for HBV infection, the standard of care for prophylactic therapy is currently lamivudine in combination with HBIG. Shorter courses and lower doses of HBIG and other forms of prophylaxis, including tenofovir with emtricitabine or entecavir monotherapy , are being studied. Recently, entecavir prophylaxis without HBIG was shown to be safe and effective in preventing HBV recurrence. . Prevention of recurrent hepatitis B after liver transplantation:

Prevention of recurrent hepatitis B after liver transplantation::

In the setting of liver transplantation, nephrotoxicity should be always considered and renal function should be carefully monitored. Recurrent HBV infection in the transplanted liver has previously been a major problem. Pre-transplant therapy with a potent NA with a high barrier to resistance is recommended for all HBsAg positive patients undergoing liver transplantation for HBV related end-stage liver disease or HCC , to achieve the lowest possible level of HBV DNA before transplantation. Lamivudine and/or adefovir in combination with hepatitis B immunoglobulin (HBIG) have reduced the risk of graft infection to less than10 %. Prevention of recurrent hepatitis B after liver transplantation :

Dialysis and renal transplant patients:

HBV is prevalent in patients with end-stage renal disease including renal transplant patients. Patients with renal disease should be screened for HBV infection. Though vaccine responsiveness is impaired, HBV sero negative patients should be vaccinated. PEG-IFN or NAs can be used for CHB patients with renal dysfunction. All drugs and particularly NAs should be dose-adjusted and used with caution in patients with renal impairment. Hypertension and coexisting diabetes mellitus should be optimally controlled. Dialysis and renal transplant patients

Dialysis and renal transplant patients::

Renal function should be monitored during antiviral treatment. Unexpected deterioration of renal function during antiviral treatment may necessitate a change of treatment or further dose adaptation. PEG-IFN should be avoided in renal transplant patients because of the risk of rejection. Every HBsAg positive patient who undergoes renal transplantation and receives immunosuppressive agents should receive anti-HBV prophylaxis with a NA . The need for antiviral prophylaxis or treatment should be constantly and frequently evaluated for all HBV positive renal transplant patients. Dialysis and renal transplant patients:

Extrahepatic manifestations:

HBsAg positive patients with extra-hepatic manifestations and active HBV replication may respond to antiviral therapy. (PEG)-IFN may worsen some immune mediated extra-hepatic manifestations . Controlled studies of antiviral therapy are limited, but case reports suggest that it may be of benefit. Lamivudine has been most widely used to date, entecavir and tenofovir are expected to have enhanced efficacy in this group. Plasmapheresis and corticosteroids during the initial phase can be useful in addition to NA therapy in special cases. Extrahepatic manifestations

Conclusion:

HBV is a life long, dynamic disease: Changes over time. Risk of end stage liver disease and cancer increases with ongoing inflammation and viremia in adults. Fibrosis can be reversible. Drugs can decrease fibrosis progression. HBV can be controlled but not cured. Reactivation can occur even in those who have lost HBsAg. Conclusion

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