Hepatitis B

Hepatitis B virus (HBV) is a partially double stranded DNA virus.

It is a spherical 42 nanometer virion comprises an envelope that is outside at 30 nm nucleocapsid that encloses is circular 32 KB DNA genome.

The lipid bilayer of the virion envelope incorporates the large (42-kD) hepatitis B virus surface protein (LHBs), the medium (33-kD) surface protein (MHBs), and the small (26-kD) surface protein (SHBs). 

HBV has 10 listed genotypes and at least 24 subtypes, which influence clinical outcomes, the risk of cirrhosis and hepatocellular carcinoma and treatment response.

Hepatitis B is caused by the hepatitis B virus (HBV), a hepatotropic DNA virus that can replicate at high levels and cause minimal disease or severe liver injury. 

HBV generally causes a self limited illness, with viral control, mediated, primarily by the adaptive immune response.

Hepatitis B is caused by the hepatitis B virus (HBV), a hepatotropic DNA virus that can replicate at high levels and cause minimal disease or severe liver injury. 

In contrast to the above, more than 90% of cases of perinatal infection, develop into chronic infection.

The screening for hepatitis B, and 85 to 90% of pregnant people in the US has resulted in a significant decrease in perinatal chronic hepatitis B through prophylaxis and hepatitis B vaccine and immune globulin.

An estimated 296 million people have chronic hepatitis B, of whom 221 million live in low- and middle-income countries.

Without intervention, deaths from HBV are expected to peak at 1.14 million by 2035.

Chronic infection accounts for 5%-10% of chronic liver disease and cirrhosis in the U.S.

Affects 4% of the population worldwide, and accounts for more than a half million deaths yearly.

The most common chronic viral infection worldwide.

The highest prevalence are found in Asia and Africa, whereas the prevalence in the US, of 0.3%,  is among the lowest.

An estimated 296 million people have chronic hepatitis B of whom 221 million live in low and middle income countries.

Chronic hepatitis B is caused by the hepatitis B virus, a hepato-tropic DNA virus that can replicate at high levels and cause minimal or severe liver injury.

The clinical spectrum of chronic hepatitis B ranges from asymptomatic status to progressive hepatic fibrosis, advanced cirrhosis, and hepatocellular carcinoma.

Approximately 2,000,000,000  people worldwide had been infected by HBV.

HBV life cycle. Step 1: viral particles are first internalized through receptor-mediated endocytosis by binding cell surface transporters.

Step 2: nucleocapsids are then uncoated in the cytoplasm, releasing the partially double-stranded viral genomes that are imported into the nucleus. 

Step 3: viral genomes are converted to cccDNA molecules. 

Step 4: cccDNA serves as a template for viral mRNA, which in step 5 is exported to the cytoplasm. 

Step 6: cytoplasmic mRNA is translated to produce the viral surface, core, polymerase, and X proteins. 

Viral capsids assemble, incorporating genomic viral RNA, which is reverse transcribed back into a viral DNA genome. 

Step 7: the resulting nucleocapsid cores can either enter the endoplasmic reticulum to be exported from the cell or recycle their genomes into the nucleus to replenish the reservoir of cccDNA.

Hepatitis B infections can cause an acute liver inflammation more by malaise, fever, nausea, anorexia, abdominal pain and arthralgia, followed by jaundice, liver tenderness, liver swelling, and acholic stools.
Rarely fulminant infection can occur, leading to death or liver failure that requires liver transplant.
Half of all individuals with acute infection have no symptoms.
Most acutely infected patients clearly infection in develop immunity for life, but the infection can persist for decades, leading to cirrhosis or hepatocellular carcinoma.

Worldwide number of chronically infected persons is 250-400 million.

Estimated more than 1.25 million cases of chronic disease in the U.S.

 The prevalence of chronic hepatitis B virus infection based on positive hepatitis B surface antigen is estimated to be 0.3% overall, 0.15% in US-born individuals, and 1.28% in non-US-born individuals, with the highest prevalence among non-US-born Asian individuals of 3.9%.
Approximately 600,000 people die each year due to acute and chronic consequences of HBV infection.

Approximately  7000 new cases of chronic hepatitis B infection occur per year in the US.

Accounts for approximately 45% of the cases of hepatocellular carcinoma and 30% of cases of cirrhosis and causes nearly 1,000,000 deaths each year.

The annual incidence of hepatocellular carcinoma is low among patients without cirrhosis, but is increased up to 10% among those with cirrhosis.

Chronic infection associated with serious complications of liver failure, cirrhosis and hepatocellular carcinoma.

HBsAg, HBeAg, anti-HBc and hepatitis B are established markers of chronic hepatitis B.

 HBV DNA levels are an indicator of HBV replication and is used to identify the phase of chronic hepatitis B infection, determine indications for treatment and assess the efficacy of antiviral therapy.

HBe in serum signals high levels of replication and infectivity, but it may not necessarily correlate with HBV DNA levels.

Of the 7000 thousand new cases of chronic infection that occur per year a quarter are associated with either cirrhosis of the liver cancer, from which 4000 people die every year in the US.

Accounts for up to half of all cases of cirrhosis, end-stage liver disease and hepatocellular carcinoma, worldwide.

Hepatocellular carcinoma can occur in the absence of cirrhosis in HBV disease.

Known to be carcinogenic by integration in the host genome, direct actions of the HBV particles on host cells, and by mechanisms of inflammation leading to genetic damage over time.

Persistent replication of the virus is an independent risk factor for progression to cirrhosis and hepatocellular carcinoma, and reduction of the HBV DNA concentrations by the use of nucleoside or nucleotide analogue therapy reduces the risk of a hepatocellular carcinoma and mortality in patients with chronic hepatitis B.

Hepatitis B virus is rarely eradicated and most patients require a long time nucleoside or nucleotide analogue therapy

Prevalence estimated at 4.9% in the U.S.

Approximately 350 million people, 5% of the world’s population, have been exposed to the hepatitis B virus as characterized by HBV surface antigen.

Carriers of HBV have undetectable or very low levels of HBV DNA with normal ALT levels, while individuals with active HBV have higher HBV DNA levels, and may have elevated ALT levels.

Many exposed clear the virus with negative HBV surface antigen tests with absence of HBV DNA levels, but have HBV core antibody.

Other suggest prevalence in the United States is less than 1%, and as high as 15% in populations from endemic countries period.

In the Asia Pacific region and Africa, the incidence ranges from 5 to 15%.

Underlying host of factors, genetic in nature, affect the chronicity and outcome of the disease such that even in the most endemic area, the incidence seldom exceeds 20%.

Chronic HBV infection runs in families, but usually it is the male patients who suffer from the disease with female siblings having a much lower chance of developing serious clinical sequelae.

Female siblings of patients with HPV infection have a higher chance of recovering spontaneously with the development of natural immunity against the disease.

An intact immune system suppresses HBV replication in exposed patients and prevents flares of hepatitis.

Immunosuppression from chemotherapy increases the risk of HBV reactivation, including the risk of death from liver insufficiency.

HBV reactivation risk is higher among patients on chemotherapy with lymphoma than solid tumors.

In lymphoma patients on chemotherapy, HBV reactivation occurs in up to 50% of patients sero-positive for HBV surface antigen,..

The most serious complications such as hepatocellular carcinoma, and cirrhosis tend to run in families.

Purpose of treatment of hepatitis B is to prevent cirrhosis, hepatocellular carcinoma and hepatic failure.

The infection passes at the time of parturition from a mother to child: this form of transmission results in possibly as many as 1000 infant infections per year in the US, despite universal infant immunization.
Hepatitis B infection can be spread by exposure to blood or semen.
High-risk groups include those who abuse injecting drugs, the promiscuous, men who have sex with men, healthcare workers, young people with diabetes, and those undergoing dialysis.

Is not a directly cytopathic and development of hepatocellular cancer is a multistage, multifactorial process.

15-40% of patients with chronic disease will develop serious hepatic disease sequelae.

As many as 25% of chronically infected patients will develop hepatocellular cancer.

Majority of cases of hepatocellular carcinoma cases worldwide are associated with hepatitis B.

In infants and young children acute hepatitis B progresses to a chronic infection at high rates, from 30-90%, compared to 2-6% in adolescents and adults.

Approximately 85% of infants infected at birth will go on to develop chronic infection.

Young children who are  infected have a 30% chance of developing chronic infection, whereas older children and adults have a 5% risk of not clearing the infection.

Higher conversion rates to chronic infection felt to be due to impaired immune clearing of the virus or immaturity, as in the newborn or the presence of comorbidities.

Responsible for 1.2 million deaths annually, worldwide.

Responsible for 4000-5500 deaths in the U.S. yearly.

A mostly double-stranded DNA virus in the Hepadnaviridae family.

Eight genotypes, A-H.

Genotypes B and C most common in Asia.

Genotype C associated with higher prevalence of hepatitis B e antigen (HBeAg) more active hepatitis and more serious liver disease than with genotype B.

Genotype C associated with hepatocellular carcinoma.

There are 4 genotype C sub genotypes, HBV/C1-4, with C2 having the highest risk for hepatocellular carcinoma.

Transmitted by skin and mucous membrane exposure to infected blood or infected body fluids that contain blood.

Major routes of infectivity are illicit injections, drug use and sexual activity.

Blood screening procedures has made blood transfusion transmission extremely rare in developed countries.

Hepatitis B screening should be carried out in all individuals with high risk of infection with hepatitis B surface antigen, surface antibody, and core antigen in high-risk populations: include people born in high prevalence areas, unvaccinated infants whose parents are from high prevalence areas, patients with HIV virus, injection drug users and men having sex with men, and household contacts of hepatitis B infected persons.

Screening for the hepatitis B antigen may fail to prevent transmission early in the acute phase when the viral load is below the tests limit of detection and during a late chronic phase with hepatitis B antigen levels gradually become undetectable although infectivity remains.

Majority of cases in Asia and Africa occur perinatally or in early childhood, with a prevalence of 8%.

Almost 1000 infants born to HBV infected mothers become chronically infected at birth, but immediate vaccination could prevent such transmission.

In areas of endemic HBV infection, such as Southeast Asia and Africa, the most common virus transmission is from mother to newborn.

The vertical route of transmission is associated with a chronic disease course in 90% of infected children.

Hepatocellular carcinoma occurs in these patients without significant fibrosis and screening in Asians in Africans infected with HBV should begin an early age.

In North America infection more related to sexual contact and intravenous drug abuse with a peak incidence occurring between ages 15-25 years, and a prevalence of chronic infection of less than 1%.

Testing for early detection should be done in endemic areas such as Africa and Southeast Asia, and other individuals that should be tested are illicit drug users, dialysis patients, HIV infected patients, and family members of HBV infected patients.

Prior to chemotherapy or immunosuppression with tumor necrosis factor inhibitors or organ transplant patients should have testing for chronic or inactive hepatitis B to prevent reactivation of disease: If positive for HBsAg , antiviral therapy should be initiated before immunosuppression and continued for 6 months.

Can be transmitted by hetero and homosexual activity, with men who have sex with men having one of the highest groups for infection.

Patients on dialysis and their healthcare workers are at increased infection.

Approximately 70% of patients with acute Hepatitis B have subclinical or anicteric hepatitis, while 30% develop icteric hepatitis.

Fulminant infection can cause acute liver failure and is responsible for 100-200 deaths per year in the U.S.

Associated with an increased incidence of cirrhosis in patients co-infected with HIV.

Initial tests for hepatitis B include serologic tests for hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody.

In the U.S. sexual transmission is the most common source of HBV infection.

Sexual route of transmission can be prevented year vaccination of spouses and with the use of barrier contraception.

Most infections occur in adolescents and adults.

Transmission of Hepatitis B by blood transfusion is 7 to 32 cases per million units collected.

Standard care in obstetrics includes routine screening of hepatitis B surface antigen in all pregnant women.

200,000 to 300,000 new cases occur each year.

An estimated 300 million carriers worldwide.

5,000 people die annually in the U.S.

Estimates of prevalence 0.4% and incidence 0.033 cases/1000 person-years in the general U.S. population.

Markers of active viral replication hepatitis B e antigen (HBeAg) and HBV DNA.

Hbe antigen (HbeAg)-negative disease represents a late phase of infection with progressive liver damage abolishing or suppressing the expression of HBeAg.

Hbe antigen (HbeAg)-negative disease is characterized by periods of exacerbation and quiescent disease.

Common variant of hepatitis B is hepatitis B e antigen (HbeAg) negativity and positive for antibodies to hepatitis BeAg (anti-HBe) and in whom HBV DNA and alanine aminotransferase levels remain persistently or intermittently elevated.

The median worldwide prevalence of hepatitis HbeAg negative patients who are carriers of hepatitis B surface antigen (HBsAg) is about 33%.

HBV carrier state is characterized by persistent HBV infection without ongoing inflammation of hepatic cells negative hepatitis B E antigen (HBeAg), and positive anti-hbe and HbsAG.

Carrier state is associated with serum HBV DNA LESS than 2000 international units per milliliter normal AST and ALT levels.

Resolved HBV occurs after previous infection without further virologic, biochemical or histologic evidence of active viral infection or disease in patients with a known history of acute or chronic HBV, with the presence of hepatitis B core antibody (HBcAb) with or without HBsAB.

Patients with resolved HPV are HBsAG- negative, and her undetectable or very low levels of serum HBV DNA and normal ALT levels.

HPV infection can be prevented by immunization, safe sex practices, occupational safety precautions.

Chronic hepatitis B includes the criteria of: Positive HBsAg for more than 6 months, serum HBV DNA greater than 20,000 international units per milliliter, and persistent or intermittent elevations of AST and or ALT levels.

HBV reactivation is noted by elevation of serum HBV DNA, abnormal LFTs, and clinical features of hepatitis in patients with previously latent or resolved HPV infection.

Hepatitis is defined by a threefold or more increase in the ALT above normal, while reactivation hepatitis is defined by a tenfold or more increase of HBV DNA level above baseline, or an absolute increase in the HBV DNA level more than 20,000 international units per middle in the absence of other systemic infection.

HBV reactivation can be spontaneous, but is usually caused by immunosuppression or in immune deficiency states.

HBV reactivation varies from being asymptomatic to lethal from liver failure.

Reactivation of HBV may occur with the use of chemotherapy, and the median interval between initiation of such drugs in the onset of reactivation is 4 months.

The rate of HBV reactivation ranges from 24-88% in patients with chronic HBV infection who have positive serum HBsAg and from 3-22% in patients who are HbcAb-positive.

Reactivation of HBV infection mortality rate ranges from 23-71%.

Indication for therapy includes evidence of ongoing viral replication with presence of HbeAg and HBV DNA, persistent elevation of aminotransferase levels and evidence of chronic HBV infection on liver biopsy.

Monitoring therapy should include monthly evaluations of serum levels of HBV DNA, HbeAg, anti-Hbe, and alanine aminotransferase.

Response rate to interferon only 40% and the response rate to second treatment with lamivudine is only about 30%.

Goal of treatment is to eradicate hepatitis B before irreversible liver damage occurs.

The presence of extrahepatic reservoirs of HBV, integration of HBV DNA into host genome, and the presence of an intracellular pathway that replenishes transcriptional templates in the hepatocyte nucleus without the need for reinfection prevent the eradication of the HBV.

Approved therapies include alpha interferon, lamivudine adefovir, tenofovir, entecavir and pegylated interferon.

Entecavir and tenofovir are potent nucleoside or nucleotide analogues, respectively, with high genetic barriers to viral resistance.

Entecavir and tenofovir are equally recommended now, for first line treatment for chronic hepatitis B.

The use of tenofovir resulted in lower rate of risk of the development of hepatocellular cancer than Entecavir.

In adolescents infected with hepatitis B virus (HBV), once-daily tenofovir treatment for 72 weeks effectively suppresses HBV DNA and normalizes alanine aminotransferase (ALT) values, regardless of prior HBV treatment (Murray KF et al).

Combination of alpha-interferon and lamivudine associated with a mortality benefit and sustained virologic response of 40-50%.

Even with the clearance of serum, HBV DNA, and of hepatitis B e antigen, the replicated backbone of HBV  can persist in hepatocytes, protected in a microchromosome.

Most patients who receive nucleotide analogues remain positive for hepatitis B surface antigen, and are at risk for relapse if therapy is stopped.

The withdrawal of treatment is usually associated with a rapid rebound in the viral titer.

Endemic in parts of Asia and Africa.

China has nearly one-third of world’s infected individuals and hepatoma is the first or second leading cause of death.

Agents approved for treatment of chronic hepatitis includes Alpha and pegylated interferon, lamivudine, adefovir dipivoxil, and entecavir.

Long-term lamivudine improves survival and decreases hepatocellular carcinoma in patients with cirrhosis and advanced fibrosis.

Many factors affect hepatocellular carcinoma recurrence risk after resection including: tumor size and stage, serum alpha-fetoprotein level, the presence cirrhosis, hepatitis B e antigen status and hepatitis B virus viral load.

Higher HBV viral load is an independent risk factor for hepatocellular carcinoma recurrence in patients with HBV related hepatoma.

Anti-viral prophylaxis is standard therapy for patients with HBV sero-positivity undergoing chemotherapy, and agents include lamivudine and entecavir.

Antiviral prophylactic therapy should be continued six months after completion of chemotherapy.

HBV serology should be assessed with surface antigen and core antibody in all patients prior to initiating chemotherapy particularly if utilizing rituximab in patients with leukemia or lymphoma.

In HBV carriers and patients with cleared HBV infection entecavir prophylaxis is recommended to reduce the rate of HBV reactivation and hepatitis.

Treatment for the hepatitis B virus (HBV) was 100% effective treatment as a combination of the antiviral drug entecavir and the anti-cancer drug birinapant.

Bepirovirsen, an anti-sense oligo nucleotide that targets all hepatitis B virus messenger RNAs and acts to decrease levels of viral proteins in a phase 2 trial resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HPV infection.

Bepirovirsen may clear both HBV, DNA, and HBsAG.

All adolescents and adults at an increased risk for Hepatitis B infection should undergo screening USPSTF).

In the US universal childhood vaccination with HPV was in the year 1991 and it is now made hepatitis B rare in the US in persons younger than 30 years of age.

HBV vaccine should be given, or at least offered,  to all adults.

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