Hepatitis B Flashcards
(93 cards)
1
Q
What kind of virus is HBV?
A
HBV is one of a family of animal viruses, hepadnaviridae (hepatotropic DNA viruses), and is classified as hepadnavirus type 1.
2
Q
What is the prevalence and associated geographic distribution of HBV infection?
A
The overall prevalence of HBsAg is reported to be 3.6 percent; however, it varies depending upon the geographic area. The prevalence of chronic HBV ranges from <2 percent in low-prevalence areas (eg, United States, Canada, Western Europe) to 2 to 7 percent in intermediate-prevalence areas (eg, Mediterranean countries, Japan, Central Asia, Middle East, and parts of South America) to ≥8 percent in high-prevalence areas (eg, Western Africa, South Sudan).
3
Q
What is the rate of progression from acute HBV infection to chronic HBV infection?
A
The rate of progression from acute to chronic HBV infection is approximately 90 percent for perinatally acquired infection, 20 to 50 percent for infections between the age of one and five years, and less than 5 percent for adult-acquired infection.
4
Q
What are some of the mortality statistics associated with HBV infection?
A
In 2013, viral hepatitis, primarily due to HBV and hepatitis C virus, was the seventh leading cause of death worldwide. Most mortality was attributable to liver cancer and cirrhosis. Globally, the total number of deaths due to hepatitis B in 2013 was estimated to be 686,000. In the United States, the rate of HBV-related mortality from 2009 to 2013 was 0.5 deaths/100,000 population; among the various subpopulations, HBV-related mortality was highest among Asians and Pacific Islanders at 2.6 deaths/100,000 population. In China, the age-standardized death rate for HBV-related liver cancer and cirrhosis in 2013 was 10.95 and 4.91 per 100,000 people, respectively.
5
Q
How is HBV transmitted?
A
The predominant mode of HBV transmission varies in different geographical areas. Mother-to-child transmission is the predominant mode of transmission in high-prevalence areas. In comparison, horizontal transmission, particularly in early childhood, accounts for most cases of chronic HBV infection in intermediate-prevalence areas, while unprotected sexual intercourse and injection drug use in adults are the major routes of spread in low-prevalence areas.
6
Q
Provide brief notes for the following forms of transmission:
- MTC
- Breastfeeding
- Paternal
- Transfusion
- Sexual
- Percutaneous
- Nosocomial
- Transplant
- Other
A
- Mother-to-child transmission — The infection rate of infants born to hepatitis B surface antigen (HBsAg)-positive mothers is as high as 90 percent among infants who do not receive hepatitis B immune globulin and hepatitis B vaccination at birth [5]. Mother-to-child transmission may occur in utero, at the time of birth, or after birth. However, most infections occur at or before birth.
- Breastfeeding — Breastfeeding does not appear to increase the risk of transmission.
- Paternal transmission — Transmission of HBV from fathers to their infants is possible based upon genotypic and phylogenetic analysis. In a study conducted in Taiwan, the HBV infection rate was 65 percent among neonates born to HBsAg-negative mothers and HBsAg-positive fathers.
- Transfusion
- Sexual
- Percutaneous transmission usually happens among injection drug users (IDU) who share syringes and needles. In addition to drug use, certain practices such as acupuncture, tattooing, and body piercing have also been associated with transmission of HBV through the use of equipment that is contaminated with HBV-infected blood.
- Nosocomial infection — HBV can be transmitted in the healthcare setting. Transmission generally occurs from patient to patient or from patient to healthcare providers (HCP) via contaminated instruments or an accidental needle stick.
- Transplant recipients — HBV infection can be transmitted from HBsAg-positive donors to HBsAg-negative recipients, with severe clinical consequences when the recipient is nonimmune (ie, anti-HBs-negative). Transmission of HBV infection has been reported after hematopoietic stem cell and solid organ transplantation.
- Other modes of transmission — Adults and children may acquire HBV infection via blood exposure to minor breaks in the skin or mucous membranes. In addition, transmission can occur via exposure to household articles that have been contaminated with blood, such as toothbrushes, razors, and toys, since HBV can survive outside the human body for a prolonged period. Although HBV DNA has been detected in various bodily secretions of hepatitis B carriers, there is no firm evidence of HBV transmission via body fluids other than blood or semen.
7
Q
Comment on the two major forms of prevention of HBV infection.
A
Pre-exposure vaccination — Vaccination against hepatitis B virus (HBV) prior to an exposure is the best way to prevent HBV infection. Universal vaccination of newborns is recommended in most countries.
Postexposure prophylaxis — Postexposure prophylaxis to prevent HBV infection should be considered for individuals who have had an exposure that could potentially transmit HBV. These include percutaneous (eg, bite or needlestick) or mucosal exposures to blood or infectious secretions (eg, semen, body fluids that contain blood) of a patient who is HBsAg-positive or whose HBsAg status is unknown.
8
Q
Briefly discuss the spectrum of clinical manifestations of HBV infection.
A
The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease. During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis; during the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations can also occur with both acute and chronic infection.
9
Q
Describe the acute phase of HBV infection under the following headings:
- Anicteric, icteric and fulminant disease
- The incubation period
- Prodromal features
- Lab abnormalities (excl. HBV serology)
- Outcome
A
- Approximately 70 percent of patients with acute hepatitis B have subclinical or anicteric hepatitis, while 30 percent develop icteric hepatitis. The disease may be more severe in patients coinfected with other hepatitis viruses or with underlying liver disease.
Fulminant hepatic failure is unusual, occurring in approximately 0.1 to 0.5 percent of patients. Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This explains why many patients with fulminant hepatitis B have no evidence of HBV replication at presentation.
The reasons that HBV has a fulminant course in some patients are not well-understood.
- The incubation period lasts one to four months.
- A serum sickness-like syndrome may develop during the prodromal period (fever, arthralgia/arthritis, and rash, which is most commonly maculopapular or urticarial), 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.
- Laboratory testing during the acute phase reveals elevations in the concentration of alanine and aspartate aminotransferase levels (ALT and AST); values up to 1000 to 2000 int. unit/L are typically seen during the acute phase with ALT being higher than AST. The serum bilirubin concentration may be normal in patients with anicteric hepatitis. The prothrombin time is the best indicator of prognosis. In patients who recover, the normalization of serum aminotransferases usually occurs within one to four months. A persistent elevation of serum ALT for more than six months indicates a progression to chronic hepatitis.
- Among patients who recover from acute hepatitis B, it has been thought that the virus is completely cleared by antiviral antibodies and specific cytotoxic T lymphocytes. Subsequent observations suggest that complete eradication of HBV rarely occurs after recovery from acute HBV infection and that latent infection can maintain the T cell response for decades following clinical recovery, thereby keeping the virus under control. Immunosuppression in such patients can lead to reactivation of the virus.
10
Q
Describe the chronic phase of HBV infection under the following headings:
- History of previous hepatitis
- Symptoms
- Signs
- Lab abnormalities
A
- 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 (unless they progress to decompensated cirrhosis or have extrahepatic manifestations), 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.
- Physical examination may be normal, or there may be stigmata of chronic liver disease. Jaundice, splenomegaly, ascites, peripheral edema, and encephalopathy may be present in patients with decompensated cirrhosis.
- Laboratory tests may be normal, but most patients have a mild to moderate elevation in serum AST and ALT. During exacerbations, the serum ALT concentration may be as high as 50 times the upper limit of normal, and alfa-fetoprotein (AFP) concentrations as high as 1000 ng/mL may be seen. A progression to cirrhosis is suspected when there is evidence of hypersplenism (decreased white blood cell and platelet counts) or impaired hepatic synthetic function (hypoalbuminemia, prolonged prothrombin time, hyperbilirubinemia).
11
Q
Describe the extra-hepatic manifestations of HBV infection. Please include the reason why these conditions are important to recognize and a sentence or two on their pathogenesis.
A
Extrahepatic manifestations, which are thought to be mediated by circulating immune complexes, occur in 10 to 20 percent of patients with chronic HBV infection. They are important to recognize because they may occur without clinically apparent liver disease and may be mistaken for other independent disease processes in other organ systems. The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease.
- Arthritis-Dermatitis: The constellation of fever, arthralgias, rash, angioneurotic oedema, and, less commonly, haematuria and proteinuria is seen as a prodromal manifestation of acute HBV and rarely in patients with chronic HBV. The proximal interphanageal joints, knees, ankles, shoulders and wrists are the joints most commonly affected. During the period of acute joint symptoms, HBsAg titers in the blood are high and complement levels are low.
- PAN: Develops in <1% of patients with HBV; acute < chronic HBV. Clinical features are the same in PAN with no HBV infection. No apparent relationship exists between the severity of the vasculitis and the severity of the hepatic disease, and the hepatic disease is often relatively mild despite high levels of viral replication.
- GN: HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis. Most cases of HBV-related glomerulonephropathy occur in children. The typical presentation is with nephrotic range proteinuria. A progression to renal failure can occur, particularly in adults.
- Cryoglobulinaemia: Type II and III cryoglobulinaemia have been associated with HBV but the association is uncommon. Cryoglobulinaemia may be associated with systemic vasculitis (purpura, arthralgias, PN, and GN) but is often pauci-symptomatic or asymptomatic.
- Aplastic anemia has been described in association with HBV infection, although most cases of post-hepatitis aplastic anemia are not due to HBV.
12
Q
Give a brief overview of the natural history of chronic HBV infection and the factors that may play a role in its progression.
A
The natural course of chronic hepatitis B virus (HBV) infection is determined by the interplay between virus replication and the host immune response. Other factors that may play a role in the progression of HBV-related liver disease include gender, alcohol consumption, and concomitant infection with other hepatitis virus(es). The outcome of chronic HBV infection depends upon the severity of liver disease at the time HBV replication is arrested.
13
Q
What are the 2 phases of chronic HBV infection?
A
Chronic HBV infection generally consists of two phases: an early replicative phase with active liver disease, and a later phase with low replication and remission of liver disease. In some patients, reactivation of HBV replication occurs after a varying period of quiescence.
14
Q
Discuss the immune tolerance phase of chronic HBV infection.
A
In patients with a perinatally acquired HBV infection, the initial phase is characterized by high levels of HBV replication—the presence of hepatitis B e antigen (HBeAg) and high levels of HBV DNA in serum—but no evidence of active liver disease as manifested by lack of symptoms, normal serum ALT concentrations, and minimal changes on liver biopsy. The lack of liver disease despite high levels of HBV replication has typically been attributed to immune tolerance to HBV. The immune tolerance phase usually lasts 10 to 30 years, during which there is a very low rate of spontaneous HBeAg clearance.
15
Q
Discuss the immune clearance phase of chronic HBV infection.
A
The transition from the immune tolerance to the immune clearance phase occurs during the second and third decades in patients with perinatally acquired HBV infection. During the immune clearance phase, spontaneous HBeAg clearance increases to an annual rate of 10 to 20 percent.
HBeAg seroconversion is frequently, but not always, accompanied by biochemical exacerbations (abrupt increases in serum ALT). Exacerbations are believed to be due to a sudden increase in immune-mediated lysis of infected hepatocytes. They are often preceded by an increase in serum HBV DNA and a shift of HBcAg (hepatitis B core antigen) from nuclear to cytoplasmic sites within hepatocytes.
Most exacerbations are asymptomatic and are discovered during routine follow-up. However, some are accompanied by symptoms of acute hepatitis and may lead to the incorrect diagnosis of acute hepatitis B in patients who are not previously known to have chronic HBV infection. Exacerbations may be associated with an elevation in the IgM anti-HBc titer, which may lead to misdiagnosis of acute HBV infection and an increase in the serum alpha-fetoprotein concentration, which may raise concerns about the diagnosis of HCC. As noted above, exacerbations are more commonly observed in men than in women. In a small percentage of patients, exacerbations result in hepatic decompensation and rarely death from hepatic failure. Patients with severe exacerbations should be referred to specialized centers for liver transplantation and receive treatment with nucleos/tide analogues. Interferon is not indicated in this setting since it can cause further exacerbation of the disease.
Not all exacerbations lead to HBeAg seroconversion and clearance of HBV DNA from the serum, a phenomenon termed abortive immune clearance. These patients may develop recurrent exacerbations with an intermittent disappearance of serum HBV DNA with or without a transient loss of HBeAg. Such repeated episodes of hepatitis may increase the risk of developing cirrhosis and hepatocellular carcinoma (HCC).
16
Q
Describe the inactive carrier state.
A
Patients in the low or nonreplicating phase/inactive carrier state are HBeAg negative and anti-HBe positive. In some patients, HBV DNA is undetectable in serum, even when tested by polymerase chain reaction assays, and liver disease is in remission as evidenced by normal serum ALT concentrations and the resolution of necroinflammation in liver biopsies. One study found that about 40 percent of inactive carriers had HBV DNA levels of 10(4) copies/mL or greater.
Significant liver disease can be found in patients with HBeAg-negative chronic HBV, but this is rare in those with truly persistent normal ALT defined by at least three normal ALT over a 12-month period and HBV DNA <4 log10 copies/mL (<2000 int. unit/mL).
Because of the fluctuating nature of chronic HBV infection, patients should not be categorized as inactive carriers unless there are at least three ALT levels and two to three HBV DNA levels over a 12-month period of observation. Studies suggest that combined quantification of HBsAg level and HBV DNA at a single time point may help in differentiating inactive carrier phase versus HBeAg-negative chronic hepatitis. HBsAg <1000 int. units/mL in an HBeAg-negative patient with serum HBV DNA <2000 int. units/mL identifies the inactive carrier phase with a high diagnostic accuracy (94 percent).
17
Q
Describe HBeAg-negative hepatitis.
A
Some patients continue to have moderate levels of HBV replication and active liver disease (elevated serum ALT and chronic inflammation on liver biopsies), but remain HBeAg negative. Such patients are said to have HBeAg-negative chronic hepatitis. They have a residual wild-type virus or HBV variants that cannot produce HBeAg due to precore or core promoter genetic variations.
Patients with HBeAg-negative chronic hepatitis are older and have more advanced liver disease. They also tend to have fluctuations in HBV DNA and ALT levels.
18
Q
Discuss briefly the resolution of chronic HBV infection.
A
Some patients with chronic HBV infection become HBsAg negative. The annual rate of delayed clearance of HBsAg has been estimated to be 0.5 to 2 percent in Western patients and much lower (0.1 to 0.8 percent) in Asian countries.
In most reports, patients without cirrhosis who cleared HBsAg appeared to have a good prognosis. Despite a generally favorable prognosis, clearance of HBsAg does not preclude the development of cirrhosis or hepatocellular carcinoma. Many patients who cleared HBsAg remained HBV DNA positive when tested by PCR assays, particularly during the first 10 years of HBsAg clearance.
19
Q
What is the spectrum of sequelae following chronic HBV infection?
A
The sequelae of chronic hepatitis B virus (HBV) infection vary from an inactive carrier state to the development of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), extrahepatic manifestations, and death.
20
Q
What are the 5-yr rates of progression from:
- Chronic HBV to cirrhosis?
- Compensated cirrhosis to decompensated disease?
- Compensated cirrhosis to HCC?
A
- Chronic hepatitis to cirrhosis – 12 to 20 percent
- Compensated cirrhosis to hepatic decompensation – 20 to 23 percent
- Compensated cirrhosis to HCC – 6 to 15 percent
(It should be noted that the rates of progression and rates of survival cited above were based on data in the pre-nucleos/tide analogue era and prognosis of patients with chronic hepatitis B have improved markedly in the last 10 years.)
21
Q
What are the 5-yr survival rates for:
- Compensated cirrhosis?
- Decompensated cirrhosis?
A
- Compensated cirrhosis – 85 percent at five years.
- Decompensated cirrhosis – 55 to 70 percent at one year and 14 to 35 percent at five years.
(It should be noted that the rates of progression and rates of survival cited above were based on data in the pre-nucleos/tide analogue era and prognosis of patients with chronic hepatitis B have improved markedly in the last 10 years.)
22
Q
Which virological and non-virological factors influence disease progression and survival in chronic HBV infection?
A
Factors related to HBV infection include the individual’s HBeAg status, the HBV DNA and HBsAg levels, and the HBV genotype. The HBV DNA level is the most important virologic predictor of disease progression in patients with a high HBV viral load (≥2000 IU/mL), whereas the HBsAg level helps determine the risk of progression in those with a HBV DNA <2000 IU/mL.
Factors not associated with HBV include those related to the host (gender, age, diabetes) and environment (alcohol, smoking, carcinogens) as well as coinfection with other viruses (eg, HCV, HDV, HIV).
23
Q
Write short notes on acute flares in chronic HBV infection.
A
Chronic HBV is often punctuated by sudden flares of disease activity that are reflected by a rise in serum aminotransferases. Although a uniform definition is lacking, a flare has frequently been described as a rise in serum ALT levels to at least two times the baseline value. Spontaneous flares are an important part of the natural history of HBV infection because when they occur repeatedly, they lead to histologic progression. Most flares result from a change in the balance between immunologic responses to HBV and the level of virasl proliferation.
Causes:
- Spontaneous
- Immunosuppressive therapy-induced
- Antiviral therapy-induced
- Flares associated with genotypic variation
- Flares caused by infection with other viruses (viz. HAV, HCV, HDV and/or HEV).
24
Q
Describe spontaneous flares in chronic HBV infection.
A
Spontaneous flares of chronic HBV often result from reactivated infection, and an increase in serum HBV DNA levels often precedes an increase in serum aminotransferase levels.
The reasons for reactivated infection are unknown but likely relate to subtle changes in the immunological control of viral replication.
Fatigue may be reported during flares of chronic HBV but in many instances, patients remain asymptomatic. Occasionally symptoms and signs of frank liver failure become apparent, particularly when the flare is superimposed on advanced chronic HBV.
Most clinically recognizable flares occur in patients who are in the non-replicative phase of HBV infection (ie. initially testing positive for for anti-HBe and negative for serum HBV DNA). During such flares, serum HBV DNA levels increase, and HBeAg often re-appears in serum (seroconversion). HBV DNA and HBeAg are often detectable in the serum when the patient is first seen, but if the flare has been ongoing for several weeks or longer, the accompanying enhancement of the immune response may make it difficult to detect a rise in serum HBV DNA levels. Frequently, subsidence of these flares of hepatitis is accompanied by loss of HBV DNA and HBeAg in serum.
Flares can also occur in patients who are in the replicative phase of infection (i.e., already positive for HBV DNA and HBeAg in serum). In these instances, HBV replication intensifies, serum HBV DNA levels rise, and liver biochemical deterioration occurs, often without the subsequent loss of HBeAg. Multiple episodes of reactivation and remission have been shown to accelerate the progression of chronic HBV and are particularly likely to occur in patients infected with the precore mutant form of chronic HBV.
25
What is the mechanism of flare in those on antivirals?
Either withdrawal of medication or development of resistance.
26
Is surveillance for HCC necessary in chronic HBV infected patients?
Yes.
27
Comment on the relationship between alcoholism and HBV infection. Mention:
* Prevalence in alcoholics
* Risk of chronic infection
* Influence on liver disease
* The prevalence of serum HBV markers among alcoholics has been estimated to be two- to fourfold higher than a corresponding control population, suggesting an increased rate of HBV infection.
* There is no clear evidence that alcoholics have an enhanced risk of chronic HBV infection.
* However, HBV DNA has been detected in the sera and liver tissues in some HBsAg negative alcoholics who present with liver disease, implying that occult HBV infection may have contributed to liver disease in these patients. Alcoholics with HBV infection have been reported to have accelerated liver injury, increased risk of developing cirrhosis and hepatocellular carcinoma (HCC), and reduced survival compared with alcoholics who are not HBV-infected.
28
Write short notes on HCV coinfection.
Acute coinfection with HBV and HCV may shorten the duration of HBs antigenemia and lower the peak serum aminotransferase concentration compared with acute HBV infection alone. These findings suggest that HCV coinfection may interfere with the replication of HBV, leading to attenuation of liver damage. However, acute coinfection 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. Similarly, acute HBV in patients with chronic HCV can lead to severe hepatitis, but may also lead to clearance of HCV.
Liver disease is usually more severe than in patients infected by HBV alone. Patients with dual HBV and HCV infection may also have a higher rate of HCC compared with patients infected by either virus alone, particularly those who are anti-HCV and HBeAg positive.
29
Should patients with chronic liver disease get vaccinated against HAV?
Yes.
30
Which patients should be screened for HBV infection?
●Individuals who have signs and symptoms of acute hepatitis;
●Individuals with chronic liver disease (eg, chronically elevated ALT or AST);
●Pregnant women;
●Those requiring immunosuppressive therapy;
●Persons with HIV or HCV;
●Injection drug users;
●Men who have sex with men;
●Individuals with multiple sexual partners and/or a history of sexually transmitted diseases;
●Patients undergoing hemodialysis;
●Household and sexual contacts of HBV infected persons;
●Inmates of correctional facilities.
31
Which tests are used in screening?
We test for hepatitis B virus infection using HBsAg, hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) in certain groups of patients.
32
Write short notes on hepatits B antigens and antibodies.
Hepatitis B surface antigen (HBsAg) is the serologic hallmark of HBV infection.
HBsAg appears in serum 1 to 10 weeks after an acute exposure to HBV, prior to the onset of hepatitic symptoms or elevation of serum alanine aminotransferase (ALT). In patients who subsequently recover, HBsAg usually becomes undetectable after four to six months. Persistence of HBsAg for more than six months implies chronic infection. It is estimated that less than 5 percent of immunocompetent adult patients with genuine acute hepatitis B progress to chronic infection. Among patients with chronic HBV infection, the rate of clearance of HBsAg is approximately 0.5 percent per year.
The disappearance of HBsAg is followed by the appearance of hepatitis B surface antibody (anti-HBs). In most patients, anti-HBs persists for life, thereby conferring long-term immunity. In some patients, however, anti-HBs may not be detectable until after a window period of several weeks to months, during which neither HBsAg nor anti-HBs can be detected. At this time, the serologic diagnosis may be made by the detection of IgM antibodies against hepatitis B core antigen (IgM anti-HBc).
Coexistence of HBsAg and anti-HBs has been reported in 5 to 30 percent of HBsAg positive individuals. In most instances, the antibodies are unable to neutralize the circulating virions. These individuals should therefore be regarded as carriers of the hepatitis B virus.
33
Write short notes on hep B core antigen and antibody.
Hepatitis B core antigen (HBcAg) is an intracellular antigen that is expressed in infected hepatocytes. It is not detectable in serum. Anti-HBc can be detected throughout the course of HBV infection.
The detection of IgM anti-HBc is usually regarded as an indication of acute HBV infection. However, IgM anti-HBc may remain detectable up to two years after the acute infection. Furthermore, the titer of IgM anti-HBc may increase to detectable levels during exacerbations of chronic hepatitis B.
IgG anti-HBc persists along with anti-HBs in patients who recover from acute hepatitis B. It also persists in association with HBsAg in those who progress to chronic HBV infection.
34
Describe the entity of isolated anti-HepBc.
Isolated detection of anti-HBc can occur in three settings: during the window period of acute hepatitis B when the anti-HBc is predominantly IgM class; many years after recovery from acute hepatitis B when anti-HBs has fallen to undetectable levels; and after many years of chronic HBV infection when the HBsAg titer has decreased below the cutoff level for detection.
In some cases, isolated anti-HBc may be due to a false positive test result. Thus, the evaluation of individuals with isolated anti-HBc should include repeat testing for anti-HBc, HBsAg, anti-HBe, and anti-HBs. In addition:
●Patients who remain positive for isolated anti-HBc IgG, have evidence of a recent HBV exposure, have symptoms of acute hepatitis, and/or have markedly elevated ALT levels should be tested for the presence of anti-HBc IgM to rule out recent HBV infection.
●Individuals with evidence of chronic liver disease should be tested for HBV DNA to exclude low level chronic HBV infection. HBV DNA has been detected in the serum of individuals with isolated anti-HBc when tested by PCR assays; however, the frequency of detection varies from 0 to 20 percent with most studies showing <5 percent detection.
The clinical significance of isolated anti-HBc is unclear. Occult HBV infection (ie, isolated anti-HBc with a detectable HBV DNA) has been associated with chronic liver disease and hepatocellular carcinoma.
In addition, transmission of HBV infection has been reported from blood and organ donors with isolated anti-HBc. Reactivation of HBV replication with reverse seroconversion (ie, reappearance of HBsAg) can also occur in patients with isolated anti-HBc in the setting of intense immunosuppression. Prophylactic antiviral therapy may reduce the risk of reactivation in certain patients.
35
Write short notes on Hep B e antigen and antibody.
Hepatitis B e antigen (HBeAg) is a secretory protein that is processed from the precore protein. It is generally considered to be a marker of HBV replication and infectivity. The presence of HBeAg is usually associated with high levels of HBV DNA in serum and higher rates of transmission of HBV infection from carrier mothers to their babies and from patients to health care workers.
HBeAg to anti-HBe seroconversion occurs early in patients with acute infection, prior to HBsAg to anti-HBs seroconversion. However, HBeAg seroconversion may be delayed for years to decades in patients with chronic HBV infection. In such patients, the presence of HBeAg is usually associated with the detection of high levels of HBV DNA in serum and active liver disease.
Seroconversion from HBeAg to anti-HBe is usually associated with a decrease in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease after HBeAg seroconversion.
36
Write short notes on the use of HBV DNA assays.
Mention:
* Levels in acute infection
* Levels in HBeAg-negative chronic infection
* Use in chronic HBV infection
* Use in HBsAg-negative liver disease
Recovery from acute hepatitis B is usually accompanied by the disappearance of HBV DNA in serum as determined by hybridization or bDNA assays. However, HBV DNA may remain detectable in serum for many years if tested by PCR assays. This observation suggests that the virus persists after "recovery" but is controlled by the immune system.
HBV DNA levels are also detectable in patients with HBeAg-negative chronic hepatitis, although levels are generally lower than in patients with HBeAg positive chronic hepatitis. A serum HBV DNA level of >2,000 int. unit/mL has been proposed as a cutoff level to differentiate patients with HBeAg-negative chronic hepatitis from those in an inactive carrier state (ie, HBeAg-negative, persistently normal ALT).
Clinical use — The major clinical role of serum HBV DNA assays in patients with chronic HBV infection is to assess HBV replication and candidacy for antiviral therapy. Indications for HBV treatment are based upon the presence of active liver disease and high HBV DNA levels. A cutoff of 20,000 int. unit/mL has been proposed for treatment initiation in HBeAg positive patients, and a lower threshold 2000 int. unit/mL for HBeAg-negative patients.
Patients with high pretreatment serum HBV DNA levels are less likely to respond to interferon. In contrast, pretreatment serum HBV DNA levels do not appear to predict response to nucleos/tide analogue therapy. However, it may take longer for the HBV DNA to become undetectable in patients treated with nucleos/tide analogue therapy if pretreatment levels are high.
Suppression of serum HBV DNA is also used as one of the end-points in assessing response to antiviral treatment and to detect virologic breakthrough. With the availability of potent antiviral agents, suppression of HBV DNA to undetectable levels by PCR is the goal. Monitoring of serum HBV DNA using sensitive quantitative assays such as real time PCR assays with lower limit of detection of <20 int. unit/mL will identify patients who have suboptimal response that may benefit from additional therapy, and patients who have virologic breakthrough (>1 log increase in HBV DNA from nadir while on treatment).
Rarely, tests for HBV DNA in serum help to identify HBV as the etiology of liver disease in HBsAg-negative patients. This is especially important in patients with fulminant hepatitis B, who may have cleared HBsAg by the time they present.
37
How is acute HBV infection diagnosed?
The diagnosis of acute hepatitis B is based upon the detection of HBsAg and IgM anti-HBc. During the initial phase of infection, markers of HBV replication, HBeAg and HBV DNA, are also present. Recovery is accompanied by the disappearance of HBV DNA, HBeAg to anti-HBe seroconversion, and subsequently HBsAg to anti-HBs seroconversion.
38
What is the differential diagnosis of acute HBV infection?
The differential diagnosis of HBsAg-positive acute hepatitis includes acute hepatitis B, exacerbations of chronic hepatitis B (eg, around the time of HBeAg seroconversion), reactivation of chronic hepatitis B, superinfection of a hepatitis B carrier with hepatitis A, C, D, or E virus, and acute hepatitis due to drugs and other toxins in a hepatitis B carrier.
39
How is past HBV infection diagnosed?
Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-HBc. Immunity to HBV infection after vaccination is indicated by the presence of anti-HBs only.
40
How is chronic HBV infection diagnosed?
The diagnosis of chronic HBV infection is based upon the persistence of HBsAg for more than six months. Additional tests for HBV replication — HBeAg and serum HBV DNA — should be performed to determine if the patient should be considered for antiviral therapy.
However, serial tests are necessary to accurately differentiate them from patients with HBeAg-negative chronic hepatitis who have fluctuating ALT and/or HBV DNA levels. Thus, it is recommended that these patients have repeat ALT +/- HBV DNA tests at three-month intervals during the first year. Patients who are truly inactive carriers should continue to be monitored but at less frequent intervals.
41
How is occult HBV infection diagnosed?
There exists a subset of patients with occult HBV infection defined as the presence of detectable HBV DNA by PCR in patients who are negative for HBsAg. Such patients have been further subclassified as having "seropositive" or "seronegative" HBV depending upon whether they are positive or negative for other HBV markers, most commonly anti-HBc.
Occult HBV infection has been associated with chronic liver disease and hepatocellular carcinoma.
42
What is the mainstay of therapy for patients with acute HBV infection?
Treatment of acute HBV depends upon the clinical setting. However, appropriate measures should be taken to prevent infection in all exposed contacts, and hepatitis B immune globulin and hepatitis B vaccine should be administered to all household and sexual contacts who are not known to be immune.
For most patients, treatment is mainly supportive. The likelihood of liver failure from acute HBV is less than 1 percent, and in immunocompetent adults, the likelihood of progression to chronic HBV infection is less than 5 percent.
43
In which patients with acute HBV infection might more definitive therapy be required?
As a general rule, we treat patients with a severe or a protracted course (eg, those who develop a coagulopathy [international normalized ratio (INR) >1.5], those with persistent symptoms or marked jaundice [bilirubin >10 mg/dL] for more than four weeks after presentation). We also treat patients with acute liver failure due to HBV to reduce the likelihood of reinfection post-liver transplant.
For those who require treatment, tenofovir or entecavir are acceptable options given as monotherapy. Treatment can be stopped after confirmation that the patient has cleared HBsAg (two consecutive tests four weeks apart). Lamivudine or telbivudine can also be used, as the duration of treatment is generally short. However, since severe exacerbations of chronic HBV in previously undiagnosed patients can be difficult to differentiate from acute HBV, tenofovir or entecavir are preferred. Interferon should be avoided because of the risk of bacterial infections and a further increase in hepatic necroinflammation in patients with severe hepatitis or acute liver failure.
44
Outline the approach to the management of chronic HBV infection.
The management of chronic HBV infection is complex and depends upon multiple factors including clinical variables (eg, the presence or absence of liver inflammation and/or cirrhosis), the patient's immunologic response to infection (eg, hepatitis B e antigen status), virologic factors (eg, the HBV viral load and genotype), and risk factors for disease progression (eg, age >40 and family history of hepatocellular carcinoma).
45
What investigations are typically undertaken prior to initiating therapy in chronic HBV patients?
The initial evaluation of patients with chronic HBV infection should include:
●A history and physical examination, emphasizing: risk factors for coinfection with hepatitis C virus (HCV), hepatitis delta virus (HDV), and/or HIV; use of alcohol; family history of HBV infection and liver disease; and signs and symptoms of cirrhosis.
●Laboratory tests, including: a complete blood count with platelets, liver chemistry tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, alkaline phosphatase, albumin), international normalized ratio (INR), and tests for HBV replication (hepatitis B e antigen [HBeAg], antibody to HBeAg [anti-HBe], HBV DNA). Testing for immunity to hepatitis A virus (HAV) with HAV IgG antibody should be performed in patients who are not known to be immune.
●Evaluation for other causes of liver disease (eg, hemochromatosis, HCV, HDV) by testing for iron, total iron binding capacity, and HCV antibody in all patients, and HDV antibody in injection drug users and persons from countries where HDV is endemic (eg, Eastern Europe, Mediterranean countries, and the Amazon basin).
●Screening for HIV infection in those who have not undergone routine screening, and in those persons with ongoing risk factors for HIV (eg, injection drug use, multiple sexual exposures, men who have sex with men).
●Screening for hepatocellular carcinoma if indicated.
●Screening for fibrosis using noninvasive tests (eg, vibration-controlled transient elastography, serum fibrosis panel) or liver biopsy.
46
Write short notes on need for liver biopsy prior to initiating therapy in chronic HBV patients.
Liver biopsy may be reasonable for patients who do not meet criteria for treatment, but have risk factors for developing fibrosis and inflammation, since patients with histologically active or advanced liver disease may benefit from treatment.
We consider a biopsy for patients who are older than 40 or who have a family history of hepatocellular carcinoma, and have ALT levels that are mildly elevated (elevated but <2 x upper limit of normal [ULN]) or have ALT levels that are normal but a viral load that is persistently elevated (eg, >2000 international units/mL [104 copies/mL] for HBeAg-negative patients or >20,000 international units/mL [>105 copies/mL] for HBeAg-positive patients). A normal serum ALT level alone in patients with active viral replication does not predict mild or normal histologic findings.
47
What is the decision to give antivirals based on?
The decision to initiate treatment is primarily based upon the presence or absence of cirrhosis, the ALT level, and the HBV DNA level. However, there are additional indications for patients with certain concurrent conditions, such as malignancy and pregnancy.
Patients who are not deemed to be treatment candidates at presentation, and those who decide to defer treatment, should undergo monitoring of liver biochemical tests, HBV DNA, and HBeAg status since liver disease and/or HBV replication may become active later.
48
How are patients with acute liver failure or decompensated cirrhosis treated?
Patients with life-threatening liver disease secondary to HBV should initiate antiviral therapy. This includes patients with acute liver failure (eg, fulminant acute HBV, severe exacerbation of chronic HBV), as well as those with decompensated cirrhosis and a detectable HBV DNA by polymerase chain reaction (PCR) assay (regardless of the ALT level). Such patients should also be evaluated for liver transplant.
Nucleos(t)ide analogue treatment has been shown to stabilize liver disease, and in some cases reverse liver failure. Antiviral treatment also reduces the risk of recurrent HBV should these patients require liver transplantation.
For patients with decompensated cirrhosis, interferon is contraindicated, and either entecavir or tenofovir should be used. We avoid monotherapy with lamivudine, adefovir, or telbivudine given the high risk of developing resistance with long-term use, and in the case of adefovir, its weak antiviral activity. Treatment of such patients should be coordinated with a transplant center.
We prefer entecavir for patients with decompensated cirrhosis who are treatment-naïve. Such patients are at risk for acute kidney injury secondary to the hepatorenal syndrome, and entecavir has not been shown to be nephrotoxic, whereas tenofovir disoproxil fumarate has been associated with reduced kidney function. Tenofovir alafenamide is an alternative agent, but efficacy and safety data in patients with decompensated liver disease are lacking. Lactic acidosis has been reported in patients with severe liver dysfunction receiving entecavir; however, this is likely a class effect of nucleos(t)ide analogs.
49
How are patients with compensated cirrhosis treated?
Patients with compensated cirrhosis and an HBV DNA >2000 international units/mL (>104 copies/mL) should be treated with antiviral therapy regardless of the HBeAg status or the serum ALT level. Treatment should be considered even if HBV DNA levels are lower than 2000 international units/mL, since there are data showing that patients with cirrhosis and low HBV DNA levels have a higher risk of hepatocellular carcinoma than those with undetectable HBV DNA levels.
In patients with clinically compensated cirrhosis, we generally administer entecavir or tenofovir (tenofovir alafenamide or tenofovir disoproxil fumarate ). Although interferon may be used with caution in patients with compensated cirrhosis, normal hepatic synthetic function, and minimal or no evidence of portal hypertension, nucleos(t)ide analogues are safer.
50
How are HBeAg-positive patients without cirrhosis treated?
For HBeAg-positive patients without cirrhosis, treatment should be initiated when the HBV DNA is >20,000 international units/mL (>105 copies/mL) and the ALT is >2 x ULN. The ULN should be considered 30 U/L for males and 19 U/L for females; these levels should be used rather than individual laboratory cut-off levels. Treatment should be delayed for three to six months in newly diagnosed HBeAg-positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur.
Patients with chronic hepatitis whose serum ALT is persistently below 2 X ULN can be observed, considering treatment if and when the serum ALT becomes higher. Exceptions to this rule include: those who have recurrent hepatitis flares that fail to clear HBeAg, patients with icteric flares, those with active or advanced histologic findings (such as moderate/severe inflammation or bridging fibrosis/cirrhosis), patients with extrahepatic manifestations (eg, HBV-related polyarteritis nodosa), patients above the age of 40 who remain HBeAg-positive with persistently high HBV DNA levels, those with a family history of hepatocellular carcinoma (there is a lower threshold for HBV DNA and ALT in these patients), and health care providers performing exposure-prone procedures (as required by local guidelines).
Although treatment can lead to virus suppression in HBeAg-positive patients with normal ALT, the likelihood of HBeAg seroconversion on treatment is low. The benefits of long-term treatment in such patients, most of whom are young Asians with perinatally acquired HBV infection, must be balanced against the risks of drug resistance, side effects, and costs, particularly since some of these individuals will undergo spontaneous HBeAg seroconversion and remain in remission for many years afterwards.
51
How are HBeAg-negative patients without cirrhosis managed?
Treatment may be initiated immediately once a diagnosis of HBeAg-negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 international units/mL) is established because sustained remission is rare in the absence of treatment. However, delaying treatment for two to three months to allow patients to understand the disease, the need for long-term (and often lifelong) treatment, and the importance of adherence is reasonable in patients with no evidence of cirrhosis.
For those with an ALT <2 x ULN, serial follow-up is needed to differentiate an inactive carrier state from HBeAg-negative chronic hepatitis because of the fluctuating course of HBeAg-negative chronic hepatitis. Liver biopsy should be considered in HBeAg-negative patients who have serum HBV DNA levels >2000 international units/mL and normal or mildly elevated ALT to determine if treatment is warranted. Patients with low HBsAg levels (<1000 international units/mL) are more likely to be in the inactive phase than those with higher HBsAg levels.
52
How are patients with chronic HBV and imminent immunosuppression managed?
Antiviral therapy should be administered to most patients with chronic HBV prior to initiating immunosuppressive therapy, regardless of the HBV DNA or aminotransferase levels. Such patients are at risk for HBV reactivation if they receive immunosuppressive therapy.
53
How are pregnant patients with HBV infection treated?
For pregnant women, the indications for antiviral therapy are generally the same as those for patients who are not pregnant. However, women with high viral loads (>2 x 105 international units/mL) should initiate therapy in the third trimester, even if the aminotransferase levels are normal, to prevent transmission to their child.
54
How are HBV-infected HCC patients treated?
All patients with hepatocellular carcinoma (HCC) should be treated with a nucleos(t)ide analogue (eg, tenofovir or entecavir). Treatment with nucleos(t)ide analogues can reduce the risk of recurrence and improve the prognosis of HBV-related HCC after curative therapy.
55
How are HBV/HCV coinfected patients treated (from a HBV POV)?
Patients who have coinfection with HBV and HCV are at risk for HBV reactivation if they are being treated for HCV with direct-acting antiviral therapy and are not receiving treatment for HBV.
●For HBsAg-positive patients who meet criteria for antiviral treatment of HBV, HBV treatment should be initiated prior to or at the same time as HCV therapy. For those who do not meet criteria for HBV therapy, the HBV DNA levels should be monitored at regular intervals (eg, every four weeks) during and for up to 12 weeks after HCV therapy. HBV therapy should be initiated if HBV DNA levels meet criteria for treatment.
●For HBsAg-negative, hepatitis B core antibody-positive patients, data on the risk of HBV reactivation during HCV direct-acting therapy are limited. Monitoring of ALT is recommended, and if the ALT increases during treatment, HBV markers (HBsAg and HBV DNA) should be tested.
56
What are the goals of antiviral therapy?
The goals of antiviral therapy are suppression of HBV DNA, loss of HBeAg (in patients who were initially HBeAg-positive), and loss of HBsAg. A sustained viral response, particularly in those who clear both HBeAg and HBsAg, is almost invariably accompanied by normalization of serum ALT, a decrease in necroinflammatory activity, and over time, a decrease in fibrosis as well. Antiviral treatment can also reduce the risk of long-term complications from chronic HBV (eg, liver failure and hepatocellular carcinoma) as well as the transmission of HBV to others. For some patients, immediate antiviral therapy is indicated, whereas for others, treatment may be deferred with careful monitoring.
57
Which two broad classes of antivirals are used in the management of HBV infection?
Treatment strategies for chronic HBV typically include pegylated interferon (PegIFN) or nucleos(t)ide analogs (eg, entecavir and tenofovir).
58
Which two broad classes of antivirals are used in the management of HBV infection?
Treatment strategies for chronic HBV typically include pegylated interferon (PegIFN) or nucleos(t)ide analogs (eg, entecavir and tenofovir).
59
How are patients with acute liver failure or decompensated cirrhosis treated?
Patients with life-threatening liver disease secondary to HBV should initiate antiviral therapy. This includes patients with acute liver failure (eg, fulminant acute HBV, severe exacerbation of chronic HBV), as well as those with decompensated cirrhosis and a detectable HBV DNA by polymerase chain reaction (PCR) assay (regardless of the ALT level). Such patients should also be evaluated for liver transplant.
Nucleos(t)ide analogue treatment has been shown to stabilize liver disease, and in some cases reverse liver failure. Antiviral treatment also reduces the risk of recurrent HBV should these patients require liver transplantation.
For patients with decompensated cirrhosis, interferon is contraindicated, and either entecavir or tenofovir should be used. We avoid monotherapy with lamivudine, adefovir, or telbivudine given the high risk of developing resistance with long-term use, and in the case of adefovir, its weak antiviral activity. Treatment of such patients should be coordinated with a transplant center.
We prefer entecavir for patients with decompensated cirrhosis who are treatment-naïve. Such patients are at risk for acute kidney injury secondary to the hepatorenal syndrome, and entecavir has not been shown to be nephrotoxic, whereas tenofovir disoproxil fumarate has been associated with reduced kidney function. Tenofovir alafenamide is an alternative agent, but efficacy and safety data in patients with decompensated liver disease are lacking. Lactic acidosis has been reported in patients with severe liver dysfunction receiving entecavir; however, this is likely a class effect of nucleos(t)ide analogs.
60
How are patients with compensated cirrhosis treated?
Patients with compensated cirrhosis and an HBV DNA >2000 international units/mL (>104 copies/mL) should be treated with antiviral therapy regardless of the HBeAg status or the serum ALT level. Treatment should be considered even if HBV DNA levels are lower than 2000 international units/mL, since there are data showing that patients with cirrhosis and low HBV DNA levels have a higher risk of hepatocellular carcinoma than those with undetectable HBV DNA levels.
In patients with clinically compensated cirrhosis, we generally administer entecavir or tenofovir (tenofovir alafenamide or tenofovir disoproxil fumarate ). Although interferon may be used with caution in patients with compensated cirrhosis, normal hepatic synthetic function, and minimal or no evidence of portal hypertension, nucleos(t)ide analogues are safer.
61
How are HBeAg-positive patients without cirrhosis treated?
For HBeAg-positive patients without cirrhosis, treatment should be initiated when the HBV DNA is >20,000 international units/mL (>105 copies/mL) and the ALT is >2 x ULN. The ULN should be considered 30 U/L for males and 19 U/L for females; these levels should be used rather than individual laboratory cut-off levels. Treatment should be delayed for three to six months in newly diagnosed HBeAg-positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur.
Patients with chronic hepatitis whose serum ALT is persistently below 2 X ULN can be observed, considering treatment if and when the serum ALT becomes higher. Exceptions to this rule include: those who have recurrent hepatitis flares that fail to clear HBeAg, patients with icteric flares, those with active or advanced histologic findings (such as moderate/severe inflammation or bridging fibrosis/cirrhosis), patients with extrahepatic manifestations (eg, HBV-related polyarteritis nodosa), patients above the age of 40 who remain HBeAg-positive with persistently high HBV DNA levels, those with a family history of hepatocellular carcinoma (there is a lower threshold for HBV DNA and ALT in these patients), and health care providers performing exposure-prone procedures (as required by local guidelines).
Although treatment can lead to virus suppression in HBeAg-positive patients with normal ALT, the likelihood of HBeAg seroconversion on treatment is low. The benefits of long-term treatment in such patients, most of whom are young Asians with perinatally acquired HBV infection, must be balanced against the risks of drug resistance, side effects, and costs, particularly since some of these individuals will undergo spontaneous HBeAg seroconversion and remain in remission for many years afterwards.
62
How are HBeAg-negative patients without cirrhosis managed?
Treatment may be initiated immediately once a diagnosis of HBeAg-negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 international units/mL) is established because sustained remission is rare in the absence of treatment. However, delaying treatment for two to three months to allow patients to understand the disease, the need for long-term (and often lifelong) treatment, and the importance of adherence is reasonable in patients with no evidence of cirrhosis.
For those with an ALT <2 x ULN, serial follow-up is needed to differentiate an inactive carrier state from HBeAg-negative chronic hepatitis because of the fluctuating course of HBeAg-negative chronic hepatitis. Liver biopsy should be considered in HBeAg-negative patients who have serum HBV DNA levels >2000 international units/mL and normal or mildly elevated ALT to determine if treatment is warranted. Patients with low HBsAg levels (<1000 international units/mL) are more likely to be in the inactive phase than those with higher HBsAg levels.
63
Suggest a program for monitoring patients on antiviral therapy.
To monitor the response to nucleos(t)ide therapy we measure:
●HBV DNA every three months until undetectable for at least two consecutive visits. We then decrease the frequency to every six months.
●Aminotransferases every three months. The frequency can be decreased to every six months in patients with an undetectable HBV DNA or normalized ALT.
●HBeAg and antibody to HBeAg (anti-HBe) every six months in patients who are HBeAg-positive to determine if seroconversion has occurred. If HBeAg seroconversion has occurred, we repeat the HBeAg to confirm the result.
●HBsAg should be tested yearly.
In addition, we monitor for adverse reactions to the antiviral medications. If tenofovir disoproxil fumarate or adefovir are used, creatinine and phosphate should be monitored every three to six months. For those with decompensated cirrhosis, the creatinine should be monitored more frequently (eg, every one to three months). The frequency of monitoring can probably be reduced (but not eliminated) if tenofovir alafenamide is used, although there are no clear guidelines.
64
Give a broad overview of the duration of treatment for HBV infection.
Patients receiving interferon therapy receive a finite duration of therapy.
The optimal duration of therapy for the oral drugs is not well-established. Most patients receiving nucleos(t)ide analogue therapy will require at least four to five years of treatment, and some may require indefinite treatment.
Long-term treatment is particularly important for patients with cirrhosis.
65
How are HBV-infected HCC patients treated?
All patients with hepatocellular carcinoma (HCC) should be treated with a nucleos(t)ide analogue (eg, tenofovir or entecavir). Treatment with nucleos(t)ide analogues can reduce the risk of recurrence and improve the prognosis of HBV-related HCC after curative therapy.
66
How are HBV/HCV coinfected patients treated (from a HBV POV)?
Patients who have coinfection with HBV and HCV are at risk for HBV reactivation if they are being treated for HCV with direct-acting antiviral therapy and are not receiving treatment for HBV.
●For HBsAg-positive patients who meet criteria for antiviral treatment of HBV, HBV treatment should be initiated prior to or at the same time as HCV therapy. For those who do not meet criteria for HBV therapy, the HBV DNA levels should be monitored at regular intervals (eg, every four weeks) during and for up to 12 weeks after HCV therapy. HBV therapy should be initiated if HBV DNA levels meet criteria for treatment.
●For HBsAg-negative, hepatitis B core antibody-positive patients, data on the risk of HBV reactivation during HCV direct-acting therapy are limited. Monitoring of ALT is recommended, and if the ALT increases during treatment, HBV markers (HBsAg and HBV DNA) should be tested.
67
What are the goals of antiviral therapy?
The goals of antiviral therapy are suppression of HBV DNA, loss of HBeAg (in patients who were initially HBeAg-positive), and loss of HBsAg. A sustained viral response, particularly in those who clear both HBeAg and HBsAg, is almost invariably accompanied by normalization of serum ALT, a decrease in necroinflammatory activity, and over time, a decrease in fibrosis as well. Antiviral treatment can also reduce the risk of long-term complications from chronic HBV (eg, liver failure and hepatocellular carcinoma) as well as the transmission of HBV to others. For some patients, immediate antiviral therapy is indicated, whereas for others, treatment may be deferred with careful monitoring.
68
How do you manage patients who have persistent viraemia/breakthrough infection whilst on interferon?
Patients who failed to respond to interferon therapy (ie, failure to achieve HBeAg seroconversion posttreatment month 6 for HBeAg-positive patients or failure to achieve HBV DNA <2000 international units/mL posttreatment month 6 for HBeAg-negative patients) can be treated with any of the nucleos(t)ide analogs with the expectation of a similar response as treatment-naïve patients. Because most patients require a long duration of treatment, entecavir or tenofovir is preferred.
69
Which two broad classes of antivirals are used in the management of HBV infection?
Treatment strategies for chronic HBV typically include pegylated interferon (PegIFN) or nucleos(t)ide analogs (eg, entecavir and tenofovir).
70
Write short notes on interferon in the management of HBV infection. Cover:
* Indications
* Advantages
* Contra-indications
* Dosing and administration
The main role of interferon is primarily treatment of young patients with well compensated liver disease who do not wish to be on long-term treatment. Among HBeAg-positive patients, HBV genotype A (and to a less extent, genotype B), as well as low HBV DNA and high ALT levels are predictive of response to interferon therapy.
The advantages of interferon compared to nucleos(t)ide analogues are its finite duration of treatment, the absence of selection of resistant variants, and a more durable response. On the other hand, side effects from interferon are troubling for many patients, and (less commonly) can be severe. Furthermore, interferon should not be used in pregnant women and patients with decompensated disease or compensated cirrhosis and portal hypertension.
Interferon alfa is administered by subcutaneous injection. The preferred formulation is peginterferon alfa-2a, which should be administered as 180 microG once weekly for 48 weeks for HBeAg-positive or HBeAg-negative chronic HBV.
71
Write short notes on the nucleos(t)ide-analogues used in the management of HBV infection. Cover:
* Predictors of response
* Available agents
The predictors of response depend in part upon the HBeAg-status of the patient:
●For HBeAg-positive patients, the likelihood of a virologic response to nucleos(t)ide analogues is independent of ALT levels and HBV genotype; however, the serologic response, like interferon, depends upon the degree of elevation of the serum aminotransferases. As a general rule, treatment with any of these drugs does not result in higher rates of HBeAg seroconversion compared with no treatment in those who have a serum ALT ≤2 X ULN.
In patients with high HBV DNA levels, it takes more time to become undetectable after initiating nucleos(t)ide analogues. For such patients, the HBV DNA often remains detectable after one and sometimes two years of treatment.
●For HBeAg-negative patients, prediction of response (eg, HBsAg loss or sustained virologic response after discontinuation of treatment) is less precise. Because of the need for long-term treatment, therapy is recommended only for those with persistent or intermittent elevation in ALT and/or substantial histologic abnormalities (moderate/severe inflammation or bridging fibrosis/cirrhosis).
```
Available agents:
●Entecavir
●Tenofovir
●Lamivudine
●Adefovir
●Telbivudine
```
72
Discuss the use of Tenofovir in the management of HBV infection.
Tenofovir can be used as first-line therapy in treatment-naïve patients and also in those who have had prior exposure, or developed drug resistance, to other nucleos(t)ide analogues (eg, lamivudine). In clinical trials of patients receiving tenofovir disoproxil fumarate, resistance to tenofovir has not been documented, even among those who have been treated for up to eight years.
There are two formulations of tenofovir, tenofovir disoproxil fumarate and tenofovir alafenamide. For most patients, we recommend tenofovir alafenamide (25 mg daily) rather than tenofovir disoproxil fumarate (300 mg daily), if available. For those who were originally started on tenofovir disoproxil fumarate, we generally suggest switching to tenofovir alafenamide.
Although there is more experience with tenofovir disoproxil fumarate compared with tenofovir alafenamide, tenofovir alafenamide appears to be equally effective and is associated with less renal and bone toxicity.
73
Discuss the use of Lamivudine in the management of HBV infection.
The main advantages of lamivudine are its lower cost compared with the other oral agents and the many years of experience confirming its safety. However, the role of lamivudine in the care of patients with chronic HBV is diminishing given the high rate of drug resistance and the availability of new therapies, such as entecavir and tenofovir, which are associated with lower rates of resistance.
Lamivudine (or the closely related agent emtricitabine) may still have a role in patients coinfected with HIV when used as part of an antiretroviral regimen that contains a second drug with anti-HBV activity, such as tenofovir. A detailed discussion of the treatment of HBV in HIV-infected patients is found elsewhere.
The recommended dose of lamivudine for adults with normal renal function without concomitant HIV infection is 100 mg daily. Dose adjustment is required in those with decreased renal function. For patients with HIV, a higher dose (lamivudine 300 mg once daily or emtricitabine 200 mg once daily) is used as part of an HIV antiretroviral regimen.
74
Which epitope do the vaccines induce immunity against?
The vaccines induce HBsAg-specific helper T cells and T cell-dependent B cells to produce neutralizing antibody against the "a" epitope of HBsAg (the only epitope common across HBV subtypes).
75
Give a broad overview of the duration of treatment for HBV infection.
Patients receiving interferon therapy receive a finite duration of therapy.
The optimal duration of therapy for the oral drugs is not well-established. Most patients receiving nucleos(t)ide analogue therapy will require at least four to five years of treatment, and some may require indefinite treatment.
Long-term treatment is particularly important for patients with cirrhosis.
76
What are the duration of treatment and the treatment endpoints for HBeAg-positive chronic HBV patients without cirrhosis?
The endpoint of treatment for HBeAg-positive patients is HBeAg seroconversion (ie, HBeAg undetectable and the development of hepatitis B e antibodies confirmed by testing on two occasions at least two months apart). For patients being treated with nucleos(t)ide analogues, a prolonged duration of therapy is often required since HBeAg seroconversion only occurs in about 40 percent of patients after five years of treatment.
Treatment should be continued until the patient has persistently normal ALT levels and undetectable serum HBV DNA for at least 12 more months to reduce the rate of relapse after HBeAg seroconversion has been confirmed. Patients who discontinue treatment should be closely monitored as viral relapse may lead to hepatitis flares and hepatic decompensation. For patients without cirrhosis, the ALT, HBV DNA, and HBeAg should be monitored every three months for at least one year.
Because relapse can occur even after completion of 12 months consolidation treatment following HBeAg seroconversion, an alternative is to continue treatment until HBsAg loss, but this would mean most patients will have to be on lifelong treatment.
77
What are the duration of treatment and the treatment endpoints for HBeAg-negative chronic HBV patients without cirrhosis?
Treatment may be discontinued in patients with HBeAg-negative hepatitis who have confirmed loss of HBsAg (by testing on two occasions at least two months apart). However, only a small minority of patients (approximately 5 percent) lose HBsAg after five years of continued therapy.
For patients who remain HBsAg-positive, we generally continue treatment since most will experience a virologic relapse after therapy is stopped. However, some patients are unable to, or do not want to, continue life-long therapy because of its associated risk of adverse events or cost. For such patients, we discuss the risks and benefits of stopping treatment if they have received nucleos(t)ide analogue therapy for at least four to five years and have achieved an undetectable HBV DNA on therapy for the last three years. Patients who understand the risks of relapse, and who agree to close monitoring, may have a trial of treatment discontinuation.
Patients who have received a longer duration of therapy are less likely to relapse or develop a flare. However, the optimal duration of oral antiviral therapy and the duration of virologic response needed to reduce the risk of relapse are unknown, and some patients may require indefinite treatment.
78
What are the duration of treatment and the treatment endpoints for patients with cirrhosis?
For patients with cirrhosis, life-long therapy with oral agents is typically administered to reduce the risk of clinical decompensation if a relapse occurs. Therapy should be continued even with those who are HBeAg-positive and have seroconverted to anti-HBe on nucleos(t)ide therapy, as well as those with decompensated cirrhosis who have resolution of cirrhosis complications on treatment.
Although it is possible that treatment may be discontinued in those with compensated cirrhosis who have lost HBsAg, or those who have documentation of cirrhosis regression by histology or noninvasive assessment of liver fibrosis, there is insufficient evidence to guide treatment decisions for this group of patients. If a patient with compensated cirrhosis does discontinue therapy (eg, due to toxicity), the patient should be monitored by testing for ALT and HBV DNA monthly for the first six months, and then every three months for another year. Thereafter, the frequency of monitoring may be decreased in patients who remain in remission.
79
How do you manage patients who have persistent viraemia/breakthrough infection whilst on tenofovir or entecavir?
For patients receiving tenofovir or entecavir, the AASLD considers a virologic response as an undetectable HBV DNA after 96 weeks of treatment. Although most HBeAg-negative patients have undetectable HBV DNA after 48 weeks of treatment, some HBeAg-positive patients with high baseline HBV DNA may remain viremic at week 96.
For patients who remain viremic after 48 or 96 weeks, or have breakthrough infection (an increase in serum HBV DNA by >1 log10 [10-fold] from nadir or after HBV had been undetectable), we verify medication adherence since tenofovir- or entecavir-resistant virus rarely occurs in treatment-naïve patients. This is in contrast to patients receiving therapy with nucleos(t)ide analogues with a low barrier to resistance, such as lamivudine, adefovir, and telbivudine.
In patients who are adherent, we do not modify our therapy if there is persistent viremia as long as the HBV DNA levels are low (ie, <2000 international units/mL) and/or continue to decrease. However, we obtain resistance testing if the HBV DNA has plateaued after 96 weeks of treatment, or if there is virologic breakthrough.
For those failing entecavir, we add tenofovir until the HBV DNA becomes undetectable; at that point, we discontinue entecavir and treat with tenofovir alone. Some providers switch to tenofovir without an overlap period since data suggest that monotherapy with tenofovir disoproxil fumarate has similar efficacy compared with combination therapy (ie, tenofovir disoproxil fumarate plus entecavir). For those failing tenofovir, we add entecavir until the HBV DNA becomes undetectable; at that point, we discontinue tenofovir. Information on the individual agents is found above.
80
How do you manage patients who have persistent viraemia/breakthrough infection whilst receiving other nucleos(t)ide analogues?
Although nucleos(t)ide analogues with a low barrier to resistance (eg, lamivudine, adefovir, or telbivudine) are not generally recommended for initial therapy, these agents are sometimes used in settings where cost is a consideration. Patients receiving these agents should be switched to tenofovir if the HBV DNA remains >4 log10 international units/mL after 12 months or the patients develop confirmed breakthrough infection (an increase in serum HBV DNA by >1 log10 [10-fold] from nadir or after HBV had been undetectable). Tenofovir monotherapy is effective in suppressing HBV replication in patients who have lamivudine-, telbivudine-, or adefovir-resistant virus. By contrast, there is a high risk of entecavir resistance developing in patients with pre-existing drug-resistant virus after lamivudine or telbivudine treatment.
Therapy should be changed promptly once virologic breakthrough is confirmed to prevent a biochemical breakthrough. This is particularly important in those with worsening liver disease, decompensated cirrhosis, recurrent HBV after transplantation, or immunosuppression.
Testing for antiviral drug-resistant variants is desirable but not essential for most patients. However, a genotype should be obtained to guide selection of salvage therapy if the patient received sequential nucleos(t)ide analogue therapy.
81
Is there any benefit to combination therapy? If so, which combinations are best?
In general, there is no evidence that initiating combination therapy with two nucleos(t)ide analogues (eg, entecavir and tenofovir disoproxil fumarate) is superior to monotherapy. Although combination therapy results in more rapid viral suppression in patients with high baseline HBV DNA, it has not been determined whether accelerating viral suppression improves clinical outcomes. However, if entecavir or tenofovir are not available, lamivudine or telbivudine should be used in combination with adefovir to reduce the risk of developing drug-resistant virus.
82
How should HBV infected patients be counselled, in terms of lifestyle and vaccinations?
●Alcohol use – Heavy use of alcohol (>40 g/day for men and >20 g/day for women), has been associated with worsening liver disease and an increased risk of hepatocellular carcinoma. Although the exact amount of alcohol that can be safely consumed is unclear, advising patients to be completely abstinent is reasonable in those who have cirrhosis.
●Immunizations – Patients with chronic HBV should receive appropriate immunizations, particularly hepatitis A vaccination.
●Preventing transmission to others – Carriers of HBV should be counseled regarding the risk of transmission to others. Patients should be advised regarding prevention of sexual transmission (ie, vaccination of spouses and steady sex partners in individuals with monogamous partners, and safe sex practice including use of condoms in subjects with multiple partners), perinatal transmission, and risk of environmental exposure from blood.
83
What are the two types of immunoprophylaxis against HBV available?
Passive immunization using HBIG and active immunization using inactive HBsAg.
84
Which epitope do the vaccines induce immunity against?
The vaccines induce HBsAg-specific helper T cells and T cell-dependent B cells to produce neutralizing antibody against the "a" epitope of HBsAg (the only epitope common across HBV subtypes).
85
How effective is the HBV vaccine?
Using the definition of >10 mIU/mL anti-HBs as a positive response, the overall seroconversion rate is about 95 percent in healthy adults. The rate decreases with increasing age to 86 percent in the fourth decade and 47 percent in the sixth decade. The response rate is slightly lower in obese individuals, smokers, and men, and significantly lower in patients with cirrhosis or chronic renal failure, organ transplant recipients, children with celiac disease, and immunosuppressed patients.
86
Is post-vaccination testing required?
As discussed above, the current hepatitis B vaccines have a response rate of 95 percent. Thus, routine post-vaccination testing to document hepatitis B surface antibody (anti-HBs) seroconversion is generally unnecessary, except in health care workers, patients on chronic hemodialysis, other immunocompromised patients (including those with HIV infection), and individuals who are at risk for recurrent exposure to hepatitis B virus (eg, spouses or sexual partners of carriers and infants of carrier mothers). Testing should be performed one to two months after completion of the primary vaccination series.
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What is the duration of protection given by the vaccine?
Although hepatitis B surface antibody (anti-HBs) titers decrease with time, the duration of protection is long. Among those who responded to the initial vaccine series, protection has been estimated to persist for up to 30 years. Protection from clinical disease is felt to occur even in the setting of declining or undetectable anti-HBs levels, due to the priming of memory cells, which are capable of eliciting an anamnestic response when challenged, and long-lasting cellular immunity.
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Are booster doses of this vaccine required? If so, when?
In most countries, including the United States, a booster dose of vaccine is not routinely recommended for immunocompetent children and adults who have responded to a complete three-dose vaccine series.
However, booster doses should be administered to certain patients who are at high risk for both waning immunity and HBV transmission. Most health authorities agree that booster vaccination is recommended for patients on hemodialysis, in whom vaccine-induced protection may persist only as long as the antibody level is ≥10 mIU/mL. For these patients, the need for a booster dose should be assessed annually and a booster dose administered if the antibody level declines to <10 mIU/mL. For other immunocompromised persons, anti-HBs levels should be monitored in those with an ongoing risk for exposure, and a booster dose should be administered to those individuals whose anti-HBs falls below 10 mIU/mL.
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What adverse reactions have been reported in vaccine users?
The most common adverse reaction is soreness over the site of injection, which occurs in fewer than 25 percent of the vaccinees. Other adverse reactions reported by 1 to 3 percent of vaccinees include low grade fever, malaise, headache, joint pain and myalgia. These adverse reactions are usually mild and do not result in any serious clinical sequelae. Hepatitis B vaccines have no teratogenic effects and can be administered during pregnancy.
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How should vaccine non-responders be managed?
The current recommendation for all healthy individuals who do not develop an adequate anti-HBs response to the primary vaccine series is to administer one or more additional doses. An adequate antibody response is seen in 15 to 25 percent after one additional dose and in 50 percent after three additional doses. As a result, it may be reasonable to repeat a three-dose schedule, retesting two to three months after the third dose. Individuals who fail to respond after three additional doses of vaccine that have been appropriately administered are unlikely to benefit from further vaccination. However, these individuals may still mount an adequate immune response and recover from HBV infection.
Individuals who fail to respond after two courses of HepB vaccine should be tested for HBsAg, particularly in countries where pre-vaccination testing is not performed or performed using anti-HBs test only. Non-responders who test negative for HBsAg should be educated on how to prevent HBV infection, including the need for hepatitis B immune globulin (HBIG) if they have an exposure to blood or other body fluids of a person who is HBsAg-positive.
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What is the dosing schedule for HBV vaccine?
Doses vary by preparation (read package insert)
The typical vaccination schedule is zero, one and six months. The first two doses have no effect on on the final anti-HBs titer. The third dose acts as a booster to achieve a high anti-HBs titer.
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What if a vaccine dose is missed?
Longer than recommended intervals between doses do not reduce final antibody concentrations, although protection might not be attained until the recommended number of doses has been administered. Thus, an interruption in the vaccination schedule does not require restarting the entire series of vaccination or adding extra doses. If the vaccination series is interrupted after the first dose, the second dose should be administered as soon as possible. The second and third doses should be separated by an interval of at least two months. If only the third dose is delayed, it should be administered when convenient.
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Where should the vaccine be administered?
Vaccines should be administered intramuscularly since deposition of the vaccine into adipose tissue result in a lower seroconversion rate. Thus, the deltoid is the preferred site in adults. Longer needles should be used in overweight individuals.
