Hepatitis B

1. Hepatitis B Review by Brent Whitworth, MD

2. Hepatitis B Virus • Hepatitis B virus (HBV) infection is a global public health problem. • It is estimated that there are more than 350 million HBV carriers in the world, of whom 1 million will die annually from HBV-related liver disease. • Some references have placed the number of affected persons as much as 5% of the total world population. • In the United States, there are an estimated 1.25 million hepatitis B carriers, defined as persons positive for hepatitis B surface antigen (HBsAg) for more than 6 months.

3. Hepatitis B Virus • The spectrum of clinical manifestations of HBV infection varies in both acute and chronic disease. • During the acute phase, manifestations range from subclinical hepatitis to fulminant hepatitis. • During the chronic phase, manifestations range from an asymptomatic carrier state to cirrhosis, and hepatocellular carcinoma.

4. Hepatitis B Virus • Hepatitis B virus belongs to the family of hepadnaviruses, which include duck hepatitis virus, woodchuck hepatitis virus, and ground squirrel hepatitis virus. • The genome of HBV is a relaxed circular, partially double stranded DNA of approximately 3200 base pairs in length. • The complete virion or Dane particle is 42 nm in diameter. • HBV has traditionally been classified into seven genotypes (A to G) the clinical significance of which is yet to be determined. • Integration of HBV DNA into the host genome is not necessary for viral RNA synthesis, and HBV transcripts are synthesized entirely from episomal DNA.

5. Hepatitis B Virus • In addition to intact virions, serum and HBV-infected hepatocytes contain subviral particles, which are produced in great excess. • These 20-nm spheres and long filamentous proteins. • These subviral particles are not infectious because they contain no viral DNA but are stongly immunogenic and stimulate the production of antibodies. • This property was exploited in the development of the first HBV vaccines. • The function of these subviral particles in the life cycle of the virus is unknown.

6. Panel A shows HBV virions (Dane particles) and filaments. • Panel B shows 20-nm HBsAg particles

7. Epidemiology • In the Far East, the Middle East, Africa, and parts of South America, the prevalence of HBV is high, with HBsAg positivity rates ranging from 8% to 15%. • Perinatal transmission is most common in high prevalence areas such as southeast Asia and China. • It is well established that the risk of persistent infection is much greater in infants than in adults. • Sexual contact and percutaneous transmission (eg, intravenous drug use) are most common in the United States, Canada, and western Europe.

8. Epidemiology • In the United States, the estimated incidence of acute HBV infection has been falling from a peak in 1985 of 70 cases per 10,000 population to 40 cases per 100,000 in 1991 likely as a result of safer sexual practices. • The only region in the United States of high prevalence is Alaska, where the prevalence rate in the native population is 6.4%. • HBV infection is more common in men than in women, with the peak prevalence in men occurring between the ages of 10 and 29.

9. Epidemiology • Sexual activity is probably the single most important mode of HBV transmission in areas of the world like the US. • Heterosexual sex now accounts for the majority of cases of HBV infection (26%) in the US. • Sexual partners of persons infected with HBV are at risk for infection, even in the absence of high-risk behavior. • The risk of heterosexual transmission is greater when the infected person is female. • Because many patients with chronic HBV infection are unaware of their infection, sexual contact is likely to be an important mode of transmission worldwide. • The use of condoms appears to reduce the risk of sexual transmission.

10. Epidemiology • Children of HBsAg-positive mothers who are not infected at birth remain at high risk of early childhood infection; 60% become infected by the age of 5 years. • The mechanism of this later infection, which is neither perinatal nor sexual, is unknown. • Even with active and passive immunization, 5% to 10% of babies may acquire HBV infection at birth. • In the United States and Western Europe, injection drug use remains a very important mode of HBV transmission (23% of all cases).

12. Pathogenisis • The pathogenisis of HBV-related liver disease is generally thought to be related to cytotoxic T cell-mediated lysis of infected hepatocytes. • Patients with chronic hepatitis B who clear HBeAg have more vigorous CTL responses to HBV antigens than those who remained HBeAg positive. • In one study HBV-specific cytotoxic T cells from patients studied up to 23 years after clinical and serologic recovery expressed activation markers indicating recent contact with HBV antigens. • This observation suggests that complete eradication of HBV rarely occurs after recovery from acute hepatitis and that traces of virus can maintain the T cell response for decades following clinical recovery, which in turn keeps the virus under control.

13. Pathogenisis • Maximal reduction in HBV-DNA levels occurred prior to peak increase in serum ALT levels, suggesting that viral control is mediated through noncytolytic as well as cytolytic mechanisms. • HBV is generally not a cytopathic virus, however direct cytopathic liver injury can occur if the viral load is very high in certain patients. • In most patients with chronic hepatitis B, for example, there is no direct correlation between viral load and the severity of liver disease.

15. Acute HBV Infection • In primary infection, HBsAg becomes detectable in the bloodafter an incubation period of 4 to 10 weeks, followed shortlyby antibodies against the HBV core antigen. • A serum sickness-like syndrome may develop during the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice and right upper quadrant discomfort. • Viremiais well established by the time HBsAg is detected, and titersof virus in acute infection are very high — frequently109 to 1010 virions per milliliter. • When liver injury does occur in primary infection, ALTlevels do not increase until after viral infection is well established,reflecting the time required to generate the T-cell–mediatedimmune response that triggers liver injury.

16. Acute HBV Infection • Values up to 1000 to 2000 IU/L are typically seen during the acute phase with ALT being higher than AST. • With clearance of the infection, the viralantigens HBsAg and HBeAg disappear from the circulation, andfree anti-HBs antibodies become detectable. • In patients who recover, normalization of serum aminotransferases usually occurs within one to four months. • Approximately 70 percent of patients with acute hepatitis B have subclinical or anicteric hepatitis, while 30 percent develop icteric hepatitis.

17. Acute HBV Infection • The disease may be more severe in patients coinfected with other hepatitis viruses or with underlying liver disease. • Persistent elevation of serum ALT for more than six months indicates progression to chronic hepatitis. • The rate of progression from acute to chronic hepatitis B is primarily determined by the age at infection.

18. Fulminat Hepatitis • The most feared complication of acute HBV infection is fulminant hepatic failure, defined as the onset of hepatic encephalopathy within 8 weeks of the onset of symptoms. • The prognosis is poor once encephalopathy has developed. • 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.

19. Chronic Hepatitis • Chronic HBV infection is usually defined as detectable hepatitis B surface antigenemia for a period of six months or more. • One feature of chronic HBV infection that is not widely appreciatedis its dynamic natural history. • The natural course of chronic hepatitis B virus infection is determined by the interplay between virus replication and the host immune response. • The risk of chronic infection is related to two major factors: the age at which infection is acquired and the immune state of the host. • A history of acute hepatitis is elicited in only a small percentage of patients with chronic HBV infection.

20. Chronic Hepatitis • The risk of developing chronic HBV infection after acute exposure ranges from 90 percent in newborns of HBeAg-positive mothers to 25 to 30 percent in infants and children under 5 and less than 10 percent in adults. • Many patients with chronic hepatitis B are asymptomatic while others have nonspecific symptoms such as fatigue. • People with subclinical persistent infection,normal serum aminotransferase levels, and normal or nearly normalfindings on liver biopsy are termed asymptomatic chronic HBVcarriers. • Those with abnormal liver function and histologicfeatures are classified as having chronic hepatitis B.

21. Chronic Hepatitis • Some patients experience exacerbations of the infection which may be asymptomatic, mimic acute hepatitis, or manifest as hepatic failure. • During exacerbations, the serum ALT concentration may be as high as 50 times the upper limit of normal . • Most exacerbations are asymptomatic and are discovered during routine follow-up. • Exacerbations are more commonly observed in men than women. • In a small percentage of patients, exacerbations result in hepatic decompensation and rarely death from hepatic failure.

22. Chronic Hepatitis • Chronic HBV infection generally consists of two phases: an early replicative phase with active liver disease; and a late or nonreplicative phase with remission of liver disease. • In patients with perinatally acquired HBV infection, there is an additional immune tolerance phase in which virus replication is not accompanied by active liver disease • In perinatally acquired HBV, the initial phase is characterized by high levels of HBV replication but no evidence of active liver disease as manifested by lack of symptoms, normal serum ALT concentrations and minimal changes on liver biopsy. • The exact mechanisms by which this occurs are unknown but is thought to be from tranplacental transfer of HbeAg affecting the responsiveness of T cells. This is referred to immune tolerance.

23. Chronic Hepatitis HBeAg • High titers of HBV in the blood are often indicatedby the continued presence of HBeAg. • With the passage of time, there is alsoa tendency for HBeAg to disappear from the blood, along withseroconversion to positivity for anti-HBe antibodies —a progression that occurs at a rate of 5 to 10 percent per yearin persistently infected people. • In light of the cross-immunoreactivity between HBcAg and HBeAg, a possible function of HBeAg is to divert the immune response of the host away from virally infected hepatocytes that express HBcAg on their surfaces. • The absence of HBeAg production would be associated with a vigorous and, for the virus, potentially lethal immune response against the hepatocyte. This is not proven.

24. Chronic Hepatitis HBeAg • HBeAg-negative carriers are a heterogeneous group. • Most suchcarriers have low levels of viral DNA, relatively normal levelsof alanine aminotransferase, and a good prognosis. • Patients in the low replicating phase are HBeAg negative and anti-HBe positive. • In some patients, virus replication has ceased although they remain HBsAg (hepatitis B surface antigen) positive. • These patients with HBeAg-negative chronic hepatitis may have residual wild type virus or HBV variants that cannot produce HBeAg due to precore or core promoter variants.

25. Chronic Hepatitis • The cumulative rate of spontaneous HBeAg clearance is estimated to be approximately 2 percent during the first three years and only 15 percent after 20 years of infection. • 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, noncirrhotic patients who cleared HBsAg appeared to have a good prognosis. • The ability of hepatitis B virus to cause complications despite clearance of HBsAg probably results from its integration into the genome.

26. Chronic Hepatitis • These patients may have low level HBV replication, but liver disease is usually inactive. • The natural history of HBV persistence suggeststhat there is an ongoing immune attack on infected cells inthe liver — an attack that is usually inadequate to eradicateinfection altogether, but that does reduce the number of infectedcells and thereby lowers the circulating viral load. • 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. • Cirrhosis develops in about 20 percent of peoplewith chronic hepatitis

27. Solid lines indicate a smooth transition from replicative to nonreplicative or minimally replicative infection and remission of liver disease. • Dotted lines indicate flares of hepatitis associated with abortive immune clearance or reactivation of HBV.

29. Hepatocellular Carcinoma • The majority of patients with HBV remain asymptomatic with a very low risk of cirrhosis or HCC. • Risk factors for HCC in patients with chronic HBV infection include male gender, family history of HCC, older age, presenceof HBeAg in an adult, history of reversions from anti-HBe to HBeAg, presence of cirrhosis, and coinfection with hepatitis C virus. • It is important to note that, although HCC is more common in persons with cirrhosis, 30 to 50 percent of HCC associated with HBV occurs in the absence of cirrhosis. • The prognosis is not so good in HBV-infected patients from endemic areas and in patients with chronic hepatitis B.

30. Hepatocellular Carcinoma • The estimated five-year rates of progression are: • 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 • Among Chinese patients with chronic HBV infection, the life-time risk of a liver-related death has been estimated at 40 to 50 percent for men and 15 percent for women.

33. Hepatitis B - Prognosis • Patients with a prolonged replication phase have a worse prognosis mostly due to the development of cirrhosis and hepatocellular carcinoma • Recurrent episodes of hepatitis may, either directly or indirectly through immune-mediated injury, increase the risk of fibrosis, cirrhosis, and perhaps carcinogenesis • Clearance of HBeAg was associated with a 2.2-fold decrease in death rate. • Other independent factors associated with poor survival were older age, hypoalbuminemia, thrombocytopenia, splenomegaly, and hyperbilirubinemia. • Even among patients with decompensated cirrhosis, suppression of HBV replication and delayed HBsAg clearance can result in improvement in liver disease.

34. Hepatitis C and HBV • 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. • 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. • Coexistent HCV infection has been estimated to be present in 10 to 15 percent of patients with HBV-associated chronic hepatitis, cirrhosis, or HCC. • Most patients who have dual HCV and HBV infections have detectable serum HCV RNA but undetectable or low HBV DNA levels, indicating that HCV is the predominant cause of liver disease in these patients. • Nevertheless, the liver disease is usually more severe than in patients infected by HBV alone and are at greater risk for HCC

35. Hepatitis D and HBV • Although HDV can replicate autonomously, the simultaneous presence of HBV is required for complete virion assembly and secretion. • Patients with hepatitis D are always dually infected with HDV and HBV. • Acute HBV and HDV coinfection tends to be more severe than acute HBV infection alone and is more likely to result in fulminant hepatitis. • HBV/HDV coinfection most commonly occurs in the Mediterranean area and parts of South America. • The availability of HBV vaccines and public health education on prevention of transmission of HBV infection has led to a significant decline in the prevalence of HDV infection in the past decade.

36. Hepatitis D and HBV • Coinfection of HBV and HDV usually results in a more severe acute hepatitis with a higher mortality rate than is seen with acute hepatitis B alone, but rarely results in chronic infection. • HDV superinfection can manifest as a severe "acute" hepatitis in previously asymptomatic HBV carriers or exacerbations of underlying chronic hepatitis B. • Unlike coinfection, HDV superinfection in HBV carriers almost always results in chronic infection with both viruses. • Although persons with chronic HBV/HDV infection can exhibit a wide spectrum of liver pathology, a higher proportion develops cirrhosis, hepatic decompensation, and HCC compared with those with chronic HBV infection alone.

37. Extraheaptic Manifestations • The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease. • Extrahepatic manifestations, which are thought to be mediated by circulating immune complexes, occur in 10 to 20 percent of patients with chronic HBV infection. • HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis. • Most cases of HBV-related glomerulonephropathy occur in children. • Polyarteritis nodosa with a systemic vasculitis can occur with either acute or chronic HBV infection. • This syndrome typically presents with abdominal pain resulting from arteritis of the medium-sized arteries with ischemia to the intestine or gallbladder.

38. Extraheaptic Manifestations • Other manifestations of HBV-associated vasculitis include neuropathy, cutaneous vasculitis, arthritis, and Raynaud’s phenomenon, membranoproliferative • Neurologic manifestations of HBV infection include Guillain-Barré syndrome and a polyneuropathy (usually related to polyarteritis). • Rarely HBV is associated with pericarditis and pancreatitis.

39. Testing for HBV • The following groups should be tested for HBV infection by testing for HbSAg and anti-HBs: • Persons born in hyperendemic area, men who have sex with men, injecting drug users, dialysis patients, HIV-infected individuals, pregnant women, and family members, household members, and sexual contacts of HBV-infected persons.

40. Testing for HBV • Testing should be performed for HBsAg and anti-HBs. • A positive result for antibody to hepatitis B core antigen does not differentiate between recovered and chronic infection. • In addition, false-positive test results are not uncommon in persons with isolated antibodies to hepatitis B core antigen. • The appropriate HBV DNA assay to use for initial evaluation of patients with chronic HBV infection has not been determined. • An arbitrary value of >10(5) copies/mL was chosen as a diagnostic criterion for chronic hepatitis B at a recent NIH conference. • The problem is assays for HBV DNA are not well standardized, HBV DNA levels fluctuate, and the theshold associated with progressive disease is unkown.

41. Prevention of HBV • Three main strategies exist for the prevention of HBV infection: 1) behavior modification to prevent disease transmission, 2) passive immunoprophylaxis, and 3) active immunization. • Patients with chronic HBV infection should be counseled regarding lifestyle modifications and prevention of transmission. • Carriers of HBV should be counseled as to the risk of transmission to others. • Counseling should include precautions to prevent sexual transmission, perinatal transmission, and risk of inadvertent transmission via environmental contamination from a blood spill. • Household members are at increased risk of HBV infection and therefore should be vaccinated if they test negative for HBV serologic markers. • Carriers should be advised to cover open cuts and scratches and clean up blood spills with bleach, because HBV can survive on environmental surfaces for at least 1 week.

42. Prevention of HBV • Passive immunoprophylaxis is used in four situations: • 1) neonates born to HBsAg-positive mothers; • 2) after needlestick exposure • 3) after sexual exposure • 4) after liver transplantation in patients who are HBsAg positive pretransplantation. • The mechanism by which hepatitis B immune globulin (HBIG) prevents HBV infection is uncertain. • Effective vaccines have been available since the early to mid-1980s. • In areas of the world with high endemism of HBV infection, current recommendations are for universal vaccination. • HBV vaccine is highly effective. Anti-HBs develops in over 95% of vaccine recipients

43. Treatment of HBV • The aims of treatment of chronic hepatitis B are to achieve sustained suppression of HBV replication and remission of liver disease. • The end points used to assess treatment response include normalization of serum ALT level, undetectable serum HBV DNA by an unamplified assay, loss of HBeAg with or without detection of anti-HBe, and improvement in liver histology. • In patients with HBeAg-positive chronic hepatitis, a responseto treatment is usually defined by the reduction of serum HBVDNA to levels that cannot be detected with non–polymerase-chain-reactionassays and by the loss of HBeAg. • Inconsistencies in the definition of response, lack of standardization of HBV DNA assays, and heterogeneity in patient populations make it difficult to compare response rates in clinical trials of treatment of chronic hepatitis B. • Currently, three therapeutic agents have been approved by the FDA for the treatment of chronic hepatitis B.

44. Who should be treated? • There are clear indications for therapy in HBeAg-positivepatients. • They have an increased risk of early progression tochronic active hepatitis and cirrhosis, and they have a riskof hepatocellular carcinoma that is substantially higher thanthat for other carriers. • By contrast, asymptomatic HBeAg-negativechronic carriers with viral loads below 105 genomes per milliliterand normal alanine aminotransferase values tend to have a relativelystable course, with low rates of clinical or pathological progression. • At present, therapy is usually not offered to such persons. • Some HBeAg-negative patients have liver dysfunctionand substantial viremia (>105 molecules per milliliter) • A recent trial suggestthat many of these patients would also benefit from effectiveantiviral therapy.

45. Who should be treated? • True cure of infection (loss of HBsAg and complete disappearanceof viremia, as measured by stringent PCR assays) is achievedonly infrequently (in 1 to 5 percent of patients) with currentregimens. • In the case of patients with HBeAg-negative chronichepatitis, there is no information about which markers bestmeasure the response to therapy. • Quantitation of viremia byPCR assays would seem a logical starting place, but there havebeen no systematic studies to guide the clinical interpretationof results.

46. Interferon • Interferons (IFNs) have antiviral, antiproliferative, and immunomodulatory effects. • Interferon alfa (IFN-alpha) has been shown to be effective in suppressing HBV replication and in inducing remission of liver disease. • A major problem with IFN-alpha treatment is relapse; approximately half of the responders relapse when therapy is discontinued, and relapses can occur up to 5 years post-therapy. • Overall, sustained response can be achieved in 15 to 30 percent of patients and long-term follow-up showed that 15 to 50 percent of sustained responders cleared HBsAg. • 20 to 40 percent of patients with HBeAg-positive chronic hepatitis B develop a flare in their ALT values during IFN-alpha treatment which can be severe in patients with cirrhosis.

47. Interferon • IFN-alpha is administered as subcutaneous injections. 5 MU daily or 10 MU 3x weekly for 16 to 24 weeks for HbeAg (+) chronic and 12 months for HbeAg(-) chronic hepatitis. • Clinical trials of pegylated IFN-alpha singly and in combination with other antivirals are ongoing. • IFN-alpha therapy is associated with many adverse effects. • Of these, flu-like symptoms, fatigue, leucopenia, and depression are the most common. • Most patients develop tolerance to the flu-like symptoms after the first week, but fatigue, anorexia, hair loss, and mood swings including anxiety, irritability, and depression may persist throughout the course of treatment and for a few weeks after discontinuation of therapy. • IFN-alpha may also unmask or exacerbate underlying autoimmune disorders.

48. Lamivudine (Epivir, 3TC) • Epivir works by incorporating (3TC-TP) into growing DNA chains causing premature chain termination thereby inhibiting HBV DNA synthesis. • Pretreatment ALT has been found to be the most important predictor of response. • It has been shown to benefit patients with HBeAg-negative chronic hepatitis B. • In one study, virologic and biochemical response was achieved in 63 percent patients who received 24 weeks of lamivudine therapy versus 6 percent patients on placebo. • However, the vast majority (~90 percent) of patients relapsed when treatment was stopped. • Unfortunately, extending the duration of treatment resulted in progressively lower rate of response due to the selection of lamivudine-resistant mutants.

49. Lamivudine (Epivir, 3TC) • Studies in patients with decompensated cirrhosis showed that lamivudine treatment is well tolerated and results in clinical improvement in many patients • Various adverse events including a mild (two- to threefold) increase in ALT level have been reported in patients receiving lamivudine, but these events occurred in the same frequency among the controls. • A major concern with early treatment is the selection of resistant mutants • The optimal duration of lamivudine therapy in persons who have an initial response is unknown. • Treatment may be discontinued in patients who have completed 1 year of treatment and have persistent HBeAg seroconversion (HBeAg loss, anti-HBe detection, and serum HBV DNA undetectable by non-PCR assays on more than one occasion determined 2 to 3 months apart). • Durability of response after cessation of treatment is expected to be 60 to 80 percent.

50. Adefovir • Adefovir dipivoxil is a nucleotide analog of adenosine monophosphate. • It can inhibit both the reverse transcriptase and DNA polymerase activity and is incorporated into HBV DNA causing chain termination. • In patients receiving adefovir, HBV DNA is reduced by 3.5 to 3.9 log10 from baseline. • Adefovir has been shown to be effective in suppressing not only wild-type HBV but also lamivudine-resistant HBV mutants in both in vitro and in vivo studies. • Adefovir when used in high doses has been reported to be associated with renal tubular dysfunction resembling Fanconi syndrome as well as deterioration in renal function. • Data on the durability of HBeAg seroconversion after adefovir is discontinued have not been presented. • Preliminary data indicate that most patients with HBeAg negative chronic hepatitis will relapse when adefovir is withdrawn after 1 year.