The Management of Viral Hepatitis

Canadian Association for Study of the Liver

Proceedings of a consensus conference held in
Montreal, Quebec in March 1999

HEPATITIS B VIRUS

1. EPIDEMIOLOGY OF HEPATITIS B IN CANADA

The prevalence of hepatitis B (HBV) infection varies considerably across Canada because of the heterogeneity of the Canadian population. If the Canadian population can be described by three groups - Native/Inuit, Immigrant and Non-immigrant then the estimated prevalence and number of cases in Canada are shown in Table 1^(1-6). Immigrants constitute the largest group of HBV carriers, particularly those from regions with high endemic rates of HBV, such as Asia. The proportion of HBV infected patients who are HBeAg-positive also varies amongst the different groups⁽¹⁾. HBeAg-positivity ranges from <9% in the Inuit population, to <15% for non-immigrants, to 46% for Asian immigrants and 55% for Indochinese immigrants. The majority of HBeAg-positive cases occur in the young immigrant population.

Following acute HBV infection, the percent-age of infected patients who become carriers varies with age. The risk is greatest in the very young and in the elderly (see later). Although acute hepatitis B continues to be an important clinical problem in Canada the majority of acute cases will resolve and clear HBsAg spontaneously. Chronic HBV infection, established when HBsAg is detectable for longer than 6 months with or without continuing liver enzyme abnormalities, accounts for the greatest burden of disease.

Table 1 Hepatitis B in Canada

2. NATURAL HISTORY OF CHRONIC HEPATITIS B

The course of chronic hepatitis B is highly variable, characterized in some patients by exacerbation and remission of inflammatory activity in the liver, in others by continuous active hepatitis of varying degrees of severity, and in yet others by trivial inflammation. The disease can be described by three phases⁽⁷⁾. The first phase, the so-called immuno-tolerant phase, is characterized by high levels of virus in serum, and no or minimal hepatic inflammation⁽⁸⁾. These patients are HBeAg-positive. This is followed by the "active" phase, during which there is intermittent or continuous hepatitis of varying degrees of severity^(8-11). Seroconversion to anti-HBe-positive may occur during this phase⁽¹²⁾, but cessation of inflammatory activity does not always follow. The third phase is the inactive phase during which viral concentrations are low, and there is minimal inflammatory activity in the liver⁽³⁾. In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time do⁽¹⁴⁾. About 1%/year of anti-HBe-positive patients will clear HBsAg⁽¹⁵⁾. However these patients remain at risk for hepatocellular carcinoma.

One of the major mechanisms by which seroconversion occurs (possibly the only mechanism) is by the development of the so-called "pre-core mutant"⁽¹⁶⁾. This is a mutation which arises during the course of infection, and which results in inability of the virus to produce HBeAg. The virulence of this mutant is uncertain. Patients who are anti-HBe-positive with elevated ALT concentrations and detectable HBV DNA almost all carry the pre-core mutant. However, anti-HBe-positive patients with normal ALT levels and undetectable HBV DNA also frequently carry the mutant. It may be that virulence is determined by another related mutation in pre-core mutants.

Patients with hepatitis B-induced cirrhosis who are anti-HBe-positive have a 97% 5-year survival, compared to a 72% survival for those who are HBeAg-positive⁽¹⁷⁾. Once hepatic decompensation occurs in anti-HBe-positive patients, the survival at 5 years is only 28%, whereas in HBeAg-positive patients the 4-year survival is zero⁽¹⁸⁾. Factors predicting an adverse outcome include active hepatitis, bridging necrosis on biopsy, older age, and persistent HBV DNA in serum⁽¹⁹⁾.

Patients with chronic hepatitis B are at risk for the development of hepatocellular carcinoma⁽²⁰⁾. The relative risk has been prospectively determined to be about 100, but that is highly dependent on the population being studied. Studies in Asian populations describe a much higher risk than Caucasian populations. However, even in a Caucasian population the 10 year incidence of HCC may be as high as 15%⁽¹⁷⁾.

3. EVALUATION OF THE HBsAg-POSITIVE PATIENT

Who should be tested?

Any patient with clinical or laboratory evidence for either acute or chronic liver disease should be considered as possibly infected with HBV. Individuals engaged in high-risk activities such as intravenous drug use or high-risk sexual activity are at risk, as well as individuals exposed to blood by reason of their occupation. In addition, being a member of a population with a high endemic rate of HBV is a risk factor for infection.

The diagnosis of HBV infection is based on the detection of HBsAg in serum. All HBsAg-positive individuals require further detailed assessment. The objectives are to characterize the nature of the infection and the extent and severity of any underlying liver disease. Other objectives include identifying patients who may benefit from anti-viral treatment, early diagnosis and management of cirrhosis and its complications, timely detection of HBV-associated hepatocellular carcinoma, and immunization of contacts at risk.

Chronic hepatitis B - Initial Investigations

The laboratory tests needed in the initial assessment in all cases of chronic HBV infection are listed in table 2. Measurements of the aminotransferases provide a measure of ongoing inflammation, whereas the bilirubin, albumin and INR estimate liver function. Anemia, leukopenia or thrombocytopenia may indicate cirrhosis with portal hypertension. A positive HBeAg is associated with the continued presence of actively replicating HBV in the liver and detectable HBV DNA in the blood. Such patients are at risk for ongoing liver injury. Their blood and body fluids are highly infectious. Anti-HBe-positive patients may have much lower viral loads, which may be undetectable in blood by standard assays. These patients usually have little ongoing liver damage. Anti-HBe-positive patients may be infected with the so-called "pre-core" mutant, which does not produce HBeAg. These patients may have detectable HBV DNA and may develop progressive liver disease leading to cirrhosis, and therefore merit life-long observation.

In selected cases additional tests are needed. Anti-HCV should be requested in patients at high risk (IVDU, high risk sexual exposures, and origin in countries of high HCV prevalence). For those at risk for hepatocellular carcinoma (long term and childhood infections, positive family history), and those in whom cirrhosis is suspected an ultrasound is Bly advised.

Table 2. Initial investigation of the hepatitis B carrier

Table 3. Manufacturer's reported dynamic ranges for HBV DNA assays

Chronic hepatitis B - Special Investigations

HBV DNA Assays

HBV DNA can be detected in serum by several commercially available methods (see later). Table 3 lists the current tests, their limits and ranges. There is poor inter-assay standardization so that quantification of HBV DNA when tested on different assays can vary by approximately 10 fold or more when testing the same specimen. There is also considerable intra-assay variation so that repeat testing of the same sample will result in a significant difference in results (coefficient of variation for bDNA assay is 10-20%, and for PCR assays is 20-40%). It is therefore important for the clinician to understand the type of assay methodology used, and its limitations, and that a consistent methodology be used for all assays.

HBV DNA testing should be limited to those patients being considered for treatment and to evaluate response to treatment. It is not indicated routinely in the evaluation of all HBsAg-positive patients. HBV DNA testing should be readily available to qualified practitioners regularly involved in the treatment of HBV.

Liver Biopsy

Biochemical or serological tests, including HBV DNA, cannot predict histopathology with adequate precision. Therefore liver bi-opsy may be required to determine the severity of permanent liver injury (fibrosis or cirrhosis). The biopsy appearances may help in choosing appropriate therapy.

Ancillary tests

The detection of IgM anti-HBc in the serum is not a reliable surrogate for HBV DNA testing. Its use is not recommended for this purpose. Positive immunostaining of hepatocyte nuclei and cytoplasm for HBcAg reliably predicts the presence of HBV DNA in serum.

4. TREATMENT OF THE HEPATITIS B CARRIER

The licensing of the nucleoside analogue, lamivudine, has significantly increased the therapeutic options available for the management of HBV-infected patients. Clinical trials indicate that the response rates, as measured by HBeAg seroconversion to anti-HBe-positive, after lamivudine therapy in HBeAg-positive patients with elevated liver enzymes range from 17-33%, and are comparable to seroconversion rates documented with interferon therapy^(21-23). Loss of HBsAg with lamivudine therapy occurs in less than 5% of patients, compared to 8-33% with interferon⁽²³⁾. Response to lamivudine therapy is associated with improved liver histology. Preliminary results suggest that combined therapy with interferon and lamivudine has no advantage over the use of interferon or lamivudine alone. Lamivudine is well tolerated with minimal side effects. It use is associated with the development of viral mutants, the so-called YMDD mutants⁽²⁴⁾, which may develop in 16-32% of treated patients after one year of therapy^(21,22). Although these mutants often appear to be less virulent than the wild-type HBV, they have been associated with rapidly progressive liver disease in some patients. There are no data on the long-term benefits of lamivudine therapy.

The initial trigger for consideration of treatment is an abnormal ALT level. This is defined as an elevated ALT on at least three consecutive occasions over a three-month period. For interferon therapy the cut-off is twice the upper limit of normal, and for lamivudine therapy the cut off is 1.3 times the upper limit of normal.

A response to therapy is defined as loss of HBeAg, development of anti-HBe, clearance of HBV DNA from serum (by the bDNA, solution hybridization or hybrid capture assays), and normalization of the aminotransferases. This response is seen at the end or within 3-6 months of the end of interferon therapy, whereas on lamivudine therapy this response is usually seen while still on treatment.

The recommendations below apply only to patients > 18 years of age (see later for recommendations for children).

In the HBeAg-positive patient with abnormal ALT levels liver biopsy is Bly recommended, but not mandatory. Treatment is recommended regardless of the stage of fibrosis. However, the degree of fibrosis may influence the choice of therapy. Therapy may be with either interferon or lamivudine. Interferon is given at a dose of 27-35 mu weekly (5-6 mu daily or 9-10 mu TIW) for 16 weeks^(25-32). Lamivudine is given at a dose of 100 mg daily for 52 weeks⁽²¹⁾. Factors which should be considered in choosing an appropriate regimen include age, pre-treatment liver histology (amount of fibrosis), HBV viral load, and the potential side effects of the drugs⁽³³⁾. Other important considerations are the risk of development of mutant viruses, and its implications for future antiviral therapy, and the likelihood of pregnancy. Interferon therapy results in a delayed but enhanced clearance of HBsAg compared to untreated patients. Treated patients have a 5-year rate of clearance of HBsAg of 16% vs. 4% in the untreated group⁽¹⁵⁾. The data on the efficacy of lamivudine on clearance of HBsAg are not yet available.

In patients treated with interferon, development of anti-HBe with normalization of ALT is a good surrogate marker for clearance of HBV DNA. Therefore, monitoring with HBV DNA is not essential. In patients treated with lamivudine, clearance of HBV DNA is a marker of efficacy of treatment. The ALT response may be delayed or incomplete. Therefore, HBV DNA testing is essential to evaluate the response to therapy. In addition, an increase in ALT levels while on treatment may be a marker of the development of viral resistance to lamivudine, and should be followed by quantitative assessment of hepatitis B viral DNA levels.

In anti-HBe-positive patients with elevated ALT and detectable HBV DNA (pre-core mutant) therapy is more difficult. These patients do not respond well to interferon^(33,34). There are reports of extended treatment (6-12 months) interferon with sustained viral clearance. However, this remains controversial. Lamivudine treatment will suppress viral replication in these patients with improvement in ALT⁽³⁵⁾. However, the relapse rate is high once treatment is stopped. The consensus was that these patients should be treated in expert centers. Lamivudine therapy for patients who are anti-HBe-positive and HBV DNA-positive is still considered experimental.

The use of prednisone withdrawal prior to interferon therapy is contraindicated in the management of HBV-associated disease.

Interferon use in the immunosuppressed patient is not effective. In the setting of organ transplant up-regulation of HLA display may also enhance rejection. The optimal management of HBV-infected patients who are immunosuppressed has not yet been defined. These include patients who have been transplanted with an organ other than the liver, or who are being treated for autoimmune disease, or malignancy. Routine screening of patients undergoing organ transplantation is standard practice. At the present time there is insufficient information to support routine screening of other immunosuppressed patients for HBV infection. However, patients with risk factors should be screened. There is also insufficient information to recommend lamivudine anti-viral prophylaxis for immunosuppressed patients who are known to be hepatitis B carriers.

There are several case reports of the use of lamivudine in patients following renal transplantation and bone marrow transplantation, indicating that suppression of virus is possible, with resolution of the hepatitis^(36,37). However, there are no reports of long term outcome, and therefore no recommendations could be made for or against the use of lamivudine in immunosuppressed patients.

SPECIAL CASES

Hepatitis D Virus

Hepatitis D virus (HDV) is a small, defective RNA virus that requires the presence of a coating of hepatitis B surface antigen (HBsAg) for entry into and exit from the hepatocyte. HDV therefore may be acquired as a co-infection simultaneously with hepatitis B or as a super-infection in a patient who already is a carrier of HBV. Infection with hepatitis D usually causes an aggressive hepatitis⁽³⁸⁾.

Interferon at a dose of 9 Mu three times a week for a year can induce a virological response but this is only sustained in 21% of cases when assessed six months after completing therapy⁽³⁹⁾. Whether or not interferon therapy alters outcome in terms of morbidity or mortality is unknown.

Patients with active hepatitis D should be treated in expert centres.

Decompensated Hepatitis B Cirrhosis:

Patients with decompensated HBV-associated liver disease have a poor prognosis, particularly those with active viral replication. Low-dose interferon therapy in such patients (HBeAg-positive) may result in one-third responding with seroconversion and improvement in liver function, but some 20 to 70% of patients have significant complications from the treatment⁽⁴⁰⁾. Lamivudine appears to yield a better response rate, approaching 80%, without significant side effects (JP Villeneuve, personal communication). Whether or not this changes the overall outcome remains to be determined.

Patients with decompensated chronic hepatitis B are candidates for liver transplantation. Prior to the availability of anti-viral therapy re-infection of the graft was common. Chronic hepatitis B post-liver transplant causes aggressive disease and a rapid evolution to cirrhosis and liver failure. Many liver transplant centres are currently treating these patients with lamivudine before transplantation. Some patients may improve sufficiently to avoid or delay the need for transplantation. Timing of the introduction of lamivudine is important. Waiting times for liver transplantation are long. Prolonged use of lamivudine pre-transplant may allow the appearance of the YMDD-variant. These patients develop HBV DNA in serum once more, and may lose their opportunity for transplantation. Therefore the possibility of improved liver function must be balanced by the risk of emergence of viral resistance. Furthermore some patients in transplant studies experience a return of active hepatitis after developing YMDD-variant HBV; and may progress to liver failure and death. Loss or partial loss of lamivudine virologic efficiency in patients with advanced disease and/or immunosuppression may also be associated with more frequent or more severe disease progression than is observed in non-decompensated patients.

Low dose interferon is not recommended in decompensated hepatitis B cirrhosis. Patients with decompensated chronic hepatitis B should be referred to a liver transplant center, and treatment with lamivudine coordinated with the transplant center.

Extra Hepatic Manifestations of Hepatitis B:

Glomerulonephritis

Both acute and chronic HBV infections have been associated with membranoproliferative glomerulonephritis, in which immune complexes are deposited in the basement membrane of the glomerulus. Interferon therapy is very effective for hepatitis B-induced membranous glomerulonephritis, but response is poor in those with membranoproliferative glomerulonephritis^(41,42). In membranoproliferative glomerulo-nephritis HBeAg clearance occurs in the same proportion of patients as with standard indications for chronic liver hepatitis B. Corticosteroid therapy is contraindicated. There are no reports on the use of lamivudine in these patients.

The indications for interferon therapy in patients with hepatitis B-induced membranproliferative glomerulonephritis are the same as for hepatitis B patients without glomerulonephritis, i.e., the indication for treatment is the liver disease. In membranous glomerulonephritis, the renal disease per se is an indication for interferon therapy (because the response rate is so good). No recommendations for or against the use of lamivudine could be made.

Chronic Hepatitis B in Children

The risk of chronicity in hepatitis B infections in newborns and early childhood is high (see table 4). In addition, most infants and young children infected with hepatitis B have normal aminotransferases and are not candidates for therapy^(8,43).

Children who are first infected at ages over 7 years of age have a low risk of developing chronic disease. The prognosis of hepatitis B in children is generally good, cirrhosis and hepatocellular carcinoma are only rarely seen in the childhood years. Spontaneous seroconversion from HBeAg to anti-HBe antibody occurs in between 6-12% of infected children per year. In randomized controlled trials treatment with alpha-interferon in children resulted in 35% clearance of HBV DNA and HBeAg (11% in controls) and 7% clearance of HBsAg (1% in controls)⁽⁴⁴⁾. Optimal treatment is between 3-6 mu/m2 of interferon TIW for 6 months. The indications for treatment are similar to those in adults. There is no information on the use of lamivudine in children. Normally treatment should not begin before two years of age, because of the side effects of alpha-interferon. In older children the side effects of interferon appear to be well-tolerated. Weight loss can be offset by dietary interventions.

5. COMMENT

The treatment of chronic hepatitis B is complex, and is evolving rapidly. Only physicians who are familiar with the disease and its management should undertake to treat chronic hepatitis B. Appropriate therapy may require consultation with experts, because inappropriate therapy may limit future therapeutic options.

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