Canadian Association for the Study of the Liver
Therapy of chronic hepatitis B
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 (recommendations for children).
In the HBeAg-positive patient with abnormal ALT levels liver biopsy is strongly 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.