The Body Covers: The 66th Annual Scientific Meeting of the American College of Gastroenterology
October 23, 2001
The endpoints of treatment according to Dr. Schiff are the following:
Of these, goals one through three are usually achieved. To increase the likelihood of a sustained response, one would like to see "e antigen seroconversion," defined as loss of HBeAG and appearance of HBeAB. Traditionally this has been the endpoint of therapy; once this occurs, therapy may be discontinued. Loss of HBsAG is exceedingly rare during treatment, but usually occurs one to five years after a patient achieves e antigen seroconversion.
Two agents are currently available for the treatment of chronic hepatitis B infection: interferon and lamivudine. Interferon therapy is more toxic and less tolerated than lamivudine, but the duration of therapy is shorter (four to six months vs. one to three years) and the response rate is similar. Ideal candidates for treatment with interferon are those with no cirrhosis, who have ALT levels at least twice the upper limit of normal, are HBeAG positive and HBV-DNA positive. Those who have normal ALT levels, very high viral load or are infected with HBeAG-negative variants of the hepatitis B virus are less likely to respond to interferon.
Dr. Schiff stated that lamivudine is a very attractive drug to treat hepatitis B infection because it is given orally and has virtually no side effects. Results after one year of lamivudine therapy show e-antigen loss in 55% of patients who had elevated ALT levels prior to treatment. In comparison, e-antigen loss occurs in only 0% to 5% of those with normal ALT levels prior to therapy. Treatment with lamivudine for longer than one year increases response rates. In patients with elevated ALT levels prior to treatment, three, four and five years of lamivudine therapy achieve e-antigen loss in 55%, 73% and 77% of patients respectively.
Increasing duration of therapy with lamivudine carries the risk of lamivudine-resistant mutants, also known as YMDD mutants. Appearance of these escape mutants should be suspected in patients who became HBV-DNA negative on therapy and then become positive again despite continuation of therapy. After one year of lamivudine therapy, the incidence of escape mutants is 24%; this rises to 38% after two years, 49% after three years and 66% after four years of lamivudine therapy.
The YMDD mutants appear to be "defective" and neither replicate as fast nor are as virulent as the "wild" strain. For this reason, Dr. Schiff recommends that when a lamivudine-escape mutant is detected, lamivudine therapy should be continued to prevent relapse of the more virulent "wild" strain.
Once treatment is started, it is often difficult to decide when to stop. In general, a minimum of one year of treatment is recommended with lamivudine. Treatment should be stopped once a patient has lost HBeAG and has developed HBeAB, as confirmed on two different occasions at least three to six months apart. Dr. Schiff stressed that for patients infected with the e-antigen negative strain of hepatitis B (also known as the pre-core mutant), e-antigen loss cannot be used as an endpoint. In this case, discontinuation of therapy may be considered in those patients who have had low HBV-DNA levels (<10,000 copies) on two or more occasions three to six months apart.
A more difficult scenario according to Dr. Schiff is what to do if the HBeAG is negative, but the HBeAB is also negative. It is not clear if these patients will remain in remission if treatment is stopped. Dr. Schiff recommended that if the HBV-DNA is low (<10,000) on 2 or more occasions, treatment may be discontinued and the patient monitored for relapse.
During treatment, Dr. Schiff recommends that patients be followed with ALT determinations every three months, HBV-DNA levels every six months, HBeAG and HBeAB determination at twelve months, and then every six months thereafter. For patients infected with the pre-core (e-antigen negative) mutant, there is no point in following HBeAG and HBeAB. For those patients, the ALT should be monitored every three months, and the HBV-DNA level every six months.
After treatment is completed, Dr. Schiff recommends follow up with ALT levels every three months. If the ALT becomes elevated, the HBeAG should be measured -- if positive, consider re-starting antiviral therapy. If the HBeAG is negative despite elevated ALT levels, then an evaluation to exclude other causes of ALT elevation is recommended.
Hepatitis B during pregnancy poses a dilemma. Transmission to the child is a concern, but the safety of interferon and lamivudine during pregnancy is unknown. For this reason, treatment with these medications during pregnancy is not recommended. Some investigators have used lamivudine during the last trimester of pregnancy to reduce viral load and decrease the likelihood of perinatal transmission of hepatitis B to the child and they have noted no adverse effects on the newborn child. These results are very preliminary and should not be taken as evidence of the safety of lamivudine use during pregnancy.
Extensive research is taking place in the development of other antiviral agents for the treatment of hepatitis B infection. One or more of these agents is likely to become available in the near future. Some of the drugs under development are effective against lamivudine-resistant strains of the hepatitis B virus. Dr. Schiff stressed that those patients who develop lamivudine-resistant strains should continue therapy with lamivudine and await availability of newer agents that may be active against those strains.
Dr. Schiff summarized the current status of the treatment of hepatitis B by stating that two effective drugs are currently available: interferon and lamivudine. Which one to use depends on the severity of the liver disease and the pre-treatment characteristics including the presence or absence of cirrhosis, the severity of the liver disease, the ALT level and the presence of e-antigen mutants. For patients with cirrhosis or advanced liver disease, lamivudine is definitely the agent of choice -- interferon is relatively contraindicated in that situation. For patients with elevated ALT levels, low HBV-DNA and HBeAG positive infection, interferon would be the drug of choice if no cirrhosis or advanced liver disease were present.
The role of combination therapy with interferon and lamivudine is not clear. Most studies have failed to show an advantage to combination therapy and at present it is not recommended outside of clinical trials.
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