Re-Treatment of Patients With Anti-HBe-Positive Chronic Hepatitis B Who Relaps

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Discussion

In patients with HBeAg-negative/HBV-DNA-positive chronic hepatitis B (pre-core mutant), a 12-month course of lamivudine monotherapy provides promising on-therapy results, but poor efficacy off therapy due to virological and biochemical relapses.[7] For this reason, long-term therapy with lamivudine has been recommended in order to suppress viral replication and control liver disease.[6] The major shortcoming of this approach is the development of resistance, which limits efficacy in a high proportion of patients. In a previous controlled study, we demonstrated that the emergence of lamivudine-resistant mutations can be prevented by combining lamivudine with interferon: no patient receiving combination therapy developed YMDD mutants as long as therapy was administered, whereas 19% of patients treated with lamivudine alone experienced a virological breakthrough due to YMDD mutants during the 12-month course of monotherapy. However, this beneficial effect was lost after discontinuation of therapy, when marked increases in HBV-DNA and serum alanine transaminase levels were observed in all patients.[12] Although it remains to be ascertained whether prolonging combination therapy for more than 12 months could maintain the response and avoid the appearance of mutants, dual therapy with lamivudine and interferon rather than lamivudine monotherapy alone may be suggested as a first-line therapeutic option for anti-HBe-positive patients with chronic hepatitis B.

At present, therapeutic options for anti-HBe-positive patients with chronic hepatitis B who develop resistance to lamivudine, and for those who relapse after the discontinuation of lamivudine, are being evaluated. Adefovir has been proven to be effective in both instances;[13] however, at the time of initiation of the present study, this drug was available only in the liver transplant setting and interferon had been temporarily withdrawn from prescription by Italian health authorities. Therefore, we were forced to rely on lamivudine. In the present study, we evaluated the efficacy of a second lamivudine course in anti-HBe-positive patients who had failed a previous course.

Our study demonstrated that the 6- and 12-month virological responses were 94.4% and 66.7%, respectively, which are comparable with the 81.7% and 65% response rates reported in the largest published trial by Tassopoulos et al.[7] For the first time, these results establish the benefit of re-treatment with lamivudine monotherapy for anti-HBe-positive patients.

A crucial issue is how long re-treatment with lamivudine monotherapy should be maintained in this setting. In the industry-sponsored multi-national ongoing study of extended lamivudine therapy in anti-HBe-positive patients naive to this drug, the response declined from 67% at 6 months, to 51%, 34% and 29% after 12, 24 and 36 months, respectively.[16] In four additional clinical studies, approximately 30% of patients maintained a full virological and biochemical response after 3 years of therapy.[17-20] The observed 60% response rate at 24 months of therapy found in our study, together with the actuarial 39% response rate at 42 months, are similar to the results obtained in published series and establish the benefit of long-term re-treatment with lamivudine monotherapy in anti-HBe-positive patients who have failed a previous course of treatment with the drug. In our trial, responders are still on lamivudine therapy and are scheduled to undergo repeat liver biopsy after 5 years of continuous therapy in order to evaluate the benefits of continuing lamivudine therapy. Moreover, long-term re-treatment was associated with the development of resistance and a loss of response in 21 of the 36 enrolled patients after 6-38 months of lamivudine monotherapy.

Interestingly, the first appearance of mutants in patients from Group 1 was delayed by 6 months compared with that in patients from Group 2. In addition, at 12 and 24 months of re-treatment, the rates of breakthrough were 25% and 37.5%, respectively, in Group 1, and 36.8% and 57.9%, respectively, in Group 2; by Kaplan-Meier analysis, breakthroughs at month 42 of re-treatment were 42% in Group 1 and 82% in Group 2. These differences, although not significant, probably due to the small sample size, underline the beneficial effect of combination therapy in preventing or delaying the emergence of drug-resistant mutants.

Only one patient in this study did not respond; in this patient, the presence of subpopulations of YMDD mutants at low levels in the serum sample obtained before treatment was shown by INNO LiPA HBV-DR assay, but not by direct sequencing. This observation confirms the clinical importance of methods which are more sensitive than direct DNA sequencing for the detection of mixed viral populations and are especially useful for predicting the response to therapy in patients already exposed to lamivudine.

In conclusion, in patients with anti-HBe-positive chronic hepatitis B with a relapse after lamivudine therapy, re-treatment is capable of controlling viral replication. This effect is maintained for the initial 12 months of therapy, after which a high rate of viral resistance limits the long-term efficacy of this therapeutic strategy.

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