Combination Therapy with Intron A Plus Epivir-HBV

拉米夫定

12-Month Combination Therapy with Intron A Plus Epivir-HBV Is Effective As Initial Treatment of Patients with Chronic Hepatitis B

Researchers in Turkey studied the use of prolonged synchronous combination therapy with Intron A (interferon (IFN)-alfa 2b) and Epivir-HBV (lamivudine) with the use of IFN alfa-2b monotherapy in patients with untreated hepatitis B e antigen (HBeAg) positive chronic hepatitis B virus (HBV) infection.
Thirty-three patients received therapy with lamivudine (100 mg daily) and IFN alfa-2b (10 million U 3 times per week) for 12 months; 16 patients received IFN alfa-2b alone (10 million U 3 times per week for 12 months).

The primary end point was sustained suppression of HBV DNA and HBeAg seroconversion, which was observed in 15 (45%) of 33 patients treated with combination therapy and in 3 (19%) of 16 patients treated with monotherapy
(P = .133). Both therapeutic regimens were well tolerated.

Combination therapy increased the rate of sustained suppression of HBeAg and resulted in significant improvement in Knodell histologic activity index scores, compared with monotherapy. However, there was no significant difference in rates of sustained suppression between the 2 groups at the end of follow-up.

Discussion

Until now, the short-term use of IFN-alfa alone or in combination with lamivudine has not been reported to be effective for treatment of chronic hepatitis B infection. Data on combination therapy are few and are restricted to studies of courses of treatment of 4 6 months' duration. Moreover, the 4 published trials of combination therapy provide little support for the use of the IFN alfa lamivudine combination.

Also, the design of the initial studies of combination therapy may not have been optimal for showing the full effects of combination therapy. On the other hand, in many controlled trials, it has been shown that there was an increased clearance of both HBeAg and HBV DNA after prolonged IFN alfa therapy, compared with treatment for the standard period of 16 weeks.

The current study demonstrates that administration of combination therapy for 12 months to HBeAg-positive patients induces rapid inhibition of viral replication, normalization of liver function, and histologic evidence of improvement in liver disease.

The study found a high rate of HBeAg seroconversion (54% of patients) after 12 months of combination therapy, a finding that is not in accordance with the seroconversion rate of 29% after 16 weeks of combination therapy reported by Schalm et al., nor with the seroconversion rate of 33% after 24 weeks of therapy reported by Barbaro et al.

The enhanced efficacy of prolonged treatment was so pronounced that, in future treatment regimens that include combination therapy, prolongation of therapy for up to 52 weeks should be considered.

Unfortunately, despite the impressive HBeAg seroconversion rates achieved at month 24, the difference in sustained response rates between the 2 groups remained non-significant at that time. Viral persistence was observed after anti-HBeAg seroconversion in 3 patients in the combination therapy group, and this influenced the level of significance.

Histologic evidence of improvement in liver disease is a significant marker of biologic improvement after therapy, especially when the number of patients is low. In the present study, combination therapy significantly reversed necroinflammatory activity, compared with IFN alfa monotherapy. This large benefit occurred regardless of patients' HBeAg seroconversion status and treatment response status in the combination therapy group.

The 84% rate of improvement in hepatic inflammation observed in these study patients was higher than the rate of 46% reported by Barbaro et al., the rate of 56% after 1 year of lamivudine therapy reported by Lai et al., and the rate of 54% after a 24-month course of IFN alfa therapy reported by Lampertico et al. Adding a prolonged course of IFN alfa therapy to a course of lamivudine therapy seems to double the substantial beneficial effect of lamivudine on liver disease.

In the present study, both treatment regimens were safe and well tolerated, and the efficacy of concomitant IFN alfa and lamivudine therapy appears to be better than that of IFN alfa monotherapy and the previously studied sequential administration of IFN and lamivudine.

Several factors may possibly explain this difference:

(1) A synchronous combination regimen is superior to a sequential combination regimen;

(2) A prolonged course of combination therapy is more effective than shorter course of combination therapy;

(3) Combination therapy is better than monotherapy; and

(4) Patients enrolled in this study tended to have a higher mean ALT levels, a higher HAI score, and a lower stage of fibrosis.

The authors conclude, "We conclude that IFN alfa and lamivudine combination therapy, in combination with a longer duration of therapy, appears to be a therapeutic regimen and might be considered for the initial treatment of patients with chronic hepatitis B."