Superior Results Using Antiviral Agents Before Pegylated Interferon to Treat Hepatitis B

Several nucleoside/nucleotide analog antiviral agents are active against hepatitis B virus (HBV), including lamivudine (Epivir-HBV), adefovir (Hepsera), entecavir (Baraclude), telbivudine (Tyzeka), and tenofovir (Viread; not yet approved for this indication). The immunomodulators interferon alfa-2b and pegylated interferon alfa-2a are also approved therapies for chronic hepatitis B.

Studies have shown that lower pre-treatment HBV viral load is associated with better treatment response. As reported in the January 2007 American Journal of Gastroenterology, researchers from India conducted a study to assess whether use of lamivudine to lower HBV DNA levels before adding an immunomodulator is more effective than using an immunomodulator from the outset.

The study included 63 treatment-naive HBeAg-positive chronic hepatitis B patients with alanine aminotransferase (ALT) levels > 1.2 x the upper limit of normal. Participants received either 100 mg/day lamivudine (n = 36) or placebo (n = 27) for 4 weeks, followed by 1.0 mcg/kg/week pegylated interferon for 24 additional weeks.

Patients were followed for 24 weeks after completion of therapy, and biochemical and virological responses were assessed at weeks 4, 28, and 52 using an intention-to-treat analysis.

Results

• At week 4, the mean log changes in HBV DNA from baseline were 1.2186 in the lamivudine group and 0.2594 in the placebo group (P = 0.032).

• At week 28, 16 patients (44.4%) in the lamivudine group and 8 (29.6%) in the placebo group had undetectable HBV DNA (P = 0.298).

• At week 28, HBeAg loss occurred in 15 subjects (41.7%) in the lamivudine group and 8 (29.6%) in the placebo group (P = 0.43).

• 6 months after treatment (week 52), 18 patients (50%) who received lamivudine and 4 (14.8%) who received placebo had sustained undetectable HBV DNA (P = 0.028).

• HBeAg loss was maintained in 14 (38.9%) and 4 (14.8%) patients, respectively (P = 0.05).

• In terms of biochemical response, 10 patients (27.8%) in the lamivudine arm and 5 (18.5%) in the placebo group had normalized ALT at week 28 (P = 0.552).

• At week 52, the respective normal ALT figures were 13 (36.1%) and 5 (18.5%) (P = 0.159).

• There was a significant correlation among HBeAg loss, appearance of anti-HBe antibodies, and undetectable HBV DNA levels at week 28 (P = 0.008) and week 52 (P < 0.001) and HBV DNA levels at week 4.

Conclusion

In conclusion, the authors wrote, "The strategy of using an antiviral [agent] initially to decrease HBV DNA levels before adding an immunomodulatory agent leads to improved sustained virological response as compared with using [an] immunomodulator from the start."

In their discussion, they noted that past studies have not shown that simultaneous therapy using a combination of lamivudine plus pegylated interferon works better than either drug used alone.

"The results of the present study clearly show that the strategy of using a potent antiviral such as lamivudine before adding an immunomodulator is a novel approach for improving the efficacy of the treatment of chronic hepatitis B," they wrote, suggesting that, "This approach, besides giving a better response compared with [pegylated interferon] alone, would also reduce the frequency of antiviral resistance associated with the use of long-term antivirals."

Editorial

In an accompanying editorial, Man-Fung Yuen and Ching-Lung Lai of the University of Hong Kong presented an overview of simultaneous versus sequential therapy for chronic hepatitis B.

“Various regimens of combination or sequential therapy using nucleoside/nucleotide analogues and interferon-alfa have been tried for the treatment of chronic hepatitis B,” they summarized. “To date, combination therapy of two [nucleoside/nucleotide analogues] and of [interferon-alfa] and [nucleoside/nucleotide analogues] fails to achieve extra viral suppression. Sequential therapy with lamivudine followed by interferon-alfa seems to have better sustained virologic response.”

However, they added, the long-term benefits of this approach remains to be determined.

“[E]ven if the better virologic and biochemical responses shown with sequential therapy are confirmed with larger studies, the question still remains as to whether achieving HBeAg seroconversion and partial reduction of HBV DNA by treatment of a limited duration can reduce the long-term complications of cirrhosis and hepatocellular carcinoma,” they wrote. “It has been shown that with the cessation of interferon-alfa treatment, the median HBV DNA levels of the treated patients return to the pretreatment levels. With the return of viral replication, these patients are still at a considerable risk for the development of complications of cirrhosis and hepatocellular carcinoma.”

“On the other hand,” they continued, “it has been proven that long-term viral suppression with lamivudine can successfully reduce or delay the development of cirrhosis and hepatocellular carcinoma in spite of the development of lamivudine-resistant virus. With the newer [nucleoside/nucleotide analogues], which can achieve better viral suppression, lower or negligible resistant profile, and minimal side effects, long-term suppression of HBV by these agents may become the mainstay treatment strategy.”

G.B. Pant Hospital, New Delhi; Dayanand Medical College and Hospital, Ludhiana; Sir Ganga Ram Hospital, New Delhi; Bombay Hospital, Mumbai; Peerless Hospital and B.K. Roy Research Centre, Kolkata; Post Graduate Institute of Medical Education and Research, Chandigarh; Gandhi Medical College and Associated Hospital, Bhopal, M.P.; Life Line Hospital, Jalandhar; Pushpawati Singhania Research Institute, Sheikh Sarai, New Delhi; Jahangir Hospital and Medical Centre in Association with Apollo Hospitals, Pune; Railway Hospital, New Delhi, India

01/26/07

References

S Kumar Sarin, A Sood, M Kumar, and other (National Collaborative Group on Hepatitis B, India). Effect of Lowering HBV DNA Levels by Initial Antiviral Therapy Before Adding Immunomodulator on Treatment of Chronic Hepatitis B. American Journal of Gastroenterology 102(1): 96-104. January 2007.

M-F Yuen and C-L Lai. Combination Therapy for Chronic Hepatitis B: Simultaneous or Sequential? American Journal of Gastroenterology 102(1): 105-106. January 2007.