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Combination Therapy for Chronic Hepatitis B: Simultaneous or Sequential? EDITORIAL
  Note From Jules Levin: certainly what is needed are studies of different combinations of new oral HBV drugs and peginterferon looking at sequential and simultaneous therapy, as well as combination of 2 oral HBV agents such as tenofovir plus entecavir.
The American Journal of Gastroenterology
Volume 102 Issue 1 Page 105 - January 2007
Man-Fung Yuen, M.D., Ph.D.11Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, and Ching-Lung Lai, M.D.11Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong 1Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
Various regimens of combination or sequential therapy using nucleoside/nucleotide analogues (NAs) and interferon-alfa (IFN-α) have been tried for the treatment of chronic hepatitis B. To date, combination therapy of two NAs and of IFN-α and NAs fails to achieve extra viral suppression. Sequential therapy with lamivudine followed by IFN-α seems to have better sustained virologic response. However, the long-term beneficial effect of using this approach remains to be defined.
(Am J Gastroenterol 2007;102:105-106)
Unlike the treatment of chronic hepatitis C, total eradication of the hepatitis B virus (HBV) is still elusive. There are two groups of agents for the treatment of chronic hepatitis B (CHB): nucleoside/nucleotide analogues (NAs) and interferon-alfa (IFN-α). Many studies have been performed to determine whether combination of various drugs for CHB can; (a) synergistically increase the efficacy; (b) minimize side effects; and (c) reduce the rate of emergence of drug-resistant mutations. One can combine two or three NAs, or IFN-α (conventional or pegylated) with NAs.
Disappointingly, nearly all trials with different combinations of NAs show no added advantage in HBV DNA reduction compared to that achieved by the more potent of the two agents used alone (1-3). The chance of emergence of drug-resistant mutations is reduced with some of these combinations, especially if the study is extended beyond 1 yr.
Combining IFN-α with NAs seems to be a logical approach alternative, because IFN-α and NAs act through different mechanisms for the control of CHB. There are two differing strategic plans for such combination. First, combination of IFN-α and lamivudine is given to patients at the same time. Secondly, lamivudine is given to patients several weeks before the administration of IFN-α.
In the studies using lamivudine and IFN-α simultaneously, the IFN-α treatment is usually given for 16-24 wk or 48-52 wk. However, the lamivudine is also given for only 48-52 wk and then stopped. These trials consistently show that there is no difference observed in the HBV DNA reduction between combination therapy and lamivudine or IFN-α monotherapy after 6 months of cessation of treatment (4-7). Some trials, however, show that addition of IFN-α reduces the chance of emergence of lamivudine-resistant mutations (8, 9). This advantage may not be of great significance, because the newer NAs such as adefovir and entecavir are associated with a much lower rate of drug-resistant mutations. However, the major fault in the design of all these trials that renders their results of dubious significance is that lamivudine is stopped after 1 yr of therapy. In the first place, this is not consistent with the usual clinical practice in the use of NAs, it being well established that for durable response, NAs should not be stopped until 6-12 months after stable HBeAg seroconversion for HBeAg-positive patients and should be maintained on a long-term basis for HBeAg-negative patients. In the second place, at the end of combination therapy with lamivudine and IFN-α, the different trials consistently show that combination is better than either lamivudine or IFN-α monotherapy (10-12). Moreover, lamivudine monotherapy is also superior to IFN-α monotherapy. The failure to demonstrate that combination therapy or lamivudine monotherapy is superior to IFN-α monotherapy after cessation of treatment is attributable to the rebound in HBV DNA that occurs when lamivudine is stopped at 48-52 wk. For more meaningful investigation of the efficacy of combination therapy with NAs and IFN-α in the future, it is important that the NAs should be continued beyond the cessation of IFN-α according to the criteria established for the use of NAs mentioned above.
In the study conducted by Sarin and his colleagues published in the current issue of the Journal (13), a novel sequential approach is adopted. They find that, when compared with pegylated IFN-α monotherapy, lamivudine given 4 wk before 24 wk of pegylated IFN-α treatment was associated with a better sustained response with a higher proportion of patients with undetectable HBV DNA levels and sustained HBeAg loss 24 wk after off-treatment, though these differences were not shown at the end of treatment. Serfaty and his colleagues also show similar findings, that pretreatment with 20 wk of lamivudine before IFN-α is associated with a better-sustained virologic response (14). Pretreatment HBV DNA level has been shown to an important predictive factor for treatment response with IFN-α. Lowering the HBV DNA level by lamivudine before administering IFN-α is a logical approach in achieving a better response rate. In addition, there may also be a partial restoration of the immune response after HBV DNA reduction by short-term lamivudine therapy.
However, even 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. It has been shown that with the cessation of IFN-α treatment, the median HBV DNA levels of the treated patients return to the pretreatment levels (10-12). With the return of viral replication, these patients are still at a considerable risk for the development of complications of cirrhosis and hepatocellular carcinoma. In fact, a long-term follow-up of Asian patients (i.e., patients who acquire hepatitis B infection at birth or early childhood) who received conventional IFN-α for 16-24 wk does not show a reduction in the development of complications of cirrhosis and hepatocellular carcinoma (15). Unless the use of IFN-α, conventional or pegylated, is associated with a sustained long-term viral suppression maintaining the HBV DNA levels to at least less than 104 copies/mL, its efficacy in reducing the development of long-term complications has yet to be proven for Asian patients. On the other hand, 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 (16, 17). With the newer NAs, 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. One looks forward to future studies of combination therapy using different NAs, which can maintain a maximal suppression of HBV DNA with the lowest rate of emergence of drug resistance during long-term therapy.
1.Fung J, Yuen JCH, Wong DKH, et al. Adefovir dipivoxil monotherapy and combination therapy with lamivudine in the treatment of chronic hepatitis B in an Asian population. Antivir Ther 2006 [in press].
2.Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129:528-36. CrossRef, Medline, ISI
3.Lim SG, Krastev Z, Ng TM, et al. Randomized, double-blind study of emtricitabine (FTC) plus clevudine versus FTC alone in treatment of chronic hepatitis B. Antimicrob Agents Chemother 2006;50:1642-8. CrossRef, Medline, ISI
4.Sypsa VA, Mimidis K, Tassopoulos NC, et al. A viral kinetic study using pegylated interferon alfa-2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative. Hepatology 2005;42:77-85. CrossRef, Medline, ISI
5.Yurdaydin C, Bozkaya H, Cetinkaya H, et al. Lamivudine vs lamivudine and interferon combination treatment of HBeAg(-) chronic hepatitis B. J Viral Hepat 2005;12:262-8. Synergy, Medline, ISI
6.Akarca US, Ersoz G, Gunsar F, et al. Interferon-lamivudine combination is no better than lamivudine alone in anti-HBe-positive chronic hepatitis B. Antivir Ther 2004;9:325-34. Medline, ISI
7.Hasan F, al-Khaldi J, Asker H, et al. Treatment of chronic hepatitis B with the sequential administration of interferon and lamivudine. Hepatogastroenterology 2003;50:2040-2. Medline, ISI
8.Jang MK, Chung YH, Choi MH, et al. Combination of alpha-interferon with lamivudine reduces viral breakthrough during long-term therapy. J Gastroenterol Hepatol 2004;19:1363-8. Synergy, Medline, ISI
9.Santantonio T, Niro GA, Sinisi E, et al. Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients: A controlled pilot study. J Hepatol 2002;36:799-804. CrossRef, Medline, ISI
10.Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: A randomised trial. Lancet 2005;365:123-9. CrossRef, Medline, ISI
11.Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-95. CrossRef, Medline, ISI
12.Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17. CrossRef, Medline, ISI
13.Sarin SK, Sood A, Kumar M, et al. Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic hepatitis B. Am J Gastroenterol 2006 [in press].
14.Serfaty L, Thabut D, Zoulim F, et al. Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: Results of a pilot study. Hepatology 2001;34:573-7. CrossRef, Medline, ISI
15.Yuen MF, Hui CK, Cheng CC, et al. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: The effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology 2001;34:139-45. CrossRef, Medline, ISI
16.Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-31. CrossRef, Medline, ISI
17.Yuen MF, Seto WK, Chow DHF, et al. Long-term beneficial outcome of Chinese asymptomatic patients with HBeAg-positive chronic hepatitis B on continuous lamivudine therapy: 7-year experience. Hepatology 2005;42(suppl 1):583A.
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