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Combination therapy of chronic viral hepatitis B with lamivudine and interferon: better than what?
572
Letters to the Editor
Combination therapy of chronic viral hepatitis B with lamivudine and interferon: better than what? To the Editor: In the September issue of the Journal of Hepatology, Barbaro et al. [1] published the results of a randomized trial aimed to assess the efficacy of lamivudine and interferon for treatment of chronic viral hepatitis B. The authors, as well as the accompanying editorial, conclude that the combination of lamivudine and interferon, used simultaneously, appears to be a therapeutic regimen that deserves consideration. However, we did not find in this study, nor in the available literature, any evidence to support this conclusion. In the study by Barbaro et al., combination of lamivudine and interferon produced better sustained response than lamivudine alone. The response was assessed, according to the recommended gold standard [2], by HBe seroconversion and undetectable level of DNA, 48 weeks after cessation of therapy. Before reaching any conclusion, the design of a study with a control arm treated with lamivudine alone has to be discussed. Indeed, although lamivudine use is approved as first line treatment, there is no available demonstration yet of its efficacy to achieve a sustained response in patients with chronic viral hepatitis B. In HBe positive patients results after cessation of a 1-year lamivudine treatment have been evaluated in four studies, including this one. In these four studies, sustained response, defined by the above-mentioned criteria, was obtained in 5, 17, 21 and 15% [1,3–5]. However, it must be kept in mind that previous randomized trials aimed to assess interferon efficacy showed that spontaneous response ranged from 0 to 38% in untreated patients [6]. The only study [4] comparing lamivudine and placebo failed to demonstrate any statistical difference between the two groups after a similar duration of treatment and follow up. In the three other studies no conclusion could be achieved, since they did not compare untreated patients with similar follow up. Others studies with duration of lamivudine treatment longer than 1 year did not analyse results after cessation of treatment, nor in control patients. In HBe negative patients there is no study comparing results of lamivudine with untreated patients followed after cessation of therapy. On the other hand, efficacy of interferon monotherapy has been demonstrated in many controlled trials and metaanalyses [6]. Therefore, the apparent superiority of the combination of lamivudine and interferon versus lamivudine alone in the Barbaro’s study could be assigned to interferon alone. The appropriate control arm should have been interferon alone, because, as a general rule in controlled trials, it is the only treatment with demonstrated efficacy. Such a comparison was done in only one previous trial with a follow-up after cessation of therapy [5]: although better results were observed with combination therapy than with interferon
alone at the end of the treatment, sustained response was not different (31 vs. 29%). Another similar randomized trial was performed, but results after cessation of therapy were not available [7]. It must be emphasized that the sustained response is the most clinically relevant result, and therefore, as is the case of hepatitis C virus, it should be the major criterion used in therapeutic trials. Unfortunately, some confusion about the true efficacy of lamivudine resulted from analyses of trials based mainly on favourable results obtained at the end of treatment. We agree that in cases of failure or contra-indication to interferon, the only alternative therapy at the present time is lamivudine that represents a highly valuable contribution to patients with severe liver disease. However, it must be realized that this is only a palliative treatment that, most of time, has to be used on a long-term basis, with the inconvenience of a limited duration of efficacy because of the emergence of mutations. Therefore, maximum efforts must be made in order to find a treatment that really cures the virus. Combination of antiviral and immunostimulant has often been quoted as the best way to achieve this goal. Strong short-term effect of lamivudine on viral replication, as well as immunostimulant effect of interferon, suggests that these two drugs do have a privileged place in this kind of combination. Before turning toward replacing or modifying this combination with other drugs, it must be explored whether different timings of administration could be more effective. We recently suggested that combination of the two treatments administered sequentially could be more appropriate than combination administered at the same time, but this remains to be confirmed [8]. Tony Andreani, Lawrence Serfaty, Olivier Chazouille`res, Raoul Poupon Service d’He´pato-Gastroenterologie, Hoˆpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Ce´dex 12, France
References [1] Barbaro G, Zechini F, Pellicelli AM, Francavilla R, Scotto G, Bacca D, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter randomized trial. J Hepatol 2001;35:406–411. [2] Lok AS, Heathcote J, Hoofnagle J. Management of hepatitis B: 2000summary of a workshop. Gastroenterology 2001;120:1828–1853. [3] Liaw YF, Leung NWY, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172–180. [4] Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman
Letters to the Editor Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263. [5] Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46:562–568. [6] Wong DKH, Cheung AM, O’Rourke K, Naylor CD, Detxky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis. Ann Intern Med 1993;119:312–323.
573
[7] Schiff ER, Karayalcin S, Grimm I, Perillo R, Dienstag J, Husa P, et al. A placebo controlled study of lamivudine and interferon alpha-2b in patients with chronic hepatitis B who previously failed interferon therapy. Hepatology 1998;28:388A. [8] Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouilleres O, Carbonell N, 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;34:573–577. PII: S0168 -8 278(02)00032 -6
Reply To the Editor: In reply to Andreani’s letter some remarks have to be pointed out. 1. Lamivudine use is approved as first line treatment in patients with chronic hepatitis B. Its therapeutic efficacy has been proved in caucasian patients with a difference statistically significant compared to placebo in terms of both histological and virological response [1,2]. 2. The apparent superiority of the combination therapy should not be assigned to interferon alone. Schalm et al. reported a similar rate of virological response in patients treated either with interferon or lamivudine monotherapy (19 vs. 18%), whereas patients treated with interferon alpha-2b and lamivudine in combination showed a greater rate of response (29%) [3]. These rates are in agreement with those reported in our study [4]. It is possible that the immunomodulating effect of interferon alpha-2b may enhance the antiviral effect of lamivudine in inducing a sustained virological response. 3. In our study 16% of patients treated with combination therapy and 12% of patients treated with lamivudine monotherapy were non-responders to a previous interferon alpha-2b therapy. Of them 63% of patients treated with combination therapy and 55% treated with lamivudine monotherapy showed a sustained virological response. 4. The rates of sustained virological response are associated with some specific clinical variables. In agreement with other trials [1,3], in our study population, the baseline viral load, the baseline serum ALT values, the baseline histological score and the estimated duration of the disease influenced significantly the rate of sustained virological response according to stepwise logistic regression analysis [4]. Moreover, in this analysis, the combination therapy was an independent variable associated with a sustained virological response (OR: 2.37; 95% CI: 0.99–5.77; P ¼ 0:032) [4]. 5. With reference to the study recently published by Serfaty et al. [5] we wish to point out: † In our study all enrolled patients were HBeAg positive; alpha-IFN is not indicated for patients infected with precore mutants (HBeAg negative). † Liver histology is a significant marker of biologic
improvement after every hepatic therapy, especially when the number of considered cases is low. In the Serfaty’s study liver biopsy was performed in only 7/ 14 patients. † The sequential administration of the two treatments suggested by authors is interesting. However, the results of their pilot study have to be confirmed by controlled clinical trials with a lower beta error, although the antiviral therapies for chronic hepatitis B will include in the near future combinations of antiviral drugs and recently tested immunomodulators (e.g. thymosin alpha1, BetaIFN, GammaIFN, IL-12) or a combination with vaccine strategies.
1
Giuseppe Barbaro 1, Giorgio Barbarini 2 Department of Emergency Medicine,University ‘La Sapienza’, Viale Anicio Gallo N. 63, 00174 Rome, Italy, 2 Department of Infectious and Tropical Diseases, Policlinico S.Matteo, University of Pavia, Pavia, Italy
References [1] Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263. [2] Dienstag JL, Schiff ER, Mitchell M, Casey DE, Gitlin N, Lissoos T, et al. Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy. Hepatology 1999;30:1082–1087. [3] Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46:562–568. [4] Barbaro G, Zechini F, Pellicelli AM, Francavilla R, Scotto G, Bacca D, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An italian multicenter, randomized trial. J Hepatol 2001;35:406–411. [5] Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouilleres O, Carbonell N, 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;34:573–577. PII: S0168 -8 278(02)00031 -4
Letters to the Editor
Combination therapy of chronic viral hepatitis B with lamivudine and interferon: better than what? To the Editor: In the September issue of the Journal of Hepatology, Barbaro et al. [1] published the results of a randomized trial aimed to assess the efficacy of lamivudine and interferon for treatment of chronic viral hepatitis B. The authors, as well as the accompanying editorial, conclude that the combination of lamivudine and interferon, used simultaneously, appears to be a therapeutic regimen that deserves consideration. However, we did not find in this study, nor in the available literature, any evidence to support this conclusion. In the study by Barbaro et al., combination of lamivudine and interferon produced better sustained response than lamivudine alone. The response was assessed, according to the recommended gold standard [2], by HBe seroconversion and undetectable level of DNA, 48 weeks after cessation of therapy. Before reaching any conclusion, the design of a study with a control arm treated with lamivudine alone has to be discussed. Indeed, although lamivudine use is approved as first line treatment, there is no available demonstration yet of its efficacy to achieve a sustained response in patients with chronic viral hepatitis B. In HBe positive patients results after cessation of a 1-year lamivudine treatment have been evaluated in four studies, including this one. In these four studies, sustained response, defined by the above-mentioned criteria, was obtained in 5, 17, 21 and 15% [1,3–5]. However, it must be kept in mind that previous randomized trials aimed to assess interferon efficacy showed that spontaneous response ranged from 0 to 38% in untreated patients [6]. The only study [4] comparing lamivudine and placebo failed to demonstrate any statistical difference between the two groups after a similar duration of treatment and follow up. In the three other studies no conclusion could be achieved, since they did not compare untreated patients with similar follow up. Others studies with duration of lamivudine treatment longer than 1 year did not analyse results after cessation of treatment, nor in control patients. In HBe negative patients there is no study comparing results of lamivudine with untreated patients followed after cessation of therapy. On the other hand, efficacy of interferon monotherapy has been demonstrated in many controlled trials and metaanalyses [6]. Therefore, the apparent superiority of the combination of lamivudine and interferon versus lamivudine alone in the Barbaro’s study could be assigned to interferon alone. The appropriate control arm should have been interferon alone, because, as a general rule in controlled trials, it is the only treatment with demonstrated efficacy. Such a comparison was done in only one previous trial with a follow-up after cessation of therapy [5]: although better results were observed with combination therapy than with interferon
alone at the end of the treatment, sustained response was not different (31 vs. 29%). Another similar randomized trial was performed, but results after cessation of therapy were not available [7]. It must be emphasized that the sustained response is the most clinically relevant result, and therefore, as is the case of hepatitis C virus, it should be the major criterion used in therapeutic trials. Unfortunately, some confusion about the true efficacy of lamivudine resulted from analyses of trials based mainly on favourable results obtained at the end of treatment. We agree that in cases of failure or contra-indication to interferon, the only alternative therapy at the present time is lamivudine that represents a highly valuable contribution to patients with severe liver disease. However, it must be realized that this is only a palliative treatment that, most of time, has to be used on a long-term basis, with the inconvenience of a limited duration of efficacy because of the emergence of mutations. Therefore, maximum efforts must be made in order to find a treatment that really cures the virus. Combination of antiviral and immunostimulant has often been quoted as the best way to achieve this goal. Strong short-term effect of lamivudine on viral replication, as well as immunostimulant effect of interferon, suggests that these two drugs do have a privileged place in this kind of combination. Before turning toward replacing or modifying this combination with other drugs, it must be explored whether different timings of administration could be more effective. We recently suggested that combination of the two treatments administered sequentially could be more appropriate than combination administered at the same time, but this remains to be confirmed [8]. Tony Andreani, Lawrence Serfaty, Olivier Chazouille`res, Raoul Poupon Service d’He´pato-Gastroenterologie, Hoˆpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75571 Paris Ce´dex 12, France
References [1] Barbaro G, Zechini F, Pellicelli AM, Francavilla R, Scotto G, Bacca D, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multicenter randomized trial. J Hepatol 2001;35:406–411. [2] Lok AS, Heathcote J, Hoofnagle J. Management of hepatitis B: 2000summary of a workshop. Gastroenterology 2001;120:1828–1853. [3] Liaw YF, Leung NWY, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology 2000;119:172–180. [4] Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman
Letters to the Editor Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263. [5] Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46:562–568. [6] Wong DKH, Cheung AM, O’Rourke K, Naylor CD, Detxky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis. Ann Intern Med 1993;119:312–323.
573
[7] Schiff ER, Karayalcin S, Grimm I, Perillo R, Dienstag J, Husa P, et al. A placebo controlled study of lamivudine and interferon alpha-2b in patients with chronic hepatitis B who previously failed interferon therapy. Hepatology 1998;28:388A. [8] Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouilleres O, Carbonell N, 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;34:573–577. PII: S0168 -8 278(02)00032 -6
Reply To the Editor: In reply to Andreani’s letter some remarks have to be pointed out. 1. Lamivudine use is approved as first line treatment in patients with chronic hepatitis B. Its therapeutic efficacy has been proved in caucasian patients with a difference statistically significant compared to placebo in terms of both histological and virological response [1,2]. 2. The apparent superiority of the combination therapy should not be assigned to interferon alone. Schalm et al. reported a similar rate of virological response in patients treated either with interferon or lamivudine monotherapy (19 vs. 18%), whereas patients treated with interferon alpha-2b and lamivudine in combination showed a greater rate of response (29%) [3]. These rates are in agreement with those reported in our study [4]. It is possible that the immunomodulating effect of interferon alpha-2b may enhance the antiviral effect of lamivudine in inducing a sustained virological response. 3. In our study 16% of patients treated with combination therapy and 12% of patients treated with lamivudine monotherapy were non-responders to a previous interferon alpha-2b therapy. Of them 63% of patients treated with combination therapy and 55% treated with lamivudine monotherapy showed a sustained virological response. 4. The rates of sustained virological response are associated with some specific clinical variables. In agreement with other trials [1,3], in our study population, the baseline viral load, the baseline serum ALT values, the baseline histological score and the estimated duration of the disease influenced significantly the rate of sustained virological response according to stepwise logistic regression analysis [4]. Moreover, in this analysis, the combination therapy was an independent variable associated with a sustained virological response (OR: 2.37; 95% CI: 0.99–5.77; P ¼ 0:032) [4]. 5. With reference to the study recently published by Serfaty et al. [5] we wish to point out: † In our study all enrolled patients were HBeAg positive; alpha-IFN is not indicated for patients infected with precore mutants (HBeAg negative). † Liver histology is a significant marker of biologic
improvement after every hepatic therapy, especially when the number of considered cases is low. In the Serfaty’s study liver biopsy was performed in only 7/ 14 patients. † The sequential administration of the two treatments suggested by authors is interesting. However, the results of their pilot study have to be confirmed by controlled clinical trials with a lower beta error, although the antiviral therapies for chronic hepatitis B will include in the near future combinations of antiviral drugs and recently tested immunomodulators (e.g. thymosin alpha1, BetaIFN, GammaIFN, IL-12) or a combination with vaccine strategies.
1
Giuseppe Barbaro 1, Giorgio Barbarini 2 Department of Emergency Medicine,University ‘La Sapienza’, Viale Anicio Gallo N. 63, 00174 Rome, Italy, 2 Department of Infectious and Tropical Diseases, Policlinico S.Matteo, University of Pavia, Pavia, Italy
References [1] Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256–1263. [2] Dienstag JL, Schiff ER, Mitchell M, Casey DE, Gitlin N, Lissoos T, et al. Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy. Hepatology 1999;30:1082–1087. [3] Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000;46:562–568. [4] Barbaro G, Zechini F, Pellicelli AM, Francavilla R, Scotto G, Bacca D, et al. Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An italian multicenter, randomized trial. J Hepatol 2001;35:406–411. [5] Serfaty L, Thabut D, Zoulim F, Andreani T, Chazouilleres O, Carbonell N, 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;34:573–577. PII: S0168 -8 278(02)00031 -4