- Email: [email protected]
Entecavir versus lamivudine for HBeAg positive and negative chronic hepatitis B
Journal of Hepatology 45 (2006) 457–460 www.elsevier.com/locate/jhep
Journal Club Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Entecavir versus lamivudine for HBeAg positive and negative chronic hepatitis B Pietro Lampertico* Division of Gastroenterology, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli, Regina Elena, University of Milan, Via Francesco Sforza 35, 20122 Milano, Italy
Entecavir versus lamivudine for patients with HBeAgnegative chronic hepatitis B. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70%), as compared with 174 of 287 such patients in the lamivudine group (61%, P = 0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerasechain-reaction assay (90% vs. 72%, P < 0.001) and normalization of alanine aminotransferase levels (78% vs. 71%, P = 0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a
*
Tel.: +390255035432. E-mail address: [email protected].
base-10 scale] copies per milliliter, P < 0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.). [Abstract reproduced by permission of N Engl J Med 2006;354:1011–1020] A comparison of entecavir and lamivudine for HBeAgpositive chronic hepatitis B. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. BACKGROUND: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). METHODS: In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level.
0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.06.012
458
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
RESULTS: Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, P = 0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67% vs. 36%, P < 0.001) and normalization of alanine aminotransferase levels (68% vs. 60%, P = 0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P < 0.001). HBeAg seroconversion occurred in 21% of entecavir-treated patients and 18% of those treated with lamivudine (P = 0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035633.). [Abstract reproduced by permission of N Engl J Med 2006;354:1001–1010]
Lai and co-workers recently published a randomized controlled trial comparing the administration of 0.5 mg/ day entecavir and 100 mg/day lamivudine for the treatment of nucleoside-naı¨ve HBeAg-negative chronic hepatitis B [1]. After 52 weeks of treatment, significantly more patients in the entecavir than in lamivudine group achieved undetectable HBV DNA by PCR assay (90% vs. 72%), normalized ALT (78% vs. 71%) and improved histology (70% vs. 61%). Moreover, virological rebound and genotypically confirmed drug resistance occurred less frequently in the former than in the latter group (2% vs. 8%, 0% vs. 6%). The safety profile was similar in both groups. This is an important study since it highlights how far the antiviral treatment for hepatitis B has come, further improving the already excellent efficacy and safety profile of lamivudine and adefovir towards previously unthinkable response rates. A 90% virological response coupled with a 2% virological rebound and 0% genotypic resistance are the best one year rates ever achieved with any monotherapy so far. However, the current paradigm of nucleos(t)ide analogues treatment of HBeAg-negative chronic hepatitis B is a long-term challenge, possibly a lifetime therapy if HBsAg seroconversion is not achieved. The latter endpoint has been reported in less than 5% of the patients following 5 years of continuous treatment with nucle-
os(t)ide analogues. As neither lamivudine nor adefovir can suppress HBV replication in all patients over a 5 year period of therapy because of the emergence of viral resistance, a second drug with a favourable cross resistance profile may better serve the purpose of controlling HBV replication long-term [2,3]. ‘‘On demand’’ lamivudine–adefovir combination therapy is the prototype of this strategy: lamivudine monotherapy rapidly drops viremia and adefovir is added at the time when genotypic resistance to lamivudine develops to keep viremia below detectable levels in the following years. This ‘‘on demand’’ combination showed an excellent virological and clinical response over a 5 year time period [4]. Likewise, in adefovir monotherapy treated patients, lamivudine can be added to further prolong HBV suppression. What role can entecavir play in the long-term control of viral replication in HBeAg-negative patients? The low rates of virological rebound and genotypic resistance with entecavir should not lead physicians to believe that the ‘‘holy grail’’ of antiviral treatment has come. The rate of genotypic resistance to adefovir was not fully appreciated in the pivotal studies of 1 year treatment, but it progressively emerged as a real problem with 29% rates after 5 years of continuous therapy [3], further confirming the belief of an increased risk of resistance associated to antiviral monotherapy. It should not be a surprise, therefore, if some patients on long-term entecavir monotherapy will develop drug resistance sooner or later too, even though a rescue drug, yet to be identified, is likely to be available by the time entecavir monotherapy will have failed. Although entecavir may not revolutionise the current antiviral strategy it may significantly improve it from many aspects. First, the need for a rescue therapy in nucleos(t)ide analogues naı¨ve patients treated with entecavir monotherapy is significantly lower than the 15– 20% yearly rate in lamivudine monotherapy treated patients. Second, given the greater magnitude of reduction of HBV DNA levels from baseline showed by entecavir compared to lamivudine, entecavir might become a first choice for rapidly suppressing viral replication in patients with exceptionally high levels of HBV at baseline. As a consequence, early rescue therapy with adefovir in partial responders to lamivudine may be significantly limited. Third, due to the higher genetic barrier of entecavir compared to lamivudine, monitoring of serum HBV DNA would require less intense sampling, hospital check ups, HBV DNA assays, and loss of precious time at work. Fourth, compared to adefovir monotherapy, entecavir may increase the rates of virological response by both shortening the time to undetectable HBV DNA and reducing the proportion of patients with partial response. Chang and colleagues recently reported the results of a large phase III double-blind trial comparing entecavir and lamivudine in nucleoside naı¨ve HBeAg positive
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
patients with chronic hepatitis B [5]. Histological improvement, virological and biochemical responses were significantly greater in entecavir than in lamivudine treated patients, but the rates of HBeAg seroconversion were similar in both groups (21% vs. 18%) while viral resistance was restricted to lamivudine treated patients. These results should be interpreted carefully, in light of the two different therapeutic strategies that can be offered to HBeAg positive patients. The first strategy relies on short-term treatment aimed at tipping the balance between the virus and immune system, ending with a stronger control of viral replication during and off treatment. This goal can be achieved by short-term therapy with either interferon or nucleos(t)ide analogues with the endpoint of achieving HBeAg loss and antiHBe seroconversion [6,7]. Entecavir is a poor candidate for this strategy since the potent antiviral activity of this compound does not translate into higher rates of HBeAg seroconversion than to the old lamivudine treatment. The second strategy of HBeAg positive patients’ therapy relies on long-term, undefined, suppressive treatment by continuous antiviral therapy with nucles(t)ide analogues, i.e., the same strategy previously illustrated for HBeAg negative patients. For those nucleoside-naı¨ve patients in whom this strategy is selected, entecavir is the ideal drug to start with, because of its potent antiviral activity coupled with its high genetic barrier. However, the pros and cons of long-term antiviral treatment should be carefully weighed on an individual basis. It remains to be elucidated also whether prolonged treatment improves the HBeAg seroconversion rates allowing to stop treatment and whether this serological response is durable after treatment is stopped. Many relevant questions have yet to be answered. What is the long-term virological response to entecavir monotherapy? Unfortunately, because of the far from ideal study design, the recently presented 2-year data do not provide any convincing evidence on this issue and more data are awaited [8]. What is the long-term safety of entecavir? Again, long-term data are not available yet and it should be taken into account that the excellent safety record of competitors, such as lamivudine and adefovir, has been confirmed over 10 and 5 years, respectively. What drug can be used to rescue entecavir resistance? The high genetic barrier of entecavir lowers the rates of early resistance but impairs in vitro studies aimed at investigating the rescue candidate for this drug. What is the off-treatment durability of entecavir induced virological and biochemical responses? The off-treatment follow-up in both studies was too short to draw any clinically meaningful conclusion. These features weaken the indication for the use of entecavir. Not to mention the fact that already many thousands of patients worldwide are lamivudine-experienced, many already lamivudine-resistant, and any new compound
459
should ideally demonstrate its ability to suppress HBV replication in these patients, too. Recently, Sherman and co-workers reported the 48 week rates of virological, biochemical and histological responses to entecavir compared to lamivudine in HBeAg-positive, lamivudine-resistant patients [9]. Unfortunately, 1.0 mg/day entecavir showed only limited activity in these patients, with 19% of them achieving undetectable HBV DNA, only. Furthermore, entecavir substitutions were observed before exposure to entecavir in 6% of lamivudine-refractory patients, genotypic resistance to entecavir developed in 7% of the patients and a virological rebound occurred in 2% of them. Indeed, the molecular resistance profile of entecavir requires pre-existing lamivudine-resistance substitutions and an additional substitution at residues T184, S202, or M250. These findings point to a limited use of entecavir in areas where lamivudine-resistant patients cluster. In conclusion, long-term inhibition of HBV replication is the key factor to halt the progression of chronic hepatitis B and, in cirrhotics, to lower the rates of liver-related complications and improve survival. This can be achieved either by standard or pegylated interferon or by long-term suppressive treatment with nucleos(t)ide analogues. Compared to the currently available suppressive strategies based upon ‘‘on demand’’ lamivudine–adefovir or adefovir–lamivudine combination therapy, entecavir is likely to be a step forward since it couples potent anti-HBV activity and a high genetic barrier. However, the risk of developing resistance is pending. Naı¨ve but not lamivudine-resistant patients are the best candidates for this new therapy, and HBeAg seroconversion rates following short-term treatment do not exceed those achieved by lamivudine monotherapy. Overall, entecavir represents a significant step ahead, but not the final solution, for the long-term management of patients with chronic hepatitis B. References [1] Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z et al., for the BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011–1020. [2] Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al., for the Italian Association for the Study of the Liver (AISF) Lamivudine Study Group. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004;40:883–891. [3] Hadziyannis S, Tassopoulos N, Chang T, Heathcote J, Kitis G, Rizzetto M, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy. Hepatology 2005;42:754A. [4] Lampertico P, Vigano` M, Manenti E, Iavarone M, Lunghi G, Colombo M. Five years of sequential LAM to LAM + ADV therapy suppresses HBV replication in most HBeAg-negative cirrhotics, preventing decompensation but not hepatocellular carcinoma. J Hepatol 2006;44:S38.
460
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
[5] Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al., for the BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–1010. [6] Janssen HLA, Van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. for the HBV 99-01 Study Group. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–29. [7] Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al., for the Peginterferon Alfa-2a HBeAg-Positive
Chronic Hepatitis B Study Group. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682–2695. [8] Shouval D, Akarca US, Hatzis G, Kitis G, Lai CL, Cheinquer H, et al. Continued virologic and biochemical improvement through 96 weeks of entecavir treatment in HBeAg( ) chronic hepatitis B patients (Study ETV-027). J Hepatol 2006;44:S21. [9] Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al., for the AI463026 BEHoLD Study Group. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130:2039–2049.
Journal Club Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Entecavir versus lamivudine for HBeAg positive and negative chronic hepatitis B Pietro Lampertico* Division of Gastroenterology, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli, Regina Elena, University of Milan, Via Francesco Sforza 35, 20122 Milano, Italy
Entecavir versus lamivudine for patients with HBeAgnegative chronic hepatitis B. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L; BEHoLD AI463027 Study Group. BACKGROUND: Entecavir is a potent and selective antiviral agent that has demonstrated efficacy in phase 2 studies in patients with hepatitis B e antigen (HBeAg)negative chronic hepatitis B. METHODS: In this phase 3, double-blind trial, we randomly assigned 648 patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue to receive 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis). RESULTS: Histologic improvement after 48 weeks of treatment occurred in 208 of 296 patients in the entecavir group who had adequate baseline liver-biopsy specimens that could be evaluated (70%), as compared with 174 of 287 such patients in the lamivudine group (61%, P = 0.01). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus (HBV) DNA levels according to a polymerasechain-reaction assay (90% vs. 72%, P < 0.001) and normalization of alanine aminotransferase levels (78% vs. 71%, P = 0.045). The mean reduction in serum HBV DNA levels from baseline to week 48 was greater with entecavir than with lamivudine (5.0 vs. 4.5 log [on a
*
Tel.: +390255035432. E-mail address: [email protected].
base-10 scale] copies per milliliter, P < 0.001). There was no evidence of resistance to entecavir. Safety and adverse-event profiles were similar in the two groups. CONCLUSIONS: Among patients with HBeAg-negative chronic hepatitis B who had not previously been treated with a nucleoside analogue, the rates of histologic improvement, virologic response, and normalization of alanine aminotransferase levels were significantly higher at 48 weeks with entecavir than with lamivudine. The safety profile of the two agents was similar, and there was no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035789.). [Abstract reproduced by permission of N Engl J Med 2006;354:1011–1020] A comparison of entecavir and lamivudine for HBeAgpositive chronic hepatitis B. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, Lok AS, Han KH, Goodman Z, Zhu J, Cross A, DeHertogh D, Wilber R, Colonno R, Apelian D; BEHoLD AI463022 Study Group. BACKGROUND: Entecavir is a potent and selective guanosine analogue with significant activity against hepatitis B virus (HBV). METHODS: In this phase 3, double-blind trial, we randomly assigned 715 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who had not previously received a nucleoside analogue to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks. The primary efficacy end point was histologic improvement (a decrease by at least two points in the Knodell necroinflammatory score, without worsening of fibrosis) at week 48. Secondary end points included a reduction in the serum HBV DNA level, HBeAg loss and seroconversion, and normalization of the alanine aminotransferase level.
0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2006.06.012
458
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
RESULTS: Histologic improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, P = 0.009). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV DNA levels according to a polymerase-chain-reaction assay (67% vs. 36%, P < 0.001) and normalization of alanine aminotransferase levels (68% vs. 60%, P = 0.02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log [on a base-10 scale] copies per milliliter, P < 0.001). HBeAg seroconversion occurred in 21% of entecavir-treated patients and 18% of those treated with lamivudine (P = 0.33). No viral resistance to entecavir was detected. Safety was similar in the two groups. CONCLUSIONS: Among patients with HBeAg-positive chronic hepatitis B, the rates of histologic, virologic, and biochemical improvement are significantly higher with entecavir than with lamivudine. The safety profile of the two agents is similar, and there is no evidence of viral resistance to entecavir. (ClinicalTrials.gov number, NCT00035633.). [Abstract reproduced by permission of N Engl J Med 2006;354:1001–1010]
Lai and co-workers recently published a randomized controlled trial comparing the administration of 0.5 mg/ day entecavir and 100 mg/day lamivudine for the treatment of nucleoside-naı¨ve HBeAg-negative chronic hepatitis B [1]. After 52 weeks of treatment, significantly more patients in the entecavir than in lamivudine group achieved undetectable HBV DNA by PCR assay (90% vs. 72%), normalized ALT (78% vs. 71%) and improved histology (70% vs. 61%). Moreover, virological rebound and genotypically confirmed drug resistance occurred less frequently in the former than in the latter group (2% vs. 8%, 0% vs. 6%). The safety profile was similar in both groups. This is an important study since it highlights how far the antiviral treatment for hepatitis B has come, further improving the already excellent efficacy and safety profile of lamivudine and adefovir towards previously unthinkable response rates. A 90% virological response coupled with a 2% virological rebound and 0% genotypic resistance are the best one year rates ever achieved with any monotherapy so far. However, the current paradigm of nucleos(t)ide analogues treatment of HBeAg-negative chronic hepatitis B is a long-term challenge, possibly a lifetime therapy if HBsAg seroconversion is not achieved. The latter endpoint has been reported in less than 5% of the patients following 5 years of continuous treatment with nucle-
os(t)ide analogues. As neither lamivudine nor adefovir can suppress HBV replication in all patients over a 5 year period of therapy because of the emergence of viral resistance, a second drug with a favourable cross resistance profile may better serve the purpose of controlling HBV replication long-term [2,3]. ‘‘On demand’’ lamivudine–adefovir combination therapy is the prototype of this strategy: lamivudine monotherapy rapidly drops viremia and adefovir is added at the time when genotypic resistance to lamivudine develops to keep viremia below detectable levels in the following years. This ‘‘on demand’’ combination showed an excellent virological and clinical response over a 5 year time period [4]. Likewise, in adefovir monotherapy treated patients, lamivudine can be added to further prolong HBV suppression. What role can entecavir play in the long-term control of viral replication in HBeAg-negative patients? The low rates of virological rebound and genotypic resistance with entecavir should not lead physicians to believe that the ‘‘holy grail’’ of antiviral treatment has come. The rate of genotypic resistance to adefovir was not fully appreciated in the pivotal studies of 1 year treatment, but it progressively emerged as a real problem with 29% rates after 5 years of continuous therapy [3], further confirming the belief of an increased risk of resistance associated to antiviral monotherapy. It should not be a surprise, therefore, if some patients on long-term entecavir monotherapy will develop drug resistance sooner or later too, even though a rescue drug, yet to be identified, is likely to be available by the time entecavir monotherapy will have failed. Although entecavir may not revolutionise the current antiviral strategy it may significantly improve it from many aspects. First, the need for a rescue therapy in nucleos(t)ide analogues naı¨ve patients treated with entecavir monotherapy is significantly lower than the 15– 20% yearly rate in lamivudine monotherapy treated patients. Second, given the greater magnitude of reduction of HBV DNA levels from baseline showed by entecavir compared to lamivudine, entecavir might become a first choice for rapidly suppressing viral replication in patients with exceptionally high levels of HBV at baseline. As a consequence, early rescue therapy with adefovir in partial responders to lamivudine may be significantly limited. Third, due to the higher genetic barrier of entecavir compared to lamivudine, monitoring of serum HBV DNA would require less intense sampling, hospital check ups, HBV DNA assays, and loss of precious time at work. Fourth, compared to adefovir monotherapy, entecavir may increase the rates of virological response by both shortening the time to undetectable HBV DNA and reducing the proportion of patients with partial response. Chang and colleagues recently reported the results of a large phase III double-blind trial comparing entecavir and lamivudine in nucleoside naı¨ve HBeAg positive
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
patients with chronic hepatitis B [5]. Histological improvement, virological and biochemical responses were significantly greater in entecavir than in lamivudine treated patients, but the rates of HBeAg seroconversion were similar in both groups (21% vs. 18%) while viral resistance was restricted to lamivudine treated patients. These results should be interpreted carefully, in light of the two different therapeutic strategies that can be offered to HBeAg positive patients. The first strategy relies on short-term treatment aimed at tipping the balance between the virus and immune system, ending with a stronger control of viral replication during and off treatment. This goal can be achieved by short-term therapy with either interferon or nucleos(t)ide analogues with the endpoint of achieving HBeAg loss and antiHBe seroconversion [6,7]. Entecavir is a poor candidate for this strategy since the potent antiviral activity of this compound does not translate into higher rates of HBeAg seroconversion than to the old lamivudine treatment. The second strategy of HBeAg positive patients’ therapy relies on long-term, undefined, suppressive treatment by continuous antiviral therapy with nucles(t)ide analogues, i.e., the same strategy previously illustrated for HBeAg negative patients. For those nucleoside-naı¨ve patients in whom this strategy is selected, entecavir is the ideal drug to start with, because of its potent antiviral activity coupled with its high genetic barrier. However, the pros and cons of long-term antiviral treatment should be carefully weighed on an individual basis. It remains to be elucidated also whether prolonged treatment improves the HBeAg seroconversion rates allowing to stop treatment and whether this serological response is durable after treatment is stopped. Many relevant questions have yet to be answered. What is the long-term virological response to entecavir monotherapy? Unfortunately, because of the far from ideal study design, the recently presented 2-year data do not provide any convincing evidence on this issue and more data are awaited [8]. What is the long-term safety of entecavir? Again, long-term data are not available yet and it should be taken into account that the excellent safety record of competitors, such as lamivudine and adefovir, has been confirmed over 10 and 5 years, respectively. What drug can be used to rescue entecavir resistance? The high genetic barrier of entecavir lowers the rates of early resistance but impairs in vitro studies aimed at investigating the rescue candidate for this drug. What is the off-treatment durability of entecavir induced virological and biochemical responses? The off-treatment follow-up in both studies was too short to draw any clinically meaningful conclusion. These features weaken the indication for the use of entecavir. Not to mention the fact that already many thousands of patients worldwide are lamivudine-experienced, many already lamivudine-resistant, and any new compound
459
should ideally demonstrate its ability to suppress HBV replication in these patients, too. Recently, Sherman and co-workers reported the 48 week rates of virological, biochemical and histological responses to entecavir compared to lamivudine in HBeAg-positive, lamivudine-resistant patients [9]. Unfortunately, 1.0 mg/day entecavir showed only limited activity in these patients, with 19% of them achieving undetectable HBV DNA, only. Furthermore, entecavir substitutions were observed before exposure to entecavir in 6% of lamivudine-refractory patients, genotypic resistance to entecavir developed in 7% of the patients and a virological rebound occurred in 2% of them. Indeed, the molecular resistance profile of entecavir requires pre-existing lamivudine-resistance substitutions and an additional substitution at residues T184, S202, or M250. These findings point to a limited use of entecavir in areas where lamivudine-resistant patients cluster. In conclusion, long-term inhibition of HBV replication is the key factor to halt the progression of chronic hepatitis B and, in cirrhotics, to lower the rates of liver-related complications and improve survival. This can be achieved either by standard or pegylated interferon or by long-term suppressive treatment with nucleos(t)ide analogues. Compared to the currently available suppressive strategies based upon ‘‘on demand’’ lamivudine–adefovir or adefovir–lamivudine combination therapy, entecavir is likely to be a step forward since it couples potent anti-HBV activity and a high genetic barrier. However, the risk of developing resistance is pending. Naı¨ve but not lamivudine-resistant patients are the best candidates for this new therapy, and HBeAg seroconversion rates following short-term treatment do not exceed those achieved by lamivudine monotherapy. Overall, entecavir represents a significant step ahead, but not the final solution, for the long-term management of patients with chronic hepatitis B. References [1] Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z et al., for the BEHoLD AI463027 Study Group. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354:1011–1020. [2] Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al., for the Italian Association for the Study of the Liver (AISF) Lamivudine Study Group. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004;40:883–891. [3] Hadziyannis S, Tassopoulos N, Chang T, Heathcote J, Kitis G, Rizzetto M, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy. Hepatology 2005;42:754A. [4] Lampertico P, Vigano` M, Manenti E, Iavarone M, Lunghi G, Colombo M. Five years of sequential LAM to LAM + ADV therapy suppresses HBV replication in most HBeAg-negative cirrhotics, preventing decompensation but not hepatocellular carcinoma. J Hepatol 2006;44:S38.
460
P. Lampertico / Journal of Hepatology 45 (2006) 457–460
[5] Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al., for the BEHoLD AI463022 Study Group. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354:1001–1010. [6] Janssen HLA, Van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. for the HBV 99-01 Study Group. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123–29. [7] Lau GKK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al., for the Peginterferon Alfa-2a HBeAg-Positive
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