Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2012)

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5 yearsJournal of HepatologyVol. 56Issue 6PreviewIn long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated. Full-Text PDF The original observation reported in 1991 that lamivudine, the 2′,3′-dideoxy-3′-thiacytidine nucleoside analogue, inhibits hepatitis B virus (HBV) replication in vitro has revolutionized the treatment of chronic hepatitis B (CHB) [[1]Doong S.L. Tsai C.H. Schinazi R.F. Liotta D.C. Cheng Y.C. Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues.Proc Natl Acad Sci USA. 1991; 88: 8495-8499Crossref PubMed Scopus (523) Google Scholar]. Subsequent clinical trials confirmed at that time the anti-viral potency of this agent in vivo. Lamivudine was repeatedly shown to suppress viral replication, improve hepatocellular injury as well as fibrosis progression and reduce the risk of evolving hepatocellular carcinoma. Consequently, between 1998 and 2005, lamivudine became the backbone for anti-viral therapy in HBeAg positive and negative, treatment naïve CHB patients and in CHB patients who failed interferon α therapy. Despite the initial excellent safety and tolerability record, it soon became clear that treatment with lamivudine is associated with a significant and progressively rising risk for developing a viral breakthrough with genotypic and phenotypic resistance, which may exceed >70% within 5 years of treatment. However, some patients continue to benefit from long-term lamivudine therapy beyond 5 years of intake without emerging resistance. The factor(s) associated with maintaining long-term anti-viral activity of lamivudine in these sub-cohorts are not entirely known. Information on follow-up of patients treated with lamivudine for more than 5 years is scarce, although early and maximal suppression of viral load and adequate compliance seem to play a major role in successfully treated patients. Fortunately, newer and significantly more potent anti-viral nucleos(t)ide analogues, including entecavir, telbivudine, and tenofovir were developed and introduced into clinical practice. These agents and especially entecavir and tenofovir, which provide a much higher barrier to resistance, have further improved our ability to control persistent HBV infection and its complications. The high risk for emerging resistance to lamivudine in the first 5–6 years of treatment is well recognized [2Zoulim F. Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.Gastroenterology. 2009; 137: 1593-1608Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 3Zoulim F. Hepatitis B virus resistance to antiviral drugs: where are we going?.Liver Int. 2011; 31: 1478-3231Google Scholar]. Consequently the European (EASL) and American (AASLD) Associations for the Study of the Liver strongly recommend that treatment naïve CHB patients who are not candidates for interferon therapy as well as experienced patients not responding to interferon, should be treated with one of the newer, most potent anti-viral agents to reduce the risk of emerging resistance [4Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2382) Google Scholar, 5EASL Clinical Practice Guidelines Management of chronic hepatitis B. European Association For The Study Of The Liver.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar]. Management of resistant patients to lamivudine through add on therapy i.e. with adefovir, entecavir or tenofovir or switching to monotherapy with entecavir or tenofovir has also received much attention in recent years [2Zoulim F. Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.Gastroenterology. 2009; 137: 1593-1608Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 3Zoulim F. Hepatitis B virus resistance to antiviral drugs: where are we going?.Liver Int. 2011; 31: 1478-3231Google Scholar, 4Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2382) Google Scholar, 5EASL Clinical Practice Guidelines Management of chronic hepatitis B. European Association For The Study Of The Liver.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar, 6Marcellin P. Sung J. Piratvisuth T. Avoiding and managing lamivudine resistance in chronic hepatitis B: current approaches and potential strategies including pegylated interferon.Liver Int. 2010; 30: 657-668Crossref PubMed Scopus (8) Google Scholar]. Yet, current guidelines do not provide clear recommendations whether stable patients who are on long-term lamivudine treatment without evidence for emerging resistance should be switched to a more potent anti-viral agent. There are quite a number of arguments to support such a switch. However, replacement of lamivudine by one of the newer anti-virals is associated with a more than 10× increase in cost/pill. In this context, it should be remembered that generic lamivudine remains sometimes the only affordable anti-viral agent, especially in low income countries in Asia and Africa where CHB is most prevalent. Following the rapid progress in development of more potent anti-viral agents against HBV and despite the lack of evidence, hepatologists frequently advise their stable patients treated successfully with lamivudine who still did not develop resistance, to switch to a more potent anti-viral agent. Convincing evidence to justify such a switch in anti-viral agents in this particular cohort of patients, which is of particular relevance in low-income regions, is still lacking. Thus, in view of the rather large number of patients in different continents who continue to receive lamivudine, it is important to collect more information through monitoring efficacy and safety of lamivudine in patients treated for more than 5 years.In the present issue of the Journal, Fasano and co-workers report their follow-up of 191 Italian patients with HBeAg negative CHB who responded favorably to lamivudine for at least 5 years and continued intake of lamivudine for another median period of 36 months (range: 1–108) [[7]Fasano M. Lampertico P. Marzano A. Di Marco V. Anna Niro G. Brancaccio G. et al.HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years.J Hepatol. 2012; 56: 36-40Abstract Full Text Full Text PDF Scopus (31) Google Scholar]. Interestingly, a favorable virologic response was still documented in 67% of the 191 original patients of whom 72 had compensated cirrhosis. Lamivudine resistant mutations were detected in 33% of patients who continued treatment beyond 5 years within a median period of 15 months. Furthermore, 11.7% of responders cleared HBsAg within a median period of 32 months.Several conclusions can be drawn from the study of Fasano and co-workers including: (1) about two thirds of stable HBeAg negative CHB patients treated successfully with lamivudine for 5 years will continue to maintain a virologic response for at least an additional median period of 3 years, which occasionally may end up with clearance of HBsAg. Consequently, switching of a stable patient on lamivudine therapy to a more potent but also higher cost anti-viral agent is not an absolute must, provided that patients are monitored periodically for signs of liver injury and emerging resistance to lamivudine. (2) Even low-level residual viremia at year five of therapy is most probably posing a risk for emerging breakthrough mutants and such patients may benefit from switching to a more potent anti-viral agent after all. Furthermore, the successful suppression of viral load during the first 5 years of lamivudine treatment does not guarantee continued control of HBV infection beyond this period. (3) Although one third of patients treated for an additional median period of 36 months developed resistance to lamivudine, the risk for viral breakthrough after 5 years of successful treatment is lower as compared to a ∼70% risk in the first 5 years. (4) Confirmation of the results of this interesting retrospective multi-center study justifies planning of a prospective, randomized controlled trial. Such a study should compare long-term monotherapy with lamivudine beyond 5 years of successful treatment to switching to a more potent anti-viral agent at year five. (5) EASL and AASLD guidelines provide clear instructions regarding treatment with the most potent anti-viral agents in CHB patients. It should however be remembered that results of the study by Fasano et al. provide some limited justification for continued lamivudine treatment for a defined sub-cohort of HBeAg negative CHB patients who successfully passed the first 5 years of treatment without emerging resistance. This option may especially be relevant for patients who are unable to afford the more potent but also more costly anti-viral agents against HBV.Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The original observation reported in 1991 that lamivudine, the 2′,3′-dideoxy-3′-thiacytidine nucleoside analogue, inhibits hepatitis B virus (HBV) replication in vitro has revolutionized the treatment of chronic hepatitis B (CHB) [[1]Doong S.L. Tsai C.H. Schinazi R.F. Liotta D.C. Cheng Y.C. Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues.Proc Natl Acad Sci USA. 1991; 88: 8495-8499Crossref PubMed Scopus (523) Google Scholar]. Subsequent clinical trials confirmed at that time the anti-viral potency of this agent in vivo. Lamivudine was repeatedly shown to suppress viral replication, improve hepatocellular injury as well as fibrosis progression and reduce the risk of evolving hepatocellular carcinoma. Consequently, between 1998 and 2005, lamivudine became the backbone for anti-viral therapy in HBeAg positive and negative, treatment naïve CHB patients and in CHB patients who failed interferon α therapy. Despite the initial excellent safety and tolerability record, it soon became clear that treatment with lamivudine is associated with a significant and progressively rising risk for developing a viral breakthrough with genotypic and phenotypic resistance, which may exceed >70% within 5 years of treatment. However, some patients continue to benefit from long-term lamivudine therapy beyond 5 years of intake without emerging resistance. The factor(s) associated with maintaining long-term anti-viral activity of lamivudine in these sub-cohorts are not entirely known. Information on follow-up of patients treated with lamivudine for more than 5 years is scarce, although early and maximal suppression of viral load and adequate compliance seem to play a major role in successfully treated patients. Fortunately, newer and significantly more potent anti-viral nucleos(t)ide analogues, including entecavir, telbivudine, and tenofovir were developed and introduced into clinical practice. These agents and especially entecavir and tenofovir, which provide a much higher barrier to resistance, have further improved our ability to control persistent HBV infection and its complications. The high risk for emerging resistance to lamivudine in the first 5–6 years of treatment is well recognized [2Zoulim F. Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.Gastroenterology. 2009; 137: 1593-1608Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 3Zoulim F. Hepatitis B virus resistance to antiviral drugs: where are we going?.Liver Int. 2011; 31: 1478-3231Google Scholar]. Consequently the European (EASL) and American (AASLD) Associations for the Study of the Liver strongly recommend that treatment naïve CHB patients who are not candidates for interferon therapy as well as experienced patients not responding to interferon, should be treated with one of the newer, most potent anti-viral agents to reduce the risk of emerging resistance [4Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2382) Google Scholar, 5EASL Clinical Practice Guidelines Management of chronic hepatitis B. European Association For The Study Of The Liver.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar]. Management of resistant patients to lamivudine through add on therapy i.e. with adefovir, entecavir or tenofovir or switching to monotherapy with entecavir or tenofovir has also received much attention in recent years [2Zoulim F. Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues.Gastroenterology. 2009; 137: 1593-1608Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 3Zoulim F. Hepatitis B virus resistance to antiviral drugs: where are we going?.Liver Int. 2011; 31: 1478-3231Google Scholar, 4Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2382) Google Scholar, 5EASL Clinical Practice Guidelines Management of chronic hepatitis B. European Association For The Study Of The Liver.J Hepatol. 2009; 50: 227-242Abstract Full Text Full Text PDF PubMed Scopus (1465) Google Scholar, 6Marcellin P. Sung J. Piratvisuth T. Avoiding and managing lamivudine resistance in chronic hepatitis B: current approaches and potential strategies including pegylated interferon.Liver Int. 2010; 30: 657-668Crossref PubMed Scopus (8) Google Scholar]. Yet, current guidelines do not provide clear recommendations whether stable patients who are on long-term lamivudine treatment without evidence for emerging resistance should be switched to a more potent anti-viral agent. There are quite a number of arguments to support such a switch. However, replacement of lamivudine by one of the newer anti-virals is associated with a more than 10× increase in cost/pill. In this context, it should be remembered that generic lamivudine remains sometimes the only affordable anti-viral agent, especially in low income countries in Asia and Africa where CHB is most prevalent. Following the rapid progress in development of more potent anti-viral agents against HBV and despite the lack of evidence, hepatologists frequently advise their stable patients treated successfully with lamivudine who still did not develop resistance, to switch to a more potent anti-viral agent. Convincing evidence to justify such a switch in anti-viral agents in this particular cohort of patients, which is of particular relevance in low-income regions, is still lacking. Thus, in view of the rather large number of patients in different continents who continue to receive lamivudine, it is important to collect more information through monitoring efficacy and safety of lamivudine in patients treated for more than 5 years. In the present issue of the Journal, Fasano and co-workers report their follow-up of 191 Italian patients with HBeAg negative CHB who responded favorably to lamivudine for at least 5 years and continued intake of lamivudine for another median period of 36 months (range: 1–108) [[7]Fasano M. Lampertico P. Marzano A. Di Marco V. Anna Niro G. Brancaccio G. et al.HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years.J Hepatol. 2012; 56: 36-40Abstract Full Text Full Text PDF Scopus (31) Google Scholar]. Interestingly, a favorable virologic response was still documented in 67% of the 191 original patients of whom 72 had compensated cirrhosis. Lamivudine resistant mutations were detected in 33% of patients who continued treatment beyond 5 years within a median period of 15 months. Furthermore, 11.7% of responders cleared HBsAg within a median period of 32 months. Several conclusions can be drawn from the study of Fasano and co-workers including: (1) about two thirds of stable HBeAg negative CHB patients treated successfully with lamivudine for 5 years will continue to maintain a virologic response for at least an additional median period of 3 years, which occasionally may end up with clearance of HBsAg. Consequently, switching of a stable patient on lamivudine therapy to a more potent but also higher cost anti-viral agent is not an absolute must, provided that patients are monitored periodically for signs of liver injury and emerging resistance to lamivudine. (2) Even low-level residual viremia at year five of therapy is most probably posing a risk for emerging breakthrough mutants and such patients may benefit from switching to a more potent anti-viral agent after all. Furthermore, the successful suppression of viral load during the first 5 years of lamivudine treatment does not guarantee continued control of HBV infection beyond this period. (3) Although one third of patients treated for an additional median period of 36 months developed resistance to lamivudine, the risk for viral breakthrough after 5 years of successful treatment is lower as compared to a ∼70% risk in the first 5 years. (4) Confirmation of the results of this interesting retrospective multi-center study justifies planning of a prospective, randomized controlled trial. Such a study should compare long-term monotherapy with lamivudine beyond 5 years of successful treatment to switching to a more potent anti-viral agent at year five. (5) EASL and AASLD guidelines provide clear instructions regarding treatment with the most potent anti-viral agents in CHB patients. It should however be remembered that results of the study by Fasano et al. provide some limited justification for continued lamivudine treatment for a defined sub-cohort of HBeAg negative CHB patients who successfully passed the first 5 years of treatment without emerging resistance. This option may especially be relevant for patients who are unable to afford the more potent but also more costly anti-viral agents against HBV. Conflict of interestThe author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.