Combination Therapies for Treatment-Naive Chronic Hepatitis B
Combination Therapies for Treatment-Naive Chronic Hepatitis B
Background: There is a renewed interest in use of combination therapies in treatment-nave chronic hepatitis B (CHB) because of limitations of monotherapies.
Aim: To discuss the current status of combination therapies in treatment-nave CHB.
Methods: PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms.
Results: The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons.
Conclusions: The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.
More than 400 million people worldwide are chronically infected with hepatitis B virus (HBV). Effective therapy is necessary to prevent the progression of chronic hepatitis B (CHB) to cirrhosis, hepatocellular carcinoma and death.
Agents currently used for the treatment of chronic HBV infection are divided into two main groups based on their primary mode of action: the immunomodulators e.g. interferons (IFNs), thymosin, interleukins, etc. and the nucleos(t)ide analogues.
IFNs [including standard IFN and pegylated IFN (peg-IFN)] and other immunomodulators act by promoting cytotoxic T-cell activity for lysis of infected hepatocytes and by stimulating cytokine production for control of viral replication. The introduction of nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbuvidine, tenofovir, etc.) heralded a new era in the treatment of CHB, and provided a safe, effective and well-tolerated alternative to IFN. Nucleos(t)ide analogues target the reverse transcriptase of HBV and are potent inhibitors of viral replication. Although treatment with nucleos(t)ide analogues profoundly suppresses serum HBV DNA levels and response can be maintained over prolonged periods with ongoing therapy, response to treatment may not be durable in a large proportion of patients after discontinuation of therapy, indicating the necessity for a long-term, and maybe indefinite, treatment. However, development of anti-viral resistance is a major limitation to long-term efficacy of nucleos(t)ide analogues.
HBV therapy must provide potent long-term viral suppression and at the same time avoid development of resistance. To prevent development of anti-viral drug resistance, a judicious use of nucleos(t)ide analogues in patients with chronic HBV infection is needed. The first manifestation of anti-viral resistance is virological breakthrough, which is defined as a > 1 log10 increase in serum HBV DNA from nadir during treatment in a patient who had an initial virological response. It is usually also followed by a biochemical breakthrough. Emergence of anti-viral resistance can eventually lead to reversion of virological and histological improvement, and enhance the rate of disease progression. The best strategy to avoid the emergence of drug resistance during therapy is to suppress viral replication strongly. A diversity of viruses (quasispecies), including mutants with mutations potentially associated with drug resistance, may exist prior to therapy. Moreover, development of mutant populations is replication-dependent, and resistance emerges only when replication occurs in the presence of the drug selection pressure. Complete suppression of viral replication therefore allows little opportunity for resistance to develop. Several studies have shown that an initial virological response is associated with lower rates of anti-viral drug resistance in HBV patients in the long term (see below). Therefore, anti-viral therapy, once initiated, should aim to suppress viral replication as quickly and completely as possible.
Background: There is a renewed interest in use of combination therapies in treatment-nave chronic hepatitis B (CHB) because of limitations of monotherapies.
Aim: To discuss the current status of combination therapies in treatment-nave CHB.
Methods: PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms.
Results: The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons.
Conclusions: The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.
More than 400 million people worldwide are chronically infected with hepatitis B virus (HBV). Effective therapy is necessary to prevent the progression of chronic hepatitis B (CHB) to cirrhosis, hepatocellular carcinoma and death.
Agents currently used for the treatment of chronic HBV infection are divided into two main groups based on their primary mode of action: the immunomodulators e.g. interferons (IFNs), thymosin, interleukins, etc. and the nucleos(t)ide analogues.
IFNs [including standard IFN and pegylated IFN (peg-IFN)] and other immunomodulators act by promoting cytotoxic T-cell activity for lysis of infected hepatocytes and by stimulating cytokine production for control of viral replication. The introduction of nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbuvidine, tenofovir, etc.) heralded a new era in the treatment of CHB, and provided a safe, effective and well-tolerated alternative to IFN. Nucleos(t)ide analogues target the reverse transcriptase of HBV and are potent inhibitors of viral replication. Although treatment with nucleos(t)ide analogues profoundly suppresses serum HBV DNA levels and response can be maintained over prolonged periods with ongoing therapy, response to treatment may not be durable in a large proportion of patients after discontinuation of therapy, indicating the necessity for a long-term, and maybe indefinite, treatment. However, development of anti-viral resistance is a major limitation to long-term efficacy of nucleos(t)ide analogues.
HBV therapy must provide potent long-term viral suppression and at the same time avoid development of resistance. To prevent development of anti-viral drug resistance, a judicious use of nucleos(t)ide analogues in patients with chronic HBV infection is needed. The first manifestation of anti-viral resistance is virological breakthrough, which is defined as a > 1 log10 increase in serum HBV DNA from nadir during treatment in a patient who had an initial virological response. It is usually also followed by a biochemical breakthrough. Emergence of anti-viral resistance can eventually lead to reversion of virological and histological improvement, and enhance the rate of disease progression. The best strategy to avoid the emergence of drug resistance during therapy is to suppress viral replication strongly. A diversity of viruses (quasispecies), including mutants with mutations potentially associated with drug resistance, may exist prior to therapy. Moreover, development of mutant populations is replication-dependent, and resistance emerges only when replication occurs in the presence of the drug selection pressure. Complete suppression of viral replication therefore allows little opportunity for resistance to develop. Several studies have shown that an initial virological response is associated with lower rates of anti-viral drug resistance in HBV patients in the long term (see below). Therefore, anti-viral therapy, once initiated, should aim to suppress viral replication as quickly and completely as possible.
Source...