Guest guest Posted March 5, 2008 Report Share Posted March 5, 2008 Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to Change Therapy-2 of 2 When to Stop Therapy Patients should be monitored at least every 3 to 6 months while receiving therapy with the oral agents, and more frequently when treated with peginterferon alfa-2a due to higher rates of side effects and potential inability to tolerate therapy. Patients who are treated with peginterferon alfa-2a receive therapy for a fixed duration of 1 year,[7,8,16] but it is possible that a shorter duration of therapy may achieve the same outcomes. Therapy is stopped prior to the standard treatment period of 1 year only if side effects are intolerable, which occurs in less than 5% of patients.[7,8,16] The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B who are treated with the oral antiviral agents is HBeAg seroconversion to anti-HBe in association with very low or undetectable serum HBV DNA.[6-11] Based on the experience with lamivudine showing a lower rate of relapse when therapy is continued an additional 6 to 12 months beyond this point,[21] this practice has also been applied to the other oral agents. Some guidelines suggest that patients with cirrhosis should be treated long-term with oral agents, even after HBeAg seroconversion has been achieved, to avoid the risk of relapse.[7,16] Because patients with HBeAg-negative chronic hepatitis B invariably relapse when therapy is stopped after 1 year, even when serum HBV DNA is undetectable, current guidelines recommend long-term therapy.[6-11] Although some recent studies have demonstrated that relapse rates are lower if treatment with lamivudine or adefovir is stopped after several years of undetectable serum HBV DNA,[22,23] current recommendations for the management of patients with HBeAg-negative chronic hepatitis B continue to support long-term treatment.[6-8,16] It is unknown but possible that loss of HBsAg with seroconversion to anti-HBs is an acceptable endpoint in patients with HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a long course of antiviral therapy for chronic hepatitis B with the goal of reducing the potential complications of cirrhosis or HCC are often reassured by the analogy of long-term treatment of hypercholesterolemia, hypertension, or diabetes mellitus to prevent stroke or heart disease. When to Change Therapy An appropriate time to alter therapy by switching to or adding another drug is treatment failure, either primary treatment failure or an inadequate response while receiving treatment with oral agents.[7,8,24] The definition of primary treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from baseline at week 12 of treatment, whereas an inadequate virologic response is defined as a serum HBV DNA ™ 2000 IU/mL at week 24 of treatment.[24] The first step in the evaluation of potential primary treatment failure is to exclude patient nonadherence to prescribed therapy as a potential cause. With respect to oral antiviral therapy, if the agent has indeed been taken on a regular/prescribed basis, the patient is considered to have primary treatment failure and should be switched to a more potent drug or possibly a combination of drugs.[24] An inadequate virologic response (serum HBV DNA ™ 2000 IU/mL after 24 weeks of oral antiviral therapy) is a much more common reason for altering therapy, and a " roadmap " outlining the management of these patients was recently published.[24] Patients who have an inadequate response need to have their treatment changed to an alternative regimen, with either a different drug that is more potent and not cross-resistant or the addition of a second drug. Patients who only achieve a partial response after 24 weeks of treatment (serum HBV DNA ™ 60 IU/mL to < 2000 IU/mL) may also need to change to a different therapeutic regimen. For some, a second drug can be added that is not cross-resistant with the first drug. However, if patients are being treated with a drug that has a low rate of resistance development, such as entecavir, they can continue treatment to and beyond 48 weeks. In this situation, patients should undergo serum HBV DNA testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed antiviral effect. These patients should remain on therapy but be monitored every 3 months, with further assessment after 48 weeks of therapy. If their response remains partial or becomes inadequate at this time point, as defined by the " roadmap " concept, therapy should be changed.[24] Chronic hepatitis B patients with an inadequate response after 24 weeks of therapy with a drug with a risk of resistance, such as telbivudine, need to switch to a different, more effective drug.[24] Alternatively, a second drug without cross-resistance to the first drug can be added to the regimen. The patient should then be monitored every 3 months up to week 48. If the serum HBV DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6 months. However, patients with advanced disease should continue to be monitored every 3 months, regardless of their response to treatment.[24] Another appropriate time to alter therapy by switching or adding another drug to the treatment regimen is when there is development of HBV antiviral drug resistance. Treatment with adefovir is associated with a 29% rate of resistance in HBeAg-negative patients after 5 years of therapy.[25] Entecavir is associated with one of the lowest cumulative rates of resistance in treatment-naive patients, < 1% after 4 years of therapy.[26] Resistance with telbivudine occurs at intermediate rates, with 25% of HBeAg-positive patients and 11% of HBeAg-negative patients experiencing resistance after 2 years of therapy.[27] The pivotal telbivudine trial demonstrated that the greater the degree of viral suppression at week 24 of therapy, the better the outcomes after 1 and 2 years of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT normalization, and rate of HBV antiviral drug resistance.[17,27] Finally, HBV antiviral resistance was not noted in the tenofovir pivotal trials in HBeAg-positive and HBeAg-negative patients treated for 1 year.[18,19] Table 4 summarizes the potential management of HBV antiviral resistance based on the US treatment algorithm and the AASLD guidelines.[7,8,16] The general principle of the recommendations outlined in Table 4 is to add a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine, or entecavir is detected. The opposite concept applies to the patient with adefovir resistance (ie, add a nucleoside agent). This strategy of adding a second drug vs sequential treatment is supported by studies showing that the rate of subsequent adefovir resistance is considerably higher using the switch strategy in the setting of preexisting lamivudine resistance.[28-30] Table 4. Potential Management of Hepatitis B Antiviral Drug Resistance[7,8] Lamivudine resistance Continue lamivudine and add adefovir or tenofovir* Switch to emtricitabine/tenofovir* Adefovir resistance Continue adefovir and add lamivudine or telbivudine Switch to or add entecavir (if no prior lamivudine resistance) Switch to emtricitabine/tenofovir* Entecavir resistance Switch to or add adefovir or tenofovir* Switch to emtricitabine/tenofovir* Telbivudine resistance Continue telbivudine and add adefovir or tenofovir* Switch to emtricitabine/tenofovir* *Not approved by US Food and Drug Administration Conclusion The treatment of chronic hepatitis B has evolved rapidly over the past 10 years since the licensure of lamivudine as the first oral agent in 1998. The future prospects for yet improved therapy are bright and will bring new drugs, such as tenofovir, as well as better approaches to on-treatment management that will reduce the likelihood of resistance and optimize outcomes. Editor's note: Medscape would like to thank Dr. Keeffe for his many excellent contributions to our site over the past years. Dr. Keeffe's commitment to providing the highest quality clinical education has made him one of Medscape Gastroenterology's most read and respected authors. In early 2008, Dr. Keeffe will be embarking on an exciting new phase of clinical research as Vice President and Chief Medical Officer of Romark Laboratories. The Medscape Gastroenterology team wishes Dr. Keeffe much success in his future endeavors. This activity is supported by an independent educational grant from Gilead. http://www.medscape.com/viewarticle/570478 _________________________________________________________________ Connect and share in new ways with Windows Live. http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008 Quote Link to comment Share on other sites More sharing options...
Guest guest Posted March 5, 2008 Report Share Posted March 5, 2008 Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to Change Therapy-2 of 2 When to Stop Therapy Patients should be monitored at least every 3 to 6 months while receiving therapy with the oral agents, and more frequently when treated with peginterferon alfa-2a due to higher rates of side effects and potential inability to tolerate therapy. Patients who are treated with peginterferon alfa-2a receive therapy for a fixed duration of 1 year,[7,8,16] but it is possible that a shorter duration of therapy may achieve the same outcomes. Therapy is stopped prior to the standard treatment period of 1 year only if side effects are intolerable, which occurs in less than 5% of patients.[7,8,16] The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B who are treated with the oral antiviral agents is HBeAg seroconversion to anti-HBe in association with very low or undetectable serum HBV DNA.[6-11] Based on the experience with lamivudine showing a lower rate of relapse when therapy is continued an additional 6 to 12 months beyond this point,[21] this practice has also been applied to the other oral agents. Some guidelines suggest that patients with cirrhosis should be treated long-term with oral agents, even after HBeAg seroconversion has been achieved, to avoid the risk of relapse.[7,16] Because patients with HBeAg-negative chronic hepatitis B invariably relapse when therapy is stopped after 1 year, even when serum HBV DNA is undetectable, current guidelines recommend long-term therapy.[6-11] Although some recent studies have demonstrated that relapse rates are lower if treatment with lamivudine or adefovir is stopped after several years of undetectable serum HBV DNA,[22,23] current recommendations for the management of patients with HBeAg-negative chronic hepatitis B continue to support long-term treatment.[6-8,16] It is unknown but possible that loss of HBsAg with seroconversion to anti-HBs is an acceptable endpoint in patients with HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a long course of antiviral therapy for chronic hepatitis B with the goal of reducing the potential complications of cirrhosis or HCC are often reassured by the analogy of long-term treatment of hypercholesterolemia, hypertension, or diabetes mellitus to prevent stroke or heart disease. When to Change Therapy An appropriate time to alter therapy by switching to or adding another drug is treatment failure, either primary treatment failure or an inadequate response while receiving treatment with oral agents.[7,8,24] The definition of primary treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from baseline at week 12 of treatment, whereas an inadequate virologic response is defined as a serum HBV DNA ™ 2000 IU/mL at week 24 of treatment.[24] The first step in the evaluation of potential primary treatment failure is to exclude patient nonadherence to prescribed therapy as a potential cause. With respect to oral antiviral therapy, if the agent has indeed been taken on a regular/prescribed basis, the patient is considered to have primary treatment failure and should be switched to a more potent drug or possibly a combination of drugs.[24] An inadequate virologic response (serum HBV DNA ™ 2000 IU/mL after 24 weeks of oral antiviral therapy) is a much more common reason for altering therapy, and a " roadmap " outlining the management of these patients was recently published.[24] Patients who have an inadequate response need to have their treatment changed to an alternative regimen, with either a different drug that is more potent and not cross-resistant or the addition of a second drug. Patients who only achieve a partial response after 24 weeks of treatment (serum HBV DNA ™ 60 IU/mL to < 2000 IU/mL) may also need to change to a different therapeutic regimen. For some, a second drug can be added that is not cross-resistant with the first drug. However, if patients are being treated with a drug that has a low rate of resistance development, such as entecavir, they can continue treatment to and beyond 48 weeks. In this situation, patients should undergo serum HBV DNA testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed antiviral effect. These patients should remain on therapy but be monitored every 3 months, with further assessment after 48 weeks of therapy. If their response remains partial or becomes inadequate at this time point, as defined by the " roadmap " concept, therapy should be changed.[24] Chronic hepatitis B patients with an inadequate response after 24 weeks of therapy with a drug with a risk of resistance, such as telbivudine, need to switch to a different, more effective drug.[24] Alternatively, a second drug without cross-resistance to the first drug can be added to the regimen. The patient should then be monitored every 3 months up to week 48. If the serum HBV DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6 months. However, patients with advanced disease should continue to be monitored every 3 months, regardless of their response to treatment.[24] Another appropriate time to alter therapy by switching or adding another drug to the treatment regimen is when there is development of HBV antiviral drug resistance. Treatment with adefovir is associated with a 29% rate of resistance in HBeAg-negative patients after 5 years of therapy.[25] Entecavir is associated with one of the lowest cumulative rates of resistance in treatment-naive patients, < 1% after 4 years of therapy.[26] Resistance with telbivudine occurs at intermediate rates, with 25% of HBeAg-positive patients and 11% of HBeAg-negative patients experiencing resistance after 2 years of therapy.[27] The pivotal telbivudine trial demonstrated that the greater the degree of viral suppression at week 24 of therapy, the better the outcomes after 1 and 2 years of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT normalization, and rate of HBV antiviral drug resistance.[17,27] Finally, HBV antiviral resistance was not noted in the tenofovir pivotal trials in HBeAg-positive and HBeAg-negative patients treated for 1 year.[18,19] Table 4 summarizes the potential management of HBV antiviral resistance based on the US treatment algorithm and the AASLD guidelines.[7,8,16] The general principle of the recommendations outlined in Table 4 is to add a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine, or entecavir is detected. The opposite concept applies to the patient with adefovir resistance (ie, add a nucleoside agent). This strategy of adding a second drug vs sequential treatment is supported by studies showing that the rate of subsequent adefovir resistance is considerably higher using the switch strategy in the setting of preexisting lamivudine resistance.[28-30] Table 4. Potential Management of Hepatitis B Antiviral Drug Resistance[7,8] Lamivudine resistance Continue lamivudine and add adefovir or tenofovir* Switch to emtricitabine/tenofovir* Adefovir resistance Continue adefovir and add lamivudine or telbivudine Switch to or add entecavir (if no prior lamivudine resistance) Switch to emtricitabine/tenofovir* Entecavir resistance Switch to or add adefovir or tenofovir* Switch to emtricitabine/tenofovir* Telbivudine resistance Continue telbivudine and add adefovir or tenofovir* Switch to emtricitabine/tenofovir* *Not approved by US Food and Drug Administration Conclusion The treatment of chronic hepatitis B has evolved rapidly over the past 10 years since the licensure of lamivudine as the first oral agent in 1998. The future prospects for yet improved therapy are bright and will bring new drugs, such as tenofovir, as well as better approaches to on-treatment management that will reduce the likelihood of resistance and optimize outcomes. Editor's note: Medscape would like to thank Dr. Keeffe for his many excellent contributions to our site over the past years. Dr. Keeffe's commitment to providing the highest quality clinical education has made him one of Medscape Gastroenterology's most read and respected authors. In early 2008, Dr. Keeffe will be embarking on an exciting new phase of clinical research as Vice President and Chief Medical Officer of Romark Laboratories. The Medscape Gastroenterology team wishes Dr. Keeffe much success in his future endeavors. This activity is supported by an independent educational grant from Gilead. http://www.medscape.com/viewarticle/570478 _________________________________________________________________ Connect and share in new ways with Windows Live. http://www.windowslive.com/share.html?ocid=TXT_TAGHM_Wave2_sharelife_012008 Quote Link to comment Share on other sites More sharing options...
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