Approach to the Hepatitis B Patient With Lamivudine Resistance
Approach to the Hepatitis B Patient With Lamivudine Resistance
A patient with chronic hepatitis B has developed resistance to lamivudine. Is it reasonable to continue lamivudine in combination with a second antiviral medication for a short period of time before stopping the lamivudine? What are alternative options for the management of antiviral drug resistance emerging during treatment of chronic hepatitis B with lamivudine?
Emmet B. Keeffe, MD, MACP
Professor of Medicine, Stanford University School of Medicine, Stanford, California; Chief of Hepatology, Co-Director of Liver Transplant Program, Stanford University Medical Center, Stanford, California
Management options for patients who develop hepatitis B virus (HBV) antiviral drug resistance during treatment with lamivudine are summarized in the Table , which was developed on the basis of the updated US treatment algorithm. The oral antiviral agents adefovir and entecavir are both acceptable alternatives that are licensed by the US Food and Drug Administration (FDA) for the treatment of patients with lamivudine resistance. However, adefovir may be preferred over entecavir on the basis of emerging data showing a cumulative 32% rate of entecavir resistance after 3 years of therapy in patients with preexisting lamivudine resistance. Whether adefovir is given as monotherapy or in combination with continued lamivudine may depend on the status of the patient's liver disease. Data from a recent study in compensated patients revealed mild increases in alanine aminotransferase (ALT) levels in some patients when switching from lamivudine to adefovir, but no patient experienced clinically significant ALT elevations. These observations suggest that switching patients from lamivudine to adefovir, with or without an overlap period of combination lamivudine and adefovir, may be a safe strategy in many patients.
However, because the consequences of returning wild-type HBV infection are potentially more hazardous in patients with advanced liver disease and switching to adefovir is associated with a 15% to 19% rate of adefovir resistance after 2 years in lamivudine-resistant patients, the addition of adefovir to continued lamivudine therapy is preferred in patients with cirrhosis. Pending the availability of future data from studies currently under way, the addition of adefovir to lamivudine may be preferred to switching to adefovir monotherapy in all patients with lamivudine resistance, in order to avoid the increased rate of developing adefovir genotypic resistance in lamivudine-resistant patients (15% to 19%) when compared with naive patients treated with adefovir (0% at Year 1, 2% at Year 2, 11% at Year 3, 18% at Year 4, and 29% at Year 5). Entecavir is associated with a 5-log10 reduction in serum HBV DNA levels in lamivudine-refractory patients, but this potency needs to be weighed against the development of genotypic resistance and virologic breakthrough, which occur in 6% and 1% of patients, respectively, at Year 1, and increase by Year 3 to 32% and 25%, respectively. Potential future therapy for managing lamivudine resistance may involve adding tenofovir or switching to the combination of emtricitabine and tenofovir, which preliminary data suggest are effective regimens (not currently FDA approved), or switching to the combination of telbivudine plus tenofovir, which theoretically should be effective but has not been studied.
Question
A patient with chronic hepatitis B has developed resistance to lamivudine. Is it reasonable to continue lamivudine in combination with a second antiviral medication for a short period of time before stopping the lamivudine? What are alternative options for the management of antiviral drug resistance emerging during treatment of chronic hepatitis B with lamivudine?
Response From the Expert
Emmet B. Keeffe, MD, MACP
Professor of Medicine, Stanford University School of Medicine, Stanford, California; Chief of Hepatology, Co-Director of Liver Transplant Program, Stanford University Medical Center, Stanford, California
Management options for patients who develop hepatitis B virus (HBV) antiviral drug resistance during treatment with lamivudine are summarized in the Table , which was developed on the basis of the updated US treatment algorithm. The oral antiviral agents adefovir and entecavir are both acceptable alternatives that are licensed by the US Food and Drug Administration (FDA) for the treatment of patients with lamivudine resistance. However, adefovir may be preferred over entecavir on the basis of emerging data showing a cumulative 32% rate of entecavir resistance after 3 years of therapy in patients with preexisting lamivudine resistance. Whether adefovir is given as monotherapy or in combination with continued lamivudine may depend on the status of the patient's liver disease. Data from a recent study in compensated patients revealed mild increases in alanine aminotransferase (ALT) levels in some patients when switching from lamivudine to adefovir, but no patient experienced clinically significant ALT elevations. These observations suggest that switching patients from lamivudine to adefovir, with or without an overlap period of combination lamivudine and adefovir, may be a safe strategy in many patients.
However, because the consequences of returning wild-type HBV infection are potentially more hazardous in patients with advanced liver disease and switching to adefovir is associated with a 15% to 19% rate of adefovir resistance after 2 years in lamivudine-resistant patients, the addition of adefovir to continued lamivudine therapy is preferred in patients with cirrhosis. Pending the availability of future data from studies currently under way, the addition of adefovir to lamivudine may be preferred to switching to adefovir monotherapy in all patients with lamivudine resistance, in order to avoid the increased rate of developing adefovir genotypic resistance in lamivudine-resistant patients (15% to 19%) when compared with naive patients treated with adefovir (0% at Year 1, 2% at Year 2, 11% at Year 3, 18% at Year 4, and 29% at Year 5). Entecavir is associated with a 5-log10 reduction in serum HBV DNA levels in lamivudine-refractory patients, but this potency needs to be weighed against the development of genotypic resistance and virologic breakthrough, which occur in 6% and 1% of patients, respectively, at Year 1, and increase by Year 3 to 32% and 25%, respectively. Potential future therapy for managing lamivudine resistance may involve adding tenofovir or switching to the combination of emtricitabine and tenofovir, which preliminary data suggest are effective regimens (not currently FDA approved), or switching to the combination of telbivudine plus tenofovir, which theoretically should be effective but has not been studied.