Long-Term Therapy With Adefovir Dipivoxil in Hep B e Antigen-Negative Pts.
Long-Term Therapy With Adefovir Dipivoxil in Hep B e Antigen-Negative Pts.
Background: The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation.
Aim: To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants.
Methods: Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy.
Results: The median follow-up after adefovir's onset was 31 (18-40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10 copies/mL (P >0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P >0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months.
Conclusion: In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) predominates in the Mediterranean area and Asia and has an increasing prevalence in Western Europe and North America. The HBeAg-negative CHB is characterized by intermittent periods of exacerbation and quiescence and often runs a more aggressive course resulting frequently in cirrhosis, liver failure and hepatocellular carcinoma (HCC). The principal goal of therapy in patients with HBeAg-negative CHB is the sustained suppression of viral replication to arrest and reverse the progression of the liver injury.
Current therapeutic approach of HBeAg-negative CHB includes treatment with interferon-alpha, lamivudine (LAM), adefovir dipivoxil (ADV), entecavir and telbivudine. The excellent safety and tolerability profile of LAM leads to long-term therapies which, however, have been associated with the emergence of viral resistance because of selection of resistant mutants. Clinical data showed that emergence of LAM-resistant mutations can be associated with hepatitis flares, hepatic decompensation and death. ADV is active against not only wild, but also LAM-resistant HBV strains. In contrast to LAM, resistance to ADV seems to occur less frequently and later in the course of long-term treatment. Resistance to ADV is related mostly to the emergence of mutation at codon 236 (asparagine to threonine, rtN236T) or at codon 181 (alanine to valine, rtA181V) of the HBV polymerase gene. In naive patients receiving ADV, genotypic resistance is observed in 3% of patients at year 2, 11% at year 3, 18% at year 4 and 29% at year 5. Although in vitro susceptibility to ADV is reduced only by two- to 13-folds, ADV resistance can be associated with viral rebound and decompensation.
Clinical studies have shown that virological and biochemical improvements are observed in LAM-resistant patients after the addition of ADV to ongoing LAM or with ADV monotherapy. In a randomized-controlled trial in HBeAg-positive CHB, ADV alone and ADV plus LAM combination therapy were found to achieve similar reductions of serum HBV-DNA after 1 year of treatment. The efficacy of long-term ADV monotherapy or combination of ADV and LAM in HBeAg-negative CHB patients with LAM-resistant CHB is still under investigation.
When ADV was first available in an expanded access programme for patients with LAM resistance, two different strategies (adding vs. switching) were followed by the clinicians regarding the continuation of LAM. In this prospective nonrandomized study, we report the efficacy and safety of long-term LAM and ADV combination therapy compared with ADV monotherapy in HBeAg-negative CHB patients with LAM resistance. In addition, we determined the incidence and risk factors of resistance to ADV in this setting in clinical practice.
Summary and Introduction
Summary
Background: The efficacy of long-term adefovir dipivoxil monotherapy or combination of adefovir and lamivudine in hepatitis B e antigen (HBe-Ag)-negative lamivudine-resistant chronic hepatitis B (CHB) patients is still under investigation.
Aim: To assess the safety and efficacy of the long-term adefovir treatment alone or in combination with lamivudine in HBe-Ag-negative CHB patients who had developed breakthrough because of lamivudine-resistant mutants.
Methods: Fifty-nine patients received combination therapy, while 23 switched to adefovir alone after a 3-month course of combination therapy.
Results: The median follow-up after adefovir's onset was 31 (18-40) months. Baseline characteristics were similar between the two groups. At 12 and 24 months, 69% and 89% of patients receiving combination therapy and 73% and 82% of patients receiving adefovir monotherapy had serum HBV-DNA <10 copies/mL (P >0.5). Normalization of alanine aminotransferase levels occurred in 81% and 79% of patients receiving combination vs. 61% and 53% receiving adefovir monotherapy at 12 and 24 months, respectively (P >0.50). Virological breakthroughs because of adefovir-resistant mutants occurred in five patients under adefovir monotherapy and in none receiving combination therapy (P = 0.001). No one developed decompensated liver disease or hepatocellular carcinoma during follow-up. Re-introduction of lamivudine in adefovir-resistant patients achieved reduction in HBV-DNA and biochemical remission, but re-emergence of lamivudine mutants was observed in one patient after 7.5 months.
Conclusion: In HBe-Ag-negative CHB patients with lamivudine resistance, adding adefovir to continuing lamivudine therapy maximizes anti-viral efficacy because of absence of viral resistance.
Introduction
Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) predominates in the Mediterranean area and Asia and has an increasing prevalence in Western Europe and North America. The HBeAg-negative CHB is characterized by intermittent periods of exacerbation and quiescence and often runs a more aggressive course resulting frequently in cirrhosis, liver failure and hepatocellular carcinoma (HCC). The principal goal of therapy in patients with HBeAg-negative CHB is the sustained suppression of viral replication to arrest and reverse the progression of the liver injury.
Current therapeutic approach of HBeAg-negative CHB includes treatment with interferon-alpha, lamivudine (LAM), adefovir dipivoxil (ADV), entecavir and telbivudine. The excellent safety and tolerability profile of LAM leads to long-term therapies which, however, have been associated with the emergence of viral resistance because of selection of resistant mutants. Clinical data showed that emergence of LAM-resistant mutations can be associated with hepatitis flares, hepatic decompensation and death. ADV is active against not only wild, but also LAM-resistant HBV strains. In contrast to LAM, resistance to ADV seems to occur less frequently and later in the course of long-term treatment. Resistance to ADV is related mostly to the emergence of mutation at codon 236 (asparagine to threonine, rtN236T) or at codon 181 (alanine to valine, rtA181V) of the HBV polymerase gene. In naive patients receiving ADV, genotypic resistance is observed in 3% of patients at year 2, 11% at year 3, 18% at year 4 and 29% at year 5. Although in vitro susceptibility to ADV is reduced only by two- to 13-folds, ADV resistance can be associated with viral rebound and decompensation.
Clinical studies have shown that virological and biochemical improvements are observed in LAM-resistant patients after the addition of ADV to ongoing LAM or with ADV monotherapy. In a randomized-controlled trial in HBeAg-positive CHB, ADV alone and ADV plus LAM combination therapy were found to achieve similar reductions of serum HBV-DNA after 1 year of treatment. The efficacy of long-term ADV monotherapy or combination of ADV and LAM in HBeAg-negative CHB patients with LAM-resistant CHB is still under investigation.
When ADV was first available in an expanded access programme for patients with LAM resistance, two different strategies (adding vs. switching) were followed by the clinicians regarding the continuation of LAM. In this prospective nonrandomized study, we report the efficacy and safety of long-term LAM and ADV combination therapy compared with ADV monotherapy in HBeAg-negative CHB patients with LAM resistance. In addition, we determined the incidence and risk factors of resistance to ADV in this setting in clinical practice.