Entecavir in HBV After Suboptimal Response to Adevofir
Entecavir in HBV After Suboptimal Response to Adevofir
Background An increasing number of patients with chronic hepatitis B (CHB) have experienced treatment failure to adefovir (ADV) and their management poses a growing challenge. Very limited data are available on the efficacy of entecavir (ETV) in patients previously treated with ADV.
Aim To examine the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response.
Methods Study candidates were enrolled from five community gastroenterology clinics in the U.S. Each completed at least 12 months of ETV treatment after being previously treated with ADV and experiencing suboptimal response. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV DNA <100 IU/mL) and biochemical response (BR, ALT <40 U/L), respectively.
Results A total of 60 patients were included in this analysis. Twelve were lamivudine (LAM)-experienced and none were LAM-resistant. At time of switch to ETV, no patients had experienced CVS. The CVS rate was 68% after 12 months of ETV therapy. The BR rate was 67% at switch to ETV and 80% after 12 months. There was no significant difference in response rates between LAM-experienced and naïve patients. Among the eight patients with ADV resistance, each achieved CVS after 12 months of ETV therapy and seven achieved BR.
Conclusions In patients with suboptimal response to adefovir, complete viral suppression and biochemical response can be achieved in the majority by 12 months after switching to entecavir, including patients with prior exposure to lamivudine and those with adefovir resistance.
One of the primary objectives of anti-viral therapy for chronic hepatitis B (CHB) is complete suppression of viral replication. The importance of suppressing serum hepatitis B virus (HBV) DNA levels has been extensively studied. The degree of HBV viremia correlates with reduced risk for disease progression, cirrhosis and hepatocellular carcinoma. Rapid complete virological response after starting nucleos(t)ide analogue therapy is further associated with a lower rate of resistance development to anti-viral drugs over the long-term.
Adefovir (ADV) is the second oral drug approved for treatment of chronic hepatitis B. It is an acyclic phosphonate nucleotide analogue of adenosine monophosphate. Originally developed for the treatment of HIV, the FDA decided in 1999 against awarding approval for this indication due to concerns about renal toxicity. ADV was approved for the treatment of HBV in 2002 after demonstrating effectiveness at a much lower dose. Studies have demonstrated that after 48 weeks of treatment, ADV yields virological, biochemical and histological improvement in a significant number of both HBeAg positive and HBeAg negative HBV patients. ADV has demonstrated limited resistance during the first 1–2 years of treatment. It has also been a valuable alternative for lamivudine (LAM)-resistant HBV infection with its absence of cross-resistance with L-nucleosides. The durability of HBeAg seroconversion is similar to that of other oral anti-virals. However, ADV has significant limitations. It has a high rate of primary nonresponse, defined as failure to achieve a 1–log10 reduction in viral load after 12 weeks of therapy possibly because of the low dosage needed to avoid renal toxicity. In addition, though they may appear to be low at first, resistance rates can approach up to 30% after five years of treatment
Entecavir (ETV) is a selective cyclopentyl guanosine analogue with potent activity against HBV. It is potent because of its unique mechanism of inhibiting the three functions of the HBV DNA polymerase: priming, reverse transcription and synthesis of positive-strand HBV DNA. ETV also has a long intracellular half-life enabling accumulation of intracellular entecavir triphosphate. In two large phase III double-blind trials, ETV demonstrated higher rates of histological, virological and biochemical improvement than LAM after 48 weeks of treatment in both nucleoside-naïve HBeAg positive and HBeAg negative patients. The high potency of ETV is complemented by a very low resistance rate (≤1%) after four years of treatment. This may be due to rapid and sustained suppression of serum HBV DNA and high genetic barrier to resistance requiring three or more substitutions. ETV also has an excellent safety profile, equivalent to that of LAM, which has a similar safety profile as placebo in clinical trials.
Due to the low potency of ADV, a significant population of patients treated with ADV have only experienced suboptimal response with incomplete viral suppression, which predisposes them to the consequences of unsuppressed HBV viral load and future anti-viral resistance. Alternative therapy with a more potent agent such as ETV or combination therapy is recommended in this setting. There are very limited data available on the treatment efficacy of ETV in patients previously treated with ADV. This study examines the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response to ADV.
Abstract and Introduction
Abstract
Background An increasing number of patients with chronic hepatitis B (CHB) have experienced treatment failure to adefovir (ADV) and their management poses a growing challenge. Very limited data are available on the efficacy of entecavir (ETV) in patients previously treated with ADV.
Aim To examine the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response.
Methods Study candidates were enrolled from five community gastroenterology clinics in the U.S. Each completed at least 12 months of ETV treatment after being previously treated with ADV and experiencing suboptimal response. Primary and secondary outcome measurements were complete viral suppression (CVS, HBV DNA <100 IU/mL) and biochemical response (BR, ALT <40 U/L), respectively.
Results A total of 60 patients were included in this analysis. Twelve were lamivudine (LAM)-experienced and none were LAM-resistant. At time of switch to ETV, no patients had experienced CVS. The CVS rate was 68% after 12 months of ETV therapy. The BR rate was 67% at switch to ETV and 80% after 12 months. There was no significant difference in response rates between LAM-experienced and naïve patients. Among the eight patients with ADV resistance, each achieved CVS after 12 months of ETV therapy and seven achieved BR.
Conclusions In patients with suboptimal response to adefovir, complete viral suppression and biochemical response can be achieved in the majority by 12 months after switching to entecavir, including patients with prior exposure to lamivudine and those with adefovir resistance.
Introduction
One of the primary objectives of anti-viral therapy for chronic hepatitis B (CHB) is complete suppression of viral replication. The importance of suppressing serum hepatitis B virus (HBV) DNA levels has been extensively studied. The degree of HBV viremia correlates with reduced risk for disease progression, cirrhosis and hepatocellular carcinoma. Rapid complete virological response after starting nucleos(t)ide analogue therapy is further associated with a lower rate of resistance development to anti-viral drugs over the long-term.
Adefovir (ADV) is the second oral drug approved for treatment of chronic hepatitis B. It is an acyclic phosphonate nucleotide analogue of adenosine monophosphate. Originally developed for the treatment of HIV, the FDA decided in 1999 against awarding approval for this indication due to concerns about renal toxicity. ADV was approved for the treatment of HBV in 2002 after demonstrating effectiveness at a much lower dose. Studies have demonstrated that after 48 weeks of treatment, ADV yields virological, biochemical and histological improvement in a significant number of both HBeAg positive and HBeAg negative HBV patients. ADV has demonstrated limited resistance during the first 1–2 years of treatment. It has also been a valuable alternative for lamivudine (LAM)-resistant HBV infection with its absence of cross-resistance with L-nucleosides. The durability of HBeAg seroconversion is similar to that of other oral anti-virals. However, ADV has significant limitations. It has a high rate of primary nonresponse, defined as failure to achieve a 1–log10 reduction in viral load after 12 weeks of therapy possibly because of the low dosage needed to avoid renal toxicity. In addition, though they may appear to be low at first, resistance rates can approach up to 30% after five years of treatment
Entecavir (ETV) is a selective cyclopentyl guanosine analogue with potent activity against HBV. It is potent because of its unique mechanism of inhibiting the three functions of the HBV DNA polymerase: priming, reverse transcription and synthesis of positive-strand HBV DNA. ETV also has a long intracellular half-life enabling accumulation of intracellular entecavir triphosphate. In two large phase III double-blind trials, ETV demonstrated higher rates of histological, virological and biochemical improvement than LAM after 48 weeks of treatment in both nucleoside-naïve HBeAg positive and HBeAg negative patients. The high potency of ETV is complemented by a very low resistance rate (≤1%) after four years of treatment. This may be due to rapid and sustained suppression of serum HBV DNA and high genetic barrier to resistance requiring three or more substitutions. ETV also has an excellent safety profile, equivalent to that of LAM, which has a similar safety profile as placebo in clinical trials.
Due to the low potency of ADV, a significant population of patients treated with ADV have only experienced suboptimal response with incomplete viral suppression, which predisposes them to the consequences of unsuppressed HBV viral load and future anti-viral resistance. Alternative therapy with a more potent agent such as ETV or combination therapy is recommended in this setting. There are very limited data available on the treatment efficacy of ETV in patients previously treated with ADV. This study examines the effect of ETV monotherapy on HBV DNA and ALT levels in CHB patients previously treated with ADV, but switched to ETV due to suboptimal response to ADV.