Two-Year Assessment of Entecavir Resistance in Lamivudine-Refractory Hepatitis B Virus Patients Reveals Different Clinical Outcomes Depending on the Resistance Substitutions Present

Abstract

Entecavir (ETV) is a deoxyguanosine analog approved for use for the treatment of chronic infection with wild-type and lamivudine-resistant (LVDr) hepatitis B virus (HBV).In LVD-refractory patients, 1.0 mg ETV suppressed HBV DNA levels to below the level of detection by PCR (<300 copies/ml) in 21% and 34% of patients by Weeks 48 and 96, respectively. Prior studies showed that virologic rebound due to ETV resistance (ETVr) required preexisting LVDr HBV reverse transcriptase substitutions M204V and L180M plus additional changes at T184, S202, or M250. To monitor for resistance, available isolates from 192 ETV-treated patients were sequenced, with phenotyping performed for all isolates with all emerging substitutions, in addition to isolates from all patients experiencing virologic rebounds. The T184, S202, or M250 substitution was found in LVDr HBV at baseline in 6% of patients and emerged in isolates from another 11/187 (6%) and 12/151 (8%) ETV-treated patients by Weeks 48 and 96, respectively. However, use of a more sensitive PCR assay detected many of the emerging changes at baseline, suggesting that they originated during LVD therapy. Only a subset of the changes in ETVr isolates altered their susceptibilities, and virtually all isolates were significantly replication impaired in vitro. Consequently, only 2/187 (1%) patients experienced ETVr rebounds in year 1, with an additional 14/151 (9%) patients experiencing ETVr rebounds in year 2. Isolates from all 16 patients with rebounds were LVDr and harbored the T184 and/or S202 change. Seventeen other novel substitutions emerged during ETV therapy, but none reduced the susceptibility to ETV or resulted in a rebound. In summary, ETV was effective in LVD-refractory patients, with resistant sequences arising from a subset of patients harboring preexisting LVDr/ETVr variants and with approximately half of the patients experiencing a virologic rebound.More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV) (32); and many will ultimately develop severe liver disease, including cirrhosis, hepatocellular carcinoma, and liver failure. Significant improvements in patient outcomes have been realized since the use of antiviral therapy for HBV. Due to the poor efficacies of these therapies and the emergence of viral resistance, however, additional therapies are needed (16). Prior to 2005, HBV therapies included parenteral regimens containing interferon alfa and the oral nucleoside/nucleotide analogs lamivudine (LVD) and adefovir dipivoxil (ADV). However, interferon alfa shows poor response rates and poor sustained efficacy (ϳ30 to 40% [reviewed in reference 18]), has low tolerability, and is contraindicated in patients with decompensated liver disease. LVD and ADV are associated with the development of viral resistance. LVD resistance (LVDr) is reported to occur in 24% of patients treated for 1 year, and this rate increases to 70% after 4 years (19). The rate of ADV resistance (ADVr) in nucleoside-naïve HBeAg-negative HBV patients has been r...

A comparison of lamivudine vs entecavir for prophylaxis of hepatitis B virus reactivation in allogeneic hematopoietic stem cell transplantation recipients: a single-institutional experience

“…Several studies have revealed that the 2-year incidence rate of drug-resistance mutations for lamivudine is significantly higher than that of entecavir (18% vs 1%) in immunocompetent patients with chronic HBV infection. 16,17 Our study showed that the 2-year incidences of drug-resistance mutations were 21.0% for lamivudine and 1.0% for entecavir in allo-HSCT recipients, and this is consistent with outcomes seen in immunocompetent patients. These findings imply that the incidence of drug-resistance mutations might not be associated with impaired immune function in allo-HSCT patients.…”

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

“…In this study, there was no evidence of emerging substitutions associated with virologic resistance to entecavir. Extended treatment and observation through 2 years in a similar trial with entecavir in this patient population showed that virologic breakthrough due to entecavir resistance was observed in 9% of patients [29].…”

Two cases of development of entecavir resistance during entecavir treatment for nucleoside-naive chronic hepatitis B

“…However, in LVD-refractory patients, the barrier to resistance is lower because the suppression of HBV replication is not as great and these patients mostly harbor virus with two of the three substitutions required for high-level ETVr [26]. This results in virologic breakthrough with ETVr in LVD-refractory patients at 1% in the first year but increasing to 39.5% after 4 years of therapy [15].…”

“…In the first case, the patient received a lower dose of ETV (0.1 mg daily for 52 weeks) than is currently recommended in product labeling. It was shown that LVD-ADV combination therapy was apparently effective for the ETV-resistant strain, presumably because there is no cross-resistance between ETV and ADV [26,27].…”