703 Multidrug-Resistant Chronic Hepatitis B -Impact on Therapy Outcome

Abstract

BACKGROUND: The occurrence of Hepatitis B virus (HBV) polymerase mutations was a major limitation of chronic hepatitis B (CHB) treatment until the introduction of entecavir (ETV) and tenofovir (TDF). Cross-resistance to ETV is well documented in the presence lamivudine (LAM) resistance mutations and ETV specific mutations. To date, no mutations that confer resistance to TDF have been described, nevertheless adefovir (ADF)-associated resistance mutation N236T proved to confer low-level resistance to TDF in studies in vitro. METHODS AND AIMS: Retrospective analysis of HBV monoinfected patients treated with TDF or ETV that performed viral mutations testing (mostly INNO-LiPA hybridization assays, Innogenetics, Belgium) in a single center. Evaluation of the efficacy of antiviral therapy in the presence of multidrug-resistantmutants (MDR). RESULTS: In a group of 181CHBpatients treated with TDF or ETV (5% combination TDF+ETV), 89 (49%) had HBV polymerase gene mutation analysis. Sixty-eight patients (76% of tested) presented several mutations including N236T and 8% had only nucleoside resistant strains. MDR were detected in 9% of naive patients and 49.5% of previously treated patients. Fifty-three (78%) of the MDRHBV patients were treated with TDF and 15 (22%) were taking ETV. MDR were more frequent in HBeAg positive hepatitis (p 250 IU/mL at the beginning of therapy (p=0.002) and baseline HBV viral load >100000 IU/mL (p=0.008) were predictive of MDR presence. During therapy, patients without MDR achieved more HBeAg negativation (p=0.007), anti-HBe seroconversion (p=0.019) and more frequently achieved HBV DNA suppression (p=0.003). Globally, mean treatment duration until HBV DNA undetectability was 24.8 months with MDR versus 8.2 months without (p<0.001). In MDR CHB patients, treatment with TDF was associated with greater HBV DNA supression than ETV (p<0.001), and shorter time to undetectability (18.9 versus 45.2 months, p=0.001). In multivariate analysis, baseline MDR (p<0.001), HbeAg positive (p<0.001) and viremia (p=0.043) were independently associated with longer time to HBV DNA undetectability. CONCLUSIONS: Multidrug-resistant CHB was detected in 9% of naive patients and in half of those previously treated. Its occurrence was associated with more difficult to treat CHB and slower treatment response. TDF was more effective than ETV in MDR HBV patients. This impact in antiviral therapy could have implications in CHB management, particularly in severe cases with decompensated cirrhosis and/or indication for liver transplantation.