engleski

Resistance of hepatitis B virus to lamivudine and adefovir in patients with chronic hepatitis B treated at the University Hospital for infectous diseases ˝dr. Fran Mihaljevic˝ during 2008 and 2009

Background: Current treatment options for chronic hepatitis B include pegylated interferon alpha, lamivudine, adefovir, entecavir, telbivudine and tenofovir. The development of resistance to nucleotide analogues is a recognized challenge to successful treatment of chronic hepatitis B. Lamivudine monotherapy is the predominant therapeutic option in Croatia. Objective: To analyze molecular patterns of HBV resistance to lamivudine and adefovir in patients with chronic hepatitis B treated at the Croatian Reference Center for Viral Hepatitis. Patients and methods: The study enrolled 54 patients (66 resistance tests) treated at the Outpatient Clinics for Viral Hepatitis and Department of Viral Hepatitis at the University Hospital for Infectious Diseases in Zagreb, Croatia in the period 2008-2009. All patients included in the study were treated with lamivudine (median of treatment duration 28 months, range 9-72 months) and nine of them were also previously treated with interferon-alpha. Two patients that were treated with interferon alpha and lamivudine, also received adefovir (n=1) or adefovir and entecavir (n=1). Plasma viremia was determined by using COBAS AmpliPrep-COBAS TaqMan (Roche, Branchburg, NJ, USA). In patients with viremia > 1000 copies of HBV DNA per ml, resistance mutations were analyzed by INNO-LIPA HBV DR v2 line probe assay (Innogenetics, Solvay Pharmaceuticals, Brussles, Belgium). Results: HBV resistance to antiviral drugs was detected in 28 of 54 patients that were treated with lamivudine for a median of 31.5 months (range 9-72 months). Five of 28 patients with antiviral resistance were previously also underwent interferon treatment. HBV resistance was also shown in two patients treated with lamivudine, interferonalpha, adefovir (one of them also with entecavir). The most frequent resistance mutations associated with resistance to lamivudine were M204V/I (n=28 patients). Combination of primary and compensatory mutations associated with resistance to lamivudine (M204V + L180M) were detected in 16 of 28 patients with resistance. More complex patterns of both M204I and M204V in association with compensatory mutation L180M were shown in 7 of 28 patients that underwent lamivudine treatment for 2 to 6 years. Mutations associated with resistance to adefovir (A181T/V and N236T) were detected only in the patient that was treated with adefovir for 3 years. Twenty-six of 54 patients showed no evidence of resistance to antiviral drugs. Median lamivudine treatment duration in patients without resistance to antiviral drugs was 26.5 months (range 14-60 months). Conclusion: Analysis of molecular patterns associated with drug resistance in the patients treated at the Croatian Reference Center for Viral Hepatitis showed the predominance of rtM204V/I mutations associated with lamivudine resistance. These mutations are also associated with cross-resistance to telbivudine and intermediate resistance to entecavir limiting future therapeutic options.

Treatment; hepatitis B; lamivudine; adefovir

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