Sustained virological and biochemical responses to lamivudine and adefovir dipivoxil combination in a chronic hepatitis B infection despite mutations conferring resistance to both drugs

A patient with chronic hepatitis B was successively treated with lamivudine monotherapy, lamivudine-adefovir dual therapy, adefovir monotherapy and again with an adefovir-lamivudine dual therapy. Lamivudine-associated mutations (rtL180M and rtM204V/I) followed by adefovir-associated mutations (rtN236T and rtA181V) emerged during the two monotherapy regimens. Despite the presence of rtM204V/I, rtA181V, and rtN236T mutations at the beginning of the second dual therapy, sustained biochemical and virological responses have been observed thus far after 23 months.This case illustrates that rtM204V/I, rtA181V, and rtN236T resistance mutations can coexist in a patient but do not preclude the recycling of lamivudine and adefovir in combination therapy, when no other therapeutic choices are available.The treatment of chronic hepatitis B with oral nucleoside (e.g., lamivudine, entecavir) and nucleotide (e.g., adefovir) analogs that inhibit viral polymerase reverse transcriptase activity has dramatically modified the management of infected patients but is hampered by the emergence of resistant strains containing mutation in the reverse transcriptase (rt) part of the HBV polymerase gene (HBV Pol). The main lamivudine resistance mutations were mapped in the C and B domains of HBV Pol, and the specific mutations selected were rtM204I/V/S (domain C) and rtL180M (domain B) [1]. Resistance to adefovir is associated with B and D domain enzyme mutations. The major mutations observed with adefovir-resistant HBV are identified as rtN236T (domain D) and rtA181V (domain B) [2-5]. Lamivudine-resistance mutations were detected in 15–30% of treated patients after 1 year of therapy and up to 70% after 5 years [6]. Resistance to adefovir is thought to be less common and occurs later in the course of treatment as compared to lamivudine [7,8]. Nevertheless, a rate of 29% has been described after 5 years of therapy [9].In 2000, a 35-year-old Turkish man (91 kg for 1.70 m; BMI: 31.5) was found to h