[159, 161, 166] Reported factors related to HBeAg negative conversion were ALT level (high), and the history of IFN therapy in the past.[159, 166] If hepatitis associated with lamivudine-resistant HBV occurs, adefovir resistance develops if therapy is changed from lamivudine to adfovir, but if lamivudine+adefovir combination therapy is administered, PD98059 clinical trial the reported incidence of HBV resistant to both agents is low.[191] Entecavir therapy is also administered to patients with lamivudine-resistant HBV (including cases unresponsive to lamivudine). The short-term results for entecavir therapy are good, and in some USA studies reported an HBV DNA negative

conversion rate of 21% at 1 year, and 34–40% at 2 years, and an ALT normalization rate of 65% at 1 year, and 81% at 2 years.[192, 193] However, the appearance of entecavir-resistant HBV associated with long term administration of entecavir has been confirmed. The incidence of entecavir-resistant HBV was 6% at 1 year and 8–13% at 2 years, and rebound of the HBV DNA load due to entecavir-resistant

HBV was 1% at 1 year and 9% at 2 years. A Japanese study reported favorable results with a HBV DNA negative conversion rate of 16% at 6 months and 33% at 1 year, and ALT normalization rate of 78% at 6 months and 81% at 1 year,[194-196] although entecavir-resistant HBV was detected in 26% Natural Product Library nmr of cases up to year 3, in whom hepatitis rebounded in 40%.[196] In this way, entecavir therapy for lamivudine-resistant (or unresponsive) HBV may also produce viral strains resistant to entecavir. Recommendations Lamivudine+adefovir combination therapy is recommended for treatment of lamivudine-resistant HBV. Entecavir therapy of lamivudine-resistant HBV may also produce viral strains resistant to entecavir. Reported adefovir-resistant

mutations include rtA181V/T, rtI233V and rtN236T in the HBV polymerase reverse transcriptase (rt) region. Of these mutations, in vitro and in vivo testing has demonstrated sensitivity to both lamivudine and entecavir for the rtN236T mutation, but lamivudine resistance for the rtA181V mutation.[7, 197] 上海皓元医药股份有限公司 In 132 patients with lamivudine-resistant HBV treated with lamivudine+adefovir combination therapy, multiple resistant strains were seen in 3 cases before the commencement of adefovir therapy, and in 2 further cases after therapy commenced (overall incidence 4%).[168] Entecavir+adefovir combination therapy is administered to patients with HBV resistant to both lamivudine and adefovir, with undetermined results. On the other hand, in reports from Europe, in cases with resistance to lamivudine or adefovir monotherapy, or resistant/unresponsive to lamivudine+adefovir combination therapy, administration of the new agent tenofovir (median treatment period 23 months) yielded HBV DNA negative conversion in 79% of cases, HBeAg negative conversion in 24%, and HBsAg negative conversion in 3%.