ENTECAVIR MONOTHERAPY VERSUS ENTECAVIR PLUS ADEFOVIR COMBINATION FOR CHRONIC HEPATITIS B PATIENTS WITH SEQUENTIAL LAMIVUDINE-ADEFOVIR RESISTANCE

초록

Background Multi-drug resistance development after sequential nucleos(t)ide therapy emerged as a major clinical concern in chronic hepatitis B (CHB) infections. Therapeutic options are still limited in countries where the reimbursement policy of new antiviral drugs is restricted. Aim of our study is to compare the efficacy and clinical outcomes of entecavir (ETV) 1.0 mg monotherapy with ETV plus adefovir (ADV) combination therapy in CHB patients who developed multi-drug resistance after sequential lamivudine (LAM)-ADV therapy. Methods A total of 45 CHB patients with the documented presence of genotypic resistance mutation to ADV after sequential LAM-ADV therapy were enrolled. Of these, 22 patients were treated with ETV 1mg (ETV group) and 23 patients were treated with ETV 1 mg plus ADV 10 mg combination (ETV/ADV combination group). Results There were no significant differences in baseline characteristics except serum ALT levels (45.05 ±29.95 in ETV group versus 74.09 ±80.94 in ETV/ADV combination group). After ADV resistance development, median duration of rescue therapy was 19.5 months in the ETV group and 24 months in the ETV/ADV combination group. After 12 months of ETV monotherapy or ETV-ADV combination therapy, mean reduction of serum HBV DNA levels (log10 copies/ml) were 2.36 ±1.69, and 2.96 ±1.72 respectively (p=0.049). Virologic response (defined as serum HBV less than 300 copies/ml)occurred in 8 of 22 (36.4%) in the ETV group and 10 of 23(43.5%) in the ETV/ADV combination group (p=0.626) during the rescue therapy. Virologic breakthrough occurred in 16 of 22 (72.7%) in the ETV group and 3 of 23 (13.0%) in the ETV/ADV combination group (p=0.000) during the rescue therapy. Median time of virologic breakthrough occurrence was 18 months in the ETV group and 12 months in the ETV/ADV group. During the rescue therapy, cumulative rate of virologic breakthrough was significantly higher in the ETV group (p=0.001). Genotypic resistance for ETV was detected in 11 of 16 in the ETV group and none of 3 in the ETV/ADV combination group. Cumulative rate of genotypic resistance development for ETV was also significant higher in the ETV group (p=0.000). Conclusion ETV plus ADV combination therapy was more effective in suppressing serum hepatitis B virus DNA and in preventing antiviral resistance development than ETV monotherapy in CHB patients who developed sequential LMV-ADV resistance. Because tenofovir is still not available in some countries, these results have clinical implications in managing multi-drug resistant CHB infections.