Randomized Trial of Entecavir plus Adefovir in Patients with Lamivudine-Resistant Chronic Hepatitis B Who Show Suboptimal Response to Lamivudine plus Adefovir

Abstract

A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudineresistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV؉ADV, n ‫؍‬ 45) or continuation of lamivudine plus adefovir (LAM؉ADV, n ‫؍‬ 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log 10 IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV؉ADV group than in the LAM؉ADV group (n ‫؍‬ 13, 29%, versus n ‫؍‬ 2, 4%, respectively; P ‫؍‬ 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV؉ADV group than in the LAM؉ADV group (؊2.2 log 10 IU/ml versus ؊0.6 log 10 IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV؉ADV group but in 15% of patients in the LAM؉ADV group (P ‫؍‬ 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.

Randomized Trial of the Virologic Response during up to Two Years of Entecavir-Adefovir Combination Therapy in Multiple-Drug-Refractory Chronic Hepatitis B Virus Patients

“…The study cohort originally participated in a 52-week randomized controlled trial comparing the efficacy of ETV plus ADV with that of continued LAM plus ADV (18). All but one of the 90 subjects enrolled in this extension study and received ETV plus ADV for an additional 52 weeks (Fig.…”

“…The two a Baseline, week 0 in the original 52-week study (18). LA-EA, group of patients who were treated with combination of lamivudine (100 mg/day) and adefovir (10 mg/day) for 52 weeks and then with a combination of entecavir (1 mg/day) and adefovir for 52 weeks.…”

“…Consequently, a substantial proportion of patients have a suboptimal virological response (VR) during LAM plus ADV combination therapy (12)(13)(14). The efficacy of ETV or TDF monotherapy may also be lower in patients who fail to respond to LAM plus ADV than in treatment-naive patients (15)(16)(17).The combination of ETV, a nucleoside analogue, and ADV, a nucleotide analogue, has been shown to be a useful treatment option for patients who have failed various NUC therapies (18)(19)(20). This combination was assessed in a 52-week randomized trial in 90 CHB patients with suboptimal VRs after combination treatment with LAM plus ADV for lamivudine-resistant HBV (18).…”

“…This combination was assessed in a 52-week randomized trial in 90 CHB patients with suboptimal VRs after combination treatment with LAM plus ADV for lamivudine-resistant HBV (18). Patients treated with ETV plus ADV had a significantly higher rate of VR (serum HBV DNA Ͻ 60 IU/ml) than those who continued treatment with LAM plus ADV (29% versus 4%).…”

“…The combination of ETV, a nucleoside analogue, and ADV, a nucleotide analogue, has been shown to be a useful treatment option for patients who have failed various NUC therapies (18)(19)(20). This combination was assessed in a 52-week randomized trial in 90 CHB patients with suboptimal VRs after combination treatment with LAM plus ADV for lamivudine-resistant HBV (18).…”