Efficacy of entecavir-tenofovir combination therapy for chronic hepatitis B patients with multidrug-resistant strains

Abstract

The emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P = 0.072 and P = 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.

FIG 1

Changes in HBV viral loads during the rescue therapy. The changes in serum HBV DNA levels from baseline during the treatment period, plotted as mean log₁₀ change from baseline values, are shown for each group. The data represent the means for 45 patients in the LAM/ETV-R group, 28 patients in the LAM/ADV-R group, and 20 patients in the LAM/ETV/ADV-R group at months 3, 6, and 12. Among the three groups, the declines in serum HBV DNA levels differed significantly at month 3 (P = 0.008) but not at months 6 and 12 (P = 0.719 and P = 0.377, respectively). The error bars represent the standard deviations. HBV, hepatitis B virus; LAM, lamivudine; ETV, entecavir; ADV, adefovir.

FIG 2

Cumulative probability of complete virologic suppression during the rescue therapy. Cumulative probabilities of complete virologic suppression, i.e., undetectable levels of HBV DNA according to PCR assays, during the treatment period are shown for each group. LAM, lamivudine; ETV, entecavir; ADV, adefovir.

FIG 3

Weighted cumulative probability of complete virologic suppression during the rescue therapy. Weighted cumulative probabilities of complete virologic suppression during the treatment period are shown for each group. LAM, lamivudine; ETV, entecavir; ADV, adefovir.