Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir

Abstract

Aim: To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV.

Methods: This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48.

Results: The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m(2) in the LdT + ADV group increased from 49.1% (26/53) at baseline to 58.5% (31/53) at week 48, while that in the LAM + ADV group decreased from 37.7% (20/53) at baseline to 30.2% (16/53) at week 48.

Conclusion: The switch to LdT + ADV in suboptimal responders to LAM + ADV showed a significantly higher rate of virologic response at week 48. These results suggest that LdT + ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.

Trial registration: ClinicalTrials.gov NCT01270165.

Keywords: Antiviral resistance; Chronic hepatitis B; Lamivudine; Suboptimal response; Telbivudine.

Figures

Figure 1

Flow diagram of study participants. LMA: Lamivudine; ADV: Adefovir; LdT: Telbivudine; HBV: High hepatitis B virus; HBeAg: Hepatitis Be antigen.

Figure 2

Proportion of patients with undetectable serum hepatitis B virus DNA (1Undetectable < 12 IU/mL. LAM: Lamivudine; ADV: Adefovire; HBV: High hepatitis B virus; LdT: Telbivudine; PCR: Polymerase chain reaction.

Figure 3

Mean hepatitis B virus DNA levels over time in the two groups. LAM: Lamivudine; ADV: Adefovire; HBV: Hepatitis B virus; LdT: Telbivudine.

Figure 4

Mean reduction of serum hepatitis B virus DNA levels from baseline. Mean hepatitis B virus (HBV) DNA (log10 IU/mL) were plotted over time. Error bars indicate the standard deviation (aP value < 0.05). LAM: Lamivudine; ADV: Adefovire; LdT: Telbivudine.

Figure 5

Estimated glomerular filtration rate over time in the two groups (A), and proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m2 at baseline and week 48 (B). LAM: Lamivudine; ADV: Adefovire; HBV: High hepatitis B virus; LdT: Telbivudine. GFR: Glomerular filtration rate

Figure 6

Serial changes of mean serum hepatitis B virus DNA levels. Serum hepatitis B virus DNA levels decreased significantly not only from baseline to 12 wk but also from 12 wk to 24 wk in the LdT + ADV group. LAM: Lamivudine; ADV: Adefovire; HBV: High hepatitis B virus; LdT: Telbivudine.