Evaluating the efficacy of switching from lamivudine plus adefovir to tenofovir disoproxil fumarate monotherapy in lamivudine-resistant stable hepatitis B patients

Heon Ju Lee, Sang Jin Kim, Young Oh Kweon, Soo Young Park, Jeong Heo, Hyun Young Woo, Jae Seok Hwang, Woo Jin Chung, Chang Hyeong Lee, Byung Seok Kim, Jeong Ill Suh, Won Young Tak, Byoung Kuk Jang, Heon Ju Lee, Sang Jin Kim, Young Oh Kweon, Soo Young Park, Jeong Heo, Hyun Young Woo, Jae Seok Hwang, Woo Jin Chung, Chang Hyeong Lee, Byung Seok Kim, Jeong Ill Suh, Won Young Tak, Byoung Kuk Jang

Abstract

Background: The efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear.

Methods: In this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96.

Results: Patients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000).

Conclusions: Stable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function.

Trial registration: ClinicalTrials.gov NCT01732367.

Conflict of interest statement

Competing Interests: This investigator-initiated trial was supported by the grant from Gilead science.(IN-US-174-0209, http://www.gilead.com) Gilead science was permitted to review the manuscript, but had no role in the study design, data collection, analysis, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study design and patient flow…
Fig 1. Study design and patient flow for both arms.

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