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

<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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)</p><p>Conclusions</p><p>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.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01732367" target="_blank">NCT01732367</a></p></div

LAM-resistance mutation profiles and previous treatment period.

<p>LAM-resistance mutation profiles and previous treatment period.</p

Comparison between two groups after 96-week follow-up.

<p>Comparison between two groups after 96-week follow-up.</p

Baseline characteristics of patients.

<p>Baseline characteristics of patients.</p

Details of the 25 patients with transient virologic rebound or withdrawal from the trial.

<p>Details of the 25 patients with transient virologic rebound or withdrawal from the trial.</p

Kaplan-Meier survival curves according to the time of ACLF development.

<p>(A) AARC definition, (B) CLIF-C definition. Abbreviations: ACLF, Acute-on-chronic liver failure; AARC, Asian Pacific Association for the Study of the Liver ACLF Research Consortium; CLIF-C, Chronic liver failure consortium</p

Twenty-eight- and 90-day mortality.

<p>(A) According to the presence of cirrhosis (*15 of patients without LC and 148 patients with LC were lost to follow-up) and (B) according to the presence of ACLF (**138 of patients without ACLF and 31 patients with ACLF were lost to follow-up). Abbreviations: LC, liver cirrhosis; ACLF, acute-on-chronic liver failure</p

Diagram of the total enrolled patients.

<p>(A) acute deterioration with chronic liver disease (enrolled patients) (N = 1470); (B) CLD patients without prior history of decompensation (N = 1021); (C) cirrhotic patients regardless of prior history of decompensation (N = 1352); (D) ACLF development according to the AARC definition (N = 140); (E) ACLF development according to the CLIF-C definition (N = 274); (F) ACLF development according to the AARC and CLIF-C definitions (N = 74). Abbreviations: CLD, chronic liver disease; ACLF, acute-on-chronic liver failure; AARC, Asian Pacific Association for the Study of the Liver ACLF Research Consortium; CLIF-C, Chronic liver failure consortium</p

Ninety-day survival curves according to previous acute decompensation.

<p>(A) Without previous AD vs. with previous AD and (B) without previous AD vs. AD more than 1 year prior vs. AD within 1 year. Abbreviation: AD, acute decompensation</p

Twenty-eight- and 90-day mortality of patients with ACLF.

<p>(A) AARC definition, (B) CLIF-C definition. *One hundred sixty-three patients were lost to follow up. Abbreviations: AARC, Asian Pacific Association for the Study of the Liver ACLF Research Consortium; CLIF-C, Chronic liver failure consortium</p