Treatment Efficacy and Safety of Tenofovir-Based Therapy in Chronic Hepatitis B: A Real Life Cohort Study in Korea

<div><p>Background & Aims</p><p>We evaluated the efficacy and safety of Tenofovir disoproxil fumarate (TDF)-based therapy in naïve and treatment-experienced chronic hepatitis B (CHB) patients for 96 weeks in Korean real life practice.</p><p>Methods</p><p>A total of 209 CHB patients with a prescription for TDF at the Seoul and Daejeon St. Mary’s hospitals were enrolled from December 2012 to October 2014. We compared the virological responses and evaluated the renal safety of treatment-naive and treatment-experienced patients.</p><p>Results</p><p>An overall complete virological response (CVR) was achieved in 80.4% and 84.6% of patients at weeks 48 and 96, respectively. In a subgroup analysis, CVR at week 96 was present in 88.4%, 75.0%, 75.5%, and 83.3% of participants in the lamivudine-resistant (LAM-R) group, adefovir-resistant (ADV-R) group, multidrug-resistant (MDR) group, and suboptimal response group, respectively. In a multivariate analysis, ADV-R, MDR, hepatitis B virus DNA, and hepatitis B e antigen were independent predictors for CVR. With regard to renal safety, diabetes mellitus, cirrhosis, and an initial low estimated glomerular filtration rate were independent factors affecting creatinine elevation (≥0.5 mg/dL). Moreover, two patients with DM and cirrhosis experienced TDF-related Fanconi syndrome.</p><p>Conclusions</p><p>TDF-based therapy demonstrated sustained viral suppression and favorable safety during a 2-year treatment period. The LAM-R and suboptimal response groups showed comparable efficacy to the naïve group, while the ADV-R and MDR groups were significantly associated with a low CVR. Close monitoring of renal safety should be mandatory when treating CHB patients receiving TDF, particularly those with DM and cirrhosis.</p></div

Univariate and multivariate Cox proportional hazard analyses predicting factors for CVR.

<p>Univariate and multivariate Cox proportional hazard analyses predicting factors for CVR.</p

Cumulative rates of a complete virological response (CVR) at week 96 according to HBeAg status.

<p>Comparison of CVR between HBeAg (+) patients and HBeAg (-) patients (80.0% vs. 93.2%, <i>P</i> < 0.001). HBeAg, hepatitis B e antigen.</p

Flow chart of the enrolled participants.

<p>CHB, chronic hepatitis B; TDF, tenofovir disoproxil fumarate; HCC, hepatocellular carcinoma; LAM-R, lamivudine-resistant; ADV-R, adefovir-resistant; MDR, multidrug-resistant.</p

Cumulative rates of a complete virological response (CVR) at week 96 according to subgroup.

<p>(A) Comparison of CVR between NA-naïve and LAM-R patients, (91.5% vs. 88.4%, <i>P</i> = 0.677) and between NA-naïve patients and the suboptimal response group (91.5% vs. 83.3%, <i>P</i> = 0.761). (B) Comparison of CVR between NA-naïve and ADV-R patients, (91.5% vs. 75.0%, <i>P</i> = 0.023) and between NA-naïve patients and the MDR group (91.5% vs. 75.5%, <i>P</i> = 0.256). NA, nucleos(t)ide analogue; LAM, lamivudine; R, resistant; ADV, adefovir; MDR, multidrug-resistant.</p

Univariate and multivariate logistic regression analyses predicting factors for creatinine elevation of ≥ 0.5 mg/dL.

<p>Univariate and multivariate logistic regression analyses predicting factors for creatinine elevation of ≥ 0.5 mg/dL.</p

Comparison of subgroup treatment responses at weeks 48 and 96.

<p>Comparison of subgroup treatment responses at weeks 48 and 96.</p

Liver/body weight ratio and results of biochemical analyses according to the duration of DEN administration in each group.

<p>Values shown are means ± SD.</p>*<p>Significantly different from the 3% casein group at <i>P</i><0.05.</p>**<p>Significantly different from the 3% casein group at <i>P</i><0.005.</p>***<p>Significantly different from the 3% casein group at <i>P</i><0.0005.</p

Microscopic analyses of DEN-induced HCC with liver cirrhosis.

<p>Pathologic findings after 16 weeks of DEN administration; hematoxylin and eosin (H&E) staining. DN, dysplastic nodule, black arrowheads; early HCC, green arrowheads; HCC, blue arrowheads; A, original magnification ×5; B, normal; C, DN; D, early HCC; E, HCC; B–E, original magnification ×200. The mean areas (F and H) and numbers (G and I) of DNs and tumors after 16 and 19 weeks of DEN administration were evaluated and compared. Values shown are means ± standard deviation (n = 5/group). *<i>P</i><0.05; **<i>P</i><0.005.</p

Effects of BCAA on DEN-induced liver fibrosis.

<p>Paraffin-embedded sections were stained with Masson’s trichrome to evaluate the progression of fibrosis after 14 and 16 weeks of DEN administration (A–F, original magnification ×5 and ×50). Index of fibrosis (G). The expression of α-smooth muscle actin (SMA) protein in livers was evaluated by Western blot analysis at 16 weeks post-DEN injection (H). An anti-β-actin antibody served as the loading control. Values shown are means ± standard deviation (n = 5/group). *<i>P</i><0.05. Relative fibrosis area: rMA = (MA/FA)×100. FA, overall field area (mm²); MA, overall mask area (mm²), which is the summed areas for each detected object in each layer.</p