Comparison of renal safety of tenofovir and entecavir in patients with chronic hepatitis B: Systematic review with meta-analysis

Abstract

Background: Recently, the American Association for the Study of Liver Disease suggested no preference between tenofovir (TDF) and entecavir (ETV) regarding potential long-term risks of renal complications. Over the years, renal safety has become a critical concern in nucleos(t)ide analog-treated patients due to the long-term use of these drugs. However, existing studies do not show significant differences in renal dysfunction between these two drugs. Further, there is a paucity of studies comparing the long-term renal effects of TDF and ETV.

Aim: To investigate the effects of TDF and ETV on renal function, we performed systematic review and meta-analysis.

Methods: Two investigators independently searched the Cochrane Library, MEDLINE, and Embase databases for randomized controlled trials and nonrandomized studies (NRSs) using the keywords "CHB", "Tenofovir", and "Entecavir", and additional references were obtained from the bibliographies of relevant articles published through December 2017. The quality of each study was assessed using the Newcastle-Ottawa scale and the Grading of Recommendations Assessment, Development and Evaluation criteria. The primary outcome was the change in serum creatinine level in the TDF and ETV groups at baseline, 6 mo, 12 mo and 24 mo.

Results: Nine NRSs comprising 2263 participants met the inclusion criteria. Changes in creatinine levels were higher in the TDF group than in the ETV group at 6 mo [mean difference (MD) = 0.03 mg/dL; 95%CI: 0.02-0.04; I ² = 0%], 12 mo (MD = 0.05 mg/dL; 95%CI: 0.02-0.08; I ² = 78%), and 24 mo (MD = 0.07 mg/dL; 95%CI: 0.01-0.13; I ² = 93%). The change in estimated glomerular filtration rate (eGFR) was significantly higher in the TDF group than in the ETV group at 6 mo [standardized mean difference (SMD), -0.22; 95%Cl: -0.36--0.08; I ² = 0%], 12 mo (SMD = -0.24; 95%Cl: -0.43--0.05; I ² = 50%), and 24 mo (-0.35; 95%Cl: -0.61- -0.09; I ² = 67%).

Conclusion: TDF statistically significantly increased serum creatinine levels and decreased the eGFR in 6-24 mo compared to ETV, with moderate to low quality of evidence. However, the differences are negligible.

Keywords: Chronic; Entecavir; Hepatitis B; Meta-analysis; Review; Safety; Systematic; Tenofovir.

Figure 1

PRISMA diagram of the literature search. TDF: Tenofovir; ETV: Entecavir; SD: Standard deviation.

Figure 2

Forest plot for the change of serum creatinine. In each enrolled study, the change (between post-treatment and baseline) is calculated in each arm [tenofovir (TDF) vs entecavir (ETV)]. The difference in mean change between the two changes (δ TDF - δ ETV) is then calculated. TDF: Tenofovir; ETV: Entecavir; SD: Standard deviation; CI: Confidence interval.

Figure 3

Forest plot for the change of estimated glomerular filtration rate. In each enrolled study, the change (between post-treatment and baseline) is calculated in each arm [tenofovir (TDF) vs entecavir (ETV)]. The difference in standardized mean change between the two changes (δ TDF - δ ETV) is then calculated, since each study utilized different formulas. TDF: Tenofovir; ETV: Entecavir; SD: Standard deviation; CI: Confidence interval.

Figure 4

Subgroup analysis. Likewise, the change is calculated using a common formula in each arm to assess the effect size. A: Modification of diet in renal disease, B: Chronic kidney disease epidemiology collaboration. TDF: Tenofovir; ETV: Entecavir; SD: Standard deviation; CI: Confidence interval.

Figure 5

Sensitivity analysis. Meta-regression of difference in mean age (A) and creatinine (B). The circles on the graph represent included studies; the size of the circle indicates the weight of each study. To check the robustness of this study, we tentatively excluded one heterogeneous study[19] (C). TDF: Tenofovir; ETV: Entecavir; SD: Standard deviation; CI: Confidence interval.

Figure 6

Funnel plot for publication bias in all included studies. The empty circles represent the observed studies and empty and black-filled diamonds represent the overall random effects means and 95% confidence intervals of the observed studies.