Long-term Renal Safety Between Patients With Chronic Hepatitis B Receiving Tenofovir vs. Entecavir Therapy

A Multicenter Study

Young Eun Chon; Soo Young Park; Seung Up Kim; Han Pyo Hong; Jae Seung Lee; Hye Won Lee; Mi Na Kim; Jun Yong Park; Do Young Kim; Sang Hoon Ahn; Beom Kyung Kim


J Viral Hepat. 2022;29(4):289-296. 

In This Article


Baseline Characteristics

A total of 3033 patients with CHB who were treated with daily ETV (0.5 mg) or TDF (300 mg) as the first-line antiviral regimen for at least 1 year were analyzed. Table 1 describes the clinical characteristics of these patients at the first year of AVT. The mean age of the cohort was 48.8 years, and men were predominant (63.8%). Liver cirrhosis was noted in 852 (28.1%) patients, with mean APRI and FIB-4 scores of 0.63, and 2.38, respectively. The mean creatinine and eGFR calculated using the CKD-EPI equation were 0.9 mg/dl, and 92.8 ml/min/1.73 m2, respectively.

At the beginning of the observation period, patients in the ETV group (n = 1793) had significantly unfavorable conditions (higher aspartate aminotransferase level, serum creatinine level, FIB-4 score, and APRI score) than patients in the TDF group (n = 1240) (all p < .05) (Table 1). In particular, patients in the ETV group had lower eGFRs (mean, 96.0 vs. 101.9 ml/min/1.73 m2, p < .001) than those in the TDF group.

Changes in Renal Function During AVT Among the Entire Cohort

For the entire cohort (n = 3033), eGFR was measured annually for 6 years after the commencement of AVT (Figure 1). The mean eGFR reduced progressively with statistical significance during 444,673 person-years of follow-up; 98.9, 98.3, 98.0, 97.9, 97.2, and 96.2 ml/min/1.73 m2 at 1, 2, 3, 4, 5, and 6 years, respectively. The AAPC in eGFR was −0.49% (95% CI; −0.61 to −0.37, p < .001), showing a trend of significant decrease in the mean eGFR during the 6 year-observation period.

Figure 1.

Changes in estimated glomerular filtration rate (eGFR) during long-term antiviral therapy (AVT) among the entire population

Changes in Renal Function According to Antiviral Regimen

We computed the eGFR at each time point according to treatment with either ETV or TDF (Figure 2 and Table 2). During the 6-year observation period after the commencement of AVT, the mean eGFR was maintained in the ETV group at 96.0 ml/min/1.73 m2 in the first year and 95.6 ml/min/1.73 m2 in the sixth year (p > .05). In contrast, the mean eGFR significantly reduced in the TDF group from 101.9 ml/min/1.73 m2 after the first of AVT to 96.9 ml/min/1.73 m2 after 6 years (p < .001). In the ETV group, the mean eGFR was similarly maintained with an AAPC in eGFR of −0.09% (95% CI, −0.25 to −0.08; p = .322). In contrast, among the TDF group, the mean eGFR decreased significantly every year with an AAPC of −0.88% (95% CI, −1.05 to −0.71; p < .001). TDF dose adjustment was made in one patient at 4 years after AVT, and switched to ETV due to renal dysfunction in 3 patients after 3 years of AVT.

Figure 2.

Changes in estimated glomerular filtration rate (eGFR) according to treatment with either entecavir (ETV) or tenofovir disoproxil fumarate (TDF)

Changes in Renal Function According to Comorbidities

In the ETV group, there was no decrease in the eGFR of patients without diabetes mellitus (AAPC of eGFR, −0.01%; 95% CI, −0.23 to 0.22; p = .959) or hypertension (AAPC of eGFR, 0.01%; 95% CI, −0.19, 0.21; p = .901). However, when diabetes mellitus or hypertension was present, a significant decrease in eGFR was observed; AAPC in eGFR was −0.84% (95% CI, −0.98 to −0.70; p < .001) in patients with diabetes, and −1.01% (95% CI, −1.38 to −0.63; p = .01) in those with hypertension.

In contrast, among the TDF group, there was a significant decrease in eGFR even in patients without diabetes mellitus or hypertension, with an AAPC of −0.80% (95% CI −0.99 to −0.62; p = .002), and 0.87% (95% CI −1.07 to −0.67; p = .001), respectively. If either diabetes or hypertension was present, the decline in eGFR showed a trend toward more accelerated patterns; an AAPC of −1.59% (95% CI, −2.29 to −0.89; p = .011) and −1.00% (95% CI, −1.29 to −0.70; p = .002) in patients with diabetes and hypertension, respectively.

Predictors of Ongoing Renal Dysfunction

During the 6-year observation period after the commencement of AVT, a total of 681 (22.4%) patients developed ongoing renal dysfunction, which was defined as a negative slope of the mean change in eGFR during AVT. Table 3 shows the comparison of the characteristics of patients with and without ongoing renal dysfunction. The group with ongoing renal dysfunction had older patients, a higher proportion of those with diabetes mellitus, hypertension, and liver cirrhosis, who received treatment with TDF (all p < .05), and had lower serum albumin and eGFR at 1 year of AVT, compared with those without.

On univariate analysis, significant factors associated with ongoing renal dysfunction were age >60 years (OR 1.557, 95% CI 1.169–2.075; p = .002), hypertension (OR 2.667, 95% CI 1.931–3.684; p < .001), diabetes mellitus (OR 1.861, 95% CI 1.292–2.681; p < .001), eGFR <60 ml/min/1.73 m2 at 1 year of AVT (OR 1.963, 95% CI 1.285–2.996; p = .002), serum albumin <3.5 mg/dl at 1 year of AVT (OR 2.128, 95% CI 1.453–3.117; p < .001), and treatment with TDF (OR 1.572, 95% CI 1.242–1.989; p < .001). Subsequently, these univariate predictors were entered into the multivariate logistic regression model, showing that treatment with TDF (adjusted OR [aOR], 1.656; 95% CI 1.303–2.107; p < .001; Table 4) proved to be an independent risk factor, along with hypertension (aOR 2.356, 95% CI 1.664–3.334; p < .001), eGFR <60 ml/min/1.73 m2 at 1 year of AVT (aOR 1.823, 95% CI 1.179–2.821; p = .001), and serum albumin at 1 year of AVT (aOR 2.023, 95% CI 1.370–2.988; p < .001).

Liver-related Clinical Outcomes

During follow-up, 8.0% (243/3033) of patients developed HCC, and 4.6% (141/3033) of patients died. Baseline eGFR or ongoing renal dysfunction was not significant predictors for HCC development or death.