Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B

Abstract

Background: Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD).

Aim: To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B.

Methods: A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria.

Results: Among 51 patients treated for 1-10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0-3.0 mg/dL), creatinine (1.6-1.1 mg/dL), uric acid (2.7-3.8 mg/dL) and proteinuria.

Conclusions: Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2-9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.

Figure 1

Life-table analysis of time to renal tubular dysfunction (RTD). Each vertical line in the graph represents a case of adefovir or tenofovir induced RTD. As depicted, the first case occurred at 22 months and the seventh case at 95 months. About 15% of patients developed RTD at the time of last recorded data for the entire 51 patients.

Figure 2

Changes in serum markers of RTD with therapy. (a) Mean serum uric acid, phosphate and creatinine levels from six patients from before therapy, at the time of diagnosis of renal tubular dysfunction (RTD: *mean 48 months), and at the time of last follow-up after switching to entecavir (**mean 24 months later). Mean values improve but remain lower than pre-treatment values. (b) Mean serum FGF23 levels in 6 patients who developed RTD during adefovir or tenofovir therapy from before treatment (Baseline), at the time of diagnosis (RTD: *mean 48 months), and at the time of last follow-up after switching to entecavir (**mean 24 months later). FGF23 levels decreased during therapy and rose to baseline values after adefovir and tenofovir were stopped. Also shown are mean values of serum FGF23 in 7 control subjects who did not develop RTD from before therapy and at the time of last follow-up.

Figure 3

Patient with adefovir-induced RTD. Panel A shows that serial serum creatinine (Cr) levels rose and phosphate (P) levels began to decline after 24 months of adefovir therapy but returned to normal levels after switching to entecavir. Panel B shows a concomitant rise in alkaline phosphatase (Alk P) which fell back to baseline levels within 12 months of switching to entecavir. Also shown are serial levels of ALT which fell and remained normal on antiviral therapy as did HBV DNA levels. Results of liver histology are given in the right corner based upon biopsies done before treatment and after 4 years. The histology activity index (HAI) decreased from 10 to 3 and the Ishak fibrosis score from 3 to 1.