Comparison of Renal Function Between Tenofovir Disoproxil Fumarate and Other Nucleos(t)ide Reverse Transcriptase Inhibitors in Patients With Hepatitis B Virus Infection
Background: Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) have become a standard treatment for both HIV and hepatitis B virus (HBV) infections. Tenofovir disoproxil fumarate (TDF) has been associated with kidney injury and possible long-term damage in patients with HIV. Few studies have examined whether this holds true for patients treated for HBV.
Methods: Data were gathered from the Veterans Health Administration Corporate Data Warehouse between July 1, 2005 and July 31, 2015. Patients aged ≥ 18 years with HBV infection and prescribed a NRTI for > 1 month were included in the study and followed for 36 months. Patients with HIV infection were excluded, and patients treated with combination TDF/emtricitabine were analyzed separately from patients receiving only TDF. A linear mixed model was used to examine the effects of time and specific agent on renal function, which was measured with estimated glomerular filtration rate (eGFR) at various time intervals.
Results: There were 413 incidences of NRTI use in 308 subjects during the 10 years of the study with 39 cases of TDF use. There was a significant fixed effect of time, with eGFR reduction of 4.6 mL/min ( P < .001) over the course of the study for the full cohort, but the effects of each medication were not significant.
Conclusions: This multicenter, retrospective study did not demonstrate an association between TDF use and a greater degree of kidney injury compared with other NRTIs in patients with HBV, but further studies are warranted.
How data are received from CDW bears some explanation. A basic way to understand the way data are received is that questions can be asked such as “for X population, at this point in time, was the patient on Y drug and what was the SCr value.” Therefore, inclusion and exclusion must first be specified to define the population, after which point certain data points can be received depending on the specifications made. For this reason, there is no way to determine, for example, whether a certain patient continued TDF use for the duration of the study, only at the defined points in time (described below) to receive the specific data.
For the patients included, information was retrieved from the first receipt of the NRTI prescription to 36 months after initiation. Baseline characteristics included age, sex, race, and ethnicity, and were defined at time of NRTI initiation. Values for SCr were compared at baseline, 3, 6, 12, 24, and 36 months after prescription of NRTI. The date of laboratory results was associated with the nearest date of comparison. Values for eGFR were determined by the modification of diet in renal disease equation. Values for eGFR are available in the CDW, whereas there is no direct means to calculate creatinine clearance with the available data, so eGFR was used for this study.
The primary endpoint was a change in eGFR in patients taking TDF after adjustment for time with the full cohort. Secondary analyses included the overall effect of time for the full cohort and change in renal function for each NRTI group. Mean and standard deviation for eGFR were determined for each NRTI group using the available data points. Analyses of the primary and secondary endpoints were completed using a linear mixed model with terms for time, to account for fixed effects, and specific NRTI used to account for random effects. A 2-sided α of .05 was used to determine statistical significance.
Results
A total of 413 drug episodes from 308 subjects met inclusion criteria for the study. Of these subjects, 229 were still living at the time of query. Most study participants were male (96%), the mean age was 62.1 years for males and 55.9 years for females; 49.5% were White and 39.7% were Black veterans (Table 1).
The NRTIs received by patients during the study period included TDF, TDF/emtricitabine, adefovir, entecavir, and lamivudine. No patients were on telbivudine. Formulations including TAF had not been approved by the US Food and Drug Administration (FDA) by the end of the study period, and as such were not found in the study.13 A plurality of participants received entecavir (94 of 223 at baseline), followed by TDF (n = 38) (Table 2). Of note, only 8 participants received TDF/emtricitabine at baseline. Differences were found between the groups in number of SCr data points available at 36 months vs baseline. The TDF group had the greatest reduction in data points available with 38 laboratory values at baseline vs 15 at 36 months (39.5% of baseline). From the available data, it is not possible to determine whether these represent medication discontinuations, missing values, lost to follow-up, or some other cause. Baseline eGFR was highest in the 2 TDF groups, with TDF alone at 77.7 mL/min (1.4-5.5 mL/min higher than the nontenofovir groups) and TDF/emtricitabine at 89.7 mL/min (13.4-17.5 mL/min higher than nontenofovir groups) (Table 3).
Table 4 contains data for the primarily and secondary analyses, examining change in eGFR. The fixed-effects analysis revealed a significant negative association between eGFR and time of −4.6 mL/min (P < .001) for all the NRTI groups combined. After accounting for this effect of time, there was no statistically significant correlation between use of TDF and change in eGFR (+0.2 mL/min, P = .81). For the TDF/emtricitabine group, a positive but statistically nonsignificant change was found (+1.3 mL/min, P = .21), but numbers were small and may have been insufficient to detect a difference. Similarly, no statistically significant change in eGFR was found after the fixed effects for either entecavir (−0.2 mL/min, P = .86) or lamivudine (−0.8 mL/min, P = .39). While included in the full analysis for fixed effects, random effects data were not received for the adefovir group due to heterogeneity and small quantity of the data, producing an unclear result.
