Published online Dec 27, 2020. doi: 10.4254/wjh.v12.i12.1326
Peer-review started: June 11, 2020
First decision: September 18, 2020
Revised: October 7, 2020
Accepted: October 28, 2020
Article in press: October 28, 2020
Published online: December 27, 2020
Processing time: 189 Days and 14.9 Hours
Proximal tubular renal toxicity is a main concern in prolonged nucleot(s)ide analogue therapy in hepatitis B virus (HBV)-infected patients. Currently available data for HBV-monoinfected patients are either retrospective or cross-sectional. The recommended screening tools for renal toxicity, estimated glomerular filtration rate (eGFR) and phosphatemia, are late markers for subclinical proximal tubular (SPT) damage. Thus, early SPT detection with tools that are simple, inexpensive, and repeatable over time are needed. Moreover, preclinical studies have reported that HBV exhibits potential toxicity in proximal tubular cells before any antiviral treatment.
Early detection of tubulopathy could allow clinicians to choose less toxic therapeutic alternatives such as tenofovir alafenamide (TAF), particularly in patients with renal comorbidities. TAF is not available in all countries for HBV-monoinfected patients, but its use may be transitionally authorized. Clinical evidence in favor of HBV-induced renal toxicity may assist in improving interpretations of SPT markers over time, as well as explain why these markers improve under antiviral use.
The main objective was to determine the prevalence of SPT at month 24 (M24) in three populations: Treatment-naïve patients and patients starting entecavir (ETV) or tenofovir disoproxil (TDF) at M0. The secondary objectives were to evaluate the cumulative incidence of SPT over 24 mo in the three groups as well as the prevalence of SPT in the naïve population at baseline.
This first real-life, prospective, multicenter, French study of patients with low renal risk aimed to determine SPT in three groups of HBV-monoinfected patients: Treatment-naïve and those starting ETV or TDF. Markers for SPT, the eGFR and phosphatemia, were assessed quarterly. SPT was defined using early and low-cost simple markers: TmPi/eGFR below 0.8 mmoL/L and/or fractional excretion rate of uric acid above 10%. Confounding factors potentially impacting kidney function across the groups were assayed.
At M24, the prevalence of SPT was 30.7% in the naïve group, 21.1% in the ETV-treated group, and 50.0% in the TDF-treated group. However, differences in SPT prevalence between the naïve group and each treatment group (ETV and TDF groups) were not significantly different. In the multivariate analysis, no post-adjustment variables were identified. The incidence of SPT over 24 mo (25.5%, 13.3%, and 52.9% in the naïve, ETV-treated, and TDF-treated groups, respectively) tended to be higher in the TDF group compared to the naïve group (hazard ratio: 2.283; P = 0.05). The median survival time without SPT was 5.9 mo in the TDF group. In patients without SPT at baseline, no renal insufficiency or hypophosphatemia was observed at M24.
This prospective, multicenter study is the first to evaluate the prevalence and incidence of SPT in low renal risk HBV-monoinfected patients using early markers. Patients were divided into treatment-naïve, ETV-treated, or TDF-treated groups. The prevalence of SPT at M24 was high (21%–50%), but it had no clinical impacts in terms of renal insufficiency or hypophosphatemia. The incidence of SPT tended to be higher in the TDF group. Moreover, the detection of SPT in HBV-monoinfected naïve patients supports the hypothesis of HBV-specific tubular toxicity.
To better evaluate the clinical impacts of nucleot(s)ide analogue-induced SPT on renal function, future prospective studies tracking both simple and sophisticated SPT markers over a longer period of time are warranted. Furthermore and paradoxically, these early markers may be also used to evaluate treatment reversibility of HBV-induced SPT.