Long-Term Treatment With Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety

Abstract

Introduction: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years.

Methods: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses.

Results: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA <29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined <2.5 mL/min, and mean declines of <1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF.

Discussion: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.

Trial registration: ClinicalTrials.gov NCT01940341 NCT01940471.

Graphical abstract

Figure 1.

Study design. ^aAmendment 3 enacted to extend DB period to week 144 and OL to week 384 (year 8); shaded areas represent patients who rolled over to OL TAF at week 96 (OL3y) or week 144 (OL2y). DB, double blind; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; OL, open label; QD, once daily; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Figure 2.

Patient disposition at week 240. DB, double blind; HBsAg, hepatitis B surface antigen; OL, open label; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Figure 3.

Efficacy results over time to 5 years (240 weeks), M = F analysis. (a) Proportion of patients with HBV DNA <29 IU/mL by study week. Bars are 95% CIs. (b) Proportion of patients achieving ALT normalization by central laboratory criteria (≤43 U/L for men and ≤34 U/L for women <69 years of age; ≤35 U/L for men and ≤32 U/L for women ≥69 years of age) by study week. (c) Proportion of patients achieving ALT normalization by AASLD criteria (≤19 U/L for women and ≤30 U/L for men) by study week. (d) Proportion of patients with HBeAg loss by study week, Study 110 patients only. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; M = F, missing equals failure; OL, open label; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

Figure 4.

Fasting lipid changes over time to 5 years (240 weeks). HDL, high-density lipoprotein; LDL, low-density lipoprotein; OL, open label; Q1, first quartile; Q3, third quartile; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir disoproxil fumarate.

Figure 5.

Bone and renal parameters over time to 5 years (240 weeks). BMD, bone mineral density; eGFR_CG, estimated glomerular filtration rate by Cockcroft-Gault method; OL, open label; Q1, first quartile; Q3, third quartile; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.