Eight-year efficacy and safety of tenofovir alafenamide for treatment of chronic hepatitis B virus infection: Final results from two randomised phase 3 trials

Abstract

Background: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB).

Aims: Here, we report the studies' final 8-year results.

Methods: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping.

Results: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFR_CG) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFR_CG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF.

Conclusion: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance.

Clinicaltrials: gov numbers NCT01940341 and NCT01940471.

FIGURE 1

Patient disposition. Two patients in the TAF group and one patient in the TDF→TAF group completed DB study treatment but did not enter the OL phase. DB, double‐blind; HBsAg, hepatitis B surface antigen; OL, open‐label; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

FIGURE 2

Pooled changes in fasting lipids over 8 years. (A) Pooled median changes in TC (mg/dL), (B) HDL cholesterol (mg/dL), (C) LDL cholesterol (mg/dL), (D) triglycerides (mg/dL), (E) TC:HDL ratio and (F) body weight (kg) from baseline by year. Safety analysis set. Missing‐equals‐excluded analysis. HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; Q, quartile; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir disoproxil fumarate.

FIGURE 3

Pooled changes in renal and bone safety parameters over 8 years. (A) Pooled median change in eGFR_CG (mL/min) from baseline by year. (B) Pooled median percent change in the B₂M:Cr ratio from baseline by year. (C) Pooled mean percent change in hip BMD and (D) spine BMD from baseline by year. (E) Pooled median percent change in CTX and (F) P1NP from baseline by year. Safety analysis set. Missing‐equals‐excluded analysis. B₂M:Cr, beta‐2‐microglobulin to creatinine ratio; BMD, bone mineral density; CTX, C‐terminal telopeptide of type 1 collagen; eGFR_CG, estimated glomerular filtration rate by Cockcroft‐Gault; P1NP, N‐terminal propeptide of type 1 procollagen; Q, quartile; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.