Advertisement

Drugs

, Volume 77, Issue 9, pp 1017–1028 | Cite as

Tenofovir Alafenamide: A Review in Chronic Hepatitis B

  • Lesley J. ScottEmail author
  • Henry L. Y. Chan
Adis Drug Evaluation

Abstract

Tenofovir alafenamide (AF) [Vemlidy®], an oral prodrug of tenofovir, was developed to optimize the antiviral potency and clinical safety of the active moiety tenofovir diphosphate (selective reverse transcriptase nucleotide inhibitor). In two identically designed, ongoing, multinational trials in treatment-naive and -experienced adult patients with hepatitis B e antigen (HBeAg)-positive or -negative chronic hepatitis B virus (HBV) infection, once-daily tenofovir AF 25 mg provided effective and sustained viral suppression (120-week analysis), and was generally well tolerated. In the primary 48-week analysis, tenofovir AF was noninferior to once-daily tenofovir disoproxil fumarate (DF) 300 mg in terms of the proportion of patients achieving viral suppression (HBV DNA <29 IU/mL) and was associated with significantly higher alanine aminotransferase (ALT) normalization rates than tenofovir DF based on AASLD criteria (but not central laboratory criteria). In pooled analyses and/or individual trials, ALT normalization rates by AASLD and central laboratory criteria were significantly higher in tenofovir AF than tenofovir DF recipients at most assessed timepoints up to 96 weeks. Given the bone and renal safety concerns associated with long-term tenofovir DF treatment, the more favourable pharmacological profile of tenofovir AF permits a marked reduction in the dosage of this tenofovir prodrug and thereby reduces systemic exposure to tenofovir, potentially improving the bone and renal safety of tenofovir AF versus tenofovir DF. Long-term clinical experience will more definitively establish the relative bone and renal safety of these tenofovir prodrugs. With its potential for an improved safety profile, tenofovir AF is an important emerging first-line option for the treatment of chronic HBV infection in adults and adolescents (aged ≥12 years and with a bodyweight of ≥35 kg).

Keywords

Tenofovir Tenofovir Disoproxil Fumarate HBsAg Level HBeAg Loss Tenofovir Diphosphate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

During the peer review process, the manufacturer of tenofovir alafenamide was offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Henry L. Y. Chan is an advisor and speaker for AbbVie, Bristol Meyers Squibb, Gilead and Roche, and a speaker for Echosens and Novartis. Lesley J. Scott is a salaried employee of Adis/Springer and declares no relevant conflicts of interest.

References

  1. 1.
    World Health Organization. Global health sector strategy on viral hepatitis 2016–2021: towards ending viral hepatitis. 2016. http://www.who.int. Accessed 14 Jan 2017.
  2. 2.
    World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015. http://who.int. Accessed 16 Jan 2016.
  3. 3.
    European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017. doi: 10.1016/j.jhep.2017.03.021.Google Scholar
  4. 4.
    Tang C-M, Yau TO, Yu J. Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments. World J Gastroenterol. 2014;20(20):6262–78.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58:593–608.CrossRefPubMedGoogle Scholar
  6. 6.
    National Institute for Health and Care Excellence. Hepatitis B (chronic): diagnosis and management. 2013. http://nice.org.uk/guidance/cg165. Accessed 1 Feb 2017.
  7. 7.
    European Medicines Agency. Viread 245 mg film-coated tablets: summary of product characteristics. 2016. https://www.medicines.org.uk/. Accessed 13 Feb 2017.
  8. 8.
    Woodward CLN, Hall AM, Williams IG, et al. Tenofovir-associated renal and bone toxicity. HIV Med. 2009;10:482–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Murakami E, Wang T, Park Y, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother. 2015;59(6):3563–9.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Birkus G, Bam RA, Willkom M, et al. Intracellular activation of tenofovir alafenamide and the effect of viral and host protease inhibitors. Antimicrob Agents Chemother. 2015;60(1):316–22.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Birkus G, Wang R, Liu X, et al. Cathepsin A is the major hydrolase catalyzing the intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340 and GS-9131. Antimicrob Agents Chemother. 2007;51(2):543–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Agarwal K, Fung SK, Nguyen TT, et al. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J Hepatol. 2015;62(3):533–40.CrossRefPubMedGoogle Scholar
  13. 13.
    Bam RA, Yant SR, Cihlar T. Tenofovir alafenamide is not a substrate for renal organic anion transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antivir Ther. 2014;19(7):687–92.CrossRefPubMedGoogle Scholar
  14. 14.
    De Clercq E. Clinical potential of the acyclic nuceloside phosphonates cidofovir, adefovir and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev. 2003;16(4):569–96.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    European Medicines Agency. Vemlidy 25 mg film-coated capsules: summary of product characteristics. 2017. http://www.ema.europa.eu. Accessed 18 Jan 2017.
  16. 16.
    Liu Y, Miller MD, Kitrinos KM. Tenofovir alafenamide demonstrates broad cross-genotype activity against wild-type HBV clinical isolates and maintains susceptibility to drug-resistant HBV isolates in vitro. Antiviral Res. 2017;139:25–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Ray AS, Fordyce MW, Hitchcock MJM. Tenofovir alafenamide: a novel prodrug of tenofovir for the treatment of human immunodeficiency virus. Antiviral Res. 2016;125:63–70.CrossRefPubMedGoogle Scholar
  18. 18.
    Peyière H, Reynes J, Rouanet I, et al. Renal tubular dysfunction associated with tenofovir therapy: 7 case reports. J Acquir Immune Defic Syndr. 2004;35:269–73.CrossRefGoogle Scholar
  19. 19.
    Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):196–206.CrossRefPubMedGoogle Scholar
  20. 20.
    Chan HLY, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):185–95.CrossRefPubMedGoogle Scholar
  21. 21.
    Brunetto M, Lim YS, Gane E, et al. A phase 3 study comparing tenofovir alafenamide to tenofovir disoproxil fumarate in patients with HBeAg-negative chronic hepatitis B: efficacy and safety results at week 96 [abstract no. PS-042 plus oral presentation]. J Hepatol. 2017;66(Suppl):S25–6.CrossRefGoogle Scholar
  22. 22.
    Agarwal K, Fung S, Seto WK, et al. A phase 3 study comparing tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate in patients with HBeAg-positive, chronic hepatitis B (CHB): efficacy and safety results at 96 weeks [abstract no. FRI-153 plus poster]. J Hepatol. 2017;66(Suppl):S478.CrossRefGoogle Scholar
  23. 23.
    Chan HLY, Fung S, Cathcart AL, et al. No resistance to tenofovir alafenamide detected through 48 weeks of treatment in patients with chronic hepatitis B [abstract no. 1843 plus poster]. Hepatology. 2016;64(1 Suppl):909A.Google Scholar
  24. 24.
    Custodio JM, Ma G, Cuvin J, et al. Pharmacokinetics and safety of tenofovir alafenamide in subjects with severe hepatic impairment [abstract no. FRI-127]. J Hepatol. 2016;64(2):S594–5.CrossRefGoogle Scholar
  25. 25.
    Custodio JM, Fordyce M, Garner W, et al. Pharmacokinetics and safety of tenofovir alafenamide in HIV-uninfected subjects with severe renal impairment. Antimicrob Agents Chemother. 2016;60(9):5135–40.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gane EJ, Saito M, Bae S-H, et al. Characterization of host, viral, and treatment-related factors associated with antiviral efficacy of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) [abstract no. 1879 plus poster]. Hepatology. 2016;64(1 Suppl):929-30A.Google Scholar
  27. 27.
    Pan CQ, Li MKK, Lee KS, et al. Predictors of HBeAg loss in HBeAg-positive patients with chronic hepatitis B during treatment with tenofovir alafenamide or tenofovir disoproxil fumarate [abstract no. 1882 plus poster]. Hepatology. 2016;64(1 Suppl):931A.Google Scholar
  28. 28.
    Izumi N, Tsang OTY, Ahn SH, et al. Characterization of changes in FibroTest values during treatment with tenofovir alfenamide (TAF) or tenofovir disproxil fumarate (TDF) in patients with CHB [abstract no. 1904 plus poster]. Hepatology. 2016;64(1 Suppl):941-2A.Google Scholar
  29. 29.
    Acharya S, Lee K, Kao J-H, et al. HBV genotype is associated with early (week 12) virologic response during tenofovir disoproxil fumarate or tenofovir alafenamide therapy in patients with chronic hepatitis B [abstract no. 1859 plus poster]. Hepatology. 2016;64(1 Suppl):918-9A.Google Scholar
  30. 30.
    Brunetto MR, Ahn SH, Chang T-T, et al. Correlation of early biochemical and virologic responses during oral antiviral therapy for chronic hepatitis B [abstract no: 1857 plus poster]. Hepatology. 2016;64(1 Suppl):917A.Google Scholar
  31. 31.
    Fung S, Yatsuhashi H, Tak WY, et al. Features of the metabolic syndrome are associated with lack of serum ALT normalization during therapy for chronic hepatitis B [abstract no. 1852]. Hepatology. 2016;64(1 Suppl):914-5A.Google Scholar
  32. 32.
    Marcellin P, Seto W-K, Hu CT, et al. Genotype-specific differences in magnitude of HBsAg reduction during TDF or tenofovir alafenamide (TAF) therapy in CHB patients [abstract no. 1858 plus poster]. Hepatology. 2016;64(1 Suppl):918A.Google Scholar
  33. 33.
    Pan C, Chang T-T, Bae S-H, et al. Viral kinetics in women of child bearing potential with chronic hepatitis B virus following treatment with tenofovir alafenamide or tenofovir disoproxil fumarate [abstract no. THU-159]. J Hepatol. 2017;66(Suppl.):S258–9.Google Scholar
  34. 34.
    Chan HL, Fung S, Seto WK, et al. Improved bone and renal safety of switching from tenofovir disoproxil fumarate to tenofovir alafenamide: preliminary results from 2 phase 3 trials in HBeAg-positive and HBeAg-neagtive patients with chronic hepatitis B [abstract no. PS-041 plus oral presentation]. J Hepatol. 2017;66(Suppl):S25.CrossRefGoogle Scholar
  35. 35.
    Seto W-K, Asahina Y, Peng C-Y, et al. Reduced changes in bone mineral density in chronic HBV (CHB) patients receiving tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) [abstract no. 67]. Hepatology. 2016;64(1 Suppl):35A.Google Scholar
  36. 36.
    Fung S, Chuang WL, Nishiguchi S, et al. Smaller decreases in bone mineral density in chronic hepatitis B patients receiving tenofovir alafenamide compared with tenofovir disoproxil fumarate over 96 weeks [abstract no. SAT-162]. J Hepatol. 2017;66(Suppl):S691–2.CrossRefGoogle Scholar
  37. 37.
    Chuang W-L, Seto W-K, Inokuma T, et al. Comparison of markers of bone turnover demonstrates less changes in CHB patients receiving tenofovir alafenamide compared with tenofovir disoproxil fumarate (TDF) [abstract no. 1856]. Hepatology. 2016;64(1 Suppl):916-7A.Google Scholar
  38. 38.
    Agarwal K, Furusyo N, Byun K-S, et al. Improved renal laboratory parameters in CHB patients treated with TAF compared with tenofovir disoproxil fumarate (TDF) [abstract no. 1844 plus poster]. Hepatology. 2016;64(1 Suppl):910A.Google Scholar
  39. 39.
    Lin CL, Yang HC, Kao JH. Hepatitis B virus: new therapeutic perspectives. Liver Int. 2016;36(Suppl 1):85–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Tajiri K, Shimizu Y. New horizon for radical cure of chronic hepatitis B virus infection. World J Hepatol. 2016;8(21):863–73.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Coffin CS, Lee SS. New paradigms in hepatitis B management: only diamonds are forever. Br Med Bull. 2015;116:79–91.PubMedGoogle Scholar
  42. 42.
    Liu Y, Corsa AC, Buti M, et al. No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg− patients with chronic hepatitis after 8 years of treatment. J Viral Hepat. 2016;24:68–74.CrossRefPubMedGoogle Scholar
  43. 43.
    Lampertico P, Maini M, Papatheodoridis G. Optimal management of hepatitis B virus infection: EASL special conference. J Hepatol. 2015;63:1238–53.CrossRefPubMedGoogle Scholar
  44. 44.
    Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324–34.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand
  2. 2.Department of Medicine and Therapeutics and Institute of Digestive DiseaseThe Chinese University of Hong KongHong Kong SARChina

Personalised recommendations