One-year safety and efficacy of tenofovir alafenamide (TAF) in chronic hepatitis B (CHB): a HEllenic multicenter ReAl-life CLInical Study (HERACLIS-TAF)

George Papatheodoridis1 ([email protected]), Kostas Mimidis2 ([email protected]), Spilios Manolakopoulos1,3 ([email protected]), Nikolaos Gatselis4 ([email protected]), John Goulis5 ([email protected]), Andreas Kapatais6 ([email protected]), Emanuel Manesis7 ([email protected]), Themistoklis Vasiliadis8 ([email protected]), Christos Triantos9 ([email protected]), Dimitrios Samonakis10 ([email protected]), Vasilios Sevastianos11 ([email protected]), Stelios Karatapanis12 ([email protected]), Ioannis Elefsiniotis13 ([email protected]), Melanie Deutsch3 ([email protected]), Theodora Mylopoulou2 ([email protected]), Margarita Papatheodoridi1 ([email protected]), Hariklia Kranidioti3 ([email protected]), Polyxeni Agorastou5 ([email protected]), Theofani Karaoulani6 ([email protected]), Anastasia Kyriazidou8 ([email protected]), Konstantinos Zisimopoulos9 ([email protected]), George Dalekos4 ([email protected]).

G Papatheodoridis1, K Mimidis2, S Manolakopoulos1,3, N Gatselis4, J Goulis5, A Kapatais6, E Manesis7, T Vasiliadis8, C Triantos9, D Samonakis10, V Sevastianos11, S Karatapanis12, I Elefsiniotis13, M Deutsch3, T Mylopoulou2, M Papatheodoridi1, H Kranidioti3, P Agorastou5, T Karaoulani6, A Kyriazidou8, K Zisimopoulos9, G Dalekos4.

1Department of Gastroenterology, Medical School of National & Kapodistrian University of , Laiko General Hospital, Athens; 2Α' Department of Internal Medicine, Democritus University of Thrace, ; 32nd Department of Internal Medicine, Medical School of National & Kapodistrian University of Athens, Hippokratio General Hospital of Athens; 4Department of Medicine and Research Laboratory of Internal Medicine, General University Hospital of , Larissa; 54th Department of Internal Medicine, Hippokratio Hospital, Aristotle University of Thessaloniki; 6General Hospital Nikaia- Agios Panteleimon, General Hospital of Western Agia Varvara; 7Liver Unit, Euroclinic SA, Athens; 83rd Department of Internal Medicine, Aristotle University of Thessaloniki, "Papageorgiou" Hospital, Thessaloniki; 9Department of Gastroenterology, University Hospital of Patras; 10Department of Gastroenterology & Hepatology, University Hospital of Heraklion ; 114th Department of Internal Medicine and Liver Outpatient Clinic, Evangelismos General Hospital, Athens; 121st Department of Internal Medicine, General Hospital of , Rhodes; 13University Department of Internal Medicine, General and Oncology Hospital of Kifisia Agioi Anargyroi, Athens,

Background and Aims: In the registrational trials, TAF compared to tenofovir disoproxil fumarate (TDF) was shown to have similar efficacy and improved safety in renal function and bone mineral density (BMD) parameters, but CHB patients with significant renal and/or bone disorders were not included. In Greece, TAF has been reimbursed since 02/2018 for CHB patients with estimated glomerular filtration rate (eGFR) <60 ml/min, serum phosphate <2.5 mg/dl or osteoporosis (T-score <-2.5). This study assessed the safety and efficacy of one-year TAF therapy in CHB patients treated in Greek tertiary liver centers.

Method: Adult (≥18 years old) CHB patients who started TAF between 02/2018-10/2019 at 13 clinics participating in the HERACLIS-TAF registry were included. Main exclusion criteria were coinfection with HDV, active malignancy and biphosphates use in the last 6 months. Clinical and laboratory characteristics were recorded at onset and 6 and 12 months of TAF. MDRD formula was used for eGFR (ml/min) estimation.

Results: TAF was initiated in 176 patients: age 64±12 years, 71% males, 85% undetectable HBV DNA, 86% ALT<40, 45% eGFR<60, 94% nucleos(t)ide analogue (NA) experienced (91% directly switched to TAF from another NA – 81% from TDF; 3% NA discontinuation >2 months). At month-12 of TAF, HBV DNA was undetectable (<15 IU/mL) in 97% and ALT was <40 IU/L in 96% of cases. In cases switching to TAF from other NA, median ALT decreased from onset to month-12 of TAF (23 to 21 IU/L, P<0.001). Mean eGFR had decreased from previous NA onset (74±28) to TAF onset (65±27, P<0.001) and then increased at 6 (69±26, P<0.001) or 12 months of TAF (71±29, P<0.001). eGFR difference between 12 months and onset of TAF was ≥0 in 71% and ≥10 in 65% of cases; eGFR difference >0 was not associated with any patients’ characteristic, while eGFR difference >10 was associated with BMI>25 [OR:2.4 (1.1-5.1), P=0.024] and no hemodialysis. In cases starting TAF with phosphate <2.5, mean phosphate levels increased from onset to month-12 (2.1 to 2.7, P<0.001). Mean BMD did not change significantly from onset to month-12 of TAF (T-score: -2.1 to -1.9, P=0.164).

Conclusion: In mostly NA experienced CHB patients with renal and/or bone disorders/risks, one year of TAF achieves maintenance of virological suppression and improvement of ALT, eGFR and serum phosphate levels. eGFR improvement >10 ml/min can be achieved in >2/3 of non-hemodialysis patients and seems to be associated with BMI >25 kg/m2.

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This work was supported by an unrestricted research grant from Gilead Sciences and by the Hellenic Foundation of Gastroenterology and Nutrition.

GV Papatheodoridis: advisor/lecturer for Abbvie, Bristol-Myers Squibb, Dicerna, Gilead, GlaxoSmithKline, Ipsen, Janssen, Merck Sharp & Dohme, Roche, Spring Bank; research grants Abbvie, Bristol- Myers Squibb, Gilead. K Mimidis: advisor / lecturer for AbbVie, Bristol-Myers Squibb, Gilead, MSD, Novartis; Research grants: AbbVie, Bristol Meyer Squibb, Gilead, Novartis, Vianex

S Manolakopoulos: advisor/lecturer for Abbvie, Gilead, Ipsen, Merck Sharp & Dohme; research grants from Abbvie, Gilead.

N Gatselis: Nothing to declare.

J Goulis: advisor/lecturer for Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Roche; research grant from Gilead.

Andreas Kapatais: Nothing to declare.

Emanuel Manesis: Nothing to declare.

Themistoklis Vasiliadis: Nothing to declare.

Christos Triantos: advisor/lecturer for Abbvie, Bayer, Bristol-Myers Squibb, Gilead, MSD, Roche

Dimitrios Samonakis: Advisor for Abbvie, Gilead; Lecturer for Abbvie, Gilead, Ipsen, MSD, Novartis; research grants from Abbvie, Bayer, Gilead.

Vasilios Sevastianos: Nothing to declare.

Stelios Karatapanis: Nothing to declare.

Ioannis Elefsiniotis: advisor for Abbvie, Gilead.

Melanie Deutsch: Nothing to declare.

Theodora Mylopoulou: Nothing to declare.

M Papatheodoridi: Nothing to declare.

Hariklia Kranidioti: Nothing to declare.

Polyxeni Agorastou: Nothing to declare.

Theofani Karaoulani: Nothing to declare.

Anastasia Kyriazidou: Nothing to declare. Konstantinos Zisimopoulos: Nothing to declare.

GN Dalekos: Advisor/Lecturer: Ipsen, Pfizer, Genkyotex, Novartis; research grants: Abbvie, Gilead.