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( Scott Fung ),( Wan Long Chuang ),( Shuhei Nishiguchi ),( Wai Kay Seto ),( Won Young Tak ),( Elke M. Erne ),( Maciej,Jablkowski ),( Vyacheslav Morozov ),( Audrey H. Lau ),( Vithika Suri ),( John F. F 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: Compared with TDF, smaller declines in bone mineral density (BMD) were demonstrated with TAF vs. TDF over 48 weeks. Presented here are bone safety results at Week 96. Methods: In two Phase 3 studies, 1301 patients were randomized (2:1) to receive TAF 25 mg QD or TDF 300 mg QD. Dual energy X-ray absorptiometry (DXA) scans were evaluated for mean percent change from baseline and by the proportion with >3% declines in hip and spine BMD. BMD changes were also assessed in the subset of patients at higher risk for bone loss (females, advanced age [≥ 50 y], Asian race, eGFR <90 mL/min). Serum markers of bone resorption (CTX) and formation (osteocalcin, bone-specific alkaline phosphatase, P1NP) were also assessed serially. Results: Patients with TAF experienced lesser declines in hip and spine BMD over 96 weeks(Table, p< 0.001). A higher proportion of subjects treated with TDF also experienced >3% declines in hip and spine BMD compared with TAF-treated patients (Table, p < 0.0001). Greater declines in BMD were seen in patients with >1 risk factor for bone loss at baseline; however, in comparison to TDF, the proportion with >3% declines in hip and spine BMD were lower in the TAF group (p<0.0001 for all) and were less impacted by the presence of multiple risk factors (Table, p< 0.005 for all). By multivariate analysis baseline predictors for >3% decline in hip or spine BMD at Week 96 were: treatment with TDF, female gender, and older age. The smaller changes in BMD seen with TAF were associated with minimal changes in markers of bone turnover compared with TDF. Conclusions: Through 96 weeks, TAF was associated with had less impact on BMD and bone parameters compared to TDF. The magnitude of these differences was most pronounced in those at higher risk for bone loss.
( Florence Wong ),( Scott Fung ),( Hie-won Hann ),( Magdy Elkhashab ),( Thomas Berg ),( Milotka J. Fabri ),( Andrzej Horban ),( Mijomir Pelemis ),( Ioan Sporea ),( John F. Flaherty ),( Benedetta Masse 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: In CHB patients with LAM-R, TDF has shown efficacy comparableto FTC/TDF and no detectable TDF resistance at 2 years. The final5 year efficacy and safety results from this trial are presented.Methods: CHB patients on LAM with HBV DNA >3 log10 IU/mL andwith documented LAM-R were randomized (1:1) to TDF or FTC/TDFand followed for 5 years.Results: Two hundred eighty patients were randomized; 232 (83%)completed 5 years of treatment. At baseline, mean age was 47 years,most were male (75%) and non-Asian (66%); 53% were HBeAgnegative. Mean HBV DNA was 5.7 log10 IU/mL and 42% had ALT≤ULN at baseline. At Year 5, virologic, serologic, and biochemicalresponses were similar among groups, and remained stable. Ninepatients (4-TDF, 5-FTC/TDF) discontinued due to an adverse event,including increased serum creatinine in 1 patient. For both groupscombined, confirmed renal safety endpoints over 5 years were: CrCL<50 mL/min in 19 (6.8%) patients (12 requiring dose modification),increases in serum creatinine of ≥0.3 and ≥0.5 mg/dL from baselinein 21 (7.5%) and 2 (0.7%) patients, respectively, and serum phosphorus<2 mg/dL in 3 (1.1%) patients. Mean declines in BMD (g/cm2)from baseline for hip and spine BMD, respectively, were 1.7% and1.5% at Year 2, and 2.5%, and 1% at Year 5. Seven patientsexperienced fracture (all except 1 were trauma-related). No TDF resistancewas detected through 5 years by population sequencing.Conclusions: In LAM R patients with CHB treated for 5 years withTDF, a high rate of HBV DNA suppression was achieved and maintainedwith no detectable TDF resistance. There is no apparent ad advantageof combination FTC/TDF in this population. Renal eventsassociated with TDF occurred in up to 7.5% of patients, and averagelosses in bone mineral density of 1 2.5% were observed.
( Young Suk Lim ),( Henry L. Chan ),( Scott Fung ),( Wai Kay Seto ),( Ed Gane ),( John F. Flaherty ),( Vithika Suri ),( Lanjia Lin ),( Anuj Gaggar ),( G Mani Subramanian ),( Wan Long Chuang ),( Kosh A 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: TAF has shown less bone and renal effects with similar efficacy rates compared to TDF in two Phase 3 studies after 48 weeks treatment. Here, we evaluate patients completed 96 weeks of double blind(DB) treatment with TAF or TDF and have switched to open label(OL) treatment with TAF to determine changes in bone mineral density(BMD), creatinine clearance(CrCl), and the maintenance of viral suppression. Methods: Immune active CHB patients who were HBeAg negative (Study 0108; N=425) or HBeAg positive (Study 0110; N=873) were randomized to and treated with TAF 25 mg QD or TDF 300 mg QD. A subset of patients (N=200 in Study 0108 and N=340 in Study 0110) in these ongoing 8 year studies had completed 96 weeks of DB treatment with TAF or TDF and switched to OLTAF at Week 96 analysis. Dual energy X-ray absorptiometry (DXA) scans were evaluated every 24 weeks as were serial assessments of CrCl and viral suppression. Results: CrCl improved significantly in patients switched from DB TDF to OL TAF at Week 120 compared to Week 96 (N=117, mean (SD) change=+2.43 (12.81) ml/min, p=0.04); and remained stable in those previously receiving TAF (Figure A). BMD also showed improvement at Week 120 from Week 96 among patients switched from DB TDF to OL TAF (hip: N=58, mean (SD) % change=+0.71% (1.43), p=0.0004; spine: N=60, mean (SD) % change=+1.41% (2.30), p<.0001). BMD changes in hip and spine for DB TAF patients entering the OL TAF period were relatively stable (Figure B). Compared to results at Week 96, high rates of virologic control were maintained across subjects in both studies during the OL period. Conclusions: Patients who switched from TDF to TAF treatment demonstrated rapid improvements in BMD and CrCl within the first 24 weeks of treatment, and virologic control was maintained.
( Sang Hoon Ahn ),( Kosh Agarwal ),( Scott Fung ),( Wai Kay Seto ),( Young Suk Lim ),( Ed Gane ),( Harry L. Janssen ),( Manoj Sharma ),( Wan Long Chuang ),( Ho Bae ),( Ki Tae Yoon ),( John F. Flaherty 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Aims: In this randomized, double blind study in HBeAg- positive patients, the efficacy of TAF was demonstrated to be noninferior to that of TDF at Week 48 in the proportion with HBV DNA <29 IU/mL with improved bone and renal effects. Here we present the results after two years of treatment. Methods: 873 patients were randomized to receive TAF 25 mg QD (n=581) or TDF 300 mg QD (n=292) and treated for 144 weeks. Efficacy analyses included virologic (HBV DNA <29 IU/mL), biochemical, and serologic responses; key secondary safety endpoints Results: Baseline characteristics included: mean age 38 years, 64% males, 82% Asians, 52% genotypes C, 47% had HBV DNA ≥ 8 log10 IU/mL, and 26% were treated previously with nucleos(t)ides. Efficacy and safety end points are summarized in the Table. At Week 96, virologic response rates were similer between TAF and TDF groups. A greater percentage of TAF patients achieved normalization of serum ALT values with similar proportions of TAF and TDF patients experiencing HBeAg loss. Patients on TAF experienced smaller changes in hip and spine BMD than TDF patients through 96 weeks. The smaller decline in eGFRCG and smaller changes in renal tubular markers observed with TAF through Week 96. The rates of treatment discontinuations for adverse events (<1.5%) and serious adverse events (≤6%) were low and similar in the two arms. Conclusions: At Week 96, similar rates of virologic suppression were seen with a higher rate of ALT normalization seen in TAF patients relative to TDF and continued improved bone and renal safety with TAF compared with TDF.
( Edward Gane ),( Amoreena C Corsa ),( Yang Liu ),( Ben C Mitchell2 ),( John F Flaherty ),( Michael D Miller ),( Kathryn M Kitrinos ),( Scott Fung ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1
Background/Aim: To evaluate amino acid changes within HBV pol/RT after 96 weeks of treatment with TDF or FTC/ TDF and determine their potential association with TDF resistance. Methods: In Study GS-US-174-0121, 280 patients receiving lamivudine (LAM) with detectable LAM-resistance mutations in HBV pol/RT (LAM-R: rtM204V/I±rtL180M) were randomized 1:1 to receive blinded treatment with TDF or FTC/TDF for 96 weeks. Virologic breakthrough (VB) was defined as confirmed HBV DNA >1 log10 increase from nadir or HBV DNA ≥400 copies/mL (69 IU/mL) after <400 copies/mL. Resistance genotyping by HBV pol/RT sequencing was attempted for all patients at baseline and if viremic (HBV DNA ≥400 copies/ mL) at Week 96/study discontinuation. Results: Overall, 18 patients (9 TDF, 9 FTC/TDF) were viremic viremic at Week 96/last visit. The mean baseline HBV DNA was significantly higher for viremic patients (8.04 log10 copies/mL) compared to patients who did not qualify for genotyping (6.39 log10 copies/mL). In the TDF arm, 3 patients had conserved site changes/reversions (1 with VB), 1 had unique polymorphic site changes, 2 had no change, and 3 were unable to be genotyped. In the FTC/TDF arm, 2 patients had conserved site changes/reversions, 1 had unique polymorphic site changes, 4 had no change, and 2 were unable to be genotyped. No phenotypic resistance to TDF was observed. Four of eight (50%) patients had LAM-R reversions (rtV/I204M±rtM180L) on TDF while 1/8 (12.5%) patients on FTC/TDF had LAM-R reversions. Thirteen patients (4.6%) with prior entecavir (ETV) exposure and 25 patients (8.9%) with baseline ETV-R were enrolled; neither had an impact on viral kinetics. Conclusions: No TDF resistance has been detected through 96 weeks of treatment with either TDF or FTC/TDF in LAM-R patients. The presence of ETV-R or ETV exposure did not impact viral kinetics through 96 weeks. Resistance surveillance in this population will continue through Year 5.
( Won Young Tak ),( Sang Hoon Ahn ),( Seung Woon Paik ),( Jia-Horng Kao ),( Hie-won Hann ),( Fung Scott ),( Trinh Huy ),( Nguyen Tuan Trong ),( Gaggar Anuj ),( Flaherty John ),( Yee Leland J ),( Jump 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1
Aims: In a recent Phase 3 study (Study 4018) in HBV patients suppressed on TDF treatment, switching to TAF demonstrated noninferior efficacy to continued TDF with superior bone and renal safety at Week 48. This study aims assess the safety and efficacy of switching to TAF from TDF in patients of Asian descent with risk factors for TDF toxicity as per current EASL and AASLD guidelines. Methods: Virally suppressed patients (HBV DNA <20 IU/mL at screening) on TDF were randomized (1:1) to switch to TAF or continue TDF for 48 weeks in a double-blind fashion. Viral suppression and changes in bone (BMD by DXA) and renal (creatinine clearance [eGFR<sub>CG</sub>]) parameters were assessed over 48 weeks. Results: Among the 400 Asian patients enrolled, 288 (72%) had at least 1 TDF RF. At Week 48, similar proportions with ≥1 RF had HBV-DNA <20IU/mL (TAF 97%; TDF 97%) and normal ALT by 2018 AASLD criteria (TAF 76%; TDF 73%). TAF subjects with ≥1 RF had increases in eGFR<sub>CG</sub> compared to decreases on TDF [median (Q1, Q3) change; TAF: +2.6 (-2.01, 7.34); TDF: -2.7 (-7.56, +15.79); P<0.0001)]. Among patients with ≥1 RF, improvements were seen in BMD for TAF vs. continued declines in TDF patients at both spine (P<0.0001) and hip (P<0.0001). Conclusions: Virally suppressed Asian patients with CHB and risk factors for TDF who switched to TAF showed improved bone and renal safety while efficacy was well-maintained.
( Hyung Joon Kim ),( Young-Suk Lim ),( Ki Tae Yoon ),( Won Young Tak ),( Sang Hoon Ahn ),( Jae-Seok Hwang ),( Henry LY Chan ),( Scott Fung ),( Wai Kay Seto ),( Wan-Long Chuang ),( Chi-Yi Chen ),( Aric 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV),is more stable in plasma and enhances delivery of TFV into hepatocyteswhile lowering circulating levels of TFV by approximately 90% comparedto tenofovir disoproxil fumarate (TDF).Methods: In this Phase 3 study, patients with HBeAg-positive chronichepatitis B (CHB) were randomized 2:1 to TAF 25 mg QD or TDF300 mg QD and treated for 96 weeks. After Week 96, patients receiveopen label TAF for 48 weeks. The primary efficacy analysis was thepercent of patients with HBV DNA <29 IU/mL at Week 48. Key secondarysafety endpoints were assessed sequentially: changes in hip andspine bone mineral density (BMD), changes in serum creatinine (sCr),and dipstick proteinuria. Markers of bone formation and resorption,and renal tubular function were also assessed.Results: 873 patients were randomized and treated at 164 sites in19 countries. Baseline characteristics included: mean age 38 years,83% males, 82% Asians; 47% had HBV DNA ≥ 8 log10 IU/mL, and26% were treated previously with nucleos(t)ides. At Week 48, TAFwas non-inferior in efficacy to TDF with virologic response rates of63.9% with TAF and 66.8% with TDF. A greater percentage of patientstreated with TAF achieved normalization of serum ALT values.Patients on TAF experienced significantly less declines in hip and spineBMD, and a smaller increase in sCr than TDF; eGFRCG, and renaltubular markers also changed less with TAF. No viral resistance wasobserved in 22/581 (3.8%) and 11/292 (3.8%) of TAF and TDF patients,respectively, who qualified for testing.Conclusions: Compared to TDF 300 mg, the efficacy of TAF 25 mgin patients with HBeAg-positive CHB was noninferior. Safety wasalso improved, with less change in bone and renal parameters.