No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B

( Won Young Tak ),( Henry Lik-yuen Chan ),( Patrick Marcellin ),( Calvin Q. Pan ),( Andrea L Cathcart ),( Neeru Bhardwaj ),( Yang Liu ),( Stephanie Cox ),( Bandita Parhy ),( Eric Zhou ),( John F Flahe 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Presented herein are the post Week 48 through Week 96 resistance analyses for Phase 3 studies evaluating tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF). Methods: Patients were randomized 2:1. HBV pol/RT population or deep sequencing was conducted for patients with viremia at Week 96 or at early discontinuation post Week 48. Deep sequencing was conducted for patients with HBV DNA >159 IU/mL and sequence changes at the consensus sequence level are reported. Phenotypic analysis was performed for Virologic breakthrough (VB) patients who were adherent to study drug, patients with conserved site substitutions, or for polymorphic substitutions emergent in >1 patient. Results: TAF and TDF were treated in 866 and 432 patients, respectively. A similar percentage of patients in the arms qualified for sequence analysis. In the TAF arm, 87 (10.5%) patients qualified: 31 had no sequence change from baseline, 15 were unable to sequence (UTS), 32 had polymorphic site substitutions, and 9 had conserved site substitutions. In the TDF arm, 45 (10.9%) patients qualified: 26 had no sequence change, 6 were UTS, 11 had polymorphic site substitutions, and 2 had conserved site substitutions. Each detected conserved site substitution other than rtA181T was observed in one patient. The rtA181T substitution in 2 patients, 1 from each arm, was not associated with increasing plasma HBV DNA levels. At Week 96, a small percentage of patients experienced VB, and VB was often associated with nonadherence. 27 patients qualified for phenotypic analysis and no patient isolates tested showed a reduction in susceptibility to TAF or tenofovir, respectively. Conclusions: The proportion of patients analyzed and the HBV sequence changes observed were similar between patients in the TAF and TDF arms. Most substitutions occurred at polymorphic positions and no substitutions associated with resistance to TAF were detected through 96 weeks of treatment.

Improved Bone and Renal Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) in CHB Patients

( 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.

Ixabepilone Plus Capecitabine for Metastatic Breast Cancer Progressing After Anthracycline and Taxane Treatment

Thomas, Eva S.,Gomez, Henry L.,Li, Rubi K.,Chung, Hyun-Cheol,Fein, Luis E.,Chan, Valorie F.,Jassem, Jacek,Pivot, Xavier B.,Klimovsky, Judith V.,de Mendoza, Fernando Hurtado,Xu, Binghe,Campone, Mario,L Grune & Stratton 2007 Journal of clinical oncology Vol.25 No.33

<B>Purpose</B><P>Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer.</P><B>Patients and Methods</B><P>Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m<SUP>2</SUP>intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m<SUP>2</SUP>orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m<SUP>2</SUP>on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review.</P><B>Results</B><P>Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [≥ grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups.</P><B>Conclusion</B><P>Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.</P>

Impact of Treatment with Tenofovir Alafenamide (TAF) or Tenofovir Disoproxil Fumarate (TDF) on Hepatocellular Carcinoma (HCC) Incidence in Patients with Chronic Hepatitis B (CHB)

( Young-Suk Lim ),( Henry Lik Yuen Chan ),( Wai-Kay Seto ),( Qing Ning ),( Kosh Agarwal ),( Harry L. A. Janssen ),( Calvin Q. Pan ),( Wan Long Chuang ),( Namiki Izumi ),( Scott K Fung ),( Dr Shalimar 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Potent antiviral treatment can reduce HCC incidence in CHB patients. TAF has shown antiviral efficacy similar to TDF, with higher rates of ALT normalization and no resistance in Phase 3 studies. We evaluated the impact of TAF or TDF on HCC in the ongoing Phase 3 studies. Methods: HBeAg-positive (n=1039) and -negative (n=593) patients with HBV DNA≥20,000 IU/mL and ALT >60 U/L (males) or >38 U/L (females) were recruited from 190 sites in 20 countries and randomized (2:1) to TAF or TDF. HCC was assessed at 6-monthly intervals by hepatic ultrasonography introduced after Week 96 and throughout by local standards of care. The standardized incidence ratio (SIR) for HCC was calculated for observed cases relative to predicted risk using the REACH-B model. Results: Through 5 years of follow-up, HCC occurred in 21 patients (1.0% [11/1,093] with TAF, 1.9% [10/539] with TDF). Median (Q1, Q3) time to HCC onset was 104 (55, 191) weeks. At baseline, relative to those without HCC, patients with HCC were more likely to be older (median age 53 vs 39y; P<0.001), male (90% vs 65%; P=0.014), and cirrhotic (FibroTest ³0.75; 33% vs 9%; P<0.001). The overall SIR was significantly reduced with TAF or TDF (SIR 0.42, 95% CI 0.27-0.64). HCC incidence was significantly reduced in noncirrhotic patients (SIR 0.37, 95% CI 0.22 to 0.63), and in patients receiving TAF (SIR 0.35, 95% CI 0.19-0.62). Lack of ALT normalization at Week 24 (HR 6.90; P=0.011), cirrhosis (HR 4.18; P=0.006), baseline HBsAg level (HR 0.53; P=0.006), and baseline hypertension (HR 5.55; P<0.001) were significant predictors of HCC development by multivariable analysis. Conclusions: In CHB patients receiving TAF or TDF, the incidence of HCC was reduced comparing with expected HCC incidence from REACH-B model. In patients treated with TAF, a significant reduction in SIR was seen, whereas those treated with TDF showed a trend toward a reduction.