Evaluation of Renal and Bone and Safety in Patients with CHB and CKD Treated with TAF in Post Liver Transplantation

( Anuj Gaggar ),( Bibin George ),( Stephen Munn ),( Hongyuan Wang ),( Vithika Suri ),( John Flaherty ),( Ed Gane ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Chronic Hepatitis B(CHB) remains a leading indication for orthotopic liver transplantation(OLT) worldwide. Common complications following OLT include renal dysfunction secondary to perioperative renal injury and post-operative nephrotoxicity from calcineurin inhibitors; osteoporosis is also observed secondary to preoperative malnutrition and post-operative corticosteroids. In this setting, antiviral prophylaxis to prevent recurrent HBV infection with TAF may have advantages over TDF due to its improved renal and bone safety profile. Methods: In this Phase 2 study (NCT02862548), LT recipients with stage 2 or greater CKD and receiving antiviral prophylaxis with TDF were randomized 1:1 to either receive TAF 25 mg or continue TDF . The primary efficacy analysis was the percent of patients who maintained viral suppression at Week 24. Key pre-specified secondary safety endpoints were changes in hip and spine BMD, changes in sCr, estimated GFR and direct GFR assessment over 48 weeks. Results: 51 patients were randomized and treated at a single site in New Zealand. Baseline characteristics included: mean age 60 years, 75% males, 53% Pacific Islander and mean baseline eGFRCKD-EPI 52mL/min/1.73m2 with 53% of patients with <50mL/min/1.73m2. The median baseline surface area corrected GFRCr-EDTA was 58 mL/min/1.73m2. The median interval since transplantation was approximately 9 years. Of the 47 patients that have reached Week 12, all patients maintained viral suppression. There were no treatment discontinuations and serious adverse events were numerically lower in TAF arm compared to the TDF arm. Switching to TAF treatment resulted in a trend toward improved sCr levels (median change: -0.07 for TAF vs. -0.02 for TDF; P=0.09) and improved eGFRCKD-EPI (median change: 2.7 for TAF vs. 0.8 for TDF; P=0.14) as early as week 12 (Figure 1). Conclusions: Early after switching from TDF to TAF in LT recipients, viral suppression is maintained while smaller changes in renal function were observed.

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.

Predictors of HBeAg Loss and Seroconversion by Clinical Features and Viral Sequencing after 144 Weeks of Treatment with Tenofovir Alafenamide or Tenofovir Disoproxil Fumarate

( Yoon Jun Kim ),( Young-suk Lim ),( Shalimar ),( Xiaoli Ma ),( Akash Shukla ),( Huy N. Trinh ),( Pietro Andreone ),( Jae-seok Hwang ),( Vithika Suri ),( George Wu ),( Ondrej Podlaha ),( Anuj Gaggar ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: HBeAg seroconversion remains an important endpoint for antiviral therapy. We previously reported on HBeAg loss following 48 weeks of oral antiviral therapy in the ongoing phase 3 study described below. Here we present an updated evaluation of factors associated with HBeAg loss with/without anti-HBe seroconversion following 3 years of antiviral therapy. Methods: The study included adults with HBeAg-positive CHB enrolled in a Phase 3 trial(Study GS-US-320-0110) comparing TAF 25mg QD vs. TDF 300mg QD. At Week144, 340(39%; TAF 226; TDF 114) patients had received 1year of open label TAF 25mg QD after switching from double blind(DB) treatment. The associations between HBeAg loss at Week144 with host, viral, and treatment-related factors, including on-treatment virologic suppression, were determined using logistic regression analyses. Results: Among 873 ipatients, the median age was 36yrs, 82% were Asian, and median baseline (BL) ALT and HBV DNA were 85U/L (IQR 60-138) and 7.9 log10IU/mL (IQR 6.9- 8.6), respectively. At Week144, a total of 194patients (22%) experienced HBeAg loss and 142 patients (16%) underwent HBeAg seroconversion (Figure 1). Compared with subjects with persistent HBeAg-positivity, those with HBeAg loss were older (median age, 35 vs. 40yrs), were infected with non-genotype D HBV (75% vs 86%), had lower median HBsAg levels (4.3 vs 3.8 log10 IU/mL), a higher median BL ALT (83 vs. 101U/L), a higher prevalence of presumed cirrhosis (Fibro Test ≥0.75:6.4% vs. 13.2%), and lower median BL serum HBV DNA (8.1 vs. 7.7 log10 IU/mL) (all P≤0.005). In multivariate analysis, baseline HBV DNA<8 log10 was an independent predictor of both HBeAg loss(OR: 1.816 [1.174-2.808]; P=0.007) and seroconversion (OR: 2.512 [1.684-3.746]; P<0.001); treatment with TAF in the DB period was a predictor of seroconversion (OR:1.596 [1.044-2.439]; P=0.031) but not loss. Conclusions: Following 144 weeks of treatment, HBeAg loss/ seroconversion rates remains low in subjects treated with TAF or TDF with lower baseline HBV DNA levels associated with higher rates of response.

Smaller Decreases in Bone Mineral Density in CHB Patients Receiving Tenofovir Alafenamide Compared with Tenofovir Disoproxil Fumarate Over 96 Weeks

( 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.

Improvement in Renal Parameters in CHB Patients Treated with Tenofovir Alfenamide (TAF) versus Tenofovir Disoproxil Fumarate (TDF) over 96 Weeks

( Hyung Joon Kim ),( Wan Long Chuang ),( Kosh Agarwal ),( Jae Seok Hwang ),( Florin Caruntu ),( Florence Wong ),( Hie Won Hann ),( John Flaherty ),( Audrey Lau ),( Anuj Gaggar ),( Vithika Suri ),( Shu 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In Phase 3 studies in CHB patients the efficacy of TAF was found smaller changes in renal parameters compared with TDF treatment. This benefit was particularly evident in patients with risk factors for renal impairment.Here, we present renal safety results after 96 weeks of treatment. Methods: In Phase 3 studies (HBeAg positive patients [N=873] and HBeAg negative patients [N=425]), patients were randomized 2:1 to TAF 25 mg QD or TDF 300 mg QD, and treated for 144 weeks. Renal parameters including estimated glomerular filtration rate (eGFR) calculated by the Cockcroft-Gault method were evaluated. Chronic kidney disease (CKD) staging was categorized by the National Kidney Foundation KDOQI guidelines. Evaluated risk factors for kidney disease included older age (age ≥ 50), female gender, renal impairment (eGFR <90mL/min) and presence of comorbidities (hypertension, cardiovascular disease and diabetes). Urine markers of renal glomerular dysfunction (urine protein and albumin to creatinine ratio) and tubular dysfunction (retinol binding protein (RBP) and beta-2 microglobulin [B2M] to creatinine ratio) were serially assessed. Results: Patients treated with TAF continued to show smaller changes in serum creatinine (p=0.001) and eGFRCG (p<0.001) at 96 weeks. Similarly, median percentage changes in renal tubular markers, were also smaller in TAF-treated patients compared with TDF patients at Week 96; RBP/Cr (p<0.0001) and B2M/Cr (p<0.0001). A lower percentage of patients experienced ≥1 stage worsening in NKF CKD stage when treated with TAF compared with TDF at Week 96 overall and when evaluated by risk factors for kidney disease.Furthermore, CKD stage progression increased disproportionately in the TDF group in patients with ≥2 risk factors (Table). Conclusions: Treatment with TAF for 96 weeks continued to be associated with smaller changes in renal parameters compared with TDF treatment. The benefits of TAF are particularly evident in patients with risk factors for kidney disease.

Efficacy and safety of sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir for hepatitis C in Korea: a Phase 3b study

Jeong Heo,Yoon Jun Kim,Sung Wook Lee,Youn-Jae Lee,Ki Tae Yoon,Kwan Soo Byun,Yong Jin Jung,Won Young Tak,Sook-Hyang Jeong,Kyung Min Kwon,Vithika Suri,Peiwen Wu,Byoung Kuk Jang,Byung Seok Lee,Ju-Yeon Ch 대한내과학회 2023 The Korean Journal of Internal Medicine Vol.38 No.4

Background/Aims: Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir for 12 weeks in HCV-infected Korean adults. Methods: This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir–velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir–velpatasvir–voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment. Results: Of 53 participants receiving sofosbuvir–velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir–velpatasvir–voxilaprevir achieved SVR 12. Overall, sofosbuvir–velpatasvir and sofosbuvir–velpatasvir–voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported. Conclusions: Treatment with sofosbuvir–velpatasvir or sofosbuvir–velpatasvir–voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.