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.

Viral Kinetics in Women of Child Bearing Potential with Chronic HBV Following Treatment with Tenofovir Alafenamide or Tenofovir Disoproxil Fumarate

( Brunetto ),( Carla Coffin ),( Audrey Lau ),( Shuyuan Mo ),( John F. Flaherty ),( Anuj Gaggar ),( G Mani Subramanian ),( Mindie H. Nguyen ),( Selim Gurel ),( Alexander Thompson ),( Edward J. Gane ) 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Suppression of the HBV in women of childbearing potential (WOCBP) has important implications in preventing transmission of HBV from mother to infant. Antiviral therapy that reduces HBV DNA to < 2x105 IU/mL at delivery in mothers can substantially reduce the risk of perinatal transmission. We evaluated the viral kinetics of TAF and TDF in WOCBP. Methods: : In two Phase 3 studies (HBeAg positive and negative patients), 1301 patients (37% female) were randomized (2:1) to receive TAF 25 mg QD or TDF 300 mg QD. All patients were required to have HBV DNA >2x104 IU/mL at screening and serum ALT >2 times AASLD criteria.WOCBP were defined as nonmenopausal females 18 years or older without history of hysterectomy, bilateral oophorectomy, or ovarian failure. For this subanalysis, patients were stratified by baseline HBV DNA levelsand the endpoints were virologic suppression to HBV DNA <29 IU/mL or < 2x105 IU/mL. Results: 365(76%) female were identified as WOCBP with 118 (32%) having HBV DNA >1x108 IU/mL at baseline. Suppression rates were generally similar between TAF and TDF groups and within viral load strata for HBeAg positive and negative patients. After 12 weeks of treatment with TAF or TDF, 77% of WOCBP with baseline HBV DNA <2x105 IU/mL had full suppression to <29 IU/mL compared to 1% of those at the highest baseline viral load (Figure A). By Week 24, 54% of all WOCBP had achieved complete viral suppression. Of WOCBP with baseline viral load ≥2x105 IU/mL (n=305), 76%, 89%, and 93% achieved viral load reduction to <2x105 IU/mL by Weeks 4, 8, and 12, respectively (Figure B). Conclusions: After 12 weeks of treatment the majority of WOCBP had HBV DNA to <2x105 IU/mL. In women with higher baseline viral loads, longer treatment duration may be necessary to achieve viral suppression below recommended thresholds.

Determinants of Variability in ISG15 Gene Expression in Patients with Chronic Hepatitis B (CHB) Infection during Treatment with Oral TLR7 Agonist GS-9620

Yoon Jun Kim,Stuart Gordon,Shyamasundaran Kottili,BenedettaMassetto,Anuj Gaggar,Scott Stem,Stefan Pflanz,Zhishen Ye,Mani Subramanian,John McHutchison,Young-Suk Lim,Ed Gane 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

Safety of Sofosbuvir-Based Regimens for the Treatment of Chronic HCV Infection in Patients with Mild or Moderate Renal Impairment

( Sulkowski M ),( Durand F ),( Reddy Kr ),( Lawitz E ),( Bourlière M ),( Cheinquer N ),( Scherbakovsky S ),( Chokkalingam A ),( Ni L ),( Gaggar A ),( Colombo M ),( Kyung Min K ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: The major metabolite of sofosbuvir (SOF), GS-331007, is cleared renally and tends to accumulate in patients with chronic kidney disease (CKD). However, there are a substantial amount of data showing that this accumulation is not clinically significant, even in patients with end stage renal disease. Methods: This retrospective analysis of 37 Phase 2 and 38 Phase 3 studies presents the safety profile of SOF-based therapies (LDV/SOF, SOF/VEL and SOF/VEL/VOX) in patients with mild to moderate CKD as well as in patients with normal renal function. Results: 8,181 patients were included in this analysis. Mean baseline eGFR was 118.2, 69.3, and 43.6 mL/min/1.73m2 for patients with normal renal function (n=6575), mild (n=1499), or moderate (n=107) renal impairment, respectively. The mean eGFR at post-treatment follow-up week 4 was 114.4, 69.9, and 46.3 mL/min/1.73m2 for patients with normal renal function (n=5519), mild (n=1285), or moderate (n=90) renal impairment, respectively. When comparing baseline levels with those of post-treatment follow-up week 4, there was no clinical difference observed. Baseline characteristics were generally similar across groups, except patients with impaired renal function were older. Table 1 provides a summary of adverse events (AEs). Rates of Grade 3-4 AEs and discontinuations due to AEs were similar across groups. Patients with moderate renal impairment had higher rates of SAEs but most were not treatment-related. Conclusions: Sofosbuvir-based regimens were safe and well-tolerated in patients with mild or moderate renal impairment. Renal function remained stable throughout treatment, and similar rates of AEs were observed across all treatment groups.

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.

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.

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.

48-Week Safety and Efficacy of Switching to Tenofovir Alafenamide (TAF) from Tenofovir Disoproxil Fumarate (TDF) in Asian Patients with TDF Risk Factors (RF)

( 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_CG]) 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_CG 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.