Long-Term Follow-Up of Patients with Chronic HCV Infection and Compensated or Decompensated Cirrhosis Following Treatment with Sofosbuvir-Based Regimens

( Alessio Aghemo ),( Alessandra Mangia ),( Eric Lawitz ),( Ed Gane ),( Brian Conway ),( Peter J. Ruane ),( Armando Abergel ),( Sooji Lee ),( Brian McNabb ),( Anu Osinusi ),( Frances Chen ),( Hadas Dvo 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Early results from registries and cohort studies have demonstrated that patients with cirrhosis who achieve SVR with DAA experience improvements in liver-related morbidity, HCC risk, and mortality. However, follow-up time for these studies is generally short. This analysis from the Gilead Cirrhosis Registry evaluates long-term outcomes in patients with cirrhosis who achieved SVR following treatment with a sofosbuvir-(SOF) based regimen. Methods: Patients with cirrhosis who achieved SVR after receiving a SOF-based regimen were eligible for enrollment. Patients enrolled within 60 weeks of completing a treatment study or transfer from another SVR registry study, or within 2 years of achieving SVR following treatment in a clinical practice setting. Patients return for visits every 24 weeks for 5 years for laboratory, clinical, and radiographic assessments of durability of SVR and clinical progression of liver disease. In this abstract we report the HCC incidence, CTP scores, and SVR durability. Results: As of 5 OCT 2017, 1564 patients have been enrolled in the cirrhosis registry. Mean age (range) is 59 (26-86) years, 68% are male, and 84% of patients had pretreatment CTP scores A. Median (range) of registry follow-up time was 53 (<1-144) weeks. Overall, there were 55 observed events of HCC in 3922 person-years (PYs) of follow-up since the start of DAA treatment (34 cases in 3292 PYs of follow-up for CTP-A patients and 21 in 601 PYs of follow-up for CTP B+C patients). Overall, patients with pretreatment CTP-A cirrhosis maintained CTP-A status while patients with pretreatment CTP B or C cirrhosis showed improvement. Conclusions: In this ongoing registry of patients with cirrhosis who achieved SVR after treatment with a SOF-based regimen, HCC was uncommon and occurred more often in patients with decompensated cirrhosis. The majority of patients maintained or improved their CTP category relative to pretreatment through up to week 96.

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.

A Phase 3 Study Comparing Tenofovir Alafenamide (TAF) to Tenofovir Disoproxil Fumarate (TDF) in HBeAg-Negative CHB Patients at Week 96

( Seung Kew Yoon ),( Maurizia Brunetto ),( Young Suk Lim ),( Ed Gane ),( Wai Kay Seto ),( Marina Osipenko ),( Sang Hoon Ahn ),( Harry L. Janssen ),( Akash Shukla ),( Wan Long Chuang ),( Huy Trinh ),( 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In this randomized, double blind study in HBeAg- negative patients comparing TAF to TDF, 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: 425 patients were randomized to receive TAF 25 mg QD (n=285) or TDF 300 mg QD (n=140) and treated for 144 weeks.. Efficacy analyses at Week 96 included virologic (HBV DNA <29 IU/mL), and biochemical (ALT normalization) responses; key secondary safety endpoints were changes in hip and spine bone mineral density (BMD), and changes in serum creatinine and estimated GFR by Cockcroft- Gault method (eGFRCG). Serum markers of bone turnover and urine markers of renal tubular function were also assessed. Results: Baseline characteristics included: mean age 46 years, 61% males, 72% Asians, genotypes A through D (5%, 24%, 38%, 31%); 19% had HBV DNA ≥ 7 log10 IU/mL, and 21% were previously treated with nucleos(t)ides. Efficacy and safety results are summarized in the Table. At Week 96, virologic response rates were similar in the TAF and TDF groups.A greater percentage of TAF patients achieved normalization of serum ALT valuesPatients receiving TAF showed smaller declines in hip and spine BMD compared with TDF patients through Week 96. The smaller decline in eGFRCG and smaller changes in renal tubular markers observed with TAF. The rates of treatment discontinuations for adverse events (<2%) and serious adverse events were (≤11%) were similar. Conclusions: At Week 96, high rates of virologic suppression were maintained 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.

A Phase 3 Study Comparing Tenofovir Alafenamide (TAF) to Tenofovir Disoproxil Fumarate (TDF) in Patients with HBeAg-positive CHB patients

( 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.

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