Efficacy of Ledipasvir/Sofosbuvir plus Rivabirin among Patients with Decompensated Cirrhosis Who Underwent Liver Transplant during Participation in the SOLAR-1/-2 Studies

( Beat Müllhaupt ),( Paul Kwo ),( Kosh Agarwal ),( Christophe Duvoux ),( Francois Durand ),( Marcus Peck-Radosavljevic ),( Eric M. Yoshida ),( Leslie Lilly ),( Bernard Willems ),( Hugo Vargas ),( Prin 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The aim of this analysis is to evaluate outcomes in patients who underwent liver transplant after initiating treatment with ledipasvir (LDV)/sofosbuvir (SOF)+ribavirin (RBV) in the SOLAR-1 and SOLAR-2 trials. Methods: We combined data from the SOLAR-1 and SOLAR-2 studies, in which 7 groups of patients with HCV genotype (GT) 1 or 4 were randomized to receive 12 or 24 weeks of LDV/SOF+ RBV: patients without a transplant with 1) Child-Pugh-Turcotte (CPT) B or 2) CPT C cirrhosis; or transplanted patients with 3) no cirrhosis (F0 to F3), 4) CPT A, 5) CPT B or, 6) CPT C cirrhosis, or 7) fibrosing cholestatic hepatitis. Results: Seventeen patients underwent liver transplantation during the study. For all but one patient, this was the first liver transplant. Six were CPT B at screening (5 Group 1, 1 Group 5) and 11 were CPT C (Group 2). Median baseline MELD score was 17 (range 7-23), with the majority (11/17) having scores ≥15. Seven patients underwent transplant prior to completing their full course of treatment. All patients were HCV RNA <LLOQ at the time of liver transplant. All but one patient (94%, 16/17) maintained virologic response 12 weeks after transplant (pTVR12). All patients who achieved pTVR12 received at least 11 weeks of LDV/SOF+RBV. The one patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. Conclusions: Few patients with decompensated cirrhosis treated in the SOLAR studies underwent liver transplantation after initiating LDV/SOF+RBV therapy. For the 17 who did undergo transplant, 94% achieved pTVR12. The data suggest that 11 weeks of treatment prior to transplantation can prevent reinfection of the graft. Future studies are needed to assess the optimal timing and length of treatment in the peri-transplant setting.

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.

Sustained Viral Response Following Treatment with Direct Acting Antiviral Agents for Chronic Hepatitis C and the Risk of Hepatocellular Carcinoma

( K Rajender Reddy ),( Marc Bourliere ),( Kosh Agarwal ),( Eric Lawitz ),( Leia Kim ),( Anu Osinusi ),( Kathryn Kersey ),( Gerald Crans ),( Stephanie Moody ),( Liyun Ni ),( Diana M. Brainard ),( John 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: Sustained virologic response (SVR) after interferon (IFN)-based treatment for HCV infection is associated with reduced risk of hepatocellular cancer (HCC), although the risk is not eliminated. Less is known regarding the risk of de novo HCC following SVR with IFN-free direct acting antiviral (DAA) therapy. In this analysis, a review of incident HCC in patients treated with SOF-containing regimens was performed. Methods: Data from Gilead HCV clinical trials (from treatment start to 24 weeks post-treatment) and registry studies (3 to 5 year follow-up observation) were analyzed to evaluate the incidence of de novo HCC. The clinical database was searched to identify adverse events of liver tumors; the occurrence of HCC is recorded at each visit in the registry studies. Incidence rates and exposure-adjusted incidence rates, time to development, and risk factors for development of HCC were assessed in patients with and without cirrhosis (compensated and decompensated) who received IFN- containing (Peg- IFN+RBV±SOF) vs IFN-free treatment (SOF, ledipasvir/SOF, SOF/velpatasvir ± RBV), and SVR vs no SVR. Results: In the clinical trial database, 0.3% (36 of 13,525) patients had AEs of HCC or suspected HCC while in the registry study database, 0.5% (33 of 6675) were reported to have HCC. The rate was similar in non-cirrhotic patients who achieved SVR with an IFN-containing vs IFN-free regimen (0.09 vs 0.03 per 100 patient years of follow-up, respectively); few patients with compensated cirrhosis and none with decompensated cirrhosis received IFN-containing regimens. Among subjects treated with IFN-free regimens, higher rates were observed with advanced liver disease and non SVR (see table). Conclusions: Data from the Gilead clinical trial and registry study databases show incidence of HCC in subjects treated with IFN-free regimens is similar to that reported in the IFN-era in similar populations. While SVR significantly reduces the risk of HCC, the risk is not completely eliminated, particularly among patients with decompensated cirrhosis.

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.

Sofosbuvir/Velpatasvir (SOF/VEL) for 12 Weeks in Genotype 1, 2, 4, 5, 6 HCV Patients: Results of the ASTRAL-1 Study

( Mark S. Sulkowski ),( Henry Lik Yuen Chan ),( Jordan J. Feld ),( Kosh Agarwal ),( Christophe Hezode ),( Tarik Asselah ),( Peter J. Ruane ),( Norbert Gruener ),( Armand Abergel ),( Alessandra Mangia 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Background: Velpatasvir (VEL) is a pangenotypic HCV-NS5A inhibitor. This Phase 3 study evaluated treatment with a fixed dose combination of SOF/VEL for 12 weeks in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Methods: Patients with genotype 1, 2, 4, or 6 chronic HCV infection were randomized 5:1 to received SOF/VEL (400 mg /100 mg daily) or placebo for 12 weeks. Patients with genotype 5 infection were enrolled to the SOF/VEL treatment group and patients with genotype 3 were evaluated in a separate study. Results: 740 patients were enrolled at 81 international sites: 60% male, 79% white, 32% treatment-experienced (TE), and 19% compensated- cirrhosis. Of the 624 patients treated with SOF/VEL, the genotype distribution was 53% GT1, 17% GT2, 19% GT4, 6% GT5 and 7 % GT6. Overall SVR12 for SOF/VEL-treated patients was 99.0% and the study met its primary efficacy endpoint. SVR12 rates by HCV genotype are presented in the table. Two of 328 patients (0.6%) with genotype-1 infection had virologic relapse. No patients with genotype 2, 4, 5, or 6, including 48 with cirrhosis, had virologic failure. Four patients did not achieve SVR12 for non-virologic reasons. AEs and laboratory abnormalities were similar in the SOF/VEL-treated patients compared with the 116 placebo-treated patients. One patient discontinued SOF/VEL treatment due to adverse-events. Conclusions: Treatment with the once daily, all-oral, single tablet regimen of SOF/VEL for 12 weeks is well tolerated and results in high SVR12 rates in treatment-naive and treatment-experienced genotype 1, 2, 4, 5, and 6 HCV-infected patients with and without cirrhosis.

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.