Ledipasvir/Sofosbuvir for 12 or 24 Weeks Is Safe and Effective in Kidney-transplant Recipients with Genotype 1 or 4 HCV Infection

( Massimo Colombo ),( Alessio Aghemo ),( Lin Liu ),( Robert H. Hyland ),( Chohee Yun ),( Diana M. Brainard ),( John G. Mchutchison ),( Sunjin Hwang ),( Marc Bourliere ),( Markus Peck-radosavljevic ),( 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Methods: Kidney transplant recipients with chronic GT1 or GT4 HCV infection, treatment-naive and treatment-experienced, with or without compensated cirrhosis were randomized 1:1 at 5 sites in Europe to receive LDV/SOF (90 mg/400 mg) for 12 or 24 weeks. Randomization was stratified by HCV genotype, treatment history and presence or absence of cirrhosis. Cirrhosis was determined by liver biopsy (Metavir score = 4 or Ishak score ≥5), Fibroscan® >12.5 kPa, or Fibrotest® >0.75 and APRI >2. A pretreatment creatinine clearance <40 mL/min was an exclusionary criterion. The primary endpoint was SVR12. Results: 114 patients were randomized and treated; median age was 53, 58% were male, 94% were white, 72% carried the non-CC IL28B allele, 91% had GT 1 infection, 69% were treatment-naive, and 15% had compensated cirrhosis. The median eGFR was 56ml/min (range 35-135ml/min). All 92 patients with SVR4 data available achieved SVR4 including a patient discontinuing treatment at Week 4 due to an AE. SAEs were reported in 12 (11%) patients; 3 were assessed as treatment related: syncope, pulmonary embolism, and blood creatinine increased. The most frequent AEs were headache (19%), asthenia (13%), and fatigue (10%). Conclusions: Administration of LDV/SOF for 12 or 24 weeks in patients with chronic HCV genotype 1 or 4 patients who have undergone kidney transplant was safe and highly effective with an SVR4 rate of 100%. Treatment was well-tolerated. SVR12 data for all patients will be presented.

SOF/VEL/VOX for 12 Weeks is a Safe and Effective Salvage Regimen for NS5A Inhibitor-experienced Patients with Genotype 1-6 HCV Infection

( Eric Lawitz ),( Michael Manns ),( Marc Bourliere ),( Sooji Lee ),( Nelson Cheinquer ),( Luisa Stamm ),( Robert H. Hyland ),( Liyun Ni ),( Hadas Dvory-sobol ),( Diana Brainard ),( Mani Subramanian ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: The pangenotypic fixed-dose combination (FDC) of sofosbuvir (SOF), a HCV NS5B inhibitor, velpatasvir (VEL), a HCV NS5A inhibitor, and voxilaprevir (VOX), a HCV NS3/4A protease inhibitor, is an salvage regimen for direct acting antiviral (DAA)-experienced patients based on the safety and efficacy demonstrated in Phase 2 and Phase 3 trials in this population. Methods: This was a retrospective analysis of data from 454 NS5A inhibitor-experienced patients treated with SOF/VEL FDC+VOX or SOF/VEL/VOX FDC in the Phase 2 and Phase 3 trials. Efficacy was assessed by SVR12 and relapse rates. Safety was assessed by treatment-emergent adverse events (AEs) and laboratory abnormalities. Results: Of 454 NS5A inhibitor-experienced patients treated, 77% were male, 41% had compensated cirrhosis, 86% had NS5A and NS3 baseline resistance-associated substitutions (RASs), 74% had genotype 1 HCV infection. Most patients (53%) had previously been exposed to NS5A inhibitor+NS5B inhibitor, with 39% exposed to NS5A inhibitor+NS3/4A protease inhibitor±NS5B inhibitor and 8% exposed to NS5A inhibitor±another DAA. Overall, the SVR12 rate was 97% with a relapse rate of 2%. The SVR12 rate in patients with compensated cirrhosis was 95% and in patients with baseline RASs was 97%. The SVR12 rates by prior regimen were: NS5A inhibitor+NS5B inhibitor 95%; NS5A inhibitor+NS3/4A protease inhibitor±NS5B inhibitor 99%; and NS5A inhibitor±another DAA 100%. Treatment-emergent RASs were uncommon, present in 3 of 10 patients who relapsed. Only 1 patient (0.2%) discontinued treatment due to an AE. No serious adverse events attributed to study medication were reported. Conclusions: Results in over 450 NS5A inhibitor-experienced patients enrolled in Phase 2 or Phase 3 trials demonstrate that the 3-DAA combination of SOF, VEL and VOX for 12 weeks is a safe, well tolerated and effective treatment for patients who previously failed an NS5A inhibitor-containing regimen, irrespective of the other drugs in the prior treatment.

Long-term Follow-up of Patients with Chronic HCV Following Treatment with DAAs: Maintenance of SVR, Persistence of Resistance and Clinical Outcomes

( W. Ray Kim ),( Eric J. Lawitz ),( Peter Ruane ),( Catherine Stedman ),( Graham Foster ),( Robert H. Hyland ),( Sarah Coogan ),( Stephanie Moody ),( Hadas Dvory-sobo ),( Steven J. Knox ),( Diana M. B 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Significant advances in the treatment of chronic hepatitis C have been made with direct acting antiviral (DAA) regimens. While SVR rates may now be achieved in the majority of patients, data describing long-term virologic and clinical outcomes with these regimens are needed. Methods: We report interim data from two 3-year registry studies capturing long-term outcomes in patients with chronic hepatitis C treated with DAAs. Subjects are enrolled into two registries according to SVR status; SVR (SVR registry) versus non-SVR (Sequence registry). We determined the durability of SVR, relapse and reinfection rates. The persistence of resistance associated variants (RAVs) in treatment failures is followed. Liver disease progression is assessed by periodic clinical & labroratory evaluations. Results: 5433 patients enrolled in the SVR registry with a median (range) follow-up of 71 (0-156) weeks. 536 patients enrolled in the Sequence registry with a median (range) of follow-up of 44 (0-159) weeks. Demographic and disease characteristics are described below. In the SVR registry, at the time of data analysis, 99.7% (5414/5433) of patients have maintained SVR with 0.3% (19/5433) having emergent virus (6 relapses, 8 new infections, 5 to be confirmed). Viral emergence occurred by Week 96 in all patients. In the Sequence registry of 89 patients who received an NS5A inhibitor and had baseline sequencing data, 91.0% (81/89) had NS5A RAVs at Week 96. HCC was reported in 0.3% (16/5433) and 0.9% (5/536) of patients in the SVR and Sequence registries through Week 96 respectively. There were no significant changes in laboratory evaluations or liver disease assessments. Conclusions: SVR achieved following treatment with DAA regimens is durable. In patients failing NS5A-containing regimens, treatment- emergent NS5A RAVs persist. Rates of clinical disease progression and HCC are low. Ongoing reporting from these registry studies will be required to confirm these findings.

The Safety and Tolerability of SOF/VEL/VOX for 8/12 Weeks in >1,000 Patients Treated in the POLARIS Studies: An Integrated Analysis

( Michael Manns ),( Edward J. Gane ),( Bernard E. Willems ),( Stuart K. Roberts ),( Steven Flamm ),( Marc Bourlière ),( Tarik Asselah ),( Laurent Alric ),( Sunjin Hwang ),( Robert H. Hyland ),( Luisa 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: The once-daily fixed-dose combination tablet of sofosbuvir/ velpatasvir/voxilaprevir (SOF/VEL/VOX) was evaluated for the treatment of genotype 1-6 HCV patients with and without compensated cirrhosis. Treatment was for 12 weeks for DAA-experienced patients (POLARIS-1 and POLARIS-4) and for 8 weeks for DAA-naive patients (POLARIS-2 and POLARIS-3). This analysis describes the safety of these 4 Phase 3 studies. Methods: Treatment-emergent adverse events (AEs) and laboratory abnormalities were assessed in patients who received SOF/VEL/VOX or placebo for 12 weeks(POLARIS-1), SOF/VEL/VOX or SOF/VEL for 12 weeks(POLARIS-4), or SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks(POLARIS-2 and POLARIS-3). SAEs and deaths were followed until post-treatment Week 24. Results: 1056 patients were treated with SOF/VEL/VOX for 8 (n=611) or 12 (n=445) weeks, 700 received SOF/VEL for 12 weeks, and 152 received placebo. 38% had compensated cirrhosis, 28% had a BMI ≥30 kg/m2, 36% were female, and 12% were ≥65 years old. Two deaths were reported, one illicit drug overdose and one attributed to hypertension, neither were related to treatment. SAEs and discontinuations were more frequent in the placebo group and occurred with similar frequency in the other groups; none were related to study treatment. Headache, fatigue, nausea, and diarrhea were the most common AEs. Mild diarrhea and nausea occurred more frequently in the SOF/VEL/VOX groups. Overall, 5.1 - 6.6% of patients who received SOF/VEL/VOX or SOF/VEL had Grade 3 or 4 laboratory abnormalities. Among patients receiving VOX, one patient each had a Grade 3 elevation in ALT and bilirubin. Conclusions: SOF/VEL/VOX for 8 or 12 weeks in the POLARIS studies was well tolerated with a low frequency of Grade 3 or 4 AEs, SAEs, and AEs leading to discontinuation. The frequency of AEs in the SOF/VEL/VOX groups was similar to SOF/VEL and placebo groups, with higher rates of mild diarrhea and nausea compared to SOF/VEL.

A Randomized, Controlled Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Experienced Patients with GT1-6 HCV Infection: The POLARIS-4 Study

( Paul Kwo ),( Stefan Zeuzem ),( Steven L. Flamm ),( Myron Tong ),( John M Vierling ),( Stephen Pianko ),( Peter Buggisch ),( Victor de Lédinghen ),( Robert H. Hyland ),( Xiaoru Wu ),( Evguenia S. Sva 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: DAAs provide safe and highly efficacious therapies for HCV infection. However, the small proportion of patients who do not achieve a sustained virologic response with DAA-based regimens represent a population with an unmet medical need. Sofosbuvir(SOF) and velpatasvir(VEL) are pangenotypic inhibitors of the HCV NS5B and NS5A proteins, respectively, and voxilaprevir(VOX) is a pangenotypic HCV NS3/4A protease inhibitor. This study evaluates treatment with a SOF/VEL/VOX for 12weeks and a SOF/VEL for 12weeks as salvage regimens in DAA-experienced patients who had not previously received an NS5A inhibitor. Methods: Patients with genotypes 1-3 were randomized 1:1 to receive open-label SOF/VEL/VOX or SOF/VEL for 12weeks, stratified according to genotype and cirrhosis status. Patients of all other genotypes were assigned to receive SOF/VEL/VOX for 12weeks. DAA-experienced patients who previously were treated with an NS5A inhibitor or with only an NS3/4A protease inhibitor in combination with ribavirin and Peg-IFN were excluded. The primary endpoint evaluates the superiority of the SVR12 of each treatment to a prespecified goal of 85%. Results: Of the 333 patients who were randomized and treated, 77% were male, 19% had the IL28B CC genotype, 46% had compensated cirrhosis and 43% had genotype 1 infection. Most patients had prior DAA experience with either an NS5B inhibitor alone(73%) or an N5SB inhibitor and an NS3/4A protease inhibitor(25%); the most common prior treatment regimens were SOF with ribavirin ±Peg-IFN and SOF combined with simeprevir. Treatment was well tolerated.No SAE was assessed to be attributable to study drug. Overall, SVR12 was achieved in 97%(177/182) of patients treated with SOF/VEL/VOX and 90%(136/151) patients treated with SOF/VEL. SOF/VEL/VOX met the prespecified 85% SVR12 performance goal(p<0.001); SOF/VEL did not. Conclusions: SOF/VEL/VOX for 12 weeks provides a safe, well tolerated and effective retreatment options for patients who did not previously achieve SVR following treatment with non-NS5A inhibitor-containing DAA regimens.