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Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.

BACKGROUND Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. METHODS We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. RESULTS Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). CONCLUSIONS In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850, respectively.).

Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

BACKGROUND High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial

BACKGROUND The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING Gilead Sciences.

Sofosbuvir with peginterferon‐ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis

Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment‐experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg‐IFN+RBV) administered for 12 weeks to treatment‐experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open‐label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77‐97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78‐100) and 83% (95% CI: 62‐95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza‐like illness, fatigue, anemia, and neutropenia. Conclusion: In treatment‐experienced patients with HCV genotypes 2 and 3, 12‐week administration of SOF+Peg‐IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified. (Hepatology 2015;61:769–775)

A phase 2B study of MK-7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment

BACKGROUND & AIMS MK-7009 (vaniprevir) is a non-covalent competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease. This report presents the primary analysis results (safety and sustained viral response) of a phase 2b study of MK-7009 given in combination with peginterferon (PegIFN) alfa2a 180 μg weekly and ribavirin (RBV) 1000-1200 mg/day, for 24-48 weeks to non-cirrhotic patients who have failed previous PegIFN and RBV treatment. METHODS We present results of a randomized, placebo-controlled, double-blind study of MK-7009 administered for 24-48 weeks in combination with PegIFN and RBV in 4 regimens to at least 40 patients per arm. Stratification by prior response to PegIFN and RBV was as follows: null response, partial response, breakthrough and relapse. HCV RNA was determined by Roche Cobas Taqman with a lower limit of detection (LLoD) of 10 IU/ml and a lower limit of quantification (LLoQ) of 25 IU/ml. RESULTS SVR24 in patients on MK-7009+PegIFN and ribavirin (P/R) was statistically superior to placebo+P/R in all treatment groups (p<0.001). MK-7009 at 300 mg b.i.d. and 600 mg b.i.d. is generally well tolerated for use for up to 48 weeks of therapy. Patients in MK-7009 regimens had higher rates of gastrointestinal adverse events as compared to control (mostly mild to moderate). There were no significant differences in rates of anemia and rash between the MK-7009 regimens and control. CONCLUSIONS In conclusion, patients treated with MK-7009 plus P/R experienced significant improvement in SVR compared to P/R control in a population of GT 1 experienced patients.

Ledipasvir and sofosbuvir for HCV-infection in patients coinfected with HBV.

BACKGROUND Currently there are no all-oral treatment regimens for HCV in patients coinfected with HBV. In this pilot study, we evaluated whether ledipasvir and sofosbuvir therapy can suppress HCV infection in patients coinfected with HBV. METHODS Patients with HBV and genotype-1 HCV received 90 mg ledipasvir and 400 mg sofosbuvir daily for 12 weeks. The efficacy end point was sustained virological response (HCV RNA <15 IU/ml) 12 weeks after the end of treatment. RESULTS Of the eight patients enrolled, six (75%) were male, five (63%) were Polynesian, seven (88%) had the CC IL28B genotype and two (25%) had cirrhosis. All eight patients (100%; 95% CI 63%, 100%) reached the primary end point of HCV RNA <15 IU/ml 12 weeks after treatment. In seven of eight patients (88%), serum HBV DNA levels increased during treatment, but none of the increases were greater than 20,000 IU/ml, and none were associated with clinical HBV flares or required treatment. The most common adverse events were viral infection (63%), fatigue (25%) and upper respiratory tract infection (25%). No patients had serious adverse events and none discontinued treatment for any reason. CONCLUSIONS In this small sample, 12 weeks of ledipasvir/sofosbuvir was a safe and effective treatment for genotype-1 HCV infection in patients coinfected with HBV. Larger studies with longer follow-up are warranted.

GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

GS‐9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1–6 and improved coverage against commonly encountered NS3 resistance‐associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS‐9857 were evaluated in patients with chronic HCV genotype 1–4 infection. Patients with genotype 1–4 infection received placebo or once‐daily GS‐9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS‐9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS‐9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS‐9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100‐mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS‐9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1–4 infection, GS‐9857 exhibited linear PK and was associated with a median half‐life of 29–42 h, supporting once‐daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS‐9857 support its further evaluation for treatment of patients with chronic HCV infection.

Effect of viral suppression on hepatic venous pressure gradient in hepatitis C with cirrhosis and portal hypertension.

Portal hypertension is a predictor of liver‐related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon‐free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child‐Pugh‐Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open‐label sofosbuvir plus ribavirin at Day 1 or after a 24‐week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by ‐1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG <12 mm Hg at the end of treatment. Of nine patients with pretreatment HVPG ≥12 mm Hg who achieved SVR12 and completed 48 weeks of follow‐up, eight (89%) had a ≥20% reduction in HVPG, and three reduced their pressure to <12 mm Hg. Patients with chronic HCV and compensated or decompensated cirrhosis who achieve SVR can have clinically meaningful reductions in HVPG at long‐term follow‐up. (EudraCT 2012‐002457‐29).

Short Duration Treatment with Sofosbuvir/Velpatasvir plus GS-9857 in Treatment-Naive Genotype 1-6 HCV-Infected Patients with or without Cirrhosis

Edward J. Gane, Mindie Nguyen, Paul Kwo, Kris Kowdley, Nancy Reau, Ira Jacobson, Michael Curry, Brian Pearlman, Omer Khalid, Gregory Everson, Stuart Gordon, John Poulos, Aasim Sheikh, David Bernstein, Jenny C. Yang, Luisa M. Stamm, Di An, Hadas Dvory-Sobol, Diana M. Brainard, John G. McHutchison, Myron Tong, Naoky Tsai, Kimberly L. Beavers, Mordechai Rabinovitz, Mitchell Shiffman, Catherine Stedman, Eric Lawitz Abstract SAT-138

O56 SOFOSBUVIR/LEDIPASVIR WITH AND WITHOUT RIBAVIRIN FOR 8 WEEKS COMPARED TO SOFOSBUVIR/LEDIPASVIR FOR 12 WEEKS IN TREATMENT-NAÏVE NON-CIRRHOTIC GENOTYPE-1 HCV-INFECTED PATIENTS: THE PHASE 3 ION-3 STUDY

Biliary atresia (BA) is a progressive fibro-inflammatory cholangiopathy affecting the intraand extrahepatic bile ducts of neonates. Although BA is the most common identifiable cause of obstructive jaundice in infants, and is the leading indication for pediatric liver transplantation, the etiology remains elusive. We investigated the importance of genes identified in genome-wide association studies (GWAS) of BA patients using zebrafish. The Matthewss lab has demonstrated the utility of the zebrafish system to test the functionality of genes identified in GWAS of BA by demonstrating that knockdown of gpc1 leads to biliary defects. A prior GWAS examined single-nucleotide polymorphisms in 200 Han Chinese BA patients and 481 ethnically matched controls. The strongest association was found for a region located between the XPNPEP1 and ADD3 genes on 10q24.2. Our genetic analysis confirmed the importance of this region in a separate cohort of patients. To determine whether loss of xpnpep1 and/or add3a leads to biliary defects we performed knockdown studies of the respective genes using morpholino antisense oligonucleotides (MO). We then examined their biliary function using the lipid reporter PED6, biliary development using cytokeratin immunostaining, and gene expression using quantitative PCR. We confirmed that xpnpep1 and add3a are expressed in the developing zebrafish liver. Knockdown of add3a led to decreased biliary function by PED6 screening, while xpnpep1 knockdown had only a mild effect. There were developmental biliary defects in the add3a morphants, as demonstrated by cytokeratin immunostaining. The transcription factor vhnf1, implicated in biliary development, was significantly downregulated in add3a morphants but not xpnpep1 morphants. add3a morphants also demonstrated increased expression of gli2a, a Hedgehog target, which is consistent with prior studies of BA patients and of zebrafish models of BA such as gpc1 knockdown. Interestingly, knockdown of both add3a and gpc1 resulted in a synergistic disruptive effect on biliary development. While GWAS identified ADD3 and XPNPEP1 as potential BA susceptibility genes, our results suggest that ADD3 is likely the more important gene in this regard. Like gpc1, add3a acts via Hedgehog signaling, supporting a role for this important pathway in BA pathogenesis.