Stephen Pianko

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.).

Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection

BACKGROUND In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. METHODS We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. CONCLUSIONS Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).

The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity

BACKGROUND/AIMS Interferon plus ribavirin is the most effective therapy for chronic hepatitis C. The aim of this study was to evaluate the effect of chronic hepatitis C and therapy on health-related quality of life and work functioning. METHODS Nine hundred and twelve patients with hepatitis C infection were randomized in a controlled trial of Interferon alpha 2b 3 MU tiw for 24 or 48 weeks plus ribavirin 1000-1200 mg or placebo. Questionnaire-based assessments of health-related quality of life and work functioning were performed before, during, and after treatment. Outcome measures included the SF-36 Health Survey and additional generic and specific scales. Work functioning was assessed as missed days, shorter hours or less productivity at work. RESULTS Pre-treatment, patients had significant impairment in five of eight SF-36 concepts compared to matched population norms. Sustained responders had a return to normal for four of these five concepts. Quality of life did not improve in non-responders. Improvements in histology, viral load or ALT values predicted improvements in quality of life. Sustained responders also had improvements in work functioning and productivity. CONCLUSIONS Hepatitis C patients had impaired quality of life. After combination therapy, sustained virologic responders achieved benefits in their quality of life and work functioning.

Risks of a range of alcohol intake on hepatitis C-related fibrosis.

Heavy alcohol use contributes to liver disease in the setting of chronic hepatitis C virus (HCV) infection. Whether this is true for light or moderate alcohol use has not been demonstrated. Light alcohol use has survival benefits at a population level and is practiced by most patients with chronic HCV infection. In this study, 800 patients with HCV undergoing liver biopsy at three sites had detailed alcohol histories recorded and the relationship between alcohol and hepatic fibrosis was assessed. On univariate analysis, heavy alcohol use (>50 g/day) was associated with an increase in mean fibrosis (P = .01). Such an association could not be demonstrated for light and moderate alcohol use. For each category of alcohol intake (none, light, moderate, and heavy), a spectrum of fibrosis was observed. On multivariate analysis, age, serum alanine aminotransferase (ALT), and histological inflammation were the independent predictors of fibrosis (P = <.0001, .0003, <.0001, respectively). In conclusion, heavy alcohol use exerts a greater effect on fibrosis than light or moderate use. There is a range of fibrosis at each level of alcohol use. Age, serum ALT, and inflammation are independently associated with fibrosis in multivariate analysis, highlighting the fact that variables other than alcohol intake predominate in the production of hepatic fibrosis. (HEPATOLOGY 2004;39:826–834.)

Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+)

Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY‐3+ study (N = 50) evaluated DCV‐SOF with ribavirin (RBV) in treatment‐naïve (n = 13) or treatment‐experienced (n = 37) genotype 3‐infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open‐label DCV‐SOF (60 + 400 mg daily) with weight‐based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post‐treatment week 12 (SVR12). SVR12 (intention‐to‐treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12‐week (91% observed) and 92% (24 of 26) in the 16‐week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12‐week (88% observed) and 89% (16 of 18) in the 16‐week group; for treatment‐experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12‐week group) did not enter post‐treatment follow‐up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment‐related serious AEs. Conclusion: The all‐oral regimen of DCV‐SOF‐RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3‐infected patients with advanced liver disease, irrespective of past HCV treatment experience. (Hepatology 2016;63:1430‐1441)

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection

BACKGROUND Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct‐acting antiviral agents (DAAs) have limited retreatment options. METHODS We conducted two phase 3 trials involving patients who had been previously treated with a DAA‐containing regimen. In POLARIS‐1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. In POLARIS‐4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir‐velpatasvir‐voxilaprevir (163 patients) or sofosbuvir‐velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir‐velpatasvir‐voxilaprevir group. RESULTS In the three active‐treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS‐1, the rate of sustained virologic response was 96% with sofosbuvir‐velpatasvir‐voxilaprevir, as compared with 0% with placebo. In POLARIS‐4, the rate of response was 98% with sofosbuvir‐velpatasvir‐voxilaprevir and 90% with sofosbuvir‐velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active‐treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS Sofosbuvir‐velpatasvir‐voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS‐1 and POLARIS‐4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247.)

Fas‐mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection

Epidemiological studies have established that heavy alcohol consumption in persons with chronic hepatitis C virus (HCV) infection is associated with advanced liver disease, including cirrhosis. The aims of this study were to evaluate the relationship between alcohol consumption and hepatocyte apoptosis in HCV‐infected patients and to determine the role of Fas in HCV‐mediated apoptosis. Liver tissue from 44 HCV‐infected patients with variable alcohol consumption, and 10 normal control subjects who did not consume alcohol was examined for hepatocyte apoptosis, proliferation and Fas expression. Alcohol consumption was assessed using the ‘Lifetime Drinking History’ alcohol questionnaire. HCV RNA, alanine aminotransferase (ALT) and ferritin were also assessed in addition to demographic data. Hepatocyte apoptosis was significantly greater in HCV‐infected patients compared to controls. Expression of Fas (CD95) was found in HCV patients but not in controls. The degree of Fas expression correlated with hepatocyte apoptosis as detected by terminal UTP nick end labelling (TUNEL). Active ethanol consumption led to a significant increase in hepatocyte apoptosis. Fas expression correlated with fibrosis in HCV‐infected patients who were not actively drinking ethanol. In summary, HCV leads to increased apoptotic cell death in hepatocytes. Programmed cell death can be further up‐regulated by active ethanol consumption. The correlation between Fas expression and TUNEL supports the hypothesis that the Fas–Fas ligand interaction is the major mechanism for HCV‐induced hepatocyte apoptosis.

Clinical use of hyaluronic acid as a predictor of fibrosis change in hepatitis C

Background and Aim: Hyaluronic acid (HA) is a glycosaminoglycan synthesized by hepatic stellate cells that has been shown to correlate with liver fibrosis in chronic hepatitis C (HCV) patients. However, its use in monitoring fibrosis over time has not been established. The aim of the present study was to assess the serial relationships between HA and liver fibrosis before and after treatment.

Albinterferon alfa-2b dosed every two or four weeks in interferon-naïve patients with genotype 1 chronic hepatitis C†‡

The efficacy and safety of albinterferon alfa‐2b (alb‐IFN), a novel recombinant protein consisting of interferon alfa‐2b genetically fused to human albumin, was evaluated in a phase 2b, open‐label study of patients with genotype 1, chronic hepatitis C. In all, 458 IFN‐alfa treatment‐naïve patients were randomized to 48‐week treatment with peginterferon alfa (PEG‐IFNα)‐2a 180 μg one time per week (qwk), or alb‐IFN 900 or 1,200 μg once every two weeks (q2wk), or 1,200 μg once every four weeks (q4wk), administered subcutaneously, plus weight‐based oral ribavirin 1,000 or 1,200 mg/day. Hepatitis C virus RNA was measured by real‐time polymerase chain reaction (limit of detection: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (hepatitis C virus RNA <10 IU/mL 24 weeks after the end of treatment). By intention‐to‐treat analysis, sustained virologic response rates were 58.5% (69/118) with alb‐IFN 900 μg q2wk, 55.5% (61/110) with 1,200 μg q2wk, and 50.9% (59/116) with 1,200 μg q4wk, and 57.9% (66/114) with PEG‐IFNα‐2a (P = 0.64 for overall test). Discontinuation rates due to adverse events were 9.3% with alb‐IFN 900 μg q2wk, 18.2% with 1,200 μg q2wk and 12.1% with 1,200 μg q4wk, and 6.1% with PEG‐IFNα‐2a (P = 0.04). Hematologic reductions were lowest in the q4wk group and comparable across other groups. At week 12, mean treatment‐associated missed workdays were significantly lower with alb‐IFN 900 μg q2wk versus PEG‐IFNα‐2a (1.1 versus 4.3 days; P = 0.006). Conclusion: Alb‐IFN administered q2wk or q4wk may offer comparable efficacy, with an improved dosing schedule, compared with PEG‐IFNα‐2a. (HEPATOLOGY 2008;48:407–417.)

NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome

BACKGROUND & AIMS The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. METHODS NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. RESULTS Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. CONCLUSIONS Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. LAY SUMMARY The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8-16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.