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Item does not contain fulltext, BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis using 3-year interim data from the 5-year open-label extension of the pivotal phase 3 POISE trial. METHODS: In the double-blind phase of POISE, 217 patients with primary biliary cholangitis with inadequate response to or intolerance to ursodeoxycholic acid were randomised to receive placebo, obeticholic acid 5 to 10 mg, or obeticholic acid 10 mg once daily for 12 months. During the open-label extension phase, patients received variable, adjusted doses of obeticholic acid. Markers of cholestasis and liver injury, alkaline phosphatase (ALP), and total and direct bilirubin were evaluated, and safety was assessed for up to 48 months of treatment with obeticholic acid. All analyses in the open-label extension were done in the safety population, defined as any patient randomised in the double-blind phase who received at least one dose of obeticholic acid during the open-label extension. This trial is registered at ClinicalTrials.gov (NCT01473524) and with EudraCT (2011-004728-36). FINDINGS: 193 patients were treated during the open-label extension. In this 3-year interim analysis, ALP concentrations were significantly reduced compared with baseline at 12 months (mean change -105.2 U/L [SD 87.6]), 24 months (-101.0 U/L [98.5]), 36 months (-108.6 U/L [95.7]), and 48 months (-95.6 U/L [121.1]; p<0.0001 for all yearly time points). Total bilirubin concentrations were stabilised, with significant reductions versus baseline at 12 months (mean change -0.9 mumol/L [SD 4.1]; p=0.0042) and 48 months (-0.8 mumol/L [3.8]; p=0.016). Stabilisation was also noted for direct bilirubin, with a significant change from baseline at 12 months (mean change -0.5 mumol/L [SD 3.0]; p=0.021). However, changes in total and direct bilirubin were not significant at other time points. Obeticholic acid was generally well tolerated, with pruritus (149 [77%

Background: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. Objective(s): To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. Design(s): Randomized, phase 2, open-label study. (ClinicalTrials .gov: NCT01909804) Setting: 58 sites in Australia, New Zealand, and the United States. Patient(s): Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). Intervention(s): All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. Measurements: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). Result(s): In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. Limitation(s): Treatment assignments were not blinded, and no inferential statistics were planned. Conclusion(s): Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12

Introduction: The combination of sofosbuvir (SOF) and GS-5816 for 12 weeks has demonstrated high efficacy in treatment naive patients without cirrhosis with chronic genotype 1-6 HCV infection. This Phase 2 study evaluated SOF + GS-5816 +/- RBV for 12 weeks in treatment experienced patients with genotype 1 or 3 HCV infection with or without cirrhosis. Method(s): Three cohorts of treatment experienced patients were evaluated: patients with genotype 3 HCV infection without cirrhosis, patients with genotype 3 HCV infection with cirrhosis, and patients with genotype 1 HCV infection with and without cirrhosis who had failed treatment with a protease-inhibitor containing regimen. Within each cohort, patients were randomized 1:1:1:1 to SOF+GS-5816 25mg, SOF+GS-5816 25mg+RBV, SOF+GS-5816 100mg or SOF+GS-5816 100 mg+RBV. The SOF dose was 400 mg. Ribavirin was administered 1000-1200mg in a divided daily dose. Result(s): 321 patients were randomized and treated; 65% had genotype 3 HCV infection, 69% were male, 89% were white, 27% had IL28B CC genotype and 43% had cirrhosis. The SVR12 rates in treatment experienced genotype 3 infected patients with and without cirrhosis administered SOF +GS-5816 100mg were 88% and 100%, respectively. The SVR12 rate was 100% in genotype 1 HCV infected patients administered SOF +GS-5816 100mg. Relapse accounted for all virologic failures. The most frequently reported adverse events (> 10%) in patients were fatigue, headache, nausea and insomnia. Patients administered RBV containing regimens also commonly reported pruritus and rash. One patient discontinued treatment with SOF +GS-5816 25mg +RBV after 81 days of treatment due to elevated ALT and GGT. Nine patients reported 10 SAEs; none were considered related to study treatment. Anemia was only observed in patients receiving RBV. Conclusion(s): High SVR12 rates were achieved in treatment experienced patients with genotype 1 or genotype 3 HCV infection administered SOF +GS-5816 100 mg for 12 weeks.

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. METHOD(S): 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. RESULT(S): 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%). CONCLUSION(S): 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. Ef

Background: Patients infected with chronic hepatitis C virus (HCV) genotype (GT) 2 and 3 who are ineligible or unwilling to receive interferon or who have failed previous treatment with interferon currently have limited treatment options. The nucleotide HCV polymerase inhibitor sofosbuvir (SOF) in combination with ribavirin (RBV) has provided high rates of response in treatment-naive and treatment experienced patients with HCV GT 2 or 3. Method(s): We conducted 2 phase 3 studies in patients infected with HCV GT 2 and 3. In the POSITRON study, patients who were interferonineligible, -intolerant or -unwilling were randomly assigned (3:1) to receive SOF 400 mg daily and RBV 1000-1200 mg daily for 12 weeks or placebo. In the FUSION study, patients who had failed prior interferon therapy were randomly assigned (1:1) to receive 12 or 16 weeks of SOF 400 mg daily and ribavirin 1000-1200 mg daily. The primary efficacy end point was sustained virologic response (SVR) 12 weeks after the end of treatment. Result(s): In POSITRON, 207 patients (53% GT 2, 47% GT 3) were randomized to SOF+RBV and 71 (48% GT 2, 52% GT 3) received placebo; 54% were male, 16% had compensated cirrhosis, and 45% carried the IL28B CC genotype. In the FUSION study, 103 patients (35% GT 2, 62% GT 3) were randomized to receive SOF +RBV for 12 weeks and 98 patients (33% GT 2, 64% GT 3) were randomized to receive SOF +RBV for 16 weeks; 70% were male, 34% had compensated cirrhosis, and 30% carried the IL28B CC genotype. SVR12 rates are given in table. Extending treatment duration to 16 weeks improved SVR12 rate in patients with genotype 3 HCV infection, whereas the SVR12 rates for patients with GT 2 infection were similar in the 12- and 16-week arms. Relapse accounted for all virologic failure and no S282T variant was observed in patients with relapse. SOF with RBV for 12 or 16 weeks had a safety profile similar to that expected for RBV. There were few SAEs, and rates of discontinuation of the treatment regim

BACKGROUND: In preclinical and phase 2 studies, adefovir dipivoxil demonstrated potent activity against hepatitis B virus (HBV), including lamivudine-resistant strains. METHOD(S): We randomly assigned 515 patients with chronic hepatitis B who were positive for hepatitis B e antigen (HBeAg) to receive 10 mg of adefovir dipivoxil (172 patients), 30 mg of adefovir dipivoxil (173), or placebo (170) daily for 48 weeks. The primary end point was histologic improvement in the 10-mg group as compared with the placebo group. RESULT(S): After 48 weeks of treatment, significantly more patients who received 10 mg or 30 mg of adefovir dipivoxil per day than who received placebo had histologic improvement (53 percent [P<0.001], 59 percent [P<0.001], and 25 percent, respectively), a reduction in serum HBV DNA levels (by a median of 3.52 [P<0.001], 4.76 [P<0.001], and 0.55 log copies per milliliter, respectively), undetectable levels (fewer than 400 copies per milliliter) of serum HBV DNA (21 percent [P<0.001], 39 percent [P<0.001], and 0 percent, respectively), normalization of alanine aminotransferase levels (48 percent [P<0.001], 55 percent [P<0.001], and 16 percent, respectively), and HBeAg seroconversion (12 percent [P=0.049], 14 percent [P=0.01], and 6 percent, respectively). No adefovir-associated resistance mutations were identified in the HBV DNA polymerase gene. The safety profile of the 10-mg dose of adefovir dipivoxil was similar to that of placebo; however, there was a higher frequency of adverse events and renal laboratory abnormalities in the group given 30 mg of adefovir dipivoxil per day. CONCLUSION(S): In patients with HBeAg-positive chronic hepatitis B, 48 weeks of 10 mg or 30 mg of adefovir dipivoxil per day resulted in histologic liver improvement, reduced serum HBV DNA and alanine aminotransferase levels, and increased the rates of HBeAg seroconversion. The 10-mg dose has a favorable risk-benefit profile for long-term treatment. No adefovir-associated resistan

Background: Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. Methods: In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. Results: At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P = 0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P = 0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profil