Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

Background Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis. Methods Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks. Results At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P\u3c0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy. Conclusions Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.

Serum proteomic analysis focused on fibrosis in patients with hepatitis C virus infection

<p>Abstract</p> <p>Background</p> <p>Despite its widespread use to assess fibrosis, liver biopsy has several important drawbacks, including that is it semi-quantitative, invasive, and limited by sampling and observer variability. Non-invasive serum biomarkers may more accurately reflect the fibrogenetic process. To identify potential biomarkers of fibrosis, we compared serum protein expression profiles in patients with chronic hepatitis C (CHC) virus infection and fibrosis.</p> <p>Methods</p> <p>Twenty-one patients with no or mild fibrosis (METAVIR stage F0, F1) and 23 with advanced fibrosis (F3, F4) were retrospectively identified from a pedigreed database of 1600 CHC patients. All samples were carefully phenotyped and matched for age, gender, race, body mass index, genotype, duration of infection, alcohol use, and viral load. Expression profiling was performed in a blinded fashion using a 2D polyacrylamide gel electrophoresis/LC-MS/MS platform. Partial least squares discriminant analysis and likelihood ratio statistics were used to rank individual differences in protein expression between the 2 groups.</p> <p>Results</p> <p>Seven individual protein spots were identified as either significantly increased (α₂-macroglobulin, haptoglobin, albumin) or decreased (complement C-4, serum retinol binding protein, apolipoprotein A-1, and two isoforms of apolipoprotein A-IV) with advanced fibrosis. Three individual proteins, haptoglobin, apolipoprotein A-1, and α₂-macroglobulin, are included in existing non-invasive serum marker panels.</p> <p>Conclusion</p> <p>Biomarkers identified through expression profiling may facilitate the development of more accurate marker algorithms to better quantitate hepatic fibrosis and monitor disease progression.</p

Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury

The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean ± standard deviation age at protocol-defined onset was 44.8 ± 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from −7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus

Outcomes of hepatitis C virus (HCV) infection and treatment depend on viral and host genetic factors. Here we use human genome-wide genotyping arrays and new whole-genome HCV viral sequencing technologies to perform a systematic genome-to-genome study of 542 individuals who were chronically infected with HCV, predominantly genotype 3. We show that both alleles of genes encoding human leukocyte antigen molecules and genes encoding components of the interferon lambda innate immune system drive viral polymorphism. Additionally, we show that IFNL4 genotypes determine HCV viral load through a mechanism dependent on a specific amino acid residue in the HCV NS5A protein. These findings highlight the interplay between the innate immune system and the viral genome in HCV control

Interferon Alfa-2b Alone or in Combination with Ribavirin as Initial Treatment for Chronic Hepatitis C

BACKGROUND Only 15 to 20 percent of patients with chronic hepatitis C have a sustained virologic response to interferon therapy. We compared the efficacy and safety of recombinant interferon alfa-2b alone with those of a combination of interferon alfa-2b and ribavirin for the initial treatment of patients with chronic hepatitis C. METHODS We randomly assigned 912 patients with chronic hepatitis C to receive standard-dose interferon alfa-2b alone or in combination with ribavirin (1000 or 1200 mg orally per day, depending on body weight) for 24 or 48 weeks. Efficacy was assessed by measurements of serum hepatitis C virus (HCV) RNA and serum aminotransferases and by liver biopsy. RESULTS The rate of sustained virologic response (defined as an undetectable serum HCV RNA level 24 weeks after treatment was completed) was higher among patients who received combination therapy for either 24 weeks (70 of 228 patients, 31 percent) or 48 weeks (87 of 228 patients, 38 percent) than among patients who received interferon alone for either 24 weeks (13 of 231 patients, 6 percent) or 48 weeks (29 of 225 patients, 13 percent) (P CONCLUSIONS In patients with chronic hepatitis C, initial therapy with interferon and ribavirin was more effective than treatment with interferon alone

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

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial

Background & Aims Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients. Methods We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naïve and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6–12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). Results After 6 weeks of treatment, SVR12s were achieved by 88% of treatment-naïve patients without cirrhosis (29 of 33; 95% confidence interval, 72%–97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naïve patients with cirrhosis (28 of 30; 95% CI, 78%–99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%–100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%–100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. Conclusions In a phase 2 open-label trial, we found sofosbuvir-velpatasvir plus GS-9857 (8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Background & AimsPatients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.MethodsIn a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.ResultsSixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).ConclusionsAdministration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844

Ribavirin Enhances IFN-α Signalling and MxA Expression: A Novel Immune Modulation Mechanism during Treatment of HCV

The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV