Gregory T. Everson

Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection

BACKGROUND Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies. METHODS We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy). RESULTS The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation. CONCLUSIONS Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.)

Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection

BACKGROUND All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. METHODS In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy. RESULTS Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

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.).

Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

BACKGROUND Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1

BACKGROUND Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen. METHODS This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period. RESULTS A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range. CONCLUSIONS This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

Objective:The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data:In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods:A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results:For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions:This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.

Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease

BACKGROUND & AIMS Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors. METHODS Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression. RESULTS 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC. CONCLUSIONS We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy

Patients with advanced hepatitis C virus (HCV) are at risk of death and are candidates for liver transplantation. After transplantation, HCV recurs and may rapidly progress to cirrhosis and graft loss. Treatment is needed to prevent progression of disease and minimize recurrence after liver transplantation. We evaluated the effectiveness, tolerability, and outcome of a low accelerating dose regimen (LADR) of antiviral therapy in the treatment of patients with advanced HCV. One hundred twenty‐four patients (male/female ratio 81:43; age range 37‐71 years; 70% genotype 1) were treated with LADR. Sixty‐three percent had clinical complications of cirrhosis (ascites, spontaneous bacterial peritonitis, varices, variceal hemorrhage, encephalopathy). The mean Child‐Turcotte‐Pugh (CTP) score was 7.4 ± 2.3, and the mean MELD score was 11.0 ± 3.7. Fifty‐six patients were CTP class A, 45 were class B, and 23 were class C. Forty‐six percent were HCV RNA–negative at end of treatment, and 24% were HCV RNA–negative at last follow‐up. Sustained virological response (SVR) was 13% in patients infected with genotype 1 HCV and 50% in patients infected with non‐1 genotypes (P < .0001). Non‐1 genotype, CTP class A (genotype 1 only), and ability to tolerate full dose and duration of treatment (P < .0001) were predictors of SVR. Twelve of 15 patients who were HCV RNA–negative before transplantation remained HCV RNA–negative 6 months or more after transplantation. In conclusion, in a sizeable proportion of patients with advanced HCV, LADR may render blood free of HCV RNA, stabilize clinical course, and prevent posttransplantation recurrence. (HEPATOLOGY 2005;42:255–262.)

All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study

BACKGROUND An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FINDINGS This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85-94) patients in the treatment-naive cohort, 168 (82%, 77-87) in the non-responder cohort, and 192 (82%, 77-87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). INTERPRETATION Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. FUNDING Bristol-Myers Squibb.

Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort†

Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver‐operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8% of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8% of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50% of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50% of patients with CHC. (HEPATOLOGY 2005.)