Steven L. Flamm

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.).

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis

BACKGROUND As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease

This document presents the official position of the American Association for the Study of Liver Diseases (AASLD) on the application of serum alanine aminotransferase (AL T) activity, based upon an analysis of the currently available scientific data. Its authorship was selected by the Public Policy Committee. The document is fully endorsed by the AASLD Governing Board.

American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Asymptomatic Neoplastic Pancreatic Cysts

This article has an accompanying continuing medical education activity on page e12. Learning Objective: At the conclusion of this exercise, the learner will understand the approach to counseling patients regarding the optimal method and frequency of radiologic imaging, indications for invasive tests like endoscopic ultrasonography (EUS) and surgery, select patients for follow-up after surgery, decide the duration of such follow-up, and decide when to stop surveillance for those with and without surgery.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

BACKGROUND & AIMS Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. METHODS This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigators request. RESULTS Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. CONCLUSIONS Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Phase 1b study of pegylated interferon lambda 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection.

Interferon lambda 1 (IFN‐λ1) is a type III IFN that produces intracellular responses similar to those of IFN‐α but in fewer cell types because of differences in the receptor distribution pattern, and this could potentially result in an improved safety profile. This was an open‐label three‐part study of patients with chronic hepatitis C virus (HCV) genotype 1 infection. Part 1 evaluated single‐agent pegylated interferon lambda (PEG‐IFN‐λ) at 1.5 or 3.0 μg/kg administered every 2 weeks or weekly for 4 weeks in patients who had relapsed after previous IFN‐α‐based treatment. Part 2 evaluated weekly doses of PEG‐IFN‐λ ranging from 0.5 to 2.25 μg/kg in combination with ribavirin (RBV) for 4 weeks in treatment‐relapse patients. Part 3 evaluated weekly PEG‐IFN‐λ at 1.5 μg/kg in combination with RBV for 4 weeks in treatment‐naive patients. Fifty‐six patients were enrolled: 24 patients in part 1, 25 patients in part 2, and 7 patients in part 3. Antiviral activity was observed at all PEG‐IFN‐λ dose levels (from 0.5 to 3.0 μg/kg). Two of seven treatment‐naive patients (29%) achieved rapid virological response. Treatment was well tolerated with minimal flu‐like symptoms and no significant hematologic changes other than RBV‐associated decreases in hemoglobin. The most common adverse events were fatigue (29%), nausea (12%), and myalgia (11%). Six patients experienced increases in aminotransferases that met protocol‐defined criteria for dose‐limiting toxicity (DLT) or temporarily holding therapy with PEG‐IFN‐λ. Most DLT occurred in patients with high PEG‐IFN‐λ exposure. Conclusion: Weekly PEG‐IFN‐λ with or without daily RBV for 4 weeks is well tolerated with minimal adverse events and hematologic effects and is associated with clear antiviral activity across a broad range of doses in patients with chronic HCV. (HEPATOLOGY 2010;)

Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis

Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis Guadalupe Garcia-Tsao, M.D.,1 Arun J. Sanyal, M.D.,2 Norman D. Grace, M.D., FACG,3 William D. Carey, M.D., MACG,4 the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and the Practice Parameters Committee of the American College of Gastroenterology 1Section of Digestive Diseases, Yale University School of Medicine and VA-CT Healthcare System, New Haven, Connecticut; 2Division of Gastroenterology, Virginia Commonwealth University Medical Center, Richmond, Virginia; 3Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts; 4The Cleveland Clinic, Cleveland, Ohio

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.)

Troglitazone-induced fulminant hepatic failure

Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey), the first marketed member of a new class of oral agents for type II diabetes mellitus, the thiazolidinediones, has a number of attractive attributes. It reduces insulin resistance and increases insulin-stimulated glucose disposal, resulting in improved glycemic control and decreased insulin requirements in treated patients (1, 2). In addition, it is dosed once a day, is readily absorbed from the gastrointestinal tract, does not induce hypoglycemia, and does not appear to interact with other medications. Because of these attributes, troglitazone has enjoyed widespread use since its introduction in March 1997. In premarketing clinical trials of troglitazone, mild hepatotoxicity identified as reversible elevations of alanine aminotransferase (ALT) greater than three times normal were seen in less than 2% of treated patients (3). However, since the drug was released, several cases of more severe, even fatal, episodes of hepatitis have been reported (4–7). Here we report three cases of apparent troglitazone-induced fulminant liver failure prospectively identified through the Acute Liver Failure Study Group (ALFSG), a consortium of 14 academic medical centers with the purpose of collecting data regarding the etiology, treatment, and outcome of patients with acute liver failure. The cases highlight the potential hepatotoxicity of troglitazone and reinforce the need for close monitoring of all patients taking the drug.The three reported cases demonstrate that troglitazone is an idiosyncratic hepatotoxin that can lead to irreversible liver injury. Thus, troglitazone should be prescribed with caution and should not be used as a first-line agent in the treatment of type II DM when potentially less toxic alternatives are available. It remains to be seen whether the hepatotoxicity associated with troglitazone is a drug-class effect or specific to troglitazone. Other thiazolidinediones currently in clinical trials may be able to provide the therapeutic benefits of troglitazone without significant hepatotoxicity. If troglitazone is used, frequent monitoring of serum aminotransferases and symptoms is mandatory. However, as illustrated by these and other cases reported to date, the onset of troglitazone-induced liver injury is insidious and temporally variable. Thus, the value of close monitoring and when, if ever, it is safe to stop such monitoring are currently unclear.

Predictive Value of Stress Myocardial Perfusion Imaging in Liver Transplant Candidates

In summary, these data indicate that SPECT imaging has a poor predictive value for CAD in OLT candidates. Coronary angiography has a primary screening role for this population, especially in patients with multiple cardiac risk factors or a known history of CAD.