AnnMarie Liapakis

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function

Renal clearance is the major elimination pathway for sofosbuvir (SOF). We assessed the safety and efficacy of SOF‐containing regimens in patients with varying baseline estimated glomerular filtration rate (eGFR).

The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation

The availability of direct‐acting antiviral agents for the treatment of hepatitis C virus (HCV) infection has resulted in a profound shift in the approach to the management of this infection. These changes have affected the practice of solid organ transplantation by altering the framework by which patients with end‐stage organ disease are managed and receive organ transplants. The high level of safety and efficacy of these medications in patients with chronic HCV infection provides the opportunity to explore their use in the setting of transplanting organs from HCV‐viremic patients into non–HCV‐viremic recipients. Because these organs are frequently discarded and typically come from younger donors, this approach has the potential to save lives on the solid organ transplant waitlist. Therefore, an urgent need exists for prospective research protocols that study the risk versus benefit of using organs for hepatitis C–infected donors. In response to this rapidly changing practice and the need for scientific study and consensus, the American Society of Transplantation convened a meeting of experts to review current data and develop the framework for the study of using HCV viremic organs in solid organ transplantation.

LP08 : Safety and efficacy of sofosbuvir-containing regimens in hepatitis C infected patients with reduced renal function: Real-world experience from HCV-target

LP08 SAFETY AND EFFICACY OF SOFOSBUVIR-CONTAINING REGIMENS IN HEPATITIS C INFECTED PATIENTS WITH REDUCED RENAL FUNCTION: REAL-WORLD EXPERIENCE FROM HCV-TARGET V. Saxena, F.M. Koraishy, M. Sise, J.K. Lim, R.T. Chung, A. Liapakis, D.R. Nelson, M. Schmidt, M.W. Fried, N. Terrault, and HCV-TARGET. University of California San Francisco, San Francisco, Saint Louis University School of Medicine, St. Louis, Massachusetts General Hospital, Boston, Yale University School of Medicine, New Haven, University of Florida, Gainesville, University of North Carolina, Chapel Hill, United States E-mail: varun.saxena@ucsf.edu

Drug Authorization for Sofosbuvir/Ledipasvir (Harvoni) for Chronic HCV Infection in a Real-World Cohort: A New Barrier in the HCV Care Cascade

Background New treatments for hepatitis C (HCV) infection hold great promise for cure, but numerous challenges to diagnosing, establishing care, and receiving therapy exist. There are limited data on insurance authorization for these medications. Materials and Methods We performed a retrospective chart review of patients receiving sofosbuvir/ledipasvir (SOF/LED) from October 11-December 31, 2014 to determine rates and timing of drug authorization. We also determined predictors of approval, and those factors associated with faster decision and approval times. Results Of 174 patients prescribed HCV therapy during this period, 129 requests were made for SOF/LED, of whom 100 (77.5%) received initial approval, and an additional 17 patients (13.9%) ultimately received approval through the appeals process. Faster approval times were seen in patients with Child-Pugh Class B disease (14.4 vs. 24.7 days, p = 0.048). A higher proportion of patients were initially approved in those with Medicare/Medicaid coverage (92.2% vs. 71.4%, p = 0.002) and those with baseline viral load ≥6 million IU/mL (84.1% vs. 62.5%, p = 0.040). Linear regression modeling identified advanced fibrosis, high Model of End Stage Liver Disease (MELD) score, and female gender as significant predictors of shorter decision and approval times. On logistic regression, Medicare/Medicaid coverage (OR 5.96, 95% CI 1.66–21.48) and high viral load (OR 4.52, 95% CI 1.08–19.08) were significant predictors for initial approval. Conclusions Early analysis of real-world drug authorization outcomes between October-December 2014 reveals that nearly one in four patients are initially denied access to SOF/LED upon initial prescription, although most patients are eventually approved through appeal, which delays treatment initiation. Having Medicare/Medicaid and advanced liver disease resulted in a higher likelihood of approval as well as earlier decision and approval times. More studies are needed to determine factors resulting in higher likelihood of denial and to evaluate approval rates and times after implementation of restrictive prior authorization guidelines.

Telaprevir User's Guide

For a decade, standard therapy for patients with genotype 1 chronic HCV (HCV G1) consisted of pegylated interferon (Peg-IFN) alfa-2a or Peg-IFN alfa-2b, combined with ribavirin. Despite the improved efficacy of this therapy over others, the overall sustained virologic response rate in patients with HCV G1 was still low. This article discusses phase I, II, and III trials examining telaprevirs role in treating patients with HCV. We have now entered an era of combination therapy utilizing direct acting anti-virals, the start of which was marked by the FDA approval of HCV protease inhibitors.

Telaprevir user's guide

Telaprevir is a potent HCV NS3/4A protease inhibitor. A completed development program has demonstrated the superior efficacy of a regimen of telaprevir combined with pegylated interferon alfa and ribavirin (PR) over PR alone in patients with HCV genotype 1. In the ADVANCE trial in treatment‐naïve patients, 12 weeks of telaprevir, peginterferon alfa‐2a and ribavirin followed by either 12 or 36 weeks of PR alone (depending upon extended rapid virologic response, or eRVR, i.e. HCV RNA undetectability at weeks 4 and 12), was associated with sustained virological response (SVR) in 75% of patients compared with 46% receiving PR for 48 weeks. The ILLUMINATE trial established the foundation for response‐guided therapy in patients with eRVR. The REALIZE trial in treatment‐experienced patients showed a gradient of SVR from prior relapsers (86%) to partial responders (57%) to null responders (31%), with rates of virologic failure and emergent resistance highest in the latter group. Incremental adverse effects of telaprevir include rash, anemia, pruritus, diarrhea, and nausea. Treatment naïve patients and relapsers are eligible for response‐guided therapy. Stopping rules of telaprevir‐based treatment include HCV RNA > 1000 IU/ml at weeks 4 and 12.

Non‐Alcoholic Fatty Liver Disease Following Liver Transplantation: A Clinical Review

Non‐alcoholic steatohepatitis (NASH) is rapidly becoming the leading indication for liver transplantation (LT) in the United States. While post‐transplantation outcomes are similar to other indications for transplant, recent evidence has suggested that reduction in risk factors for post‐transplant metabolic syndrome may impose a significant survival benefit in this patient population. Cardiovascular mortality is the leading cause of death following transplantation for NASH. While pre‐transplant pharmacologic and surgical approaches have been utilized to reduce cardiovascular risk factors following transplantation, the effectiveness of these treatment approaches in the post‐transplant setting is poorly defined. Studies are urgently needed in the treatment of this rapidly growing population.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients with Genotype 1 Hepatitis C Virus Infection and Cirrhosis

BACKGROUND & AIMS: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment‐experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi‐center, prospective, observational cohort study (HCV‐TARGET). METHODS: We collected data from 667 treatment‐experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow‐up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per‐protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS: The per‐protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16‐5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46–6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59–7.00) were associated with SVR12. CONCLUSIONS: In an analysis of safety and effectiveness data from the HCV‐TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment‐experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Is there clinical utility to IL28B genotype testing in the treatment of chronic hepatitis C virus infection

Not long ago, we wrote with Ira Jacobson about a groundbreaking advancement in the field of hepatitis C treatment in the February 2010 issue of Pharmacogenomics, in Research Highlights dedicated to the pharmacogenetics of hepatitis C therapy. Therein, we reviewed the utilization of genome-wide association studies to study genetic variation as a predictor of outcome in patients treated for chronic hepatitis C virus (HCV) infection. We highlighted recent studies that demonstrated the remarkable association between SNPs near or within the region of the IL28B gene, which encodes IFN-l3, and response rates to the standard-of-care therapy at that time, pegylated interferon (PIFN)-based HCV treatment. We commented that ‘these results promised to lead to important mechanistic findings related to interferon responsiveness in this disease and will probably have major ramifications for individualized therapeutic decision-making’ [1]. Shortly after, we began utilizing the IL28B polymorphism (rs12979860) genotype test, which became commercially available for clinical use through LabCorp as of 2 July 2010, to aid in clinical decision-making related to treatment of our HCV-positive patients. This test involves either the collection of 3-ml whole blood or two buccal swabs for real-time PCR with allelespecific TaqMan probes used to detect a SNP rs12979860 C/T on chromosome 19q13. The SNP maps 3-kb upstream of the IL28B gene (OMIM607402) [101]. The CC genotype at this SNP, as reported by Ge et al., is associated with profoundly higher response rates (p = 1.37 × 10) across all HCV population groups treated with PIFN and ribavirin (RBV; 81, 53 and 77% sustained virologic response [SVR] rates for European–Americans, African–Americans and