November 11, 2014

New England Journal of Medicine

Paul Y. Kwo, M.D., Parvez S. Mantry, M.D., Eoin Coakley, M.D., Helen S. Te, M.D., Hugo E. Vargas, M.D., Robert Brown, M.D., M.P.H., Fredric Gordon, M.D., Josh Levitsky, M.D., Norah A. Terrault, M.D., M.P.H., James R. Burton, M.D., Wangang Xie, Ph.D., Carolyn Setze, M.S., Prajakta Badri, Ph.D., Tami Pilot-Matias, Ph.D., Regis A. Vilchez, M.D., Ph.D., and Xavier Forns, M.D.

November 11, 2014DOI: 10.1056/NEJMoa1408921

Hepatitis C virus (HCV) presents a global health care challenge, with approximately 170 million people chronically infected.1 In 2012, approximately 24,000 liver transplantations were performed worldwide, with the largest proportion performed because of HCV-induced liver disease.2,3 In the United States, more than 40% of registrants on the liver-transplant waiting list are infected with HCV.3,4 After liver transplantation, recurrence of HCV infection is universal among recipients with viremia before transplantation.5,6 Fibrosis progression may be accelerated and HCV viral loads may be markedly increased in patients receiving post-transplantation immunosuppressive therapy as compared with patients not undergoing transplantation.7-9 Graft cirrhosis develops in 20 to 30% of HCV-infected persons within 5 years after transplantation.10,11 As a result of these complications, HCV infection has become the leading cause of death in liver-transplant recipients. Patient and graft survival rates are markedly lower among HCV-infected patients than among those who received a liver transplant owing to cholestatic or alcohol-related liver disease.3,12,13

Successful clearance of HCV after liver transplantation can reduce the risk of subsequent HCV-related complications such as progression to cirrhosis and graft loss.13-16 The standard of care in the treatment of recurrent HCV genotype 1 infection after liver transplantation has been 48 weeks of peginterferon with ribavirin, though the response rates of 13 to 43% are generally lower than the rates of 40 to 52% among patients not undergoing transplantation, in part because of treatment-limiting toxic effects.8,15,17-19 In addition, interferon-based therapies can induce alloimmune graft injury, reducing patient and graft survival.16,20

Calcineurin inhibitors, such as tacrolimus and cyclosporine, are key components of most current post-transplantation immunosuppressive regimens. Long-term exposure to calcineurin inhibitors can progressively impair renal function, reducing ribavirin clearance. Consequently, augmented ribavirin exposure may increase the frequency and severity of ribavirin-associated hemolytic anemia, commonly requiring the use of hematopoietic growth factors, blood transfusion, or both. HCV treatment with a first-generation protease inhibitor, boceprevir or telaprevir, in combination with peginterferon and ribavirin results in a 20 to 71% response rate among liver-transplant recipients; however, clinically significant side effects of these regimens, especially anemia and infections, were reported to limit their use.21-24 In addition, drug interactions between protease inhibitors and calcineurin inhibitors may require dose modification and monitoring.25,26

Phase 3 trials of an all-oral, interferon-free, direct-acting antiviral regimen of ombitasvir coformulated as a single tablet with ritonavir-boosted ABT-450 (ABT-50/r) plus dasabuvir and ribavirin have shown high rates of sustained virologic response among patients with HCV genotype 1 infection, irrespective of prior treatment with peginterferon–ribavirin or the presence of cirrhosis.27-31 Ombitasvir is a potent NS5A inhibitor32; ABT-450 is an NS3/4A protease inhibitor coadministered with ritonavir to increase peak, trough, and overall drug exposure, permitting once-daily dosing33; and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Next-generation interferon-free treatment regimens have not been extensively examined in transplant recipients with recurrent HCV genotype 1 infection. The CORAL-I trial assessed the safety and efficacy of ombitasvir–ABT-450/r and dasabuvir with ribavirin in this population of patients with an unmet need for safe and efficacious therapy.

Methods

Patients

Patients 18 to 70 years of age were eligible for the study if they had HCV genotype 1 infection (HCV RNA level >10,000 IU per milliliter) and had received a liver transplant at least 12 months before screening because of chronic HCV infection. Patients could have received interferon-based treatment for HCV infection before transplantation but not after transplantation. Eligible patients had no evidence of advanced fibrosis (Metavir score ≤F2) on liver biopsy performed not more than 6 months before screening. A stable tacrolimus-based or cyclosporine-based immunosuppressive regimen was required, and glucocorticoids were permitted at a dose of no more than 5 mg per day. Patients were excluded if they were coinfected with the human immunodeficiency virus or hepatitis B virus or had undergone multiple-organ transplantation or liver retransplantation. Patients were enrolled from 10 transplantation centers in the United States and Spain between May and August 2013. Detailed eligibility criteria are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Study Design and Oversight

Patients in this phase 2, open-label trial received ombitasvir–ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir) and dasabuvir (250 mg twice daily) for 24 weeks. Ribavirin dosing was at the investigator's discretion because of the known risk of ribavirin-related hematologic toxic effects in transplant recipients. Patients were followed for up to 48 weeks after the treatment period (Figure S1 in the Supplementary Appendix).

On the basis of simulations based on pharmacokinetic data from a phase 1 study that evaluated drug interaction between the study drugs and tacrolimus or cyclosporine, the following dosages of calcineurin inhibitors were recommended: for cyclosporine, one fifth of the pretreatment total daily dose, administered once daily; for tacrolimus, 0.5 mg once weekly or 0.2 mg, where available, every 3 days. Modifications in tacrolimus or cyclosporine dosing during treatment were guided by scheduled testing of trough levels of calcineurin inhibitors. Details of the dosing of ribavirin and calcineurin inhibitors are provided in the Supplementary Appendix.

The study was conducted in accordance with International Conference on Harmonisation Guidelines for Good Clinical Practice, applicable regulations, and guidelines governing clinical-study conduct that have their origin in the Declaration of Helsinki. All patients provided written informed consent. The study was designed by the sponsor (AbbVie); the investigators and the sponsor jointly conducted the study and gathered the data. The sponsor conducted the data analyses. All authors signed a confidentiality agreement with the sponsor. The first draft of the manuscript was written by a sponsor-employed medical writer, with input from all the authors. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the protocol, which is available at NEJM.org.

Efficacy and Safety Assessments

The primary efficacy end point was a sustained virologic response, defined as a plasma HCV RNA level of less than 25 IU per milliliter, 12 weeks after the end of treatment. Secondary assessments included the percentage of patients with a sustained virologic response at post-treatment week 24, virologic failure during treatment, and post-treatment relapse. A central laboratory used the COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, version 2.0 (Roche), to test plasma samples for HCV RNA. Patients were monitored for clinical and laboratory evidence of adverse events at each study visit. Nonserious adverse events were recorded during the treatment period and until 30 days after the last dose. Serious adverse events were recorded from the time of informed consent until the end of the study. Details of plasma-sample collection, HCV RNA quantification, virologic-failure criteria, and resistance testing are provided in the Supplementary Appendix.

Statistical Analysis

Analyses of efficacy, safety, and baseline patient characteristics were performed on the intention-to-treat population, defined as all enrolled patients who received at least one dose of study drugs. The two-sided 95% confidence intervals for response rates were calculated with the use of the exact method based on the beta distribution. Patients with missing data at post-treatment week 12 or 24, including those who dropped out, were counted as having had virologic failure. Descriptive statistics are provided, such as the number of observations, mean, and standard deviation for continuous variables and counts and percentages for discrete variables. SAS software for the UNIX operating system (SAS Institute) was used for all analyses.

Results

Baseline Demographic and Clinical Characteristics

The CORAL-I study enrolled 34 patients, including 29 patients (85%) with HCV genotype 1a infection. The median time since liver transplantation was 3.3 years. Overall, 76% of patients had a non-CC IL28B genotype, 71% had previously been treated with peginterferon–ribavirin therapy, and 85% were receiving a tacrolimus-based immunosuppressive regimen (Table 1)

Treatment Efficacy

By week 4 of treatment, HCV RNA levels had decreased to less than 25 IU per milliliter in all 34 patients (Table 2); all the patients also had HCV RNA levels of less than 25 IU per milliliter at the end of treatment. With regard to the primary end point, 33 of 34 patients had a sustained virologic response at post-treatment week 12, for a rate of 97% (95% confidence interval [CI], 85 to 100). One patient did not have a sustained virologic response owing to a relapse on post-treatment day 3. No relapses occurred after post-treatment week 12; 33 of 34 patients (97%) had a sustained virologic response at post-treatment week 24. All 5 patients infected with genotype 1b (100%) and 28 of 29 patients infected with genotype 1a (97%) had a sustained virologic response. The remaining patient had resistance-associated variants R155K in NS3, M28T and Q30R in NS5A, and G554S in NS5B at the time of relapse, none of which were present at baseline. The NS3 variant Q80K was present in 11 of 29 patients (38%) with HCV genotype 1a infection at baseline, including the patient with a relapse, who had had a null response to prior peginterferon–ribavirin therapy. Variants at resistance-associated positions in NS3, NS5A, and NS5B were each observed in at least 1 patient at baseline (Table S1 in the Supplementary Appendix).

Safety

Adverse events were common, though the majority were mild or moderate in severity (Table 3). The most common adverse events were fatigue, headache, and cough. None of the patients had graft rejection and there were no deaths during the study. One patient discontinued the study drugs after week 18 owing to rash, memory impairment, and anxiety. These events were assessed as having a reasonable possibility of being related to the study drugs; they were moderate in severity. This patient had a sustained virologic response 12 weeks after ending treatment prematurely. Two patients (6%) had serious adverse events. Narratives on these two patients are provided in the Supplementary Appendix.

Grade 3 laboratory abnormalities were infrequent, and no grade 4 abnormalities were observed. Grade 3 elevations in the total bilirubin level were observed in two patients (6%), occurring within the first 8 days of treatment in both. No patient had jaundice or scleral icterus. Elevations in the total bilirubin level predominantly reflected elevated values for indirect bilirubin, a finding consistent with inhibition of the organic anion–transporting protein 1B1 by protease inhibitors. In one patient, total bilirubin levels were transiently elevated on day 92, to a value that was more than 2 times the upper limit of the normal range (predominantly accounted for by an elevated indirect bilirubin level), and alanine aminotransferase levels were transiently elevated on day 85, to a value that was more than 3 times the upper limit of the normal range. The values returned to the normal range on day 120 and on post-treatment day 4, respectively. Owing to persistent low-grade elevation of alanine aminotransferase levels during treatment, a liver biopsy was performed. The biopsy revealed markedly less necroinflammation than the prestudy biopsy, a finding consistent with a resolving HCV infection (Figure S2 in the Supplementary Appendix). This patient had a sustained virologic response at post-treatment week 12.

Grade 2 declines in hemoglobin levels (8 to <10 g per deciliter) occurred in nine patients (26%). One patient had a grade 3 decline in the hemoglobin level (6.5 to <8.0 g per deciliter) on day 15 and stopped ribavirin for 10 days. Erythropoietin was subsequently administered from day 26 to day 53; the hemoglobin level normalized by treatment day 42.

Ribavirin Dosing

The initial doses of ribavirin ranged from 400 to 1200 mg daily (Table 4.). The majority of patients received 600 or 800 mg daily at study initiation (19 of 34 [56%]) and also at the completion of treatment (23 of 34 [68%]). Overall, 19 patients (56%) had a modification in the ribavirin dose during treatment; 9 patients (26%) had modifications owing to declines in hemoglobin levels. Five patients (15%) received erythropoietin after detection of a nadir hemoglobin level of 7.6 to 9.1 g per deciliter. All 5 of these patients had initial ribavirin doses of 1000 to 1200 mg daily, and all 5 had a sustained virologic response at post-treatment week 12. No patient received a blood transfusion.

Dosing of Calcineurin Inhibitors

Modifications in the dose or dosing frequency of calcineurin inhibitors were made on the basis of blood levels of tacrolimus or cyclosporine. For most patients who received tacrolimus, 0.5-mg and 0.2-mg doses of tacrolimus were administered with a median dosing frequency of 10 days and 5 days, respectively. The geometric mean and range of trough blood concentrations of tacrolimus and cyclosporine during treatment were similar to those observed in the pretreatment period and were within the desired therapeutic range (Figure S3 in the Supplementary Appendix).

The mean creatinine clearance was 90.5 ml per minute at baseline and 85.9 ml per minute at week 24. No patient had a creatinine clearance of less than 50 ml per minute during treatment. Five of 29 patients (17%) had tacrolimus concentrations of more than 15.0 ng per milliliter during the treatment period, although dosing errors accounted for the elevations in 4 of the 5 patients. Only one adverse event (mild rash) was reported in a patient with an elevated tacrolimus level. Shortly after treatment completion, 8 patients (28%) had one or more tacrolimus measurements below the laboratory reference range; in all the patients, levels returned to the therapeutic range during subsequent follow-up, and no graft rejection occurred. The suggested adjustments in the cyclosporine dose maintained trough concentrations within the therapeutic range.

Neither tacrolimus nor cyclosporine substantially altered the trough concentrations of ombitasvir, ABT-450, dasabuvir, or ribavirin. The trough concentrations of the study drugs were within the range observed in phase 2 and 3 studies of this regimen.27-31,34

Discussion

Previous studies have shown that overall graft and patient survival rates are lower among liver-transplant recipients with HCV infection than among transplant recipients without HCV infection, owing to universal reinfection and accelerated disease progression. No existing therapeutic regimens are approved for HCV-infected liver-transplant recipients. In the phase 2 CORAL-I trial of a 24-week, interferon-free, all-oral antiviral regimen for HCV genotype 1 infection, a rate of sustained virologic response of 97% (95% CI, 85 to 100) at post-treatment weeks 12 and 24 was observed among liver-transplant recipients with no fibrosis or mild fibrosis. Sustained virologic responses of 96 to 100% have been reported in phase 3 studies of 12 weeks of treatment with ombitasvir–ABT-450/r and dasabuvir with ribavirin in nonimmunosuppressed patients not undergoing liver transplantation.27-30

Studies of a first-generation protease inhibitor (boceprevir or telaprevir) in combination with peginterferon and ribavirin have shown lower rates of sustained virologic response (20 to 71%) and high rates of toxic effects among immunosuppressed patients after transplantation, and some of these toxic effects can be life-threatening.21-24 In a phase 2 evaluation, treatment with the nucleotide polymerase inhibitor sofosbuvir and ribavirin for 24 weeks resulted in a sustained virologic response at post-treatment week 12 in 28 of 40 liver-transplant recipients (70%).35 The patients included in these studies generally had advanced fibrosis, which may be associated with a decreased response rate.

Treatment of liver-transplant recipients with telaprevir or boceprevir plus peginterferon and ribavirin is associated with high rates of treatment discontinuation owing to adverse events. Side effects of these regimens result in frequent use of erythropoietin (in 77 to 100% of patients), modifications in the ribavirin dose (in 70 to 100%), and blood transfusions (in 33 to 64%) to manage anemia.21-24 Grade 3 and grade 4 laboratory abnormalities were each observed in 28% of patients receiving treatment with sofosbuvir and ribavirin, including hemoglobin levels of less than 8.0 mg per deciliter in 20% of patients,35 although this study population included patients with cirrhosis, and such abnormalities may be observed more frequently in patients with cirrhosis than in those without cirrhosis.

In our study, doses of immunosuppressive calcineurin inhibitors were modified during the treatment period to maintain therapeutic levels. No deaths or episodes of graft rejection occurred in this population of difficult-to-cure transplant recipients with HCV infection. The rates of serious adverse events and study discontinuations due to adverse events observed in this small study were lower than the rates that have been observed with the interferon-based treatments that were the previous standard of care.36 Only one patient discontinued the study treatment owing to adverse events, and this patient had a sustained virologic response. In this immunosuppressed population, no new safety signals were identified, and events related to impairment of renal function and grade 3 laboratory abnormalities were similar to those observed in larger trials of this regimen involving patients not undergoing transplantation.27-31,34 However, this study was not large enough to accurately estimate rates of adverse events or to make comparisons with rates of adverse events in prior trials. No patient needed a blood transfusion; five patients (15%) required erythropoietin, all of whom had initially received ribavirin at a total daily dose of 1000 or 1200 mg. These five patients were among the first study participants to receive the study drugs, and this observation was communicated to the investigators with a suggestion to use a lower starting dose of ribavirin. Given the high response rate that was observed, regardless of the initial ribavirin dose, an initial dose of 600 to 800 mg may provide sufficient therapeutic benefit and minimize the risk of severe anemia.

This study has limitations. Patients were excluded if they had advanced fibrosis (Metavir score >F2) or had received interferon-based treatment after transplantation; thus, the study selected patients with cases of HCV infection that have historically been easier to treat than those characterized by advanced fibrosis. In addition, patients underwent transplantation at least 12 months before study initiation, so the study excluded those with early, aggressive forms of recurrent HCV infection (e.g., fibrosing cholestatic hepatitis) that can complicate treatment. Another limitation of the study was that immunosuppressive agents other than tacrolimus and cyclosporine were not evaluated; we assessed only these two agents because previous studies of interactions between drugs were restricted to these two agents.

In light of the worldwide organ shortage, a safe and effective antiviral regimen is needed for the treatment of HCV-infected liver-transplant recipients, who have lower survival rates than other liver-transplant recipients. Treatment of recurrent HCV infection after liver transplantation is associated with improved outcomes in patients who have a sustained virologic response,13-15 including improvements in graft and patient survival, changes that may potentially reduce the demand for retransplantation.8 We found that the multitargeted regimen of ombitasvir–ABT-450/r and dasabuvir with ribavirin resulted in a 97% response rate among immunosuppressed liver-transplant recipients with recurrent HCV genotype 1 infection. This all-oral, interferon-free regimen was efficacious in eradicating HCV infection in a patient population who are at high risk for severe illness and death and for whom treatment options are currently limited.

Supported by AbbVie.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on November 11, 2014, at NEJM.org.

We thank the trial participants, investigators, and coordinators who made this study possible; Anthony “Jake” Demetris, M.D., at the University of Pittsburgh and Christine Collins, Ph.D., Barbara McGovern, M.D., Rajeev Menon, Ph.D., Preethi Krishnan, Ph.D., Gretja Schnell, Ph.D., Rakesh L. Tripathi, M.S., Michelle Irvin, and Thomas Reisch, employees of AbbVie, for contributions to the study; and Douglas E. Dylla, Ph.D., of AbbVie for medical-writing support.

Source Information

From Indiana University, Indianapolis (P.Y.K.); the Liver Institute at Methodist Dallas, Dallas (P.S.M.); AbbVie, North Chicago, IL (E.C., W.X., C.S., P.B., T.P.-M., R.A.V.); University of Chicago Medical Center (H.S.T.) and Northwestern University Comprehensive Transplant Center (J.L.) — both in Chicago; Mayo Clinic, Phoenix, AZ (H.E.V.); Columbia University Medical Center, Center for Liver Disease and Transplantation, New York (R.B.); Lahey Hospital and Medical Center, Burlington, MA (F.G.); University of California, San Francisco, San Francisco (N.A.T.); University of Colorado Denver, Aurora (J.R.B.); and the Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona (X.F.).

Address reprint requests to Dr. Kwo at the Gastroenterology/Hepatology Division, Indiana University School of Medicine, 975 W. Walnut, IB 327, Indianapolis, IN 46202-5121, or at pkwo@iu.edu.

Source

(Ref: Merck & Co., The Lancet, StreetInsider, NASDAQ)

November 11th, 2014
By: Joe Barber

Merck & Co. said Tuesday that it plans to submit a marketing application for its investigational combination regimen of grazoprevir and elbasvir to the FDA in 2015 for the treatment of chronic hepatitis C. The company also reported results from the Phase II C-WORTHy trial, showing that the treatment combination, either with or without ribavirin, was associated with sustained virologic response rates at 12 weeks of 90 percent or greater in both treatment-naïve and -experienced patients. Eliav Barr, vice president of infectious diseases at Merck Research Laboratories, commented "we are encouraged by the findings for grazoprevir/elbasvir in the C-WORTHy trial and look forward to advancing our broad Phase III programme."

Source

Does Screening Baby Boomers for Hepatitis C Work?

Attention: Medical & Science Editors/Producers

Media Contact: Gregory Bologna
703-299-9766
gbologna@aasld.org
Press Room: November 7 – 11, 2014
Hynes Convention Center, Boston, MA
Telephone: 617-954-2977

Researcher: National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
+1 404-639-8895
NCHHSTPMediaTeam@cdc.gov

For Immediate Release
Presented: Tuesday, November 11 2015, 8:15 am Eastern

Does Screening Baby Boomers for Hepatitis C Work?

A study presented at the annual meeting of the American Association for the Study of Liver Diseases reported that the current age-based screening recommendation from the Centers for Disease Control and Prevention (CDC) is five times more effective in identifying people currently or previously infected with hepatitis C virus when compared to the previous screening strategy.

The CDC currently recommends a one-time birth cohort or age-based screening for hepatitis C virus (HCV). All baby boomers -- those born between 1945 and 1965 -- should be tested for HCV. Older screening strategies relied on identifying populations at greater risk for having HCV.

While the study did not evaluate the uptake of the CDC recommendation, the study authors conclude that the results demonstrate that the implementation of birth cohort testing in the primary care setting is feasible and can be effective.

A vast majority (81 percent) of Americans living with chronic HCV are baby boomers. In that group, 2.6 percent -- or 2.16 million people -- have chronic infection yet many don’t know they have it and cannot benefit from life-saving care and treatment.

Researchers conducted birth cohort testing trials for 14 months (December 2012-February 2014) at three large primary care healthcare centers. Baby boomer patients were randomly assigned to a group and automatically tested based on the birth cohort screening recommendation or to a control group based on the previous screening strategies. Almost 33,000 patients were screened using the birth cohort recommendation or control group.

While this is the first clinical study that provides real-world evidence that the baby boomer recommendations can be implemented in practice and will result in a significant increase in new HCV diagnoses, monitoring of the recommendations will continue to be important.
Abstract title:
Effectiveness of hepatitis C virus (HCV) testing for persons born during 1945-1965 -- Summary results from three randomized controlled trials

###

AASLD is the leading medical organization for advancing the science and practice of hepatology. Founded by physicians in 1950, AASLD's vision is to prevent and cure liver diseases. This year's Liver Meeting®, held in Boston, November 7-11, will bring together more than 9,000 researchers from 55 countries.

A pressroom will be available from November 7 at the annual meeting. For copies of abstracts and press releases, or to arrange researcher interviews, contact Gregory Bologna at 703-299-9766.

Press releases and all abstracts are available online at www.aasld.org.

Source

- In adult patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) type 1 infection, TURQUOISE-I demonstrated sustained virologic response rates 12 weeks post-treatment (SVR(12)) of 93.5 percent after 12 weeks of treatment and 90.6 percent after 24 weeks of treatment, respectively

- In adult liver transplant patients with recurrent chronic GT1 HCV infection and new to treatment after transplantation, CORAL-I demonstrated 97.1 percent SVR rates at 12 and 24 weeks post-treatment after 24 weeks of treatment

- CORAL-I results published online today in The New England Journal of Medicine

Nov 11, 2014

BOSTON, Nov. 11, 2014 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced results from studies in chronic hepatitis C patients with human immunodeficiency virus type 1 (HIV-1) co-infection (TURQUOISE-I) and liver transplant recipients (CORAL-I) at The Liver Meeting®2014.

New, detailed results from part one of the Phase 2 portion of AbbVie's Phase 2/3 open-label study, TURQUOISE-I, showed patients co-infected with genotype 1 (GT1) hepatitis C virus (HCV) and HIV-1 receiving AbbVie's investigational treatment and ribavirin (RBV) for 12 weeks or 24 weeks achieved sustained virologic response rates 12 weeks post-treatment (SVR12) of 93.5 percent (n=29/31) and 90.6 percent (n=29/32), respectively. These data were presented today, November 11, as a "Poster of Distinction."

"Patients living with both chronic HCV and HIV have been historically considered more difficult to treat," said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "TURQUOISE-I is one of the few dedicated studies looking specifically at this population, who are seen in everyday clinical practice. These data will help us gain a better understanding of how our investigational treatment works in this subpopulation of genotype 1 patients." 

Additionally, results from the first cohort of AbbVie's ongoing open-label Phase 2 study, CORAL-I, were presented today during an oral session and published online in The New England Journal of Medicine. Results showed that non-cirrhotic liver transplant patients with recurrent GT1 HCV and new to treatment after transplantation achieved a SVR12 rate of 97.1 percent (n=33/34) and a sustained virologic response rate 24 weeks post-treatment (SVR24) of 97.1 percent (n=33/34) after 24 weeks of treatment.

"Recurrence of HCV infection in the new graft post-liver transplantation is universal in those that have the virus prior to transplantation, and can be associated with an aggressive disease course," explained Dr. Paul Kwo, medical director of liver transplantation and professor of medicine, Indiana University School of Medicine. "The high SVR rates seen in CORAL-I are promising and offer valuable information as we continue to assess this regimen within this specific patient population."

About TURQUOISE-I

TURQUOISE-I is an ongoing Phase 2/3, multi-center, randomized, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (weight based dosing of 1000 mg or 1200 mg per day divided twice daily) for 12 or 24 weeks in adult patients with chronic GT1 HCV infection with or without compensated liver cirrhosis who are also infected with HIV-1. Study patients were either new to therapy (treatment naïve) or had failed previous treatment with pegylated interferon and RBV (treatment-experienced), had a stable immune status (CD4+ counts of ≥200 cells/mm3 or CD4+ % ≥14%) and had HIV-1 ribonucleic acid levels suppressed on a stable atazanavir- or raltegravir-based antiretroviral HIV therapy.

No patients discontinued treatment due to adverse events in either the 12-week or 24-week arm. In the 12-week arm, no virologic breakthroughs were observed while on treatment. One patient (3.3 percent) experienced post-treatment relapse after 12 weeks of treatment. In the 24-week treatment arm, one virologic breakthrough was observed (3.1 percent). Two patients in the 24-week treatment group were believed to have been re-infected post-treatment by a different strain of HCV than the original infection. The most commonly reported adverse events (greater than 15 percent in both treatment arms combined) were fatigue (47.6 percent), insomnia (19 percent), nausea (17.5 percent), and headache (15.9 percent). Elevations in total bilirubin were the most common laboratory abnormality (68.3 percent), were mainly composed of indirect bilirubin, and were not associated with aminotransferase elevations. Reductions in RBV dose because of anemia or reduced hemoglobin occurred in 9.5 percent of patients (n=6/63); all six patients achieved SVR12.

About CORAL-I

CORAL-I is an ongoing Phase 2, multi-center, two-cohort, open-label study evaluating the efficacy and safety of AbbVie's all-oral, interferon-free investigational treatment combining three direct-acting antivirals (ombitasvir/ABT-450/ritonavir and dasabuvir) with RBV (RBV dosing left up to the discretion of the investigator) for 24 weeks in adult non-cirrhotic (screening biopsy Metavir score ≤F2) liver transplant recipients with recurrent chronic GT1 HCV infection. Patients in the study initiated therapy at least 12 months after receiving a liver transplant, had not received other HCV therapy since their liver transplant, and were on a stable immunosuppressant regimen based on either tacrolimus or cyclosporine, for which dose adjustments were advised. Enrollment in the second cohort of the study is ongoing.

One patient (2.9 percent) discontinued the study due to adverse events but still achieved SVR12. Two patients experienced serious adverse events. The most commonly reported treatment-emergent adverse events (greater than 20 percent) were fatigue (50 percent), headache (44.1 percent), cough (32.4 percent), anemia (29.4 percent), diarrhea (26.5 percent), insomnia (26.5), asthenia (23.5 percent), nausea (23.5 percent), muscle spasms (20.6 percent), and rash (20.6 percent). No patients experienced virologic breakthrough while on treatment; however, one patient experienced post-treatment relapse. Nine patients had a grade 2 reduction in hemoglobin, and one patient had a grade 3 reduction. Five patients with hemoglobin decreases (anemia) received a medication to boost their red blood cell production at the investigator's discretion. No patients discontinued study drugs because of anemia, required a blood transfusion, or experienced a rejection of their transplanted liver.

About AbbVie's Investigational Three Direct-Acting Antiviral Treatment

AbbVie's investigational treatment consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (25mg), dosed once daily, and dasabuvir (250mg) dosed twice daily with or without ribavirin. The combination of three direct-acting antivirals, each with a distinct mechanism of action, targets and inhibits specific hepatitis C virus proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program

The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's multinational program using an investigational treatment combining three direct-acting antivirals includes more than 2,300 patients in over 25 countries. The program is designed to identify ways to maximize response rates in a broad spectrum of patient populations, including those with compensated cirrhosis, liver transplant recipients and those with human immunodeficiency virus type 1 co-infection.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

AbbVie's New Drug Application to the U.S. Food and Drug Administration (FDA) and Marketing Authorization Applications to the European Medicines Agency (EMA) for its investigational, all-oral, interferon-free regimen for the treatment of adult patients with chronic genotype 1 HCV infection have been accepted and granted priority review by the FDA and validated and granted accelerated assessment by the EMA.

Safety Information for Ribavirin and Ritonavir

Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

About AbbVie

AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements

Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995.  The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements.  AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements.  Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.  Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K and in Item 1A, "Risk Factors" of Part II of AbbVie's second quarter 2014 Quarterly Report on Form 10-Q, which have been filed with the Securities and Exchange Commission.  AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

SOURCE AbbVie

For further information: Media, Stefanie Prodouz, +1 (224) 637-0971, stefanie.prodouz@abbvie.com, Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com, Investor Relations, Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

Source

-- Once-Daily Combination Achieves High SVR12 Rates Across Multiple HCV Genotypes --

BOSTON--(BUSINESS WIRE)--Nov. 11, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced data from three Phase 2 open-label studies evaluating the safety and efficacy of an investigational all-oral pan-genotypic regimen containing the nucleotide analog polymerase inhibitor sofosbuvir (SOF), approved as Sovaldi® by the U.S. Food and Drug Administration in December 2013, and the investigational NS5A inhibitor GS-5816 for the treatment of chronic hepatitis C virus (HCV) infection. These data are being presented this week at the 65th Annual Meeting of the American Association for the Study of Liver Diseases (The Liver Meeting® 2014) in Boston.

All three studies evaluated SOF 400 mg plus GS-5816 25 or 100 mg, with and without ribavirin (RBV), for eight or 12 weeks. Rates of sustained virologic response (SVR12) ranged from 88 percent to 100 percent among those receiving SOF plus GS-5816 100 mg for 12 weeks – the regimen selected for Phase 3 studies. Patients who achieve SVR12 are considered cured of HCV infection.

“There continues to be a need for simple, interferon- and ribavirin-free treatment regimens that are effective for all hepatitis C patients, regardless of genotype,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “These data demonstrate the high efficacy and tolerability of sofosbuvir plus GS-5816 among patients with varying genotypes and disease progression and we look forward to providing Phase 3 data on the combination across all six genotypes.”

The first study, GS-US-342-0109 (Oral #197), evaluated 12 weeks of SOF plus GS-5816 with and without RBV in treatment-experienced genotype 1 and 3 patients with and without cirrhosis. The genotype 1 patients had all failed a prior treatment course that included a protease inhibitor. The number and proportion of patients achieving SVR12 are summarized in the table below.

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The second study, ELECTRON 2 (Oral #79), evaluated the same combination of SOF plus GS-5816, with and without RBV, for eight weeks in non-cirrhotic, treatment-naïve genotype 3 patients. Patients receiving SOF with GS-5816 100 mg achieved SVR12 rates of 100 percent (n=26/26) with RBV and 96 percent (n=26/27) without RBV.

The third study, GS-US-342-0102, evaluated SOF plus GS-5816, with and without RBV, among non-cirrhotic treatment-naïve patients. The results of Part A of the study evaluating 12 weeks of therapy were presented at the 49th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress 2014) in April 2014.

The results of Part B, presented at the Liver Meeting this week (Oral #80), evaluated eight weeks of SOF plus GS-5816, with and without RBV, in patients with genotype 1 or 2 HCV infection. Among genotype 1 patients receiving SOF plus GS-5816 100 mg, SVR12 rates were 81 percent (n=25/31) and 90 percent (n=26/29), with and without RBV, respectively. Genotype 2 patients achieved SVR12 rates of 88 percent (n=23/26) with RBV and 88 percent (n=23/26) without RBV.

SOF plus GS-5816 was well tolerated in over 800 patients with HCV infection evaluated in these three studies. There was a low incidence of serious adverse effects and few discontinuations due to adverse events. The most frequently reported adverse events (>10%) were fatigue, headache, nausea and insomnia. The most frequently observed hematologic abnormality was hemoglobin decrease in the RBV-containing treatment groups.

GS-5816 is an investigational product and its safety and efficacy have not been established.

Additional information about these studies can be found at www.clinicaltrials.gov.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable longer-term results from these studies and other ongoing and subsequent clinical trials involving sofosbuvir plus GS-5816, alone or in combination with other products, for the treatment of HCV. In addition, Gilead may make a strategic decision to discontinue development of GS-5816 if, for example, Gilead believes commercialization will be difficult relative to other opportunities in its pipeline. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. Full Prescribing Information for Sovaldi is available at www.gilead.com.

Sovaldi is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Source

Final Results from the C-WORTHy Study (Parts A and B) Presented at The Liver Meeting® and Published in The Lancet

First Wave of Phase 3 Development Program for Grazoprevir/Elbasvir is Fully Enrolled; Merck Plans to Submit New Drug Application in 2015

Tuesday, November 11, 2014 8:00 am EST

BOSTON--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of results from a multi-arm Phase 2 clinical trial evaluating grazoprevir/elbasvir (MK-5172/MK-8742, the company’s investigational NS3/4A protease inhibitor and NS5A inhibitor, respectively) with or without ribavirin (RBV) in treatment-naïve and previously-treated (with peg-interferon/ribavirin [PR]) patients with chronic hepatitis C virus (HCV) genotype 1 (GT1) infection -- the C-WORTHy study (Parts A and B). The final results were presented in oral sessions at the 65th American Association for the Study of Liver Diseases (AASLD) Annual Meeting (also known as The Liver Meeting®) and published as separate papers online in The Lancet.

“Merck is committed to developing an efficacious, well-tolerated therapy suitable for a broad spectrum of patients with HCV,” said Dr. Eliav Barr, vice president, infectious diseases, Merck Research Laboratories. “We are encouraged by the findings for grazoprevir/elbasvir in the C-WORTHy trial and look forward to advancing our broad Phase 3 program, which includes hard-to-cure patients that are of the highest need and least studied to date.”

Interim results from the C-WORTHy study were presented in April 2014 at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL) and announced by Merck.

Results for Treatment-Naïve Cirrhotic Patients and PR Null-Responders

The results for HCV mono-infected treatment-naïve GT1 patients with cirrhosis and GT1 prior null-responders with or without cirrhosis treated with grazoprevir/elbasvir, with or without ribavirin, for 12 weeks or 18 weeks are shown in table 1. The rates of sustained viral response,i 12 weeks after the completion of therapy (SVR12) were greater than, or equal to, 90 percent regardless of treatment duration or co-administration of RBV.

Capture

The rate of virologic failure was five percent (6/123) in treatment-naïve cirrhotic patients and three percent (4/130) in the null-responder population. Treatment was generally well-tolerated. The most common adverse events associated with the administration of grazoprevir/elbasvir in combination with or without RBV were: fatigue (26%), headache (23%) and asthenia (14%). There were no early discontinuations due to adverse events with grazoprevir/elbasvir and no clinically significant abnormalities observed in routinely evaluated biomarkers.

Results for HCV Mono-Infected and HIV/HCV Co-Infected Patients

Treatment-naïve, non-cirrhotic mono-infected GT1 patients and non-cirrhotic HCV GT1 /HIV co-infected patients treated for 12 weeks with grazoprevir/elbasvir with or without RBV, demonstrated high rates of SVR12, as seen in table 2. Among this patient population treated for 12 weeks, the overall rate of virologic failure was four percent (7/188), including three breakthrough failures and four relapses, in both mono- and co-infected patients. In patients treated for eight weeks, the rate of virologic failure was 17 percent (5/30), with five relapses. The most common adverse events with or without RBV were fatigue (23%), headache (20%), nausea (15%) and diarrhea (10%). There were no early discontinuations due to adverse events with grazoprevir/elbasvir and no clinically significant abnormalities observed in routinely evaluated biomarkers.

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About the C-WORTHy Study

C-WORTHy is a randomized, dose response, parallel-group, multiple-site, double-blind clinical trial comparing diverse patient populations exposed to different durations of treatment of grazoprevir/elbasvir with or without RBV in patients with chronic HCV infection. In C-WORTHy Parts A and B, a total of 471 patients with chronic HCV GT1 infection with HCV RNA levels of ≥10,000 IU/mL were enrolled and randomized across 16 arms. The patients include hard-to-cure sub-populations, including treatment-naïve patients with liver cirrhosis (12- and 18-week arms, with and without RBV) and prior-null responder patients with and without cirrhosis (12- and 18-week arms, with and without RBV). The lead authors of The Lancet publications and presenters at The Liver Meeting® are Dr. Eric Lawitz of The Texas Liver Institute and professor of medicine at The University of Texas Health Science Center, San Antonio, TX (C-WORTHy Cirrhotic Patients and Prior Null-Responders); and Dr. Mark Sulkowski, professor of medicine at The Johns Hopkins University School of Medicine, Baltimore, MD (C-WORTHy HCV Mono-Infected and HIV/HCV Co-Infected Patients).

About C-EDGE: Merck’s Phase 3 HCV Program

The results of the C-WORTHy study supported the advancement of grazoprevir/elbasvir into the Phase 3 clinical development program called C-EDGE. The Phase 3 C-EDGE program is evaluating grazoprevir/elbasvir with and without RBV in various genotypes and across a broad range of patient populations with chronic HCV infection, including treatment-naive patients and patients who previously failed PR therapy, patients with and without cirrhosis, patients with chronic kidney disease (including those on hemodialysis), patients with HIV/HCV co-infection, patients on opiate substitution therapy and patients with inherited blood disorders. Merck initiated the first C-EDGE study in April 2014, and the grazoprevir/elbasvir registration studies within the C-EDGE program – including C-EDGE TN (treatment-naïve), C-EDGE CO-INFXN (HIV/HCV co-infected) and C-EDGE TE (treatment-experienced) -- are now fully enrolled. Results from these trials are anticipated in the first half of 2015. Learn more at http://www.merck.com/clinical-trials/.

About Grazoprevir/Elbasvir

Grazoprevir/elbasvir (MK-5172/MK-8742) is an investigational, oral, once-daily, fixed-dose combination chronic HCV treatment, consisting of grazoprevir, an investigational oral, once-daily HCV NS3/4A protease inhibitor, and elbasvir, an investigational oral, once-daily HCV NS5A replication complex inhibitor. In October 2013, Merck announced that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to grazoprevir/elbasvir for treatment of chronic HCV infection. Breakthrough Therapy designation is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. Merck plans to submit the New Drug Application for grazoprevir/elbasvir in 2015.

Merck’s Commitment to HCV

For nearly 30 years, Merck has been at the forefront of the response to the HCV epidemic. Merck employees are dedicated to applying their scientific expertise, resources and global reach to deliver innovative healthcare solutions that support people living with HCV worldwide.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include, but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation in the United States and internationally; global trends toward healthcare cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

i Defined as HCV RNA below the limit of quantification or below the limit of detection at the last visit on record – 4, 8, 12, or 24 weeks after the completion of therapy.
ii Virologic failure is the inability to achieve or maintain suppression of viral replication to an HCV RNA level <200 copies/mL.

Contact:

Merck
Media:
Pam Eisele, 267-305-3558
Sarra Herzog, 201-669-6570
or
Investors:
Joe Romanelli, 908-423-5185
Justin Holko, 908-423-5088

Source

Published: Nov 11, 2014 8:02 a.m. ET

- High Cure Rates in Nearly 800 HCV Patients with Advanced Liver Disease -

BOSTON, Nov 11, 2014 (BUSINESS WIRE) -- Gilead Sciences, Inc. GILD, +0.55% today announced results from several Phase 2 and Phase 3 studies evaluating investigational uses of Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) for the treatment of chronic hepatitis C virus (HCV) infection in patients with limited or no treatment options, including patients with decompensated cirrhosis, patients with HCV recurrence following a liver transplant and patients who failed previous treatment with other direct acting antivirals. These data will be presented this week at the 65th Annual Meeting of the American Association for the Study of Liver Diseases (The Liver Meeting2014) in Boston.

“Chronic hepatitis C patients with advanced liver disease are among the most difficult to cure and traditionally have had limited or no treatment options,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer, Gilead Sciences. “The data presented this week demonstrate that Harvoni provides high cure rates for patients with advanced liver disease, as well as for those who failed prior treatment with other antivirals, including sofosbuvir-based regimens.”

Harvoni was approved by the U.S. Food and Drug Administration and Health Canada in October 2014 and is the first once-daily single tablet regimen for the treatment of chronic HCV genotype 1 infection in adults. Applications are pending in the European Union, Japan and New Zealand.

Advanced Liver Disease

In a pooled analysis of Phase 2 and Phase 3 open-label studies (Oral #82) in more than 500 genotype 1 HCV infected patients with compensated cirrhosis who received Harvoni alone or with ribavirin (RBV) for 12 or 24 weeks, 96 percent of patients achieved sustained virologic response (SVR12). Patients who achieve SVR12 are considered cured of HCV infection.

Two prospective analyses from a Phase 2 open-label study (Study GS-US-337-0123) evaluating patients with decompensated cirrhosis and those with HCV recurrence following liver transplantation also are being presented. In the first subgroup (Oral #239), 108 genotype 1 and 4 infected patients with decompensated cirrhosis, including those with moderate hepatic impairment (Child-Pugh-Turcotte (CPT) Class B) and severe hepatic impairment (CPT Class C), received Harvoni plus RBV for 12 or 24 weeks. Overall, SVR12 rates were 87 percent (n=45/52) in the 12-week arm and 89 percent (n=42/47) in the 24-week arm.

The second subgroup (Oral #8) evaluated 12 or 24 weeks of Harvoni plus RBV among 223 genotype 1 and 4 patients who developed HCV recurrence following liver transplantation. Among non-cirrhotic patients, SVR12 rates were 96 percent (n=53/55) and 98 percent (n=55/56) following 12 and 24 weeks of treatment, respectively. For patients with compensated cirrhosis, SVR12 rates were 96 percent for both 12 weeks (n=25/26) and 24 weeks (n=24/25) of therapy. SVR12 rates among patients with decompensated cirrhosis were 81 percent for both 12 weeks (n=25/31) and 24 weeks (n=17/21) of therapy.

Retreatment of Patients Who Failed Prior Therapy

Study GS-US-337-0121 (Late Breaker Oral #LB-6) evaluated 155 genotype 1 patients with compensated cirrhosis who had failed prior treatment with pegylated interferon (PegIFN)/RBV and subsequently PegIFN/RBV plus a protease inhibitor. In this study, patients were randomized (1:1) to receive Harvoni plus RBV for 12 weeks or Harvoni alone for 24 weeks. Ninety-six percent (n=74/77) of those receiving Harvoni plus RBV for 12 weeks and 97 percent (n=75/77) of those receiving Harvoni for 24 weeks achieved SVR12.

In a second study (Oral #235), 51 genotype 1 patients who previously failed SOF/PegIFN/RBV, SOF/RBV or a SOF placebo/PegIFN/RBV treatment regimen received Harvoni plus RBV for 12 weeks. Twenty-nine percent of study patients (n=15/51) had cirrhosis. Ninety-eight percent (n=50/51) achieved SVR12 following 12 weeks of treatment with Harvoni plus RBV.

In all of these studies, Harvoni was well tolerated and its safety profile was generally consistent with that observed in clinical trials of Harvoni. Adverse events included fatigue, headache, nausea and anemia, which was more common among patients taking RBV. Grade 3/4 laboratory abnormalities were infrequent and included decreases in hemoglobin, which is consistent with RBV-associated anemia.

The safety and efficacy of Harvoni have not been established for the investigational uses described above.

Additional information about these studies can be found at www.clinicaltrials.gov.

Important Safety Information About Harvoni

Warnings and Precautions

Risk of Reduced Therapeutic Effect of Harvoni Due to P-gp Inducers: Rifampin and St. John’s wort are not recommended for use with Harvoni as they may significantly decrease ledipasvir and sofosbuvir plasma concentrations.

Related Products Not Recommended: Harvoni is not recommended for use with other products containing sofosbuvir (Sovaldi).

Adverse Reactions

Most common (greater-than or equal to 10 percent, all grades) adverse reactions were fatigue and headache.

Drug Interactions

In addition to rifampin and St. John’s wort, coadministration of Harvoni is also not recommended with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifapentine, and tipranavir/ritonavir. Such coadministration is expected to decrease the concentration of ledipasvir and sofosbuvir, reducing the therapeutic effect of Harvoni.

Coadministration of Harvoni is not recommended with simeprevir due to increased concentrations of ledipasvir and simeprevir. Coadministration is also not recommended with rosuvastatin or co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate due to increased concentrations of rosuvastatin and tenofovir, respectively.

Consult the full Prescribing Information for Harvoni for more information on potentially significant drug interactions, including clinical comments.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the possibility of unfavorable longer-term results from these studies and other ongoing and subsequent clinical trials involving Harvoni, alone or in combination with other products, for the treatment of HCV in other patient populations. As Harvoni is used over longer periods of time, Gilead may find new issues such as safety or drug resistance, which may require it to provide additional warnings or contraindications in the label, which could reduce the market acceptance of Harvoni. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. Full Prescribing Information for Harvoni is available at www.gilead.com.

Harvoni is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

SOURCE: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

Source

- Results demonstrated high response rates in adult chronic hepatitis C genotype 4 patients without cirrhosis

- Data underscore AbbVie's commitment to evaluating treatments across a range of patients with chronic hepatitis C virus infection

Nov 11, 2014

BOSTON, Nov. 11, 2014 /PRNewswire/ -- AbbVie (NYSE:ABBV) announced detailed results from its open-label Phase 2b study, PEARL-I, which demonstrated that 100 percent  of genotype  4 (GT4) patients who were new to therapy (n=42/42) or who had failed previous treatment with pegylated interferon (pegIFN) and RBV (n=49/49) achieved sustained virologic response rates at 12 weeks post-treatment (SVR12) after taking AbbVie's investigational treatment with ribavirin (RBV). Additionally, 90.9 percent of patients who were new to therapy achieved SVR12 (n=40/44) after taking the treatment without RBV. These data will be presented today during a poster session at The Liver Meeting® 2014.

"As many as 34 million people around the world are living with genotype 4 chronic hepatitis C, a population that is common in the Middle East and Africa, where it accounts for more than 80 percent of all hepatitis C cases,[i]" said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "The data from PEARL-I represent another important step forward in realizing our commitment to advancing scientific knowledge in hepatitis C with the ultimate goal of providing treatment options to as many patients as possible."

PEARL-I studied AbbVie's all-oral, interferon-free investigational treatment combining two direct-acting antivirals (ABT-450/ritonavir and ombitasvir) with and without RBV for 12 weeks in non-cirrhotic adult patients with chronic genotype 1b (GT1b) and GT4 hepatitis C virus (HCV) infection.

There were no discontinuations due to adverse events in PEARL-I. The most commonly reported treatment-emergent adverse events (greater than 15 percent in any group) were headache (29-33 percent), asthenia (weakness) (24-33 percent), fatigue (7-18 percent), nausea (9-17 percent) and insomnia (5-16 percent). One patient had a grade 3 liver function test elevation (AST> five times the upper limit of normal), which was asymptomatic and resolved during continued dosing. Four patients with hemoglobin decreases (anemia) required RBV dose reductions; however, none of these patients required blood transfusions or medication to boost their red blood cell production. In the treatment-naïve group without RBV, on-treatment virologic breakthrough was reported in one patient (2 percent) and two patients (5 percent) experienced post-treatment relapse. There were no virologic failures in the other treatment arms.

About AbbVie's Investigational Two Direct-Acting Antiviral HCV Treatment
AbbVie's proposed all-oral antiviral treatment consists of the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ombitasvir (25mg) dosed once daily, co-administered with weight-based ribavirin (1000mg or 1200mg in divided doses twice daily). The combination of two direct-acting antivirals, each with distinct mechanisms of action, targets and inhibits specific HCV proteins in the viral replication process.

About AbbVie's HCV Clinical Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating interferon-free, all-oral treatments with and without ribavirin with the goal of achieving high sustained virologic response rates in as many patients as possible. AbbVie's development programs combining two direct-acting antivirals are studying additional hepatitis C virus (HCV) genotypes.

ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of hepatitis C.

Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.

There are special safety considerations when prescribing these drugs in approved populations.

Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, autoimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score ≥6.

See approved product labels for more information.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. AbbVie employs approximately 25,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995.  The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements.  AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements.  Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.  Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2013 Annual Report on Form 10-K and in Item 1A, "Risk Factors" of Part II of AbbVie's second quarter 2014 Quarterly Report on Form 10-Q, which have been filed with the Securities and Exchange Commission.  AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

[i] Khattab MA, et al. Management of hepatitis C virus genotype 4: Recommendations of an International Expert Panel. J Hepatol. 2011; 54: 1250–1262

SOURCE AbbVie

For further information: Media: Stefanie Prodouz, +1 (224) 637-0971, stefanie.prodouz@abbvie.com; or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com; or Investor Relations:Liz Shea, +1 (847) 935-2211, liz.shea@abbvie.com

Source

Unique 'pay if you clear' proposal for new hepatitis drug

13 October 2014 Last updated at 11:35 ET

By Reevel Alderson BBC Scotland's social affairs correspondent

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More than 37,000 people in Scotland have chronic hepatitis C - but only half have been diagnosed

The NHS in Scotland could be reimbursed for the cost of a new hepatitis drug if sufferers fail to clear the virus.

The novel proposal was revealed after the drug Olysio was cleared for use by the Scottish Medicines Consortium (SMC).

The drug's manufacturer claims the move would help cut prescribing costs.

It is estimated Scotland wastes up to £44m each year on medicines for all conditions that are unused, ineffective or are taken incorrectly.

The 'Pay If You Clear' scheme would come into effect if patients treated with the drug do not become free of the hepatitis C virus (HCV) after 12 weeks.

SMC has approved the drug, whose generic name is simeprevir, for use within NHS Scotland. The 'Pay If You Clear' scheme is awaiting a formal decision by NHS Scotland.

Appropriate treatment

The drug will be used to treat patients with chronic HCV infection, including those for whom treatment has previously failed.

The manufacturer, Janssen, will pay for pre-treatment blood tests for patients to predict whether the drug is likely to be effective before treatment is initiated.

Continue reading the main story

“Start Quote

We must not forget the importance of prevention, earlier diagnosis and better testing strategies”

End Quote Charles Gore Hepatitis C Trust

Any patient who does not respond to treatment within four weeks will be offered alternative therapies.

Dr John Dillon, consultant hepatologist and gastroenterologist at Ninewells Hospital in Dundee, welcomed the decision by SMC.

"This decision provides us with another treatment option which is convenient for patients and more affordable to NHS Scotland than some other treatments," he said.

"To be able to predict a person's response to treatment, prior to them embarking on the medicine, is a particularly useful factor in managing hepatitis C care.

"It means we can select the most appropriate treatment option in a cost-efficient manner."

Charles Gore, chief executive of The Hepatitis C Trust, said: "Decisions such as this from the SMC provide us with a key milestone for our campaign to eliminate hepatitis C.

"However, we must not forget the importance of prevention, earlier diagnosis and better testing strategies."

Charities claim there are more than 37,000 Scots with chronic HCV, only 55% of whom have been diagnosed, because often it has no symptoms.

Of those who develop hepatitis C an estimated 30% will develop cirrhosis of the liver or cancer.

Hepatitis C is the most common reason for liver transplants in Europe.

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November 10, 2014

Phase 1b Clinical Studies Ongoing in Patients with Chronic HBV Infection

DOYLESTOWN, Pa., Nov. 10, 2014 /PRNewswire/ -- Novira Therapeutics, Inc., a privately held biopharmaceutical company developing novel therapies for curative treatment of chronic hepatitis B virus (HBV) infection, today announced the presentation of Phase 1a safety and pharmacokinetic data for its lead HBV antiviral candidate, NVR 3-778 (also known as NVR-1221), in a late-breaking poster presentation at the 2014 annual meeting of the American Association for the Study of Liver Diseases in Boston. Dr. Edward J. Gane, Chief Hepatologist and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital in Auckland, New Zealand is the lead author on the poster and the principal clinical investigator for the study.

The randomized, placebo-controlled Phase 1a trial enrolled 40 healthy adult volunteers to assess the safety and tolerability of NVR 3-778 after single oral doses of 50 to 800 mg/day, followed by an assessment of 200 mg once-daily dosing for 14 days. The study results indicated that NVR 3-778 was well-tolerated at all doses. There was no pattern of treatment-related or dose-related clinical adverse events (AEs), and no serious or severe AEs. All AEs were of common types, and most were not attributed to study drug treatment. The AEs were all transient and mild (grade 1) in severity except for two grade 2 AEs not attributed to study treatment (sprain and tooth pain). The pharmacokinetic profile of NVR 3-778 indicated substantial dose-related plasma levels that were consistent across the subjects within each dosing cohort. At doses of 200 mg or more, plasma concentrations of NVR 3-778 remained above in vitro HBV-inhibitory concentrations for more than 24 hours, supporting evaluation of once-daily dosing in HBV patients.

"These encouraging Phase 1a results indicate that NVR 3-778 was well-tolerated at all dose levels in human volunteers, and once-daily doses of 200 mg or more provided systemic levels of NVR 3-778 high enough to potentially be associated with antiviral efficacy in hepatitis B patients," said Nathaniel Brown MD, Novira's Chief Medical Officer. "The Phase 1a results support advancement to Phase 1b testing in patients with chronic HBV infection, which is now underway. The Phase 1b clinical study is designed to evaluate the safety and antiviral efficacy of NVR 3-778 in HBV patients as both a single agent and in combination with current HBV therapies after a four week dosing period."

About NVR 3-778

NVR 3-778 is a small molecule, direct acting antiviral, for oral administration in patients with Chronic Hepatitis B (CHB) that inhibits the HBV core or capsid protein. HBV core is a novel and promising drug target with multiple activities required for viral replication and persistence. Inhibition of HBV core protein function by NVR 3-778 offers the potential for more efficient suppression of the virus leading to improved durable viral suppression and functional cure rates.

About HBV

Hepatitis B infection presents a significant unmet medical need with an estimated 350 million people worldwide living with chronic HBV infection. A significant number of patients with chronic infection incur a higher risk of developing cirrhosis and cancer. It is estimated that 60% of hepatocellular carcinoma (liver cancer) is a direct consequence of HBV infection. Current drugs approved for the management of CHB include PEG-Interferon and nucleot(s)ides which can effectively suppress virus replication, but rarely lead to a cure.

About Novira Therapeutics

Novira Therapeutics, Inc., is a privately held biopharmaceutical company focused on discovery and development of first-in-class antiviral drugs for the treatment of chronic HBV infection (CHB), a global disease with a high level of unmet medical need. The company is employing innovative chemistry and biology technologies to discover small molecule inhibitors of the HBV core or capsid protein as well as other drugs with novel mode of action. The company's novel antivirals will offer the potential to address the limitations of current CHB therapies when used either as mono-therapy or in combination with existing standards of care.

For more information, visit www.noviratherapeutics.com.

Contacts:

Corporate Contact
Christian S. Schade
Chief Executive Officer
cschade@noviratherapeutics.com

Media Contacts
David Schull    
Matt Middleman, M.D.             
Russo Partners      
T: (212) 845-4271                
T: (212) 845-4272
david.schull@russopartnersllc.com
matt.middleman@russopartnersllc.com

SOURCE Novira Therapeutics, Inc.

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Choose Your Tests Wisely: Advice From the AASLD

Medscape Gastroenterology

Lauri R. Graham, Raphael B. Merriman, MD, FRCPI

November 10, 2014

Editor's Note: Choosing Wisely®, an initiative of the American Board of Internal Medicine (ABIM) Foundation, comprises evidence-based recommendations from specialty organizations on commonly used tests and procedures. The goal of the campaign is to use these recommendations as the starting point for discussions between clinicians and patients about avoiding unnecessary care. Choosing Wisely launched in 2012 with five recommendations each from nine specialties; more than 60 specialty societies have now joined the campaign, with new lists continuing to be published through 2014 and more planned beyond that. Medscape interviewed Raphael B. Merriman, MD, of the American Association for the Study of Liver Diseases (AASLD), who helped craft its Choosing Wisely recommendations.

Medscape: Would you give a brief history of AASLD's involvement in the Choosing Wisely campaign, and why you believed this would be important?

Dr Merriman: We welcomed the opportunity to embrace this leadership challenge to help physicians be better stewards of finite healthcare resources.

The AASLD established the Choosing Wisely task force in December 2013 to develop its list of recommendations. Members were selected from the AASLD practice guidelines committee to broadly represent varying practice settings and subspecialty expertise within the field of hepatology. Hepatologists with methodological experience in evidence-based medicine were also included. The working group solicited recommendations from the entire AASLD membership that would be considered for inclusion in the list of five tests or treatments that physicians and patients should question. These recommendations were then rated on the basis of judgments related to harm, benefit, and excess resource utilization.

On the basis of voting by the working group, as well as a literature review of supporting data, a total of 10 suggestions were identified. Subsequently, voting by the working group generated the final top five recommendations. These top five recommendations were submitted and approved by the AASLD Governing Board.

Medscape: I'd like to go through the recommendations and ask you how they were selected. Could you also speak briefly about the evidence behind the recommendations? The first recommendation is: Don't perform surveillance esophagogastroduodenoscopy (EGD) in patients with compensated cirrhosis and small varices without red signs treated with nonselective beta-blockers for preventing a first variceal bleed.

Dr Merriman: This first recommendation is based on a recommendation in the AASLD practice guidelines related to portal hypertension and variceal bleeding. It relates to patients with cirrhosis and small varices that have not bled and do not have criteria for an increased risk for bleeding (that is, Child-Pugh class A and the absence of red signs on endoscopic variceal evaluation); for these patients, beta-blockers can be used. In patients with cirrhosis and medium or large varices that have not bled and, again, are not at the highest risk for bleeding (that is, Child-Pugh class A and no red signs), beta-blockers are preferred. The doses of the beta-blockers should be adjusted to the maximum tolerated dose.

In both of these clinical scenarios, follow-up EGD is not necessary. This practice would reduce the need for non-indicated upper gastrointestinal endoscopy.

Medscape: Your second recommendation is: Don't continue treatment for hepatic encephalopathy indefinitely after an initial episode with an identifiable precipitant.

Dr Merriman: This reflects a recommendation made in the recently published practice guideline on hepatic encephalopathy, which was jointly developed by the AASLD with the European Association for the Study of the Liver.

Patients may have episodes of hepatic encephalopathy with precipitating factors that can be identified and controlled, such as recurrent infections or variceal hemorrhage. In those circumstances where the precipitating factors are clearly identified and well controlled, the treatment of hepatic encephalopathy may not necessarily be indefinite and indeed could be discontinued.

This is important because in the past, it has been common practice to continue the prophylactic treatment of hepatic encephalopathy indefinitely after it was initiated, even though there was little basis to actually support that. So this recommendation has significant implications to reduce unnecessary use of therapeutics to prevent recurrent hepatic encephalopathy.

Medscape: Your third recommendation is: Don't repeat hepatitis C viral load testing outside of antiviral therapy.

Dr Merriman: This is an important, topical, and relevant recommendation, particularly in the context of the transformative changes occurring in the field of hepatitis C therapeutics with the imminent availability of a whole host of new, highly effective hepatitis C antiviral agents that are curing hepatitis C.

Highly sensitive serum assays of hepatitis C RNA are expensive. Performing these assays is appropriate at the time of diagnosis of hepatitis C and as part of antiviral therapy, typically at the beginning of and possibly during therapy, and also after therapy is completed. Outside of these circumstances, there is little benefit to measuring the hepatitis C viral RNA load, as it typically does not affect either the clinical management or outcomes.

This recommendation is of particular relevance to patients because, oftentimes, there is a mistaken patient perception that the testing is needed, that there is significance to quite modest changes in the hepatitis C viral load, and that it actually affects clinical outcomes. Therefore, this recommendation will prompt a discussion that should hopefully reduce the need for unnecessary virologic testing.

Medscape: Your fourth recommendation is: Don't perform CT or MRI routinely to monitor benign focal lesions in the liver unless there is a major change in clinical findings or symptoms.

Dr Merriman: Many patients have focal liver lesions detected by imaging—often incidentally—who don't have underlying liver disease and that are determined to be benign. Those who demonstrate both clinical and radiologic stability do not need repeated imaging as the likelihood of evolving into neoplastic lesions is very low (with the exception of hepatocellular adenoma). Clinical stability implies the absence of any new symptoms related to these focal liver lesions. This recommendation stems from a common perception that even after clinical and radiologic stability of the benign focal lesions has been demonstrated, that imaging needs to be repeated indefinitely. This recommendation provides guidance to support discontinuing serial imaging in these patients.

Because these lesions are often found incidentally and frequently in younger people, the additional implication of this recommendation is that we can reduce and avoid both unnecessary imaging and, in the case of CT scanning, unnecessary radiation exposure in this patient population.

Medscape: You mentioned the exception to this recommendation being hepatocellular adenoma.

Dr Merriman: Yes; this recommendation does not apply to those with hepatocellular adenoma. Patients with radiologic evidence of hepatocellular adenoma may have a risk of the lesion potentially transforming into a more neoplastic variant. These patients are typically monitored more closely, often depending in part upon the size of the lesion. However, it is important to remember that this represents a very small proportion of the total number of benign focal liver lesions.

Medscape: Your fifth recommendation is: Don't routinely transfuse fresh frozen plasma (FFP) and platelets prior to abdominal paracentesis or endoscopic variceal band ligation.

Dr Merriman: This recommendation stems from the common practice of attempting to correct coagulopathies often present in patients with cirrhosis such as an elevated international normalized ratio (INR) or thrombocytopenia for procedures such as paracentesis or endoscopic variceal band ligation. Recently, it has been acknowledged that these routine tests of coagulation do not accurately reflect the bleeding risk in patients with cirrhosis. Indeed, bleeding complications associated with these procedures are very rare. So we strongly encourage patients to discuss with their physicians whether routine transfusion of FFP and/or platelets in patients with an elevated INR or thrombocytopenia is indicated for these procedures. This recommendation has the potential to reduce the unnecessary transfusion of finite and costly blood product resources.

Medscape: Is the AASLD planning to add any further recommendations beyond these first "five things"?

Dr Merriman: The AASLD, in both its stewardship and leadership capacity, would definitely be enthusiastic about adding to this first "five things" list. This, in part, also reflects the transformational changes occurring in therapeutics for such very common liver diseases as hepatitis C and nonalcoholic fatty liver disease. Those changes bring about the possibility of further optimizing the delivery of healthcare in a manner that is responsible from both the patient and the societal perspective.

Medscape: How do you see these recommendations affecting both clinicians and patients?

Dr Merriman: These recommendations really address two audiences: patients and physicians. It prompts both parties to discuss testing and treatment and to make informed and prudent decisions about the most appropriate care based upon the patient's individual clinical condition. So, in many ways, it spurs a discussion about what is clinically and medically appropriate and necessary. Conversations about the overuse of medical tests or about procedures that have little benefit (and in some cases may be harmful) are very relevant to both parties.

The Choosing Wisely campaign is an educational process and has the potential to revise and reshape both patient expectations and physician practice patterns in a beneficial way.

Finally, the broad acceptance of the Choosing Wisely campaign and the AASLD list reflects and reinforces the belief that the AASLD and physicians are responsible leaders in healthcare reform.

Medscape: Since this list was released, have you seen a change in clinical practice, or is it too soon to tell?

Dr Merriman: While formal data are not available, the positive response from patients and colleagues has been highly encouraging. I have witnessed the Choosing Wisely list posted prominently in clinics and have personally referred to it when patients have questions about topics addressed. Just last week, for example, a patient who had hepatitis C but who is not going to be treated any time soon wanted a viral load checked. I was able to point to the recommendation on the Choosing Wisely list. That initiated a conversation ultimately recommending against such testing, based upon the Choosing Wisely data and emanating from a credible and responsible organization. In that way, this list can evolve into a powerful tool in educating patients about good healthcare practices.

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