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Drugs in Development / Clinical Trials—Updated March 17, 2015

Saturday, April 25, 2015

EASL 2015: ALLY-1 Trial Results Show Investigational Daclatasvir-Based Regimen Cures 94% of Post-Liver Transplant Patients with Hepatitis C and Up to 94% of Hepatitis C Patients with Cirrhosis (Child-Pugh Class A or B)

  • 97% of post-transplant patients with HCV genotype 1a achieved cure
  • 91% of post-transplant patients with HCV genotype 3 achieved cure  
  • No need seen to alter existing transplantation medication regimens
 
Saturday, April 25, 2015 10:00 am EDT

(PRINCETON, N.J., APRIL 25, 2015)Bristol-Myers Squibb Company (NYSE:BMY) today announced that primary endpoints were successfully met in ALLY-1, a Phase III clinical trial evaluating a 12-week regimen of daclatasvir and sofosbuvir once-daily with ribavirin for the treatment of patients with chronic hepatitis C virus (HCV) with either advanced cirrhosis or post-liver transplant recurrence of HCV. The data was presented as a late-breaker at The International Liver Congress™ 2015, the 50th annual meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria from April 22-26.

“The results of the ALLY-1 trial point to the potential of this investigational daclatasvir-based regimen in a patient population with high unmet needs despite recent advances in hepatitis C treatment,” said Fred Poordad, M.D., ALLY-1 Lead Investigator and Clinical Professor of Medicine, Chief, Hepatology, University of Texas Health Science Center and VP, Academic and Clinical Affairs Texas Liver Institute. “Transplant patients take a variety of immunosuppressive medications to prevent organ rejection; that complicates the treatment of hepatitis C. In ALLY-1, we saw no drug-drug interactions between transplant and hepatitis C therapies and no need to make dose adjustments to patients’ transplant-related drugs while they received the daclatasvir-based regimen that resulted in high SVR12 rates.”

The study’s primary endpoints were reached, with 95% of post-transplant genotype 1 patients and 82% of genotype 1 patients with advanced cirrhosis achieving SVR12. Among all ALLY-1 patients, 94% of those with post-transplant HCV recurrence and 83% of all participants with advanced cirrhosis achieved cure (sustained virologic response 12 weeks after treatment; SVR12).

The Child-Pugh scoring system is commonly used to assess the severity and prognosis of chronic liver disease and cirrhosis, and uses an A through C classification (C being the most advanced) to categorize disease progression. Patients with class C cirrhosis are decompensated, often with later-stage conditions such as ascites (the build-up of fluid in the abdomen), hepatic encephalopathy (confusion or altered level of consciousness due to the liver’s inability to remove toxins from the blood), and abnormal liver function, which can complicate treatment. The ALLY-1 trial included 16 patients with decompensated cirrhosis Child-Pugh class C; nine (56%) achieved SVR12.
Over the course of the study, four advanced cirrhotic patients received a liver transplant during treatment; 3 of 4 extended treatment post-transplant (see study design below), and all 4 achieved SVR12.

In the study, there were no serious adverse events related to study medications throughout the treatment phase. The most common adverse events (≥10%) were headache (15%, 36%), fatigue (18%, 28%), anemia (20%, 19%), diarrhea (8%, 19%), nausea (17%, 6%), and arthralgia (2%, 13%) in the advanced cirrhotic and post-transplant cohorts, respectively. One patient discontinued therapy after 31 days due to headache, but still achieved SVR12. Nine patients in the cirrhosis cohort relapsed post-treatment, and one had detectable HCV RNA at the end of treatment; there were no on-treatment virologic breakthroughs. Three patients (genotypes 1a, 1b, 3) in the post-transplantation cohort relapsed. All 12 patients with relapse are being retreated with daclatasvir and sofosbuvir with ribavirin for 24 weeks.

 HCV is the leading indication for liver transplantation worldwide. Without treatment, HCV infection of the new liver after transplant is inevitable, and is associated with rapid progression to cirrhosis and death in up to 30% of patients within 5 years. The ALLY-1 study is the third study to report out of the Phase III ALLY program, which evaluates daclatasvir in combination with sofosbuvir in multiple high-unmet need patient populations and is at the center of Bristol-Myers Squibb’s HCV research focus. The ALLY-2 and ALLY-3 studies have previously been presented at the 2015 Conference for Retroviral and Opportunistic Infections and the 2014 American Association for the Study of the Liver’s The Liver Meeting, respectively, and subanalyses from each study with the ribavirin-free regimen of daclatasvir and sofosbuvir were presented as posters during EASL 2015.

Additionally, EASL issued 2015 Hepatitis C treatment guidelines that include a regimen of daclatasvir+sofosbuvir as the first 12-week treatment for patients with genotype-3 virus. The EASL guidelines now list daclatasvir+sofosbuvir regimens as options for treating all HCV genotypes and for use with patients coinfected with HCV/HIV. (Guidelines available here.)

Other Bristol-Myers Squibb presentations at The International Liver Congress included data from compassionate use programs in the EU that add to the real-world clinical evidence informing the use of daclatasvir-based regimens to treat patients with HCV conditions posing high unmet medical needs.

“The ALLY-1 trial results build off the ALLY-2 and ALLY-3 studies by demonstrating the versatility of the daclatasvir-based regimen to provide HCV cure in multiple patient populations that have been historically hard to manage, such as HCV genotype 3 patients, HIV/HCV coinfected patients, and patients with decompensated cirrhosis,” said Douglas Manion, M.D., Head of Specialty Development, Bristol-Myers Squibb. “Post-liver transplant and cirrhotic patients represent a still-unmet need and continue to present challenges to currently available regimens.”

About ALLY-1: Study Design
This Phase III open-label clinical trial enrolled treatment-naïve and treatment-experienced patients with HCV infection of any genotype in 2 cohorts: advanced cirrhosis (n=60) and post-liver transplant with HCV recurrence (n=53). All patients received daclatasvir 60 mg plus sofosbuvir 400 mg once-daily with ribavirin initially dosed at 600 mg/d (with potential for adjustment based on hemoglobin levels and creatinine clearance) for 12 weeks. Patients receiving a variety of immunosuppressive agents were permitted. In the cirrhosis cohort, patients transplanted during treatment could receive 12 weeks of extended treatment immediately post-transplant, regardless of treatment duration before transplant. The primary endpoint was the SVR12 rate (defined as HCV RNA <LLOQ (25 IU/mL) at post-treatment week 12) among genotype 1 patients in each cohort.

Read complete press release here....

EASL 2015: Statin use in HCV patients may lower risk of death, decompensation

VIENNA — Statin use in patients with hepatitis C virus and compensated cirrhosis seems to offer a protective effect against death and decompensation, according to a study presented at the 2015 International Liver Congress.

 “In compensated HCV cirrhosis, statin users have a significantly lower incidence of decompensation and better overall survival compared to statin non-users,” Arpan Mohanty, MD, from Yale School of Medicine, New Haven, Conn., said during her presentation. “Risk of decompensation and death was reduced by over 40%.”

In this retrospective cohort study, Mohanty and colleagues used the U.S. Department of Veterans HCV Clinical Case Registry, and by doing so, she said all patients would have had an equal opportunity to receive statins. 

EASL 2015: Use of direct-antiviral agents helps overcome hepatitis C recurrence in liver transplant patients

New data presented today at The International Liver Congress 2015, supports the use of sofosbuvir (SOF)- and daclatasvir (DCV)-based regimens in patients with recurrence of the hepatitis C virus (HCV) following liver transplantation (LT). The results are based on data from patients with HCV being treated with second-generation DAAs in the large French prospective ANRS CO23 CUPILT study. Among them, 296 patients were treated with a combination of SOF+DCV, with or without ribavirin.

SOF- and DCV-based regimens offered high rates of sustained virologic response (SVR) coupled with good tolerance. The presented results focus on 130 patients who achieved SVR12; end of treatment therapy and SVR12 rates are 98% and 96%, respectively.

"The use of interferon-free regimens using DAAs has dramatically improved the management of liver transplant patients infected with HCV. The outstanding efficacy and safety results that sofosbuvir- and daclatasvir-based regimens demonstrated in patients with recurrent hepatitis C are impressive and will help us identify optimal treatment strategies using these new therapies," said Audrey Coilly, MD, Paul Brousse Hospital, Villejuif.

Read more....

EASL 2015: Hepatitis C screening essential to help catch patients with advanced liver fibrosis

Research validates the current recommendation that screening for hepatitis C, particularly among high-risk groups, is vital.

April 25, 2015, Vienna, Austria: Study results presented today at The International Liver Congress™ 2015 show that the occurrence of advanced liver fibrosis is similar for patients infected with the hepatitis C virus (HCV), whether or not they have been diagnosed.

Most individuals with HCV remain asymptomatic, which makes the diagnosis difficult. The study authors used the hypothesis that individuals whose HCV is not diagnosed are less likely to have advanced fibrosis than those who have been diagnosed. They then compared liver fibrosis between respondents of the National Health and Nutrition Examination Survey (NHANES) in the USA, in patients with diagnosed and undiagnosed HCV infection.

Of the respondents with known HCV infection, the proportion with a high, intermediate and low probability of advanced fibrosis was 14.5%, 40.3%, 45.2%, respectively; in those with undiagnosed HCV the results were 19.1%, 30.9%, 50.0%, respectively.

The study highlights that even if people are unaware they are infected with HCV, the virus affects their liver in the same way, resulting in advanced fibrosis. These results validate the current recommendation that screening for HCV, particularly among high-risk groups, is vital.

Read complete press release here....

EASL 2015: Cancer rates among patients with hepatitis C are increased compared to those not infected

New results show that cancer rates in patients with the hepatitis C virus (HCV) were significantly increased compared to the non-HCV cohort. The researchers suggest an extrahepatic manifestation of HCV may be an increased risk of cancer. 

Results recently announced at The International Liver CongressTM 2015 show that cancer rates in patients with the hepatitis C virus (HCV) were significantly increased compared to the non-HCV cohort. The researchers suggest an extrahepatic manifestation of HCV may be an increased risk of cancer. When all cancers are considered the rate is 2.5 times higher in the HCV cohort; when liver cancers are excluded, the rate is still almost 2 times higher.

The aim of the study was to describe the rates of all cancers in the cohort of HCV patients compared to the non-HCV population. Known cancer types associated with hepatitis C include non-Hodgkin's lymphoma, renal and prostate cancers, as well as liver cancer.

A retrospective study at Kaiser Permanente, Southern California, USA, was conducted. The study authors recorded all cancer diagnoses in patients over 18 years of age with or without HCV during 2008-2012. Within the timeframe of the study 145,210 patient years were included in the HCV cohort, and 13,948,826 patient years were included in the non-HCV cohort.

Read more...

Friday, April 24, 2015

India: Mylan Pharmaceuticals launches generic hepatitis C drug MyHep in India

NEW DELHI: Drugmaker Mylan Pharmaceuticals today launched generic Sofosbuvir tablets, indicated for the treatment of chronic hepatitis C, in the country.

US-based company's Indian arm Mylan NV has launched generic Sofosbuvir tablets in strength of 400 mg under the name MyHep in the country, it said in a statement.

"The launch of Mylan's MyHep offers hope to millions of hepatitis C patients in India who are in need of a high quality, effective and affordable treatment option." 

Cape Cod Hepatitis C rates highest in state among young people

Users of heroin and other intravenous drugs face dangers beyond addiction, prison, and overdose. Deadly blood-borne diseases, transmitted through shared needles, are rampant among IV drug users.

For the past several years, Barnstable County has led Massachusetts in the rate of new infections of Hepatitis C among people aged 15 to 25. An especially dangerous virus that attacks its host’s liver, often resulting in cirrhosis or cancer, Hepatitis C infected 344.3 of every 100,000 residents of Barnstable County in 2012, the latest year for which figures are available. The incidence rate for Plymouth, the second leading county, was 194.57.

Read more...