Gilead's Harvoni and Sovaldi Demonstrate Efficacy/Safety with Advanced Liver Disease
-- High Cure Rates in More Than 600 Genotype 1 and 4 Patients With Limited or No Approved Treatment Options --
VIENNA, Austria--(BUSINESS WIRE)--Apr. 23, 2015-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from several Phase 2 clinical studies evaluating investigational uses of Harvoni® (ledipasvir 90 mg/sofosbuvir 400 mg) and other Sovaldi® (sofosbuvir 400 mg)-based regimens for the treatment of chronic hepatitis C virus (HCV) infection in patients with advanced liver disease, including patients with decompensated cirrhosis, patients with fibrosing cholestatic hepatitis C (a rare and severe form of the disease following liver transplantation) and patients with portal hypertension. These data will be presented this week at the 50th Annual Meeting of the European Association for the Study of the Liver (The International Liver Congress™ 2015) in Vienna, Austria.
Using Ledipasvir/Sofosbuvir in Cirrhotic, Treatment-Experienced GT1 Patients: 12 Weeks With Ribavirin or 24 Weeks Without?
Ira M. Jacobson, MD - 3/23/2015 More from this author
The recently updated AASLD/IDSA HCV management guidancerecommends the following regimens for treatment-experienced patients with genotype 1 HCV infection who have compensated cirrhosis and who experienced previous treatment failure with peginterferon and ribavirin:
Ledipasvir/sofosbuvir for 24 weeks (rating: class I, level A)
Ledipasvir/sofosbuvir plus ribavirin for 12 weeks (rating: class I, level B)
Ombitasvir/paritaprevir/ritonavir plus dasabuvir and ribavirin for 12 weeks if genotype 1b HCV and for 24 weeks if genotype 1a HCV (rating: class I, level A)
Sofosbuvir plus simeprevir with or without ribavirin for 24 weeks (rating: class IIa, level B)
In this ClinicalThought commentary, I focus on considerations for the use of ledipasvir/sofosbuvir in treatment-experienced patients with genotype 1 HCV infection and cirrhosis. In an upcoming commentary, Paul Y. Kwo, MD, will have a discussion about the use of ombitasvir/paritaprevir/ritonavir and dasabuvir in this setting....
Infectious Disease Special Edition
ISSUE: MARCH 2015 | VOLUME:
Hepatitis C - Recent Clinical Data
IDSE Staff Reports
The patient with a hard-to-treat hepatitis C infection is becoming harder to find. The fixed-dose combination of ledipasvir and sofosbuvir (Harvoni, Gilead) is effective in patients with the hepatitis C virus (HCV) who until now have been considered difficult to treat, according to new data presented at the 2014 Liver Meeting of the American Association for the Study of Liver Diseases.
One study demonstrated that 12 weeks of the fixed-dose combination plus ribavirin cured patients with decompensated cirrhosis of their HCV infection. Two other studies showed that the drug was effective in patients—including those with cirrhosis—who previously failed protease inhibitor triple therapy.
The FDA approved Harvoni in October 2014 for use in difficult-to-treat patients: a 12-week course in treatment-naive patients with or without cirrhosis, 12 weeks for treatment-experienced patients without cirrhosis, and 24 weeks for treatment-experienced patients with cirrhosis. However, the new trials are the first to test the drug in large numbers of these subpopulations.
Michael Fried, MD, the director of the University of North Carolina Liver Center, in Chapel Hill, called the results notable. “The SVR [sustained virologic response] rates demonstrate that these drugs are very effective, even in this very sick population,” Dr. Fried said.
Dr. Fried pointed out that in patients with decompensated cirrhosis, antiviral treatment was capable of improving clinical status. “Patients, including those with cirrhosis who previously failed protease inhibitor–based or sofosbuvir-based therapy, can be rescued with some of the drugs that we currently have available,” he said.
SOLAR-1Steven Flamm, MD, professor of medicine and surgery, and chief of the Liver Transplantation Program at Northwestern University, in Chicago, presented preliminary results of the prospective, multicenter SOLAR-1 trial (abstract 239). Investigators randomized patients with genotype 1 or 4 hepatitis C and decompensated cirrhosis to ledipasvir-sofosbuvir plus ribavirin for 12 (n=52) or 24 weeks (n=47). Patients had decompensated cirrhosis with Child-Pugh class B or C, determined by liver function biomarkers and symptoms. Most patients had a Model for End-Stage Liver Disease (MELD) score greater than 10. Roughly 15% of Child-Pugh class B patients and 40% of class C patients had MELD scores between 16 and 20.
In the Child-Pugh class B cohort, 60% had a history of ascites and 60% had hepatic encephalopathy. In the class C cohort, nearly all patients had a history of ascites, and 90% had hepatic encephalopathy. The investigators excluded liver transplant recipients, as well as individuals with very high MELD scores or bilirubin, extremely low platelet counts (below 30,000), serious kidney dysfunction or hepatocellular carcinoma.
Three patients discontinued treatment early because of adverse events (AEs), and 4 serious AEs were considered to be related to treatment. The SVR rate at week 12 (SVR12) was 87% in patients who received 12 weeks of treatment and 89% in patients who received 24 weeks of treatment. Response rates were similar in Child-Pugh class B and C patients.
Most individuals had an improvement in their Child-Pugh scores, with 10 having no change and only 4 having higher (worse) scores. Most patients also had improvements in their MELD scores. Dr. Flamm said the regimen “resulted in a high SVR12 rate in HCV patients with genotype 1 and 4 and advanced liver disease.”
In a second study presented at the meeting, researchers provided 12 weeks of ledipasvir-sofosbuvir plus ribavirin to 51 patients with HCV genotype 1 who had failed previous sofosbuvir-based regimens (abstract 235). Roughly 29% had cirrhosis, 59% had genotype 1a, and 12% had NS5A resistance-associated amino acid variants (RAVs) at baseline. High rates of SVR12 were seen in all patients, those who had received prior treatment with peginterferon-ribavirin-sofosbuvir (100%), sofosbuvir-ribavirin (95%), and peginterferon-ribavirin (100%). (The lone failure turned out to be a patient who was incorrectly genotyped and in fact had genotype 3 infection, according to the researchers.)
A third trial enrolled cirrhotic patients with HCV genotype 1 who had failed protease inhibitor–based triple therapy (abstract LBA6). The double-blind randomized trial involved a placebo design in which patients received either 12 weeks of placebo plus 12 weeks of fixed-dose ledipasvir-sofosbuvir plus ribavirin (n=77) or 24 weeks of ledipasvir-sofosbuvir plus placebo (n=78). Patients were included if they had not achieved an SVR after sequential peginterferon-ribavirin treatment and triple therapy (protease inhibitor plus peginterferon and ribavirin).
Approximately 18% of patients had platelet counts less than 100,000/mcL and 13% had serum albumin less than 3.5 g/dL. The average MELD score was 7. Roughly 73% had baseline NS3/4A RAVs. SVR12 rates were 96% in patients who received ledipasvir-sofosbuvir plus ribavirin for 12 weeks and 97% in patients who received the 24-week treatment.
“There was no difference in SVR12 rates among patients with or without NS3/4A RAVs at baseline,” said Marc Bourlière, MD, head of the Hepato-Gastroenterology Department at Hospital Saint-Joseph in Marseilles, France, who presented the study. Pretreatment frequencies of these RAVS have been determinants of treatment outcomes with other drugs. Ledipasvir-sofosbuvir with or without ribavirin was safe and well tolerated, with most AEs being mild or moderate in severity, Dr. Bourlière said.
Dr. Fried added that future research should examine how the new medications affect transplantation rates in the long term.
Dr. Fried has received grant/research support from and consulted for Gilead. Dr. Bourlière is on the medical advisory board of Gilead. Dr. Flamm has received research support from Gilead and is also on the company’s speakers’ bureau.
Prognostic Index May Identify HCV Patients At Risk for Deterioration
A new prognostic index shows that patients with cirrhosis related to hepatitis C virus (HCV) infection are 7 times more likely to experience hepatic decompensation, and 6 times more likely to die of liver-related illness, if they have a constellation of genetic and clinical indicators that put them at high risk for poor outcomes.
The prognostic index is composed of a 186-gene signature and several clinical measures. It was developed specifically to identify HCV patients with cirrhosis who are at high risk for disease progression. The index has several potential applications, such as stratifying patients in clinical trials and identifying those most in need of treatment with the newest—and most expensive—therapies for the infection, researchers said. It also is relevant for treated patients with liver damage even after achieving a sustained virologic response (SVR).
In addition to the highly significant prognostic accuracy for decompensation and death from liver-related causes (P<0.001 for both), patients who met the index criteria had a more than 3-fold increased risk for death from any cause (P=0.002) compared with those who did not, according to a collaboration that included investigators from the Liver Center at Massachusetts General Hospital (MGH), in Boston, and the Icahn School of Medicine at Mount Sinai Hospital, in New York City. The results of the multicenter validation study were published in a recent issue of Gut (King et al. 2014 August 20. [Epub ahead of print]).
The 186-gene signature in the tool was derived from a previously validated, genome-wide profiling study. It was coupled with other clinical factors, including an elevated bilirubin (>1 mg/dL) and a suppressed platelet count (<100,000/mm3). The index was first tested using tissue samples and clinical data in a training cohort of 216 HCV patients in Italy, for whom there was a median 10-year follow-up period. The index was then assessed in a validation cohort, which consisted of 145 patients with HCV infection in the United States, who had been followed for a median of 8 years.
The prognostic index demonstrated similar performance in the 2 tested populations. In the validation cohort, for example, hazard ratios (HRs) for patients who met criteria for high risk, compared with those having intermediate or low risk, were 7.36 for hepatic decompensation, 6.49 for liver-related death, 4.98 for liver-related adverse events, and 3.57 for all-cause mortality. All HRs were statistically significant, according to the researchers.
As assessed with the index, 16% of the validation cohort was identified as being at high risk, with the remainder evenly divided between intermediate and low risk.
The researchers, led by Lindsay Y. King, MD, of MGH, and Yujin Hoshida, MD, PhD, of Mount Sinai Hospital, characterized the prognostic index as “readily available for clinical use.” Dr. Hoshida said. that efforts to develop a commercially viable version of the index are now underway.
The data are encouraging because there is a major unmet need for better methods of predicting outcomes, said Thomas Baumert, MD, a hepatologist and professor of medicine at the University of Strasbourg, in France. Dr. Baumert noted that although the development of highly effective antiviral regimens has increased opportunities for eradication of HCV, he said patients with advanced liver disease remain at risk for liver failure even after HCV has been eradicated.
“Treatment-induced viral cure reduces, but does not eliminate, the risk for disease progression and development of liver cancer in patients with cirrhosis,” Dr. Baumert said in an interview. “Furthermore, in settings with limited resources, better tools for prognosis may identify those HCV patients most in need of the effective, but very expensive, antiviral regimens that have become available.”
Drs. King, Hoshida and Baumert reported no relevant financial conflicts of interest.
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Hepatitis C: Recent Clinical Data