April 14, 2015

logo-reutersprofessional

By Will Boggs MD

April 13, 2015

NEW YORK (Reuters Health) - An all-oral, interferon-free regimen consisting of ombitasvir, paritaprevir and ritonavir is effective at treating patients with genotype-4 chronic hepatitis C virus (HCV), according to a new report from AbbVie.

Although HCV genotype 4 accounts for only 13% of all HCV infections, it is responsible for more than 90% of HCV infections in Egypt, Dr. Christophe Hézode from Université Paris-Est, Créteil, France, and colleagues write in The Lancet, online March 31.

There are limited data on the effects of direct-acting antiviral drugs in patients with HCV genotype-4 infection, they add.

In the PEARL-I open-label trial, 86 treatment-naïve patients with genotype-4 HCV without cirrhosis were randomly assigned to receive the three-drug combination regimen with or without ribavirin; in addition, 49 treatment-experienced patients were put on the combination treatment with ribavirin.

Sustained virological response rates at 12 weeks were 100% for treatment-naïve patients in the ribavirin-containing regimen, 90.9% for treatment-naïve patients in the ribavirin-free regimen, and 100% for treatment-experienced patients.

There were no relapses between post-treatment week 12 and post-treatment week 24, according to the report.

Three treatment-naïve patients -- all subtype 4b, all with resistance-associated variants present at the time of failure, and all treated without ribavirin -- had virological failure.

The most common treatment-emergent adverse events were headache, asthenia, insomnia and nausea.

"Although no difference between the ribavirin-containing and ribavirin-free regimens was noted, the 100% SVR12 rate recorded with the ribavirin-containing regimen in treatment-naïve and treatment-experienced patients suggests that this multitargeted regimen provides the highest certainty of achieving sustained virological response in patients infected with diverse HCV genotype 4 subtypes," the researchers conclude.

Dr. Heiner Wedemeyer from Hannover Medical School in Germany, who wrote a commentary related to the report, told Reuters Health by email that there is no role for interferon in treating HCV infection outside of resource-limited settings.

According to his commentary, "all new direct-acting antivirals have been approved by the European Medicines Agency (EMA) and the US Food and Drug Administration for treatment of HCV genotype 1 infection, whereas only sofosbuvir and daclatasvir can theoretically be used for all seven HCV genotypes, frequently in the absence of clinical trial data."

Dr. Wedemeyer added to Reuters Health that the regimen in the PEARL-I study "will be one of the possible treatment options. There are also other options (ledipasvir/sofosbuvir or daclatasvir/sofosbuvir; theoretically simeprevir/sofosbuvir)."

Dr. Imam Waked from National Liver Institute in Shebeen El-Kom, Egypt, told Reuters Health, "This study was on non-cirrhotic patients, and efficacy in cirrhotic patients with genotype 4 infection (both treatment-naïve and -experienced) is still not known. An ongoing trial in Egypt will answer this question (it includes patients with cirrhosis, both treatment-naïve and previous treatment failures). The better response in the ribavirin containing arms will not allow this to become a ribavirin-free regimen."

"There is no longer any role for interferon in treating HCV infection," Dr. Waked agreed with Dr. Wedemeyer. "Only where new treatments are not available should interferon-based treatment be used."

"Access programs by Gilead and Johnson & Johnson have made their similar medications (sofosbuvir and simeprevir) available for Egypt to treat patients, and currently 40,000 patients have started treatment on the account of the Ministry of Health (100% state-covered)," Dr. Waked added.

Dr. Hézode, who has been a speaker and a consultant for AbbVie, the trial's sponsor, did not respond to a request for comments. AbbVie employed a number of his co-authors and also paid for writing assistance in preparing the report.

SOURCE: http://bit.ly/1Egp2QP and http://bit.ly/1FHRf1D

Lancet 2015.

Source

Lancet. 2015 Mar 21;385(9973):1107-13. doi: 10.1016/S0140-6736(14)61228-9. Epub 2015 Jan 13

Kohli A1, Osinusi A2, Sims Z3, Nelson A4, Meissner EG4, Barrett LL5, Bon D6, Marti MM4, Silk R7, Kotb C7, Gross C7, Jolley TA4, Sidharthan S3, Petersen T3, Townsend K4, Egerson D7, Kapoor R7, Spurlin E4, Sneller M4, Proschan M8, Herrmann E6, Kwan R4, Teferi G9, Talwani R10, Diaz G11, Kleiner DE12, Wood BJ13, Chavez J9, Abbott S9, Symonds WT14, Subramanian GM14, Pang PS14, McHutchison J14, Polis MA4, Fauci AS4, Masur H3, Kottilil S15.

Abstract

BACKGROUND: Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration.

METHODS: In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882.

FINDINGS: Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs.

INTERPRETATION: In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis.

FUNDING:

National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Comment in

Shorter treatments for hepatitis C: another step forward? [Lancet. 2015]

PMID: 25591505 [PubMed - indexed for MEDLINE]

Source