Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1
ABSTRACT An interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.
In this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.
Among previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.
In this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.).
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- "Combination of the ritonavir-boosted NS3/4A protease inhibitor ABT-450/r and the NS5A inhibitor ombitasvir (formerly ABT- 267) was first investigated in the AVIATOR study . This phase 2b open-label trial enrolled non-cirrhotic HCV genotype (GT) 1-infected patients who were either treatment-naïve or nullresponders to prior therapy with PegIFN and RBV. "
ABSTRACT: The establishment of robust HCV cell culture systems and characterization of the viral life cycle provided the molecular basis for highly innovative, successful years in HCV drug development. With the identification of direct-acting antiviral agents (DAAs), such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleotide and non-nucleoside polymerase inhibitors, as well as host cell targeting agents, novel therapeutic strategies were established and competitively entered clinical testing. The first-in-class NS3/4A protease inhibitors telaprevir and boceprevir, approved in 2011, were recently outpaced by the pan-genotypic nucleotide polymerase inhibitor sofosbuvir that in combination with pegylated interferon and ribavirin, further shortens therapy durations and also offers the first interferon-free HCV treatment option. In the challenging race towards the goal of interferon-free HCV therapies, however, several oral DAA regimens without nucleotide polymerase inhibitors that combine a NS3/4A protease inhibitor, a NS5A inhibitor and/or a non-nucleoside polymerase inhibitor yielded competitive results. Second generation NS3/4A protease and NS5A inhibitors promise an improved genotypic coverage and a high resistance barrier. Results of novel DAA combination therapies without the backbone of a nucleotide polymerase inhibitor, as well as treatment strategies involving host targeting agents are reviewed herein.Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.08.014 · 10.40 Impact Factor
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- "Importantly, Lok and co-workers evaluated the interferon-free combination of daclatasvir plus asunaprevir (NS3 protease inhibitor) in patients with HCV genotype 1 who had failed prior peginterferon/ribavirin therapy, providing the first evidence that chronic HCV infection could be eradicated without interferon . Subsequently, NS5A inhibitors have emerged as critical components of several oral HCV DAA regimens which have completed phase 3 clinical development and are expected to be approved for clinical use        . "
ABSTRACT: Due to shared routes of transmission, acute and chronic infection with hepatitis C virus is common among persons living with HIV infection in many regions of the world. In the era of effective antiretroviral therapy, acute HCV infection has been increasingly recognized in HIV-infected persons, particularly men who have sex with men, and liver disease, including hepatocellular carcinoma, has emerged as a leading cause of morbidity and mortality in those with chronic HCV infection, particularly older adults with long-standing coinfection. Over the past decade, the foundation for the management of acute and chronic HCV infection has been interferon alfa. However, due the high burden of treatment-related side effects and low likelihood of sustained virologic response, the impact of treatment with peginterferon/ribavirin on the burden of HCV disease in has been limited. However, the anticipated availability of safe, tolerable and highly efficacious interferon-free, oral HCV direct-acting antiviral combination therapies promise to dramatically change the management of acute and chronic HCV infection in HIV-infected persons. Preliminary data from studies of such oral DAA regimens in HIV/HCV coinfected patients suggest that coinfection with HIV will not impair HCV cure with these regimens. Indeed, in the coming era of high effective oral HCV DAA treatments, the only special feature concerning treatment of acute and chronic HCV infection in HIV-infected patients may be drug interactions between the antiretroviral drugs for HIV infection and direct-acting antiviral drugs for HCV infection.Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.08.006 · 10.40 Impact Factor
Arab Journal of Gastroenterology 06/2014; 15(2). DOI:10.1016/j.ajg.2014.04.003
- "SOF- SMV combination in the COSMOS trial resulted in >92% SVR rates in patients with low fibrosis, and close to 100% SVR in patients with advanced fibrosis/cirrhosis . An all-oral combination of the protease inhibitor ritonavir boosted ABT-450, the NS5A inhibitor ABT 333, and the NNI-NS5B inhibitor ABT-267 for 12 weeks in the phase III SAPPHIRE trial resulting in 96% SVR rates in HCV-G1 treatment naïve and experienced patients  . Similarly, an all-oral combination of SOF and DCV resulted in close to 100% SVR rate in treatment naïve and experienced patients , and a triple combination of DCV with asunaprevir and the NNI BMS- 791325 resulted in SVR rates in excess of 98% in HCV-G1a and HCV-G1b naïve and treatment experienced patients . "