Preliminary study of two antiviral agents for hepatitis C genotype 1.
ABSTRACT Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.
This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log(10) decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.
A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.
This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).
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ABSTRACT: Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Management of HIV-HCV coinfection is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens. To update national standards for the management of HCV-HIV coinfected adults in the Canadian context. A standing working group with specific clinical expertise in HIV-HCV coinfection was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published data regarding HCV antiviral treatments and to update the Canadian HIV-HCV coinfection guidelines. Recent data suggest that the gap in sustained virological response rates between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All HIV-HCV coinfected individuals should be assessed for HCV therapy. First-line treatment for genotypes 1 through 6 includes pegylated interferon and weight-based ribavirin dosing plus the nucleotide sofosbuvir for 12 weeks. Sofosbuvir in combination with the protease inhibitor simeprevir is another first-line consideration for genotype 1 infection. Sofosbuvir with ribavirin for 12 weeks (genotype 2) and 24 weeks (genotype 3) is also recommended as first-line treatment. Recommendations may not supersede individual clinical judgement.The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale / AMMI Canada 11/2014; 25(6):311-20. · 0.49 Impact Factor
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ABSTRACT: The development of protease inhibitors (PIs) such as telaprevir and boceprevir constitutes a milestone in chronic hepatitis C antiviral treatment since it has achieved sustained virological response (SVR) rates of up to 75% in naïve and 29-88% in treatment-experienced patients with genotype 1 infection. Both require combination treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) as PI monotherapy results in resistant mutations. New direct acting antiviral agents (DAAs) have recently been approved or their approval is imminent. Simeprevir administered orally as one pill per day in combination with PEG-IFN/RBV will be the next PI to be approved. The SVR rates at about 72-80% for treatment-naïve patients are not a major improvement over telaprevir or boceprevir. However, this treble combination has fewer side effects and drug-drug interactions and most patients undergo shorter treatment duration (24 months) due to earlier treatment responses. Sofosbuvir is the first available once-daily NS5B polymerase inhibitor which has been approved in combination with PEG-IFN/RBV for just 12 weeks with 89% SVR in treatment-naïve patients with genotype 1 infection and 83-100% in treatment-experienced patients with genotypes 2/3. The current review focuses on the recent rapid and continuous developments in the management of chronic HCV infection with DAAs in combination with PEG-IFN/RBV.
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ABSTRACT: IntroductionIn recent years, the landscape of hepatitis C virus (HCV) therapy has fundamentally changed. The first wave of direct-acting antivirals (DAAs)—the protease inhibitors telaprevir and boceprevir—was approved in 2011 and has improved the rate of cure compared with the prior long-standing standard of care, interferon and ribavirin. However, the safety and efficacy of these agents in the community setting have been associated with increased rates of toxicity and lower efficacy than originally described in pivotal trials. Other limitations of the first-wave protease inhibitors include potential drug-drug interactions, contraindications to use, and lower response rates in those with cirrhosis and advanced liver disease. The second wave of DAAs has now been approved for clinical use, and there is substantial enthusiasm for these new agents given their expected improved tolerability and efficacy across the spectrum of HCV-infected patients. The development of direct-acting antiviral ...Hepatology International 07/2014; 8(3):352-364. DOI:10.1007/s12072-014-9552-6 · 2.47 Impact Factor