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.).
- SourceAvailable from: Alexandra Alexopoulou[Show abstract] [Hide abstract]
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.Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology. 01/2015; 28(1):55-65.
- [Show abstract] [Hide abstract]
ABSTRACT: Hepatitis C virus (HCV) infection results in a chronic carrier state in 80% of individuals infected with the virus and presently affects over 170 million people worldwide. Approximately 20% of those chronically infected will ultimately progress to develop cirrhosis and death due to end-stage liver disease or hepatocellular carcinoma (HCC). Unlike many other chronic viral infections, effective treatments for HCV are available. Cure from the infection is known as a sustained virologic response (SVR). SVR is associated with reversal of the long-term outcomes of chronic liver disease, decrease in incidence of HCC, and decrease HCV attributable mortality. The current FDA approved therapies for hepatitis C virus genotype 1 (GT-1) include pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with a directly acting antiviral agent (DAA). New therapeutic advances are being made aiming to simplify management, improve the tolerability of treatment, and shorten the duration of therapy. Moreover, treatment regimens that will effectively eradicate hepatitis C without the use of interferon formulations (IFN) are being developed. In this review, we report the transition of HCV therapeutics from an interferon-α based combination therapy to an all-oral, directly acting antiviral therapy.Therapeutic advances in chronic disease. 01/2015; 6(1):4-14.
- [Show abstract] [Hide abstract]
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.11/2014; 25(6):311-20.