When education-related information on hepatitis C becomes available this blog provides readers with background information and links to the new activity.On January 9th Clinical Care Options released an expert analysis evaluating clinical studies of approved and investigational hepatitis C treatments presented at the 2012 AASLD meeting. The investigational agents include; GS-5885, ABT-450/r, ABT-333-non- nucleoside, and Daclatasvir/Asunaprevir/BMS-791325. I have provided a quick highlight of each topic below.
*In this expert analysis Jordan J. Feld, MD, MPH, David R. Nelson, MD, and Stefan Zeuzem, MD, provide an in-depth review of the most important new data on viral hepatitis.
Although, like any site offering continuing medical education (CME), it requires a free quick registration, click here to register or here to view the Expert Analysis
Updates in Viral Hepatitis from AASLD 2012
Topics
RBV Dose Reduction for Anemia
At the 2012 American Association for the Study of Liver Diseases (AASLD) meeting, studies of both current and investigational hepatitis C virus (HCV) agents were a major focus of the meeting. One such study evaluated the optimal management of anemia during PI-based HCV therapy. As background, triple therapy with an HCV PI plus peginterferon/ribavirin is associated with an increased risk of anemia when compared with peginterferon/ribavirin alone.[1,2] The multinational, randomized, open-label Anemia Management trial was designed to compare the efficacy of ribavirin dose reduction vs erythropoietin administration for anemia management in patients naive to treatment with genotype 1 HCV infection receiving boceprevir plus peginterferon/ribavirin ....
Overall, this study suggests that moving to twice-daily dosing of telaprevir can at least be considered for our patients. Of note, this has not yet been reviewed by the US Food and Drug Administration; thus, every-8-hours dosing remains the recommended approach......
Sulkowski and colleagues[10] presented the results from Study 110, a multicenter, randomized, double-blind, placebo-controlled phase II trial evaluating the coadministration of telaprevir with peginterferon/ribavirin in patients with HIV/HCV coinfection. This significant subpopulation was excluded from the initial telaprevir registration trials and neither telaprevir nor boceprevir is currently approved specifically for use in patients with HCV/HIV coinfection. The primary concern with using HCV PIs in this group is drug–drug interactions, and a secondary question is whether these drugs will be as effective in the coinfected population as they are in the setting of HCV monoinfection....
Cheinquer and colleagues[14] presented results from the N-CORE study, a multicenter, international trial that evaluated the benefit of extending peginterferon/ribavirin from 24 weeks to 48 weeks in patients naive to treatment with genotype 2/3 who do not attain a rapid virologic response (RVR) but then go on to achieve an early virologic response (EVR) . Although this question has been considered for some time, this large study was designed to answer the question definitively...
D-LITE: Peginterferon Lambda/Ribavirin Plus Daclatasvir or Asunaprevir in Patients
With Genotype 1 HCV
Although direct-acting antivirals (DAAs) are expanding treatment options in HCV, interferon is still a very effective anti-HCV drug, especially in patients with IL28B CC genotype, in whom peginterferon/ribavirin alone delivers response rates similar to those attained with direct-acting antivirals.[20] Moreover, in some areas of the world, such as Asia, very high proportions of HCV-infected individuals have the IL28B C allele.[21] Therefore, although interferon will probably not be used extensively in the United States several years from now, it will likely continue to be extensively used worldwide. In thinking about HCV therapy, economic issues must also be considered. With peginterferon coming off patent in the next few years, it will be a relatively inexpensive therapy, particularly in comparison with new all-oral therapies. Therefore, I think interferon will remain available and will potentially be the preferred backbone of therapy for many parts of the world....
PILLAR/ASPIRE: Simeprevir Plus Peginterferon/Ribavirin in GT1 Patients With Advanced Fibrosis
Simeprevir (TMC435) is a NS3/4A PI that is administered once daily and has demonstrated a better AE profile than first-generation PIs.[26,27] In randomized, phase IIb trials, simeprevir plus peginterferon/ribavirin was associated with rapid and potent viral suppression in genotype 1 treatment-naive (PILLAR trial)[26] and treatment-experienced patients (ASPIRE trial).[27] To better understand the efficacy and safety of simeprevir-based therapy in patients with advanced disease, Poordad and colleagues[28] analyzed outcomes in the subset of patients with F3 or F4 fibrosis enrolled in those trials ...
MATTERHORN: Quadruple Therapy With Danoprevir/Ritonavir, Mericitabine, and Peginterferon in Genotype 1 Partial/Null RespondersThe MATTERHORN study was a multicenter, randomized, open-label, parallel phase II trial that evaluated various combinations of the second-generation HCV PI danoprevir boosted with ritonavir and the HCV polymerase inhibitor mericitabine, with or without peginterferon/ribavirin, in HCV genotype 1-infected patients with a previous null or partial response to peginterferon/ribavirin .33] In most cases, patients were treated for 24 weeks. Although an interferon-free regimen was initially evaluated in both genotype 1a and genotype 1b patients, high relapse rates in genotype 1a patients led to the addition of peginterferon/ribavirin in those patients.....
Zeuzem and colleagues[35] presented the final results of the SOUND-C2 trial, a multicenter, randomized, open-label, phase IIb study evaluating an interferon-free combination of the PI faldaprevir (BI 201335) plus the nonnucleoside polymerase inhibitor BI 207127, with or without ribavirin, in patients naive to treatment with genotype 1 HCV . In the interim results from this trial, presented at the 2012 meeting of the European Association for the Study of the Liver, this combination was most effective in patients with genotype 1b infection and those with genotype 1a and IL28B genotype CC .[36] The current analysis confirmed the efficacy and safety of the combination, with SVR12 rates of 52% to 69%....
Sulkowski and colleagues[38] reported results from study AI444-040, a randomized, open-label, phase IIa trial . The study evaluated various combinations of sofosbuvir (formerly GS-7977), a nucleotide analogue that inhibits NS5B polymerase, in combination with the potent NS5A inhibitor daclatasvir, with or without ribavirin, in patients naive to treatment and without cirrhosis....
Sofosbuvir Plus GS-5885 Plus RBV
As Dr. Nelson alluded, Gane and colleagues[39] presented additional information from the ELECTRON trial, which is evaluating the nucleotide polymerase inhibitor sofosbuvir/ribavirin, with or without the HCV NS5A inhibitor GS-5885, in various combination regimens in patients with genotypes 1, 2 or 3 HCV. Previous reports from other arms of this study have demonstrated promising activity with sofosbuvir/ribavirin in genotype 2/3 HCV and in genotype 1 patients naive to treatment, whereas there was lower activity in genotype 1 previous null responders
Osinusi and colleagues[44] at the National Institute of Allergy and Infectious Diseases presented results of a randomized, open-label, phase II study designed to further investigate the optimal use of sofosbuvir-based therapy in genotype 1 patients. The trial evaluated whether lengthening the duration of therapy to 24 weeks would increase the SVR rate and compared different ribavirin dosing strategies....
Hassanein and colleagues[46] reported final efficacy data from the ATOMIC trial, a randomized, open-label, phase II study comparing different regimens of sofosbuvir/peginterferon/ribavirin in patients who were naive to treatment
The AVIATOR trial[49] was designed to evaluate various interferon-free regimens containing up to 3 DAAs administered for up to 24 weeks. The backbone of the therapy was the potent PI ABT-450 boosted with ritonavir 100 mg. Other components included the potent NS5A inhibitor ABT-267 and the non-nucleoside HCV NS5B polymerase inhibitor ABT-333 with or without ribavirin....
Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Genotype 1 Patients
A combination of the PI asunaprevir and the NS5A inhibitor daclatasvir has demonstrated significant activity in genotype 1b patients and less activity in genotype 1a.[54,55] Everson and colleagues[56] evaluated whether adding a third antiviral drug—in this case a nonnucleoside inhibitor of NS5B polymerase—would improve the efficacy in genotype 1a patients. In this randomized, open-label phase IIa study, 32 patients naive to treatment without cirrhosis but with genotype 1 HCV received triple therapy with daclatasvir/asunaprevir/BMS-791325 for 24 weeks (n = 16) or 12 weeks (n = 16) . Patients were stratified by HCV genotype 1 subtype based on the importance of subtype in previous dual-therapy trials of daclatasvir plus asunaprevir...
Lok and colleagues[57] presented results from the expanded AI447-011 study, a randomized, open-label phase IIa study of daclatasvir/asunaprevir–based therapy in patients with HCV genotype 1 and a previous null response to peginterferon/ribavirin . In an initial report, the combination of daclatasvir/asunaprevir showed promising activity in genotype 1b previous null responders, but it was not as active in genotype 1a previous null responders......
As we move toward a cure for hepatitis C worldwide, effective hepatitis B treatment remains one of the biggest unmet needs. Hepatitis B has enormous world penetrance and loss of hepatitis B surface antigen (HBsAg) remains the “holy grail” that many therapies cannot provide. Peginterferon therapy has typically provided the best chance for HBsAg loss and a result that we may equate with a long-term cure. However, very few patients with chronic hepatitis B are receiving peginterferon, at least in the United States and Western Europe, due to its onerous nature. Therefore, defining earlier stopping rules for patients receiving peginterferon would be very advantageous.
Overall, even though we still see a lot of data being generated with peginterferon and ribavirin in studies initiated 18-32 months ago, this meeting is clearly indicating the beginning of the end of an interferon and ribavirin backbone in well-resourced settings. Even among the more difficult-to-treat nonresponders, there is little indication that an interferon/ribavirin backbone will be required as part of future regimens.....
No comments:
Post a Comment