Archive for May 20, 2013

HCV Treatment — No More Room for Interferonologists?

N Engl J of Medic May 16, 2013 V.368 P.1931-1932

EDITORIAL

Joost P.H. Drenth, M.D., Ph.D.

From the Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

The landscape of therapy for hepatitis C virus (HCV) infection is changing rapidly. Until recently, the standard of care for HCV infection was a combination of peginterferon and ribavirin. Our increased understanding of the basic biology of HCV led to the identification of specific proteins involved in the replication of the virus. These proteins can be targeted by protease and polymerase inhibitors….

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http://www.nejm.org/doi/pdf/10.1056/NEJMe1303818

May 20, 2013 at 3:06 pm

Current and Future Therapies for Hepatitis C Virus Infection

N Engl J of Medic May 16, 2013 V.368 P.1907-1917

REVIEW ARTICLE

DRUG THERAPY

T. Jake Liang, M.D., and Marc G. Ghany, M.D., M.H.Sc.

From the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Only 20 years after the discovery of the hepatitis C virus (HCV), a cure is now likely for most people affected by this chronic infection, which carries a substantial disease burden, not only in the United States but also worldwide.1 The recent approval of two direct-acting antiviral agents that specifically inhibit viral replication has dramatically increased the viral clearance rate, from less than 10% with the initial regimen of interferon monotherapy to more than 70% with current therapy. Moreover, many other drugs targeting viral or host factors are in development, and some will almost certainly be approved in the coming years. The questions of who should be treated and with what regimen will be increasingly complex to address and will require careful consideration. As therapy improves, systemwide identification and care of patients who need treatment will be the next challenge. Because most infected persons are unaware of their diagnosis, the Centers for Disease Control and Prevention recently recommended screening for HCV all persons born between 1945 and 1965. 2,3 It is anticipated that in the course of such a screening process, a large number of persons will be found to be infected with the virus; whether it will be possible to treat all these people is unclear. This article reviews the current therapy for HCV infection and the landscape of drug development….

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http://www.nejm.org/doi/pdf/10.1056/NEJMra1213651

May 20, 2013 at 3:05 pm

Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection

N Engl J of Medic May 16, 2013 V.368 P.1878-1887

Eric Lawitz, M.D., Alessandra Mangia, M.D., David Wyles, M.D., Maribel Rodriguez-Torres, M.D., Tarek Hassanein, M.D., Stuart C. Gordon, M.D., Michael Schultz, M.D., Ph.D., Mitchell N. Davis, D.O., Zeid Kayali, M.D., K. Rajender Reddy, M.D., Ira M. Jacobson, M.D., Kris V. Kowdley, M.D., Lisa Nyberg, M.D., G. Mani Subramanian, M.D., Ph.D., Robert H. Hyland, D.Phil., Sarah Arterburn, M.S., Deyuan Jiang, Ph.D., John McNally, Ph.D., Diana Brainard, M.D., William T. Symonds, Pharm.D., John G. McHutchison, M.D., Aasim M. Sheikh, M.D., Zobair Younossi, M.D., M.P.H., and Edward J. Gane, M.D.

BACKGROUND

In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection.

METHODS

We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy.

RESULTS

In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir–ribavirin group and the peginterferon–ribavirin group. Response rates in the sofosbuvir–ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon.

CONCLUSIONS

In a single-group study of sofosbuvir combined with peginterferon–ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.)

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http://www.nejm.org/doi/pdf/10.1056/NEJMoa1214853

 

May 20, 2013 at 3:04 pm

Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options

N Engl J of Medic May 16, 2013 V.368 P.1867-1877

Ira M. Jacobson, M.D., Stuart C. Gordon, M.D., Kris V. Kowdley, M.D., Eric M. Yoshida, M.D., Maribel Rodriguez-Torres, M.D., Mark S. Sulkowski, M.D., Mitchell L. Shiffman, M.D., Eric Lawitz, M.D., Gregory Everson, M.D., Michael Bennett, M.D., Eugene Schiff, M.D., M. Tarek Al-Assi, M.D., G. Mani Subramanian, M.D., Ph.D., Di An, Ph.D., Ming Lin, Ph.D., John McNally, Ph.D., Diana Brainard, M.D., William T. Symonds, Pharm.D., John G. McHutchison, M.D., Keyur Patel, M.D., Jordan Feld, M.D., M.P.H., Stephen Pianko, M.D., Ph.D., and David R. Nelson, M.D.

BACKGROUND

Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection.

METHODS

We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy.

RESULTS

Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, −23 percentage points; 95% CI, −35 to −11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%).

CONCLUSIONS

In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov numbers, NCT01542788 and NCT01604850, respectively.)

PDF

http://www.nejm.org/doi/pdf/10.1056/NEJMoa1214854

May 20, 2013 at 3:03 pm

Hepatitis C in the United States

N Engl J of Medic May 16, 2013 V.368 P.1859-1861

Perspective

Scott D. Holmberg, M.D., M.P.H., Philip R. Spradling, M.D., Anne C. Moorman, M.P.H., and Maxine M. Denniston, M.S.P.H.

From the Epidemiology and Surveillance Branch, Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta.

Care for hepatitis C is evolving rapidly, with increasingly effective and better-tolerated antiviral therapies being evaluated and approved for use. It’s clear, however, that not everyone who would qualify for therapy has been tested and identified, referred for appropriate care, and offered or given the best therapy available. Furthermore, currently used antiviral drugs — pegylated interferon and ribavirin “base” plus either telaprevir or boceprevir — can cost more than $70,000 for a full course of therapy. It is expected that the new oral antiviral agents will be just as expensive, at least in the short term. All these factors affect personal, medical, public health, and national policy decisions. One fundamental problem in making such decisions is that it’s difficult to estimate the number of people with chronic hepatitis C virus (HCV) infection in the United States who have been identified and have received appropriate care…

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http://www.nejm.org/doi/pdf/10.1056/NEJMp1302973

May 20, 2013 at 3:01 pm


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