Rodriguez-Torres M, Yoshida EM, Marcellin P, Srinivasan S, Purohit VS, Wang C, Hammond JL

Language: English
References: 13
Page: 364-375
PDF size: 157.23 Kb.

ABSTRACT

Objectives. Filibuvir is a non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study evaluated the safety and efficacy of filibuvir plus pegylated interferon alfa-2a (pegIFN)/ribavirin. Material and methods. Treatment-naïve, HCV genotype-1 patients were randomized to receive filibuvir 300 or 600 mg twice daily (BID) or placebo plus pegIFN (180 µg/wk) and ribavirin (1,000/1,200 mg BID) for 24 weeks. Filibuvir patients who achieved defined response through week 24 discontinued therapy at week 24. All other patients continued on open-label pegIFN/ribavirin through week 48. The primary endpoint was the proportion of patients who achieved sustained virologic response (SVR) defined as HCV RNA ‹ 15 IU/mL at end of treatment (weeks 24 or 48) and week 72. Results. Overall, 288 patients were randomized and treated. SVR was achieved by 41.7, 39.6, and 45.8% of patients in the filibuvir 300 mg, 600 mg, and placebo arms, respectively. While the addition of filibuvir to pegIFN/ribavirin improved on-treatment virologic response parameters, this did not translate into improved SVR rates due to a high rate of virologic relapse following completion of therapy (300 mg: 35.9%; 600 mg: 42.9%; placebo: 25.4%). The most commonly reported adverse events were nausea, fatigue, headache, and insomnia, and were reported at similar rates across arms. Conclusions. Filibuvir plus pegIFN/ribavirin did not improve the percentage of patients achieving SVR compared with administration of pegIFN/ribavirin alone. However, the agent was well tolerated and was associated with higher on-treatment virologic response parameters. Further evaluation of filibuvir in combination with other direct-acting antiviral agents may be considered.

REFERENCES

1. Shi ST, Herlihy KJ, Graham JP, Nonomiya J, Rahavendran SV, Skor H, Irvine R, et al. Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother 2009; 53: 2544-52.

2. Wagner F, Thompson R, Kantaridis C, Simpson P, Troke P, Jagannatha S, Neelakantan S, et al. Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir administered as monotherapy in HCV genotype 1 infected patients. Hepatology 2011; 54: 50-9.

3. Jacobson I, Pockros PJ, Lalezari, J, Lawitz E, Rodriguez- Torres M, DeJesus E, Haas F, et al. Virologic response rates following 4 weeks of filibuvir in combination with pegylated interferon alfa-2a and ribavirin in chronically-infected HCV genotype-1 patients. Program and abstracts of the 45th Annual Meeting of the European Association for the Study of Liver (EASL); April 24-28, 2010; Vienna, Austria.

4. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Available from: http://www.wma.net/en/30publications/ 10policies/b3/index.html (accessed January 17, 2013).

5. Troke PJ, Lewis M, Simpson P, Gore K, Hammond J, Craig C, Westby M. Characterization of resistance to the nonnucleoside NS5B inhibitor filibuvir in hepatitis C virus-infected patients. Antimicrob Agents Chemother 2012; 56: 1331-41.

6. Cochran WG. Some methods of strengthening the common χ2 tests. Biometrics 1954; 10: 417-51.

7. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-48.

8. Jacobson IM, McHutchison JG, Dusheiko GM, Di Bisceglie AM, Reddy R, Bzowej NH, Marcellin P, et al. Telaprevir for previously untreated chronic hepatitis C infection. N Engl J Med 2011; 364: 2405-16.

9. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns M, Sulkowski M, Jacobson IM, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195-206.

10. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-93. Erratum in: N Engl J Med 2009; 361: 1027.

11. Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S. Rapid virological response is the most important predictor of sustained virologic response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 2011; 55: 69-75.

12. Lawitz E, Rodriguez-Torres M, Rustgi VK, Hassanein T, Rahimy MH, Crowley CA, Freddo JL, et al. Safety and antiviral activity of ANA598 in combination with pegylated interferon á2A plus ribavirin in treatment-naive genotype-1 chronic HCV patients. Program and abstracts of the 61st Annual Meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2010; Boston, Massachusetts. Abstract 31.

13. Ferenci P, Nyberg A, Bernstein D, et al. PEARL III: SVR ≥ 99% after 12 wks of ABT-450/r/267 + ABT-333 ± RBV in treatment naive HCV GT1b infection. Conference on Retroviruses and Opportunistic Infections: March 3-6, 2014; Boston, Massachusettes. Abstract 29LB.