IJCM  Vol.5 No.3 , January 2014
Improved Sustained Virological Response Following Treatment with Pegylated-Interferon Alpha-2b Compared with Alpha-2a, Both with Ribavirin, for Chronic Hepatitis C Infection with Genotypes 2 and 3
ABSTRACT

Purpose: The optimal formulation of pegylated interferon a (PEG-IFa) as a part of combination therapy with ribavirin (RBV) is uncertain for patients infected with hepatitis C Genotypes 2 and 3. Methods: A multivariate analysis of prospectively collected treatment data from two tertiary centres on 351 treatment na?ve HCV Genotype 2 or 3 patients who received PEG-IFa-2a or b plus ribavirin. Results: Univariate analyses demonstrate that PEG-IFa-2b based on regimens achieved a higher sustained virological response (SVR) than PEG-IFa-2a (77.9% versus 62.0%, P = 0.0012). On multivariate analyses, PEG-IFa-2b appeared superior to PEG-IFa-2a with an odds ratio (OR) and 95% confidence interval (CI95) for SVR of 2.19 (CI95 1.35-3.52, P = 0.0005). Genotype was a significant predictor of outcome in the multivariate model with 80% of Genotype 2 but only 67.7% of Genotype 3 subjects achieving SVR (OR 2.66 [CI95 1.35-5.92]). Increasing age was negatively associated with SVR (OR 0.97 [CI95 0.94-0.99]). Some of the differences in SVR are explained by higher relapse rates with PEG-IFa-2a (P = 0.009). Conclusions: PEG-IFa-2b and RBV achieve higher SVR rates than PEG-IFa-2a and RBV in Genotypes 2 and 3 chronic HCV infections. There is less relapse with PEG-IFa-2b. Genotype 2 infections are considerably easier to cure. SVR is higher in younger patients. These findings should influence a choice of PEG-IFa in the era of direct acting anti-viral drugs in therapy of Genotypes 2 and 3.


Cite this paper
L. Mollison, L. Manning, S. Miczkova and W. Cheng, "Improved Sustained Virological Response Following Treatment with Pegylated-Interferon Alpha-2b Compared with Alpha-2a, Both with Ribavirin, for Chronic Hepatitis C Infection with Genotypes 2 and 3," International Journal of Clinical Medicine, Vol. 5 No. 3, 2014, pp. 111-117. doi: 10.4236/ijcm.2014.53019.
References
[1]   D. Lavanchy, “The Global Burden of Hepatitis C. Liver International,” Official Journal of the International Association for the Study of the Liver, Vol. 29, Suppl. 1, 2009, pp. 74-81.

[2]   Digestive Health Foundation, “Facts about Hepatitis C,” The Gastroenterological Society of Australia, 2007.

[3]   World Health Organization (WHO), “Hepatitis C fact sheet,” World Health Organization, Geneva, 2011.

[4]   J. H. Hoofnagle, K. D. Mullen, D. B. Jones, V. Rustgi, A. Di Bisceglie, M. Peters, J. G. Waggoner, Y. Park and E. A. Jones, “Treatment of Chronic Non-A, Non-B Hepatitis with Recombinant Human Alpha Interferon. A Preliminary Report,” The New England Journal of Medicine, Vol. 315, No. 25, 1986, pp. 1575-1578.
http://dx.doi.org/10.1056/NEJM198612183152503

[5]   J. G. McHutchison, S. C. Gordon, E. R. Schiff, M. L. Shiffman, W. M. Lee, V. K. Rustgi, Z. D. Goodman, M.-H. Ling, S. Cort and J. K. Albrecht, for the Hepatitis Interventional Therapy Group, “Interferon Alfa-2b alone or in Combination with Ribavirin as Initial Treatment for Chronic Hepatitis C. Hepatitis Interventional Therapy Group,” The New England Journal of Medicine, Vol. 339, No. 21, 1998, pp. 1485-1492.
http://dx.doi.org/10.1056/NEJM199811193392101

[6]   T. Poynard, P. Marcellin, S. S. Lee, C. Niederau, G. S., Minuk, G. Ideo, et al., “Randomised Trial of Interferon Alpha2b plus Ribavirin for 48 Weeks or for 24 Weeks versus Interferon Alpha2b plus Placebo for 48 Weeks for Treatment of Chronic Infection with Hepatitis C Virus,” International Hepatitis Interventional Therapy Group (IHIT),” Lancet, Vol. 352, No. 9138, 1998, pp. 1426-1432. http://dx.doi.org/10.1016/S0140-6736(98)07124-4

[7]   K. L. Lindsay, C. Trepo, T. Heintges, M. L. Shiffman, S. C. Gordon, J. C. Hoefs, E. R. Schiff, Z. D. Goodman, M. Laughlin, R. Yao and J. K. Albrecht, “A Randomized, Double-Blind Trial Comparing Pegylated Interferon Alfa2b to Interferon alfa-2b as Initial Treatment for Chronic Hepatitis C,” Hepatology, Vol. 34, No. 2, 2001, pp. 395-403. http://dx.doi.org/10.1053/jhep.2001.26371

[8]   M. Simin, J. Brok, D. Stimac, C. Gluud and L. L. Gluud, “Cochrane Systematic Review: Pegylated Interferon plus Ribavirin vs. Interferon plus Ribavirin for Chronic Hepatitis C,” Alimentary Pharmacology & Therapeutics, Vol. 25, No. 10, 2007, pp. 1153-1162.
http://dx.doi.org/10.1111/j.1365-2036.2007.03294.x

[9]   M. P. Manns, J. G. McHutchison, S. C. Gordon, V. K. Rustgi, M. Shiffman, R. Reindollar, et al., “Peginterferon Alfa-2b plus Ribavirin Compared with interferon alfa-2b plus Ribavirin for Initial Treatment of Chronic Hepatitis C: A Randomised Trial,” Lancet, Vol. 358, 9286, 2001, pp. 958-965.
http://dx.doi.org/10.1016/S0140-6736(01)06102-5

[10]   M. W. Fried, M. L. Shiffman, K. R. Reddy, C. Smith, G. Marinos, F. L. Goncales, Jr., D. Häussinger, M. Diago, G. Carosi, D. Dhumeaux, A. Craxi, A. Lin, J. Hoffman and J. Yu, “Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection,” The New England Journal of Medicine, Vol. 347, No. 13, 2002, pp. 975-982.
http://dx.doi.org/10.1056/NEJMoa020047

[11]   S. Zeuzem, T. Berg, B. Moeller, H. Hinrichsen, S. Mauss, H. Wedemeyer, C. Sarrazin, D. Hueppe, E. Zehnter and M. P. Manns, “Expert Opinion on the Treatment of Patients with Chronic Hepatitis C,” Journal of Viral Hepatitis, Vol. 16, No. 2, 2009, pp. 75-90.
http://dx.doi.org/10.1111/j.1365-2893.2008.01012.x

[12]   J. H. Hoofnagle, “A Step forward in Therapy for Hepatitis C,” The New England Journal of Medicine, Vol. 360, No. 18, 2009, pp. 1899-1901.
http://dx.doi.org/10.1056/NEJMe0901869

[13]   D. M. Jensen, “A New Era of Hepatitis C Therapy Begins,” The New England Journal of Medicine, Vol. 364, No. 13, 2011, pp. 1272-1274.
http://dx.doi.org/10.1056/NEJMe1100829

[14]   H. Ochi, C. N. Hayes, H. Abe, Y. Hayashida and T. Uchiyama, N. Kamatani, Y. Nakamura and K. Chayama, “Toward the Establishment of a Prediction System for the Personalized Treatment of Chronic Hepatitis C,” The Journal of Infectious Diseases, Vol. 205, No. 2, 2012, pp. 204-210. http://dx.doi.org/10.1093/infdis/jir726

[15]   European Association for the Study of the Liver, “EASL Clinical Practice Guidelines: Management of Hepatitis C Virus Infection,” Journal of Hepatology, Vol. 55, No. 2, 2011, pp. 245-264.
http://dx.doi.org/10.1016/j.jhep.2011.02.023

[16]   T. Awad, K. Thorlund, G. Hauser, D. Stimac, M. Mabrouk and C. Gluud, “Peginterferon Alpha-2a Is Associated with Higher Sustained Virological Response than Peginterferon Alfa-2b in Chronic Hepatitis C: Systematic Review of Randomized Trials,” Hepatology, Vol. 51, No. 4, 2010, pp. 1176-1184.
http://dx.doi.org/10.1002/hep.23504

[17]   P. Bedossa and T. Poynard, “An Algorithm for the Grading of Activity in Chronic Hepatitis C. The METAVIR Cooperative Study Group,” Hepatology, Vol. 24, No. 2, 1996, pp. 289-293.
http://dx.doi.org/10.1002/hep.510240201

[18]   R Development Core Team, “R: A Language and Environment for Statistical Computing,” R Foundation for Statistical Computing, Vienna, 2012.

[19]   J. Honaker, G. King and M. Blackwell, “Amelia II: A Program for Missing Data,” Journal of Statistical Software, Vol. 45, No. 7, 2011, pp. 1-47.

[20]   D. Ge, J. Fellay, A. J. Thompson, J. S. Simon, K. V. Shianna, T. J. Urban, E. L. Heinzen, P. Qiu, A. H. Bertelsen, A. J. Muir, M. Sulkowski, J. G. McHutchison and D. B. Goldstein1, “Genetic Variation in IL28B Predicts Hepatitis C Treatment-Induced Viral Clearance,” Nature, Vol. 461, No. 7262, 2009, pp. 399-401.
http://dx.doi.org/10.1038/nature08309

[21]   V. Suppiah, M. Moldovan, G. Ahlenstiel, T. Berg, M. Weltman, M. L. Abate, M. Bassendine, U. Spengler, G. J Dore, E. Powell, S. Riordan, D. Sheridan, A. Smedile, V. Fragomeli, T. Müller, M. Bahlo, G. J. Stewart, D. R. Booth and J. George for the Hepatitis C Study, “IL28B Is Associated with Response to Chronic Hepatitis C Interferon-Alpha and Ribavirin Therapy,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1100-1104.
http://dx.doi.org/10.1038/ng.447

[22]   Y. Tanaka, N. Nishida, M. Sugiyama, M. Kurosaki, K. Matsuura, N. Sakamoto, et al., “Genome-Wide Association of IL28B with Response to Pegylated InterferonAlpha and Ribavirin Therapy for Chronic Hepatitis C,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1105-1109.
http://dx.doi.org/10.1038/ng.449

[23]   J. G. McHutchison, E. J. Lawitz, M. L. Shiffman, AJ Muir, GW Galler, J McCone, L. M. Nyberg, W. M. Lee, R. H. Ghalib, E. R. Schiff, J. S. Galati, B. R. Bacon, M. N. Davis, P. Mukhopadhyay, K. Koury, S. Noviello, L. D. Pedicone, C. A. Brass, J. K. Albrecht and M. S. Sulkowski for the IDEAL Study Team, “Peginterferon alfa-2b or alfa-2a with Ribavirin for Treatment of Hepatitis C infection,” The New England Journal of Medicine, Vol. 361, No. 6, 2009, pp. 580-593.
http://dx.doi.org/10.1056/NEJMoa0808010

[24]   S. M. Alavian, B. Behnava and S. V. Tabatabaei, “The Comparative Efficacy and Safety of Peginterferon Alpha-2a vs. 2b for the Treatment of Chronic HCV infection: A Meta-Analysis,” Hepatitis Monthly, Vol. 10, No. 2, 2010, pp. 121-131.

[25]   D. Kershenobich, L. Munoz, R. Male, J. Gaytan and F. Sanchez, “Proceed with Caution: Peginterferon Alpha-2a versus peginterferon alfa-2b in Chronic Hepatitis C. A Systematic REVIEW of Randomized trials,” Hepatology, Vol. 52, No. 6, 2010, pp. 2240-2241.
http://dx.doi.org/10.1002/hep.24025

[26]   A. Kolakowska, H. Berok, M. Wasilewski and A. Horbon, “Relevance between Fibrosis and Response to Treatment with Peginterferon Alfa2a vs Alfa2b with Ribavirin in Chronic Hepatitis C Genotype 3 Patients. Randomized open label study,” Hepatology [ABSTRACT], Vol. 48, 2008, p. 1278.

[27]   M. Laguno, C. Cifuentes, J. Murillas, S. Veloso, M. Larrousse, A. Payeras, L. Bonet, F. Vidal4, A. Milinkovic1, A. Bassa, C. Villalonga, I. Pérez, C. Tural, M. Martínez-Rebollar, M. Calvo, J. L. Blanco, E. Martínez, J. M. Sánchez-Tapias, J. M. Gatell and J. Mallolas, “Randomized Trial Comparing Pegylated Interferon Alpha-2b versus Pegylated Interferon Alpha-2a, Both plus Ribavirin, to Treat Chronic Hepatitis C in Human Immunodeficiency virus Patients,” Hepatology, Vol. 49, No. 1, 2009, pp. 22-31. http://dx.doi.org/10.1002/hep.22598

[28]   G. Scotto, V. Fazio, C. Fornabaio, A. Tartaglia, R. Di Tullio, A. Saracino and G. Angarano, “Peg-Interferon Alpha-2a versus Peg-Interferon Alpha-2b in Nonresponders with HCV Active Chronic Hepatitis: A Pilot Study,” Journal Interferon and Cytokine Research, Vol. 28, No. 10, 2008, pp. 623-629.
http://dx.doi.org/10.1089/jir.2007.0116

[29]   M. G. Rumi, A. Aghemo, G. M. Prati, R. D’Ambrosio, MF Donato, R Soffredini, E. Del Ninno, A. Russo and M. Colombo, “Randomized Study of Peginterferon-Alpha2a plus Ribavirin vs Peginterferon-alpha2b plus Ribavirin in Chronic Hepatitis C,” Gastroenterology, Vol. 138, No. 1, 2010, pp. 108-115.
http://dx.doi.org/10.1053/j.gastro.2009.08.071

[30]   A. Ascione, M. De Luca, M. T. Tartaglione, F. Lampasi, G. G. Di Costanzo, A. G. Lanza, F. P. Picciotto, G. Marino-Masrsilia, L. Fontanella and G. Leandro, “Peginterferon Alfa-2a plus Ribavirin Is More Effective than Peginterferon Alfa-2b plus Ribavirin for Treating Chronic Hepatitis C virus Infection,” Gastroenterology, Vol. 138, No. 1, 2010, pp. 116-122.
http://dx.doi.org/10.1053/j.gastro.2009.10.005

[31]   A. Escudero, F. Rodriguez, M. A. Serra, J. A. Del Olmo, F. Montes and J. M. Rodrigo, “Pegylated α-Interferon-2a Plus Ribavirin Compared with Pegylated α-Interferon-2b Plus Ribavirin for Initial Treatment of Chronic Hepatitis C Virus: Prospective, Non-Randomized Study,” Journal of Gastroenterology and Hepatology, Vol. 23, No. 6, 2008, pp. 861-866.
http://dx.doi.org/10.1111/j.1440-1746.2008.05397.x

[32]   D. C. Malone, T. T. Tran and F. F. Poordad, “Cost-Efficacy Analysis of Peginterferon Alfa-2b Plus Ribavirin Compared with Peginterferon Alfa-2a Plus Ribavirin for the Treatment of Chronic Hepatitis C,” Journal of Managed Care Pharmacy, Vol. 11, No. 8, 2005, pp. 687-694.

[33]   K. R. Reddy, M. L. Shiffman, T. R. Morgan, S. Zeuzem, S. Hadziyannis, F. M. Hamzeh, T. L. Wright and M. Fried, “Impact of Ribavirin Dose Reductions in Hepatitis C Virus Genotype 1 Patients Completing Peginterferon Alfa-2a/Ribavirin Treatment,” Clinical Gastroenterology and Hepatology, Vol. 5, No. 1, 2007, pp. 124-129.
http://dx.doi.org/10.1016/j.cgh.2006.10.008

[34]   S. Zopf, C. Herold, E. G. Hahn and M. Ganslmayer, “Peginterferon Alfa-2a Relapse Rates Depend on Weight-Based Ribavirin Dosage in HCV-Infected Patients with Genotype 1: Results of a Retrospective Evaluation,” Scandinavian Journal of Gastroenterology, Vol. 44, No. 4, 2009, pp. 486-490.
http://dx.doi.org/10.1080/00365520802647400

[35]   C. Dhalluin, A. Ross, W. Huber, P. Gerber, D. Brugger, B. Gsell and H. Senn, “Structural, Kinetic, and Thermodynamic Analysis of the Binding of the 40 kDa PEG-Interferon-α2a and Its Individual Positional Isomers to the Extracellular Domain of the Receptor IFNAR2,” Bioconjugate Chemistry, Vol. 16, No. 3, 2005, pp. 518-527.
http://dx.doi.org/10.1021/bc049780h

[36]   M. Silva, J. Poo, F. Wagner, M. Jackson, D. Cutler, M. Grace, R. Bordens, C. Cullen, J. Harvey and M. Laughlin, “A Randomised Trial to Compare the Pharmacokinetic, Pharmacodynamic, and Antiviral Effects of Peginterferon Alfa-2b and Peginterferon Alfa-2a in Patients with Chronic Hepatitis C (COMPARE),” Journal of Hepatology, Vol. 45, No. 2, 2006, pp. 204-213.
http://dx.doi.org/10.1016/j.jhep.2006.03.008

[37]   M. O. Silva, “Compare Trial: Updated Data,” Journal of Hepatology, Vol. 49, No. 2, 2008, pp. 288-289.
http://dx.doi.org/10.1016/j.jhep.2008.05.009

[38]   C. Sarrazin, S. Susser, A. Doehring, C. M. Lange, T. Muller, C. Schlecker, E. Herrmann, J. Lötsch and T. Berg, “Importance of IL28B Gene Polymorphisms in Hepatitis C Virus Genotype 2 and 3 Infected Patients,” Journal of Hepatology, Vol. 54, No. 3, 2011, pp. 415-421.
http://dx.doi.org/10.1016/j.jhep.2010.07.041

[39]   J. G. McHutchison, M. Manns, K. Patel, T. Poynard, K. L. Lindsay, C. Trepo, J. Dienstag, W. M. Lee, C. Mak, J. J. Garaud and J. K. Albrecht, “Adherence to Combination Therapy Enhances Sustained Response in Genotype-1-Infected Patients with Chronic Hepatitis C,” Gastroenterology, Vol. 123, No. 4, 2002, pp. 1061-1069.
http://dx.doi.org/10.1053/gast.2002.35950

 
 
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