Correspondence

Antibodies Neutralizing Peginterferon Alfa during Retreatment of Hepatitis C

N Engl J Med 2006; 354:1323-1324March 23, 2006

Article

To the Editor:

Peginterferons are widely used to treat chronic hepatitis C virus (HCV) infection, an important cause of liver cirrhosis and hepatocellular carcinoma.1-4 We describe a patient who did not have a virologic response to peginterferon and had a virtual absence of circulating peginterferon alfa-2a but had neutralizing antibodies against interferon alfa.

A 38-year-old man with liver cirrhosis (Child–Pugh class A; score, 5) was referred to our hospital for evaluation of his chronic HCV infection. He had had no response to a 16-week course of treatment with peginterferon alfa-2b and ribavirin during the previous year. We enrolled him in an 18-month study of high-dose peginterferon alfa-2a (at a dose of 360 μg per week during the first 4 weeks) in combination with ribavirin (at a dose based on weight). The study enrolled patients with genotype 1, and the index patient was the second of nine patients to enroll. The study was approved by our institutional review board, and patients provided written informed consent. At the start of treatment, the index patient's serum level of alanine aminotransferase was 106 IU per milliliter (normal, <41), and the serum level of HCV RNA was 6.8 log copies per milliliter.

To determine the effect of the administration of peginterferon alfa-2a on pharmacokinetic and plasma viral kinetic profiles, peginterferon alfa-2a levels were measured with the use of a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) for interferon alfa (Bender MedSystems Diagnostics GmbH), and HCV RNA levels were quantitated (Cobas Amplicor HCV test, Roche Diagnostics) at baseline and at days 1, 2, 4, 7, 14, 21, and 28 after the start of treatment. We observed a variation in pharmacokinetic profiles among patients. In contrast to the other eight patients, the index patient's levels of peginterferon alfa-2a were virtually undetectable, and he did not have any virologic response to treatment (Figure 1AFigure 1Pharmacokinetics, Viral Kinetics, and Production of Antibodies to Interferon Alfa during the First 28 Days of Treatment with Peginterferon Alfa-2a among Patients with Chronic HCV Genotype 1 Infection. and Figure 1B). This finding led us to measure the level of specific antibodies to interferon alfa by ELISA. Interferon alfa–specific antibodies were detected at low levels before the start of treatment and increased after the first week of therapy (Figure 1C). With the use of a sensitive HCV replicon-based interferon bioassay,5 we confirmed that serum from the index patient abrogated antiviral activity of peginterferon alfa-2a (Pegasys, Roche), interferon alfa-2a (Roferon, Roche), and peginterferon alfa-2b (PegIntron, Schering-Plough), whereas other interferon subtypes, such as interferon alfa-C and interferon beta, were still biologically active. Consequently, the effect of antibodies to these interferon-alfa–subtypes on neutralization of endogenously produced type 1 interferons may be limited. The presence of peginterferon alfa-2a in the serum of the index patient could be demonstrated by ELISA that detected the pegylated modification, confirming that peginterferon alfa-2a had been administered.

In conclusion, our findings suggest that individual peginterferon-alfa pharmacokinetic profiles can be used to identify patients who do not have a response to treatment because of low levels of circulating peginterferon alfa. This case of a patient with antibodies that neutralize peginterferon alfa in vivo points to the need to assess the incidence and effect of neutralizing antibodies to interferon alfa among patients who do not have a response to treatment with peginterferon alfa.

Annemiek A. van der Eijk, M.D., Ph.D.
Jan Maarten Vrolijk, M.D., Ph.D.
Bart L. Haagmans, Ph.D.
Erasmus Medical Center, 3015 GE Rotterdam, the Netherlands
b.haagmans@erasmusmc.nl

5 References

1. 1

   Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666-1672
   Full Text | Web of Science | Medline

2. 2

   Lindsay KL, Trepo C, Heintges T, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology 2001;34:395-403
   CrossRef | Web of Science | Medline

3. 3

   Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982
   Full Text | Web of Science | Medline

4. 4

   Manns MP, McHutchison JG, Gordon SC, 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 2001;358:958-965
   CrossRef | Web of Science | Medline

5. 5

   Vrolijk JM, Kaul A, Hansen BE, et al. A replicon-based bioassay for the measurement of interferons in patients with chronic hepatitis C. J Virol Methods 2003;110:201-209
   CrossRef | Web of Science | Medline

Citing Articles (10)

Citing Articles

1. 1

   David R. Strayer, William A. Carter. (2011) Recombinant and Natural Human Interferons: Analysis of the Incidence and Clinical Impact of Neutralizing Antibodies. Journal of Interferon & Cytokine Research111201131520004
   CrossRef

2. 2

   Ela Markovsky, Hemda Baabur-Cohen, Anat Eldar-Boock, Liora Omer, Galia Tiram, Shiran Ferber, Paula Ofek, Dina Polyak, Anna Scomparin, Ronit Satchi-Fainaro. (2011) Administration, distribution, metabolism and elimination of polymer-drug conjugates. Journal of Controlled Release
   CrossRef

3. 3

   Carolina Scagnolari, Simona Trombetti, Annalisa Soldà, Michele Milella, Giovanni Battista Gaeta, Gioacchino Angarano, Gaetano Scotto, Nicola Caporaso, Filomena Morisco, Raffaele Cozzolongo, Gianluigi Giannelli, Massimo Fasano, Teresa Santantonio, Guido Antonelli. (2011) Development and Specificities of Anti-Interferon Neutralizing Antibodies in Patients with Chronic Hepatitis C Treated with Pegylated Interferon Alpha. Clinical Microbiology and Infectionno-no
   CrossRef

4. 4

   Akihiro Tamori, Kiyohide Kioka, Osamu Kurai, Hiroki Sakaguchi, Masaru Enomoto, Hideki Fujii, Sawako Kobayashi, Shuji Iwai, Hiroyasu Morikawa, Seiko Yamaguchi, Yasuko Kawasaki, Hiroko Oka, Yasuhito Tanaka, Norifumi Kawada. (2011) Favorable factors for re-treatment with pegylated interferon α2a plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus. Hepatology Researchno-no
   CrossRef

5. 5

   Christophe Lallemand, Michael G. Tovey. 2011. A Novel One-Step Cell-Based Assay for Quantification of Neutralizing Antibodies to Biopharmaceuticals. , 383-398.
   CrossRef

6. 6

   Philippe Halfon, Sophie Pérusat, Marc Bourlière, Jean-Pierre Bronowicki, Pascale Trimoulet, Yves Benhamou, Vincent Leroy, Patrick Marcellin, Juliette Foucher, Guillaume Penaranda, Geneviève Chêne, Patrice Couzigou. (2010) Neutralizing antibodies to interferon-α and circulating interferon in patients with chronic hepatitis C non-responding to pegylated interferon plus ribavirin re-treated by pegylated interferon-α-2a and ribavirin (ANRS HC16 GAMMATRI substudy*). Journal of Medical Virology 82:12, 2027-2031
   CrossRef

7. 7

   Florence Nicot, Florence Legrand-Abravanel, Thierry Lafont, Martine Dubois, Karine Sauné, Christophe Pasquier, Etienne Chatelut, Jacques Izopet. (2008) Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV. Journal of Medical Virology 80:9, 1523-1529
   CrossRef

8. 8

   Jonathan K. Armstrong, Georg Hempel, Susanne Koling, Linda S. Chan, Timothy Fisher, Herbert J. Meiselman, George Garratty. (2007) Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110:1, 103-111
   CrossRef

9. 9

   Valerie Touitou, Damien Sene, Christine Fardeau, Thi-Huong-Du Boutin, Pierre Duhaut, Jean-Charles Piette, Phuc LeHoang, Patrice Cacoub, Bahram Bodaghi. (2007) Interferon-α2a and Vogt–Koyanagi–Harada disease: a double-edged sword?. International Ophthalmology 27:2-3, 211-215
   CrossRef

10. 10

    Belen Ramos, Julie Sheldon, Andres Ruiz-Sancho, Carlos Toro, Pilar Ríos, Vincent Soriano. (2007) Prevalence and therapeutic significance of anti-interferon antibodies in hepatitis C virus/HIV-co-infected patients. AIDS 21:5, 652-653
    CrossRef