Antibodies Neutralizing Peginterferon Alfa during Retreatment of Hepatitis C
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《新英格兰医药杂志》
To the Editor: Peginterferons are widely used to treat chronic hepatitis C virus (HCV) infection, an important cause of liver cirrhosis and hepatocellular carcinoma.1,2,3,4 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 1A 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.
Figure 1. Pharmacokinetics, 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.
Samples were taken from each patient at baseline and at days 1, 2, 4, 7, 14, 21, and 28 after the start of therapy, and measurements were made of levels of peginterferon alfa-2a (Panel A), log HCV RNA (Panel B), and antibodies to interferon alfa (Panel C). Data are expressed as means ±SE for eight patients, and those of the index patient are shown separately.
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
References
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.
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.
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.
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.
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.
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 1A 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.
Figure 1. Pharmacokinetics, 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.
Samples were taken from each patient at baseline and at days 1, 2, 4, 7, 14, 21, and 28 after the start of therapy, and measurements were made of levels of peginterferon alfa-2a (Panel A), log HCV RNA (Panel B), and antibodies to interferon alfa (Panel C). Data are expressed as means ±SE for eight patients, and those of the index patient are shown separately.
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
References
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.
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.
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.
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.
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.