Correspondence

Interferon Alfa-2a for Cryoglobulinemia Associated with Hepatitis C Virus

N Engl J Med 1994; 331:400-401August 11, 1994

Article

To the Editor:

Misiani and colleagues (March 17 issue)1 conclude that the therapeutic efficacy of interferon alfa-2a in cryoglobulinemia associated with hepatitis C virus (HCV) is closely related to the drug's antiviral activity. However, the authors do not present sufficient data to justify this conclusion. The demonstration that HCV is specifically concentrated in type II cryoglobulins suggests that the virus may be involved in the development of the disease and that the effect of interferon alfa may be due to its antiviral activity2; however, it has also been demonstrated that mixed cryoglobulins diminish immune-complex clearance mechanisms3.

In view of the well-established immunomodulatory effects of interferon alfa, the decreased concentrations of serum HCV RNA may be related to an effect on immune viral clearance. Demonstration of the inhibition of viral replication in the liver is possible with in situ hybridization techniques for detecting the positive and negative strands of HCV.

Because of the inefficiency of the reverse-transcriptase step in the polymerase chain reaction (PCR) assay, the minimal number of detectable HCV RNA molecules is 10⁴ to 10⁵ per milliliter. Hence, a negative PCR assay does not exclude the possibility of viral infection. At present, we believe the best possible approach to evaluating the effectiveness of interferon alfa in patients with mixed cryoglobulinemia is to determine the HCV RNA level in serum and in cryoglobulins because of the concentration of the virus by cryoprecipitation2. Once the results of these assays are negative, in situ hybridization studies of HCV RNA in the liver should be performed. The end point for therapy should be the absence of HCV RNA in the liver. Until there is a culture system for HCV or an assay capable of detecting a single molecule of HCV RNA, the possibility of residual infection cannot be excluded.

Vincent Agnello, M.D.
Edith Nourse Rogers Memorial Veterans Affairs Hospital, Bedford, MA 01730

Glenn Knight, Ph.D.
Gyorgy Abel, M.D.
Lahey Clinic, Burlington, MA 01805

3 References

1. 1

   Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751-756
   Full Text | Web of Science | Medline

2. 2

   Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327:1490-1495
   Full Text | Web of Science | Medline

3. 3

   Madi N, Steiger G, Estreicher J, Schifferli JA. Defective immune adherence and elimination of hepatitis B surface antigen/antibody complexes in patients with mixed essential cryoglobulinemia type II. J Immunol 1991;147:495-502
   Web of Science | Medline

To the Editor:

Interferon therapy is generally safe, but side effects can occur. Early identification of patients who do not have a response to the drug could spare them unnecessary therapy. It is not clear from the article by Misiani et al. whether an effective response to interferon alfa-2a can be accurately predicted by the decrease in cryoglobulin levels and the absence of detectable HCV RNA after 16 weeks of treatment. In other words, can the patients who have no change in their cryoglobulin levels by 16 weeks be considered not to have had a response to interferon, and can therapy be discontinued for such nonresponders?

Daniel R. Ganger, M.D.
Donald M. Jensen, M.D.
Rush Medical College, Chicago, IL 60612

Author/Editor Response

The authors reply:

To the Editor: Dr. Agnello and his colleagues suggest that the disappearance of HCV RNA from the serum of patients with HCV-associated cryoglobulinemia may be due to the immunomodulatory rather than the antiviral activity of interferon alfa. They postulate that interferon alfa may act primarily by inhibiting the formation of cryoglobulins, with the ensuing accelerated clearance of HCV-containing immune complexes.

To test this hypothesis, and assuming that the cryoglobulins would have delayed the disappearance of HCV RNA, we performed serial analyses of serum samples and cryoprecipitates from patients who had a response to interferon alfa. Regardless of the initial levels of cryoglobulins, HCV RNA was not detected in the serum samples from 13 of the 15 responders after 4 to 12 weeks of treatment, a result similar to that reported in patients with chronic hepatitis C1. In several cases, HCV viremia disappeared before there was any measurable decrease in cryoglobulin levels. Moreover, in all but 1 of the 15 patients, HCV RNA was cleared simultaneously from both serum and cryoprecipitate.

The disappearance of HCV RNA from serum and cryoprecipitate does not establish eradication of the virus from the body. In situ hybridization of HCV RNA in the liver is considered a more sensitive method for detecting replicating HCV. A negative result, however, does not invariably rule out ongoing infection, possibly because HCV may be present in extrahepatic sites2. In addition, this technique requires a liver biopsy, which we consider unwarranted in patients who do not have obvious signs of liver disease.

Drs. Ganger and Jensen wonder whether the decrease in serum cryoglobulin levels can be used as an early marker of a response to interferon alfa therapy. In our study, in spite of the significant difference between patients who had a response to interferon and those who did not, changes in cryoglobulin levels after 16 weeks of treatment were not helpful in making decisions about therapy for individual patients. At 16 weeks, the serum level of cryoglobulins was decreased in 2 of the 10 nonresponders, whereas it remained unchanged in 2 of the 15 patients who subsequently had a response to interferon alfa therapy. A positive PCR assay at 16 weeks of treatment could not be used to identify the nonresponders, since at that time serum samples from 2 of the 15 responders were still positive for HCV RNA.

Rocco Misiani, M.D.
Piermario Bellavita, M.D.
Omar Vicari, Biol.Sc.D.
Ospedali Riuniti, 24128 Bergamo, Italy

2 References

1. 1

   Garson JA, Brillanti S, Ring C, et al. Hepatitis C viraemia rebound after “successful” interferon therapy in patients with chronic non-A, non-B hepatitis. J Med Virol 1992;37:210-214
   CrossRef | Web of Science | Medline

2. 2

   Nouri Aria KT, Sallie R, Sangar D, et al. Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization. J Clin Invest 1993;91:2226-2234
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   ANGELA RUIZ-EXTREMERA, JAVIER SALMERÓN, CRISTINA TORRES, PALOMA MUÑOZ DE RUEDA, FRANCISCO GIMÉNEZ, CONCEPCIÓN ROBLES, MARIA TERESA MIRANDA. (2000) Follow-up of transmission of hepatitis C to babies of human immunodeficiency virus-negative women: the role of breast-feeding in transmission. The Pediatric Infectious Disease Journal 19:6, 511-516
   CrossRef

2. 2

   Björn Fischler, Gudrun Lindh, Susanne Lindgren, Marianne Forsgren, Madeleine Von Sydow, Per Sangfelt, Anette Alaeus, Lena Harland, Erik Enockson, Antal Nemeth. (1996) Vertical Transmission of Hepatitis C Virus Infection. Scandinavian Journal of Infectious Diseases 28:4, 353-356
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