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HCV and Intravenous Immune Globulin

Journal of American Medical Association 1997;277:627-628
JAMA Letters - February 26, 1997

To the Editor.--The diagnosis of common variable immunodeficiency (CVI) is made by demonstrating the lack of the ability to generate new antibody responses or recall antibody responses against protein antigens, such as tetanus and diphtheria, coupled with low serum immunoglobulin levels and recurrent infections. It is interesting that in the cohort described by Dr Bresee and colleagues,[1] 26 of 29 immune-deficient patients (the bulk of whom appear to have CVI) who were documented to be positive for hepatitis C virus (HCV) nucleic acid were able to generate an antibody response against HCV proteins. Is there some special feature on the protein constituents of HCV that enables it to overcome the profound immune dysfunction characteristic of CVI?

Eric Macy, MD; Kaiser Permanente Health Care Program; San Diego, Calif

1. Bresee JS, Mast EE, Coleman PJ, et al. Hepatitis C virus infection associated with administration of intravenous immune globulin: a cohort study. JAMA. 1996;276:1563-1567.
(JAMA. 1997;277:627)

To the Editor.--Dr Bresee et al[ 1] reported an epidemic of HCV infection among immunodeficient persons treated with Gammagard intravenous immune globulin (IGIV). The aggregate of 23 cases in 1 clinic was convincingly attributed to 9 or more lots. Related cases are known elsewhere in the United States, as well as in the United Kingdom, Sweden, and Spain. Investigators of the Boston, Mass, aspect of the epidemic concluded that the introduction of more sensitive donor screening for the antibody to HCV (anti-HCV) resulted in increased amounts of uncomplexed virus entering the IGIV fraction.[2] However, other factors may have been equally or more important for this product.

The HCV cases in 1983 associated with Gammagard from a pilot plant[ 3] provoked only a brief postmarketing surveillance study, interpreted as showing safety. The subsequent absence of reported cases until 1994 associated with any US Gammagard IGIV preparation does not mean that none occurred. For the Boston lots, Gammagard had an infection rate of just 11%. At that level in more typically sized immunology clinics, no more than a single case might occur and be dismissed as community acquired. Suspicion about Gammagard IGIV would be low because of the usual safety of all immunoglobulin preparations. Only routine monitoring of aminotransferase levels demonstrated the Gammagard-spread cases in the United Kingdom.[4]

The investigators suggest differences in manufacture may have contributed to Gammagard transmission, but they believe that no single manufacturing error would persist over several months. The latter statement, however, deserves scrutiny. The investigators similarly mention but fail to discuss any coinciding changes in paid plasmapheresis donor sources that could have increased the HCV load in plasma pools. In addition, the manufacturer's Polygam IGIV, made for the American Red Cross from voluntary donations, did not transmit to the study population. The Food and Drug Administration (FDA) stated that the same manufacturing process was used for both Gammagard and Polygam.[ 5] In Boston, Polygam was given to 129 persons without implication in HCV transmission.

The lack of HCV cases from other IGIV brands, particularly Polygam, must mean epidemiologically that there were other factors that placed Gammagard beyond the margin of safety compared with other brands. The present use of viral inactivation steps in all products should not end the inquiry into manufacture and viral burden, because all contributions to virus transmission must be identified to minimize them in the future.

James W. Mosley, MD; University of Southern California; Los Angeles

1. Bresee JS, Mast SE, Coleman PJ, et al. Hepatitis C virus infection associated with administration of intravenous immune globulin: a cohort study. JAMA. 1996;276:1563-1567.
2. Yei S, Yu MW, Tankersley DL. Partitioning of hepatitis C virus during Cohn-Oncley fractionation of plasma. Transfusion. 1992;32:824-828.
3. Ochs HD, Fischer SH, Virant FS, et al. Non-A, non-B hepatitis and intravenous immune globulin. Lancet. 1985;1:404-405.
4. Healey CJ, Sabharwal NK, Daub J, et al. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus screened intravenous immunoglobulin therapy. Gastroenterology. 1996;110:1120-1126.
5. Yu MW, Finlayson JS, Tankersley DL. Hepatitis C virus transmission by intravenous immunoglobulin. Lancet. 1995;346:374-375.
(JAMA. 1997;277:627)

In Reply.--We, like Dr Macy, did not expect the high rate of detection of anti-HCV in this cohort of immunodeficient patients. In prior reports of HCV transmission to patients with primary hypogammaglobulinemia following IGIV administration, 2% to 27% of patients with HCV RNA detected by reverse transcriptase-polymerase chain reaction had detectable anti-HCV.[1,2] Variability in the proportion of immunodeficient patients with detectable anti-HCV may reflect differences in the patient population, differences in the timing of anti-HCV testing, or both. We are not aware of any unique features of HCV or the recombinant HCV antigens in the antibody test that would account for immunodeficient patients responding at a higher rate to these antigens than to other viral antigens.

We agree with Dr Mosley that further laboratory studies are needed to determine the exact reasons for the infectivity of Gammagard. However, there was no evidence that changes in either plasma donor sources or manufacturing practices played a significant role.[3] At least 2 factors may be related to transmission being associated with Gammagard, but not with Polygam, which was produced using an identical manufacturing process.

Although the first lot of Gammagard derived exclusively from second-generation anti-HCV enzyme immunoassay (EIA) (HCV EIA 2.0, Abbott Laboratories, North Chicago, Ill)-screened plasma was manufactured in February 1993, the first lot of Polygam made only from EIA-screened plasma was manufactured in August 1993 and was not available for distribution until October 1993.[3] Thus, few lots of Polygam derived entirely from EIA-screened plasma were used before the products were withdrawn in February 1994. In addition, Gammagard was produced using plasma from paid donors, which probably had higher HCV titers compared with the recovered plasma from volunteer donors that was used to produce Polygam.

Although sporadic HCV cases associated with IGIV administration could be missed by passive surveillance, this outbreak was detected because of reports by observant physicians who cared for only a few patients receiving IGIV. Based on epidemiologic evidence from our investigation, we believe the period of risk for HCV transmission from Gammagard was confined to a relatively short period that began coincident with changes in plasma-screening policies. All symptomatic cases among Gammagard recipients reported in the United States and from other countries had onset of illness after the distribution of Gammagard lots produced with EIA-screened plasma. Infection was also strongly associated with receipt of Gammagard produced from EIA-screened plasma and not with Gammagard produced from unscreened or first-generation screened plasma. In addition, although detection of HCV RNA by reverse transcriptase-polymerase chain reaction does not necessarily indicate the presence of infectious virus, HCV RNA was detected in a substantially larger proportion of Gammagard lots manufactured using EIA-screened plasma, and in greater titers, compared with lots produced from unscreened or first-generation-screened plasma.[ 4,5] Moreover, the HCV RNA in Gammagard made from EIA-screened plasma had a buoyant density of free (not complexed) hepatitis C virions.[5]

Currently, all US-licensed IGIV products have a viral inactivation step(s) included in the manufacturing process, and no hepatitis C cases have been documented in patients who have received such products.

Joseph S. Bresee, MD; Eric E. Mast, MD, MPH; Mei-ying W. Yu, PhD; Lynda C. Schneider, MD; Miriam J. Alter, PhD; Centers for Disease Control and Prevention, Atlanta, Ga

1. Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T. Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl J Med. 1994;331:1607-1611.
2. Healey CJ, Sabharwal NK, Daub J, et al. Outbreak of acute hepatitis C following the use of anti-hepatitis C virus-screened intravenous immunoglobulin therapy. Gastroenterology. 1996;110:1120-1126.
3. Yu MW, Finlayson JS, Tankersley DL. Hepatitis C virus transmission by intravenous immune globulin. Lancet. 1995;346:374-375.
4. Yu MW, Mason BL, Guo ZP, et al. Hepatitis C transmission associated with intravenous immunoglobulin. Lancet. 1995;345:1173-1174.
5. Yu MW, Mason BL, Guo ZP, Renzi PM, Tankersley DL. Detection and characterization of HCV RNA in an intravenous immune globulin preparation associated with hepatitis C transmission. In: Rizetto M, ed. Proceedings of the 1996 International Symposium on Viral Hepatitis and Liver Disease. Rome, Italy. In press.
(JAMA. 1997;277:627-628)

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