Hepatitis C from Gammagard®


 What is Hepatitis

 How is it Transmitted

 Long Term Prognosis

 Complications of HCV

 Liver Biopsy

 Treatment Info (Interferon, Herbal, etc)

 Lab Tests (PCR, Genotype,etc.)

 Nutrition & Alternative Info

 Patient Information (Support Groups, Doctor Listing, etc)

 Related Webpages

 Transplant Info

 HCV Webrings

 My guestbookbook

 Site Awards

 FAQ & Disclaimers

Hepatitis C from Gammagard®, An Intravenous Immunoglobulin [IGIV]
By Richard Alexander, Esq.

San Jose, California attorney Richard Alexander, a National Honor Scholar at The Law School, University of Chicago, was certified as a civil trial advocate by the National Board of Trial Advocacy in 1980, has been specially recognized as a Trial Lawyer by the California Trial Lawyers Association, is a former member of the Board of Governors of The State Bar of California, currently serves as Vice President of Consumer Attorneys of California and is a founding member of the National Association of Consumer Advocates. He is the founder of The Alexander Law Firm [http://www.alexanderlaw.com], a medium size law firm specializing in individual and class action litigation arising from negligence, toxic chemical, defective product, mass accident, environmental and fraud cases on behalf of consumers and small businesses. The firm holds Martindale-Hubbell's highest rating and is recognized in the List of Preeminent Law Firms in the United States. The firm sponsors The Consumer Law Page [http://consumerlawpage.com] on the World Wide Web. Copyright Richard Alexander 1996.

In February, 1994 Baxter Healthcare Corporation withdrew from world markets Gammagard®, an immunoglobulin administered intravenously to those with acquired or congential immune disorders, after 112 people in the U.S. were reported having symptoms of hepatitis C, the most fatal form of the this liver disease. Also withdrawn at the same time was a companion drug, Polygam®, also an IGIV product. Hepatitis C is the leading cause of liver failure and is a recognized precursor to cancer of the liver, taking nearly 10,000 Americans every year. The virus is particularly dangerous because even though a person is infected he/she may show no signs of any disease until many years later. In the meantime, the virus can be transferred to others, primarily by sexual intercourse. Anyone with hepatitis C is a considered a lifelong carrier. Gammagard® was introduced to the U. S. in 1986. It is made by extracting human proteins from plasma. Plasma is obtain from blood donors by centrifuging donated blood, separating the plasma and returning the red blood cells to the donor. Plasma donors can sell or provide plasma several times a week. Polygam® differs only to the extent that it is made from American Red Cross plasma. Gammagard® was most commonly used in the treatment of children with leukemia. Beginning in early 1994 Baxter learned that Gammagard® recipients were being diagnosed with hepatitis. At that time Baxter withdrew both drugs due to possible contamination with hepatitis C virus. Reports of hepatitis C infections in the U.S. spiked dramatically in March, 1994 among persons who had received Gammagard® or Polygam®. The Center for Disease Control reports that the "absence of other risk factors among these patients" indicates that hepatitis "was most likely transmitted by administration of Gammagard®." The Center is actively seeking people who have received Gammagard® or Polygam® between September 1992 and February 1994 and who probably have been exposed to contaminated product. Not everyone who received either gamma globulin product will develop hepatitis. Those who have been exposed to the Hepatitis C Virus through contaminated Gammagard have a 60-70% probability of suffering chronic hepatitis, which can be fatal. For those who have been exposed, early diagnosis and treatment increases the chances for a positive outcome. The CDC has written medical care providers to notify Gammagard® patients to be tested for hepatitis. It is unknown how successful that notification effort has been. In May, 1994 Baxter was authorized by the FDA to sell a new, purified version of Gammagard® now labeled as Gammagard® S/D. The "S/D" designation refers to treatment of gamma globulin with solvents and detergents that sterilize the drug of viruses, including HIV and hepatitis. Nationwide litigation has developed as a result of the injuries and exposures caused by this contaminated drug. Anyone who received Gammagard, whether or not that person has tested positive for hepatitis, probably has a claim and should not delay in taking action once they discover the IGIV they received was a Baxter product. In all cases of delayed injury, the statute of limitations presents a serious concern. By way of a general explanation, which is not intended to be legal advice since that can only come from a lawyer who knows all the facts concerning a particular case or claim, statutes of limitations are in effect in every state in the United States. These laws require that a person who knows, or reasonably should know, that they have been injured must file suit within a limited time frame. The most common limit is two years, although several states, including California, have a one year statute of limitations. In cases where an action for damages is filed one day after the allowable period for filing suit, the wrongdoer is judgment proof because the statute provides a complete and total defense. Anyone believing they may have a valid claim should take immediate action to make sure they have filed suit before the running of the statutory period.

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

Hepatitis C Virus and Intravenous Immune Globulin

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)


BACKGROUND: Three reported Swedish cases of hepatitis C in patients receiving an intravenous immunoglobulin (Gammagard, Baxter Healthcare, Deerfield, IL) were among the first to bring to light a worldwide outbreak of hepatitis C associated with non- solvent/detergent (SD)-treated Gammagard. In February 1994, all implicated batches of Gammagard were recalled and exposed patients traced.

STUDY DESIGN AND METHODS: Sera from all identified and hepatitis C- viremic Swedish and Danish patients (n = 14) exposed to the implicated batches underwent hepatitis C virus genotyping and sequencing of the core region and hypervariable region 1 of E2. Genomic amplification was also done on 15 non-SD-treated batches of Gammagard.

RESULTS: Twelve patients were infected with subtype la and surprisingly, two with subtype 2b. Analysis of the core region showed identical sequences in four patients and the only consistently positive batch. Five patients shared another sequence, whereas three other subtype la patients each manifested unique sequences. The two subtype 2b isolates were identical. Genomic fingerprinting of the hypervariable region confirmed identity within each group with great stringency. Amplification with isolate- specific primers showed mixed infection in one patient whose exposure was confined to a single batch.

CONCLUSION: The few batches implicated presumably were contaminated with several strains.

Source: TRANSFUSION 1997 MAR;37(3):313-320

Home | What is HCV | Transmission | Future | Complications | Biopsy | Treatment | Lab | Nutrition | Patient | Links | Transplant | Webrings | guestbookbook | Awards | FAQ |