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Intravenous immunoglobulin and hepatitis C virus: the British episode
CLINICAL THERAPEUTICS®/VOL. 18, SUPPL. B, 1996
Intravenous Immunoglobulin and Hepatitis C Virus: The British Episode Christopher Healey, MBChB, MRCP, 1 and Helen Chapel, MA, MD, MRCP, FRCPath 2 1Departmentof Gastroenterology,and 2Departmentof Immunology, OxfordRadcliffe Hospital, Oxford, England
Gammagard ®*has been used in the United Kingdom to prevent bacterial infections in patients with primary and secondary antibody deficiencies since the initial clinical trial in patients with chronic lymphocytic leukemia in 1984.1 Routine monitoring of liver function tests before any intravenous immunoglobulin (IGIV) is administered and at regular intervals (usually every 3 to 6 weeks) has been the policy of clinical immunologists in the United Kingdom. 2 Outbreaks of hepatitis C virus (HCV) in the United Kingdom, 3,4 as well as elsewhere in Europe and the United States, ensured that such monitoring was widespread. The first abnormal liver function tests in patients receiving IGIV encountered in our center in more than 10 years were
*Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
0149-2918/96/$3.50
confirmed in February 1994 and caused considerable concern. Initially, there were four patients with acute hepatitis, two of whom had jaundice. A search of infusion records showed that all four patients were receiving Gammagard; two batches were identified that were common to these four patients. The same day, Gammagard was withdrawn worldwide because HCV had been confirmed the previous weekend in patients in Spain and Sweden. Three batches had been identified in Europe as being associated with these cases of HCV; only one of these was imported into the United Kingdom. This batch (namely, 93F21) was one of the two suspected batches in our center. An immediate scrutiny of all other batches of Gammagard used in our center during the preceding 6 months revealed that patients who had not received batch 93F21 had no record of detectable changes in liver function assays. 93
CLINICAL THERAPEUTICS*
Patient records were examined to identify which of the 31 patients receiving Gammagard received batch 93F21, either in the hospital or as home therapy. Patients who received this batch were contacted to verify the batch number, to provide counseling, and to draw blood for liver function and polymerase chain reaction (PCR) testing. Twenty patients in our center had received this infected lot. We contacted other clinical immunologists in the United Kingdom to alert them to the contaminated batch number and to set up a UK collaboration with other immunologists involved. Investigation and treatment protocols were planned in conjunction with hepatologists. Dr. Peter Simmonds of the University of Edinburgh Medical School in Scotland agreed to genotype all Gammagard recipients. A meeting was arranged with European colleagues and representatives of the US Food and Drug Administration to plan a further European collaboration in early March 1994. Thirty-six patients in 19 UK centers had received the contaminated batch 93F21. To date, 34 patients have been followed up for 14 months. Of these, 29 were shown on PCR tests to be HCV-positive on two or more occasions within 3 months. Almost all had abnormal serum alanine aminotransferase levels, often reaching levels above 1000 U/L. The time from the infusion of contaminated material to abnormal liver function tests also varied; in one patient, the time was more than 250 days. Sera collected before administration of Gammagard were retrieved from storage and tested using PCR for evidence of previous HCV contamination. There were no obvious distinguishing features between patients who became HCV-positive after an infusion of contam94
inated material and those who did not, although the number of patients studied are few. Two patients who were persistently HCV-PCR-negative underwent HCV antibody seroconversion between 4 and 6 months after exposure and both had transient increases in alanine aminotransferase levels during that period. Treatment in the acute phase of HCV infection with interferon alfa (Wellcome Ltd., Beckenham, Kent, United Kingdom) 6 million units subcutaneously three times a week was begun in 17 patients. Most patients had a rapid biochemical response and became asymptomatic. Liver biopsies were done in eight patients, six of whom completed interferon alfa therapy at the initial dose. However, chronic hepatitis, fibrosis, and, in one patient, cirrhosis have developed. Further combination therapy is necessary. This episode in the United Kingdom reflects the experience of patients similarly contaminated in Sweden and Boston. Details of the transmission of HCV infection and patients' response to treatment can be found elsewhere. 5,6
REFERENCES 1. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection of chronic lymphocytic leukemia. NEJM. 1988;319: 902-907. 2. Chapel HM. Consensus on diagnosis and management of primary antibody deficiencies. BMJ. 1994;308:581-585. 3. Lever AM, Webster AD, Brown D, Thomas HC. Non-A non-B hepatitis occurring in agammaglobulinaemic patients after intra-
C. HEALEY AND H. CHAPEL
venous immunoglobulin. Lancet. 1984;2: 1062-1064.
interferon in agammaglobulinaemia. Gastroenterology. In press.
4. Williams PE, Yap PL, Gillon J, et al. Transmission of non-A, non-B hepatitis by pH4-treated intravenous immunoglobulin. Vox Sang. 1989;57:15-18.
6. Healey C J, Sabharwal NK, McOmish E et al. Outbreak of acute hepatitis C following intravenous immunoglobulin therapy. Hepatology. 1994;20:249A. Abstract.
5. Healey CJ, Watson J, Durridge M, et al. Treatment of acute hepatitis C with alpha
95
Intravenous Immunoglobulin and Hepatitis C Virus: The British Episode Christopher Healey, MBChB, MRCP, 1 and Helen Chapel, MA, MD, MRCP, FRCPath 2 1Departmentof Gastroenterology,and 2Departmentof Immunology, OxfordRadcliffe Hospital, Oxford, England
Gammagard ®*has been used in the United Kingdom to prevent bacterial infections in patients with primary and secondary antibody deficiencies since the initial clinical trial in patients with chronic lymphocytic leukemia in 1984.1 Routine monitoring of liver function tests before any intravenous immunoglobulin (IGIV) is administered and at regular intervals (usually every 3 to 6 weeks) has been the policy of clinical immunologists in the United Kingdom. 2 Outbreaks of hepatitis C virus (HCV) in the United Kingdom, 3,4 as well as elsewhere in Europe and the United States, ensured that such monitoring was widespread. The first abnormal liver function tests in patients receiving IGIV encountered in our center in more than 10 years were
*Trademark: Baxter Healthcare Corporation, Hyland Division, Glendale, California.
0149-2918/96/$3.50
confirmed in February 1994 and caused considerable concern. Initially, there were four patients with acute hepatitis, two of whom had jaundice. A search of infusion records showed that all four patients were receiving Gammagard; two batches were identified that were common to these four patients. The same day, Gammagard was withdrawn worldwide because HCV had been confirmed the previous weekend in patients in Spain and Sweden. Three batches had been identified in Europe as being associated with these cases of HCV; only one of these was imported into the United Kingdom. This batch (namely, 93F21) was one of the two suspected batches in our center. An immediate scrutiny of all other batches of Gammagard used in our center during the preceding 6 months revealed that patients who had not received batch 93F21 had no record of detectable changes in liver function assays. 93
CLINICAL THERAPEUTICS*
Patient records were examined to identify which of the 31 patients receiving Gammagard received batch 93F21, either in the hospital or as home therapy. Patients who received this batch were contacted to verify the batch number, to provide counseling, and to draw blood for liver function and polymerase chain reaction (PCR) testing. Twenty patients in our center had received this infected lot. We contacted other clinical immunologists in the United Kingdom to alert them to the contaminated batch number and to set up a UK collaboration with other immunologists involved. Investigation and treatment protocols were planned in conjunction with hepatologists. Dr. Peter Simmonds of the University of Edinburgh Medical School in Scotland agreed to genotype all Gammagard recipients. A meeting was arranged with European colleagues and representatives of the US Food and Drug Administration to plan a further European collaboration in early March 1994. Thirty-six patients in 19 UK centers had received the contaminated batch 93F21. To date, 34 patients have been followed up for 14 months. Of these, 29 were shown on PCR tests to be HCV-positive on two or more occasions within 3 months. Almost all had abnormal serum alanine aminotransferase levels, often reaching levels above 1000 U/L. The time from the infusion of contaminated material to abnormal liver function tests also varied; in one patient, the time was more than 250 days. Sera collected before administration of Gammagard were retrieved from storage and tested using PCR for evidence of previous HCV contamination. There were no obvious distinguishing features between patients who became HCV-positive after an infusion of contam94
inated material and those who did not, although the number of patients studied are few. Two patients who were persistently HCV-PCR-negative underwent HCV antibody seroconversion between 4 and 6 months after exposure and both had transient increases in alanine aminotransferase levels during that period. Treatment in the acute phase of HCV infection with interferon alfa (Wellcome Ltd., Beckenham, Kent, United Kingdom) 6 million units subcutaneously three times a week was begun in 17 patients. Most patients had a rapid biochemical response and became asymptomatic. Liver biopsies were done in eight patients, six of whom completed interferon alfa therapy at the initial dose. However, chronic hepatitis, fibrosis, and, in one patient, cirrhosis have developed. Further combination therapy is necessary. This episode in the United Kingdom reflects the experience of patients similarly contaminated in Sweden and Boston. Details of the transmission of HCV infection and patients' response to treatment can be found elsewhere. 5,6
REFERENCES 1. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. Intravenous immunoglobulin for the prevention of infection of chronic lymphocytic leukemia. NEJM. 1988;319: 902-907. 2. Chapel HM. Consensus on diagnosis and management of primary antibody deficiencies. BMJ. 1994;308:581-585. 3. Lever AM, Webster AD, Brown D, Thomas HC. Non-A non-B hepatitis occurring in agammaglobulinaemic patients after intra-
C. HEALEY AND H. CHAPEL
venous immunoglobulin. Lancet. 1984;2: 1062-1064.
interferon in agammaglobulinaemia. Gastroenterology. In press.
4. Williams PE, Yap PL, Gillon J, et al. Transmission of non-A, non-B hepatitis by pH4-treated intravenous immunoglobulin. Vox Sang. 1989;57:15-18.
6. Healey C J, Sabharwal NK, McOmish E et al. Outbreak of acute hepatitis C following intravenous immunoglobulin therapy. Hepatology. 1994;20:249A. Abstract.
5. Healey CJ, Watson J, Durridge M, et al. Treatment of acute hepatitis C with alpha
95