EDITORIALS
ANNALS of Internal Medicine Volume 9 1 • Number 6 December 1 9 7 9
P U B L I S H E D monthly by the American College of Physicians under t h e direction of the Publications Committee of the Board of Regents; see advertising page 1-5 for listing of the Committee, the Editorial Staff, the Editorial Board, and the Business Staff. Editorial Policy A N N A L S O F I N T E R N A L M E D I C I N E pub-
lishes original articles, case reports, topical reviews, editorials, book reviews, and medical news for internal medicine and related fields. F u r t h e r details on the kinds of manuscripts that will be considered for possible publication are given in " I N F O R M A T I O N F O R A U T H O R S " on advertising page 1-6. Selected books will be critically reviewed or briefly described monthly. Review copies should be sent to the Assistant Editor. T h e content of A N N A L S O F I N T E R N A L
M E D I C I N E is protected by copyright. Manuscripts are accepted for publication with the understanding that their contents, all or in part, have not been published elsewhere and will not be published elsewhere, except in abstract form or by the express consent of t h e Editor. A N N A L S O F I N T E R -
N A L M E D I C I N E accepts n o responsibility for statements made by contributors. Subscriptions A N N A L S O F I N T E R N A L M E D I C I N E is is-
sued monthly; new volumes begin with the January a n d July issues each year. Subscription price per year, net postpaid, A R E A I (North a n d Central America, Puerto Rico, Canal Zone): Students, $12.50; physicians out of medical school 4 years o r less, $18.75; all others, $25.00. A R E A II (all countries not in Area I): Students, $14.00; physicians out of medical school 4 years o r less, $21.00; all others, $28.00. Single copies of recent issues: $3.00 in N o r t h a n d Central American countries, Puerto Rico, and Canal Zone; $3.25 in other countries; price of supplements provided on request. Checks should be made payable to the American College of Physicians and remitted to the Circulation Manager. Communications to the Editor or the Circulation Manager should be sent to
Annals of Internal Medicine 4 2 0 0 Pine St. Philadelphia, PA 1 9 1 0 4 USA Phone: 2 1 5 / 2 4 3 - 1 2 0 0
914
December
Hepatitis B Immune Globulin: Some Progress and Some Problems T H E DISCOVERY at the end of the 1960s that the Australia antigen (now called hepatitis B surface antigen [HBsAg]) is a component of hepatitis B virus (HBV) opened the door to preparation of hepatitis B immune globulin (HBIG) having titers of specific antibody (anti-HBs) many hundredfold times higher than those in standard immune serum globulin (ISG). As rapidly as anti-HBs-rich units of plasma could be identified and batches of HBIG prepared, studies of prophylaxis of type B hepatitis were carried out (1-6). Unfortunately, these investigations did not provide an easily interpretable answer to relative usefulness of HBIG and ISG. Hence, there has been controversy and confusion. Although data about the protective efficiency of HBIG had limitations, their cumulative weight was sufficient for the Food and Drug Administration (FDA) to approve the product in June 1977. The use accepted for purposes of licensure was accidental exposure of health-care personnel. The fact that other indications have not been added to the packaging insert, however, does not preclude administration for other purposes considered appropriate by the medical community. The first set of recommendations on HBIG use was that of the Public Health Service Advisory Committee on Immunization Practices (ACIP), issued in late December 1977 (7). This group accepted the value of HBIG for accidental percutaneous and mucosal exposures and endorsed potential usefulness for infants whose mothers had acute type-B hepatitis in the third trimester. The ACIP, however, placed particular emphasis on the investigations in which HBIG and ISG had apparently had similar effects; in the actual recommendations for HBIG, the committee mentioned substitution of ISG for HBIG in terms that could be interpreted as implying equality in effectiveness. Since issuance of these guidelines, those persons particularly concerned with the evaluation of HBIG have increasingly believed that the ACIP statement overemphasized the actual value of ISG and was too restrictive in the uses of HBIG it recommended. This attitude was voiced by Prince (8) in July 1978 in a call for a broad reassessment. More recently, Seeffand Hoofnagle (9), on the basis of a very detailed review, recommended a broadening of indications of HBIG to include infants born to mothers with either acute or chronic type B hepatitis, as well as seronegative sexual contacts. In accompanying editorials, Krugman and Mosley (10) generally agreed with their suggestions. There seemed, however, no great likelihood that new information to resolve some of the perplexities would be immediately forthcoming. A thorough reconsideration is now needed because of unexpected findings reported in this issue (11) by Hoofnagle and colleagues. In their large-scale comparison of HBIG and ISG for needle-stick exposures (6), they used a batch of ISG manufactured long before HBsAg screening of the starting material was possible. Serologic studies of its recipients showed that about one third were actively immunized, including persons whose accidental exposure was belatedly found to be to HBsAg-negative blood. Laboratory studies of that ISG preparation revealed complexed
1979 • Annals of Internal Medicine • Volume 91 • Number
Downloaded from https://annals.org by Tulane University user on 01/13/2019
6
HBsAg in an amount that must have been sufficient to induce active anti-HBs production even though there was no viral replication. Active immunization by such preparations would be expected to have a definite effect in preexposure prophylaxis, and perhaps even in some instances of postexposure administration. Thus, the amount of HBsAg rather than anti-HBs in ISG may well have been the responsible factor in some investigations in which I S G seemed to be useful (2, 12). This finding would perhaps account for the lack of correlation between anti-HBs content and putative protection in a set of retrospective assays by Ginsberg and co-workers (13). While these re-evaluations are going on, what should the physician d o when dealing with a patient exposed to HBV? It is my own feeling that whenever he makes the decision that prophylaxis should be attempted, H B I G rather than I S G should be used. By F D A regulation, H B I G must have an anti-HBs titer at least equal to the Bureau of Biologies' standard of 1:100 000. Some lots of ISG manufactured after initiation of HBsAg screening of plasma donors may have anti-HBs titers of 1:100 t o even 1:1000 (14), but such levels are not necessarily found in all batches. Anti-HBs-positive units of plasma may now be diverted to the production of H B I G , and lots of ISG presently on pharmacy shelves may have lower titers than they did 5 years ago. What situations of potential exposure to HBV carry a sufficient risk to justify the high cost of prophylaxis with HBIG? These include inadvertent administration of HBsAg-positive units of blood or blood derivatives; accidental exposures of health-care personnel; sexual exposure to acute disease when nonpromiscuity makes subsequent re-exposure unlikely; and birth to a mother with acute type-B hepatitis. On the other hand, exposure in a work situation and nonsexual contact even in a household setting seem to pose no real risk in most cases. Under any circumstances, one must consider the level of infectivity of the source, the severity of the exposure, and the consequences of infection for the potential host. As an example of the last point, Dosik and Jhaveri (15) gave six doses of 5 m L each at intervals of 3 weeks to the newborn child of a carrier mother who had lost a previous infant from fulminant hepatitis. One of the major problems at present is timely availability of pertinent serologic results concerning the source case and the exposed person. Reliable and sensitive radioimmunoassays are commercially available for HBsAg and anti-HBs. Radioimmunoassay kits, however, are sold only in lots of 100 tests and have an expiration date of 30 d from release by the manufacturer. These facts make it economically unfeasible for many hospitals and clinical laboratories to carry out a few tests on unexpected demand. Thus, it is common for there to be a delay of several days before the physician is certain whether the source is HBsAg-positive or the person exposed is susceptible. Even more delay is then imposed if it is decided to ascertain the hepatitis B e antigen (HBeAg) status of an HBsAg-positive source. Detectability of HBeAg indeed correlates with likelihood of transmission, and testing can decrease the number of instances in
which H B I G is indicated (16). Unfortunately, no HBeAg test has yet been licensed, and it is not advisable to delay the decision about prophylaxis until arrangements can be made for it. After licensure and prompt availability are general, then the HBeAg result should be taken into account. Recognizing that delay after exposure to H B I G administration progressively lessens the likelihood of benefit, how long is too long? Studies of postexposure prophylaxis for practical purposes (that is, to maximize the chance of showing an effect) used 7 d. Although arbitrary, it seems worthwhile to continue to impose that limit upon ourselves in the gathering of data to make a decision. Otherwise, we unduly jeopardize the chances of success when we use H B I G . All of these considerations place a considerable burden upon the physician to be aware of the relative risks from various types of exposure, and the meaning of a number of tests not routinely used. Unfortunately, there is no foreseeable substitute for being well informed if the physician is t o make the best possible decision about benefit and cost. ( J A M E S W. M O S L E Y , M . D . ; Department
References 1. K R U G M A N S, G I L E S J P . Viral hepatitis, type B (MS-2-strain): further observations on natural history and prevention. N Engl J Med. 1973;288:755-60. 2. S Z M U N E S S W, P R I N C E A M , G O O D M A N M, E H R I C H C, P I C K R, A N S A R I
M. Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med. 1974;290:701-6. 3. IWARSON S, A H L M E N J, ERIKSSON E, et al. Hepatitis B immune globulin in prevention of hepatitis B among hospital staff members. / Infect Dis. 1977;135:473-7. 4. P R I N C E A M , S Z M U N E S S W, M A N N MK, et al. Hepatitis B immune
5.
6.
7.
8. 9.
globulin: final report of a controlled, multicenter trial of efficacy in prevention of dialysis-associated hepatitis. J Infect Dis. 1978;137:131-44. G R A D Y G F , L E E VA, P R I N C E AM, et al. Hepatitis B immune globulin for accidental exposures among medical personnel: final report of a multicenter controlled trial. J Infect Dis. 1978;138:625-38. SEEFF LB, W R I G H T EC, ZIMMERMAN HJ, et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin. Ann Intern Med. 1978;88:285-93. C E N T E R FOR DISEASE CONTROL. Immune globulins for protection against viral hepatitis. Morbid Mortal Weekly Rep. 1977;26:425-8, 4412. PRINCE AM. Use of hepatitis B immune globulin: reassessment needed. N Engl J Med. 1978;299:198-9. SEEFF LB, HOOFNAGLE JH. Immunoprophylaxis of viral hepatitis. Gastroenterology. 1979;77:161-82.
10. K R U G M A N S, H O L L I N G E R FB, M O S L E Y JW, M A Y N A R D JE. Immuno-
prophylaxis for viral 1979;77:186-91.
hepatitis—other
views.
Gastroenterology.
11. H O O F N A G L E J H , S E E F F LB, B A L E S ZB, W R I G H T EC, Z I M M E R M A N HJ, V E T E R A N S A D M I N I S T R A T I O N C O O P E R A T I V E S T U D Y G R O U P . Passive-
active immunity from hepatitis B immune globulin: reanalysis of a Veterans Administration cooperative study of needle-stick hepatitis. Ann Intern Med. 1979;91:813-8. 12. COOPERATIVE STUDY G R O U P . Prophylactic gamma globulin for prevention of endemic hepatitis: effects of US gamma globulin upon the incidence of viral hepatitis and other infectious diseases in US soldiers abroad. Arch Intern Med. 1971;128:723-37. 13. G I N S B E R G AL, C O N R A D M E , B A N C R O F T W H , L I N G CM, O V E R B Y LR.
Antibody to Australia antigen: detection with a simple radioimmune assay, incidence in military populations, and role in the prevention of hepatitis B with gamma globulin. J Lab Clin Med. 1973;82:317-25. 14. G R A D Y G F , R O D M A N M, LARSEN LH. Hepatitis B antibody in conventional y-globulin. J Infect Dis. 1975;132:474-7. 15. DOSIK H, JHAVERI R. Prevention of neonatal hepatitis B infection by Editorials
Downloaded from https://annals.org by Tulane University user on 01/13/2019
of
Medicine, University of Southern California School of Medicine, Los Angeles, and Liver Unit, Rancho Los Amigos Hospital, Downey, California)
915
high-dose hepatitis B immune globulin. N Engl J Med. 1978;298:602-3. 16. A L T E R HJ, SEEFF LB, K A P L A N PM, et al. Type B hepatitis: the infec-
916
tivity of blood positive for e antigen and D N A polymerase after accidental needlestick exposure. N Engl J Med. 1976;295:909-13. © 1 9 7 9 American College of Physicians
December 1979 • Annals of Internal Medicine • Volume 91 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/13/2019
ANNALS of Internal Medicine Volume 9 1 • Number 6 December 1 9 7 9
P U B L I S H E D monthly by the American College of Physicians under t h e direction of the Publications Committee of the Board of Regents; see advertising page 1-5 for listing of the Committee, the Editorial Staff, the Editorial Board, and the Business Staff. Editorial Policy A N N A L S O F I N T E R N A L M E D I C I N E pub-
lishes original articles, case reports, topical reviews, editorials, book reviews, and medical news for internal medicine and related fields. F u r t h e r details on the kinds of manuscripts that will be considered for possible publication are given in " I N F O R M A T I O N F O R A U T H O R S " on advertising page 1-6. Selected books will be critically reviewed or briefly described monthly. Review copies should be sent to the Assistant Editor. T h e content of A N N A L S O F I N T E R N A L
M E D I C I N E is protected by copyright. Manuscripts are accepted for publication with the understanding that their contents, all or in part, have not been published elsewhere and will not be published elsewhere, except in abstract form or by the express consent of t h e Editor. A N N A L S O F I N T E R -
N A L M E D I C I N E accepts n o responsibility for statements made by contributors. Subscriptions A N N A L S O F I N T E R N A L M E D I C I N E is is-
sued monthly; new volumes begin with the January a n d July issues each year. Subscription price per year, net postpaid, A R E A I (North a n d Central America, Puerto Rico, Canal Zone): Students, $12.50; physicians out of medical school 4 years o r less, $18.75; all others, $25.00. A R E A II (all countries not in Area I): Students, $14.00; physicians out of medical school 4 years o r less, $21.00; all others, $28.00. Single copies of recent issues: $3.00 in N o r t h a n d Central American countries, Puerto Rico, and Canal Zone; $3.25 in other countries; price of supplements provided on request. Checks should be made payable to the American College of Physicians and remitted to the Circulation Manager. Communications to the Editor or the Circulation Manager should be sent to
Annals of Internal Medicine 4 2 0 0 Pine St. Philadelphia, PA 1 9 1 0 4 USA Phone: 2 1 5 / 2 4 3 - 1 2 0 0
914
December
Hepatitis B Immune Globulin: Some Progress and Some Problems T H E DISCOVERY at the end of the 1960s that the Australia antigen (now called hepatitis B surface antigen [HBsAg]) is a component of hepatitis B virus (HBV) opened the door to preparation of hepatitis B immune globulin (HBIG) having titers of specific antibody (anti-HBs) many hundredfold times higher than those in standard immune serum globulin (ISG). As rapidly as anti-HBs-rich units of plasma could be identified and batches of HBIG prepared, studies of prophylaxis of type B hepatitis were carried out (1-6). Unfortunately, these investigations did not provide an easily interpretable answer to relative usefulness of HBIG and ISG. Hence, there has been controversy and confusion. Although data about the protective efficiency of HBIG had limitations, their cumulative weight was sufficient for the Food and Drug Administration (FDA) to approve the product in June 1977. The use accepted for purposes of licensure was accidental exposure of health-care personnel. The fact that other indications have not been added to the packaging insert, however, does not preclude administration for other purposes considered appropriate by the medical community. The first set of recommendations on HBIG use was that of the Public Health Service Advisory Committee on Immunization Practices (ACIP), issued in late December 1977 (7). This group accepted the value of HBIG for accidental percutaneous and mucosal exposures and endorsed potential usefulness for infants whose mothers had acute type-B hepatitis in the third trimester. The ACIP, however, placed particular emphasis on the investigations in which HBIG and ISG had apparently had similar effects; in the actual recommendations for HBIG, the committee mentioned substitution of ISG for HBIG in terms that could be interpreted as implying equality in effectiveness. Since issuance of these guidelines, those persons particularly concerned with the evaluation of HBIG have increasingly believed that the ACIP statement overemphasized the actual value of ISG and was too restrictive in the uses of HBIG it recommended. This attitude was voiced by Prince (8) in July 1978 in a call for a broad reassessment. More recently, Seeffand Hoofnagle (9), on the basis of a very detailed review, recommended a broadening of indications of HBIG to include infants born to mothers with either acute or chronic type B hepatitis, as well as seronegative sexual contacts. In accompanying editorials, Krugman and Mosley (10) generally agreed with their suggestions. There seemed, however, no great likelihood that new information to resolve some of the perplexities would be immediately forthcoming. A thorough reconsideration is now needed because of unexpected findings reported in this issue (11) by Hoofnagle and colleagues. In their large-scale comparison of HBIG and ISG for needle-stick exposures (6), they used a batch of ISG manufactured long before HBsAg screening of the starting material was possible. Serologic studies of its recipients showed that about one third were actively immunized, including persons whose accidental exposure was belatedly found to be to HBsAg-negative blood. Laboratory studies of that ISG preparation revealed complexed
1979 • Annals of Internal Medicine • Volume 91 • Number
Downloaded from https://annals.org by Tulane University user on 01/13/2019
6
HBsAg in an amount that must have been sufficient to induce active anti-HBs production even though there was no viral replication. Active immunization by such preparations would be expected to have a definite effect in preexposure prophylaxis, and perhaps even in some instances of postexposure administration. Thus, the amount of HBsAg rather than anti-HBs in ISG may well have been the responsible factor in some investigations in which I S G seemed to be useful (2, 12). This finding would perhaps account for the lack of correlation between anti-HBs content and putative protection in a set of retrospective assays by Ginsberg and co-workers (13). While these re-evaluations are going on, what should the physician d o when dealing with a patient exposed to HBV? It is my own feeling that whenever he makes the decision that prophylaxis should be attempted, H B I G rather than I S G should be used. By F D A regulation, H B I G must have an anti-HBs titer at least equal to the Bureau of Biologies' standard of 1:100 000. Some lots of ISG manufactured after initiation of HBsAg screening of plasma donors may have anti-HBs titers of 1:100 t o even 1:1000 (14), but such levels are not necessarily found in all batches. Anti-HBs-positive units of plasma may now be diverted to the production of H B I G , and lots of ISG presently on pharmacy shelves may have lower titers than they did 5 years ago. What situations of potential exposure to HBV carry a sufficient risk to justify the high cost of prophylaxis with HBIG? These include inadvertent administration of HBsAg-positive units of blood or blood derivatives; accidental exposures of health-care personnel; sexual exposure to acute disease when nonpromiscuity makes subsequent re-exposure unlikely; and birth to a mother with acute type-B hepatitis. On the other hand, exposure in a work situation and nonsexual contact even in a household setting seem to pose no real risk in most cases. Under any circumstances, one must consider the level of infectivity of the source, the severity of the exposure, and the consequences of infection for the potential host. As an example of the last point, Dosik and Jhaveri (15) gave six doses of 5 m L each at intervals of 3 weeks to the newborn child of a carrier mother who had lost a previous infant from fulminant hepatitis. One of the major problems at present is timely availability of pertinent serologic results concerning the source case and the exposed person. Reliable and sensitive radioimmunoassays are commercially available for HBsAg and anti-HBs. Radioimmunoassay kits, however, are sold only in lots of 100 tests and have an expiration date of 30 d from release by the manufacturer. These facts make it economically unfeasible for many hospitals and clinical laboratories to carry out a few tests on unexpected demand. Thus, it is common for there to be a delay of several days before the physician is certain whether the source is HBsAg-positive or the person exposed is susceptible. Even more delay is then imposed if it is decided to ascertain the hepatitis B e antigen (HBeAg) status of an HBsAg-positive source. Detectability of HBeAg indeed correlates with likelihood of transmission, and testing can decrease the number of instances in
which H B I G is indicated (16). Unfortunately, no HBeAg test has yet been licensed, and it is not advisable to delay the decision about prophylaxis until arrangements can be made for it. After licensure and prompt availability are general, then the HBeAg result should be taken into account. Recognizing that delay after exposure to H B I G administration progressively lessens the likelihood of benefit, how long is too long? Studies of postexposure prophylaxis for practical purposes (that is, to maximize the chance of showing an effect) used 7 d. Although arbitrary, it seems worthwhile to continue to impose that limit upon ourselves in the gathering of data to make a decision. Otherwise, we unduly jeopardize the chances of success when we use H B I G . All of these considerations place a considerable burden upon the physician to be aware of the relative risks from various types of exposure, and the meaning of a number of tests not routinely used. Unfortunately, there is no foreseeable substitute for being well informed if the physician is t o make the best possible decision about benefit and cost. ( J A M E S W. M O S L E Y , M . D . ; Department
References 1. K R U G M A N S, G I L E S J P . Viral hepatitis, type B (MS-2-strain): further observations on natural history and prevention. N Engl J Med. 1973;288:755-60. 2. S Z M U N E S S W, P R I N C E A M , G O O D M A N M, E H R I C H C, P I C K R, A N S A R I
M. Hepatitis B immune serum globulin in prevention of nonparenterally transmitted hepatitis B. N Engl J Med. 1974;290:701-6. 3. IWARSON S, A H L M E N J, ERIKSSON E, et al. Hepatitis B immune globulin in prevention of hepatitis B among hospital staff members. / Infect Dis. 1977;135:473-7. 4. P R I N C E A M , S Z M U N E S S W, M A N N MK, et al. Hepatitis B immune
5.
6.
7.
8. 9.
globulin: final report of a controlled, multicenter trial of efficacy in prevention of dialysis-associated hepatitis. J Infect Dis. 1978;137:131-44. G R A D Y G F , L E E VA, P R I N C E AM, et al. Hepatitis B immune globulin for accidental exposures among medical personnel: final report of a multicenter controlled trial. J Infect Dis. 1978;138:625-38. SEEFF LB, W R I G H T EC, ZIMMERMAN HJ, et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin. Ann Intern Med. 1978;88:285-93. C E N T E R FOR DISEASE CONTROL. Immune globulins for protection against viral hepatitis. Morbid Mortal Weekly Rep. 1977;26:425-8, 4412. PRINCE AM. Use of hepatitis B immune globulin: reassessment needed. N Engl J Med. 1978;299:198-9. SEEFF LB, HOOFNAGLE JH. Immunoprophylaxis of viral hepatitis. Gastroenterology. 1979;77:161-82.
10. K R U G M A N S, H O L L I N G E R FB, M O S L E Y JW, M A Y N A R D JE. Immuno-
prophylaxis for viral 1979;77:186-91.
hepatitis—other
views.
Gastroenterology.
11. H O O F N A G L E J H , S E E F F LB, B A L E S ZB, W R I G H T EC, Z I M M E R M A N HJ, V E T E R A N S A D M I N I S T R A T I O N C O O P E R A T I V E S T U D Y G R O U P . Passive-
active immunity from hepatitis B immune globulin: reanalysis of a Veterans Administration cooperative study of needle-stick hepatitis. Ann Intern Med. 1979;91:813-8. 12. COOPERATIVE STUDY G R O U P . Prophylactic gamma globulin for prevention of endemic hepatitis: effects of US gamma globulin upon the incidence of viral hepatitis and other infectious diseases in US soldiers abroad. Arch Intern Med. 1971;128:723-37. 13. G I N S B E R G AL, C O N R A D M E , B A N C R O F T W H , L I N G CM, O V E R B Y LR.
Antibody to Australia antigen: detection with a simple radioimmune assay, incidence in military populations, and role in the prevention of hepatitis B with gamma globulin. J Lab Clin Med. 1973;82:317-25. 14. G R A D Y G F , R O D M A N M, LARSEN LH. Hepatitis B antibody in conventional y-globulin. J Infect Dis. 1975;132:474-7. 15. DOSIK H, JHAVERI R. Prevention of neonatal hepatitis B infection by Editorials
Downloaded from https://annals.org by Tulane University user on 01/13/2019
of
Medicine, University of Southern California School of Medicine, Los Angeles, and Liver Unit, Rancho Los Amigos Hospital, Downey, California)
915
high-dose hepatitis B immune globulin. N Engl J Med. 1978;298:602-3. 16. A L T E R HJ, SEEFF LB, K A P L A N PM, et al. Type B hepatitis: the infec-
916
tivity of blood positive for e antigen and D N A polymerase after accidental needlestick exposure. N Engl J Med. 1976;295:909-13. © 1 9 7 9 American College of Physicians
December 1979 • Annals of Internal Medicine • Volume 91 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/13/2019
