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Antiviral drugs for the neonate — the risk-benefit ledger
EDITOR'S COLUMN
Antiviral drugs for the neonate 9the risk-benefit
ledger THE USE O F A N T I V I R A L A G E N T S in the newborn infant poses yet a new set of problems which illustrate the uniqueness of the very young. Viruses depend on host cell enzymes to synthesize the components required for their r e p l i c a t i o n . C u r r e n t c a n d i d a t e a n t i v i r a l agents, e.g., c y t o s i n e a r a b i n o s i d e ( A r a - C ) , a d e n o s i n e arabinoside (Ara-A), and iododoxyuridine, interfere with viral synthesis by inhibiting the host cells' ability to synthesize new virus components. In preventing virus replication, however, these agents also interfere with normal cell functions. This is of particular concern in the neonate whose cells are also engaged in synthesizing new components required for growth. That the risk of antiviral therapy to normal developm e n t may be more than theoretical can be gleaned from some revealing animal experiments. ~Mice, given only three doses of Ara-C during the first week of life, developed irreversible retinal and brain damage. By the second week of life, these animals developed ataxia. The reason for the ataxia was apparent when we examined the brains of these mice; the postnatal development of the cerebellum was almost completely prevented. The experiment may be criticized because the dose of drug was relatively large and postnatal brain development is not identical in mouse and man. Since h u m a n brain d e v e l o p m e n t may c o n t i n u e long after birth the potential for damage is certainly present, The dosages of D N A inhibitors cannot realistically be expressed on a weight basis. A n effective level should be considered that dose which results in curing the infection without devastating the patient. Newer compounds which inhibit D N A synthesis e.g., Ara-A, are now being evaluated as antiviral agents. AraA appears to be less harmful to man and experimental animals than some previous candidate antiviral drugs. Th~us far, however, Ara-A has had only moderate antiviral effects in the dosages used. As dosages are increased to produce greater antiviral activity, increased toxicity may well follow. One of the advantages of A r a - A is that it produces relatively little myelosuppression. Toxicity is monitored
in adults by decreased white blood cell and platelet counts and by gastrointestinal symptoms. If these same measures are used for the newborn infant, however, one may be badly misled. Gastrointestinal upset may be impossible to discern in a sick infant who is being alimented intravenously. Bone marrow depression, moreover, may be such an insensitive measure of injury that damage to other organ systems which may be more sensitive to Ara-A might occur before myelosuppression is detected. Abbreviations used Ara-C: cytosine arabinoside Ara-A: adenosine arabinoside The developing brain may be particularly susceptible to the effects of Ara-A, since brain tissue is relatively poor in adenosine deaminase, the enzyme responsible for metabolizing Ara-A to its hypoxanthine derivative. Damage that is produced, moreover, might not be obvious at the time of therapy. Derangements in myelinzation or dendritization, for instance, might not be discernible until years later. Since immunologically compromised adults who received Ara-C for treatment of zoster did less well than untreated patients, 2, 3 it is unclear whether newborn infants stand to benefit from similar therapy. It is obvious that the neonate manages herpesvirus infections less well than the normal adult. The chink in the defenses of the newborn infant against herpes viruses has not been clearly defined. That the defect might be cellular rather than humoral is suggested by the observation that the survival of baby mice infected with herpes viruses is e n h a n c e d white blood cells from adult mice. 4 Indeed, it is t h e a d u l t p a t i e n t w i t h c o m p r o m i s e d c e l l u l a r responses, namely, those with late stage Hodgkin's disease, who are sensitive to Ara-C therapy. 2,3 Do these warnings mean that we should abandon the development of antiviral drugs for the neonate? Absolutely n o t - - w e have no alternative. The traditional m e t h o d o f reducing m o r b i d i t y p r o d u c e d by viral a g e n t s - - p r e v e n t i o n - - m a y not be a feasible approach to
VoL 86, No. 2, pp. 317-318
318
Editor's column
this problem at the present time. The infections with which we are most c o n c e r n e d are those caused by herpes simplex or cytomegalovirus. Since these viruses characteristically persist following recovery from the initial infection, the use of live vaccines for "prevention" of these infections may not be appropriate. It is unclear, at this time, whether fetal involvement may occur in w o m e n with p e r s i s t e n t i n f e c t i o n s or only following primary i n f e c t i o n d u r i n g p r e g n a n c y . U n t i l one is able to assure that immunization of potential mothers with live herpes vaccines will not result in more, rather than less fetal morbidity, development of live herpes virus vaccines for fetal protection would be foolhardy. The potential for doing harm by treating infants with antiviral drugs should stimulate us to formulate a plan 9 for the use of these drugs. Many will choose to treat all infected infants in the belief that these infants will die or be badly damaged it they are not treated. As our diagnostic procedures have become more sophisticated it has become obvious that this is not the case. Herpes simplex virus 5 and c y t o m e g a l o v i r u s 6 each produce a spectrum of illness. Recovery from herpetic infection of the central nervous system in an untreated neonate without sequelae is possible. 7 It would appear at this time that a controlled doubleblind study is the only method by which we will learn w h e t h e r antiviral therapy will favorably alter the natural history of congenital virus infections. Some of the infants must receive a placebo, since the natural history of these infections is still not entirely clear. If antiviral drugs prove to be harmful to the newborn infant and have little effect on the infection, these infants will fare better than those who receive therapy. Such a study will also permit standardization of dosages and
The Journal of Pediatrics February 1975
methods of administration of drugs and the testing of new drugs as they become available. Since it is unlikely that a single center could amass enough cases to carry out an adequate study, a collaborative effort was organized. Approximately twenty centers throughout the United States are carefully evaluating the use of antiviral drugs in the newborn infants with congenital virus infections.* We should all join in this effort. Philip Brunell, M.D. Department of Pediatrics New York University School of Medicine 550 First Ave. New York, N. Y. 10016 *Dr. Larry Ch'ien, Departmentof Pediatrics,Universityof Alabama, UniversityStation, Birmingham,Ala. 35294. REFERENCES
1 Ashwal S, Fish l, Finegold M, and Brunell P: Effect of cytosine arabinoside on the developing nervous system, abstract, Thirteenth lnterscience Conference on Antimicrobial Agents and Chemotherapy, Am Soc Microbiol 1973, Pediatr Res. (in press). 2. Davis CM, Van Dersari JV, and Coltman CA: Failure of cytarbine in varicella-zoster infections, JAMA 224:122, 1973. 3. Stevens DA, Jordan GW, Waddell TF, and Merigan TC: Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial, N Engl J Med 289:873, 1973. 4. Hirsch MS, Zisman B, and Allison AC: Macrophages and age-dependent resistance to herpes simplex virus in mice, J Immunol 106:1160, 1970. 5. Hanshaw JB: Herpesvirus hominis infections in the fetus and the newborn, Am J Dis Child 126:546, 1973. 6. Weller, TH: The cytomegaloviruses: Ubiquitous agents with protean clinical manifestations, N Engl J Med 285:203, 1971. 7. Gershon AA, Fish I, and Brunell PA: Herpes simplex infection of the newborn, Am J Dis Child 124:739, 1972.
Antiviral drugs for the neonate 9the risk-benefit
ledger THE USE O F A N T I V I R A L A G E N T S in the newborn infant poses yet a new set of problems which illustrate the uniqueness of the very young. Viruses depend on host cell enzymes to synthesize the components required for their r e p l i c a t i o n . C u r r e n t c a n d i d a t e a n t i v i r a l agents, e.g., c y t o s i n e a r a b i n o s i d e ( A r a - C ) , a d e n o s i n e arabinoside (Ara-A), and iododoxyuridine, interfere with viral synthesis by inhibiting the host cells' ability to synthesize new virus components. In preventing virus replication, however, these agents also interfere with normal cell functions. This is of particular concern in the neonate whose cells are also engaged in synthesizing new components required for growth. That the risk of antiviral therapy to normal developm e n t may be more than theoretical can be gleaned from some revealing animal experiments. ~Mice, given only three doses of Ara-C during the first week of life, developed irreversible retinal and brain damage. By the second week of life, these animals developed ataxia. The reason for the ataxia was apparent when we examined the brains of these mice; the postnatal development of the cerebellum was almost completely prevented. The experiment may be criticized because the dose of drug was relatively large and postnatal brain development is not identical in mouse and man. Since h u m a n brain d e v e l o p m e n t may c o n t i n u e long after birth the potential for damage is certainly present, The dosages of D N A inhibitors cannot realistically be expressed on a weight basis. A n effective level should be considered that dose which results in curing the infection without devastating the patient. Newer compounds which inhibit D N A synthesis e.g., Ara-A, are now being evaluated as antiviral agents. AraA appears to be less harmful to man and experimental animals than some previous candidate antiviral drugs. Th~us far, however, Ara-A has had only moderate antiviral effects in the dosages used. As dosages are increased to produce greater antiviral activity, increased toxicity may well follow. One of the advantages of A r a - A is that it produces relatively little myelosuppression. Toxicity is monitored
in adults by decreased white blood cell and platelet counts and by gastrointestinal symptoms. If these same measures are used for the newborn infant, however, one may be badly misled. Gastrointestinal upset may be impossible to discern in a sick infant who is being alimented intravenously. Bone marrow depression, moreover, may be such an insensitive measure of injury that damage to other organ systems which may be more sensitive to Ara-A might occur before myelosuppression is detected. Abbreviations used Ara-C: cytosine arabinoside Ara-A: adenosine arabinoside The developing brain may be particularly susceptible to the effects of Ara-A, since brain tissue is relatively poor in adenosine deaminase, the enzyme responsible for metabolizing Ara-A to its hypoxanthine derivative. Damage that is produced, moreover, might not be obvious at the time of therapy. Derangements in myelinzation or dendritization, for instance, might not be discernible until years later. Since immunologically compromised adults who received Ara-C for treatment of zoster did less well than untreated patients, 2, 3 it is unclear whether newborn infants stand to benefit from similar therapy. It is obvious that the neonate manages herpesvirus infections less well than the normal adult. The chink in the defenses of the newborn infant against herpes viruses has not been clearly defined. That the defect might be cellular rather than humoral is suggested by the observation that the survival of baby mice infected with herpes viruses is e n h a n c e d white blood cells from adult mice. 4 Indeed, it is t h e a d u l t p a t i e n t w i t h c o m p r o m i s e d c e l l u l a r responses, namely, those with late stage Hodgkin's disease, who are sensitive to Ara-C therapy. 2,3 Do these warnings mean that we should abandon the development of antiviral drugs for the neonate? Absolutely n o t - - w e have no alternative. The traditional m e t h o d o f reducing m o r b i d i t y p r o d u c e d by viral a g e n t s - - p r e v e n t i o n - - m a y not be a feasible approach to
VoL 86, No. 2, pp. 317-318
318
Editor's column
this problem at the present time. The infections with which we are most c o n c e r n e d are those caused by herpes simplex or cytomegalovirus. Since these viruses characteristically persist following recovery from the initial infection, the use of live vaccines for "prevention" of these infections may not be appropriate. It is unclear, at this time, whether fetal involvement may occur in w o m e n with p e r s i s t e n t i n f e c t i o n s or only following primary i n f e c t i o n d u r i n g p r e g n a n c y . U n t i l one is able to assure that immunization of potential mothers with live herpes vaccines will not result in more, rather than less fetal morbidity, development of live herpes virus vaccines for fetal protection would be foolhardy. The potential for doing harm by treating infants with antiviral drugs should stimulate us to formulate a plan 9 for the use of these drugs. Many will choose to treat all infected infants in the belief that these infants will die or be badly damaged it they are not treated. As our diagnostic procedures have become more sophisticated it has become obvious that this is not the case. Herpes simplex virus 5 and c y t o m e g a l o v i r u s 6 each produce a spectrum of illness. Recovery from herpetic infection of the central nervous system in an untreated neonate without sequelae is possible. 7 It would appear at this time that a controlled doubleblind study is the only method by which we will learn w h e t h e r antiviral therapy will favorably alter the natural history of congenital virus infections. Some of the infants must receive a placebo, since the natural history of these infections is still not entirely clear. If antiviral drugs prove to be harmful to the newborn infant and have little effect on the infection, these infants will fare better than those who receive therapy. Such a study will also permit standardization of dosages and
The Journal of Pediatrics February 1975
methods of administration of drugs and the testing of new drugs as they become available. Since it is unlikely that a single center could amass enough cases to carry out an adequate study, a collaborative effort was organized. Approximately twenty centers throughout the United States are carefully evaluating the use of antiviral drugs in the newborn infants with congenital virus infections.* We should all join in this effort. Philip Brunell, M.D. Department of Pediatrics New York University School of Medicine 550 First Ave. New York, N. Y. 10016 *Dr. Larry Ch'ien, Departmentof Pediatrics,Universityof Alabama, UniversityStation, Birmingham,Ala. 35294. REFERENCES
1 Ashwal S, Fish l, Finegold M, and Brunell P: Effect of cytosine arabinoside on the developing nervous system, abstract, Thirteenth lnterscience Conference on Antimicrobial Agents and Chemotherapy, Am Soc Microbiol 1973, Pediatr Res. (in press). 2. Davis CM, Van Dersari JV, and Coltman CA: Failure of cytarbine in varicella-zoster infections, JAMA 224:122, 1973. 3. Stevens DA, Jordan GW, Waddell TF, and Merigan TC: Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial, N Engl J Med 289:873, 1973. 4. Hirsch MS, Zisman B, and Allison AC: Macrophages and age-dependent resistance to herpes simplex virus in mice, J Immunol 106:1160, 1970. 5. Hanshaw JB: Herpesvirus hominis infections in the fetus and the newborn, Am J Dis Child 126:546, 1973. 6. Weller, TH: The cytomegaloviruses: Ubiquitous agents with protean clinical manifestations, N Engl J Med 285:203, 1971. 7. Gershon AA, Fish I, and Brunell PA: Herpes simplex infection of the newborn, Am J Dis Child 124:739, 1972.