1154

7. Rubin J, Nagler R, Spiro HM, Pilot ML. Measuring the effect of emotions onesophageal motility. Psychosom Med 1962, 24: 170-76.

8. Stacher G, Schimierer G, Landcraf M. Tertiary oesophageal contractions evoked byacoustical stimuli Gastroenterology 1979; 77: 49-54.

9. Christiansen J, Lund GF. Esophageal responses to distention and electricalstimulation J Clin Invest 1969, 48: 408-19.

10. Creamer B, Schlegel J. Motor response of the esophagus to distention. J Appl Physiol1957; 10: 498-504

11. Sear JW, Phillips KC, Andrews CJH, Prys-Roberts C. Dose-response relationship forinfusions of althesin or methohexitone. Anesthesia 1983; 38: 931-36.

12 Evans JM, Fraser A, Wise CC, Davies WL. Computer controlled anaesthesia. In:Prakash O, ed. Computing in anaesthesia and intensive care. The Hague: MartinusNijhoff, 1983: 279-91.

13. Higgs BD, Behrakis PK, Bevan DR, Milie-Emili MD Measurement of pleuralpressure with esophageal balloon in anesthetized humans. Anesthesiology 1983; 59:340-43

14. Simons AJR, Pronk RAF. Automated EEG monitoring during anaesthesia. In: PrakashO, ed Computing in anaesthesia and intensive care. The Hague: Martinus Nijhoff,1983: 227-57

HypothesisPROPHYLAXIS: A STRATEGY TO MINIMISE

ANTIVIRAL RESISTANCE

RICHARD F. AMBINDERPAUL S. LIETMAN

WILLIAM H. BURNSREIN SARAL

Oncology Center, Johns Hopkins Medical Institutions, Baltimore,Maryland, USA

. THE entry of acyclovir into the clinical armamentarium

marks the beginning of an era of antiviral chemotherapybased on selective interaction with viral enzymes. As with theantibacterial agents that selectively interact with bacterialenzymes, it is likely that in time selection pressure actingtogether with random mutations will yield viruses resistant tochemotherapy. Thus, if we are to preserve the efficacy ofacyclovir and other antiviral agents, we will have to devisestrategies to minimise the opportunities for the developmentof resistance. In bacterial infection it may be argued thatprophylaxis fosters the emergence of resistance, but theoutlook is quite different for infections with viruses that havea latent state in their life cycles-eg, herpes simplex,cytomegalovirus, and the adenoviruses. Our experience ofherpes simplex infection in bone-marrow-transplantrecipients and in leukaemic patients undergoing intensivecytotoxic chemotherapy shows that the prophylacticadministration of acyclovir to these at-risk populations is

highly effective in reducing morbidity.I-4 We believe that inaddition to being effective, prophylactic therapy reduces thelikelihood of acyclovir resistance emerging. Furthermore, webelieve our argument can be generalised to the many viralinfections in which the clinical disease is due to predictablereactivation of the virus from the latent state.

ACYCLOVIR: MECHANISM OF ACTION AND RESISTANCE

Viral DNA synthesis is the target of acyclovir action. ViralDNA polymerase is inhibited by acyclovir triphosphate; italso incorporates acyclovir triphosphate into the growingviral DNA chain, leading to chain termination.5-9 Acyclovirtriphosphate accumulates selectively in herpes-simplex-infected cells because the virus-specified thymidine kinasephosphorylates acyclovir, but host cellular enzymes do not. 5,6Resistance can arise from mutations in the viral DNA

polymerase gene, which alter the enzyme’s specificity so thatit is no longer inhibited by acyclovir triphosphate and/or doesnot recognise acyclovir triphosphate as a substrate, or frommutations in or deletions of the viral thymidine kinasegene. JO,11 Mutations may occur in the protein-coding region

of the gene, causing the synthesis of inactive protein or ofthymidine kinase that does not recognise acyclovir as

substrate but does act on its natural substrates. Alternatively,regulatory sequences in the thymidine kinase gene may be

affected in such a way that little or no enzyme of any

specificity is produced.Loss of thymidine kinase activity is the most common

pathway to resistance in vitro and the only one so far

demonstrated clinically. Thymidine-kinase-deficient virus iseven detectable in clinical isolates from patients who havenever been treated with acyclovir. 12,13 1 Balfour 14 took comfortin reports of patients whose herpetic infections resolveddespite in-vitro data showing acyclovir resistance due toreduced thymidine kinase activity. There is also evidence thatthymidine-kinase-deficient mutants are less virulent and lessable to establish ganglionic latency in experimentalinfections. 15 However, in our experience clinically activedisease may be associated with thymidine-kinase-deficientvirus. We have identified seven patients shedding suchresistant virus while receiving acyclovir.3,4,16 In four of thesepatients there was clinically active disease associated withshedding. Restriction-enzyme analysis showed straindifferences among the resistant virus isolates, indicating thateach represented a separate mutation-to-resistance event andnot cross-infection.17 Others have reported cases of clinicallyactive disease despite acyclovir therapy in patients sheddingthymidine-kinase-deficient viruses.18,19DNA polymerase mutants arise less frequently in the

laboratory and have yet to be reported in a clinical setting, butin experimental infections they seem to have normal

pathogenicity.2o It is probably only a matter of time beforepathogenic acyclovir-resistant DNA polymerase mutantsappear clinically. As other antivirals are introduced we canexpect resistance to emerge by way of changes in the

specificity or level of target enzyme activity as a result ofselection pressure and mutation.

SOURCE OF RESISTANCE

The second part of our hypothesis is that antiviralresistance will occur predominantly among patients beingtreated for active disease rather than in those being treatedprophylactically. The likelihood of mutation to resistance isproportional to the number of replicating virions. Whenacyclovir is used prophylactically, the number of replicatingherpes simplex virions, if any, is small. However, establishedherpetic lesions in immunocompromised patients containperhaps hundreds of millions of replicating virions; a muchlarger population in which mutation and selection may occur.In the analogous situation of isoniazid treatment of

tuberculosis, the mycobacterial burden is low and resistanceis rarely encountered after prophylactic isoniazid treatment.However, when isoniazid is used to treat a cavitary lesion, thelikelihood of resistance is great because of the highmycobacterial load.

TESTING THE HYPOTHESIS

These ideas could be tested in a multicentre study. If theyare correct, viral resistance should arise with

disproportionate frequency in patients being treated foractive disease compared with patients receiving prophylaxis.Resistance should occur especially frequently in severelyimmunocompromised patients with heavy viral burdens,such as bone-marrow-transplant recipients, and patients withacute leukaemia, acquired immunodeficiency syndrome, andsevere recurrent genital herpes. Data for our hospital are

1155

consistent with the hypothesis. We are now treating severalhundred patients per year with intravenous acyclovir. Inroughly 80% of these patients the treatment is prophylactic.Nonetheless, all seven cases of resistance arose duringtherapy given to patients with established disease; no caseshave been detected among patients treated prophylactically.3Similarly, cases of resistant virus reported by the Seattlebone-marrow-transplant group were also limited to patientstreated for active disease. 18Prophylaxis already has a defined role in hospital settings,

such as bone-marrow transplantation, where herpesreactivation is associated with significant morbidity and ishighly predictable. 21-24 Availability of oral acyclovir forclinical use will broaden the potential role of prophylacticacyclovir therapy to include outpatient settings. For instance,oral acyclovir might be used to prevent the predictablerecurrence of genital herpes in women 5-12 days before theonset of menses. 25 The assessment of the role of prophylaxisin this and other settings awaits determination of efficacy andperhaps more information on long-term toxicity, but wesuggest that considerations of resistance favour prophylactictreatment. As new antiviral chemotherapy becomes availableprophylaxis may be a strategy which maximises antiviralefficacy and minimises the emergence of resistance in thetreatment of various viral diseases.

This work was supported by Public Health Service grants NIH-NCI-CA06973 and NIH-NCI-CA15396, Caswell Caplan, the Harley HowellFoundation, and the Hodson Beneficial Trust.

Correspondence should be addressed to R. F. A., Oncology 3-120, JohnsHopkins Hospital, 610 North Wolfe Street, Baltimore, Maryland 21205,USA.

REFERENCES

1 Saral R, Burns WH, Laskin OL, et al. Acyclovir prophylaxis of herpes simplex virusinfections: a randomized, double-blind controlled trial in bone marrow transplantrecipients. N Engl J Med 1981; 305: 63-67

2. Saral R, Ambinder RF, Burns WH, et al. Acyclovir prophylaxis against herpes simplexinfection in patients with leukemia. A randomized, double-blind placebo controlledstudy. Ann Intern Med 1983; 99: 773-76.

3 Saral R, Burns WH. Viral infections and antiviral chemotherapy. In: Gale RP, ed.Recent advances in bone marrow transplantation. New York: Alan R. Liss, 1983:461-69.

4 Burns WH, Saral R. Chemotherapy of herpes simplex virus infections. In: Ennis FA,ed. Human immunity to viruses. New York: Academic Press, 1983: 203-18.

5. Elion GB. Mechanism of action and selectivity of acyclovir Am J Med 1982; 73: 7-136. Elion GB, Furman PA, Fyfe JA, De Miranda P, Beauchamp L, Schaeffer HJ.

Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine.Proc Natl Acad Sci USA 1977; 74: 5716-20.

7. Schaeffer HJ. Acyclovir chemistry and spectrum of activity. Am J Med 1982; 73: 4-6.8. McGuirt PV, Furman PA. Acyclovir inhibition of viral DNA chain elongation in

herpes simplex virus-infected cells. Am J Med 1982; 73: 67-71.9. Allaudeen HS, Descamps J, Sehgal RK. Mode of action of acyclovir triphosphate on

herpes viral and cellular DNA polymerases. Antiviral Res 1982; 2: 123-33.10. Coen DM, Schaffer PA. Two distinct loci confer resistance to acycloguanosine in

herpes simplex type 1. Proc Natl Acad Sci USA 1980; 77: 2265-69.11. Schnipper LE, Crumpacker CS. Resistance of herpes simplex virus to

acycloguanosine: role of viral thymidine kinase and DNA polymerase loci. Proc NatlAcad Sci USA 1980; 77: 2270-73.

12. Parris DS, Harrington JE. Herpes simplex virus variants resistant to highconcentrations of acyclovir exist in clinical isolates Antimicrob Ag Chemother 1982;22: 71-77

13. McLaren C, Corey L, Dekket C, Barry DW In vitro sensitivity to acyclovir in genitalherpes simplex viruses from acyclovir-treated patients. J Infect Dis 1983; 148:868-75.

14. Balfour HH Resistance of herpes simplex to acyclovir. Ann Intern Med 1983; 98:404-06.

15. Field HJ, Wildy P The pathogenicity of thymidine kinase-deficient mutants of herpessimplex virus in mice. J Hyg Lond 1978; 81: 267-77.

16. Burns WH, Saral R, Santos GW, et al. Isolation and characterisation of resistant herpessimplex virus after acyclovir therapy. Lancet 1982; i: 421-23.

17. Ambinder RF, Burns WH, Saral R, et al Restriction endonuclease fingerprinting ofacyclovir resistant herpes simplex infections occurring in an oncology unit. In:Program and Abstracts of the American Society for Microbiology General Meeting.St Louis, Washington, DC: American Society for Microbiology, 1984.

18. Wade JC, McLaren C, Meyers JD. Frequency and significance of acyclovir-resistantherpes simplex virus isolated from marrow transplant patients receiving multiplecourses of treatment with acyclovir. J Infect Dis 1983; 148: 1077-82.

19 Sibrack CD, Gutman CT, Wilfert CM, et al. Pathogenicity of acyclovir-resistantherpes simplex virus type I from an immunodeficient child. J Infect Dis 1982; 146:673-82.

20. Field HJ, Darby G Pathogenicity in mice of strains of herpes simplex virus which areresistant to acyclovir in vitro and in vivo. Antimicrob Ag Chemother 1980; 17:209-16.

21. Wade JC, Newton B, Flournoy N, Meyers JD. Oral acyclovir prophylaxis of herpessimplex infections after marrow transplant. In: Program and Abstracts of the 22ndInterscience Conference on Antimicrobial Agents and Chemotherapy Washington,DC. American Society of Microbiology, 1982: 184.

22. Gluckman E, Lotsberg J, Revegre A, et al. Prophylaxis of herpes infections after bonemarrow transplantation by oral acyclovir. Lancet 1983; ii. 706-08

23. Hann IM, Prentice HG, Blacklock HA, et al. Acyclovir prophylaxis of herpes virusinfections in severely immunocompromised patients: a randomized double-blindcontrolled trial. Exp Hematol 1982, 10: 2-4

25. Guinan ME, MacCalman J, Kern ER, et al. The course of untreated recurrent genitalherpes simplex infection m 27 women. N Engl J Med 1981, 304: 759-62.

Reviews of Books

Techniques in Diagnostic RadiologyG. H. Whitehouse, University of Liverpool, and B. S. Worthington,University of Nottingham. Oxford: Blackwell. 1984. Pp 361. £ 32.50.

HERE at last is a reference work which provides in one smallvolume an authoritative account of virtually all the practicalprocedures carried out by radiologists as part of their day-to-daywork. The subject matter is presented in six sections, the first fivebeing allocated to investigations of the gastrointestinal tract, thecardiovascular system, the respiratory tract, the genitourinarysystem, and the central nervous system. The sixth is a miscellaneoussection which includes an account of arthrography, a description ofwater-soluble contrast media, and a short and excellent account ofthe radiology of the breast. The indications and contraindicationsand the dangers and possible complications of each technique aredescribed clearly, and the relation of the various procedures to otherdiagnostic modalities is considered. Although nineteen differentauthors have contributed to the work the standard of the text is

remarkably uniform and the descriptions of the various proceduresare without exception very detailed and practical. There

are numerous high-quality illustrations. The book is intended

primarily for trainees but senior radiologists will find the

descriptions of many of the more elaborate procedures very useful ifthey have to undertake some of these investigations on their ownaway from the teaching centres. The text does not deal with

radiological interpretation but is concerned simply with choice ofprocedure, how to do the procedure, what problems may arise, andhow to deal with these. Although all the material covered will befound in standard radiological textbooks or elsewhere in the

literature, this is the only book I know which brings together somuch precise practical information in so few pages. I liked the bookso much that I read it right through at the first sitting. I wouldstrongly urge trainees working for the examinations of the RoyalCollege of Radiologists or similar examining bodies to get this bookand read it from cover to cover. It is an excellent addition to the

radiological literature.

Department of Radiology,Royal Masonic Hospital,London R. S. MURRAY

Atlas of Orthopaedic Pathology with Clinical andRadiologic Correlations

P. G. Bullough and V. J. Vigorita, Cornell University Medical College,New York. New York: Gower. London: Butterworths. 1984. Pp 278.49.50.

BASED on lectures given to medical students and to orthopaedicsurgeons, the thirteen chapters in this book deal with normalstructure, disorders of bone development and turnover, injury andrepair, the deposition of products of abnormal metabolism,haematological disorders as they affect the skeleton, the arthritides,infections of bones and joints, and skeletal tumours. The fourteenthsection contains a miscellany of conditions most of which would notfit into the preceding chapters.

Since most of the pages are occupied by illustrations, the

description of each condition is necessarily brief. The content is, in