Effects of cytarabine on virus shedding in Herpes simplex virus infections

Transcription

1 Journal of Antimicrobial Chemotherapy (1977) 3 (Suppl. A), Effects of cytarabine on virus shedding in Herpes simplex virus infections Bent Juel-Jensen Department of the Regius Professor of Medicine, Radcliffe Infirmary, Oxford, England The duration of virus shedding in 12 patients with type 1 and 5 with type 2 herpes simplex virus (HSV) infection treated with cytarabine, 3 mg/kg/day for 3 to 5 days by rapid intravenous administration was measured. In all but 2 patients the virus disappeared after a median of 4 days, when shedding normally would have been expected to continue for 2 to 3 weeks in the untreated patient, at least in those with primary infection. Two patients continued to shed virus for several weeks. It is suggested that these patients destroy the cytarabine unusually fast and that when a reliable method of estimating pyrimidine kinase activity is developed, the drug may be given more rationally to the individual patient. Measurement of the duration of virus shedding is a useful objective way of assessing the effect of a new antiviral drug and complements the double-blind controlled trial. Introduction In assessment of the efficacy of an antiviral agent in man, the double-blind controlled trial is of the greatest value. Some virus infections are of comparatively infrequent occurrence and it may be impossible to collect a sufficient number of patients for a formal trial. The effect of a potentially useful antiviral agent on virus-shedding in treated patients is an alternative/additional objective measurement. The action of cytarabine, given systemically to patients with severe herpes simplex virus (HSV) infections is described, and the results are discussed. Methods Fifteen patients with type 1 HSV infection (8 primary, 7 recurrent) and 5 with type 2 HSV infection (3 primary, 2 recurrent) were treated with cytarabine, 3 mg/kg/day for 3 to 5 days, given by rapid intravenous injection. Swabs were taken daily from the affected site in Hanks's transport medium. The virus was cultured on human amnion cells. The number of days positive cultures were obtained was recorded, as well as the clinical response. Liver function tests (SGOT, LDH, alkaline phosphatase and bilirubin), creatinine, urea, and electrolytes were monitored, as were the white blood cells, haemoglobin, reticulocytes and platelets. The urine was examined regularly. 125

2 126 B. Juel-Jensen Results Table I shows a series of severe HSV type 1 infections treated with cytarabine in the dose outlined from 3 to 5 days. Table I. Clinical and virological results in some patients with severe HSV (Type I) infection treated with systemic cytarabine M22 M28 F19 M21 F20 M5 M19 F64 F67 M47 M56 F71 Fll Cjfp + eczema herpeticum + whitlow +skin Rec. eczema herpeticum + pneumonitis + pneumonitis Widespread rec. HSV of whole face Response Clinical Virological (4) (5) Poor (20) (6) (4) (5) (5) (6) (3) (3) (2) (4) (4) (4) (4) It will be noted that virus-shedding with one exception was limited to from 2 to 6 days with a median of 4 days. The third patient, who continued to shed virus for 20 days, or the same period as one might expect virus to be shed in the untreated patient, is of special interest. The period of virus-shedding in these examples of type 1 HSV infection can be tabulated: Primary infection 4 days 2 5 days 3 6 days 2 20 days 1 Recurrent infection 2 days 1 3 days 3 4 days 3 The numbers are small, but there is a suggestion that recurrent HSV infection is more readily controlled than the primary infection. Table II gives five examples of type 2 HSV infection. Here again, we find that one patient shed virus for at least 12 days, whereas the infection as monitored by recoverable virus subsided quickly in the others. In none of the patients was any adverse effect on the blood picture, on liver and renal function, found. Some patients were nauseated, usually 3 to 4 h after administration of the drug. There is a suggestion, though it at present is no more, that these are the

3 Cytarabine and virus shedding 127 patients in whom the virus-shedding period was shortest. Time will show if these patients also are the ones in whom pyrimidine kinase activity is lowest, and those who for a short time achieve the highest cytarabine level. Table EL Type 2 HSV infection treated with cytarabine F19 F24 F27 M23 c: tp Iry severe genital Iry severe genital Rec. genital Rec. genital Response Clinical Virological (5) Poor (> 12) (2) No eruption (1) Discussion Whilst we were carrying out double-blind trials to investigate the effect of topical application of idoxuridine in recurrent herpes simplex virus infections of the skin (Juel-Jensen & MacCallum, 1965; MacCallum & Juel-Jensen, 1966) we used the methods currently being investigated in the treatment of primary HSV whitlows. Although double-blind trials showed that 01% idoxuridine in water sprayed into the skin with a pressure gun was more effective than placebo, it did not shorten the duration of virus-shedding compared to that anticipated in the untreated patient with herpetic whitlow. Five per cent idoxuridine in dimethyl sulphoxide, intermittently applied, again proved effective in recurrent HSV lesions of the skin, and was more impressive in terms of arrest of virus-shedding in herpetic whitlows, but 40 % idoxuridine in DMSO was superior to either, with a predictable virus-shedding period of seven days or less (Table III). The clinical results observed corresponded to the findings of the virus laboratory. Days 01 % IDU by gun (2) Intermittent 5% IDU DMSO S (7) Continuous 35^M)% IDU DMSO S (20) Table in. Result of treatment of herpetic whitlows Duration of pain 90 (Constant) 7-7 (Constant) 1-6 (Intermittent only) Vesicles dry Complete healing Virus isolated Since Hall and colleagues (1969) first treated varicella-zoster with systemic cytarabine and we first used it in generalized HSV infection (Juel-Jensen, 1970), we have had considerable experience of the drug both in HSV and varicella-zoster infection. The study of Stevens et al. (1973) showed cytarabine to be positively harmful compared to the placebo when given to patients with lymphoproliferative disease, proved only what could have been predicted, namely that if cytarabine is given continuously over 24 h in a modest dose it will have maximum adverse effect on the bone-marrow and at

4 128 B. Juel-Jensen no time is it likely that a virucidal level of the drug will be attained. We have always given cytarabine by rapid intravenous injection, and except in HSV encephalitis never in doses exceeding 3 mg/kg/day. Ginically all varicella-zoster cases have responded well, but, more important, none have showed adverse effects. Kernbaum (1976) using our methods of administration, achieved results similar to ours. We have at present in progress a double-blind trial of topically applied 35% idoxuridine in DMSO versus cytarabine in the treatment of zoster. It may well be that one of the soluble adeninearabinoside derivatives, such as adenine arabinoside monophosphate or hypoxanthine arabinoside monophosphate will be more effective because antiviral activity is sustained over longer periods. Many HSV lesions do not lend themselves to topical treatment especially primary HSV gingivostomatitis, eczema herpeticum, and primary genital herpes (usually due to type 2 virus) in the female. The increasing body of evidence that HSV is latent in nerve cells makes it dubious if topical treatment can do more than literally touch the surface of the problem. It is fairly certain that rational treatment of recurrences, particularly of genital HSV, must be with systemic chemotherapy. Many of these conditions are seen too rarely by any single physician to make a doubleblind controlled study feasible, but virus-shedding can be monitored, and I suggest that when virus excretion is curtailed when compared to that found in the untreated cases, this is valuable supporting evidence of efficacy. The third patient in Table I and one in Table II did not benefit from the administered cytarabine. The first continued to shed virus for 20 days after treatment had started, the second for at least 12 days. Dr Prusoff has suggested that this might be because a few humans produce very large amounts of pyrimidine kinase, and that the drug was rapidly destroyed. Only now have we, thanks to Professor Grahame-Smith and his colleagues, got a reliable method of assaying the rate of degradation of cytarabine which should make it possible to give a dose of cytarabine titrated to the needs of the individual patient. Dr Longson in his paper in this issue (page 115) has shown that cytarabine is degraded at a rate varying from patient to patient. The fourth patient in Table II is one of special interest. Each untreated attack was preceded by pain in the affected sacral segment, followed without exception some 12 h later by skin eruption. On three occasions it was possible to give him systemic cytarabine within hours of the onset of pain. No eruption followed. But on one occasion (between the first and second courses of cytarabine) he could not reach the hospital for treatment and an eruption followed as before. I have tried to convey some ideas and a few measured facts collected over several years during work with antiviral compounds. The future may not be easy but at least several systemic compounds are now available. To assess them fairly we must use every means, and I put forward virus-shedding as an additional index, particularly when the rare occurrence of cases makes double-blind trials impracticable. References Hall, T. C, Wilfert, C, Jaffe, N., Traggis, D., Lux, S., Rompt, P. & Katz, S. Treatment of varicella zoster with cytosine arabinoside. Transactions of the Association of American Physicians 82: 201 (1969). Juel-Jensen, B. E. Severe generalized primary herpes treated with cytarabine. British Medical Journal ii: 154(1970).

5 Cytarabine and virus shedding 129 Juel-Jensen, B. E. & MacCallum, F. O. Herpes simplex lesions of face treated with idoxuridine applied by spray gun: Results of a double-blind controlled trial. British Medical Journal i: (1965). Kernbaum, S. Intravenous cytarabine in treatment of herpes zoster in haematological malignancy. British Medical Journal i: 224 (1976). MacCallum, F. O. & Juel-Jensen, B. E. Herpes simplex virus skin infection in man treated with idoxuridine in dimethyl sulphoxide: results of a double-blind controlled trial. British Medical Journal ii: (1966). Stevens, D. A., Jordan, G. W., Waddell, T. F. & Merigan, T. C. Adverse effect of cytosine arabinoside on disseminated zoster in a controlled trial. New England Journal of Medicine 289: 873 (1973).