Recurrent herpes simplex: the outlook for systemic antiviral agents.

Members of the herpesvirus family typically establish intimate and lifelong relationships with their hosts. An acute primary infection generally subsides after several days and immunity may be shown by various methods. Despite this the virus may persist, often subclinically, or remain latent, sometimes giving rise to recurrent disease. For example, herpes labialis and genitalis are common diseases associated with a latent infection with herpes simplex virus in neurones of the peripheral' and possibly central nervous system.2 During the recrudescences the virus multiplies to considerable titres in the lesions, allowing transmission to a new host. In otherwise normal adults these recurrences may be painful, inconvenient, and sometimes debilitating, but are rarely life threatening. In those with impaired immunity, however, particularly when cell-mediated responses are abnormal, the recurrent infections can be prolonged and severe.3 Detection of latent infections-Whether the disease is mild or severe, once the clinical signs of herpes subside there is at present no means of predicting whether the infection has been completely eradicated. More refined immunological techniques may be informative in the future, but so far the only methods are retrospective-either observation of a further episode or culture of necropsy tissue from a sensory ganglion related to a previously affected skin site and reactivation of the hidden virus from the explant culture in vitro.4 5 These circumstances militate against clinical study of antiviral drugs that are active against herpes simplex virus; we are therefore obliged to study latent infections in animals. Inhibitory compounds active against herpes simplex virus-Idoxuridine and trifluorothymidine are useful in treating herpes in man.68 Both these compounds are "activated" by healthy cells, so their selectivity is poor and they are too toxic for systemic use. They are, however, helpful in topical treatment, particularly of ocular infections. A third compound, adenine arabinoside, is suitable as a systemic drug but is not very effective; this may be due partly to its rapid conversion in man to an inactive form as a result of deamination by the enzyme adenosine deaminase.9 Recently several new highly selective nucleoside analogues have been discovered that are extremely active against some herpesviruses in vitro yet appear to have very low toxicity in man. Foremost among these are acyclovir (acycloguanosine)'0 and bromovinyldeoxyuridine."1 The initial step in the metabolism of both these drugs is conversion to their respective nucleotides. This phosphorylation is accomplished by a virus-specified enzyme, thymidine kinase.'2 Both these nucleoside analogues are poor substrates …