Journal of Medical Virology Supplement 1:165-168 (1993)

Future Management of Herpesvirus Infections P.D. Griffiths Department of Virology, Division of Communicable Diseases, Royal Free Hospital School of Medicine, London, United Kingdom

The clinical investigations conducted to date with herpesviruses have provided a good grounding into the general principles of herpes- virus replication and pathogenesis. Multiple op- portunities for intervention include prevention of initial infection, prevention of reactivation, sup- pression of reactivated virus, and treatment of established disease. Studies have shown that each of these approaches can be effective against one or more herpesviruses. What is needed now are studies combining sequential interventions so that patients who fail, for exam- ple, prophylaxis with one drug can be entered directly into trials of suppression and then into pre-emptive therapy, each with different antiviral agents. In this way, it is t o be hoped that increas- ing proportions of cohorts of susceptible pa- tients will suffer less from herpesvirus infec- tions. Clearly, the design of such clinical trials needs to be constantly refined as methods of diagnosis and understanding of pathogenic mechanisms improve and as new agents are dis- covered. o 1993 Wiley-Liss, Inc.

KEY WORDS: diagnosis, treatment, antivirals

INTRODUCTION It is likely that the existing herpesviruses will as-

sume increasing importance in human medicine over the next few years. In addition, more recently described herpesviruses such as HHV6 [Thomson et al., 19911 and HHV7 [Frenkel et al., 19901 may become associated with particular syndromes. We should be in a strong position to deal with these increasing problems if we build upon the background of herpesviruses’ natural history, pathogenic mechanisms, development of diag- nostic methods, intervention strategies, and institution of controlled trials which have worked so well to date. Five major intervention strategies can be envisaged, which will be discussed in turn.

PREVENT INITIAL INFECTION Vaccines have been very effective a t preventing in-

fection with a variety of viruses. Indeed, immunisation allowed smallpox to be eradicated from the world. Table 0 1993 WILEY-LISS. INC.

I summarises the favourable characteristics which led to smallpox being eradicated. When these criteria are applied to herpesviruses in general, it will be seen that only one criterion, the absence of an animal reservoir, is unequivocally present in the case of herpesviruses. Other criteria can be partially satisfied by some herpes- viruses, as shown in Table I. However, it is clear that significant hurdles will have to be overcome before we have effective vaccines against herpesviruses which could be used for control and then eradication of herpes- viruses. It is true that two existing vaccines (VZV,CMV) have been shown in clinical evaluations to reduce dis- ease caused by the respective viruses [Hardy et al., 1991: Plotkin et al., 19911, but it seems unlikely that these live attenuated vaccine strains would be consid- ered for immunisation of the normal population. In or- der to satisfy regulatory authorities, we will need to identify the protective epitopes for each virus and present them to the immune system without viral rep- lication or any residual herpesvirus DNA. Examples include the use of acyclovir to treat herpes simplex infection in allograft recipients, vidarabine or acyclovir to treat HSV in neonates [Whitley et al., 19911, and acyclovir to prevent dissemination of zoster [Shepp et al., 19861. It would be worthwhile evaluating in con- trolled trials if penciclovir can provide further benefit in these patient groups.

The natural history of herpesvirus infections in- cludes reactivations of latent virus which may be fre- quent and usually asymptomatic, e.g., EBV, or infre- quent and clinically obvious, e.g., VZV. These reactivations represent a major source of virus which would persist for generations after a universal immuni- sation programme of children began. Public Health Au- thorities must therefore be prepared to undertake ex- tensive immunisation programmes for many years, without necessarily seeing a rapid reduction in disease totals, especially where disease is age-related. Educa- tion campaigns will also be necessary if public faith in the efficacy of immunisation in general is not to be undermined by the apparently slow progress towards controlling disease.

Address reprint requests to P.D. Griffiths, Division of Commu- nicable Diseases, Royal Free Hospital School of Medicine, Row- land Hill Street, London NW3 2PF, UK.

166 Griffiths

TABLE I. Characteristics Favourable to Eradication of Virus Infections

Characteristic

Only one serotype Effective vaccine No animal reservoir No carrier state Cases clinically obvious Low communicability No transmission from ASx Severe disease Potential savings in

developed countries

Smallpox

+ + + + + + + + +

Herpes

VZV, HSV, EBV vzv, CMV +

vzv EBV, HSV, CMV vzv VZV, CMV, HSV VZV, CMV, HSV

PREVENT REACTIVATION The object here is to target an individual cell contain-

ing a latent herpesvirus genome and prevent its activa- tion.

It is known that herpes simplex strains lacking the thymidine kinase (tk) protein have a very reduced abil- ity to reactivate [Efstathiou et al., 19891. Investigators therefore considered whether the use of a pharmacolog- ical agent to render a tk+ virus tk- functionally could reduce the chance of reactivation and preliminary ani- mal experiments with lead components suggest this is the case. Intuitively, these results are rather surprising since the tk protein is expressed as a B-gene and so is not one of the first expressed within the cell. On first principles, one would have expected antagonists of A-gene function to be most likely to be able to prevent reactivation in vivo and this still remains a molecular target for chemotherapy. However, the results obtained to date are encouraging and should only emphasize that we need a better understanding of in vivo latency at the molecular level in order to be able to better target new therapeutic modalities.

SUPPRESS REACTIVATED VIRUS The aim here is to ensure that, if reactivation does

occur, virus cannot initiate infection in neighbouring cells. The effect of the drug would thus be to keep virus replication below the level required to cause symptoms so that the patient’s sense of well-being was main- tained.

An example of this approach is the use of acyclovir prophylactically in individuals at risk of recurrent herpes simplex infection of either the oral or genital mucosa [Mindel e t al., 19881. Beneficial results have also been reported for topical interferon [Shupack et al., 19901, while famciclovir could also be considered for use in this way. Controlled clinical trials are required to determine whether either of these drugs represents an advantage over acyclovir.

For cytomegalovirus, prophylaxis with interferon-a [Hirsch et al., 19831, acyclovir in renal [Balfour et al, 19891 and bone marrow transplant patients [Meyers et al., 19881, and ganciclovir in heart transplant patients [Merigan et al., 19921 have been shown to suppress infection and reduce CMV disease. It is interesting that

acyclovir controls CMV infection, despite the levels of drug found in the plasma being far below those re- quired to control the virus in cell cultures [Balfour et al., 19891. This demonstrates that we need a better understanding of the pharmacokineties of drugs, espe- cially the intracellular concentration of their active forms a t the point of action in vivo. The drug valaciclo- vir (BW256) could be considered for this indication be- cause of the high plasma levels which follow oral dos- ing, and formal studies should be conducted.

Another possible strategy which could be employed is that of immunotherapy, defined as administration of a vaccine preparation to individuals already infected with the particular herpesvirus. The basic assumption is that the vaccine dose can “boost” the immune re- sponse of the individual so that reactivated virus is more rapidly destroyed [Redfield et al., 19911. However, whether such boosting depends upon B-cell or T-cell epitopes and a clear immunological explanation of the mechanism(s) remain to be defined. Pragmatically, it must be remembered that many of the herpesviruses cause severe disease in individuals with impaired T-cell immunity so that attempts to boost cytotoxic T-cell responses may be doomed to failure. Perhaps we should be aiming here to drive B-cell immunity a t a sufficiently high level to reduce herpesvirus replication below the level required to cause disease. There is some encouragement from the literature for the use of immu- notherapy for herpes simplex in a guinea pig model [Bernstein et al., 19911 so human trials of non-replicat- ing immunogens would appear warranted.

PREVENT DISSEMINATION The aim of this strategy is to keep virus localised to

the initial site of infection so that visceral organs do not become involved. Patients with relatively mild infec- tions are therefore identified and treated promptly.

For cytomegalovirus, ganciclovir has been shown to be of benefit under two circumstances. The first [Goo- drich et al., 19911 is when virus infection is detected in surveillance cultures from bone marrow transplant pa- tients (termed suppression) and the second [Schmidt et al., 19911 is where CMV is found in the lungs of bone marrow transplant patients (termed pre-emptive ther- apy 1.

Clearly, these approaches would benefit from the in- troduction of more sensitive and rapid laboratory meth- ods so that patients a t earlier and earlier stages could be recruited into controlled trials. Formal studies of the prognostic value of such diagnostic improvements are required.

TREAT ESTABLISHED DISEASE For herpes simplex, acyclovir has been shown to pro-

vide clinical benefit in controlled trials when treating established genital HSV infection [Bryson et al., 19831. Future trials could evaluate famciclovir under the same circumstances. Vidarabine was shown in seminal studies to be better than placebo for herpes encephalitis [Whitley et al., 19771, but has largely been replaced by

Future Management of Herpesvirus Infections

acyclovir in most clinical settings [Whitley et al., 19861, the exception being the treatment of neonatal HSV in- fection where the two drugs appear to be equivalent therapeutically [Whitley et al., 19911. The increasing use of acyclovir has led to the development of resistant mutants [Collins and Darby, 19911 which in some cases are associated with disease. A recent study has reported that foscarnet is superior to vidarabine in the treat- ment of such resistant episodes [Safrin et al., 19911.

For varicella zoster virus, acyclovir has been shown to provide significant clinical benefit for the treatment of chickenpox [Dunkle et al., 19911 and zoster [Shepp et al., 19861. Other potential drugs for controlled evalua- tion include bromovinyl-ara-U and BW882.

For cytomegalovirus, ganciclovir is frequently used for treating CMV retinitis or gastrointestinal infection. In the case of AIDS patients, a recent trial has reported that foscarnet, although equally effective at treating CMV retinitis, provided survival benefit when com- pared to ganciclovir [Studies of Ocular, 19921. In the case of CMV pneumonitis, there is evidence that this condition is immunopathologically mediated so that i t is found in transplant patients rather than in AIDS patients [Grundy et al., 19871. Uncontrolled studies strongly suggest that immunoglobulin in combination with ganciclovir is superior to the use of ganciclovir or immunoglobulin alone [Reed et al., 1988; Emanuel et al., 19881. Since intravenous immunoglobulin has im- munomodulatory effects which are non-antigen-spe- cific, a trial comparing a preparation from CMV posi- tive donors with CMV negative donors could be enlightening. Meanwhile, some investigators have se- lected monoclonal antibodies with neutralising activity against CMV and have begun trials. It remains to be seen whether these can substitute for polyclonal immu- noglobulin or whether they have any antiviral effect against CMV disease in vivo.

It will be clear that attempts to treat established disease represent the most complex strategy since ef- fects from the patient’s immune system and secondary pathological phenomena may be involved. We must therefore achieve a fuller understanding of pathogenic mechanisms in distinct patient groups, and evaluate critically the significance of resistant strains of virus in vivo.

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