Treatment of mucocutaneous herpes simplex infections

10

Treatment of Mucocutaneous Herpes Simplex Infections

Mindell Seidlin, M.D., and Stephen E. Straus, M.D.

From the Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Herpes simplex virus (HSV) infections are common, unpleasant, and occasionally dangerous. This has led patients and their doctors to try almost anything to shorten episodes or suppress recurrences. Despite occasionally positive anecdotal experiences, it has been difficult to assess the efficacy of many of these treatments because of the highly variable severity, duration, and frequency of episodes of herpes in individual patients, 1-j the enormous placebo effect of of patient perceptions of any new therapy,677 and the unreliability drug efficacy. The natural history of genital and orofacial HSV infections has only recently been elucidated and many of the early therapeutic trials failed to take into account such features as the differences in duration and severity of primary, initial, and recurrent infection (Table 1). There has also been considerable variability in the choice of parameters of healing used in the various studies. Some trials relied solely on patient observations of severity or duration of lesions while others, more appropriately, have required frequent examination by physicians and/or frequent viral cultures to document resolution of infection. Many therapeutic modalities have been tried in both oral and genital HSV infections. Most agents have been used in an effort to shorten or ameliorate recurrences, although some trials have focused on prevention of primary infection, treatment of first episodes, or suppression of recurrences. The many attempted approaches to therapy of these infections can be divided into several categories: palliation of symptoms, psychosocial support, enhancement of immunity for suppression of recurrences, specific vaccines to prevent primary or recurrent infection, and antiviral agents to prevent or abbreviate virus replication. In addition to these approaches, a wide variety of surfactants, nutritional therapies, and mechanical devices has been used. Palliative and Supportive

Care

Even in the absence of specific antiviral therapy, careful local therapy has been shown to diminish the discomfort and local complications associated with herpes. In order to prevent bacterial superinfection it is important t keep lesions clean and, where possible, dry. Facial, thigh, buttocks, sacral, and genital lesions 100

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TABLE

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of Mucocutaneous

1. Clinical Course of Genital Herpes Infection Mean Duration initial

Pain Viral shedding Time to healing

Infection

(Days)’

Recurrent Men

Infection Women

Men

Women

10.9

12.2

3.9

5.9

11.4

11.4

4.1

3.1

16.5

19.7

10.6

9.3

‘Data adapted from Corey et al.5

should be washed gently with a mild soap two or three times daily and blotted dry, taking special care to avoid unroofing vesicles. Prolonged soaking and sitz baths may result in maceration of tissues or fungal infections and may facilitate local spread of the HSV infection.8 Occlusive dressings and tight clothing should likewise be avoided. When intraoral lesions occur, careful attention should be paid to oral hygiene. If toothbrushing is not feasible because of local pain, the patient should be encouraged to rinse and gargle with l-3% hydrogen peroxide or a saline solution in an attempt to decrease the bacterial flora of the mouth. Bacterial infections should be treated aggressively with appropriate antibiotics. Pain management is an important element in the care of herpes patients. Topical anesthetics, such as 5% lidocaine hydrochloride ointment are of some value in temporary pain relief in patients with intraoral lesions, but many patients require systemic analgesics. Aspirin or acetaminophen is generally adequate for mild infections, but parenteral agents, including narcotics, may occasionally be necessary for more severe pain, particularly in primary infection. It should be noted that the pain can often be quite disproportionate to the visible extent of lesions. Many patients experience moderate to severe pruritus during both the prodrome and the period of active lesions. This can be managed with diphenhydramine hydrochloride or hydroxyzine hydrochloride. Satisfactory control of itching or pain, however, may require dosage levels that compromise normal activ-

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ity. Occasionally, patients with primary infections will have fever, malaise, anorexia, or dehydration. These complications should be managed with antipyretics, liquids, and parenteral fluids, if necessary. Patients often express concern over possible spread of the infection to other body areas. Although herpetic recurrences may occur spontaneously in new areas, autoinoculation can be avoided by careful hand washing after contact with lesions. There are some patients in whom recurrences appear to be precipitated by ultraviolet light, stress, certain foods, or other environmental factors. These patients can use sun blockers or try to avoid the provocative agents or situations. Psychologic support is another key element in the care of herpes patients. Patient education about the management of recurrences, the risks of contagion, the necessity for careful obstetric care, and the importance of frequent Pap smears to screen for cervical cancer is essential. One must, however, emphasize that the disease, although unpleasant, is rarely life-threatening. Many patients benefit from support groups or from the opportunity to discuss their concerns with other individuals. In some instances, patients experience severe anxiety or depression, necessitating psychiatric intervention. Unorthodox Treatments A wide variety of nonprescription drugs, nutritional supplements, and topical agents have been used to treat herpes.9 Few of these have been carefully evaluated in clinical trials. Some treatments have been “rationally” based; for instance, use of ascorbic acid to promote healing or use of ether and surfactants to disrupt the viral envelope; while in other cases, the theoretic reasons for possible efficacy are less apparent, as in the case of carbenoxolone, spermicides, or povidone iodine, For a listing of some of these agents, see Table 2. Thier@* has recently written a careful review of this subject and concludes that none has been proven effective in con-

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TABLE 2. Unconventional Treatment for Herpes Therapeutic

Agent

Reference Number

Site*

Controlled Trial

Observer?

Culture+

Authors5 Conclusion

+

Betadine

10

G

P,I

Ether

11 7

G G

P,I

+ +

Nonoxyno19

12

0

I

+

Chloroform

13

0

P,I

+

Carbonoxolone

14

0

P

+

Lysine

15 16 17 16

GO 0 GO 60

P

+

P P

+

19

0

P,l

+

20 21

0 G

P,l P,I

Boric acid

22

0

P

Cimetidine

23

0

P

+

Ice

24 25

0 0

P P

+ +

26 27

0 0

P,I P,l

Ascorbic

acid

Zinc

Surgical

excision

I

I

+

+ + +

“Site of infection, G (genital) or 0 (oral). fobserver who judged response to therapy, P (patient) or I (investigator). $Viral culture was performed (+) or was not performed (-) to evaluate response to treatment. §The authors concluded that the agent under study did (+) or did not (-) ameliorate the infection.

trolled trials, although some may provide symptomatic relief in selected cases. Perhaps the most widely used of these nonprescription treatments, and one which has received a great deal of recent attention in the lay press, is lysine. In 1964, Tankersley29 showed that arginine encouraged, while lysine inhibited, HSV replication in tissue culture. Griffith et al.15 performed an uncontrolled trial of varying doses of oral lysine in an attempt to suppress genital and oral herpetit recurrences. Patient self-assessment was the sole criterion of therapeutic effect. The authors suggested that the drug was effective and that taking lysine and avoiding arginine-rich foods could suppress recurrences. Subsequent controlled studies have failed to demonstrate the efficacy of lysine in either treatment of acute episodes or suppression of recurrences.16-l8

Photo-inactivation

In 1964, Wallis and Melnicks described complete, irreversible photo-inactivation of HSV in vitro in the presence of the heterocyclit dyes, neutral red, toluidine blue, and proflavine. This led to a variety of clinical trials using these dyes and UV light exposure to shorten the duration of episodes of recurrent disease. In an early double-blind trial, Felber et al.31 compared photo-inactivation using neutral red dye and a nonheterocyclic red compound for treatment of episodes of herpes simplex genitalis. In this study, 85% of the patients receiving neutral red and 50% of the patients receiving the other dye claimed to be improved. Unfortunately, the record of patient symptoms was the sole criterion of response to treatment, rather than objective lesion score or virus culture data. Chang et

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a1.3” performed a study comparing the efficacy of neutral red, proflavine, and methylene blueon symptomatic improvement. They reported substantial improvement in all groups, but failed to use objective measurements of clinical signs and symptoms and did not include a placebo or control group. Roome et a1.33performed a double-blind trial of neutral red and placebo and utilized frequent observation of the patients (days 1, 2, 3, and 7) to establish clinical improvement. In this trial there was no difference between the neutral red and placebo groups. Taylor and Dohertys4 compared time to healing and duration of virus shedding in patients receiving proflavine photo-inactivation, saline photo-inactivation, or iododeoxyuridine. They found the lesion area to be somewhat larger in the proflavine treated group than in the other groups, but found no difference in virus shedding. In a large placebo-controlled study (170 episodes in 96 patients), Myers et a1.35failed to demonstrate any effect of photoinactivation on time to healing or time to next recurrence. Elucidation of the mechanism of in vitro activity of photodynamic inactivation, DNA strand scission, led to concern about the possible oncogenicity of this therapeutic modality. Oncogenic transformation of mammalian cells in culture by DNA viruses following photo-inactivation had been reported,3‘Q7and in 1977 three cases of penile cancer were reported in patients treated with photodynamic dyes.38 This serious potential adverse effect. combined with less than convincing data on efficacy, has led to abandonment of this approach to therapy of HSV infections. Vaccines and Immune Stimulators The role of immunity in control of initial episodes and recurrences of HSV is complex. It is well known that individuals with antibodies to HSV-1 have less severe initial episodes of HSV-2 than those with no prior exposure to the virus, and vice versa, but the incidence of latency and recurrence is not altered by the presence of antibody.5 Recov-

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ery from episodes of HSV infection appears to relate to cell-mediated rather than humoral immunity, and patients with defects in cellmediated immunity are at risk for more frequent and more severe episodes of HSV infection.3+43 On the other hand, most individuals with HSV infections, including those with very frequent recurrences, have no demonstrable cellular immune defect. Presumably a subtle defect exists, but the failure to document one makes augmentation of the immunologic response to herpes difficult.

Nonspecific Vaccines Several nonspecific immune stimulators have been investigated for their therapeutic efficacy in the management of HSV infections. Because of its apparent efficacy as an adjuvant in patients with melanoma and some lymphoproliferative disorders, BCG (Bacillus Calmette-Guerin) was one of the first nonspecific immune stimulators tested in HSV infections. There is evidence that BCG prevents death in rabbits infected with HSV-2 by cornea1 scarification.*4 Anderson et a1.45administered BCG to 15 patients with recurrent genital herpes in an uncontrolled trial and reported a decrease in the frequency of recurrences in nonpregnant, but not in pregnant, individuals. Bierman compared the results of BCG vaccination in 38 healthy patients with reported results from studies of heterologous and inactivated vaccines and found no convincing difference in subsequent recurrence rate. A wide variety of other vaccines has been tried in an effort to augment host antiviral responses. These have ranged from smallpox*7@ to polio,*9 yellow fever,50 and influenza.5l These studies have been carefully reviewed by Bierman,* and none demonstrated convincing effect. Moreover, in view of reported cases of disseminated vaccinia after smallpox vaccination,52 as well as Guillain-Barre syndrome after influenza vaccination,53 nonspecific vaccines should probably be abandoned in that they have no proven effect and may be dangerous.

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Specific Vaccines Although, as noted above, cell-mediated immunity seems to be of primary importance in recovery from HSV infection, specific humoral immunity may have some role in protection from the virus. Vaccines containing crude extracts of HSV grown in cell culture (Lupidon G, Lupidon H) have been available in Europe for some time but have never been subjected to careful testing for safety or efficacy. The use of “attenuated” live or inactivated virus vaccines is particularly problematic in the case of HSV. In addition to the potential virulence of any live or inadequately inactivated viral preparation, one must be concerned about the potential oncogenicity of this DNAvirus. A further problem is that of latency. As neither the mechanism of viral latency nor its relationship to virulence or oncogenicity is well understood, mutants that are nonvirulent and nononcogenic may still exhibit latency. The results of studies in progress to determine which viral genes are necessary for establishment and maintenance of latency, as well as those responsible for oncogenicity, are critical to the design of safe whole virus vaccines. Currently, efforts are being directed at developing subunit vaccines, which consist of purified viral glycoproteins. Two approaches are being taken: one is to extract glycoproteins from HSV grown in tissue culture; the other is to clone the relevant genes, and then produce large amounts of the glycoproteins in bacteria. It has been demonstrated that HSV-1 glycoprotein D (gD) is type-common and, hence, antisera to HSV-1 gD neutralize both HSV-1 and HSV-ZZ~~@ It has also been shown that passively immunizing mice with a monoclonal antibody against HSV-1 gD is protective against neurologic disease caused by HSV-1 or HSV-2 in mice.s6 These experiments demonstrated the potential for prophylactic and possibly therapeutic use of a gD vaccine. To this end, Watson et a1.s7cloned and sequenced the gene for HSV-1 gD and succeeded in obtaining gene expression in Escherichia coli.

It seems likely that a vaccine may be effective in prevention of primary infection, but less likely that it will be useful for suppression of recurrence or treatment of primary or recurrent episodes. In addition, a glycoprotein vaccine would stimulate humoral but not cell-mediated immunity to HSV and, therefore, may confer only partial or shortterm protection. Augmentation of the cellular immune response in HSV patients by levamisole, interferon, and thymic hormone58 is currently under investigation. As noted above, cellmediated immunity is clearly important for recovery from HSV infection, but its role in acquisition of the infection is unclear. In addition, most individuals, even those with very frequent or severe recurrent HSV, have no demonstrable cellular immune defect.

Levamisole Levamisole is an antihelminthic phenylthiazolidine that seems to improve white blood cell chemotaxis and stimulate differentiation and effector functions of T lymphocytes. Because of this, trials were begun for therapy of recurrent mucocutaneous herpes. The reports of initial uncontrolled trials of levamisole for herpes labialis were promising.5gy60 There was further optimism when O’Reilly et a1.61 suggested that therapy with levamisole improved herpes-specific cellmediated immune responses in patients with genital HSV. The results of controlled clinical trials of levamisole have been less encouraging. Mehr and Alban showed it to be ineffective for treatment of individual episodes of genital or orolabial herpes in a double-blind, placebocontrolled study. Jose and Mintye reported on a 6-month double-blind, placebo-controlled trial of levamisole for patients with herpes simplex genitalis and labialis. This study showed that lesions were present for fewer days after the first 2 months of therapy. Chang and Fiumara64 found a slight, but significant, improvement in their patients with genital herpes after at least 6 months of therapy, but noted serious toxicity, includ-

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Treatment of Mucocutaneous

ing neutropenia and urticaria, as well as unpleasant side effects, such as malaise and dyspepsia. These side effects made it difficult to conduct double-blind, placebo-controlled studies. Interferon It is clear from invitro studies that clinical and laboratory strains of HSV-1 and -2 are sensitive to alpha, beta, and gamma interferons, although HSV-2 appears to be more sensitive than HSV-1.65 The role of endogenous interferon in recurrence of and recovery from HSV infection is less clear. The presence of interferon has been demonstrated in blood and tissues of a neonate with disseminated HSV66 and, in brain, early in the course of HSV encephalitis in adults.67 Rasmussen and Merigan68 have shown interferon production by peripheral blood mononuclear cells from individuals with recurrent herpes simplex labialis. In 1981, Overall, Spruance, and GreenGgdemonstrated the presence of interferon in vesicle fluid from herpes labialis in 18 of 19 healthy adults. In a subsequent study, 50 of 51 patients had interferon in vesicle fluid with levels that correlated with vesicle fluid virus titers, but not with the clinical severity of infection.70 It is of interest that many patients have high vesicle fluid interferon levels (1500-28,600 IU) as early as 12 hours after the appearance of lesions. Cunningham and Merigan71 studied production of gamma interferon by peripheral blood mononuclear cells of patients with recurrent herpes simplex labialis. They noticed a shorter recurrence interval in patients whose peak interferon production was lower. Peripheral blood mononuclear cell gamma interferon production peaked at 6 to 20 days after infection and was undetectable by 6 weeks, while recurrences often appeared later, as much as 14 weeks later in many patients. Rand et a1.72 showed an increased incidence of labial herpes in the first 3 months following cardiac transplantation. This time period corresponded to the period of decreased in vitro production of interferon by

HSV Infections

105

the peripheral blood mononuclear cells in response to exogenous HSV antigen. Blast transformation to phytohemagglutinin was also depressed during this period, but antibody titers to HSV remained stable. Infections in these patients were more severe and protracted than in normal hosts.‘” The above studies suggest that most normal individuals respond quickly to HSV infection by producing circulating and local levels of interferon and that this interferon may be important in recovery from infection. These results imply that interferon could be useful for prophylaxis of recurrences or for treatment of episodes in interferon-deficient hosts, but suggest that it may be less useful in the treatment of recurrences in normal hosts. Patients undergoing surgery to the trigeminal nerve root often experience HSV recurrences. Pazin et a1.74 studied the use of prophylactic human leukocyte interferon in patients about to undergo this procedure. Patients received 70,000 units per kg in two daily doses for 5 days, beginning 1 day prior to surgery, and were evaluated for the presence of lesions and for virus shedding from the throat. Of 18 placebo-treated patients, 10 developed lesions, and 15 shed virus from the oropharynx. There was a significantly lower rate of lesions and virus shedding in the interferon-treated patients. It should be noted that, in the 3 weeks after discontinuation of therapy, the interferon and placebo groups experienced equal numbers of recurrences.75 Cheeseman et al.76 devised a trial, using leukocyte interferon in renal transplant patients, that was aimed at the prevention of recurrent herpesvirus infections. The patients were given 3,000,OOO units of leukocyte interferon intramuscularly twice weekly. Although treatment decreased the incidence of cytomegalovirus (CMV) viremia and delayed CMV excretion in this population, it had no impact on the incidence of herpes simplex lesions or virus shedding. Investigation of the use of interferon as treatment for initial episodes, for prophylaxis, or for treatment of recurrences will be facilitated by the recent availability of recombinant interferon.

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Antiviral Agents

General Considerations In tissue culture, a wide variety of compounds inhibits HSV replication, but, in order for a drug to be clinically useful, it must inhibit viral replication at concentrations that are not toxic to mammalian cells. Several agents that have been used in cancer chemotherapy (eg, cytosine arabinoside6y77) have exhibited potent in vitro antiviral activity, but have been too toxic to be useful when given systemically at therapeutic doses and ineffective when used topically. Drugs that have turned out to be clinically useful are mainly nucleoside analogs that have greater affinities for virus-encoded enzymes, such as kinases and polymerases, than for the analogous mammalian enzymes. This category includes thymidine analogs, such as adenine arabinoside (Ara-A) and its derivatives, idoxyuridine (IDU), trifluridine (TFT), acyclovir (ACV), bromovinyldeoxyuridine (BVDU), phosphonoformate (PFA), fluoroiodoaracytosine (FIAC), and fluorodeoxyarabinofuranosyl thymine (FMAU). Ribavirin interferes with guanine synthesis and thus affects both DNA and RNA synthesis. Amantadine and its derivatives, rimantidine and tromantidine, interfere with viral uncoating and cell penetration, but as yet have shown little promise for therapy of herpes infections.78T7g Likewise, 2-deoxyglucose, which interferes with glycosylation of viral proteins and lipids has&vitro antiviral activity. In order for agents with potent in vitro activity against HSV to be effective in the therapy of mucocutaneous herpes, they must have access to the infected tissue. Topical agents (eg, Ara-A and IDU) are quite effective when given for treatment of herpes simplex keratitis, but are ineffective for cutaneous infections. Derivatives of these drugs with better tissue penetration, as well as mechanical techniques such as iontopheresis, may prove effective in inhibiting virus in the skin; however, it is doubtful that topical agents will be useful in suppressing reactivation of latent virus in ganglia. Prevention of latency and suppression of recurrence will

Dermatology

probably require systemic therapy. Finally, therapeutic agents that must be administered parenterally are unsuitable for the treatment of most patients with HSV infection, as treatment would necessitate hospitalization.

Idoxyuridine A thymidine analog, 5-iodo-2’deoxyuridine, was the first agent shown to be efficacious in the treatment of herpes keratitis in man.*Oy*l The drug has not been uniformly effective in this disorder because of viral resistance, ocular toxicity, and occasional hypersensitivity reactions. It cannot be used systemically because of severe toxicity. Trials of topical IDU for mucocutaneous herpes have yielded conflicting results, and there has been some controversy over the appropriate vehicle for topical administration. An early uncontrolled trial of IDU in 22 women showed no beneficial effect on herpes simplex genitalis. In a small controlled trial of 0.2% IDU in a water-soluble cream base, Burnett and Katz83 were unable to demonstrate shortening of time to healing of cutaneous herpes simplex. MacCallum and Juel-Jensen84 compared 5% IDU in DMSO to DMSO alone for treatment of facial herpes and found shortened healing time in IDUtreated patients. The same authors had previously found positive effects of IDU administered by air gun85 but not in cream base.86 They concluded that the drug was effective, but only when given with a vehicle that improved skin penetration. Kibrick and Katz*7 studied the effect of 0.5% IDU ointment and 0.1% IDU in alcohol on orolabial herpes in a placebo-controlled, double-blind trial and found no effect of drug on any criteria of pain or healing. Taylor and Dohertyz4 compared the effects of 0.5% IDU to photoinactivation and placebo in men with genital herpes and found no difference between IDU and placebo and some disadvantage to photoinactivation. Parke+ compared 20% IDU in DMSO, 5% IDU in DMSO, and DMSO alone for the treatment of recurrent genital herpes. It should be noted that there was a 40% dropout rate in this trial, and there

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Treatment of Mucocutaneous

was no recorded assessment of how long lesions had been present before therapy was initiated. The authors concluded that both 5% and 20% IDU substantially accelerated cessation of viral shedding and that 20% IDU had a greater impact on length of time to complete healing. In a double-blind trial involving men and women with primary and recurrent genital herpes, Silvestri, Corey, and HolmesBY compared the effects of 30% IDU in DMSO, DMSO alone, and saline placebo on time to cessation of viral shedding and various parameters of clinical healing. They found that IDU in DMSO significantly shortened the period of viral shedding in both primary and recurrent infection when measured either from lesion onset or from the time of initiation of therapy, but had no significant impact on the clinical course of either primary or recurrent episodes.

Adenine Arab&o&de Adenine arabinaside is a purine nucleoside that inhibits viral DNA polymerase and has documented efficacy in the treatment of a variety of herpesvirus infections, including herpes simplex encephalitis,g0 neonatal herpes,91 varicella and zoster in the immunocompromised host,g2*93 and herpes simplex keratitis.S4 When given intravenously, it is deaminated to arabinosyl hypoxanthine, which is the principal metabolite found in blood and urine. The drug is available for intravenous and topical use only. Topical application of Ara-A to genital lesions in both primary and recurrent genital herpes was shown to be ineffective in shortening duration of pain, virus shedding, or time to lesion healing and may have prolonged appearance of new lesions in men.95796Failure of therapy for mucocutaneous disease with this otherwise effective antiherpetic agent has led investigators to believe that therapeutic effectiveness depends on improved tissue penetration. This has led to studies of application of Ara-A in DMSO-containing ointment, as well as by iontophoresis,97@ and of molecular modifications on the drug, designed to increase water solubility.99

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107

Ara-A Analogs Adenine arabinoside monophosphate is a more water-soluble analog of Ara-A with similar antiviral, pharmacologic, and toxicologic properties.loO It is rapidly metabolized to its parent compound, Ara-A, by circulating and tissue enzymes. In the mouse model, both Ara-A and Ara-AMP in 10% ointment reduced the overall mortality from HSV skin infections but had no effect on the establishment of latency.lol Topical AraAMP was ineffective in hastening lesion healing or the cessation of virus shedding and failed to reduce the frequency of recurrences in human herpes labialis or genitalis.i”3 Iontophoresis of this agent onto lesions of hairless mice inoculated with HSV-2 decreased the lesion score and increased survival when compared with topical Ara-A.s7

Trifluorothymidine An inhibitor of thymidylate synthetase, 5trifluorothymidine (TFT) can be phosphorylated to the triphosphate and incorporated into DNA, thus interfering with production of late messenger RNA.104 TFT has in vitro activity comparable to IDU.105 The drug has been shown to be highly effective in the treatment of herpes keratitis and, unlike Ara-A and IDU, rarely causes hypersensitivity. The drug cannot be used systemically because of gastrointestinal and bone marrow toxicity. Drug-related mutagenicity and teratogenicity have been described in in vitro assays.

Acyclovir Acycloguanosine, (ACV) a thymidine anaagent approved log,106 is the first antiviral for therapy of mucocutaneous herpes in the United States. Studies have been performed to evaluate topical, oral, and intravenous therapy with ACV and have addressed treatment of primary and recurrent episodes, as well as suppression of recurrences in both normal and immunocompromised hosts.

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Therapy of initial episodes In 1983, Mindel and Adlerlo reported a trial of intravenous ACV for therapy of initial episodes of genital herpes and demonstrated decreased healingtime, diminished period of new lesion formation, and a shortened period of viral shedding in both men and women. The effect on clinical symptoms was less impressive. Corey et a1.1°8 confirmed the objective findings of decreased time to crusting, healing, and viral shedding and noted moderately shortened duration of pain, itching, and dysuria in both men and women. Because intravenous therapy requires hospitalization, other routes of drug administration have been attempted. Two studies using topical ACV for therapy of primary herpes simplex genitalis have been published.l09~1*0 Both showed shortened duration of virus shedding in both men and women. Only Thin et al.,log however, noted some shortening of healing time and duration of clinical symptoms. More encouraging results were obtained by Nilsen et al.“* using200 mg of oral ACV 5 times a day for therapy of initial episodes. They demonstrated shortened viral shedding, shortened time to healing, and diminished periods of pain, when compared with placebo. These findings were confirmed by Bryson et al.112

Treatment of recurrence Because recurrent infection tends to be mild and brief, it is difficult to demonstrate drug efficacy in this setting, and early implementation of treatment may be essential for therapeutic effect. Most studies have required patients to undergo an examination before medication is dispensed, substantially delaying the initiation of treatment after the onset of an outbreak. In Corey’s study of topical ACV,110~l13there was some shortening in the period of viral shedding in both men (0.8 versus 1.5 days) and women (0.5 versus 4.0 days) with recurrent infection, but no significant diminution in the duration of pain or time to healing was found. Spruance et al.114 studied therapy of herpes labialis with topical

Clinics in Dermatology

ACV. ACV diminished virus shedding in the subgroup of patients who began therapy within 8 hours from onset of lesions, but not in those in whom therapy was initiated later. There was no improvement in any of the clinical parameters. Nilsen et al.“’ treated 85 patients with recurrent genital herpes with oral ACV and found significant shortening of the duration of viral shedding and a modest decrease in time to healing and new lesion formation, but there was no significant effect on duration of pain. These patients had lesions present, on average, for 1 day prior to the initiation of therapy. Reichman et a1.‘15,“6 attempted to overcome the problem of late initiation of therapy by comparing patient-initiated with physician-initiated therapy for genital herpes. In a preliminary report, they found that patients who initiated therapy at the first signs of an outbreak had a somewhat shorter time to healing than those who had to delay treatment until an examination was performed, but there was no significant difference in the duration of pain. Other studies of patientinitiated therapy are currently in progress.115 These studies are, of course, dependent on patients accurately identifying prodromes, predicting location of lesions in the case of topical application of drug, and promptly initiating therapy without intervention by an experienced observer and without the opportunity for viral culture. It should be noted that treatment of acute episodes did not prevent or delay subsequent recurrence in any of the studies in which this was evaluated.10*,1091111It has been suggested by Corey et al.‘O* and others that very early initiation of ACV therapy for initial episodes may have some effect on delaying or preventing subsequent recurrence, but this needs to be more fully explored.

Immunocompromised Patients As noted earlier HSV can cause severe, prolonged, and occasionally fatal infection in the immunocompromised host,39-43,11*making therapy and prevention of infection particularly important in this group. Whitley et

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Treatment of Mucocutaneous

al.1’” conducted a trial of topical ACV in compromised hosts with orofacial HSV infections and found earlier cessation of viral shedding and shortened periods of pain, although time to crusting and healing was not affected. Mitchell et a1.i20 and Meyers et al.121 performed double-blind, placebo-controlled trials of 7 days of therapy with intravenous ACV in immunocompromised patients with herpes labialis. When compared with the results of placebo treatment, lesion crusting and healing occurred in a mean of 4.2 and 6.4 days sooner, respectively, in ACV-treated patients, and resolution of pain occurred 4.3 days earlier. Cessation of viral shedding and cessation of new lesion formation also occurred earlier in the ACV group. Similar results obtained in a placebo-controlled trial of intravenous ACV in heart transplant patients with recurrent mucocutaneous herpes.122 Successful treatment of recurrences in immunocompromised patients led to studies of the prophylactic use of intravenous ACV in seropositive patients about to undergo procedures that put them at risk for recurrent HSV. Sara1 et a1.iz3 performed a doubleblind, placebo-controlled trial of ACV in seropositive patients undergoing bone marrow transplantation. Therapy was begun 3 days before transplantation and was continued for 18 days. None of the 10 patients who received ACV and 7 of the 10 who received placeboexperienced HSV infections during therapy. It should be noted that 5 of the patients who had no recurrences while receiving ACV developed lesions after cessation of drug administration. In 1982 Straus et a1.1z4 reported suppression of frequently recurring HSV infections in two patients with common variable immunodeficiency with prolonged courses of oral ACV. In both cases, recurrences developed shortly after cessation of therapy, but responded quickly to reinstitution of the drug. Ne?Jer

Agents Requiring Evaluation

Further

There are a variety of new and potentially useful antiviral agents that have not as yet

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109

been fully investigated. Trisodium phosphonoformate (foscarnet, PFA) inhibits HSV DNA polymerase, probably by interfering with binding of nucleoside triphosphates to the enzyme, and hence inhibits viral replication in cell culture.125~126 Preliminary studies suggest possible efficacy of topical PFA in a guinea pigskin infection mode1127 and a genital infection model.128 Initiation of treatment soon after infection was necessary to demonstrate any effect. A preliminary report of a small trial of 3% foscarnet ointment for recurring labial herpes*2g in humans failed to demonstrate any improvement in healing time. Foscarnet is incorporated into bone, and some skin irritation does occur with application of the 3% ointment. Further toxicologic study of this agent will be necessary. The in citro antiviral activity of 2-deoxyglucose (2dG) in some cell lines is thought to involve alterations in the synthesis of viral glycoproteins or glycolipids.*“” In 1979, Blough and Giuntolii”i reported the successful use of topical 2dG for therapy of both initial and recurrent genital herpes infections in women. The average duration of lesions prior to initiation of therapy in initial episodes was 9.3 days and in recurrent episodes 4 days; the duration of lesions in the placebo-treated groups was 18 and 12 days following therapy, respectively, and in the treated groups was 8.2 and 6.8 days, respectively. The late initiation of therapy and the unusually long time to healing in placebotreated recurrent episodes suggested inaccurate classification of primary and recurrent disease1s2 or possible adverse effects of a constituent of the ointment (miconazole) on healing. Subsequently, McCray and Zugerman’“” were unable to demonstrate any effectiveness of topical 2dG in genital or oral herpes infections using an alcoholic-based vehicle. Moreover, Kern et al.ls” found no effect of 2dG on cutaneous infection of HSV-1 in miceor on genital infection with HSV-2 in mice or guinea pigs. BVDU DeClercq et al135 have investigated the in zjitro antiherpes activities of a variety of

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thymidine analogs. (E)-5-(2-bromovinyl) -2’-deoxyuridine-BVDU-appears unique among them in that it is approximately 100 times more active against HSV-1 than against HSV-2. BVDU, like some other thymidine analogs, requires activation by viral thymidine kinase and inhibits viral DNA polymerase. It appears that the type specificity resides in the polymerase rather than in the thymidine kinase.136 Mayo137 has described an accurate typing assay for HSV-1 and -2 based on this differential sensitivity to BVDU. Both topical and oral administration of BVDU were effective in blocking skin lesions and death in HSV-l-inoculated hairless mice.‘s8 Human trials for therapy of herpes keratitis are currently in progress.‘39 Because of its type-specificity, this agent is unlikely to be useful for the treatment of genital herpes, but it may be useful in the management of other herpesvirus infections, such as varicella and zoster. Ribavirin Ribavirin is a synthetic nucleoside that interferes with the conversion of guanosine to inosine in infected cells and exhibits in vitro virostatic activity against both DNA and RNA viruses. This drug has been of interest primarily because of its efficacy against influenza and other respiratory infections.140 The agent can be administered orally, topically, or by aerosol. In one small study, oral administration of 800 mg/day appeared to have some effectiveness in shortening the period of pain in both oral and genital herpes, but was associated with a significant drop in hemoglobin and hematocrit, both of which appear to be reversible on withdrawal of therapy.141 The same problem has been noted in clinical trials of ribavirin in other infections. FIA C and FMA U 2’-Fluoro-5 iodoaracytosine (FIAC)142 and 1-(2’-fluoro-2’-deoxy-p-D arabinofuranosyl thymine (FMAU)143 are newly synthesized pyrimidine analogs that have impressive in

Clinics in Dermatology

vitro activity against HSV-1 and HSV-2. Their in vitro antiviral effect is reversed by thymidine; however, their cytotoxicity, which is present at higher doses, is reversed by deoxycytidine. This suggests different mechanisms of inhibition of host and viral enzymes. The activity of both agents appears to be comparable to that of ACV in rabbits with experimental herpes keratitis.144 Further toxicologic and in viva studies will be necessary before the possible clinical utility of these drugs can be evaluated. Conclusions After many years and multiple trials of ineffective or marginally effective drugs for mucocutaneous herpes infections, developments in the field of antiviral therapy have recently accelerated and have begun to yield clinically useful agents. ACV in intravenous, oral, and topical form has been shown to shorten the course of initial episodes or”genital herpes. Oral ACV accelerates healing in recurrent infection. Intravenous and oral ACV have also been shown to be effective for the suppression and treatment of recurrences in immunocompromised hosts. Studies of the use of the oral form of the drug for the suppression of recurrences in immunocompetent patients are currently in progress. Unfortunately, no impact of ACV on latent HSV has ever been shown. Further investigation will be necessary before the clinical utility of some of the newer antiviral agents can be evaluated. Several potential problems may become manifest when ACV or any of the other nucleoside analogs become widely available. Although short-term studies have not shown significant toxicity, these drugs certainly have the potential for oncogenicity and teratogenicity. This is a particular problem in the herpes patient population, a group of young adults in their child-bearing years, who may need to use the drug for a protracted period of time. A further issue of concern is the possible emergence of drug-resistant HSV mutants.

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Treatment of Mucocutaneous HSV Infections

There have been reports of in vitro resistance to almost every agent and there have been several reports of the emergence of ACVresistant mutants in treated patients.145j146 Moreover, Crumpacker et a1.147have shown that resistance to many of the nucleoside analogs map quite closely together i? the HSV genome in an area corresponding to the viral DNA polymerase gene. This suggested the likelihood of cross-resistance to several drugs and, indeed, this phenomenon has been observed in laboratory isolates. Crude or cloned subunit vaccines hold promise for the prevention of primary infection in vaccinees, although it is unlikely that they will be useful in the treatment of individual episodes or for prophylaxis of recurrences. More information about the nature of the immune response to HSV infection, as well as a better understanding of the genetics of viral latency and reactivation, may allow more sophisticated and effective approaches to augmentation of host antiviral defense mechanisms. Drug Names acyclovir: Zovirax proflavine: Isoflav ribavirin: Viramid, Virazole trifluridine: Viroptic Acknowledgment Carol Crout, Karen Leighty, and Shirley Starnes assisted in preparation of this manuscript. References

111

3. Guinan ME, MacCalman J, Kern ER, Overall JC, Spruance SL. The course of untreated recurrent genital herpes simplex infection in 27 women. N Engl J Med. 1981;304:759-63. 4. Reeves WC, Corey L, Adams HG, Vontver LA, Holmes KK. Risk of recurrence after first episodes of genital herpes. Relation to HSV type and antibody responses. N Engl J Med. 1981;305:315-9. 5. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med. 1983:98:958-72. 6. Marks R, Koutts J. Topical treatment of recurrent herpes simplex with cytosine arabinoside. Med J Aust. 1975;1:479-80. 7. Guinan ME, MacCalman J, Kern ER, Overall JC, Spruance SL. Topical ether and herpes simplex labialis. JAMA. 1980:243: 1059-61. of herpes sim8. Chang T. Local dissemination plex following soaking or sitz bathing. Am J Obstet Gynecol. 1978;131:342-3. HSV survey 9. The Helper. HELP membership research project results. American Social Health Association. June 1981;111:1-16. EG, Masukawa T. Effect of 10. Friedrich povidone-iodine on herpes genitalis. Obstet Gynecol. 1975:45:337-g. 11. Corey L, Reeves WC, Chiang WT, et al. Ineffectiveness of topical ether for the treatment of genital herpes simplex virus infection. N Engl J Med. 1978;299:237-9. 12. Vontver LA, Reeves WC, Rattray M, et al. Clinical course and diagnosis of genital herpes simplex virus infection and evaluation of topical surfactant therapy. Am J Obstet Gynecol. 1979;133:548-54. 13. Taylor CA, Hendley JO, Greer KE, Gwaltney JM. Topical treatmentof herpes labialis with chloroform.Arch Dermatol. 1977;113:1550-2. 14. Poswillo DE, Robert GJ. Topical carbenoxolone for orofacial herpes simplex infections. Lancet. 1981;ii:143-4. 15. Griffith RS, Norins AL, Kagan C. A multicentered study of lysine therapy in herpes simplex infection. Dermatologica. 1978:156: 257-67.

1. Spruance SL, Overall JC, Kern ER, Krueger GG, Piliam V, Miller W. The natural history of recurrent herpes simplex labialis. Implications for antiviral therapy. N Engl J Med. 1977;297:69-75.

16. Milman N. Scheibel J, Jessen 0. Failure of lysine treatment in recurrent herpes simplex labialis. Lancet. 1978;ii:942.

2. Bader C, Crumpacker CS, Schnipper LE, et al. The natural history of recurrent facialoral infection with herpes simplex virus. J Infect Dis. 1978;138:897-905.

17. Scheibel NM. Jessen 0. Lysine prophylaxis in recurrent herpes simplex labialis: a doubleblind, controlled crossover study. Acta Derm Venereol (Stockh). 1979;60:85-7.

Clinics in

Seidlin and Straus

112

18. DiGiovanna JJ, Blank H. Failure of lysine in the treatment and prophylaxis of frequently recurrent herpes simplex infection. Arch Dermatol. (in press). 19. Terezhalmy GT, Bottomly WK, Pelleu GB. The use of water-soluble bioflavonoidascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surg. 1978;45: 56-62. 20. Brody 1. Topical treatment of recurrent herpes simplex and post-herpetic erythema multiforme with low concentrations of zinc sulphate solution. Br J Dermatol. 1981;104: 191-4. 21. Fahim M, Brawner T, Millikan L, Nickel1 M, Hall D. New treatment for herpes simplex virus type 2 [ultrasound and zinc, urea, and tannic acid ointment]. Part I. Male patients. J Med. 1978;9:245-64. 22. Skinner GRB, Hartley CE, Millar D, Bishop E. Possible treatment for cold sores. Br Med J. 1979;2:704. 23. Van der Spuy S, Levy DW, Levin W. Cimetidine in the treatment of herpesvirus infections. S Afr Med J. 1980;58:112-116. 24. Zimmerman DR. Self-treatment with ice. Lancet. 1978;ii:1260. 25. Danziger S. Ice-packs 1978;i:103.

of cold sores

for cold-sores.

Lancet.

for recur26. Shelley WB. Surgical treatment rent herpes simplex. Lancet. 1978;ii:1021-2. 27. Shelley WB, Wood MG. Surgical conversion of herpes simplex from an epidermal to a dermal disease. Br J Dermatol. 1979;lOO: 649-55. of herpes28. Thiers BH. Unusual treatments virus infections. I. Herpes simplex. J Am Acad Dermatol. 1982;7:811-6.

Dermatology

photoinactivation in the treatment of herpes genitalis. Br J Vener Dis. 1975;51:130-3. 34. Taylor PK, Doherty NR. Comparison of the treatment of herpes genitalis in men with proflavine photoactivation, idoxuridine ointment, and normal saline. Br J Vener Dis. 1975;51:125-9. 35. Myers MG, Oxman MN, Clark JE, Arndt KA. Therapy of local herpesviral infections. Photodynamic inactivation in recurrent infections with herpes simplex virus. J Infect Dis. 1976;133:A145-50. of 36. Rapp F, Li J, Jerkofsky M. Transformation mammalian cells by DNA-containing viruses following photodynamic inactivation. Virology. 1973;55:339-46. 37. Li JH, Jerkofsky MA, Rapp F. Demonstration of oncogenic potential of mammalian cells transformed by DNA-containing viruses following photodynamic inactivation. Int J Cancer. 1975;15:190-202. RS, Papa 38. Berger therapy-Cassandra 1977;238:133-4.

CM. Photodye confirmed?

herpes JAMA.

39. Pass RF, Whitley RJ, Whelchel JD, Dietheim AG, Reynolds DW, Alford CA. Indentification of patients with increased risk of infection with herpes simplex virus after renal transplantation. J Infect Dis. 1979;140: 487-92. 40. Meyers JD, Flournoy N. Thomas ED. Infection with herpes simplex virus and cellmediated immunity after marrow transplant. J Infect Dis. 1980;142:338-46. 41. Shneidman DW, Barr RJ, Graham JH. Chronic cutaneous herpes simplex. JAMA. 1979; 241:592-4.

of 29. Tankersley RW. Amino acid requirements herpes simplex virus in human cells. J Bacteriol. 1964;87:609-13.

EM, Seligman SJ, 42. Sutton AL, Smithwick Kim D-S. Fatal disseminated herpesvirus hominis type 2 infection in an adult with associated thymic dysplasia. Am J Med. 1974;56:545-53.

30 Wallis C, Melnick JL. Irreversible senisitization of viruses. Virology. 23:520-7.

photo1964;

43. Muller SA, Herrmann EC, Winkelmann RK. Herpes simplex infections in hematologic malignancies. Am J Med. 1972;52:102-14.

31 Felber TD, Smith EB, Knox JM, Wallis C, Melnick JL. Photodynamic inactivation of herDes SimDIex. ReDort of a clinical trial. JAMA. 197$223:28&92.

44. Larson CL, Ushijima RN, Karim R, Baker MB, Baker RE. Herpesvirus hominis type 2 infections in rabbits: effect of prior immunization with attenuated Mycobacterium bovis (BCG) cells. Infect Immun. 1972;6:465-8.

32. Chang T, Fiumara N, Weinstein L. Genital herpes: treatment with methylene blue and light exoosure. Int J Dermatol. 1975:14: 69-71.

_

33. Roome APCH, Tinkler AE, Hilton AL, Montefiore DG, Waller D. Neutral red with

45. Anderson Recurrent

FD, Ushijima RN, Larson CL. herpes genitalis. Treatment with Mycobacterium bovis (BCG). Obstet Gynecol. 1974;43:797-805.

46. Bierman

SM. BCG immunoprophylaxis

of

April-June 1984 Volume 2 Number 2

Treatment

recurrent herpes progenitalis. matol. 1976;112:1410-5.

of Mucocutaneous

Arch

Der-

60. Symoens

J, Brugmans J. Treatment of recurrent aphthous stomatitis and herpes with levamisole. Br Med J. 1974;2:592.

47. Kern AB, Schiff

BL. Smallpox vaccinations in the management of recurrent herpes simplex: a controlled evaluation. J Invest Dermatol. 1959;33:99-102.

48

Mintz L. Recurrent herpes simplex infection vaccination site.JAMA. 1982; 24712704-5. at a smallpox

49. Tager

A. Preliminary report on the treatment of recurrent herpes simplex with poliomyelitis vaccine (Sabin’s). Dermatologica. 1974;149:253-5.

50. Naumann

HH. Herpes simplex and yellowfever vaccine. Lancet. 1977;ii:250.

51. Miller

JB. Treatment of active herpes virus infections with influenza virus vaccine. Ann Allergy. 1979;42:295-305.

52. Gurwith

M, Hayner NS. Vaccinia necrosum after smallpox vaccination. Mich MMWR. 1982;31:501-2.

53. Schonberger

LB, Bregman DJ, SullivanBolyai JZ, et al. Guillain-Barre syndrome following vaccination in the national influenza immunization program, United States, 1976-1977. Am J Enidemiol. 1979: 110:105-23.

54. Showalter

SD, Zweig M, Hampar B. Monoclonal antibodies to herpes simplex virus type 1 proteins, including the immediate-early protein ICP 4. Infect Immun. 1981;34: 684-92.

55. Pereira

L, Klassen T, Baringer JR. Typecommon and type-specific monoclonal antibody to herpes simplex virus type 1. Infect Immun. 1980;29:724-32.

56. Dix

RD, Pereira L, Baringer JR. Use of monoclonal antibody directed against herpes simplex virus glycoproteins to protect mice against acute virus-induced neurological disease. Infect Immun. 1981;34:192-9.

57. Watson

RJ, Weis JH, Salstrom JS, Enquist LW. Herpes simplex virus type-l glycoprotein D gene: nucleotide sequence and expression in Escherichia coli. Science. 1982;218: 381-4.

58. Aiuti

F, Sirianni MC, Paganelli R, Stella A, Turbessi G. Fiorilli M. A olacebo-controlled trial of thymic hormone tieatment of recurrent herpes simplex labialis infection in immunodeficient hosts. Int J Clin Pharmacol Ther Toxicol. 1983;21:81-6.

59. Kint A, Verlinden

rent herpes 291:308.

labialis.

L. Levamisole for recurN Engl J Med. 1974;

113

HSV Infections

61

O’Reilly RJ, Chibbaro A, Wilmot R, Lopez C. Correlation of clinical and virus-specific immune responses following levamisole therapy of recurrent herpes progenitalis. Ann NY Acad Sci. 1977;284:161-70.

62. Mehr KA, Albano

herpes simplex.

L. Failure of levamisole Lancet. 1977;2:773-4.

63. Jose DG, Minty CCJ. Levamisole

with recurrent 1980;2:390-4.

herpes infection.

in

in patients Med J Aust.

64. Chang

T, Fiumara N. Treatment with levamisole of recurrent herpes genitalis. Antimicrob Agents Chemother. 1978;13:809-12.

65. Overall

JC. Sensitivity of herpes simplex virus types 1 and 2 to three preparations of human interferon. J Infect Dis. 1980;142:943.

66. Catalan0

LW, Safley GH, Museles M, Jarzynski DJ. Disseminated herpesvirus infection in a newborn infant. J Pediatr. 1971;79: 393-400.

67. Legaspi

RC, Gatmaitan B, Bailey EJ, Lerner AM. Interferon in biopsy and autopsy specimens of brain. Its presence in herpes simplex virus encephalitis. Arch Neurol. 1980;37: 76-9.

68. Rasmussen

L, Merigan TC. Role of T lymphocytes in cellular immune responses during herpes simplex virus infection in humans. Proc Nat1 Acad Sci USA. 1978;75:3957-61.

69. Overall

JC, Spruance SL, Green JA. Viralinduced leukocvte interferon in vesicle fluid from lesions of recurrent herpes labialis. J Infect Dis. 1981;143:543-7.

70. Spruance

SL, Green JA, Chiu G, Yeh T, Wenerstrom G, Overall JC. Pathogenesisof herpes simplex labialis: correlation of vesicle fluid interferon with lesion age and virus titer. Infect Immun. 1982;36:907-10.

71. Cunningham

AL, Merigan TC. Gamma interferon production appears to predict time of recurrence of herpes labialis. J Immunol. 1983;130:2397-400.

72. Rand KH, Rasmussen

LE, Pollard RB, Arvin A, Merigan TC. Cellular immunity and herpesvirus infections in cardiac-transplant patients. N Engl J Med. 1976;296:1372-7.

73. Rasmussen

LE, Jordan GW, Stevens DA, Merigan TC. Lymphocyte interferon production and transformation after herpes simplex infections in humans. J Immunol. 1974;112: 728-36.

114

Seidlin

Clinics in Dermatology

and Straus

74. Pazin GJ, Armstrong JA, Lam MT, Tarr GC, Jannetta PJ, Ho M. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med. 1979;301:225-30. JA, Ho 75. Haverkos HW, Pazin GJ, Armstrong M. Follow-UD of interferon treatment of herpes simplex. N Engl J Med. 1980;303: 699-700. 76. Cheeseman SH, Rubin RH, Stewart JA, et al. Controlled clinical trial of nrophvlactic human-leukocyte interferon in renai transplantation. N Engl J Med. 1979;300:1345-9. 77. Levitt J, Becker Y. The effect of cytosine arabinoside on the replication of herpes simplex virus. Virology. 1967;31:129-34. DA. Recurrent herpes simplex 78. Fisher sciatica and its treatment with amantadine hydrochloride. Cutis. 1982;29:467-72. 79. Rosenthal KS, Sokol MS, Ingram RL, Subramanian R, Fort RC. Tromantadine: inhibitor of early and late events in herpes simplex virus replication. Antimicrob Agents Chemother. 1982;22:1031-6. 80. Kaufman HE, Nesburn AB, Maloney ED. IDU therapy of herpes simplex. Arch Ophthalmol. 1962;67:583-91. SP, Corrigan MJ, Gilkes MJ. 81 Hall-Smith Treatment of heroes simplex with 5-Iodo-2’deoxyuridine. BrMed J. i962;2:1515-6. 82. Ng ABP, Reagan JW, Yen SSC. Herpesgenitalis. Clinical and cytopathologic experience with 256 patients. Obstet Gynecol. 1970;36: 645-51. 83. Burnett JW, Katz SL. A study of the use of 5 Iodo-2’-deoxyuridine in cutaneous herpes simplex. J Invest Dermatol. 1963;40:7-8. FO, Juel-Jensen BE. Herpes 84. MacCallum simplex virus skin infection in man treated with idoxuridine in dimethyl sulfoxide. Results of double-blind controlled trial. Br J Med. 1966;2:805-7. BE, MacCallum FO. Herpes 85. Juel-Jensen simplex lesions of face treated with idoxuridine applied by spray gun: results of a double-blind controlled trial. Br Med J. 1965;1:901-3. BE, MacCallum FO. Treatment 86. Juel-Jensen of herpes simplex lesions of the face with idoxuridine: results of a double-blind controlled trial. Br Med J. 1964;2:987-8. in 87. Kibrick S, Katz AS. Topical idoxuridine recurrent herpes simplex. With a note on its effect on early varicella. Ann NY Acad Sci. 1970;173:83-9.

88. Parker JD. A double-blind trial of idoxuridine in recurrent genital herpes. J Antimicrob Chemother. 1977;3:131-7. 89. Silvestri

DL, Corey L, Holmes KK. Ineffectiveness of topical idoxuridine in dimethyl sulfoxide for therapy for genital herpes. JAMA. 1982;248:953-9.

90. Whitley

XJ, Soong S, Dolin R, Galasso GJ, Chien LT. Alford CA. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. N Engl J Med. 1977;297:289-93.

91. Whitley RJ, Nahmias AJ, Soong S, Galasso GG. Fleming CL. Alford CA. Vidarabine therapy of ieonatal herpes simplex virus infection. Pediatrics. 1980;66:495-501. 92. Whitley R, Jilty M, Haynes R, et al. Vidarabine therapy of varicella in immunosuppressed patients. J Pediatr. 1982;101:125-31. 93. Whitley RJ, Soong S-J, Dolin R, Betto R, Linnemann C, Alford CA. Early vidarabine therapy to control the complications of herpes zoster in immunosuppressed patients. 1982; 307:971-5. 94. Buchanan RA, Hess F. Vidarabine (Vira-A): Pharmacology and clinical experience. Pharmacol Ther. 1980;8:143-71. ER, 95. Adams HG, Benson EA, Alexander Vontver LA, Remington MA, Holmes KK. Genital herpetic infection in men and women: clinical course and effect of topical application of adenine arabinoside. J Infect Dis. 1976;133:A151-9. 96. Goodman EL, Luby JP, Johnson MT. Prospective double-blind evaluation of topical adenine arabinoside in male herpes progenitalis. Antimicrob Agents Chemother. 1975;B: 693-7. 97. Park N, Gangarosa LP, Kwon B, Hill JM. Iontophoretic application of adenine arabinoside monophosphate to herpes simplex virus type l-infected hairless mouse skin. Antimicrab Agents Chemother. 1978;14:605-8. treatment. Oto98. Lekas MD. Iontophoresis laryngol Head Neck Surg. 1979;87:292-8. JC. Dermatologic Diseases. In: 99. Overall Galasso G. Meriaan TC. Buchanan RA. eds. Antiviral agentsand viral diseases of man. New York: Raven Press, 1979:305-83. LOO. Whitley RJ, Tucker BC, Kinkel AW, et al. Pharmacology, tolerance, and antiviral activity of vidarabine monophosphate in humans. Antimicrob Agents Chemother. 1980;18:709-15. 101. Klein R, Friedman-Kien simplex virus infections

AE. Latent herpes in sensory ganglia of

April-June 1984 Volume 2 Number 2

Treatment

of Mucocutoneous

mice after topical treatment with adenine arabinoside and adenine arabinoside monophosphate. Antimicrob Agents Chemother. 1977;12:577-81. 102. Spruance

SL, Crumpacker CS, Haines H, et al. Ineffectiveness of topical adenine arabinoside 5’-monophosphate in the treatment of recurrent herpes simnlex labialis. N Enel J Med. 1979;306:1180-4.

103. Hatcher

VA, Friedman-Kien AE, Marcus EL, Klein RJ. Arabinosyladenine monophosphate in genital herpes: a double-blind, placebo-controlled study. Antiviral Res. 1982; 2:283-90.

104. Heidelberger

dine. Pharmacol

C, King DH. TrifluorothymiTher. 1979;6:427-42.

105. Carmine

AA, Brogden RN, Heel RC, Speight TM, Avery GS. Trifluridine: a review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections. Drugs. 1982;23:329-53.

106. Elion GB. Mechanism

ity of acyclovir.

of action and selectivAm J Med. 1982;73:7-13.

107. Mindel

A, Adler MW. Intravenous acyclovir treatment for primary genital herpes. Lancet. 1982;i:697-700.

108. Corey L, Fife KH, Benedetti

JK, et al. Intravenous acyclovir for the treatment of primary genital herpes. Ann Intern Med. 1983; 98:914-21.

109. Thin RN, Nabarro

JM, Parker JD, Fiddian AP. Topical acyclovir in the treatment of initial genital herpes. Br J Vener Dis. 1983; 59:116-9.

110. Corey L, Nahmias

AJ, Guinan JK, Critchlow CW, Holmes topical acyclovir in genital virus infections. N Engl J 1313-9.

ME, Benedetti KK. A trial of herpes simplex Med. 1982;306:

111. Nilsen

AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;ii:571-3.

112. Bryson

YJ, Dillon M, Lovett M, et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. N Engl J Med. 1983;308:916-21.

113. Corey L, Benedetti

JK, Critchlow CW, et al. Double-blind controlled trial of topical acyclovir in genital herpes simplex virus infections. Am J Med. 1982;73:326-34.

114. Spruance

SL, Schnipper LE, Overall JC, et al. Treatment of herpes simplex labialis with topical acyclovir in polyethylene glycol. J Infect Dis. 1982;146:85-90.

HSV Infections

115

115. Reichman RC, Badger GJ, Mertz GJ, et al. Patient-initiated therapy of recurrent herpes simplex genitalis with orally administered acyclovir. Clin Res. 1983;31:373A. 116. Reichman RC, Ginsberg M, Barrett-Connor E. et al. Controlled trial of oral acvclovir in the therapy of recurrent herpes” simplex genitalis. Am J Med. 1982;73:338-41. 117. Nahmias A, Kerrick G, Keyserling HL, et al. Patient-initiated therapy for recurrent genital hernetic infections. Am J Med. 1982: ?3:342-6. 118. Foley FD, Greenawald KA, Nash G, Pruitt BA. Herpesvirus infection in burned patients. N Engl J Med. 1970;282:652-6. 119. Whitley R, Barton N, Collins E, Whelchel J, Diethelm AG. Mucocutaneous herpes simplex virus infections in immunocompromised patients. Am J Med. 1982;73:236-40. 120. Mitchell CD, Bean B, Boen JR, Balfour HH. mucocutaneous herpes immunocompromised i:1389-91.

Gentry SR, Groth KE, Acyclovir therapy for simplex infections in patients. Lancet. 1981;

121 Meyers JD, Wade JC, Mitchell CD, et al. Multicenter collaborative trial of intravenous acyclovir or treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med. 1982;73:22935. 122. Chou S, Gallagher JG, Merigan TC. Controlled clinical trial of intravenous acyclovir in heart-transplant patients with mucocutaneous herpes simplex infections. Lancet. 1981:ii:1392-4. 123. Sara1 R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpessimplex-virus infections. N Engl J Med. 1981; 305:63-7. 124. Straus SE, Smith HA, Brickman C, de Miranda P, McLaren C, Keeney RE. Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med. 1982;96:270-7. 125. Helgstrand E, Eriksson B, Johansson NG. Trisodium phosphonoformate, a new antiviral compound. Science. 1978;201:819-21. of 126. Reno JM, Lee LF, Boezi JA. Inhibition herpesvirus replication and herpesvirusinduced deoxyribonucleic acid polymerase by phosphonoformate. Antimicrob Agents Chemother. 1978;13:188-92. 127. Alenius S, Berg M, Broberg F, Eklind K, Lindborg B, Oberg B. Therapeutic effects of foscarnet sodium and acyclovir on cutaneous

Clinics in

Seidlin and Straus

116

infections due to herpes simplex virus type 1 in guinea pigs. J Infect Dis. 1982;145:569-73. 128. Alenius

S, Nordlinder H. Effectof trisodium phosphonoformate in genital infection of female guinea pigs with herpes simplex virus type 2. Arch Virology. 1979;60:197-206.

Dermatology

effects of 138 De Clercq E, Zhang Z. Differential (E)-5-(2-bromovinyl)-2’-deoxyuridineon infections with herpes simplex virus type 1 and type 2 in hairless mice. J Infect Dis. 1982; 145:130-5.

129. Wallin

139. Maudgal PC, Missotten L, de Clercq E, Descamps J. Evaluation of antiherpetic activity of BVDU in experimental models and man. Assoc Eye Res. 1980:274-5.

130. Courtney

140. Fernandez H. Ribavirin: A summary of clinical trials-herpes genitalis and measles. In: Smith RA. Kirkaatrick WL. eds. Ribavirin: a broad spectrum antiviral compound. New York: Academic Press, 1980:215-30.

131. Blough

141. Bierman SM, Kirkpatrick W, Fernandez H. Clinical efficacy of ribavirin in the treatment of genital herpes simplex virus infection. Chemotherapy. 1981;27:139-45.

132. Corey L, Holmes

142. Lopez C. Watanabe KA, Fox JJ. 2’-fluoro-5iodo-aracytosine, a potent and selective antiherpesvirus agent. Antimicrob Agents Chemother. 1980:17:803-6.

J. Lernestedt J, Lycke E. Treatment of recurrent herpes labialis with trisodium phosphonoformate. Curr Chemother Infect Dis. 1979; 2:1361-2. RJ, Steiner SM, Benyesh-Melnick M. Effects of 2-deoxy-D-glycose on herpes simplex virus replication. Virology. 1973;52: 447-55. HA, Giuntoli RL. Successful treatment of human genital herpes infections with 2-deoxy-D-glucose. JAMA. 1979;241: 2798-801. glucose

KK. The use of 2-deoxy-Dfor genital herpes. JAMA. 1980:

133. McCray MK, Zugerman

for herpes simplex? 1982;6:550.

C. 2-deoxy-D-glucose J Am Acad Dermatol.

134. Kern ER, Glasgow

LA, Klein RJ. FriedmanKien AE. Failure of 2-deoxy-D-glucose in the treatment of experimental cutaneous and genital infections due to herpes simplex virus. J Infect Dis. 1982;146:159-66.

135. De Clercq E, Descamps

J, Verhelst G, Walker RT, Jones AS, Torrence PF, Shugar D. Comparative efficacy of antiherpes drugs against different strains of herpes simplex virus. J Infect Dis. 1980;141:563-74.

136. Allaudeen

HS, Kozarich JW, Bertino JR, De Clercq E. On the mechanism of selective inhibition of herpesvirus replication by (E)5-(2-bromovinyl)-2’-deoxyur?dine. Proc Nat1 Acad Sci USA. 1981:78:2698-702.

137. Mayo DR. Differentiation

of herpes simplex virus types 1 and 2 by sensitivity to (E)-5-(2bromovinyl)-2’-deoxyuridine. J Clin Microbiol. 1982;15:733-6.

Address for correspondence: Clinical Investigation-NIAID, Bethesda, MD 20205.

Trousdale MD, Nesburn AB, Su T, Lopez C, Watanabe KA, Fox JJ. Activity of l-(2’fluoro-2’-deoxy-p-D-arabinofuranosyl) thymine against herpes simplex virus in cell cultures and rabbit eyes. Antimicrob Agents Chemother. 1983;23:808-13. 144. Trousdale MD, Nesburn AB, Watanabe KA, Fox JJ. Evaluation of the antiherpetic activity of 2’.fluoro-5-iodo-ara-C in rabbit eyes and cell cultures. Invest Opthalmol Vis Sci. 1981;21:826-32. 145. Crumpacker CS, Schnipper LE, Marlowe SI, Kowalsky PN, Hershey BJ, Levin MJ. Resistance to antiviral drugs of herpes simplex virus isolated from a patient treated with acyclovir. N Engl J Med. 1982:306:343-8. 146. Sibrack CD, Gutman LT, Wilfert CM, et al. Pathogenicity of acyclovir-resistant herpes simplex virus type 1 from an immunodeficient child. J Infect Dis. 1982;146:673-82. 147. Crumpacker

CS, Schnipper LE, Kowalsky PN. Sherman DM. Resistance of herpes simplex virus to adenine arabinoside and E-5(2-bromovinyl)-2’-deoxyuridine: a physical analysis. J Infect Dis. 1982;146:167-72.

Mindell Seidlin, M. D., Medical Virology Section, Laboratory of Building 10, Room llN113, National Institutes of Health,