- Email: [email protected]
Antiviral therapy
8
Antiviral Therapy
Anita R. Rachlis, MD. FRCPC
From the Lhisiox of Infectious Diseases, Departmment of Medicine, Sunnybrooke Medical Centre, Unbe-rsity of Toronto School of Medicine, Toronto, Ontario, Canada
In the past ten years, significant progress has been made in the development of antiviral agents that have demonstrated not only clinical effectiveness, but also have been associated with low toxicity. In dermatologie practice, the viral diseases most likely to be encountered, for which antiviral therapy may be of benefit, include those due to herpes simplex virus (HSV) types I and II, variceila-zoster virus, and papillomavirus. The clinical manifestations and consequences vary with respect to the immunocompetence of the host. A relatively benign viral infection in the normal host may be considerably more serious in the immunosuppressed patient; an effective antiviral agent is needed for those clinical situations. This review examines those agents which are of particular interest in dermatologic viral infections.
Acvclovlr In 197’7, Elion described a new antiviral agent: 9-(2-hydroxyethoxymethyl) guanine, or acyclovirl (Fig. 8-1). It had been recognized that viral replication was dependent on normal mammalian cellular metabolism; hence, previous antiviral agents were toxic, not onIy to the cells infected by the virus, but to normal ceils as well. Previous investigations had produced compounds that mimicked the purines or pyrimidines in nucleic acid; thus, incorporation of these analogues into the nucleic acid of the cell would prevent further replication. A compound was developed that could selectively inhibit nucleic acid replication of the viral infected cell and yet have little or no toxic effect on the normal cell. Acyclovir is an acyclic nucleoside analogue of a purine, deoxyguanosine, which is a substrate for DNA polymerase in the formation of DNA. Acyclovir is a selective inhibitor of viral DNA synthesis by several mechanisms. A virus-specified enzyme, thymidine kinase, in the infected cell converts acyclovir into a monophosphate form. Acyclovir binds 200 times more strongly to herpes simplex virus thymidine kinase than to normal cellular thymidine kinase and is phosphorylated 3 million times more quickly by the viral enzyme. The acyclovir 5’monophosphate is then phosphorylated to the diphosphate and triphosphate forms by cellular guanylate kinases. The triphcsphate is the active form of the drug and will accumulate 40- to 1Wfold more in infected cells than in uninfected cells, hence, the selectivity of this compound. 69
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A. Rachlis
70
0
3
HN
H,N
\
N
HOCH,
H2 FIG. 8-l.
N
I T I N
I ,/O\ cH2
Acyclovir.
Acyclovir triphosphate inhibits both DNA polymerase and acts as a DNA chain terminator. DNA polymerase is the crucial enzyme for the manufacture of viral DNA. Acyclovir triphosphate binds 30-50 times more avidly to herpes DNA polymerase compared with the natural substrate deoxyguanosine triphosphate. Some acyclovir triphosphate is incorporated into the developing viral DNA chain through a 5’-to-3’ phosphodiester link. The chain is terminated, as acyclovir triphosphate does not have a 3’-hydroxyl group to allow for subsequent 5’-to-3’ linkages. Acyclovir only binds weakly to the normal cellular DNA polymerase alpha and thus is a weak inhibitor of the normal enzyme as compared with the viral-specified enzyme. Bindingof acyclovir triphosphate to the viral DNA polymerase is irreversible, thus preventing it from detaching from the fragment of the inactivated chain and migrating elsewhere to continue DNA polymerization. Acyclovir triphosphate has been termed a “suicide” inactivator for this reason. Acyclovir triphosphate inhibits the DNA polymerase of the herpes virus group. In vitro susceptibility testing can be used to measure the antiviral effect of acyclovir. Concentrations of acyclovir to inhibit plaque formation or
cytopathic effects, as compared with control cultures, by half (I&O) can be measured and give some indication as to the potential clinical efficacy. The IDso for HSV is 0.1 PM; HSV II, 1.6 PM; varicella zoster virus (VZV), 3.5 PM; Epstein-Barr virus (EBV), 6-7 PM; cytomegalovirus (CMV) is resistant. Toxicity in unaffected human cells occurs with levels in excess of 300 PM, resulting in a very favorable therapeutic index.2m5 Acyclovir is available in topical, oral, and intravenous formulations. Dosing regimens have been chosen to achieve serum concentrations above the IDso of the specific herpes viruses, recognizing that acyclovir is in fact a pro-drug with the active form acyclovir triphosphate intracellularly.
Pharmacokinetics After intravenous infusion of 5 mg/kg body weight, serum levels are 30-40 PM; after 10 mg/kg body weight, serum levels are 90 PM.~ Only 15-30% of an oral dose is absorbed. Thus, serum levels of 200 mg every 4 hours (five times daily) are 2.5 FM; 800 mg 5 times daily achieves peak levels of 69 PM and trough 3.5 PM. With the knowledge of the IDSO of HSV I, II, and VZV, dosing regimens must be chosen that will achieve serum levels above these levels when given orally, depending on the specific viral infection to be treated.7 The overall plasma half-life is 3 hours. The volume of distribution corresponds to total body water, or 70% of total body weight. Acyclovir is 15% protein bound in plasma. Cerebrospinal fluid levels are 50% those of plasma; salivary levels are 13% those of plasma. The mean peak acyclovir level in vaginal fluid was 76% of the mean peak plasma level7 Acyclovir is 80-95% excreted in the urine essentially unchanged, primarily through glomerular filtration and partly by tubular secretion. Hence, in the anuric patient, the half-life is prolonged to 20 hours.* Hemodialysis removes 60% of the drug; 10-G% of acyclovir is metabolized by hydroxylation to an 8hydroxyl guanine ring derivative or by oxidation to 9-carboxymethoxymethylgua-
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Antiviral Theraw
nine. Neither of those metabolites have any antiviral activity.5
Therapeutic Action and Efficacy The viral susceptibility studies suggested that infections due to HSV I and II and VZV might be amendable to therapy with acyclovir. All three formulations have been assessed in most of these infections and the efficacy assessed. In the treatment of genital herpes simplex virus infections, Corey et al.‘3 assessed 77 patients with first clinical episodes of genital herpes, both true primary and nonprimary infections, in a placebo-controlled trial using topically applied 5% acyclovir in polyethylene glycol ointment. This study demonstrated a reduction in the mean duration of viral shedding from 7.0 days in the placebo to 4.1 days in the treated group. Time to complete crusting of lesions present at initiation of therapy was shortened from 10.5 days in placebo to 7.1 days in the treated group. Topical acyclovir did not influence the frequency of new lesions or delay the appearance of new lesions during the course of therapy. The mean duration of pain associated with genital lesions was 6.2 days in the treated group and 8.8 days in those given placebo, which was not statistically significant. Topical acyclovir appeared to have no significant effect on decreasing the subsequent recurrence rate of genital disease.‘3 These investigators, in the same study, assessed another 111 patients having recurrent episodes. Again, the acyclovir-treated patients had a reduction in the mean duration of viral shedding, from 1.9 days in the placebo group compared with 0.95 days in the treated group. In men neither the mean time to crusting of 2.7 days compared with 3.9 days and the healing time of 6.9 days compared with 8.4 days were statistically shorter for the treated groups, and there were no trends in favor of the acyclovir-treated women. Of the treated patients, 32%developed new lesions during the course of therapy as compared with 53% of those treated with placebo. There were no differences in mean duration of pain after the
71
start of therapy in either men or women; nor was there a difference in recurrence rates.13 Another study of 309 persons in a patientinitiated treatment study of recurrent genital herpes with topical acyclovir or placebo showed a reduction in the duration of viral excretion for women receiving acyclovir rather than placebo. The period required for ulceration or crusting of lesions, healing time, reduction of pain and itching, or time to formation of new lesions was not influenced by treatment.‘4 Intravenous acyclovir was assessed by Corey15and MindeP for the treatment of firstepisode genital herpes. Both studies showed an 85% decrease in the duration of viral shedding in the treated group, a 60% reduction in the duration of pain, 60% shorter time to complete healing, and a reduction in the development of new lesions. There was, however, no effect on recurrences. Bryson reported a controlled trial in the treatment of first episodes of genital herpes infection with oral acyclovir in 48 patients. Duration of viral shedding, time to crusting, time to healing, and new lesion formation were significantly reduced in both primary (seronegative for antibody to HSV I or II) and nonprimary cases (serum antibodies to HSV I or II) in both men and women. Clinical symptoms-including pain, dysuria, and urinary retention-were reduced in severity and duration in those of both sexes who received treatment. Again, recurrence rates were similar in both groups.“’ A similar study was carried out by Mertz,18 who randomized 119 patients with primary and 31 patients with nonprimary first-episode genital herpes simplex infection to receive either oral acyclovir 200 mg five times per day for 10 days or placebo. For both groups, viral shedding from all genital lesions after the onset of therapy was shortened, by 7 days in primary episodes, by 6 days in nonprimary episodes. The effect on healing of genital lesions was less pronounced, although the percentage of patients with primary infection forming new lesions after 48 hours was 18% among the acyclovir-treated group, compared with 62%in the placebo-treated patients. The median duration
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of pain was significantly reduced in those with primary infection only. The frequency of recurrences and time to first recurrence were similar in both groups.@ Oral acyclovir is now the recommended treatment for all first clinical episodes of genital herpes simplex virus infection.*9 Oral acyclovir has been studied in patients with recurrent episodes. In two placebo-controlled studies, acyclovir significantly reduced the duration of viral shedding and shortened healing time, but it did not reduce the duration of pain.20J1 Oral acyclovir has also been assessed in patients with frequent active recurrences of genital herpes. Strauss studied 35 adults with frequently recurrent genital herpes (more than one episode per month) in a placebo-controlled study. Patients were treated for a maximum of 125 days. There were fewer recurrences in the treated group (4/16) as compared with those receiving placebo (16/16). The mean time from onset of therapy to the first recurrence and from the last recurrence before treatment to the first recurrence after the onset of treatment were both significantly longer in the acyclovir-treated group. After completion of treatment, all patients experienced recurrent infection.“’ Another controlled study of 143 patients by Douglas23 to assess the efficacy of oral acyclovir in the suppression of recurrences found a significant reduction in the treated groups. At 4 months, 29% of persons receiving 200 mg acyclovir five times daily experienced recurrences, compared with 35% for those on 200 mg twice daily and 94% in those on placebo. The median time to recurrence was 18 days in placebo recipients, 120 days in those treated. Breakthrough recurrences in the acyclovir recipients were less severe. Once the medication was discontinued, recurrence rates returned to those before treatment.‘3 Similar results were found in studies by MindelZ4 and Halsos,“s who found recurrence rates while on acyclovir 800 mg daily to be 24% and 33%, respectively. A l-year study of acyclovir suppression of recurrent genital herpes infection 400 mg twice daily by Mertz confirmed its effective-
Clinics in Dermatology
ness by reducing recurrence. Of treated patients, 44% remained free of recurrences, compared with only 2% of placebo-treated patients, with a mean number of recurrences per year of 1.8 and 11.4, respectively.2” Mindel found that suppressive oral acyclovir therapy given two, three, or four times daily was more effective than once daily dosing.27 Resistant isolates have been reported to cause recurrences while the patient is on suppressive therapy. The significance of such strains is not entirely known, but continued surveillance is mandatory.22 The extent to which asymptomatic virus shedding is reduced in those persons taking suppressive acyclovir is not known, as transmission during therapy has been documented. The long-term efficacy of suppressive oral acyclovir for persons with frequent recurrences has been established. Not all patients will require indefinite suppression. Reevaluation of suppressive therapy may be done at the end of each year. Reinstitution should be considered in those patients in whom the time to recurrence after therapy is discontinued is short, suggesting that they will be at risk of frequent recurrences. Further long-term studies are still needed.28 Acyclovir has been investigated in the treatment of herpes labialis in the normal host. Spruance used topical 5% acyclovir in polyethylene glycol in a placebo-controlled trial and found that viral shedding was reduced, but overall no clinical benefit was noted.29 Short-term oral therapy has been associated with some benefit in reducing the incidence of sun-induced oral herpes in skiers.30 Perhaps the greatest benefit of acyclovir has been found in the treatment of herpes simplex virus infections occurring in the immunocompromised host. Studies have used topical, intravenous, and oral formulations, the latter showing good efficacy. Patients undergoing bone marrow or organ transplants, or receiving induction chemotherapy for hematologic malignancies, often develop severe mucocutaneous herpes simplex virus infection. Reduction in viral shedding time, local symptoms such as pain, and a decrease in time to complete healing of lesions has been noted.3im33Patients
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Antiviral Therapy
often require prolonged treatment courses. Due to the 50-8096 incidence of reactivation of herpes simplex virus infections in immunocompromised patients, a number of studies have addressed the efficacy of prophylactic acyclovir. Roth oral and intravenous routes have been effective in reducing the episodes of infection as well as their duration.‘9 Recurrences continue, however, after therapy. Acyclovir-resistant strains have been isolated in these patients on long-term acyclovir; hence, continued surveillance is recommended.34 Other indications for suppressive acyclovir therapy include erythema multiforme,a herpetit whitlow,% recurrent aseptic meningitis, eczema herpeticum, and dermabrasion to face, as well as surgery on the trigeminal ganglion or lumbar discs.33 Although the susceptibility of VZV is somewhat less to acyclovir than is the susceptibility of HSV, serum levels can be achieved to inhibit viral replication. Most varicella and zoster infections in the normal host are uncomplicated and do not merit antiviral therapy. There may be, however, certain clinical situations in which antiviral therapy could be efficacious in the immunocompetent host. The major morbidity due to acute herpes zoster is the associated pain and variable postherpetit neuralgia. Neuralgic complications, including meningoencephalitis, may occur. Intravenous acyclovir has been investigated in controlled studies in this patient population. Peterslund found that treatment shortened the period of pain in the acute phase and improved rate of healing, particularly for patients over 67 years, those with fever, and those with less than 4 days of pain before treatment. There was no reduction in the rate of pain at l-month follow-up.37 Another study by Bean was able to demonstrate a reduction in viral shedding by 3 days in the treated group, acceleration in healing, and reduction of pain in the acyclovir-treated group.38 Studies assessing the efficacy of oral acyclovir have been reported. Peterslund compared intravenous acyclovir with oral acyclovir 400 mg five times daily in patients over 60 years with symptoms for less than 96 hours. Results were comparable for both groups, and
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these were similar to those obtained in a previous placebocontrolled trial of intravenous acyclovir,31 suggesting that oral acyclovir may be advantageous in this patient population. A placebo-controlled study of acyclovir 800 mg five times daily was carried out by McKendrick in persons older than 60 years with herpes zoster. If treatment was begun within 48 hours of the onset of the rash, acyclovir was associated with significant accelerated healing. Treated patients had a significant reduction in pain during treatment, but there was no apparent effect on postherpetic neuralgia.40 A study by Huff comparing placebo to 400 mg and 800 mg doses five times daily for 10 days found that recipients of the higher dosage had a significantly reduced period of viral shedding, accelerated time to healing, lower frequency of new lesion formation, and less pain between days 5 and 10. The difference between lower-dosage acyclovir and placebo recipients were not significant. At 3-month follow-up, persistent pain was present in 16.7% of placebo recipients but in only 4.2% of those who received the higher dosage of acyclovir.41 This suggests that there may be an effect on postherpetic neuralgia. Herpes zoster ophthalmicus can be associated with ocular complications such as scleritis, keratitis, and uveitis. Cobo in a placebo-controlled trial of oral acyclovir 600 mg five times daily for 10 days found a reduction in the incidence and severity of secondary ocular inflammatory disease in the treated group. Overall, the ocular complication rate was reduced from 67% to 40% in the treated group.62 The use of intravenous or high-dose oral acyclovir for the treatment of acute herpes zoster in the immunocompetent host is recommended for the elderly and for those with ophthalmic zoster. There have been no controlled studies assessing the efficacy of intravenous acyclovir in varicella, but it may be effective in pneumonitis occurring in adults. Immunocompromised patients are at a greater risk of morbidity from varicella infection. Mortality rates in this patient population are reported to be 6-17%. Intravenous acyclovir has been shown to prevent the development
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TABLE 8-l.
Recommended for Acyclovir
Herpes simplex virus lmmunocompetent host Herpes labialis Solar-induced
Herpes genitalis First episode
Recurrent
200 mg po tid X 6-24 months
Suppression of recurrent episodes
200 mg po 5 X daily X 10 days or 5 mg/kg IV q 8h X 7-10 days 400 mg po tid or 5 mg/ kg IV q 8h X duration of risk
virus in normal
host lmmunocompromised host Herpes zoster Ophthalmicus host
200 mg po 5 X daily X 5 days
recurrent
lmmunocompromised host Oral or genital herpes Recurrent episodes
Varicella-zoster Varicella Pneumonitis
400 mg po bid 1 day pre- and 2-3 days post-exposure 200 mg po 5 X daily X 10 days or 5 mg/kg IV q 8h X 7-10 days
episodes
Suppression episodes
Treatment Regimens
10 mg/kg days
IV q 8h X 7
10 mg/kg days
IV q 8h X 10
in normal
lmmunocompromised host
800 mg po 5 X daily? 7 days 10 mg/kg IV q 8h K 10 days
of pneumonitis in chi1dren.l” Herpes zoster in the immunocompromised host is similar to that in the normal host, but the risk of cutaneous and visceral dissemination is greater. A comparison of intravenous acyclovir and vidarabine in the treatment of immunocompromised patients who presented with 72 hours of onset of infection showed the superiority of acyclovir in respect to reduction
in the frequency of cutaneous dissemination and fever, shortened viral shedding and new lesion formation, reduction in pain, and more rapid healing of lesions.4 Balfour compared placebo to intravenous acyclovir 1500 mg/mz daily for 1 week as in the previous study. Patients were grouped at entry according to whether the zoster was localized or was associated with cutaneous dissemination. Acyclovir halted progression in both groups. Significantly fewer patients treated with acyclovir within 72 hours of onset of rash had complications. In those treated 72 hours after the onset, acyclovir prevented progression. Those on acyclovir with disseminated cutaneous zoster had reduced virus shedding. Visceral dissemination did not develop in any of the acyclovir recipients compared with development in four of 42 placebo recipients. Effects on duration of pain and healing were not statistically significant.45 A summary of the recommended indications for acyclovir therapy can be found in Table 1.
Undesirable Effects Overall, acyclovir is safe and well tolerated. Due to the alkaline nature of acyclovir solution, local irritation and phlebitis have been reported. Skin lesions and nausea have been reported.” Renal toxicity may be a consequence of crystallization of acyclovir in the urine, as the drug is not very water soluble. This is usually reversible, however, and occurs with higher intravenous doses; this can be minimized by concomitant hydration and slower infusion5yio Neurologic toxicity in the form of acute psychiatric disturbances, delirium, tremors, and coma have been reported infrequently.*Oyl’ The polyethylene glycol base of the topical ointment may cause local reactions. Animal studies of high-dose parenteral acyclovir have reported it to cause testicular atrophy in rats and aspermatogenesis in dogs; these studies have raised concern about the longterm effects of chronic suppressive oral acyclovir in young, sexually active men. Patients were followed prior to and following a 6-month treatment period of oral acyclovir 1 g/day. Acyclovir was detected in semen, but there
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Antiviral Therapy
were no significant differences in sperm count, motility, or morphology comparing treated or untreated persons.‘:! Acyclovir-resistant herpes simplex virus has been isolated. The majority of clinically significant resistant isolates have been due to thymidine kinase-deficient strains or to those with thymidine kinase of altered substrate specificity. Alteration of virus-specific DNA polymerase may lead to resistance, but these strains have not been recognized as clinically significant. Resistant strains may be less virulent.395
Interferon Interferon was first described in 1957. These are species-specific glycoproteins produced only after a cell is exposed to certain agents, including viruses, double-stranded RNA, mitogens, and specific antigens. There are three major classes of interferon. Alpha-interferon, of which there are a number of species, is produced by peripheral blood leukocytes. Beta-interferon is produced by fibroblasts. These are induced by viral infections or agents containing doublestranded RNA. Their molecular weights range from 16,000-26,000 daltons. Gammainterferon is produced by T-lymphocytes in response to mitogens, antigens, and interleukin-2. It is structurally different and has a molecular weight of 20,000-25,000 daltons. Several additional types of interferon have been described, but their exact roles remain unclear. In response to a viral infection, the infected cell elaborates interferons to protect uninfected cells and hence to limit the spread of the viral infection. Only small amounts of interferon and contact between cells is sufficient. By the induction of cytoplasmic enzymes, the metabolism of the uninfected cell is altered such that transcription, translation, assembly, and release of virus is impaired, hence, viral replication is impeded. Besides its induction of a temporary antiviral state within hours that persists for several days, interferon has several nonviral effects on cellular growth, differentiation, and immune regulation.‘@+
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Interferon can be given topically or parenterally. Gastric proteolytic enzymes do not allow for its use as an orally administered preparation. Serum levels after oral doses are nondetectable. The half-life of intravenous alpha-interferon is 2-3 hours and intramuscular alpha-interferon 3-8 hours. When given intranasally, there is rapid clearance with a serum half-life of 20 minutes. As it is a small protein, it distributes widely in the intravascular and extravascular fluid compartments; however, it does not penetrate into the cerebrospinal fluid or the aqueous and vitreous humors. The metabolism of interferon is not well understood. Partial inactivation may occur in certain body fluids. Only a small amount is excreted in the urine. Renal catabolism is predominant, but degradation may also occur to some extent in the liver, skeletal muscle, and lungs.&+
Therapeutic Action and Elf icacy With identification of human interferon genes and use of recombinant DNA technology, homogenous purified preparations of interferons are available for clinical investigation as therapeutic agents. Because interferon’s potential effects on cellular growth and differentiation as well as its immunoregulatory functions, clinical applications for interferon have been assessed in the treatment of malignant disease. As an antiviral agent, interferon has been studied in the treatment of respiratory viruses, viral conjunctivitis, viral hepatitis, and HIV infection. In the treatment of viral infections involving the skin, interferon has shown some encouraging results, Merigan carried out a controlled trial of human leukocyte interferon in cancer patients with early localized herpes zoster. At higher doses there was a reduction in cutaneous dissemination, visceral complications, and new lesion formation in the primary dermatome. Treated patients had less acute pain and again, at higher dosages, less severe postherpetic neura1gia.M Comparing this study with a subsequent one that used a shorter course, which was less efficacious overall, they recommended
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that, in addition to high dosage, a longer duration of therapy was indicated.“’ Arvin evaluated human leukocyte interferon in the treatment of varicella in immunocompromised children. Forty-four children were enrolled in a placebo-controlled trial that demonstrated a significant reduction in new lesion formation and life-threatening dissemination.s2 Interferon has been evaluated in the treatment of mucocutaneous herpes simplex virus infection. In a controlled study to assess the prophylactic use of interferon in patients at risk of reactivation of herpes labialis after trigeminal ganglion surgery, interferon reduced HSV shedding and herpes labialis.=! Intramuscular alpha-interferon was given prophylactically to patients undergoing renal transplantation in an attempt to prevent reactivation of mucocutaneous HSV infection, but no clinical efficacy was demonstrated.5s A number of controlled studies have assessed the efficacy of alpha-interferon in the treatment of first-episode or recurrent genital herpes virus infections. Topical therapy with alpha-interferon plus nonoxynol-9 cream for the treatment of recurrent genital herpes showed clinical benefit.56 On the other hand, Eion found that alpha-interferon in aqueous solution did not appear to be clinically useful in the treatment of recurrent genital herpes5$ Glezerman, in a 2-year double-blind, placebocontrolled trial of beta-interferon gel studied 25 patients treated for recurrences of labial and genital lesions. They found significant reduction in the frequency and duration of episodes and also a decrease in symptoms.5R The timing of the applications and the penetration of the interferon into the lesions as a result of the delivery vehicle or status of the lesions are important factors in evaluating the different outcomes of these studies. None of the controlled studies using a subcutaneous route of administration of alpha-interferon demonstrated any beneficial clinical response in the treatment of first-episode or recurrent genital herpes infection or in the prevention of recurrences.@ In a controlled study, Pazin treated women with first episodes of genital herpes with intra-
Clinics in Dermatology
muscular human leukocyte interferon and demonstrated more rapid healing and a significant reduction in the duration of viral shedding in treated patients. There was no significant difference in the resolution of pain or on frequency of recurrences. Transient neutropenia occurred in almost one-third of treated patients.5g Kuhls demonstrated a reduction in recurrences of genital herpes virus infection in men receiving prophylactic intramuscular interferon three times a week.cO The most encouraging studies for the use of interferon as an antiviral agent are in the treatment of papilloma viruses. Specific therapeutic interventions have not been particularly successful and are difficult to assess, because the natural history of these viral infections is variable. Several previous studies using topically applied interferon suggested clinical efficacy; however, a more recently reported controlled study using topically self-applied human leukocyte interferon, human leukocyte interferon plus nonoxynol-9, or placebo in the treatment of condyloma acuminata in women by Keay failed to show any clinical benefit. Although a significantly greater rate of clearance was noted by the second week of therapy, the difference was no longer evident by the end of treatment or by the end of the study.6l Reichman compared three different interferons to placebo administered intralesionally in the treatment of condyloma acuminatum in men and women. Of the anogenital warts treated with interferon, 47% completely resolved compared with 22% of those injected with placebo. One-third of those that resolved on treatment recurred during the follow-up period. Intralesionally injected interferon appeared to influence regression of uninjected warts. There was no difference in the response rates with the different interferons. The major adverse effect was local pain on injection, and signs and symptoms consistent with systemic interferon toxicity were observed in all group~.~ Other studies have been reported to demonstrate efficacy using this mode of treatment. Iinfortunately, intralesional adminis-
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Antiviral Therapy
tration is time consuming and impractical for some patients, thus !imiting the feasibility and acceptance of such treatment. Intramuscular administration of human beta-interferon gave a complete response rate of 82% in a controlled study by Schonfeld in the treatment of condylomata acuminata in 22 patients.= The response of the common wart to intralesional and intramuscular alpha-interferon, either human or recombinant, in controlled and uncontrolled studies has been variable.18 In Canada, alpha-interferon is available only for treatment of hairy cell leukemia and AIDSrelated Kaposis sarcoma. It is not approved for use as an antiviral agent.
Undesirable Effects L.ocal reactions have been reported with topical use. Intranasal interferon causes nasal congestion, increased mucous production, bleeding, and reversible mucosal erosions. Interferon applied topically to skin has been associated with local burning or itching, and intralesional injections of interferon cause transient pain. Parenteral administration is associated with a significant number of systemic side effects, fever, chills, myalgias, headache, and gastrointestinal disturbances including nausea, vomiting, and weight loss. Neurotoxicity has been reported with confusion, coma, EEG changes, and paresthesias. Bone marrow suppression has been associated with more prolonged use. The majority of these problems resolve with discontinuation.*@
Foscamet Foscarnet (trisodium phosphonoformate hexahydrate) is a pyrophosphate analogue that was first described in 1924” and is investigational in North America. (Fig. 8-2) Its antiviral effect is likely due to noncompetitive inhibition of viral RNA or DNA polymerase interacting with the enzyme at the pyrophosphate binding site. It is active against a number of viruses, including herpes simplex I and II, cytomegalovirus, retroviruses, and influenza. Foscarnet has low cellular toxicity. This drug is not metabolized but is rapidly elimi-
HO I HO-P-C II
0 // \
OH
0 FIG. 8-2 Foscarnet.
nated from soft tissues and excreted in the urine after intravenous administration. It is known to accumulate in bone, from which it is released slowly over months. In young animals, bone accumulation is higher but significance in relation to toxicity is unknown. Other animal studies have been associated with dose-related changes in teeth, bone, and kidneys, but these effects were generally reversible. The half-life of the drug is short, and it must be given intravenously.-7 There is no oral formulation; topical preparations are available for investigational use. There is little penetration into cerebrospinal fluid.
lherapeuttc Actton and Effkacy Topical foscarnet was assessed in a placebocontrolled study for treatment of recurrent herpes labialis and showed benefit only for those 66% of subjects who began treatment in the prevesicular stage by preventing progression to vesicle formation and reducing the duration of virus shedding. Overall, however, there was no difference between the two groups in respect to time to healing, time to cessation of pain, itching, or virus shedding. The authors therefore concluded that the study did not demonstrate a clinically important therapeutic effect of topical foscarnet.68 Another trial of clinically initiated topical foscarnet for genital herpes simplex lesions did not demonstrate any benefit in the treated group. Perhaps patient initiated, and hence earlier, or prodromal application might produce better results.64 Foscarnet remains investigational at present. More controlled studies are necessary to identify those dermatologic viral infections for which this antiviral agent may be effective.
78
A. Rachlis
Undesirable Effects Foscarnet is tolerated well when given intravenously; however, prolonged use can lead to elevation in serum creatinine and nephrotoxicity as well as bone marrow suppression.
References
18. Mertz GJ. Critchlow CW. Benedetti J, et al. Doubleblind nlacebo-controlled trial of oral acvclovir in first eoisode genital herpes simplex virus infection. JAMA. 1984; 252:1147-1151. 19. Seidlin M. Natural history and treatment of mucocutaneous infection. 408-12. In: Strauss SE, moderator. Herpes simplex virus infection: biology, treatment and prevention. Ann Intern Med. 1985;103:404-419. 20. Nilson AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;2:571-573.
1. Elion GB. Furman PA, Fyfe JA, et al. Selectivity action of an antiherpetic agent 9-(2.hydroxyethoxymethyl) guanine. Proc Nat1 Acad Sci USA. 1977;74:5716-5720. 2. Elion GB. Mechanism of action and selectivity clovir. Am J Med. 1982;73(1A):7-13.
of
of acy-
3. Mertz GJ. Diagnosis and treatment of genital herpes infections. In: Knight V, Gilbert BE, eds. Antiviral chemotherapy. Philadelphia: WB Saunders, 1987:341-366. 4. Hirsch MS, Schooley RT. Treatment infections. N Engl J Med. 1983:309:963.
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of herpesvirus
5. Dorsky DI, Crumpacker CS. Drugs five years acyclovir. Ann Intern Med. 1987;107:859-874.
later.
6. Whitely RJ. Blum MR, Barton N, et al. Pharmacokinetits of acyclovir in humans following intravenous administration: a model for the development of parenteral antivirals. Am J Med. 1982;73(16):165-171. 7. Van Dyke RB. Connor JD. Wyborny C. et al. Pharmacokinetics of orally administered acyclovir in patients with herpes progenitalis. Am J Med. 1982:73(1A):172-175. 8. Laskin OL, Iongstreth JA. Whilton A. et al. The effect of renal failure on the pharmacokinetics of acyclovir. Am .I Med. 1982;73(1A):197-201. 9. Kenney RE, Kirk LE, Bridgen D. Acyclovir in humans. Am J Med 1982;73(1A):176-181.
tolerance
10. Jones PG, Beier-Hanratty SA. Acyclovir: neurologic and renal toxicity (letter). Ann Intern Med. 1986;104:892. 11. Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. ,J Infect Dis. 1988;157:385-388. 12. Douglas JM, Davis LG. Remington M, et al. A doublcblind placebo-controlled trial of the effect of chronicall> administered oral acyclovir on sperm production in men with frequently recurrent genital herpes, J Infect Dis 1988;157:588-592. 13. Corey L. Nahmias AJ, Guinan ME, et al. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982;306:1313-1319. 14. Luby JP. Grann JW, Alexander WJ, et al. A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis. 1984:15O:l6. 15. Corey L, Fife KH, Benedetti JK, et al. Intravenous clovir for the treatment of primary genital herpes. Intern Med. 1983:98:914-921.
acyAnn
16. Mindel A, Adler MW, Sutherland S, et al. Intravenous acyclovir treatment for primary genital herpes. Lancet. 1982:1:697-700. 17. Bryson YJ, Dillon M, Iovett M. et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. N Engl J Med. 1983;308:916-920.
21. Reichman R, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA. 1984:251:2103-2107. 22. Strauss SE, Takiff HC, Seidlin M, et al. Suppression of frequently recurring genital herpes. N Engl J Med 1984310: 1545-1550. 23. Douglas JM, Critchlow C, Benedetti J. et al. A doubleblind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med. 1984:310:1~551-1556. 2-l. Mindei A. Faherty A, Hindley D, et al. Prophylactic oral acyclovir in recurrent genital herpes. Lancet. 1984:‘:57-59. 25. Halsos AM, Salo OP, Lassus A, et al. Oral acyclovir suouression of recurrent genital herues. A double-blind placebb-controlled study. Acta Derm Venereal (Stockh). 1985;65:59-63. 26. Mertz GJ. Jones CC, Mills J. et al. Iung term acyclovir suppression of frequently recurring genital herpes simplex virus infection. JAMA. 1988:260:201-206. ~7. Mindel A, Faherty A, Carney 0. et al. Dosage and safety uf long term suppressive acyclovir therapy for recurrent genital herpes. Lancet. 1988;1:926-928. ZX. (;uinan ME. Oral acyclovir for treatment and suppression of genital herpes simplex virus infection. JAMA. 1986;255:1747 1749. 29 Spruance SL. Schnipper LE. Overall JC Jr, et al. Treatment of herpes simplex labialis with topical acyclovir in polyethylene glycol. .J Infect. Dis. 1982;146:85-90. :iO. Spruance S, Hamill M, IIoge W. et al. Suppression of herpes simplex labialis at ski resorts with oral acyclovir. [abstract no. 1821 In: Program and abstracts of the 26th lntersciencr Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA: American Society of Microbiology, 1986. :{l. Meyers JD. Wade .JC. Mitchell CD, et al. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med. 1982;73(1A):229“35. :X2. Whitley K. Barton N, Collins E, et al. Mucocutaneous herpes simplex virus infections in immunocompromised patients. A model for evaluation of topical antiviral agents. Am .J Med. 1982;73(1A):236-240. :X1. Gold D, Corey 1,. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother. 1987; :il:XlY67. 34. McLaren C. Chen MS. Ghazzouli I, et al. Drugresistance patterns of herpes simplex virus isolates from patients treated with acyclovir. Antimicrob Agents Chemother. 1985;28:740-744.
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35. Green JA, Spruance SL, Wenerstrom G, et al. Postherpetic erythema multiforme prevented with prophylactic oral acyclovir. Ann Intern Med. 1985;102:632. 36. Laskin OL. Acyclovir and suppression of frequently recurring herpetic whitlow. Ann Intern Med. 1985;102: 494495. 37. Peterslund NA, Ipsen J, Schonheyder in herpes zoster. Laneet. 1981;2:827-830.
79
Antiviral Therapy
H, et al. Acyclovir
38. Bean B, Braun C, Balfour HH. Acyclovir acute herpes zoster. Lancet. 1982,2:118-121.
therapy
for
39. Peterslund NA, Esmann V, Ipsen J, et al. Oral and intravenous acyclovir are equally effective in herpes zoster. J Antimicrob Chemother. 1984;14:185-189. 40. McKendrick MW, McGill JI, White JE, et al. Oral acyclovir in acute herpes zoster. Br Med J. 1985;293:1529-1532. 41. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes zoster with oral acyclovir. Am J Med. 1988;85(28):84-89. 42. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the therapy of acute herpes zoster ophthalmicus. Ophthalmology. 1985;92:1574-1583. 43. Prober CG, Kirk LE, Keeney RE. Acyclovir therapy of chickenpox in immunosuppressed children-a collaborative study. J Pediatr. 1982;101:622-625. 44. Shepp DN, Dandliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely compromised patients. N Engl J Med. 1986;314:208-212. 45. Balfour HH, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med. 1983;308:1448-1453. 46. Kronenberg LH. Cellular effects of interferon. 80-82. In: Stiehm ER, Moderator. Interferon: immunobiology and clinical significance. Ann Intern Med. 1982;96:80-93. 4’7. Ringenberg QS, Anderson PC. Interferons in the treatment of skin disease. Int J Dermatol. 1986;25:273-279. 48. Greenberg SB. Human interferon in viral disease. In: Knight V, Gilbert BE, eds. Antiviral chemotherapy. Philadelphia: WB Saunders, 1987:383-423. 49. Reines ED, Gross PA. Antiviral agents. In: Neu HC, ed. Update on Antibiotics 11. Philadelphia: WB Saunders, 1988:691-715. 50. Merigan TC, Rand KH, Pollard RB, et al. Human leukocyte interferon for the treatment of herpes zoster in patients with cancer. N Engl J Med. 1978;298:981-987. 51. Merigan TC. Interferon therapy in human viral infections and malignant disease. 88-90. In: Stiehm ER, Moderator. Interferon: immunobiology and clinical significance. Ann Intern Med. 1982;96:80-93. 52. Arvin AM, Kushner JH, Feldman S, et al. Human leukocyte interferon for the treatment of varicella in children with cancer. N Engl J Med. 1982;306:761-765.
53. Pazin GJ, Armstrong JA, Tam MT, et al. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med. 1979;301:225-230. 54. Haverkos HW, Pazin GJ, Armstrong JA, et al. Followup of interfemn treatment of herpes simplex [letter]. N Engl J Med. 1980;303:699-700. 55. Cheeseman SH, Rubin RH, Stewart JA, et al. Controlled clinical trial of prophylactic human leukocyte interferon in renal transnlantation: effects on cvtomenalovirus and herpes simplex virus infections.” N Eigl J Med. 1979;300:1345-1349. 56. Friedman-Kien AE, Klein l&J, Glaser RD, et al. Treatment of recurrent genital herpes with topical alpha interferon gel combined with nonoxyno19. J Am Acad Dermatol. 1986;15:989-994. 57. Eion LJ, Toy C, Salsitz B, et al. Therapy of genital herpes with topically applied interferon, Antimicrob Agents Chemother. 1987;31:1137-1739. 58. Glezerman M, Cohen V, Movshovitz M, et al. Placebocontrolled trial of topical interferon in labial and genital herpes. Lancet. 1988;1:150-152. 59. Pazin GJ, Harger JH, Armstrong JA, et al. Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis. 1987;156:891-898. 60. Kuhls TL, Sacter J, Pineda E, et al. Suppression of recurrent genital herpes simplex virus infection with recombinant alpha 2 interferon. J Infect Dis. 1986;154:437-442, 61. Keay S, Teng N, Eisenberg M, et al. Topical interferon for treating condyloma acuminata in women. J Infect Dis. 1988158934-939. 62. Reichman RC, Oakes D, Bonnez W, et al. Treatment of condyloma acuminatum with three different interferons administered intralesionally. Ann Intern Med. 1988;108: 675-679. 63. Schonfeld A, Nitke S, Schattner A, et al. Intramuscular human interferon-beta injections in treatment of condylomata acuminata. Lancet. 1984;2:1038-1042, 64. Foscarnet
[editorial]
Lancet. 1985;2:648-649,
65. Oberg B. Antiviral effects of phosphonoformate. macol Ther. 1983;19:387-415.
Phar-
66. Stenberg L. Larsson A. Reversible effects on cellular metabolism and proliferation by trisodium phosphonoformate. Antimicrob Agents Chemother. 1978:14:727-730. 67. Dolin R. Antiviral chemotherapy Science. 1985;227:1296-1303.
and
prophylaxis.
68. Lawee D, Rosenthal D, Aoki F, Portnoy J. Efficacy and safety of foscarnet for recurrent orolabial herpes: a multicenter randomized double-blind study. Can Med Assoc J. 1988;138:329-333. 69. Sacks SL, Portnoy J, Lawee D, et al. Clinical course of recurrent genital herpes and treatment with foscarnet cream: results of a Canadian multicenter trial. .I Infect Dis. 1987;155:178-186.
Address for correspondence: Anita R. Rachlis,, MD, FRCCPC, Centre, 2075 Bayview Avenue, Toronto, ONT M4N 3M5.
A225 Sunnybrooke
Medical
Antiviral Therapy
Anita R. Rachlis, MD. FRCPC
From the Lhisiox of Infectious Diseases, Departmment of Medicine, Sunnybrooke Medical Centre, Unbe-rsity of Toronto School of Medicine, Toronto, Ontario, Canada
In the past ten years, significant progress has been made in the development of antiviral agents that have demonstrated not only clinical effectiveness, but also have been associated with low toxicity. In dermatologie practice, the viral diseases most likely to be encountered, for which antiviral therapy may be of benefit, include those due to herpes simplex virus (HSV) types I and II, variceila-zoster virus, and papillomavirus. The clinical manifestations and consequences vary with respect to the immunocompetence of the host. A relatively benign viral infection in the normal host may be considerably more serious in the immunosuppressed patient; an effective antiviral agent is needed for those clinical situations. This review examines those agents which are of particular interest in dermatologic viral infections.
Acvclovlr In 197’7, Elion described a new antiviral agent: 9-(2-hydroxyethoxymethyl) guanine, or acyclovirl (Fig. 8-1). It had been recognized that viral replication was dependent on normal mammalian cellular metabolism; hence, previous antiviral agents were toxic, not onIy to the cells infected by the virus, but to normal ceils as well. Previous investigations had produced compounds that mimicked the purines or pyrimidines in nucleic acid; thus, incorporation of these analogues into the nucleic acid of the cell would prevent further replication. A compound was developed that could selectively inhibit nucleic acid replication of the viral infected cell and yet have little or no toxic effect on the normal cell. Acyclovir is an acyclic nucleoside analogue of a purine, deoxyguanosine, which is a substrate for DNA polymerase in the formation of DNA. Acyclovir is a selective inhibitor of viral DNA synthesis by several mechanisms. A virus-specified enzyme, thymidine kinase, in the infected cell converts acyclovir into a monophosphate form. Acyclovir binds 200 times more strongly to herpes simplex virus thymidine kinase than to normal cellular thymidine kinase and is phosphorylated 3 million times more quickly by the viral enzyme. The acyclovir 5’monophosphate is then phosphorylated to the diphosphate and triphosphate forms by cellular guanylate kinases. The triphcsphate is the active form of the drug and will accumulate 40- to 1Wfold more in infected cells than in uninfected cells, hence, the selectivity of this compound. 69
Clinics in Dermatology
A. Rachlis
70
0
3
HN
H,N
\
N
HOCH,
H2 FIG. 8-l.
N
I T I N
I ,/O\ cH2
Acyclovir.
Acyclovir triphosphate inhibits both DNA polymerase and acts as a DNA chain terminator. DNA polymerase is the crucial enzyme for the manufacture of viral DNA. Acyclovir triphosphate binds 30-50 times more avidly to herpes DNA polymerase compared with the natural substrate deoxyguanosine triphosphate. Some acyclovir triphosphate is incorporated into the developing viral DNA chain through a 5’-to-3’ phosphodiester link. The chain is terminated, as acyclovir triphosphate does not have a 3’-hydroxyl group to allow for subsequent 5’-to-3’ linkages. Acyclovir only binds weakly to the normal cellular DNA polymerase alpha and thus is a weak inhibitor of the normal enzyme as compared with the viral-specified enzyme. Bindingof acyclovir triphosphate to the viral DNA polymerase is irreversible, thus preventing it from detaching from the fragment of the inactivated chain and migrating elsewhere to continue DNA polymerization. Acyclovir triphosphate has been termed a “suicide” inactivator for this reason. Acyclovir triphosphate inhibits the DNA polymerase of the herpes virus group. In vitro susceptibility testing can be used to measure the antiviral effect of acyclovir. Concentrations of acyclovir to inhibit plaque formation or
cytopathic effects, as compared with control cultures, by half (I&O) can be measured and give some indication as to the potential clinical efficacy. The IDso for HSV is 0.1 PM; HSV II, 1.6 PM; varicella zoster virus (VZV), 3.5 PM; Epstein-Barr virus (EBV), 6-7 PM; cytomegalovirus (CMV) is resistant. Toxicity in unaffected human cells occurs with levels in excess of 300 PM, resulting in a very favorable therapeutic index.2m5 Acyclovir is available in topical, oral, and intravenous formulations. Dosing regimens have been chosen to achieve serum concentrations above the IDso of the specific herpes viruses, recognizing that acyclovir is in fact a pro-drug with the active form acyclovir triphosphate intracellularly.
Pharmacokinetics After intravenous infusion of 5 mg/kg body weight, serum levels are 30-40 PM; after 10 mg/kg body weight, serum levels are 90 PM.~ Only 15-30% of an oral dose is absorbed. Thus, serum levels of 200 mg every 4 hours (five times daily) are 2.5 FM; 800 mg 5 times daily achieves peak levels of 69 PM and trough 3.5 PM. With the knowledge of the IDSO of HSV I, II, and VZV, dosing regimens must be chosen that will achieve serum levels above these levels when given orally, depending on the specific viral infection to be treated.7 The overall plasma half-life is 3 hours. The volume of distribution corresponds to total body water, or 70% of total body weight. Acyclovir is 15% protein bound in plasma. Cerebrospinal fluid levels are 50% those of plasma; salivary levels are 13% those of plasma. The mean peak acyclovir level in vaginal fluid was 76% of the mean peak plasma level7 Acyclovir is 80-95% excreted in the urine essentially unchanged, primarily through glomerular filtration and partly by tubular secretion. Hence, in the anuric patient, the half-life is prolonged to 20 hours.* Hemodialysis removes 60% of the drug; 10-G% of acyclovir is metabolized by hydroxylation to an 8hydroxyl guanine ring derivative or by oxidation to 9-carboxymethoxymethylgua-
July-September 1989 Volume 7 Number 3
Antiviral Theraw
nine. Neither of those metabolites have any antiviral activity.5
Therapeutic Action and Efficacy The viral susceptibility studies suggested that infections due to HSV I and II and VZV might be amendable to therapy with acyclovir. All three formulations have been assessed in most of these infections and the efficacy assessed. In the treatment of genital herpes simplex virus infections, Corey et al.‘3 assessed 77 patients with first clinical episodes of genital herpes, both true primary and nonprimary infections, in a placebo-controlled trial using topically applied 5% acyclovir in polyethylene glycol ointment. This study demonstrated a reduction in the mean duration of viral shedding from 7.0 days in the placebo to 4.1 days in the treated group. Time to complete crusting of lesions present at initiation of therapy was shortened from 10.5 days in placebo to 7.1 days in the treated group. Topical acyclovir did not influence the frequency of new lesions or delay the appearance of new lesions during the course of therapy. The mean duration of pain associated with genital lesions was 6.2 days in the treated group and 8.8 days in those given placebo, which was not statistically significant. Topical acyclovir appeared to have no significant effect on decreasing the subsequent recurrence rate of genital disease.‘3 These investigators, in the same study, assessed another 111 patients having recurrent episodes. Again, the acyclovir-treated patients had a reduction in the mean duration of viral shedding, from 1.9 days in the placebo group compared with 0.95 days in the treated group. In men neither the mean time to crusting of 2.7 days compared with 3.9 days and the healing time of 6.9 days compared with 8.4 days were statistically shorter for the treated groups, and there were no trends in favor of the acyclovir-treated women. Of the treated patients, 32%developed new lesions during the course of therapy as compared with 53% of those treated with placebo. There were no differences in mean duration of pain after the
71
start of therapy in either men or women; nor was there a difference in recurrence rates.13 Another study of 309 persons in a patientinitiated treatment study of recurrent genital herpes with topical acyclovir or placebo showed a reduction in the duration of viral excretion for women receiving acyclovir rather than placebo. The period required for ulceration or crusting of lesions, healing time, reduction of pain and itching, or time to formation of new lesions was not influenced by treatment.‘4 Intravenous acyclovir was assessed by Corey15and MindeP for the treatment of firstepisode genital herpes. Both studies showed an 85% decrease in the duration of viral shedding in the treated group, a 60% reduction in the duration of pain, 60% shorter time to complete healing, and a reduction in the development of new lesions. There was, however, no effect on recurrences. Bryson reported a controlled trial in the treatment of first episodes of genital herpes infection with oral acyclovir in 48 patients. Duration of viral shedding, time to crusting, time to healing, and new lesion formation were significantly reduced in both primary (seronegative for antibody to HSV I or II) and nonprimary cases (serum antibodies to HSV I or II) in both men and women. Clinical symptoms-including pain, dysuria, and urinary retention-were reduced in severity and duration in those of both sexes who received treatment. Again, recurrence rates were similar in both groups.“’ A similar study was carried out by Mertz,18 who randomized 119 patients with primary and 31 patients with nonprimary first-episode genital herpes simplex infection to receive either oral acyclovir 200 mg five times per day for 10 days or placebo. For both groups, viral shedding from all genital lesions after the onset of therapy was shortened, by 7 days in primary episodes, by 6 days in nonprimary episodes. The effect on healing of genital lesions was less pronounced, although the percentage of patients with primary infection forming new lesions after 48 hours was 18% among the acyclovir-treated group, compared with 62%in the placebo-treated patients. The median duration
72
A. Rachlis
of pain was significantly reduced in those with primary infection only. The frequency of recurrences and time to first recurrence were similar in both groups.@ Oral acyclovir is now the recommended treatment for all first clinical episodes of genital herpes simplex virus infection.*9 Oral acyclovir has been studied in patients with recurrent episodes. In two placebo-controlled studies, acyclovir significantly reduced the duration of viral shedding and shortened healing time, but it did not reduce the duration of pain.20J1 Oral acyclovir has also been assessed in patients with frequent active recurrences of genital herpes. Strauss studied 35 adults with frequently recurrent genital herpes (more than one episode per month) in a placebo-controlled study. Patients were treated for a maximum of 125 days. There were fewer recurrences in the treated group (4/16) as compared with those receiving placebo (16/16). The mean time from onset of therapy to the first recurrence and from the last recurrence before treatment to the first recurrence after the onset of treatment were both significantly longer in the acyclovir-treated group. After completion of treatment, all patients experienced recurrent infection.“’ Another controlled study of 143 patients by Douglas23 to assess the efficacy of oral acyclovir in the suppression of recurrences found a significant reduction in the treated groups. At 4 months, 29% of persons receiving 200 mg acyclovir five times daily experienced recurrences, compared with 35% for those on 200 mg twice daily and 94% in those on placebo. The median time to recurrence was 18 days in placebo recipients, 120 days in those treated. Breakthrough recurrences in the acyclovir recipients were less severe. Once the medication was discontinued, recurrence rates returned to those before treatment.‘3 Similar results were found in studies by MindelZ4 and Halsos,“s who found recurrence rates while on acyclovir 800 mg daily to be 24% and 33%, respectively. A l-year study of acyclovir suppression of recurrent genital herpes infection 400 mg twice daily by Mertz confirmed its effective-
Clinics in Dermatology
ness by reducing recurrence. Of treated patients, 44% remained free of recurrences, compared with only 2% of placebo-treated patients, with a mean number of recurrences per year of 1.8 and 11.4, respectively.2” Mindel found that suppressive oral acyclovir therapy given two, three, or four times daily was more effective than once daily dosing.27 Resistant isolates have been reported to cause recurrences while the patient is on suppressive therapy. The significance of such strains is not entirely known, but continued surveillance is mandatory.22 The extent to which asymptomatic virus shedding is reduced in those persons taking suppressive acyclovir is not known, as transmission during therapy has been documented. The long-term efficacy of suppressive oral acyclovir for persons with frequent recurrences has been established. Not all patients will require indefinite suppression. Reevaluation of suppressive therapy may be done at the end of each year. Reinstitution should be considered in those patients in whom the time to recurrence after therapy is discontinued is short, suggesting that they will be at risk of frequent recurrences. Further long-term studies are still needed.28 Acyclovir has been investigated in the treatment of herpes labialis in the normal host. Spruance used topical 5% acyclovir in polyethylene glycol in a placebo-controlled trial and found that viral shedding was reduced, but overall no clinical benefit was noted.29 Short-term oral therapy has been associated with some benefit in reducing the incidence of sun-induced oral herpes in skiers.30 Perhaps the greatest benefit of acyclovir has been found in the treatment of herpes simplex virus infections occurring in the immunocompromised host. Studies have used topical, intravenous, and oral formulations, the latter showing good efficacy. Patients undergoing bone marrow or organ transplants, or receiving induction chemotherapy for hematologic malignancies, often develop severe mucocutaneous herpes simplex virus infection. Reduction in viral shedding time, local symptoms such as pain, and a decrease in time to complete healing of lesions has been noted.3im33Patients
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Antiviral Therapy
often require prolonged treatment courses. Due to the 50-8096 incidence of reactivation of herpes simplex virus infections in immunocompromised patients, a number of studies have addressed the efficacy of prophylactic acyclovir. Roth oral and intravenous routes have been effective in reducing the episodes of infection as well as their duration.‘9 Recurrences continue, however, after therapy. Acyclovir-resistant strains have been isolated in these patients on long-term acyclovir; hence, continued surveillance is recommended.34 Other indications for suppressive acyclovir therapy include erythema multiforme,a herpetit whitlow,% recurrent aseptic meningitis, eczema herpeticum, and dermabrasion to face, as well as surgery on the trigeminal ganglion or lumbar discs.33 Although the susceptibility of VZV is somewhat less to acyclovir than is the susceptibility of HSV, serum levels can be achieved to inhibit viral replication. Most varicella and zoster infections in the normal host are uncomplicated and do not merit antiviral therapy. There may be, however, certain clinical situations in which antiviral therapy could be efficacious in the immunocompetent host. The major morbidity due to acute herpes zoster is the associated pain and variable postherpetit neuralgia. Neuralgic complications, including meningoencephalitis, may occur. Intravenous acyclovir has been investigated in controlled studies in this patient population. Peterslund found that treatment shortened the period of pain in the acute phase and improved rate of healing, particularly for patients over 67 years, those with fever, and those with less than 4 days of pain before treatment. There was no reduction in the rate of pain at l-month follow-up.37 Another study by Bean was able to demonstrate a reduction in viral shedding by 3 days in the treated group, acceleration in healing, and reduction of pain in the acyclovir-treated group.38 Studies assessing the efficacy of oral acyclovir have been reported. Peterslund compared intravenous acyclovir with oral acyclovir 400 mg five times daily in patients over 60 years with symptoms for less than 96 hours. Results were comparable for both groups, and
73
these were similar to those obtained in a previous placebocontrolled trial of intravenous acyclovir,31 suggesting that oral acyclovir may be advantageous in this patient population. A placebo-controlled study of acyclovir 800 mg five times daily was carried out by McKendrick in persons older than 60 years with herpes zoster. If treatment was begun within 48 hours of the onset of the rash, acyclovir was associated with significant accelerated healing. Treated patients had a significant reduction in pain during treatment, but there was no apparent effect on postherpetic neuralgia.40 A study by Huff comparing placebo to 400 mg and 800 mg doses five times daily for 10 days found that recipients of the higher dosage had a significantly reduced period of viral shedding, accelerated time to healing, lower frequency of new lesion formation, and less pain between days 5 and 10. The difference between lower-dosage acyclovir and placebo recipients were not significant. At 3-month follow-up, persistent pain was present in 16.7% of placebo recipients but in only 4.2% of those who received the higher dosage of acyclovir.41 This suggests that there may be an effect on postherpetic neuralgia. Herpes zoster ophthalmicus can be associated with ocular complications such as scleritis, keratitis, and uveitis. Cobo in a placebo-controlled trial of oral acyclovir 600 mg five times daily for 10 days found a reduction in the incidence and severity of secondary ocular inflammatory disease in the treated group. Overall, the ocular complication rate was reduced from 67% to 40% in the treated group.62 The use of intravenous or high-dose oral acyclovir for the treatment of acute herpes zoster in the immunocompetent host is recommended for the elderly and for those with ophthalmic zoster. There have been no controlled studies assessing the efficacy of intravenous acyclovir in varicella, but it may be effective in pneumonitis occurring in adults. Immunocompromised patients are at a greater risk of morbidity from varicella infection. Mortality rates in this patient population are reported to be 6-17%. Intravenous acyclovir has been shown to prevent the development
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A. Rachlis
74
TABLE 8-l.
Recommended for Acyclovir
Herpes simplex virus lmmunocompetent host Herpes labialis Solar-induced
Herpes genitalis First episode
Recurrent
200 mg po tid X 6-24 months
Suppression of recurrent episodes
200 mg po 5 X daily X 10 days or 5 mg/kg IV q 8h X 7-10 days 400 mg po tid or 5 mg/ kg IV q 8h X duration of risk
virus in normal
host lmmunocompromised host Herpes zoster Ophthalmicus host
200 mg po 5 X daily X 5 days
recurrent
lmmunocompromised host Oral or genital herpes Recurrent episodes
Varicella-zoster Varicella Pneumonitis
400 mg po bid 1 day pre- and 2-3 days post-exposure 200 mg po 5 X daily X 10 days or 5 mg/kg IV q 8h X 7-10 days
episodes
Suppression episodes
Treatment Regimens
10 mg/kg days
IV q 8h X 7
10 mg/kg days
IV q 8h X 10
in normal
lmmunocompromised host
800 mg po 5 X daily? 7 days 10 mg/kg IV q 8h K 10 days
of pneumonitis in chi1dren.l” Herpes zoster in the immunocompromised host is similar to that in the normal host, but the risk of cutaneous and visceral dissemination is greater. A comparison of intravenous acyclovir and vidarabine in the treatment of immunocompromised patients who presented with 72 hours of onset of infection showed the superiority of acyclovir in respect to reduction
in the frequency of cutaneous dissemination and fever, shortened viral shedding and new lesion formation, reduction in pain, and more rapid healing of lesions.4 Balfour compared placebo to intravenous acyclovir 1500 mg/mz daily for 1 week as in the previous study. Patients were grouped at entry according to whether the zoster was localized or was associated with cutaneous dissemination. Acyclovir halted progression in both groups. Significantly fewer patients treated with acyclovir within 72 hours of onset of rash had complications. In those treated 72 hours after the onset, acyclovir prevented progression. Those on acyclovir with disseminated cutaneous zoster had reduced virus shedding. Visceral dissemination did not develop in any of the acyclovir recipients compared with development in four of 42 placebo recipients. Effects on duration of pain and healing were not statistically significant.45 A summary of the recommended indications for acyclovir therapy can be found in Table 1.
Undesirable Effects Overall, acyclovir is safe and well tolerated. Due to the alkaline nature of acyclovir solution, local irritation and phlebitis have been reported. Skin lesions and nausea have been reported.” Renal toxicity may be a consequence of crystallization of acyclovir in the urine, as the drug is not very water soluble. This is usually reversible, however, and occurs with higher intravenous doses; this can be minimized by concomitant hydration and slower infusion5yio Neurologic toxicity in the form of acute psychiatric disturbances, delirium, tremors, and coma have been reported infrequently.*Oyl’ The polyethylene glycol base of the topical ointment may cause local reactions. Animal studies of high-dose parenteral acyclovir have reported it to cause testicular atrophy in rats and aspermatogenesis in dogs; these studies have raised concern about the longterm effects of chronic suppressive oral acyclovir in young, sexually active men. Patients were followed prior to and following a 6-month treatment period of oral acyclovir 1 g/day. Acyclovir was detected in semen, but there
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Antiviral Therapy
were no significant differences in sperm count, motility, or morphology comparing treated or untreated persons.‘:! Acyclovir-resistant herpes simplex virus has been isolated. The majority of clinically significant resistant isolates have been due to thymidine kinase-deficient strains or to those with thymidine kinase of altered substrate specificity. Alteration of virus-specific DNA polymerase may lead to resistance, but these strains have not been recognized as clinically significant. Resistant strains may be less virulent.395
Interferon Interferon was first described in 1957. These are species-specific glycoproteins produced only after a cell is exposed to certain agents, including viruses, double-stranded RNA, mitogens, and specific antigens. There are three major classes of interferon. Alpha-interferon, of which there are a number of species, is produced by peripheral blood leukocytes. Beta-interferon is produced by fibroblasts. These are induced by viral infections or agents containing doublestranded RNA. Their molecular weights range from 16,000-26,000 daltons. Gammainterferon is produced by T-lymphocytes in response to mitogens, antigens, and interleukin-2. It is structurally different and has a molecular weight of 20,000-25,000 daltons. Several additional types of interferon have been described, but their exact roles remain unclear. In response to a viral infection, the infected cell elaborates interferons to protect uninfected cells and hence to limit the spread of the viral infection. Only small amounts of interferon and contact between cells is sufficient. By the induction of cytoplasmic enzymes, the metabolism of the uninfected cell is altered such that transcription, translation, assembly, and release of virus is impaired, hence, viral replication is impeded. Besides its induction of a temporary antiviral state within hours that persists for several days, interferon has several nonviral effects on cellular growth, differentiation, and immune regulation.‘@+
75
Interferon can be given topically or parenterally. Gastric proteolytic enzymes do not allow for its use as an orally administered preparation. Serum levels after oral doses are nondetectable. The half-life of intravenous alpha-interferon is 2-3 hours and intramuscular alpha-interferon 3-8 hours. When given intranasally, there is rapid clearance with a serum half-life of 20 minutes. As it is a small protein, it distributes widely in the intravascular and extravascular fluid compartments; however, it does not penetrate into the cerebrospinal fluid or the aqueous and vitreous humors. The metabolism of interferon is not well understood. Partial inactivation may occur in certain body fluids. Only a small amount is excreted in the urine. Renal catabolism is predominant, but degradation may also occur to some extent in the liver, skeletal muscle, and lungs.&+
Therapeutic Action and Elf icacy With identification of human interferon genes and use of recombinant DNA technology, homogenous purified preparations of interferons are available for clinical investigation as therapeutic agents. Because interferon’s potential effects on cellular growth and differentiation as well as its immunoregulatory functions, clinical applications for interferon have been assessed in the treatment of malignant disease. As an antiviral agent, interferon has been studied in the treatment of respiratory viruses, viral conjunctivitis, viral hepatitis, and HIV infection. In the treatment of viral infections involving the skin, interferon has shown some encouraging results, Merigan carried out a controlled trial of human leukocyte interferon in cancer patients with early localized herpes zoster. At higher doses there was a reduction in cutaneous dissemination, visceral complications, and new lesion formation in the primary dermatome. Treated patients had less acute pain and again, at higher dosages, less severe postherpetic neura1gia.M Comparing this study with a subsequent one that used a shorter course, which was less efficacious overall, they recommended
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that, in addition to high dosage, a longer duration of therapy was indicated.“’ Arvin evaluated human leukocyte interferon in the treatment of varicella in immunocompromised children. Forty-four children were enrolled in a placebo-controlled trial that demonstrated a significant reduction in new lesion formation and life-threatening dissemination.s2 Interferon has been evaluated in the treatment of mucocutaneous herpes simplex virus infection. In a controlled study to assess the prophylactic use of interferon in patients at risk of reactivation of herpes labialis after trigeminal ganglion surgery, interferon reduced HSV shedding and herpes labialis.=! Intramuscular alpha-interferon was given prophylactically to patients undergoing renal transplantation in an attempt to prevent reactivation of mucocutaneous HSV infection, but no clinical efficacy was demonstrated.5s A number of controlled studies have assessed the efficacy of alpha-interferon in the treatment of first-episode or recurrent genital herpes virus infections. Topical therapy with alpha-interferon plus nonoxynol-9 cream for the treatment of recurrent genital herpes showed clinical benefit.56 On the other hand, Eion found that alpha-interferon in aqueous solution did not appear to be clinically useful in the treatment of recurrent genital herpes5$ Glezerman, in a 2-year double-blind, placebocontrolled trial of beta-interferon gel studied 25 patients treated for recurrences of labial and genital lesions. They found significant reduction in the frequency and duration of episodes and also a decrease in symptoms.5R The timing of the applications and the penetration of the interferon into the lesions as a result of the delivery vehicle or status of the lesions are important factors in evaluating the different outcomes of these studies. None of the controlled studies using a subcutaneous route of administration of alpha-interferon demonstrated any beneficial clinical response in the treatment of first-episode or recurrent genital herpes infection or in the prevention of recurrences.@ In a controlled study, Pazin treated women with first episodes of genital herpes with intra-
Clinics in Dermatology
muscular human leukocyte interferon and demonstrated more rapid healing and a significant reduction in the duration of viral shedding in treated patients. There was no significant difference in the resolution of pain or on frequency of recurrences. Transient neutropenia occurred in almost one-third of treated patients.5g Kuhls demonstrated a reduction in recurrences of genital herpes virus infection in men receiving prophylactic intramuscular interferon three times a week.cO The most encouraging studies for the use of interferon as an antiviral agent are in the treatment of papilloma viruses. Specific therapeutic interventions have not been particularly successful and are difficult to assess, because the natural history of these viral infections is variable. Several previous studies using topically applied interferon suggested clinical efficacy; however, a more recently reported controlled study using topically self-applied human leukocyte interferon, human leukocyte interferon plus nonoxynol-9, or placebo in the treatment of condyloma acuminata in women by Keay failed to show any clinical benefit. Although a significantly greater rate of clearance was noted by the second week of therapy, the difference was no longer evident by the end of treatment or by the end of the study.6l Reichman compared three different interferons to placebo administered intralesionally in the treatment of condyloma acuminatum in men and women. Of the anogenital warts treated with interferon, 47% completely resolved compared with 22% of those injected with placebo. One-third of those that resolved on treatment recurred during the follow-up period. Intralesionally injected interferon appeared to influence regression of uninjected warts. There was no difference in the response rates with the different interferons. The major adverse effect was local pain on injection, and signs and symptoms consistent with systemic interferon toxicity were observed in all group~.~ Other studies have been reported to demonstrate efficacy using this mode of treatment. Iinfortunately, intralesional adminis-
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77
Antiviral Therapy
tration is time consuming and impractical for some patients, thus !imiting the feasibility and acceptance of such treatment. Intramuscular administration of human beta-interferon gave a complete response rate of 82% in a controlled study by Schonfeld in the treatment of condylomata acuminata in 22 patients.= The response of the common wart to intralesional and intramuscular alpha-interferon, either human or recombinant, in controlled and uncontrolled studies has been variable.18 In Canada, alpha-interferon is available only for treatment of hairy cell leukemia and AIDSrelated Kaposis sarcoma. It is not approved for use as an antiviral agent.
Undesirable Effects L.ocal reactions have been reported with topical use. Intranasal interferon causes nasal congestion, increased mucous production, bleeding, and reversible mucosal erosions. Interferon applied topically to skin has been associated with local burning or itching, and intralesional injections of interferon cause transient pain. Parenteral administration is associated with a significant number of systemic side effects, fever, chills, myalgias, headache, and gastrointestinal disturbances including nausea, vomiting, and weight loss. Neurotoxicity has been reported with confusion, coma, EEG changes, and paresthesias. Bone marrow suppression has been associated with more prolonged use. The majority of these problems resolve with discontinuation.*@
Foscamet Foscarnet (trisodium phosphonoformate hexahydrate) is a pyrophosphate analogue that was first described in 1924” and is investigational in North America. (Fig. 8-2) Its antiviral effect is likely due to noncompetitive inhibition of viral RNA or DNA polymerase interacting with the enzyme at the pyrophosphate binding site. It is active against a number of viruses, including herpes simplex I and II, cytomegalovirus, retroviruses, and influenza. Foscarnet has low cellular toxicity. This drug is not metabolized but is rapidly elimi-
HO I HO-P-C II
0 // \
OH
0 FIG. 8-2 Foscarnet.
nated from soft tissues and excreted in the urine after intravenous administration. It is known to accumulate in bone, from which it is released slowly over months. In young animals, bone accumulation is higher but significance in relation to toxicity is unknown. Other animal studies have been associated with dose-related changes in teeth, bone, and kidneys, but these effects were generally reversible. The half-life of the drug is short, and it must be given intravenously.-7 There is no oral formulation; topical preparations are available for investigational use. There is little penetration into cerebrospinal fluid.
lherapeuttc Actton and Effkacy Topical foscarnet was assessed in a placebocontrolled study for treatment of recurrent herpes labialis and showed benefit only for those 66% of subjects who began treatment in the prevesicular stage by preventing progression to vesicle formation and reducing the duration of virus shedding. Overall, however, there was no difference between the two groups in respect to time to healing, time to cessation of pain, itching, or virus shedding. The authors therefore concluded that the study did not demonstrate a clinically important therapeutic effect of topical foscarnet.68 Another trial of clinically initiated topical foscarnet for genital herpes simplex lesions did not demonstrate any benefit in the treated group. Perhaps patient initiated, and hence earlier, or prodromal application might produce better results.64 Foscarnet remains investigational at present. More controlled studies are necessary to identify those dermatologic viral infections for which this antiviral agent may be effective.
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Undesirable Effects Foscarnet is tolerated well when given intravenously; however, prolonged use can lead to elevation in serum creatinine and nephrotoxicity as well as bone marrow suppression.
References
18. Mertz GJ. Critchlow CW. Benedetti J, et al. Doubleblind nlacebo-controlled trial of oral acvclovir in first eoisode genital herpes simplex virus infection. JAMA. 1984; 252:1147-1151. 19. Seidlin M. Natural history and treatment of mucocutaneous infection. 408-12. In: Strauss SE, moderator. Herpes simplex virus infection: biology, treatment and prevention. Ann Intern Med. 1985;103:404-419. 20. Nilson AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the treatment of initial and recurrent genital herpes. Lancet. 1982;2:571-573.
1. Elion GB. Furman PA, Fyfe JA, et al. Selectivity action of an antiherpetic agent 9-(2.hydroxyethoxymethyl) guanine. Proc Nat1 Acad Sci USA. 1977;74:5716-5720. 2. Elion GB. Mechanism of action and selectivity clovir. Am J Med. 1982;73(1A):7-13.
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6. Whitely RJ. Blum MR, Barton N, et al. Pharmacokinetits of acyclovir in humans following intravenous administration: a model for the development of parenteral antivirals. Am J Med. 1982;73(16):165-171. 7. Van Dyke RB. Connor JD. Wyborny C. et al. Pharmacokinetics of orally administered acyclovir in patients with herpes progenitalis. Am J Med. 1982:73(1A):172-175. 8. Laskin OL, Iongstreth JA. Whilton A. et al. The effect of renal failure on the pharmacokinetics of acyclovir. Am .I Med. 1982;73(1A):197-201. 9. Kenney RE, Kirk LE, Bridgen D. Acyclovir in humans. Am J Med 1982;73(1A):176-181.
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10. Jones PG, Beier-Hanratty SA. Acyclovir: neurologic and renal toxicity (letter). Ann Intern Med. 1986;104:892. 11. Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. ,J Infect Dis. 1988;157:385-388. 12. Douglas JM, Davis LG. Remington M, et al. A doublcblind placebo-controlled trial of the effect of chronicall> administered oral acyclovir on sperm production in men with frequently recurrent genital herpes, J Infect Dis 1988;157:588-592. 13. Corey L. Nahmias AJ, Guinan ME, et al. A trial of topical acyclovir in genital herpes simplex virus infections. N Engl J Med. 1982;306:1313-1319. 14. Luby JP. Grann JW, Alexander WJ, et al. A collaborative study of patient-initiated treatment of recurrent genital herpes with topical acyclovir or placebo. J Infect Dis. 1984:15O:l6. 15. Corey L, Fife KH, Benedetti JK, et al. Intravenous clovir for the treatment of primary genital herpes. Intern Med. 1983:98:914-921.
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21. Reichman R, Badger GJ, Mertz GJ, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. A controlled trial. JAMA. 1984:251:2103-2107. 22. Strauss SE, Takiff HC, Seidlin M, et al. Suppression of frequently recurring genital herpes. N Engl J Med 1984310: 1545-1550. 23. Douglas JM, Critchlow C, Benedetti J. et al. A doubleblind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med. 1984:310:1~551-1556. 2-l. Mindei A. Faherty A, Hindley D, et al. Prophylactic oral acyclovir in recurrent genital herpes. Lancet. 1984:‘:57-59. 25. Halsos AM, Salo OP, Lassus A, et al. Oral acyclovir suouression of recurrent genital herues. A double-blind placebb-controlled study. Acta Derm Venereal (Stockh). 1985;65:59-63. 26. Mertz GJ. Jones CC, Mills J. et al. Iung term acyclovir suppression of frequently recurring genital herpes simplex virus infection. JAMA. 1988:260:201-206. ~7. Mindel A, Faherty A, Carney 0. et al. Dosage and safety uf long term suppressive acyclovir therapy for recurrent genital herpes. Lancet. 1988;1:926-928. ZX. (;uinan ME. Oral acyclovir for treatment and suppression of genital herpes simplex virus infection. JAMA. 1986;255:1747 1749. 29 Spruance SL. Schnipper LE. Overall JC Jr, et al. Treatment of herpes simplex labialis with topical acyclovir in polyethylene glycol. .J Infect. Dis. 1982;146:85-90. :iO. Spruance S, Hamill M, IIoge W. et al. Suppression of herpes simplex labialis at ski resorts with oral acyclovir. [abstract no. 1821 In: Program and abstracts of the 26th lntersciencr Conference on Antimicrobial Agents and Chemotherapy. New Orleans, LA: American Society of Microbiology, 1986. :{l. Meyers JD. Wade .JC. Mitchell CD, et al. Multicenter collaborative trial of intravenous acyclovir for treatment of mucocutaneous herpes simplex virus infection in the immunocompromised host. Am J Med. 1982;73(1A):229“35. :X2. Whitley K. Barton N, Collins E, et al. Mucocutaneous herpes simplex virus infections in immunocompromised patients. A model for evaluation of topical antiviral agents. Am .J Med. 1982;73(1A):236-240. :X1. Gold D, Corey 1,. Acyclovir prophylaxis for herpes simplex virus infection. Antimicrob Agents Chemother. 1987; :il:XlY67. 34. McLaren C. Chen MS. Ghazzouli I, et al. Drugresistance patterns of herpes simplex virus isolates from patients treated with acyclovir. Antimicrob Agents Chemother. 1985;28:740-744.
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35. Green JA, Spruance SL, Wenerstrom G, et al. Postherpetic erythema multiforme prevented with prophylactic oral acyclovir. Ann Intern Med. 1985;102:632. 36. Laskin OL. Acyclovir and suppression of frequently recurring herpetic whitlow. Ann Intern Med. 1985;102: 494495. 37. Peterslund NA, Ipsen J, Schonheyder in herpes zoster. Laneet. 1981;2:827-830.
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H, et al. Acyclovir
38. Bean B, Braun C, Balfour HH. Acyclovir acute herpes zoster. Lancet. 1982,2:118-121.
therapy
for
39. Peterslund NA, Esmann V, Ipsen J, et al. Oral and intravenous acyclovir are equally effective in herpes zoster. J Antimicrob Chemother. 1984;14:185-189. 40. McKendrick MW, McGill JI, White JE, et al. Oral acyclovir in acute herpes zoster. Br Med J. 1985;293:1529-1532. 41. Huff JC, Bean B, Balfour HH, et al. Therapy of herpes zoster with oral acyclovir. Am J Med. 1988;85(28):84-89. 42. Cobo LM, Foulks GN, Liesegang T, et al. Oral acyclovir in the therapy of acute herpes zoster ophthalmicus. Ophthalmology. 1985;92:1574-1583. 43. Prober CG, Kirk LE, Keeney RE. Acyclovir therapy of chickenpox in immunosuppressed children-a collaborative study. J Pediatr. 1982;101:622-625. 44. Shepp DN, Dandliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely compromised patients. N Engl J Med. 1986;314:208-212. 45. Balfour HH, Bean B, Laskin OL, et al. Acyclovir halts progression of herpes zoster in immunocompromised patients. N Engl J Med. 1983;308:1448-1453. 46. Kronenberg LH. Cellular effects of interferon. 80-82. In: Stiehm ER, Moderator. Interferon: immunobiology and clinical significance. Ann Intern Med. 1982;96:80-93. 4’7. Ringenberg QS, Anderson PC. Interferons in the treatment of skin disease. Int J Dermatol. 1986;25:273-279. 48. Greenberg SB. Human interferon in viral disease. In: Knight V, Gilbert BE, eds. Antiviral chemotherapy. Philadelphia: WB Saunders, 1987:383-423. 49. Reines ED, Gross PA. Antiviral agents. In: Neu HC, ed. Update on Antibiotics 11. Philadelphia: WB Saunders, 1988:691-715. 50. Merigan TC, Rand KH, Pollard RB, et al. Human leukocyte interferon for the treatment of herpes zoster in patients with cancer. N Engl J Med. 1978;298:981-987. 51. Merigan TC. Interferon therapy in human viral infections and malignant disease. 88-90. In: Stiehm ER, Moderator. Interferon: immunobiology and clinical significance. Ann Intern Med. 1982;96:80-93. 52. Arvin AM, Kushner JH, Feldman S, et al. Human leukocyte interferon for the treatment of varicella in children with cancer. N Engl J Med. 1982;306:761-765.
53. Pazin GJ, Armstrong JA, Tam MT, et al. Prevention of reactivated herpes simplex infection by human leukocyte interferon after operation on the trigeminal root. N Engl J Med. 1979;301:225-230. 54. Haverkos HW, Pazin GJ, Armstrong JA, et al. Followup of interfemn treatment of herpes simplex [letter]. N Engl J Med. 1980;303:699-700. 55. Cheeseman SH, Rubin RH, Stewart JA, et al. Controlled clinical trial of prophylactic human leukocyte interferon in renal transnlantation: effects on cvtomenalovirus and herpes simplex virus infections.” N Eigl J Med. 1979;300:1345-1349. 56. Friedman-Kien AE, Klein l&J, Glaser RD, et al. Treatment of recurrent genital herpes with topical alpha interferon gel combined with nonoxyno19. J Am Acad Dermatol. 1986;15:989-994. 57. Eion LJ, Toy C, Salsitz B, et al. Therapy of genital herpes with topically applied interferon, Antimicrob Agents Chemother. 1987;31:1137-1739. 58. Glezerman M, Cohen V, Movshovitz M, et al. Placebocontrolled trial of topical interferon in labial and genital herpes. Lancet. 1988;1:150-152. 59. Pazin GJ, Harger JH, Armstrong JA, et al. Leukocyte interferon for treating first episodes of genital herpes in women. J Infect Dis. 1987;156:891-898. 60. Kuhls TL, Sacter J, Pineda E, et al. Suppression of recurrent genital herpes simplex virus infection with recombinant alpha 2 interferon. J Infect Dis. 1986;154:437-442, 61. Keay S, Teng N, Eisenberg M, et al. Topical interferon for treating condyloma acuminata in women. J Infect Dis. 1988158934-939. 62. Reichman RC, Oakes D, Bonnez W, et al. Treatment of condyloma acuminatum with three different interferons administered intralesionally. Ann Intern Med. 1988;108: 675-679. 63. Schonfeld A, Nitke S, Schattner A, et al. Intramuscular human interferon-beta injections in treatment of condylomata acuminata. Lancet. 1984;2:1038-1042, 64. Foscarnet
[editorial]
Lancet. 1985;2:648-649,
65. Oberg B. Antiviral effects of phosphonoformate. macol Ther. 1983;19:387-415.
Phar-
66. Stenberg L. Larsson A. Reversible effects on cellular metabolism and proliferation by trisodium phosphonoformate. Antimicrob Agents Chemother. 1978:14:727-730. 67. Dolin R. Antiviral chemotherapy Science. 1985;227:1296-1303.
and
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68. Lawee D, Rosenthal D, Aoki F, Portnoy J. Efficacy and safety of foscarnet for recurrent orolabial herpes: a multicenter randomized double-blind study. Can Med Assoc J. 1988;138:329-333. 69. Sacks SL, Portnoy J, Lawee D, et al. Clinical course of recurrent genital herpes and treatment with foscarnet cream: results of a Canadian multicenter trial. .I Infect Dis. 1987;155:178-186.
Address for correspondence: Anita R. Rachlis,, MD, FRCCPC, Centre, 2075 Bayview Avenue, Toronto, ONT M4N 3M5.
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