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Herpes simplex virus infection
Herpes Simplex Virus Infection Richard J. Whitley, MD Herpes simplex virus (HSV) infections are among the infections most frequently encountered by humans. Two types of HSV infections have been identified—HSV-1, which usually causes orolabial disease, and HSV-2, which is associated more frequently with genital and newborn infections. Usually, HSV causes mild and selflimited disease of the mouth and lips or at genital sites. However, on occasion, the disease can be life-threatening. Such is the case with neonatal HSV infection and HSV infections of the central nervous system. Furthermore, in the immunocompromised host, severe infection has been encountered and is a source of morbidity. Even in the immunocompetent host, frequent recurrences, particularly those of the genital tract, can be debilitating. Because HSV does cause genital ulcerative disease, it is associated with an increased risk of acquiring a human immunodeficiency virus infection. During the past 2 decades, selective and specific inhibitors of HSV replication have been developed. These agents, acyclovir, valaciclovir, and famciclovir, all accelerate the events of healing and decrease the probability of excreting the virus when they are taken in a suppressive fashion. The long-term safety of acyclovir has been unequivocally established. Its prodrug, valaciclovir, and the prodrug of penciclovir, famciclovir, have not been used in practice as long and, therefore, less is known about these agents; however, neither is available as a pediatric formulation. Copyright 2002, Elsevier Science (USA). All rights reserved.
cyclovir1-3 is the prototypic antiviral drug available for the treatment of viral infections today. It is a synthetic acyclic purine nucleoside analogue of guanosine. Herpes virus simplex (HSV) and varicella zoster virus (VZV) encode thymidine kinases phosphorylate acyclovir to its monophosphate derivative. Cellular kinases then convert acyclovir monophosphate to acyclovir triphosphate, which, in turn, is both a competitive inhibitor of viral DNA polymerase activity and a DNA chain terminator. This latter quality results from acyclovir’s lack of a 3⬘ hydroxyl group and, consequently, its inability to be incorporated into the elongating DNA molecule. Among the herpesviruses, only HSV and VZV have a virally encoded thymidine kinase capable of selectively phosphorylating acyclovir; however, cytomegalo-
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From the Departments of Pediatrics, Microbiology, and Medicine, University of Alabama at Birmingham, Birmingham, AL. Supported under contract NO1-AI-65306 with the Virology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and by grants from the General Clinical Research Center Program (RR-032) and the State of Alabama. Address correspondence to Richard J. Whitley, MD, Departments of Pediatrics, Microbiology, and Medicine, The Children’s Hospital of Alabama, 1600 7th Ave S, Suite 616, Birmingham, AL 35233; e-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 1045-1870/02/1301-0004$35.00/0 doi:10.1053/spid.2002.29752
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virus (CMV) is able to metabolize acyclovir, albeit to a significantly lesser extent, and thereby suppress reactivation of CMV infection (at least in such select populations as renal transplant recipients). It has no significant activity against any other virus infection. The oral bioavailability of acyclovir is only 15 percent to 30 percent. To enhance oral bioavailabity, the L-valine ester of acyclovir, valaciclovir, was synthesized. After oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first-pass intestinal and hepatic metabolism. The bioavailability of valaciclovir exceeds 50 percent, which is 3 to 5 times greater than that of acyclovir. Currently, no pediatric valaciclovir formulation exists. Thus, at least in young children, the only available compound for treating HSV infections is acyclovir, in either its intravenous or oral formulations.
Famciclovir Famciclovir4 is a diester prodrug of penciclovir and also is a synthetic acyclic guanine derivative. After administration, famciclovir rapidly is deesterfied to penciclovir. Penciclovir then is phosphorylated to penciclovir monophosphate by HSV and VZV thymidine kinase, in a fashion similar to that which occurs with the phosphorylation of acyclovir. Cellular kinases then phosphorylate penciclovir monophosphate to the active triphosphate derivative, which is a competitive inhibitor of viral DNA polymerase. Because penciclovir has
Seminars in Pediatric Infectious Diseases, Vol 13, No 1 ( January), 2002: pp 6-11
Herpes Simplex Virus Infection a 3⬘ hydroxyl group, it is capable of being incorporated into the growing DNA radical, as opposed to being a DNA chain terminator as is acyclovir. As a consequence, the preclinical toxicology profile of famciclovir is different from that of acyclovir, indicating a propensity to be tumorigenic in the preclinical studies. Famciclovir has been evaluated only in adult populations for the treatment of herpes zoster and recurrent HSV infections. When used to treat either of these 2 infections, the benefit is similar to that achieved with the administration of either acyclovir or valaciclovir. Absorption is not affected by food. A topical formulation of penciclovir has been licensed and is marketed under the name of Denavir (Novartis Pharmaceutical Corp, East Hanover, NJ).5 It is approved for the treatment of HSV labialis; however, it is not as efficacious as is oral therapy with drugs such has acyclovir or valaciclovir.
Foscarnet Foscarnet2 is a pyrophosphate analogue. Its mechanism of action results from the selective inhibition at the pyrophosphate-binding site of virus-specific DNA polymerase of the herpesviruses, including CMV, as well as the reverse transcriptase of the human immunodeficiency virus. Inhibition of viral replication is the consequence of preventing cleavage of pyrophosphate from deoxynucleotide triphosphate, resulting in an inability to elongate the DNA. Foscarnet does not require phosphorylation, as compared with the nucleoside analogues. As a consequence, it has been used to treat patients who have HSV, VZV, and CMV isolates that are resistant to acyclovir, valaciclovir, penciclovir, and ganciclovir. Foscarnet is approved for treating CMV retinitis, as well as for the treatment of acyclovir-resistant HSV infections.
Trifluorothymidine Trifluorothymidine is a topical ophthalmic ointment licensed for treating HSV keratoconjunctivitis. It inhibits thymidylic phosphorylase and viral DNA polymerase required for the incorporation of thymidine into viral DNA. Because it has the potential to incorporate into host cell DNA, its toxicity profile is increased compared to other nucleoside analogues. Therefore, it is available only for topical application. Currently, it is the treatment of choice for HSV keratoconjunctivitis.
Idoxuridine Idoxuridine is licensed for treating HSV keratoconjunctivitis. It is available only for topical administration. This compound acts by inhibiting viral DNA polymerase. It is a thymidine analogue; therefore, it can be incorporated into host cell DNA.
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Vidarabine Vidarabine is a purine nucleoside analogue of adenine. It is phosphorylated to its active 5⬘-triphosphate derivate that inhibits DNA-dependent DNA polymerases of DNA viruses. The relative inhibition of viral polymerase is greater than that of human DNA polymerase; however, the therapeutic index is narrow. Currently, only the ophthalmic preparation of vidarabine is available for administration to humans for the treatment of HSV keratoconjunctivitis.
Indications for Antiviral Therapy Disease Syndromes Oropharyngeal HSV Infection. Primary oropharyngeal infection with HSV-1 occurs most commonly in young children between 1 and 3 years of age. It usually is asymptomatic. The incubation period ranges from 2 to 12 days, with an average of 4 days. Symptomatic disease is characterized by fever to 104°F, oral lesions, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema. Oral lesions initially are vesicular but rapidly rupture, leaving 1- to 3-mm shallow gray-white ulcers on erythematous bases. These lesions are distributed on the hard palate, the anterior portion of the tongue, along the gingiva, and around the lips. In addition, the lesions extend down the chin and neck as a result of drooling. Total duration of the illness is 10 to 21 days, as reviewed.6 Primary infection in young adults has been associated with pharyngitis and, often, a mononucleosis-like syndrome. In such patients, ulcerative lesions on erythematous bases frequently are apparent on the tonsils. Primary gingivostomatitis results in viral shedding in oral secretions for an average of 7 to 10 days. Virus can be isolated from the saliva of both asymptomatic children and adults. The virus also is shed in the stool. Recurrent orolabial HSV lesions frequently are preceded by a prodrome of pain, burning, tingling, or itching. These symptoms generally last for less than 6 hours, followed by the appearance of painful vesicles within 24 to 48 hours, typically at the vermillion border of the lip. Lesions usually crust within 3 to 4 days, and healing is complete within 8 to 10 days. Recurrences occur only rarely in the mouth or on the skin of the face of immunocompetent patients. At present, no drug is licensed to treat HSV gingivostomatitis, although the oral suspension of acyclovir has been used off-label because of data from controlled trials that indicate acceleration of clinical healing. Genital HSV Infection. Genital HSV-2 disease usually is acquired by sexual contact with an infected partner. The incubation period of the primary disease ranges from 2 to 12 days. Lesions persist for an average of 21 days. In 70 percent of patients, primary infections are associated with fever, malaise, myalgias, inguinal adenopathy, and other signs and symptoms of systemic illness. Complications include extragenital lesions, aseptic meningitis, and sacral autonomic nervous system dysfunction with associated uri-
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Richard J. Whitley
nary retention. Women tend to experience more severe primary infections and are more likely to develop complications, as reviewed.6 Other Primary HSV Skin Infections. Alteration in the barrier properties of skin, as occurs in atopic dermatitis, can result in localized HSV skin infection (eczema herpeticum). Most cases resolve over a 7- to 9-day period without specific therapy. Localized cutaneous HSV infection that occurs after trauma is known as herpes gladitorium (wrestler’s herpes or traumatic herpes). Herpes simplex virus infection of the digits results in herpetic whitlow. Such lesions may be the result of autoinoculation, as in the case of infants, or exogenous exposure, as occurs among medical and dental personnel. In males, primary genital HSV infection usually manifests as a cluster of vesicular lesions on erythematous bases on the glans or shaft of the penis. In females, primary genital HSV lesions usually involve the vulva bilaterally. Concomitant HSV cervicitis occurs in 90 percent of women with primary HSV-2 infection of the external genitalia. In women, the lesions rapidly ulcerate and become covered with a gray-white exudate. Such lesions may be exquisitely painful. Recurrent genital HSV-2 infection can be either symptomatic or asymptomatic. A prodrome of itching, burning, tingling, or tenderness may be noted several hours before a recurrence. The duration of disease is shorter during recurrent infection (7 to 10 days), and fewer lesions are present. In men, lesions usually appear on the glans or shaft of the penis. In women, lesions occur most frequently on the labia minora, labia majora, and perineum. Cervical excretion of HSV occurs in 10 percent of women with recurrent genital lesions. Systemic symptoms are uncommon occurrences in recurrent genital HSV disease. The current, oral bioavailable antiviral medications are licensed to treat genital herpetic infections; however, none has been studied in sexually active adolescent populations. Ocular HSV Infection. Herpetic infection of the eye usually presents as either a blepharitis or a follicular conjunctivitis. As the disease progresses, branching dendritic lesions develop. Symptoms include severe photophobia, tearing, chemosis, blurred vision, and preauricular lymphadenopathy. An ophthalmologist always should be involved in the care of such patients. Central Nervous System (CNS) HSV Infection. CNS signs and symptoms of HSV disease can begin suddenly or can occur after a 1- to 7-day period of nonspecific influenzalike symptoms. Prominent CNS features include headache, fever, behavioral disturbances, speech disorders, altered consciousness, and focal neurologic findings such as focal seizures. Neonatal HSV Infections. Neonatal HSV infection can be classified as a disease localized to the skin, eye, and/or mouth; encephalitis, with or without skin, eye, and/or mouth involvement; and disseminated infection that involves multiple organs, including the CNS, lung, gastrointestinal tract, liver, adrenals, skin, eye, and/or mouth. Infants with HSV disease are divided roughly evenly among these 3 categories. Infants with disseminated and skin, eye,
and/or mouth disease usually present for medical attention within the first 2 weeks of life, whereas infants with the disease localized to the CNS usually present between the second and third weeks of life. Presenting signs and symptoms can include any combination of irritability, seizures (both focal and generalized), lethargy, tremors, poor feeding, temperature instability, bulging fontanelle, respiratory distress, jaundice, disseminated intravascular coagulopathy, shock, and cutaneous vesicles. Importantly, more than 20 percent of infants with disseminated disease and 30 to 40 percent of infants with encephalitis will never have skin vesicles during the course of illness. HSV Infection in the Immunocompromised Host. Patients compromised by immunosuppressive therapy, underlying disease, or malnutrition are at increased risk for developing severe HSV infection. Disseminated disease may occur with widespread dermal, mucosal, and visceral involvement. Alternatively, the disease may remain localized but persist for much longer periods of time than would occur in immunocompetent hosts.
Diagnosis Serologic diagnosis of HSV infection is reserved for prognosis of genital herpetic and neonatal infections. Isolation of HSV by culture remains the definitive diagnostic method of determining HSV disease outside the CNS. If skin lesions are present, a scraping of the vesicles should be transferred in appropriate viral transport media on ice to a diagnostic virology laboratory. Other sites from which virus may be isolated include the cerebrospinal fluid, urine, throat, nasopharynx, conjunctivae, and duodenum. The presence of intranuclear inclusions and multinucleated giant cells on a Tzanck preparation are indicative of, but not diagnostic for, HSV infection. In HSV encephalitis, cerebrospinal fluid findings are variable but frequently include a moderate pleocytosis with a predominance of mononuclear cells, elevated protein level, and normal or slightly decreased glucose. The electroencephalogram generally localizes spike and slow wave activity to the temporal lobe, even when obtained very early in the disease course. Initially, computed tomography scans of the brain may be normal or show only edema, but as the disease progresses, they can show involvement of the temporal lobe as well. Detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction has become the diagnostic method of choice; however, it must be performed only by a reliable laboratory.7
Treatment Disease Syndromes Herpes Labialis. Topical acyclovir is not efficacious in the treatment of orolabial herpes lesions. Orally administered acyclovir at a dose of 400 mg 5 times daily for 5 days reduces duration of pain and time to the loss of crusts by about one-third, but only if treatment is started during the prodromal or erythematous stages of recurrent infection.1
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Herpes Simplex Virus Infection Table 1. Antiviral Therapy in Herpes Simplex Virus Infections*† Type of infection Genital HSV Initial episode
Recurrent episode Suppression Mucocutaneous HSV Normal host
Route and Dosage†
Drug Acyclovir Valaciclovir Famciclovir Acyclovir Valaciclovir Famciclovir Acyclovir Valaciclovir Famciclovir Acyclovir
200 mg orally 5 times a day for 10 days 5 mg/kg IV every 8 hours for 5 days 1 gm orally twice daily for 5-10 days 250 mg orally 3 times a day for 5-10 days 200 mg orally 5 times a day for 5 days 500 mg orally twice a day for 3 days 250 mg orally 3 times a day for 5-7 days 400 mg orally twice daily 500 mg orally twice daily or 1 g every day 250 mg orally 3 times a day
Immunocompromised patient
Acyclovir
200-400 mg orally 5 times a day for 10 days 5 mg/kg IV every 8 hours for 7-10 days‡
HSV encephalitis
Valaciclovir Famciclovir Acyclovir
500 mg orally twice daily 500 mg orally 3 times a day 10 mg/kg IV every 8 hours for 14-21 days§
Neonatal HSV Herpetic conjunctivitis
Acyclovir Trifluridine
20 mg/kg IV every 8 hours for 14-21 days 1 drop every 2 hours while awake for 7-14 days
Comments
Severe cases
Reserved for severe cases Serially assess renal function Titrate dose as required (alternate: vidarabine ointment)
Abbreviation: IV, intravenous. *Data from reference 1. †The doses are for adults with normal renal function unless otherwise noted. ‡A dose of 250 mg/m2 should be given to children younger than 12 years of age.
Thus, oral acyclovir has a slight clinical benefit only if initiated very early after recurrence and cannot be recommended as routine treatment for herpes labialis in immunocompetent patients. No data exist on the treatment of children or adolescents with herpes labialis. No data support the use of long-term suppressive treatment with acyclovir for the prevention of herpes labialis. Recently, denavir was licensed for the treatment of labial herpes in adults. Therapy results in approximately a 20-percent reduction in duration of disease. Genital Herpes. Acyclovir administered topically, orally, and intravenously is effective in the treatment of primary genital herpes in the normal host, decreasing the duration of symptoms, viral shedding, and time to healing of lesions (Table 1), as reviewed.8 However, neither systemic nor topical treatment of primary HSV lesions reduces the frequency or severity of recurrences. Episodic administration of oral or topical acyclovir for the treatment of recurrent genital HSV lesions provides only a modest benefit, with duration of lesions being shortened, at most, by 1 to 2 days. However, daily administration of oral acyclovir can effectively suppress recurrences of genital herpes in 60 to 90 percent of patients. Treatment should be interrupted every 12 months to reassess the need for continued suppression. Therapy usually is reserved for adolescent patients. Both valaciclovir and famciclovir are licensed for the treatment and suppression of recurrent herpes; however, no
true pediatric formulation exists. These medications have a pharmacokinetic advantage. Valaciclovir is administered at 500 mg once daily for 3 days. Famciclovir is administered at 250 mg 3 times a day. Mucocutaneous HSV Infections in Immunocompromised Patients. In immunocompromised patients, topical, oral, and intravenous acyclovir all diminish the duration of viral shedding, as well as substantially improve time to cessation of pain and to total healing of HSV lesions. In addition, prophylactic administration of oral or intravenous acyclovir to such patients significantly reduces the incidence of symptomatic HSV infection (Table 1). Valaciclovir and famciclovir also can be used in these populations. Should resistance develop, foscarnet is the treatment of choice. Herpes Simplex Keratoconjunctivitis. Idoxuridine, trifluridine (Viroptic, Monarch Pharmaceutical, Bristol, TN), and vidarabine ophthalmic drops all are effective and licensed for treating HSV keratitis. Trifluridine is the most efficacious and the easiest to administer, and, as such, is the drug of choice for HSV ocular disease (Table 1), as reviewed.9 Herpes Simplex Encephalitis. In patients with HSV encephalitis, administration of acyclovir greatly reduces mortality to about 25 percent 1 year after treatment and has a modest impact of morbidity (25% of survivors return to normal function). Dose and length of therapy are listed in Table 1. The outcome is more favorable when therapy is instituted early in the disease course.10
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Richard J. Whitley
Neonatal HSV Infections. Acyclovir is the drug of choice in the treatment of neonatal HSV infection (Table 1). Therapy significantly decreases mortality of encephalitis to approximately 5 percent and disseminated disease to 25 percent. However, morbidity of survivors remains significant. Because of the exceptional safety profile of acyclovir, an intravenous dose of 60 mg/kg/d divided every 8 hours should be given. Duration of therapy is 14 to 21 days.11 Infants with ocular involvement caused by HSV should receive topical antiviral medication in addition to parenteral therapy. Trifluridine is the treatment of choice for ocular HSV infection in the neonate (Table 1). Off-Label Uses of Antiviral Therapies. Although not licensed for the treatment of HSV gingivostomatitis,12 herpes gladiatorum, erythema multiforme (attributed to HSV), or herpetic whitlow, acyclovir, valaciclovir, and famciclovir frequently are used off label for these indications. Furthermore, all 3 drugs have been administered to organ transplant recipients to prevent the reactivation of HSV infection. No studies have been performed with valaciclovir or famciclovir in children or adolescents. However, as noted, both valaciclovir and famciclovir are licensed for treating recurrent genital herpes. Because of its enhanced oral bioavailability, it is at least as active as is acyclovir in the respective patient populations. Similarly, foscarnet has not been studied in pediatric populations. Adverse Effects. The adverse reactions associated with acyclovir and valaciclovir are limited. After intravenous administration, inflammation at the site of administration has been reported. Furthermore, if the drug is administered too rapidly, alterations in renal function, particularly elevations in blood urea nitrogen and creatinine levels, can be documented. In a few patients, acute tubular necrosis has been reported. With extremely high doses of acyclovir in adults (⬎60 mg/kg/d), encephalopathic changes have been noted. Importantly, acyclovir has not been reported as a cause of significant alterations in bone marrow (ie, neutropenia) or liver alterations when administered for standard periods of therapy (10 to 21 days). Acyclovir, as is the case with famciclovir, when administered orally is associated with few adverse events.1 The adverse event profile of acyclovir and valaciclovir administration matches closely that of placebo recipients with, perhaps, a slightly enhanced incidence of gastrointestinal complications. However, valaciclovir has been reported to cause thrombotic thrombocytopenic purpura in individuals with acquired immunodeficiency syndrome who receive more than 6 grams of medication daily.13 A detailed logistic regression analysis of concomitant drugs administered to these patients indicates a higher susceptibility for this syndrome with medications used to treat Pneumocystis carinii pneumonia and human immunodeficiency virus infection. When acyclovir is administered in an oral formulation to infants for suppressive therapy after intravenous acyclovir treatment of neonatal HSV disease, neutropenia has been documented in a significant percentage of young patients. The correlation of neutropenia with clinical adverse events is being investigated further. However, at least at this time, caution must
be used in the administration of acyclovir as suppressive therapy for newborns. Administration of foscarnet is associated with significant alterations in renal function and electrolyte abnormalities, including elevated blood urea nitrogen levels, creatinine levels, hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia. Therapy can be accompanied by fever, nausea, anemia, diarrhea, headache, and seizures. Triflurothymidine, idoxuridine, and vidarabine ophthalmic preparations all have similar adverse-effect profiles. Adverse reactions include local irritation, photophobia, corneal edema, a punctate keratopathy, and keratitis sicca.
Drug Resistance Resistance to acyclovir has been documented in individuals with both HSV and VZV infections.14,15 Mutations within the HSV or VZV viral thymidine kinase are the most common manner in which resistance is acquired. For both viruses, isolates that cannot produce a functional thymidine kinase have been identified in clinical lesions from patients whose lesions are worsening despite acyclovir therapy. Less commonly, viral isolates that produce a thymidine kinase enzyme with altered (diminished) ability to phosphorylate acyclovir also have been identified. A third mode of resistance to acyclovir can occur within the viral gene encoding DNA polymerase. The overall prevalence of resistance to acyclovir in the normal host is exceedingly low, being approximately 1 percent. However, in high-risk immunocompromised patient populations, resistance has occurred at rates of between 6 percent and 12 percent, depending on the study population and the duration of acyclovir exposure. In the presence of clinical resistance to acyclovir, valaciclovir, or famciclovir, foscarnet is the treatment of choice. HSV isolates resistant to penciclovir have been documented. The mechanism of action of the development of resistance is similar to that encountered with acyclovir, with mutations within the viral thymidine kinase and DNA polymerase genes. An HSV or VZV isolate that is resistant to penciclovir likely is resistant to acyclovir as well. Foscarnet resistance has been documented in isolates of HSV, CMV, and the human immunodeficiency virus. The mechanism of resistance relates to mutations of viral DNA polymerase.
References 1. Whitley RJ, Gnann J: Acyclovir: A decade later. N Engl J Med 327:782-789, 1992 2. Balfour HH Jr: Antiviral drugs. N Engl J Med 340:1255-1268, 1999 3. Perry CM, Faulds D: Valaciclovir: A review of its antiviral, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 52:754-772, 1996 4. Whitley RJ: Famciclovir/penciclovir: Prospects for the future. Antiviral Chem Chemoth 4:65, 1993 (suppl 1) 5. Spruance SL, Rea TL, Thoming C, et al: Penciclovir cream for the treatment of herpes simplex labialis. A randomized, mul-
Herpes Simplex Virus Infection
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ticenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA 277:1374-1379, 1997 Whitley RJ: Herpes simplex virus, in Knipe DM, Howley RM, Griffin D, Lamb R, Martin M, Straus SE, (eds): Fields Virology (ed 4). New York, NY, Lippincott, 2001, pp 2461-2509 Lakeman FD, Whitley RJ, the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain biopsied patients and correlation with disease. J Infect Dis 72:857-863, 1995 Whitley RJ, Kimberlin D: Antiviral Agents, in Burg FD, Ingelfinger JR, Polin RA, Gershon A (eds.): Gellis and Kagan’s Current Pediatric Therapy 17. Philadelphia, PA, Saunders (in press) International Herpes Management Forum: Pathogenesis and Management of HSV-1 Infection, in Stanberry L (ed): (in press) Whitley RJ: Viral encephalitis. N Engl J Med 323:242-250, 1990 Kimberlin DW, Lin CY, Jacobs RF, et al: The safety and efficacy of high-dose intravenous acyclovir in the management
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of neonatal herpes simplex virus infections. Pediatrics 108:230238, 2001 Amir J, Harel L, Smetana Z, et al: Treatment of herpes simplex gingivostomatitis with aciclovir in children: A randomized double blind placebo controlled study. BMJ 314:1800-1803, 1997 Griffiths PD, Feinberg, JE, Fry J, et al: The effect of valaciclovir on cytomegalovirus viremia and viruria detected by polymerase chain reaction in patients with advanced human immunodeficiency virus disease. AIDS Clinical Trials Group Protocol 204/ Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis 177:57-64, 1998 Gaudreau A, Hill E, Balfour HH Jr, et al: Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis 178:297-303, 1998 Shin YK, Cai GY, Weinberg A, et al: Frequency of acyclovirresistant herpes simplex virus in clinical specimens and laboratory isolates. J Clin Microbiol 39:913-917, 2001
cyclovir1-3 is the prototypic antiviral drug available for the treatment of viral infections today. It is a synthetic acyclic purine nucleoside analogue of guanosine. Herpes virus simplex (HSV) and varicella zoster virus (VZV) encode thymidine kinases phosphorylate acyclovir to its monophosphate derivative. Cellular kinases then convert acyclovir monophosphate to acyclovir triphosphate, which, in turn, is both a competitive inhibitor of viral DNA polymerase activity and a DNA chain terminator. This latter quality results from acyclovir’s lack of a 3⬘ hydroxyl group and, consequently, its inability to be incorporated into the elongating DNA molecule. Among the herpesviruses, only HSV and VZV have a virally encoded thymidine kinase capable of selectively phosphorylating acyclovir; however, cytomegalo-
A
From the Departments of Pediatrics, Microbiology, and Medicine, University of Alabama at Birmingham, Birmingham, AL. Supported under contract NO1-AI-65306 with the Virology Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and by grants from the General Clinical Research Center Program (RR-032) and the State of Alabama. Address correspondence to Richard J. Whitley, MD, Departments of Pediatrics, Microbiology, and Medicine, The Children’s Hospital of Alabama, 1600 7th Ave S, Suite 616, Birmingham, AL 35233; e-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. 1045-1870/02/1301-0004$35.00/0 doi:10.1053/spid.2002.29752
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virus (CMV) is able to metabolize acyclovir, albeit to a significantly lesser extent, and thereby suppress reactivation of CMV infection (at least in such select populations as renal transplant recipients). It has no significant activity against any other virus infection. The oral bioavailability of acyclovir is only 15 percent to 30 percent. To enhance oral bioavailabity, the L-valine ester of acyclovir, valaciclovir, was synthesized. After oral administration of valaciclovir, rapid and complete conversion to acyclovir occurs with first-pass intestinal and hepatic metabolism. The bioavailability of valaciclovir exceeds 50 percent, which is 3 to 5 times greater than that of acyclovir. Currently, no pediatric valaciclovir formulation exists. Thus, at least in young children, the only available compound for treating HSV infections is acyclovir, in either its intravenous or oral formulations.
Famciclovir Famciclovir4 is a diester prodrug of penciclovir and also is a synthetic acyclic guanine derivative. After administration, famciclovir rapidly is deesterfied to penciclovir. Penciclovir then is phosphorylated to penciclovir monophosphate by HSV and VZV thymidine kinase, in a fashion similar to that which occurs with the phosphorylation of acyclovir. Cellular kinases then phosphorylate penciclovir monophosphate to the active triphosphate derivative, which is a competitive inhibitor of viral DNA polymerase. Because penciclovir has
Seminars in Pediatric Infectious Diseases, Vol 13, No 1 ( January), 2002: pp 6-11
Herpes Simplex Virus Infection a 3⬘ hydroxyl group, it is capable of being incorporated into the growing DNA radical, as opposed to being a DNA chain terminator as is acyclovir. As a consequence, the preclinical toxicology profile of famciclovir is different from that of acyclovir, indicating a propensity to be tumorigenic in the preclinical studies. Famciclovir has been evaluated only in adult populations for the treatment of herpes zoster and recurrent HSV infections. When used to treat either of these 2 infections, the benefit is similar to that achieved with the administration of either acyclovir or valaciclovir. Absorption is not affected by food. A topical formulation of penciclovir has been licensed and is marketed under the name of Denavir (Novartis Pharmaceutical Corp, East Hanover, NJ).5 It is approved for the treatment of HSV labialis; however, it is not as efficacious as is oral therapy with drugs such has acyclovir or valaciclovir.
Foscarnet Foscarnet2 is a pyrophosphate analogue. Its mechanism of action results from the selective inhibition at the pyrophosphate-binding site of virus-specific DNA polymerase of the herpesviruses, including CMV, as well as the reverse transcriptase of the human immunodeficiency virus. Inhibition of viral replication is the consequence of preventing cleavage of pyrophosphate from deoxynucleotide triphosphate, resulting in an inability to elongate the DNA. Foscarnet does not require phosphorylation, as compared with the nucleoside analogues. As a consequence, it has been used to treat patients who have HSV, VZV, and CMV isolates that are resistant to acyclovir, valaciclovir, penciclovir, and ganciclovir. Foscarnet is approved for treating CMV retinitis, as well as for the treatment of acyclovir-resistant HSV infections.
Trifluorothymidine Trifluorothymidine is a topical ophthalmic ointment licensed for treating HSV keratoconjunctivitis. It inhibits thymidylic phosphorylase and viral DNA polymerase required for the incorporation of thymidine into viral DNA. Because it has the potential to incorporate into host cell DNA, its toxicity profile is increased compared to other nucleoside analogues. Therefore, it is available only for topical application. Currently, it is the treatment of choice for HSV keratoconjunctivitis.
Idoxuridine Idoxuridine is licensed for treating HSV keratoconjunctivitis. It is available only for topical administration. This compound acts by inhibiting viral DNA polymerase. It is a thymidine analogue; therefore, it can be incorporated into host cell DNA.
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Vidarabine Vidarabine is a purine nucleoside analogue of adenine. It is phosphorylated to its active 5⬘-triphosphate derivate that inhibits DNA-dependent DNA polymerases of DNA viruses. The relative inhibition of viral polymerase is greater than that of human DNA polymerase; however, the therapeutic index is narrow. Currently, only the ophthalmic preparation of vidarabine is available for administration to humans for the treatment of HSV keratoconjunctivitis.
Indications for Antiviral Therapy Disease Syndromes Oropharyngeal HSV Infection. Primary oropharyngeal infection with HSV-1 occurs most commonly in young children between 1 and 3 years of age. It usually is asymptomatic. The incubation period ranges from 2 to 12 days, with an average of 4 days. Symptomatic disease is characterized by fever to 104°F, oral lesions, sore throat, fetor oris, anorexia, cervical adenopathy, and mucosal edema. Oral lesions initially are vesicular but rapidly rupture, leaving 1- to 3-mm shallow gray-white ulcers on erythematous bases. These lesions are distributed on the hard palate, the anterior portion of the tongue, along the gingiva, and around the lips. In addition, the lesions extend down the chin and neck as a result of drooling. Total duration of the illness is 10 to 21 days, as reviewed.6 Primary infection in young adults has been associated with pharyngitis and, often, a mononucleosis-like syndrome. In such patients, ulcerative lesions on erythematous bases frequently are apparent on the tonsils. Primary gingivostomatitis results in viral shedding in oral secretions for an average of 7 to 10 days. Virus can be isolated from the saliva of both asymptomatic children and adults. The virus also is shed in the stool. Recurrent orolabial HSV lesions frequently are preceded by a prodrome of pain, burning, tingling, or itching. These symptoms generally last for less than 6 hours, followed by the appearance of painful vesicles within 24 to 48 hours, typically at the vermillion border of the lip. Lesions usually crust within 3 to 4 days, and healing is complete within 8 to 10 days. Recurrences occur only rarely in the mouth or on the skin of the face of immunocompetent patients. At present, no drug is licensed to treat HSV gingivostomatitis, although the oral suspension of acyclovir has been used off-label because of data from controlled trials that indicate acceleration of clinical healing. Genital HSV Infection. Genital HSV-2 disease usually is acquired by sexual contact with an infected partner. The incubation period of the primary disease ranges from 2 to 12 days. Lesions persist for an average of 21 days. In 70 percent of patients, primary infections are associated with fever, malaise, myalgias, inguinal adenopathy, and other signs and symptoms of systemic illness. Complications include extragenital lesions, aseptic meningitis, and sacral autonomic nervous system dysfunction with associated uri-
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Richard J. Whitley
nary retention. Women tend to experience more severe primary infections and are more likely to develop complications, as reviewed.6 Other Primary HSV Skin Infections. Alteration in the barrier properties of skin, as occurs in atopic dermatitis, can result in localized HSV skin infection (eczema herpeticum). Most cases resolve over a 7- to 9-day period without specific therapy. Localized cutaneous HSV infection that occurs after trauma is known as herpes gladitorium (wrestler’s herpes or traumatic herpes). Herpes simplex virus infection of the digits results in herpetic whitlow. Such lesions may be the result of autoinoculation, as in the case of infants, or exogenous exposure, as occurs among medical and dental personnel. In males, primary genital HSV infection usually manifests as a cluster of vesicular lesions on erythematous bases on the glans or shaft of the penis. In females, primary genital HSV lesions usually involve the vulva bilaterally. Concomitant HSV cervicitis occurs in 90 percent of women with primary HSV-2 infection of the external genitalia. In women, the lesions rapidly ulcerate and become covered with a gray-white exudate. Such lesions may be exquisitely painful. Recurrent genital HSV-2 infection can be either symptomatic or asymptomatic. A prodrome of itching, burning, tingling, or tenderness may be noted several hours before a recurrence. The duration of disease is shorter during recurrent infection (7 to 10 days), and fewer lesions are present. In men, lesions usually appear on the glans or shaft of the penis. In women, lesions occur most frequently on the labia minora, labia majora, and perineum. Cervical excretion of HSV occurs in 10 percent of women with recurrent genital lesions. Systemic symptoms are uncommon occurrences in recurrent genital HSV disease. The current, oral bioavailable antiviral medications are licensed to treat genital herpetic infections; however, none has been studied in sexually active adolescent populations. Ocular HSV Infection. Herpetic infection of the eye usually presents as either a blepharitis or a follicular conjunctivitis. As the disease progresses, branching dendritic lesions develop. Symptoms include severe photophobia, tearing, chemosis, blurred vision, and preauricular lymphadenopathy. An ophthalmologist always should be involved in the care of such patients. Central Nervous System (CNS) HSV Infection. CNS signs and symptoms of HSV disease can begin suddenly or can occur after a 1- to 7-day period of nonspecific influenzalike symptoms. Prominent CNS features include headache, fever, behavioral disturbances, speech disorders, altered consciousness, and focal neurologic findings such as focal seizures. Neonatal HSV Infections. Neonatal HSV infection can be classified as a disease localized to the skin, eye, and/or mouth; encephalitis, with or without skin, eye, and/or mouth involvement; and disseminated infection that involves multiple organs, including the CNS, lung, gastrointestinal tract, liver, adrenals, skin, eye, and/or mouth. Infants with HSV disease are divided roughly evenly among these 3 categories. Infants with disseminated and skin, eye,
and/or mouth disease usually present for medical attention within the first 2 weeks of life, whereas infants with the disease localized to the CNS usually present between the second and third weeks of life. Presenting signs and symptoms can include any combination of irritability, seizures (both focal and generalized), lethargy, tremors, poor feeding, temperature instability, bulging fontanelle, respiratory distress, jaundice, disseminated intravascular coagulopathy, shock, and cutaneous vesicles. Importantly, more than 20 percent of infants with disseminated disease and 30 to 40 percent of infants with encephalitis will never have skin vesicles during the course of illness. HSV Infection in the Immunocompromised Host. Patients compromised by immunosuppressive therapy, underlying disease, or malnutrition are at increased risk for developing severe HSV infection. Disseminated disease may occur with widespread dermal, mucosal, and visceral involvement. Alternatively, the disease may remain localized but persist for much longer periods of time than would occur in immunocompetent hosts.
Diagnosis Serologic diagnosis of HSV infection is reserved for prognosis of genital herpetic and neonatal infections. Isolation of HSV by culture remains the definitive diagnostic method of determining HSV disease outside the CNS. If skin lesions are present, a scraping of the vesicles should be transferred in appropriate viral transport media on ice to a diagnostic virology laboratory. Other sites from which virus may be isolated include the cerebrospinal fluid, urine, throat, nasopharynx, conjunctivae, and duodenum. The presence of intranuclear inclusions and multinucleated giant cells on a Tzanck preparation are indicative of, but not diagnostic for, HSV infection. In HSV encephalitis, cerebrospinal fluid findings are variable but frequently include a moderate pleocytosis with a predominance of mononuclear cells, elevated protein level, and normal or slightly decreased glucose. The electroencephalogram generally localizes spike and slow wave activity to the temporal lobe, even when obtained very early in the disease course. Initially, computed tomography scans of the brain may be normal or show only edema, but as the disease progresses, they can show involvement of the temporal lobe as well. Detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction has become the diagnostic method of choice; however, it must be performed only by a reliable laboratory.7
Treatment Disease Syndromes Herpes Labialis. Topical acyclovir is not efficacious in the treatment of orolabial herpes lesions. Orally administered acyclovir at a dose of 400 mg 5 times daily for 5 days reduces duration of pain and time to the loss of crusts by about one-third, but only if treatment is started during the prodromal or erythematous stages of recurrent infection.1
9
Herpes Simplex Virus Infection Table 1. Antiviral Therapy in Herpes Simplex Virus Infections*† Type of infection Genital HSV Initial episode
Recurrent episode Suppression Mucocutaneous HSV Normal host
Route and Dosage†
Drug Acyclovir Valaciclovir Famciclovir Acyclovir Valaciclovir Famciclovir Acyclovir Valaciclovir Famciclovir Acyclovir
200 mg orally 5 times a day for 10 days 5 mg/kg IV every 8 hours for 5 days 1 gm orally twice daily for 5-10 days 250 mg orally 3 times a day for 5-10 days 200 mg orally 5 times a day for 5 days 500 mg orally twice a day for 3 days 250 mg orally 3 times a day for 5-7 days 400 mg orally twice daily 500 mg orally twice daily or 1 g every day 250 mg orally 3 times a day
Immunocompromised patient
Acyclovir
200-400 mg orally 5 times a day for 10 days 5 mg/kg IV every 8 hours for 7-10 days‡
HSV encephalitis
Valaciclovir Famciclovir Acyclovir
500 mg orally twice daily 500 mg orally 3 times a day 10 mg/kg IV every 8 hours for 14-21 days§
Neonatal HSV Herpetic conjunctivitis
Acyclovir Trifluridine
20 mg/kg IV every 8 hours for 14-21 days 1 drop every 2 hours while awake for 7-14 days
Comments
Severe cases
Reserved for severe cases Serially assess renal function Titrate dose as required (alternate: vidarabine ointment)
Abbreviation: IV, intravenous. *Data from reference 1. †The doses are for adults with normal renal function unless otherwise noted. ‡A dose of 250 mg/m2 should be given to children younger than 12 years of age.
Thus, oral acyclovir has a slight clinical benefit only if initiated very early after recurrence and cannot be recommended as routine treatment for herpes labialis in immunocompetent patients. No data exist on the treatment of children or adolescents with herpes labialis. No data support the use of long-term suppressive treatment with acyclovir for the prevention of herpes labialis. Recently, denavir was licensed for the treatment of labial herpes in adults. Therapy results in approximately a 20-percent reduction in duration of disease. Genital Herpes. Acyclovir administered topically, orally, and intravenously is effective in the treatment of primary genital herpes in the normal host, decreasing the duration of symptoms, viral shedding, and time to healing of lesions (Table 1), as reviewed.8 However, neither systemic nor topical treatment of primary HSV lesions reduces the frequency or severity of recurrences. Episodic administration of oral or topical acyclovir for the treatment of recurrent genital HSV lesions provides only a modest benefit, with duration of lesions being shortened, at most, by 1 to 2 days. However, daily administration of oral acyclovir can effectively suppress recurrences of genital herpes in 60 to 90 percent of patients. Treatment should be interrupted every 12 months to reassess the need for continued suppression. Therapy usually is reserved for adolescent patients. Both valaciclovir and famciclovir are licensed for the treatment and suppression of recurrent herpes; however, no
true pediatric formulation exists. These medications have a pharmacokinetic advantage. Valaciclovir is administered at 500 mg once daily for 3 days. Famciclovir is administered at 250 mg 3 times a day. Mucocutaneous HSV Infections in Immunocompromised Patients. In immunocompromised patients, topical, oral, and intravenous acyclovir all diminish the duration of viral shedding, as well as substantially improve time to cessation of pain and to total healing of HSV lesions. In addition, prophylactic administration of oral or intravenous acyclovir to such patients significantly reduces the incidence of symptomatic HSV infection (Table 1). Valaciclovir and famciclovir also can be used in these populations. Should resistance develop, foscarnet is the treatment of choice. Herpes Simplex Keratoconjunctivitis. Idoxuridine, trifluridine (Viroptic, Monarch Pharmaceutical, Bristol, TN), and vidarabine ophthalmic drops all are effective and licensed for treating HSV keratitis. Trifluridine is the most efficacious and the easiest to administer, and, as such, is the drug of choice for HSV ocular disease (Table 1), as reviewed.9 Herpes Simplex Encephalitis. In patients with HSV encephalitis, administration of acyclovir greatly reduces mortality to about 25 percent 1 year after treatment and has a modest impact of morbidity (25% of survivors return to normal function). Dose and length of therapy are listed in Table 1. The outcome is more favorable when therapy is instituted early in the disease course.10
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Richard J. Whitley
Neonatal HSV Infections. Acyclovir is the drug of choice in the treatment of neonatal HSV infection (Table 1). Therapy significantly decreases mortality of encephalitis to approximately 5 percent and disseminated disease to 25 percent. However, morbidity of survivors remains significant. Because of the exceptional safety profile of acyclovir, an intravenous dose of 60 mg/kg/d divided every 8 hours should be given. Duration of therapy is 14 to 21 days.11 Infants with ocular involvement caused by HSV should receive topical antiviral medication in addition to parenteral therapy. Trifluridine is the treatment of choice for ocular HSV infection in the neonate (Table 1). Off-Label Uses of Antiviral Therapies. Although not licensed for the treatment of HSV gingivostomatitis,12 herpes gladiatorum, erythema multiforme (attributed to HSV), or herpetic whitlow, acyclovir, valaciclovir, and famciclovir frequently are used off label for these indications. Furthermore, all 3 drugs have been administered to organ transplant recipients to prevent the reactivation of HSV infection. No studies have been performed with valaciclovir or famciclovir in children or adolescents. However, as noted, both valaciclovir and famciclovir are licensed for treating recurrent genital herpes. Because of its enhanced oral bioavailability, it is at least as active as is acyclovir in the respective patient populations. Similarly, foscarnet has not been studied in pediatric populations. Adverse Effects. The adverse reactions associated with acyclovir and valaciclovir are limited. After intravenous administration, inflammation at the site of administration has been reported. Furthermore, if the drug is administered too rapidly, alterations in renal function, particularly elevations in blood urea nitrogen and creatinine levels, can be documented. In a few patients, acute tubular necrosis has been reported. With extremely high doses of acyclovir in adults (⬎60 mg/kg/d), encephalopathic changes have been noted. Importantly, acyclovir has not been reported as a cause of significant alterations in bone marrow (ie, neutropenia) or liver alterations when administered for standard periods of therapy (10 to 21 days). Acyclovir, as is the case with famciclovir, when administered orally is associated with few adverse events.1 The adverse event profile of acyclovir and valaciclovir administration matches closely that of placebo recipients with, perhaps, a slightly enhanced incidence of gastrointestinal complications. However, valaciclovir has been reported to cause thrombotic thrombocytopenic purpura in individuals with acquired immunodeficiency syndrome who receive more than 6 grams of medication daily.13 A detailed logistic regression analysis of concomitant drugs administered to these patients indicates a higher susceptibility for this syndrome with medications used to treat Pneumocystis carinii pneumonia and human immunodeficiency virus infection. When acyclovir is administered in an oral formulation to infants for suppressive therapy after intravenous acyclovir treatment of neonatal HSV disease, neutropenia has been documented in a significant percentage of young patients. The correlation of neutropenia with clinical adverse events is being investigated further. However, at least at this time, caution must
be used in the administration of acyclovir as suppressive therapy for newborns. Administration of foscarnet is associated with significant alterations in renal function and electrolyte abnormalities, including elevated blood urea nitrogen levels, creatinine levels, hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia. Therapy can be accompanied by fever, nausea, anemia, diarrhea, headache, and seizures. Triflurothymidine, idoxuridine, and vidarabine ophthalmic preparations all have similar adverse-effect profiles. Adverse reactions include local irritation, photophobia, corneal edema, a punctate keratopathy, and keratitis sicca.
Drug Resistance Resistance to acyclovir has been documented in individuals with both HSV and VZV infections.14,15 Mutations within the HSV or VZV viral thymidine kinase are the most common manner in which resistance is acquired. For both viruses, isolates that cannot produce a functional thymidine kinase have been identified in clinical lesions from patients whose lesions are worsening despite acyclovir therapy. Less commonly, viral isolates that produce a thymidine kinase enzyme with altered (diminished) ability to phosphorylate acyclovir also have been identified. A third mode of resistance to acyclovir can occur within the viral gene encoding DNA polymerase. The overall prevalence of resistance to acyclovir in the normal host is exceedingly low, being approximately 1 percent. However, in high-risk immunocompromised patient populations, resistance has occurred at rates of between 6 percent and 12 percent, depending on the study population and the duration of acyclovir exposure. In the presence of clinical resistance to acyclovir, valaciclovir, or famciclovir, foscarnet is the treatment of choice. HSV isolates resistant to penciclovir have been documented. The mechanism of action of the development of resistance is similar to that encountered with acyclovir, with mutations within the viral thymidine kinase and DNA polymerase genes. An HSV or VZV isolate that is resistant to penciclovir likely is resistant to acyclovir as well. Foscarnet resistance has been documented in isolates of HSV, CMV, and the human immunodeficiency virus. The mechanism of resistance relates to mutations of viral DNA polymerase.
References 1. Whitley RJ, Gnann J: Acyclovir: A decade later. N Engl J Med 327:782-789, 1992 2. Balfour HH Jr: Antiviral drugs. N Engl J Med 340:1255-1268, 1999 3. Perry CM, Faulds D: Valaciclovir: A review of its antiviral, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs 52:754-772, 1996 4. Whitley RJ: Famciclovir/penciclovir: Prospects for the future. Antiviral Chem Chemoth 4:65, 1993 (suppl 1) 5. Spruance SL, Rea TL, Thoming C, et al: Penciclovir cream for the treatment of herpes simplex labialis. A randomized, mul-
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ticenter, double-blind, placebo-controlled trial. Topical Penciclovir Collaborative Study Group. JAMA 277:1374-1379, 1997 Whitley RJ: Herpes simplex virus, in Knipe DM, Howley RM, Griffin D, Lamb R, Martin M, Straus SE, (eds): Fields Virology (ed 4). New York, NY, Lippincott, 2001, pp 2461-2509 Lakeman FD, Whitley RJ, the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group: Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain biopsied patients and correlation with disease. J Infect Dis 72:857-863, 1995 Whitley RJ, Kimberlin D: Antiviral Agents, in Burg FD, Ingelfinger JR, Polin RA, Gershon A (eds.): Gellis and Kagan’s Current Pediatric Therapy 17. Philadelphia, PA, Saunders (in press) International Herpes Management Forum: Pathogenesis and Management of HSV-1 Infection, in Stanberry L (ed): (in press) Whitley RJ: Viral encephalitis. N Engl J Med 323:242-250, 1990 Kimberlin DW, Lin CY, Jacobs RF, et al: The safety and efficacy of high-dose intravenous acyclovir in the management
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of neonatal herpes simplex virus infections. Pediatrics 108:230238, 2001 Amir J, Harel L, Smetana Z, et al: Treatment of herpes simplex gingivostomatitis with aciclovir in children: A randomized double blind placebo controlled study. BMJ 314:1800-1803, 1997 Griffiths PD, Feinberg, JE, Fry J, et al: The effect of valaciclovir on cytomegalovirus viremia and viruria detected by polymerase chain reaction in patients with advanced human immunodeficiency virus disease. AIDS Clinical Trials Group Protocol 204/ Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis 177:57-64, 1998 Gaudreau A, Hill E, Balfour HH Jr, et al: Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis 178:297-303, 1998 Shin YK, Cai GY, Weinberg A, et al: Frequency of acyclovirresistant herpes simplex virus in clinical specimens and laboratory isolates. J Clin Microbiol 39:913-917, 2001