Advertisement
Recommendations from the Fourth World Workshop on Oral Medicine| Volume 103, SUPPLEMENT , S12.e1-S12.e18, March 2007

Download started.

Ok

Management of recurrent oral herpes simplex infections

      The literature has been reviewed for evidence of the efficacy of antiviral agents in both the prophylaxis and treatment of recurrent oral herpes simplex virus (HSV) infections and discussed by a panel of experts. Emphasis was given to randomized controlled trials. Management of herpes-associated erythema multiforme and Bell palsy were also considered. The evidence suggests that 5% acyclovir (ACV) in the cream base may reduce the duration of lesions if applied early. Recurrent herpes labialis (RHL) and recurrent intraoral HSV infections can be effectively treated with systemic ACV 400 mg 3 times a day or systemic valacyclovir 500 to 1000 mg twice a day for 3 to 5 days (longer in the immunocompromised). RHL in the immunocompetent can be effectively prevented with (1) sunscreen alone (SPF 15 or above), (2) systemic ACV 400 mg 2 to 3 times a day, or (3) systemic valacyclovir 500 to 2000 mg twice a day. Valacyclovir 500 mg twice a day is also effective in suppressing erythema multiforme triggered by HSV. Further studies are needed to compare treatment efficacy between topical penciclovir, docosanol, and ACV cream for RHL.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      References

        • Langenberg A.G.
        • Corey L.
        • Ashley R.L.
        • Leong W.P.
        • Straus S.E.
        A prospective study of new infections with herpes simplex virus type 1 and type 2.
        N Engl J Med. 1999; 341: 1432-1438
        • Xu F.
        • Schillinger J.A.
        • Sternberg M.R.
        • Johnson R.E.
        • Lee F.K.
        • Nahmias A.J.
        • et al.
        Seroprevalence and coinfection with herpes simplex virus type 1 and type 2 in the United States, 1988-1994.
        J Infect Dis. 2002; 185: 1019-1024
        • Miller C.S.
        • Danaher R.J.
        • Jacob R.J.
        Molecular aspects of herpes simplex virus I latency, reactivation, and recurrence.
        Crit Rev Oral Biol Med. 1998; 9: 541-562
        • Openshaw H.
        • McNeill J.I.
        • Lin X.H.
        • Niland J.
        • Cantin E.M.
        Herpes simplex virus DNA in normal corneas: persistence without viral shedding from ganglia.
        J Med Virol. 1995; 46: 75-80
        • Syrjanen S.
        • Mikola H.
        • Nykanen M.
        • Hukkanen V.
        In vitro establishment of lytic and nonproductive infection by herpes simplex virus type 1 in three-dimensional keratinocyte culture.
        J Virol. 1996; 70: 6524-6528
        • Krone M.R.
        • Wald A.
        • Tabet S.R.
        • Paradise M.
        • Corey L.
        • Celum C.L.
        Herpes simplex virus type 2 shedding in human immunodeficiency virus-negative men who have sex with men: frequency, patterns, and risk factors.
        Clin Infect Dis. 2000; 30: 261-267
        • Miller C.S.
        • Avdiushko S.A.
        • Kryscio R.J.
        • Danaher R.J.
        • Jacob R.J.
        Effect of prophylactic valacyclovir on the presence of human herpesvirus DNA in saliva of healthy individuals after dental treatment.
        J Clin Microbiol. 2005; 43: 2173-2180
        • Knaup B.
        • Schunemann S.
        • Wolff M.H.
        Subclinical reactivation of herpes simplex virus type 1 in the oral cavity.
        Oral Microbiol Immunol. 2000; 15: 281-283
        • Kaufman H.E.
        • Azcuy A.M.
        • Varnell E.D.
        • Sloop G.D.
        • Thompson H.W.
        • Hill J.M.
        HSV-1 DNA in tears and saliva of normal adults.
        Invest Ophthalmol Vis Sci. 2005; 46: 241-247
        • Wald A.
        • Huang M.L.
        • Carrell D.
        • Selke S.
        • Corey L.
        Polymerase chain reaction for detection of herpes simplex virus (HSV) DNA on mucosal surfaces: comparison with HSV isolation in cell culture.
        J Infect Dis. 2003; 188: 1345-1351
        • Lafferty W.E.
        • Coombs R.W.
        • Benedetti J.
        • Critchlow C.
        • Corey L.
        Recurrences after oral and genital herpes simplex virus infection.
        N Engl J Med. 1987; 316: 1444-1449
        • Sawtell N.M.
        • Poon D.K.
        • Tansky C.S.
        • Thompson R.L.
        The latent herpes simplex virus type 1 genome copy number in individual neurons is virus strain specific and correlates with reactivation.
        J Virol. 1998; 72: 5343-5350
        • Wald A.
        • Ericsson M.
        • Krantz E.
        • Selke S.
        • Corey L.
        Oral shedding of herpes simplex virus type 2.
        Sex Transm Infect. 2004; 80: 272-276
        • Posavad C.M.
        • Wald A.
        • Hosken N.
        • Huang M.L.
        • Koelle D.M.
        • Ashley R.L.
        • et al.
        T cell immunity to herpes simplex viruses in seronegative subjects: silent infection or acquired immunity?.
        J Immunol. 2003; 170: 4380-4388
        • Valimaa H.
        • Waris M.
        • Hukkanen V.
        • Blankenvoorde M.F.
        • Nieuw Amerongen A.V.
        • Tenovuo J.
        Salivary defense factors in herpes simplex virus infection.
        J Dent Res. 2002; 81: 416-421
        • Stanberry L.R.
        • Cunningham A.L.
        • Mindel A.
        • Scott L.L.
        • Spruance S.K.
        • Aoki F.Y.
        • et al.
        Prospects for control of herpes simplex virus disease through immunization.
        Clin Infect Dis. 2000; 30: 549-566
        • Weathers D.R.
        • Griffin J.W.
        Intraoral ulcerations of recurrent herpes simplex and recurrent aphthae: two distinct clinical entities.
        J Am Dent Assoc. 1970; 81: 81-87
        • Murakami S.
        • Mizobuchi M.
        • Nakashiro Y.
        • Doi T.
        • Hato N.
        • Yanagihara N.
        Bell palsy and herpes simplex virus: identification of viral DNA in endoneurial fluid and muscle.
        Ann Intern Med. 1996; 124: 27-30
        • Baringer J.R.
        Herpes simplex virus and Bell palsy.
        Ann Intern Med. 1996; 124: 63-65
        • Furuta Y.
        • Fukuda S.
        • Chida E.
        • Takasu T.
        • Ohtani F.
        • Inuyama Y.
        • et al.
        Reactivation of herpes simplex virus type 1 in patients with Bell’s palsy.
        J Med Virol. 1998; 54: 162-166
        • Adour K.K.
        • Ruboyianes J.M.
        • Von Doersten P.G.
        • Byl F.M.
        • Trent C.S.
        • Quesenberry Jr, C.P.
        • et al.
        Bell’s palsy treatment with acyclovir and prednisone compared with prednisone alone: a double-blind, randomized, controlled trial.
        Ann Otol Rhinol Laryngol. 1996; 105: 371-378
        • Axelsson S.
        • Lindberg S.
        • Stjernquist-Desatnik A.
        Outcome of treatment with valacyclovir and prednisone in patients with Bell’s palsy.
        Ann Otol Rhinol Laryngol. 2003; 112: 197-201
        • Sun Y.
        • Chan R.K.
        • Tan S.H.
        • Ng P.P.
        Detection and genotyping of human herpes simplex viruses in cutaneous lesions of erythema multiforme by nested PCR.
        J Med Virol. 2003; 71: 423-428
        • Kokuba H.
        • Aurelian L.
        • Burnett J.
        Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions.
        J Invest Dermatol. 1999; 113: 808-815
        • Hedner E.
        • Vahlne A.
        • Kahnberg K.E.
        • Hirsch J.M.
        Reactivated herpes simplex virus infection as a possible cause of dry socket after tooth extraction.
        J Oral Maxillofac Surg. 1993; 51 (discussion 7-8): 370-376
        • Embil J.A.
        • Stephens R.G.
        • Manuel F.R.
        Prevalence of recurrent herpes labialis and aphthous ulcers among young adults on six continents.
        Can Med Assoc J. 1975; 113: 627-630
        • Young S.K.
        • Rowe N.H.
        • Buchanan R.A.
        A clinical study for the control of facial mucocutaneous herpes virus infections.
        Oral Surg Oral Med Oral Pathol. 1976; 41: 498-507
        • Ship I.I.
        • Brightman V.J.
        • Laster L.L.
        The patient with recurrent aphthous ulcers and the patient with recurrent herpes labialis: a study of two population samples.
        J Am Dent Assoc. 1967; 75: 645-654
        • Spruance S.L.
        • Overall Jr, J.C.
        • Kern E.R.
        • Krueger G.G.
        • Pliam V.
        • Miller W.
        The natural history of recurrent herpes simplex labialis: implications for antiviral therapy.
        N Engl J Med. 1977; 297: 69-75
        • Raborn G.W.
        • Grace M.G.
        Recurrent herpes simplex labialis: selected therapeutic options.
        J Can Dent Assoc. 2003; 69: 498-503
        • Worrall G.
        Acyclovir in recurrent herpes labialis.
        BMJ. 1996; 312: 6
        • Kibrick S.
        • Katz A.S.
        Topical idoxuridine in recurrent herpes simplex.
        Ann N Y Acad Sci. 1970; 173: 83-89
        • Marks R.
        • Koutts J.
        Topical treatment of recurrent herpes simplex with cytosine arabinoside.
        Med J Aust. 1975; 01: 479-480
        • Myers M.G.
        • Oxman M.N.
        • Clark J.E.
        • Arndt K.A.
        Failure of neutral-red photodynamic inactivation in recurrent herpes simplex virus infections.
        N Engl J Med. 1975; 293: 945-949
        • Taylor C.A.
        • Hendley J.O.
        • Greer K.E.
        • Gwaltney Jr, J.M.
        Topical treatment of herpes labialis with chloroform.
        Arch Dermatol. 1977; 113: 1550-1552
        • Guinan M.E.
        • MacCalman J.
        • Kern E.R.
        • Overall Jr, J.C.
        • Spruance S.L.
        Topical ether and herpes simplex labialis.
        JAMA. 1980; 243: 1059-1061
        • Milman N.
        • Scheibel J.
        • Jessen O.
        Lysine prophylaxis in recurrent herpes simplex labialis: a double-blind, controlled crossover study.
        Acta Derm Venereol. 1980; 60: 85-87
        • Thein D.J.
        • Hurt W.C.
        Lysine as a prophylactic agent in the treatment of recurrent herpes simplex labialis.
        Oral Surg Oral Med Oral Pathol. 1984; 58: 659-666
        • Rowe N.H.
        • Brooks S.L.
        • Young S.K.
        • Spencer J.
        • Petrick T.J.
        • Buchanan R.A.
        • et al.
        A clinical trial of topically applied 3 percent vidarabine against recurrent herpes labialis.
        Oral Surg Oral Med Oral Pathol. 1979; 47: 142-147
        • Gangarosa Sr, L.P.
        • Hill J.M.
        • Thompson B.L.
        • Leggett C.
        • Rissing J.P.
        Iontophoresis of vidarabine monophosphate for herpes orolabialis.
        J Infect Dis. 1986; 154: 930-934
        • Spruance S.L.
        • Krueger G.G.
        • MacCalman J.
        • Overall Jr, J.C.
        • Klauber M.R.
        Treatment of recurrent herpes simplex labialis with levamisole.
        Antimicrob Agents Chemother. 1979; 15: 662-665
        • Russell A.S.
        • Brisson E.
        • Grace M.
        A double-blind, controlled trial of levamisole in the treatment of recurrent herpes labialis.
        J Infect Dis. 1978; 137: 597-600
        • Spruance S.L.
        • Stewart J.C.
        • Rowe N.H.
        • McKeough M.B.
        • Wenerstrom G.
        • Freeman D.J.
        Treatment of recurrent herpes simplex labialis with oral acyclovir.
        J Infect Dis. 1990; 161: 185-190
        • Balfour Jr, H.H.
        Antiviral drugs.
        N Engl J Med. 1999; 340: 1255-1268
        • de Miranda P.
        • Blum M.R.
        Pharmacokinetics of acyclovir after intravenous and oral administration.
        J Antimicrob Chemother. 1983; 12: 29-37
        • Spruance S.L.
        • Schnipper L.E.
        • Overall Jr, J.C.
        • Kern E.R.
        • Wester B.
        • Modlin J.
        • et al.
        Treatment of herpes simplex labialis with topical acyclovir in polyethylene glycol.
        J Infect Dis. 1982; 146: 85-90
        • Fiddian A.P.
        • Ivanyi L.
        Topical acyclovir in the management of recurrent herpes labialis.
        Br J Dermatol. 1983; 109: 321-326
        • Raborn G.W.
        • McGaw W.T.
        • Grace M.
        • Percy J.
        Treatment of herpes labialis with acyclovir.
        Am J Med. 1988; 85: 39-42
        • Raborn G.W.
        • McGaw W.T.
        • Grace M.
        • Houle L.
        Herpes labialis treatment with acyclovir 5 per cent ointment.
        J Can Dent Assoc. 1989; 55: 135-137
        • Van Vloten W.A.
        • Swart R.N.
        • Pot F.
        Topical acyclovir therapy in patients with recurrent orofacial herpes simplex infections.
        J Antimicrob Chemother. 1983; 12: 89-93
        • Fiddian A.P.
        • Yeo J.M.
        • Stubbings R.
        • Dean D.
        Successful treatment of herpes labialis with topical acyclovir.
        Br Med J (Clin Res Ed). 1983; 286: 1699-1701
        • Spruance S.L.
        • Nett R.
        • Marbury T.
        • Wolff R.
        • Johnson J.
        • Spaulding T.
        Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials.
        Antimicrob Agents Chemother. 2002; 46: 2238-2243
        • Gibson J.R.
        • Klaber M.R.
        • Harvey S.G.
        • Tosti A.
        • Jones D.
        • Yeo J.M.
        Prophylaxis against herpes labialis with acyclovir cream—a placebo-controlled study.
        Dermatologica. 1986; 172: 104-107
        • Shaw M.
        • King M.
        • Best J.M.
        • Banatvala J.E.
        • Gibson J.R.
        • Klaber M.R.
        Failure of acyclovir cream in treatment of recurrent herpes labialis.
        Br Med J (Clin Res Ed). 1985; 291: 7-9
        • Raborn G.W.
        • McGaw W.T.
        • Grace M.
        • Percy J.
        • Samuels S.
        Herpes labialis treatment with acyclovir 5% modified aqueous cream: a double-blind randomized trial.
        Oral Surg Oral Med Oral Pathol. 1989; 67: 676-679
        • Ottevanger V.
        • Larsen J.
        • Hoybye S.
        • Eskerod O.
        Efficacy of 86C (acyclovir) cream 5% compared with Zovirax (acyclovir) cream 5% in the treatment of recurrent herpes labialis.
        Curr Therap Res. 1996; 57: 243-250
        • Horwitz E.
        • Pisanty S.
        • Czerninski R.
        • Helser M.
        • Eliav E.
        • Touitou E.
        A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999; 87: 700-705
        • Evans T.G.
        • Bernstein D.I.
        • Raborn G.W.
        • Harmenberg J.
        • Kowalski J.
        • Spruance S.L.
        Double-blind, randomized, placebo-controlled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis.
        Antimicrob Agents Chemother. 2002; 46: 1870-1874
        • Spruance S.L.
        • Crumpacker C.S.
        • Schnipper L.E.
        • Kern E.R.
        • Marlowe E.S.
        • Arndt K.A.
        • et al.
        Early, patient-initiated treatment of herpes labialis with topical 10% acyclovir.
        Antimicrob Agents Chemother. 1984; 25: 553-555
        • Freeman D.J.
        • Sheth N.V.
        • Spruance S.L.
        Failure of topical acyclovir in ointment to penetrate human skin.
        Antimicrob Agents Chemother. 1986; 29: 730-732
        • Trottet L.
        • Owen H.
        • Holme P.
        • et al.
        Are all aciclovir cream formulations bioequivalent?.
        Int J Pharm. 2005; 304: 63-71
        • Raborn G.W.
        • McGaw W.T.
        • Grace M.
        • Tyrrell L.D.
        • Samuels S.M.
        Oral acyclovir and herpes labialis: a randomized, double-blind, placebo-controlled study.
        J Am Dent Assoc. 1987; 115: 38-42
        • Rooney J.F.
        • Straus S.E.
        • Mannix M.L.
        • Wohlenberg C.R.
        • Alling D.W.
        • Dumois J.A.
        • et al.
        Oral acyclovir to suppress frequently recurrent herpes labialis.
        Ann Intern Med. 1993; 118: 268-272
        • Spruance S.L.
        • Hamill M.L.
        • Hoge W.S.
        • Davis L.G.
        • Mills J.
        Acyclovir prevents reactivation of herpes simplex labialis in skiers.
        JAMA. 1988; 260: 1597-1599
        • Spruance S.L.
        • Freeman D.J.
        • Stewart J.C.
        • McKeough M.B.
        • Wenerstrom L.G.
        • Krueger G.G.
        • et al.
        The natural history of ultraviolet radiation-induced herpes simplex labialis and response to therapy with peroral and topical formulations of acyclovir.
        J Infect Dis. 1991; 163: 728-734
        • Duteil L.
        • Queille-Roussel C.
        • Loesche C.
        • Verschoore M.
        Assessment of the effect of a sunblock stick in the prevention of solar-stimulating ultraviolet light-induced herpes labialis.
        J Dermatologic Treat. 1998; 9: 11-14
        • Rooney J.F.
        • Bryson Y.
        • Mannix M.L.
        • Dillon M.
        • Wohlenberg C.R.
        • Banks S.
        • et al.
        Prevention of ultraviolet-light-induced herpes labialis by sunscreen.
        Lancet. 1991; 338: 1419-1422
        • Raborn G.W.
        • Martel A.Y.
        • Grace M.G.
        • McGaw W.T.
        Oral acyclovir in prevention of herpes labialis.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998; 85: 55-59
        • Laiskonis A.
        • Thune T.
        • Neldam S.
        • Hiltunen-Back E.
        Valacyclovir in the treatment of facial herpes simplex virus infection.
        J Infect Dis. 2002; 186: S66-S70
        • Chosidow O.
        • Drouault Y.
        • Garraffo R.
        • Veyssier P.
        Valaciclovir as a single dose during prodrome of herpes facialis: a pilot randomized double-blind clinical trial.
        Br J Dermatol. 2003; 148: 142-146
        • Spruance S.L.
        • Jones T.M.
        • Blatter M.M.
        • Vargas-Cortes M.
        • Barber J.
        • Hill J.
        • et al.
        High-dose, short-duration, early valacyclovir therapy for episodic treatment of cold sores: results of two randomized, placebo-controlled, multicenter studies.
        Antimicrob Agents Chemother. 2003; 47: 1072-1080
        • Baker D.
        • Eisen D.
        Valacyclovir for prevention of recurrent herpes labialis: 2 double-blind, placebo-controlled studies.
        Cutis. 2003; 71: 239-242
        • Miller C.S.
        • Cunningham L.L.
        • Lindroth J.E.
        • Avdiushko S.A.
        The efficacy of valacyclovir in preventing recurrent herpes simplex virus infections associated with dental procedures.
        J Am Dent Assoc. 2004; 135: 1311-1318
        • Spruance S.L.
        Prophylactic chemotherapy with acyclovir for recurrent herpes simplex labialis.
        J Med Virol. 1993; : 27-32
        • Van Dyke R.B.
        • Connor J.D.
        • Wyborny C.
        • Hintz M.
        • Keeney R.E.
        Pharmacokinetics of orally administered acyclovir in patients with herpes progenitalis.
        Am J Med. 1982; 73: 172-175
        • Spruance S.L.
        • Kriesel J.D.
        • Evans T.G.
        • McKeough M.B.
        Susceptibility to herpes labialis following multiple experimental exposures to ultraviolet radiation.
        Antiviral Res. 1995; 28: 57-67
        • Hill T.J.
        • Blyth W.A.
        An alternative theory of herpes-simplex recurrence and a possible role for prostaglandins.
        Lancet. 1976; 1: 397-399
        • Soul-Lawton J.
        • Seaber E.
        • On N.
        • Wootton R.
        • Rolan P.
        • Posner J.
        Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans.
        Antimicrob Agents Chemother. 1995; 39: 2759-2764
        • Weller S.
        • Blum M.R.
        • Doucette M.
        • Burnette T.
        • Cederberg D.M.
        • Doucette M.
        • et al.
        Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers.
        Clin Pharmacol Ther. 1993; 54: 595-605
        • Spruance S.L.
        • Wenerstrom G.
        Pathogenesis of recurrent herpes simplex labialis.
        Oral Surg Oral Med Oral Pathol. 1984; 58: 667-671
        • Tyring S.K.
        • Baker D.
        • Snowden W.
        Valacyclovir for herpes simplex virus infection: long-term safety and sustained efficacy after 20 years’ experience with acyclovir.
        J Infect Dis. 2002; 186: S40-S46
        • Boyd M.R.
        • Safrin S.
        • Kern E.R.
        Penciclovir: a review of the spectrum of activity, selectivity and cross resistance pattern.
        Antiviral Chem Chemother. 1993; 4: 3-11
        • Bacon T.H.
        • Levin M.J.
        • Leary J.J.
        • Sarisky R.T.
        • Sutton D.
        Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy.
        Clin Microbiol Rev. 2003; 16: 114-128
        • Spruance S.L.
        • Rea T.L.
        • Thoming C.
        • Tucker R.
        • Saltzman R.
        • Boon R.
        Penciclovir cream for the treatment of herpes simplex labialis.
        JAMA. 1997; 277: 1374-1379
        • Raborn G.W.
        • Martel A.Y.
        • Lassonde M.
        • Lewis M.A.
        • Boon R.
        • Spruance S.L.
        Effective treatment of herpes simplex labialis with penciclovir cream: combined results of two trials.
        J Am Dent Assoc. 2002; 133: 303-309
        • Boon R.
        • Goodman J.J.
        • Martinez J.
        • Marks G.L.
        • Gamble M.
        • Welch C.
        Penciclovir cream for the treatment of sunlight-induced herpes simplex labialis: a randomized, double-blind, placebo-controlled trial.
        Clin Ther. 2000; 22: 76-90
        • Spruance S.L.
        • Tyring S.K.
        • Smith M.H.
        • Meng T.C.
        Application of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital herpes: a pilot study.
        J Infect Dis. 2001; 184: 196-200
        • Spruance S.L.
        • McKeough M.B.
        Combination treatment with famciclovir and a topical corticosteroid gel versus famciclovir alone for experimental ultraviolet radiation-induced herpes simplex labialis: a pilot study.
        J Infect Dis. 2000; 181: 1906-1910
        • Lin L.
        • Chen X.S.
        • Cui P.G.
        • Wang J.B.
        • Guo Z.P.
        • Lu N.Z.
        • et al.
        Topical application of penciclovir cream for the treatment of herpes simplex facialis/labialis: a randomized, double-blind, multicentre, aciclovir-controlled trial.
        J Dermatolog Treat. 2002; 13: 67-72
        • Femiano F.
        • Gombos F.
        • Scully C.
        Recurrent herpes labialis: efficacy of topical therapy with penciclovir compared with acyclovir (aciclovir).
        Oral Dis. 2001; 7: 31-33
        • Spruance S.L.
        • Rowe N.H.
        • Raborn G.W.
        • Thibodeau E.A.
        • D’Ambrosio J.A.
        • Bernstein D.I.
        Peroral famciclovir in the treatment of experimental ultraviolet radiation-induced herpes simplex labialis: a double-blind, dose-ranging, placebo-controlled, multicenter trial.
        J Infect Dis. 1999; 179: 303-310
        • Katz D.H.
        • Marcelletti J.F.
        • Khalil M.H.
        • Pope L.E.
        • Katz L.R.
        Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex.
        Proc Natl Acad Sci U S A. 1991; 88: 10825-10829
        • Pope L.E.
        • Marcelletti J.F.
        • Katz L.R.
        • Lin J.Y.
        • Katz D.H.
        • Parish M.L.
        • et al.
        The anti-herpes simplex virus activity of n-docosanol includes inhibition of the viral entry process.
        Antiviral Res. 1998; 40: 85-94
        • Habbema L.
        • De Boulle K.
        • Roders G.A.
        • Katz D.H.
        n-Docosanol 10% cream in the treatment of recurrent herpes labialis: a randomised, double-blind, placebo-controlled study.
        Acta Derm Venereol. 1996; 76: 479-481
        • Sacks S.L.
        • Thisted R.A.
        • Jones T.M.
        • Barbarash M.A.
        • Mikolich D.J.
        • Ruoff G.E.
        • et al.
        Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: a multicenter, randomized, placebo-controlled trial.
        J Am Acad Dermatol. 2001; 45: 222-230
        • Lawee D.
        • Rosenthal D.
        • Aoki F.Y.
        • Portnoy J.
        Efficacy and safety of foscarnet for recurrent orolabial herpes: a multicentre randomized double-blind study.
        CMAJ. 1988; 138: 329-333
        • Bernstein D.I.
        • Schleupner C.J.
        • Evans T.G.
        • Blumberg D.A.
        • Bryson Y.
        • Grafford K.
        • et al.
        Effect of foscarnet cream on experimental UV radiation-induced herpes labialis.
        Antimicrob Agents Chemother. 1997; 41: 1961-1964
        • Tatnall F.M.
        • Schofield J.K.
        • Leigh I.M.
        A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme.
        Br J Dermatol. 1995; 132: 267-270
        • Kerob D.
        • Assier-Bonnet H.
        • Esnault-Gelly P.
        • Blanc F.
        • Saiag P.
        Recurrent erythema multiforme unresponsive to acyclovir prophylaxis and responsive to valacyclovir continuous therapy.
        Arch Dermatol. 1998; 134: 876-877
        • Greenberg M.S.
        • Cohen S.G.
        • Boosz B.
        • Friedman H.
        Oral herpes simplex infections in patients with leukemia.
        J Am Dent Assoc. 1987; 114: 483-486
        • Schubert M.M.
        • Peterson D.E.
        • Flournoy N.
        • Meyers J.D.
        • Truelove E.L.
        Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection.
        Oral Surg Oral Med Oral Pathol. 1990; 70: 286-293
        • Woo S.B.
        • Lee S.F.
        Oral recrudescent herpes simplex virus infection.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 83: 239-243
        • Bergmann O.J.
        • Mogensen S.C.
        • Ellegaard J.
        Herpes simplex virus and intraoral ulcers in immunocompromised patients with haematologic malignancies.
        Eur J Clin Microbiol Infect Dis. 1990; 9: 184-190
        • Montgomery M.T.
        • Redding S.W.
        • LeMaistre C.F.
        The incidence of oral herpes simplex virus infection in patients undergoing cancer chemotherapy.
        Oral Surg Oral Med Oral Pathol. 1986; 61: 238-242
        • Meyers J.D.
        • Flournoy N.
        • Thomas E.D.
        Infection with herpes simplex virus and cell-mediated immunity after marrow transplant.
        J Infect Dis. 1980; 142: 338-346
        • Stanberry L.R.
        • Floyd-Reising S.A.
        • Connelly B.L.
        • Alter S.J.
        • Gilchrist M.J.
        • Rubio C.
        • et al.
        Herpes simplex viremia: report of eight pediatric cases and review of the literature.
        Clin Infect Dis. 1994; 18: 401-407
        • Whitley R.J.
        • Levin M.
        • Barton N.
        • Hershey B.J.
        • Davis G.
        • Keeney R.E.
        • et al.
        Infections caused by herpes simplex virus in the immunocompromised host: natural history and topical acyclovir therapy.
        J Infect Dis. 1984; 150: 323-329
        • Meyers J.D.
        • Wade J.C.
        • Mitchell C.D.
        • Saral R.
        • Lietman P.S.
        • Durack D.T.
        • 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: 229-235
        • Shepp D.H.
        • Newton B.A.
        • Dandliker P.S.
        • Flournoy N.
        • Meyers J.D.
        Oral acyclovir therapy for mucocutaneous herpes simplex virus infections in immunocompromised marrow transplant recipients.
        Ann Intern Med. 1985; 102: 783-785
        • Mitchell C.D.
        • Bean B.
        • Gentry S.R.
        • Groth K.E.
        • Boen J.R.
        • Balfour Jr, H.H.
        Acyclovir therapy for mucocutaneous herpes simplex infections in immunocompromised patients.
        Lancet. 1981; 1: 1389-1392
        • Saral R.
        • Burns W.H.
        • Laskin O.L.
        • Santos G.W.
        • Lietman P.S.
        Acyclovir prophylaxis of herpes-simplex-virus infections.
        N Engl J Med. 1981; 305: 63-67
        • Hann I.M.
        • Prentice H.G.
        • Blacklock H.A.
        • Ross M.G.
        • Brigden D.
        • Rosling A.E.
        • et al.
        Acyclovir prophylaxis against herpes virus infections in severely immunocompromised patients: randomised double blind trial.
        Br Med J (Clin Res Ed). 1983; 287: 384-388
        • Gluckman E.
        • Lotsberg J.
        • Devergie A.
        • Zhao X.M.
        • Melo R.
        • Gomez-Morales M.
        • et al.
        Prophylaxis of herpes infections after bone-marrow transplantation by oral acyclovir.
        Lancet. 1983; 2: 706-708
        • Wade J.C.
        • Newton B.
        • Flournoy N.
        • Meyers J.D.
        Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation.
        Ann Intern Med. 1984; 100: 823-828
        • Saral R.
        • Ambinder R.F.
        • Burns W.H.
        • Angelopulos C.M.
        • Griffin D.E.
        • Burke P.J.
        • et al.
        Acyclovir prophylaxis against herpes simplex virus infection in patients with leukemia.
        Ann Intern Med. 1983; 99: 773-776
        • Liesveld J.L.
        • Abboud C.N.
        • Ifthikharuddin J.J.
        • Lancet J.E.
        • Wedow L.A.
        • Oliva J.
        • et al.
        Oral valacyclovir versus intravenous acyclovir in preventing herpes simplex virus infections in autologous stem cell transplant recipients.
        Biol Blood Marrow Transplant. 2002; 8: 662-665
        • Dignani M.C.
        • Mykietiuk A.
        • Michelet M.
        • Intile D.
        • Mammana L.
        • Desmery P.
        • et al.
        Valacyclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation.
        Bone Marrow Transplant. 2002; 29: 263-267
        • Eisen D.
        • Essell J.
        • Broun E.R.
        • Sigmund D.
        • DeVoe M.
        Clinical utility of oral valacyclovir compared with oral acyclovir for the prevention of herpes simplex virus mucositis following autologous bone marrow transplantation or stem cell rescue therapy.
        Bone Marrow Transplant. 2003; 31: 51-55
        • Orlowski R.Z.
        • Mills S.R.
        • Hartley E.E.
        • Ye X.
        • Piantadosi S.
        • Ambinder R.F.
        • et al.
        Oral valacyclovir as prophylaxis against herpes simplex virus reactivation during high dose chemotherapy for leukemia.
        Leuk Lymphoma. 2004; 45: 2215-2219
        • Lazarus H.M.
        • Belanger R.
        • Candoni A.
        • Aoun M.
        • Jurewicz R.
        • Marks L.
        Intravenous penciclovir for treatment of herpes simplex infections in immunocompromised patients: results of a multicenter, acyclovir-controlled trial.
        Antimicrob Agents Chemother. 1999; 43: 1192-1197
        • Redding S.W.
        • Luce E.B.
        • Boren M.W.
        Oral herpes simplex virus infection in patients receiving head and neck radiation.
        Oral Surg Oral Med Oral Pathol. 1990; 69: 578-580
        • Oakley C.
        • Epstein J.B.
        • Sherlock C.H.
        Reactivation of oral herpes simplex virus: implications for clinical management of herpes simplex virus recurrence during radiotherapy.
        Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 84: 272-278
        • Schacker T.
        • Hu H.L.
        • Koelle D.M.
        • Zeh J.
        • Saltzman R.
        • Boon R.
        • et al.
        Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons.
        Ann Intern Med. 1998; 128: 21-28
        • Feinberg J.E.
        • Hurwitz S.
        • Cooper D.
        • Sattler F.R.
        • MacGregor R.R.
        • Powderly W.
        • et al.
        A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection.
        J Infect Dis. 1998; 177: 48-56
        • Dykewicz C.A.
        Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients.
        Clin Infect Dis. 2001; 33: 139-144
        • Gaudreau A.
        • Hill E.
        • Balfour Jr, H.H.
        • Erice A.
        • Boivin G.
        Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients.
        J Infect Dis. 1998; 178: 297-303
        • Morfin F.
        • Thouvenot D.
        Herpes simplex virus resistance to antiviral drugs.
        J Clin Virol. 2003; 26: 29-37
        • Englund J.A.
        • Zimmerman M.E.
        • Swierkosz E.M.
        • Goodman J.L.
        • Scholl D.R.
        • Balfour Jr, H.H.
        Herpes simplex virus resistant to acyclovir.
        Ann Intern Med. 1990; 112: 416-422
        • Danve-Szatanek C.
        • Aymard M.
        • Thouvenot D.
        • Morfin F.
        • Aqius G.
        • Bertin I.
        • et al.
        Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up.
        J Clin Microbiol. 2004; 42: 242-249
        • Sarisky R.T.
        • Bacon T.H.
        • Boon R.J.
        • Duffy K.E.
        • Esser K.M.
        • Leary J.
        • et al.
        Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials.
        Arch Virol. 2003; 148: 1757-1769
        • Reusser P.
        • Cordonnier C.
        • Einsele H.
        • Engelhard D.
        • Link D.
        • Locasciulli A.
        • et al.
        European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients.
        Bone Marrow Transplant. 1996; 17: 813-817
        • Chen Y.
        • Scieux C.
        • Garrait V.
        • Socie G.
        • Rocha V.
        • Molina J.M.
        • et al.
        Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation.
        Clin Infect Dis. 2000; 31: 927-935
        • Lalezari J.
        • Schacker T.
        • Feinberg J.
        • Gathe J.
        • Lee S.
        • Cheung T.
        • et al.
        A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS.
        J Infect Dis. 1997; 176: 892-898
        • Williams-Aziz S.L.
        • Hartline C.B.
        • Harden E.A.
        • Daily S.L.
        • Prichard M.N.
        • Kushner N.L.
        • et al.
        Comparative activities of lipid esters of cidofovir and cyclic cidofovir against replication of herpesviruses in vitro.
        Antimicrob Agents Chemother. 2005; 49: 3724-3733
        • Lateef F.
        • Don P.C.
        • Kaufmann M.
        • White S.M.
        • Weinberg J.M.
        Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS.
        Arch Dermatol. 1998; 134: 1169-1170
        • Snoeck R.
        • Andrei G.
        • Gerard M.
        • Silverman A.
        • Hedderman A.
        • Balzarini J.
        • et al.
        Successful treatment of progressive mucocutaneous infection due to acyclovir- and foscarnet-resistant herpes simplex virus with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC).
        Clin Infect Dis. 1994; 18: 570-578
        • Bryant P.
        • Sasadeusz J.
        • Carapetis J.
        • Waters K.
        • Curtis N.
        Successful treatment of foscarnet-resistant herpes simplex stomatitis with intravenous cidofovir in a child.
        Pediatr Infect Dis J. 2001; 20: 1083-1086
        • Bernstein D.I.
        • Spruance S.L.
        • Arora S.S.
        • Schroeder J.L.
        • Meng T.C.
        Evaluation of imiquimod 5% cream to modify the natural history of herpes labialis: a pilot study.
        Clin Infect Dis. 2005; 41: 808-814
        • Danielsen A.G.
        • Petersen C.S.
        • Iversen J.
        Chronic erosive herpes simplex virus infection of the penis in a human immunodeficiency virus-positive man, treated with imiquimod and famciclovir.
        Br J Dermatol. 2002; 147: 1034-1036
        • Bernstein D.I.
        • Aoki F.Y.
        • Tyring S.K.
        • Stanberry L.R.
        • St-Pierre C.
        • Shafran S.D.
        • et al.
        Safety and immunogenicity of glycoprotein D-adjuvant genital herpes vaccine.
        Clin Infect Dis. 2005; 40: 1271-1281
        • Spruance S.L.
        • Stewart J.C.
        • Freeman D.J.
        • Brightman V.J.
        • Cox J.L.
        • Wenerstrom G.
        • et al.
        Early application of topical 15% idoxuridine in dimethyl sulfoxide shortens the course of herpes simplex labialis: a multicenter placebo-controlled trial.
        J Infect Dis. 1990; 161: 191-197
        • Shafran S.D.
        • Sacks S.L.
        • Aoki F.Y.
        • Tyrrell S.D.
        • Schlech 3rd, W.F.
        • Mendelson J.
        • et al.
        Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial.
        J Infect Dis. 1997; 176: 78-83
        • Bolla K.
        • Djawari D.
        • Kokoschka E.M.
        • Petres J.
        • Liden S.
        • Gonseth R.
        • et al.
        Prevention of recurrences in frequently relapsing herpes labialis with thymopentin.
        Surv Immunol Res. 1985; 4: 37-47
        • Cassady K.A.
        • Whitley R.J.
        New therapeutic approaches to the alphaherpesvirus infections.
        J Antimicrob Chemother. 1997; 39: 119-128
        • Rodu B.
        • Russell C.M.
        • Mattingly G.
        Determining therapeutic efficacy in recurrent herpes labialis by lesion size analysis.
        Oral Surg Oral Med Oral Pathol. 1991; 72: 178-183
        • Kaminester L.H.
        • Pariser R.J.
        • Pariser D.M.
        • Weiss J.S.
        • Shavin J.S.
        • Landsman L.
        • et al.
        A double-blind, placebo-controlled study of topical tetracaine in the treatment of herpes labialis.
        J Am Acad Dermatol. 1999; 41: 996-1001
        • Koytchev R.
        • Alken R.G.
        • Dundarov S.
        Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis.
        Phytomedicine. 1999; 6: 225-230
        • Pedersen A.
        LongoVital and herpes labialis: a randomised, double-blind, placebo-controlled study.
        Oral Dis. 2001; 7: 221-225
        • Huleihel M.
        • Isanu V.
        Anti-herpes simplex virus effect of an aqueous extract of propolis.
        Isr Med Assoc J. 2002; 4: 923-927
        • Spruance S.L.
        • McKeough M.B.
        • Cardinal J.R.
        Penetration of guinea pig skin by acyclovir in different vehicles and correlation with the efficacy of topical therapy of experimental cutaneous herpes simplex virus infection.
        Antimicrob Agents Chemother. 1984; 25: 10-15