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Treatment of drug-resistant genital herpes simplex virus infection in HIV-infected patients

Christine Johnston, MD, MPH
Anna Wald, MD, MPH
Section Editor
Martin S Hirsch, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Genital herpes simplex is a common sexually transmitted viral infection that is found worldwide [1]. Most often genital herpes is secondary to herpes simplex virus type 2 (HSV-2), although about half of all new cases in developed countries are due to herpes simplex virus type 1 (HSV-1) [1].

Drug resistance to acyclovir and related drugs (eg, famciclovir or valacyclovir) is rare in immunocompetent hosts, but is seen more commonly among immunocompromised hosts, including HIV-infected patients and transplant recipients. This topic will review therapeutic options and strategies for prevention for drug-resistant infection in the HIV-infected patient. The epidemiology, natural history, clinical manifestations, and treatment of drug-sensitive HSV infection in the HIV-infected host are discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus in HIV-infected patients" and "Treatment of genital herpes simplex virus type 2 in HIV-infected patients" and "Effect of herpes simplex virus on HIV infection: Implications for HIV prevention".)


Acyclovir, famciclovir, and valacyclovir are antiviral agents within the nucleoside analog class. After intracellular uptake, acyclovir is converted to acyclovir monophosphate by virally-encoded thymidine kinase [2]. The monophosphate derivative is subsequently converted by cellular enzymes to acyclovir triphosphate, which is a specific inhibitor of HSV DNA polymerase. HSV drug resistance to acyclovir infers broad cross-resistance to this entire class of antiviral agents. (See "Acyclovir: An overview", section on 'Mechanism of action'.)

Three mechanisms have been found that result in resistance to acyclovir [3,4]:

Reduced or absent thymidine kinase

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Literature review current through: Oct 2017. | This topic last updated: Mar 17, 2016.
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  1. Gupta R, Warren T, Wald A. Genital herpes. Lancet 2007; 370:2127.
  2. Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med 1992; 327:782.
  3. Chatis PA, Crumpacker CS. Resistance of herpesviruses to antiviral drugs. Antimicrob Agents Chemother 1992; 36:1589.
  4. Levin MJ, Bacon TH, Leary JJ. Resistance of herpes simplex virus infections to nucleoside analogues in HIV-infected patients. Clin Infect Dis 2004; 39 Suppl 5:S248.
  5. Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med 1989; 320:293.
  6. Christophers J, Clayton J, Craske J, et al. Survey of resistance of herpes simplex virus to acyclovir in northwest England. Antimicrob Agents Chemother 1998; 42:868.
  7. Tyring SK, 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 Suppl 1:S40.
  8. Reyes M, Shaik NS, Graber JM, et al. Acyclovir-resistant genital herpes among persons attending sexually transmitted disease and human immunodeficiency virus clinics. Arch Intern Med 2003; 163:76.
  9. Stránská R, Schuurman R, Nienhuis E, et al. Survey of acyclovir-resistant herpes simplex virus in the Netherlands: prevalence and characterization. J Clin Virol 2005; 32:7.
  10. Danve-Szatanek C, Aymard M, Thouvenot D, et al. Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up. J Clin Microbiol 2004; 42:242.
  11. Lehrman SN, Douglas JM, Corey L, Barry DW. Recurrent genital herpes and suppressive oral acyclovir therapy. Relation between clinical outcome and in-vitro drug sensitivity. Ann Intern Med 1986; 104:786.
  12. Collins P, Ellis MN. Sensitivity monitoring of clinical isolates of herpes simplex virus to acyclovir. J Med Virol 1993; Suppl 1:58.
  13. Kriesel JD, Spruance SL, Prichard M, et al. Recurrent antiviral-resistant genital herpes in an immunocompetent patient. J Infect Dis 2005; 192:156.
  14. Seang S, Boutolleau D, Burrel S, et al. Long-term follow-up of HIV-infected patients once diagnosed with acyclovir-resistant herpes simplex virus infection. Int J STD AIDS 2014; 25:676.
  15. Lalezari J, Schacker T, Feinberg J, 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.
  16. Safrin S, Crumpacker C, Chatis P, et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N Engl J Med 1991; 325:551.
  17. Cury K, Valin N, Gozlan J, et al. Bipolar hypertrophic herpes: an unusual presentation of acyclovir-resistant herpes simplex type 2 in a HIV-infected patient. Sex Transm Dis 2010; 37:126.
  18. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on September 21, 2016).
  19. Lingappa JR, Celum C. Clinical and therapeutic issues for herpes simplex virus-2 and HIV co-infection. Drugs 2007; 67:155.
  20. Gupta R, Wald A. Genital herpes: antiviral therapy for symptom relief and prevention of transmission. Expert Opin Pharmacother 2006; 7:665.
  21. Safrin S, Elbeik T, Phan L, et al. Correlation between response to acyclovir and foscarnet therapy and in vitro susceptibility result for isolates of herpes simplex virus from human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1994; 38:1246.
  22. Burrel S, Deback C, Agut H, Boutolleau D. Genotypic characterization of UL23 thymidine kinase and UL30 DNA polymerase of clinical isolates of herpes simplex virus: natural polymorphism and mutations associated with resistance to antivirals. Antimicrob Agents Chemother 2010; 54:4833.
  23. Watson-Jones D, Wald A, Celum C, et al. Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials. J Clin Microbiol 2010; 48:3496.
  24. Crumpacker CS. Mechanism of action of foscarnet against viral polymerases. Am J Med 1992; 92:3S.
  25. Whitley RJ, Gnann JW Jr, Hinthorn D, et al. Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine. The NIAID Collaborative Antiviral Study Group. J Infect Dis 1992; 165:450.
  26. Hardy WD. Foscarnet treatment of acyclovir-resistant herpes simplex virus infection in patients with acquired immunodeficiency syndrome: preliminary results of a controlled, randomized, regimen-comparative trial. Am J Med 1992; 92:30S.
  27. Safrin S, Assaykeen T, Follansbee S, Mills J. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. J Infect Dis 1990; 161:1078.
  28. Chatis PA, Miller CH, Schrager LE, Crumpacker CS. Successful treatment with foscarnet of an acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with acquired immunodeficiency syndrome. N Engl J Med 1989; 320:297.
  29. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009; 15:1143.
  30. Lateef F, Don PC, Kaufmann M, et al. Treatment of acyclovir-resistant, foscarnet-unresponsive HSV infection with topical cidofovir in a child with AIDS. Arch Dermatol 1998; 134:1169.
  31. Castelo-Soccio L, Bernardin R, Stern J, et al. Successful treatment of acyclovir-resistant herpes simplex virus with intralesional cidofovir. Arch Dermatol 2010; 146:124.
  32. Martinez V, Molina JM, Scieux C, et al. Topical imiquimod for recurrent acyclovir-resistant HSV infection. Am J Med 2006; 119:e9.
  33. Abbo L, Vincek V, Dickinson G, et al. Selective defect in plasmacyoid dendritic cell function in a patient with AIDS-associated atypical genital herpes simplex vegetans treated with imiquimod. Clin Infect Dis 2007; 44:e25.
  34. Danielsen AG, Petersen CS, 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.
  35. Holmes A, McMenamin M, Mulcahy F, Bergin C. Thalidomide therapy for the treatment of hypertrophic herpes simplex virus-related genitalis in HIV-infected individuals. Clin Infect Dis 2007; 44:e96.
  36. Verberkmoes A, Boer K, Wertheim PM, et al. Thalidomide for genital ulcer in HIV-positive woman. Lancet 1996; 347:974.
  37. Piret J, Boivin G. Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management. Antimicrob Agents Chemother 2011; 55:459.
  38. Lalezari JP, Drew WL, Glutzer E, et al. Treatment with intravenous (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant mucocutaneous infection with herpes simplex virus in a patient with AIDS. J Infect Dis 1994; 170:570.
  39. Chen Y, Scieux C, Garrait V, et al. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis 2000; 31:927.
  40. Andrei G, Fiten P, Goubau P, et al. Dual infection with polyomavirus BK and acyclovir-resistant herpes simplex virus successfully treated with cidofovir in a bone marrow transplant recipient. Transpl Infect Dis 2007; 9:126.
  41. LoPresti AE, Levine JF, Munk GB, et al. Successful treatment of an acyclovir- and foscarnet-resistant herpes simplex virus type 1 lesion with intravenous cidofovir. Clin Infect Dis 1998; 26:512.
  42. Kim JH, Schaenman JM, Ho DY, Brown JM. Treatment of acyclovir-resistant herpes simplex virus with continuous infusion of high-dose acyclovir in hematopoietic cell transplant patients. Biol Blood Marrow Transplant 2011; 17:259.
  43. Erard V, Wald A, Corey L, et al. Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis 2007; 196:266.