, Volume 67, Issue 2, pp 155–174 | Cite as

Clinical and Therapeutic Issues for Herpes Simplex Virus-2 and HIV Co-Infection

  • Jairam R. Lingappa
  • Connie Celum
Therapy In Practice


A synergy between HIV type-1 (HIV-1) and herpes simplex virus-2 (HSV-2) has been demonstrated in many epidemiological and clinical studies over the last decade. HIV-1 infection exacerbates the clinical impact and frequency of HSV-2 reactivation events; furthermore, HSV-2 infection exacerbates the risk of HIV acquisition and transmission and may accentuate HIV disease progression. In order to maximise the impact of existing and future therapeutic and preventive interventions, this article reviews the epidemiological, clinical and therapeutic considerations associated with episodic treatment and suppression of HSV-2 infection in HIV-infected individuals.

Specifically, this article describes the current expanding epidemics of both HIV and HSV-2, and how high rates of asymptomatic herpes virus shedding contribute to the under-diagnosis and continued spread of both HSV-2 and HIV. Furthermore, multiple clinical trials have studied the efficacy and clinical utility of aciclovir and other nucleoside analogues for treating and suppressing HSV-2. We review these studies and summarise the guidelines for these regimens, particularly noting the accumulated experience documenting the utility of herpes treatment and suppression in altering the natural history of symptoms and documenting the low rate of HSV-2 drug resistance to nucleoside analogues observed after more that a decade of use. Finally, there are now also growing data describing the benefits of herpes suppression in the context of individuals co-infected with HIV/HSV-2, with additional clinical trials poised to further elucidate these issues in the near future.


Herpes Simplex Virus Genital Herpes Cidofovir Foscarnet Famciclovir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. Dr Celum has received research grant funding and speakers honoraria from GlaxoSmithKline, and has acted as an advisory board member for GlaxoSmithKline. Dr Lingappa has no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Corey L, Spear PG. Infections with herpes simplex viruses (1). N Engl J Med 1986; 314 (11): 686–91PubMedCrossRefGoogle Scholar
  2. 2.
    Nahmias AJ, Roizman B. Infection with herpes-simplex viruses 1 and 2. 1. N Engl J Med 1973; 289 (13): 667–74CrossRefGoogle Scholar
  3. 3.
    Christie SN, McCaughey C, McBride M, et al. Herpes simplex type 1 and genital herpes in Northern Ireland. Int J STD AIDS 1997; 8 (1): 68–9PubMedCrossRefGoogle Scholar
  4. 4.
    Lafferty WE. The changing epidemiology of HSV-1 and HSV-2 and implications for serological testing. Herpes 2002; 9 (2): 51–5PubMedGoogle Scholar
  5. 5.
    Wald A, Benedetti J, Davis G, et al. A randomized, double-blind, comparative trial comparing high- and standard-dose oral acyclovir for first-episode genital herpes infections. Antimicrob Agents Chemother 1994; 38 (2): 174–6PubMedCrossRefGoogle Scholar
  6. 6.
    Ahmed HJ, Mbwana J, Gunnarsson E, et al. Etiology of genital ulcer disease and association with human immunodeficiency virus infection in two Tanzanian cities. Sex Transm Dis 2003; 30 (2): 114–9PubMedCrossRefGoogle Scholar
  7. 7.
    Chen CY, Ballard RC, Beck-Sague CM, et al. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection. Sex Transm Dis 2000; 27 (1): 21–9PubMedCrossRefGoogle Scholar
  8. 8.
    Mertz KJ, Trees D, Levine WC, et al. Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis 1998; 178 (6): 1795–8Google Scholar
  9. 9.
    Morse SA. Etiology of genital ulcer disease and its relationship to HIV infection. Sex Transm Dis 1999; 26 (1): 63–5PubMedCrossRefGoogle Scholar
  10. 10.
    Schacker T, Ryncarz AJ, Goddard J, et al. Frequent recovery of HIV-1 from genital herpes simplex virus lesions in HIV-1-infected men. JAMA 1998; 280 (1): 61–6PubMedCrossRefGoogle Scholar
  11. 11.
    Wald A, Zeh J, Barnum G, et al. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med 1996; 124 (1 Pt 1): 8–15PubMedGoogle Scholar
  12. 12.
    Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995; 333 (12): 770–5PubMedCrossRefGoogle Scholar
  13. 13.
    Wald A, Zeh J, Selke S, et al. Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000; 342 (12): 844–50PubMedCrossRefGoogle Scholar
  14. 14.
    Corey L, Wald A, Celum CL, et al. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004; 35 (5): 435–45PubMedCrossRefGoogle Scholar
  15. 15.
    Gupta R, Wald A. Genital herpes: antiviral therapy for symptom relief and prevention of transmission. Expert Opin Pharmacother 2006; 7 (6): 665–75PubMedCrossRefGoogle Scholar
  16. 16.
    Malkin JE. Epidemiology of genital herpes simplex virus infection in developed countries. Herpes 2004; 11 Suppl. 1: 2–23AGoogle Scholar
  17. 17.
    Weiss H. Epidemiology of herpes simplex virus type 2 infection in the developing world. Herpes 2004; 11 Suppl. 1: 24–35AGoogle Scholar
  18. 18.
    Corey L, Wald A. Genital herpes. In: Holmes K, Sparling PF, Mardh P-A, et al., editors. Sexually transmitted diseases. 3rd ed. New York: McGraw-Hill, 1999Google Scholar
  19. 19.
    Xu F, McQuillan GM, Kottiri BJ, et al. National seroprevalence and trends in herpes simplex virus type 1 and type 2 infection in the United States, 1988–2000. In: 15th Biennial Congress of the International Society for Sexually Transmitted Diseases Research; 2003 Jul 27–30; Ottawa (ON). Ottawa (ON): ISSTDR, 2003: 58Google Scholar
  20. 20.
    Lai W, Chen CY, Morse SA, et al. Increasing relative prevalence of HSV-2 infection among men with genital ulcers from a mining community in South Africa. Sex Transm Infect 2003; 79 (3): 202–7PubMedCrossRefGoogle Scholar
  21. 21.
    Siegal FP, Lopez C, Hammer GS, et al. Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 1981; 305 (24): 1439–44PubMedCrossRefGoogle Scholar
  22. 22.
    Celum C, Levine R, Weaver M, et al. Genital herpes and human immunodeficiency virus: double trouble. Bull World Health Organ 2004; 82 (6): 447–53PubMedGoogle Scholar
  23. 23.
    Wald A. Synergistic interactions between herpes simplex virus type-2 and human immunodeficiency virus epidemics. Herpes 2004; 11 (3): 70–6PubMedGoogle Scholar
  24. 24.
    Reynolds SJ, Quinn TC. Developments in STD/HIV interactions: the intertwining epidemics of HIV and HSV-2. Infect Dis Clin North Am 2005; 19 (2): 415–25PubMedCrossRefGoogle Scholar
  25. 25.
    Wasserheit JN. Epidemiological synergy. Interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis 1992; 19 (2): 61–77Google Scholar
  26. 26.
    Buchbinder SP, Katz MH, Hessol NA, et al. Herpes zoster and human immunodeficiency virus infection. J Infect Dis 1992; 166 (5): 1153–6PubMedCrossRefGoogle Scholar
  27. 27.
    Holmberg SD, Gerber AR, Stewart JA, et al. Herpes simplex virus type 2 and HIV seroconversion. J Acquir Immune Defic Syndr 1991; 4 (7): 732–4PubMedGoogle Scholar
  28. 28.
    Holmberg SD, Stewart JA, Gerber AR, et al. Prior herpes simplex virus type 2 infection as a risk factor for HIV infection. JAMA 1988; 259 (7): 1048–50PubMedCrossRefGoogle Scholar
  29. 29.
    Stamm WE, Handsfield HH, Rompalo AM, et al. The association between genital ulcer disease and acquisition of HIV infection in homosexual men. Jama 1988; 260 (10): 1429–33PubMedCrossRefGoogle Scholar
  30. 30.
    Freeman EE, Weiss HA, Glynn JR, et al. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. Aids 2006; 20 (1): 73–83PubMedCrossRefGoogle Scholar
  31. 31.
    Kreiss JK, Coombs R, Plummer F, et al. Isolation of human immunodeficiency virus from genital ulcers in Nairobi prostitutes. J Infect Dis 1989; 160 (3): 380–4PubMedCrossRefGoogle Scholar
  32. 32.
    Emonyi IW, Gray RH, Zenilman J, et al. Sero-prevalence of Herpes simplex virus type 2 (HSV-2) in Rakai district, Uganda. East Afr Med J 2000; 77 (8): 428–30PubMedGoogle Scholar
  33. 33.
    Gray RH, Wawer MJ, Brookmeyer R, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357 (9263): 1149–53PubMedCrossRefGoogle Scholar
  34. 34.
    Serwadda D, Gray RH, Sewankambo NK, et al. Human immunodeficiency virus acquisition associated with genital ulcer disease and herpes simplex virus type 2 infection: a nested case-control study in Rakai, Uganda. J Infect Dis 2003; 188 (10): 1492–7PubMedCrossRefGoogle Scholar
  35. 35.
    Freeman EE, Glynn JR, Study Group on Heterogeneity of HIV Epidemics in African Cities. Factors affecting HIV concordancy in married couples in four African cities. AIDS 2004; 18 (12): 1715–21PubMedCrossRefGoogle Scholar
  36. 36.
    Brown EL, Wald A, Hughes JP, et al. High risk of human immunodeficiency virus in men who have sex with men with herpes simplex virus type 2 in the EXPLORE study. Am J Epidemiol 2006 Oct 15; 164 (8): 733–41PubMedCrossRefGoogle Scholar
  37. 37.
    Celum CL, Robinson NJ, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 2005; 191 Suppl. 1: S107–14PubMedCrossRefGoogle Scholar
  38. 38.
    Koelle DM, Posavad CM, Barnum GR, et al. Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes. J Clin Invest 1998; 101 (7): 1500–8PubMedCrossRefGoogle Scholar
  39. 39.
    Mosca JD, Bednarik DP, Raj NB, et al. Activation of human immunodeficiency virus by herpesvirus infection: identification of a region within the long terminal repeat that responds to a trans-acting factor encoded by herpes simplex virus 1. Proc Natl Acad Sci U S A 1987; 84 (21): 7408–12PubMedCrossRefGoogle Scholar
  40. 40.
    Ostrove JM, Leonard J, Week KE, et al. Activation of the human immunodeficiency virus by herpes simplex virus type 1. J Virol 1987; 61 (12): 3726–32PubMedGoogle Scholar
  41. 41.
    Popik W, Pitha PM. Inhibition by interferon of herpes simplex viras type 1-activated transcription of tat-defective proviras. Proc Natl Acad Sci U S A 1991; 88 (21): 9573–7PubMedCrossRefGoogle Scholar
  42. 42.
    Popik W, Pitha PM. Role of tumor necrosis factor alpha in activation and replication of the tat-defective human immunodeficiency viras type 1. J Virol 1993; 67 (2): 1094–9PubMedGoogle Scholar
  43. 43.
    Diaz JJ, Dodon MD, Schaerer-Uthurralt N, et al. Post-transcriptional transactivation of human retroviral envelope glycoprotein expression by herpes simplex virus Us11 protein. Nature 1996; 379 (6562): 273–7PubMedCrossRefGoogle Scholar
  44. 44.
    Mosca JD, Pitha PM, Hayward GS. Herpes simplex virus infection selectively stimulates accumulation of beta interferon reporter gene mRNA by a posttranscriptional mechanism. J Virol 1992; 66 (6): 3811–22PubMedGoogle Scholar
  45. 45.
    Palu G, Benetti L, Calistri A. Molecular basis of the interactions between herpes simplex viruses and HIV-1. Herpes 2001; 8 (2): 50–5PubMedGoogle Scholar
  46. 46.
    Moriuchi M, Moriuchi H, Williams R, et al. Herpes simplex viras infection induces replication of human immunodeficiency viras type 1. Virology 2000; 278 (2): 534–40PubMedCrossRefGoogle Scholar
  47. 47.
    Mogensen TH, Melchjorsen J, Malmgaard L, et al. Suppression of proinflammatory cytokine expression by herpes simplex viras type 1. J Virol 2004; 78 (11): 5883–90PubMedCrossRefGoogle Scholar
  48. 48.
    Singh R, Kumar A, Creery WD, et al. Dysregulated expression of IFN-g and IL-10 and impaired IFN-g mediated responses at different disease stages in patients with genital herpes simplex viras-2 infection. Clin Exp Immunol 2003; 133: 97–107PubMedCrossRefGoogle Scholar
  49. 49.
    Rebbapragada A, Petegell C, Sunderji S, et al. HSV2 and HIV interaction: negative synergy in the female genital tract. Keystone Symposia: HIV Pathogenesis; 2006 Mar 27–Apr 2; Keystone (CO), 117Google Scholar
  50. 50.
    Bryson Y, Dillon M, Bernstein DI, et al. Risk of acquisition of genital herpes simplex viras type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis 1993; 167 (4): 942–6PubMedCrossRefGoogle Scholar
  51. 51.
    Corey L, Holmes KK. Genital herpes simplex virus infections: current concepts in diagnosis, therapy, and prevention. Ann Intern Med 1983; 98 (6): 973–83PubMedGoogle Scholar
  52. 52.
    McFarland W, Gwanzura L, Bassett MT, et al. Prevalence and incidence of herpes simplex virus type 2 infection among male Zimbabwean factory workers. J Infect Dis 1999; 180 (5): 1459–65PubMedCrossRefGoogle Scholar
  53. 53.
    Augenbraun M, Feldman J, Chirgwin K, et al. Increased genital shedding of herpes simplex virus type 2 in HIV-seropositive women. Ann Intern Med 1995; 123 (11): 845–7PubMedGoogle Scholar
  54. 54.
    Krone MR, Tabet SR, Paradise M, et al. Herpes simplex viras shedding among human immunodeficiency virus-negative men who have sex with men: site and frequency of shedding. J Infect Dis 1998; 178 (4): 978–82PubMedCrossRefGoogle Scholar
  55. 55.
    Corey L, Adams HG, Brown ZA, et al. Genital herpes simplex viras infections: clinical manifestations, course, and complications. Ann Intern Med 1983; 98 (6): 958–72PubMedGoogle Scholar
  56. 56.
    Koutsky LA, Ashley RL, Holmes KK, et al. The frequency of unrecognized type 2 herpes simplex virus infection among women. Implications for the control of genital herpes. Sex Transm Dis 1990; 17 (2): 90–4Google Scholar
  57. 57.
    Koutsky LA, Stevens CE, Holmes KK, et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med 1992; 326 (23): 1533–9PubMedCrossRefGoogle Scholar
  58. 58.
    Bagdades EK, Pillay D, Squire SB, et al. Relationship between herpes simplex virus ulceration and CD4+ cell counts in patients with HIV infection. AIDS 1992; 6 (11): 1317–20PubMedCrossRefGoogle Scholar
  59. 59.
    Gresenguet G, Weiss HA, Frost E, et al. Aetiology of genital ulcer disease among women in Ghana and Central African Republic: randomised trial of episodic acyclovir treatment in addition to syndromic management (ANSR 1212 Study) [abstract no. M0-605]. 16th meeting of the International Society for Sexually Transmitted Diseases Research; 2005 Jul 10–13; AmsterdamGoogle Scholar
  60. 60.
    Strick L, Wald A, Celum C. Management of herpes simplex viras type 2 infection in HIV type-1 infected persons. Clin Infect Dis 2006 Aug 1; 43 (3): 347–56PubMedCrossRefGoogle Scholar
  61. 61.
    Herget GW, Riede UN, Schmitt-Graff A, et al. Generalized herpes simplex virus infection in an immunocompromised patient: report and review of the literature. Pathol Res Pract 2005; 201 (2): 123–9PubMedCrossRefGoogle Scholar
  62. 62.
    Quinnan Jr GV, Masur H, Rook AH, et al. Herpesvirus infections in the acquired immune deficiency syndrome. JAMA 1984; 252 (1): 72–7PubMedCrossRefGoogle Scholar
  63. 63.
    Stewart JA, Reef SE, Pellett PE, et al. Herpesvirus infections in persons infected with human immunodeficiency virus. Clin Infect Dis 1995; 21 Suppl. 1: S114–20PubMedCrossRefGoogle Scholar
  64. 64.
    Bernard E, Michiels JF, Saint-Paul MC, et al. Herpetic hepatitis in an AIDS patient. Presse Med 1994; 23 (3): 140PubMedGoogle Scholar
  65. 65.
    Calore EE. Herpes simplex type 2 pneumonia. Braz J Infect Dis 2002; 6 (6): 305–8PubMedCrossRefGoogle Scholar
  66. 66.
    Gariano RF, Berreen JP, Cooney EL. Progressive outer retinal necrosis and acute retinal necrosis in fellow eyes of a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 2001; 132 (3): 421–3PubMedCrossRefGoogle Scholar
  67. 67.
    Gateley A, Gander RM, Johnson PC, et al. Herpes simplex viras type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis 1990; 161 (4): 711–5PubMedCrossRefGoogle Scholar
  68. 68.
    Grover D, Newsholme W, Brink N, et al. Herpes simplex viras infection of the central nervous system in human immunodeficiency virus-type 1-infected patients. Int J STD AIDS 2004; 15 (9): 597–600PubMedCrossRefGoogle Scholar
  69. 69.
    Marks GL, Nolan PE, Erlich KS, et al. Mucocutaneous dissemination of acyclovir-resistant herpes simplex virus in a patient with AIDS. Rev Infect Dis 1989; 11 (3): 474–6PubMedCrossRefGoogle Scholar
  70. 70.
    Sacks SL, Wanklin RJ, Reece DE, et al. Progressive esophagitis from acyclovir-resistant herpes simplex: clinical roles for DNA polymerase mutants and viral heterogeneity? Ann Intern Med 1989; 111 (11): 893–9PubMedGoogle Scholar
  71. 71.
    Umar SH, Kanth A. Disseminated cutaneous herpes simplex virus type-1 with interstitial pneumonia as a first presentation of AIDS. J Natl Med Assoc 1999; 91 (8): 471–4PubMedGoogle Scholar
  72. 72.
    Yang CM, Wang WW, Lin CP. Progressive outer retinal necrosis syndrome as an early manifestation of human immunodeficiency viras infection. J Formos Med Assoc 1999; 98 (2): 141–4PubMedGoogle Scholar
  73. 73.
    Lafferty W, Coombs R, Benedetti J, et al. Recurrences after oral and genital herpes simplex viras infection: influence of anatomic site and viral type. N Engl J Med 1987; 316: 1444–9PubMedCrossRefGoogle Scholar
  74. 74.
    Ramaswamy M, McDonald C, Smith M, et al. Diagnosis of genital herpes by real time PCR in routine clinical practice. Sex Transm Infect 2004; 80 (5): 406–10PubMedCrossRefGoogle Scholar
  75. 75.
    Strick LB, Wald A. Newer diagnostics for HSV: is HSV culture still the gold standard? Mol Diag Ther 2006; 10 (1): 17–28CrossRefGoogle Scholar
  76. 76.
    Wald A, Huang ML, Carrell D, et al. 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 (9): 1345–51PubMedCrossRefGoogle Scholar
  77. 77.
    Corey L. Challenges in genital herpes simplex virus management. J Infect Dis 2002; 186 Suppl. 1: S29–33PubMedCrossRefGoogle Scholar
  78. 78.
    Ashley R. Type-specific antibodies to HSV-1 and -2: review of methodology. Herpes 1998; 5: 33–8Google Scholar
  79. 79.
    Liljeqvest J, Trybala E, Svennerholm B, et al. Localization of type-specific epitopes of herpes simplex virus type 2 glycoprotein G recognized by human and mouse antibodies. J Gen Virol 1998; 79: 1215–24Google Scholar
  80. 80.
    Marsden H, MacAulay K, Murray J, et al. Identification of an immunodominant sequential epitope in glycoprotein G of herpes simplex virus type 2 that is useful for serotype-specific diagnosis. J Med Virol 1998; 56: 79–84PubMedCrossRefGoogle Scholar
  81. 81.
    Turnback P, Liljeqvest J, Lowhagen G, et al. Glycoprotein G of herpes simplex type 1: identification of type-specific epitopes by human antibodies. J Gen Virol 2000; 81: 1033–40Google Scholar
  82. 82.
    Arvin A, Prober C. Herpes simples viruses. In: Murray P, Baron E, Pfaller M, et al., editors. Manual of clinical microbiology. 6th ed. Washington, DC: ASM, 1995: 876–83Google Scholar
  83. 83.
    Ashley R. Performance and use of HSV type-specific serology test kits. Herpes 2002; 9 (2): 38–45PubMedGoogle Scholar
  84. 84.
    Morrow R, Friedrich D. Inaccuracy of certain commercial enzyme immunoassays in diagnosing genital infections with herpes simplex virus types 1 and 2. Am J Clin Pathol 2003; 120 (6): 839–44PubMedCrossRefGoogle Scholar
  85. 85.
    Ashley R, Pickering N, Wei S, et al. Early diagnosis of first episode genital herpes simplex virus (HSV) infection by enzyme immunoassay (EIA) for type-specific IgM antibodies [abstract no. C-392]. 98th Annual Meeting of the American Society for Microbiology; 1998 MAy 17–21; Washington, DC: 196Google Scholar
  86. 86.
    Leach C, Ashley R, Baillargeon J, et al. Performance of two commercial glycoprotein g-based enzyme immunoassays for detecting antibodies to herpes simplex virus 1 and 2 in children and young adolescents. Clin Diagn Lab Immunol 2002; 9 (5): 1124–5PubMedGoogle Scholar
  87. 87.
    Strick L, Wald A. Type-specific testing for herpes simplex virus. Expert Rev Mol Diagn 2004; 4 (4): 443–53PubMedCrossRefGoogle Scholar
  88. 88.
    Lafferty WE, Downey L, Celum C, et al. Herpes simplex virus type 1 as a cause of genital herpes: impact on surveillance and prevention. J Infect Dis 2000; 181 (4): 1454–7PubMedCrossRefGoogle Scholar
  89. 89.
    Coyle PV, O’Neill HJ, Wyatt DE, et al. Emergence of herpes simplex type 1 as the main cause of recurrent genital ulcerative disease in women in Northern Ireland. J Clin Virol 2003; 27 (1): 22–9PubMedCrossRefGoogle Scholar
  90. 90.
    Samra Z, Scherf E, Dan M. Herpes simplex virus type 1 is the prevailing cause of genital herpes in the Tel Aviv area, Israel. Sex Transm Dis 2003; 30 (10): 794–6PubMedCrossRefGoogle Scholar
  91. 91.
    Tran T, Druce JD, Catton MC, et al. Changing epidemiology of genital herpes simplex virus infection in Melbourne, Australia, between 1980 and 2003. Sex Transm Infect 2004; 80 (4): 277–9PubMedCrossRefGoogle Scholar
  92. 92.
    Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first-episode infection. Ann Intern Med 1994; 121 (11): 847–54PubMedGoogle Scholar
  93. 93.
    Kim HN, Meier A, Huang M. Oral herpes simplex type 1 (HSV-1) reactivation in HIV-negative and HIV-positive men. J Infect Dis 2006. In pressGoogle Scholar
  94. 94.
    Kimberlin DW, Coen DM, Biron KK, et al. Molecular mechanisms of antiviral resistance. Antiviral Res 1995; 26 (4): 369–401PubMedCrossRefGoogle Scholar
  95. 95.
    Crumpacker CS, Schnipper LE, Zaia JA, et al. Growth inhibition by acycloguanosine of herpesviruses isolated from human infections. Antimicrob Agents Chemother 1979; 15 (5): 642–5PubMedCrossRefGoogle Scholar
  96. 96.
    Schacker T, Hu HL, Koelle DM, et al. Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons: a double-blind, placebo-controlled trial. Ann Intern Med 1998; 128 (1): 21–8PubMedGoogle Scholar
  97. 97.
    Conant MA, Schacker TW, Murphy RL, et al. Valaciclovir versus aciclovir for herpes simplex virus infection in HIV-infected individuals: two randomized trials. Int J STD AIDS 2002; 13 (1): 12–21PubMedCrossRefGoogle Scholar
  98. 98.
    Romanowski B, Aoki FY, Martel AY, et al. Efficacy and safety of famciclovir for treating mucocutaneous herpes simplex infection in HIV-infected individuals. Collaborative Famciclovir HIV Study Group. Aids 2000; 14 (9): 1211–7Google Scholar
  99. 99.
    DeJesus E, Wald A, Warren T, et al. Valacyclovir for the suppression of recurrent genital herpes in human immunodeficiency virus-infected subjects. J Infect Dis 2003; 188 (7): 1009–16PubMedCrossRefGoogle Scholar
  100. 100.
    Nagot N, Ouedraogo A, Mayaud P, et al. Effect of HSV-2 suppressive therapy on HIV-1 genital shedding and plasma viral load: a proof of concept randomized double-blind placebo controlled trial (ANRS 1285 Trial) [abstract no. 33LB]. 13th Conference on Retroviruses and Opportunistic Infections; 2006 Feb 5–8; Denver (CO)Google Scholar
  101. 101.
    Ouedraogo A, Nagot N, Vergne L, et al. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomised controlled trial. AIDS 2006 Nov 28; 20 (18): 2305–13PubMedCrossRefGoogle Scholar
  102. 102.
    de Miranda P, Blum MR. Pharmacokinetics of acyclovir after intravenous and oral administration. J Antimicrob Chemother 1983; 12 Suppl. B: 29–37PubMedCrossRefGoogle Scholar
  103. 103.
    Purifoy DJ, Beauchamp LM, de Miranda P, et al. Review of research leading to new anti-herpesvirus agents in clinical development: valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specific agent for varicella zoster virus. J Med Virol 1993; Suppl. 1: 139–45PubMedCrossRefGoogle Scholar
  104. 104.
    Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2006. Centers for Disease Control and Prevention. MMWR Recomm Rep 2006 Aug 4; 55 (RR-11): 1–94Google Scholar
  105. 105.
    Kaplowitz LG, Baker D, Gelb L, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recurring genital herpes simplex virus infection. The Acyclovir Study Group. JAMA 1991; 265 (6): 747–51Google Scholar
  106. 106.
    Keeney RE, Kirk LE, Bridgen D. Acyclovir tolerance in humans. Am J Med 1982; 73 (1A): 176–81PubMedCrossRefGoogle Scholar
  107. 107.
    Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol 1993; Suppl. 1: 67–73PubMedCrossRefGoogle Scholar
  108. 108.
    Tucker Jr WE. Preclinical toxicology profile of acyclovir: an overview. Am J Med 1982; 73 (1A): 27–30PubMedCrossRefGoogle Scholar
  109. 109.
    Andrews EB, Yankaskas BC, Cordera JF, et al. Acyclovir in pregnancy registry: six years’ experience. The Acyclovir in Pregnancy Registry Advisory Committee. Obstet Gynecol 1992; 79 (1): 7–13Google Scholar
  110. 110.
    Brown ZA, Baker DA. Acyclovir therapy during pregnancy. Obstet Gynecol 1989; 73 (3 Pt 2): 526–31PubMedGoogle Scholar
  111. 111.
    Horowitz GM, Hankins GD. Early-second-trimester use of acyclovir in treating herpes zoster in a bone marrow transplant patient: a case report. J Reprod Med 1992; 37 (3): 280–2PubMedGoogle Scholar
  112. 112.
    Spangler JG, Kirk JK, Knudson MP. Uses and safety of acyclovir in pregnancy. J Fam Pract 1994; 38 (2): 186–91PubMedGoogle Scholar
  113. 113.
    Reiff-Eldridge R, Heffner CR, Ephross SA, et al. Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment. Am J Obstet Gynecol 2000; 182 (1 Pt 1): 159–63PubMedCrossRefGoogle Scholar
  114. 114.
    Stone KM, Reiff-Eldridge R, White AD, et al. Pregnancy outcomes following systemic prenatal acyclovir exposure: conclusions from the international acyclovir pregnancy registry, 1984–1999. Birth Defects Res A Clin Mol Teratol 2004; 70 (4): 201–7PubMedCrossRefGoogle Scholar
  115. 115.
    ACOG. ACOG practice bulletin: management of herpes in pregnancy. Number 8 October 1999. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 2000; 68 (2): 165–73Google Scholar
  116. 116.
    Kleymann G. Agents and strategies in development for improved management of herpes simplex virus infection and disease. Expert Opin Investig Drugs 2005; 14 (2): 135–61PubMedCrossRefGoogle Scholar
  117. 117.
    Bianchetti MG, Roduit C, Oetliker OH. Acyclovir-induced renal failure: course and risk factors. Pediatr Nephrol 1991; 5 (2): 238–9PubMedCrossRefGoogle Scholar
  118. 118.
    Peterslund NA, Larsen ML, Mygind H. Acyclovir crystalluria. Scand J Infect Dis 1988; 20 (2): 225–8PubMedCrossRefGoogle Scholar
  119. 119.
    Sawyer MH, Webb DE, Balow JE, et al. Acyclovir-induced renal failure: clinical course and histology. Am J Med 1988; 84 (6): 1067–71PubMedCrossRefGoogle Scholar
  120. 120.
    Almond MK, Fan S, Dhillon S, et al. Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis. Nephron 1995; 69 (4): 428–32PubMedCrossRefGoogle Scholar
  121. 121.
    Blum MR, Liao SH, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med 1982; 73 (1A): 186–92PubMedCrossRefGoogle Scholar
  122. 122.
    Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004; 350 (1): 11–20PubMedCrossRefGoogle Scholar
  123. 123.
    de Miranda P, Burnette TC. Metabolic fate and pharmacokinetics of the acyclovir prodrug valaciclovir in cynomolgus monkeys. Drug Metab Dispos 1994; 22 (1): 55–9PubMedGoogle Scholar
  124. 124.
    Reitano M, Tyring S, Lang W, et al. Valaciclovir for the suppression of recurrent genital herpes simplex virus infection: a large-scale dose range-finding study. International Valaciclovir HSV Study Group. J Infect Dis 1998; 178 (3): 603–10Google Scholar
  125. 125.
    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: S40–6PubMedCrossRefGoogle Scholar
  126. 126.
    Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore) 1997; 76 (5): 369–80CrossRefGoogle Scholar
  127. 127.
    Pue MA, Pratt SK, Fairless AJ, et al. Linear pharmacokinetics of penciclovir following administration of single oral doses of famciclovir 125, 250, 500 and 750mg to healthy volunteers. J Antimicrob Chemother 1994; 33 (1): 119–27PubMedCrossRefGoogle Scholar
  128. 128.
    Kucers A, Crowe SM, Grayson ML, et al. The use of antibiotics. 5th ed. Oxford: Butterworth-Heinemann, 1997: 1548Google Scholar
  129. 129.
    Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in patients with herpes zoster and genital herpes. Antimicrob Agents Chemother 1994; 38 (10): 2454–7PubMedCrossRefGoogle Scholar
  130. 130.
    Gill KS, Wood MJ. The clinical pharmacokinetics of famciclovir. Clin Pharmacokinet 1996; 31 (1): 1–8PubMedCrossRefGoogle Scholar
  131. 131.
    Boyd M. Update on famciclovir. In: Mills J, Corey L, editors. Antiviral chemotherapy: new directions for clinical application and research. Upper Saddle River (NJ): Prentice Hall, 1993: 83Google Scholar
  132. 132.
    Earnshaw DL, Bacon TH, Darlison SJ, et al. Mode of antiviral action of penciclovir in MRC-5 cells infected with herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. Antimicrob Agents Chemother 1992; 36 (12): 2747–57PubMedCrossRefGoogle Scholar
  133. 133.
    Kucers A, Crowe SM, Grayson ML, et al. The use of antibiotics. 5th ed. Oxford: Butterworth-Heinemann, 1997: 1631Google Scholar
  134. 134.
    Helgstrand E, Eriksson B, Johansson NG, et al. Trisodium phosphonoformate, a new antiviral compound. Science 1978; 201 (4358): 819–21PubMedCrossRefGoogle Scholar
  135. 135.
    Stridh S, Helgstrand E, Lannero B, et al. The effect of pyrophosphate analogues on influenza virus RNA polymerase and influenza virus multiplication. Arch Virol 1979; 61 (3): 245–50PubMedCrossRefGoogle Scholar
  136. 136.
    Wagstaff AJ, Bryson HM. Foscarnet: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 1994; 48 (2): 199–226PubMedCrossRefGoogle Scholar
  137. 137.
    Wagstaff AJ, Faulds D, Goa KL. Aciclovir: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994; 47 (1): 153–205PubMedCrossRefGoogle Scholar
  138. 138.
    Deray G, Martinez F, Katlama C, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol 1989; 9 (4): 316–21PubMedCrossRefGoogle Scholar
  139. 139.
    Nyberg G, Svalander C, Blohme I, et al. Tubulointerstitial nephritis caused by the antiviral agent foscarnet. Transpl Int 1989; 2 (4): 223–7PubMedCrossRefGoogle Scholar
  140. 140.
    Javaly K, Wohlfeiler M, Kalayjian R, et al. Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study. J Acquir Immune Defic Syndr 1999; 21 (4): 301–6PubMedCrossRefGoogle Scholar
  141. 141.
    Lea AP, Bryson HM. Cidofovir. Drugs 1996; 52 (2): 225–30, discussion 231PubMedCrossRefGoogle Scholar
  142. 142.
    Cundy KC, Petty BG, Flaherty J, et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1995; 39 (6): 1247–52PubMedCrossRefGoogle Scholar
  143. 143.
    Lalezari JP, Drew WL, Glutzer E, et al. (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis 1995; 171 (4): 788–96PubMedCrossRefGoogle Scholar
  144. 144.
    Perazella MA. Drug-induced renal failure: update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci 2003; 325 (6): 349–62PubMedCrossRefGoogle Scholar
  145. 145.
    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 (4): 892–8PubMedCrossRefGoogle Scholar
  146. 146.
    Kessler HA, Hurwitz S, Farthing C, et al. Pilot study of topical trifluridine for the treatment of acyclovir-resistant mucocutaneous herpes simplex disease in patients with AIDS (ACTG 172). AIDS Clinical Trials Group. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 12 (2): 147–52CrossRefGoogle Scholar
  147. 147.
    Murphy M, Morley A, Eglin RP, et al. Topical trifluridine for mucocutaneous acyclovir-resistant herpes simplex II in AIDS patient. Lancet 1992; 340 (8826): 1040PubMedCrossRefGoogle Scholar
  148. 148.
    Bryson YJ, Dillon M, Lovett M, et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir: a randomized double-blind controlled trial in normal subjects. N Engl J Med 1983; 308 (16): 916–21PubMedCrossRefGoogle Scholar
  149. 149.
    Mertz GJ, Critchlow CW, Benedetti J, et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA 1984; 252 (9): 1147–51PubMedCrossRefGoogle Scholar
  150. 150.
    Wald A, Carrell D, Remington M, et al. Two-day regimen of acyclovir for treatment of recurrent genital herpes simplex virus type 2 infection. Clin Infect Dis 2002; 34 (7): 944–8PubMedCrossRefGoogle Scholar
  151. 151.
    Corey L, Benedetti J, Critchlow C, et al. Treatment of primary first-episode genital herpes simplex virus infections with acyclovir: results of topical, intravenous and oral therapy. J Antimicrob Chemother 1983; 12 Suppl. B: 79–88PubMedCrossRefGoogle Scholar
  152. 152.
    Bodsworth NJ, Crooks RJ, Borelli S, et al. Valaciclovir versus aciclovir in patient initiated treatment of recurrent genital herpes: a randomised, double blind clinical trial. International Valaciclovir HSV Study Group. Genitourin Med 1997; 73 (2): 110–6Google Scholar
  153. 153.
    Chosidow O, Drouault Y, Leconte-Veyriac F, et al. Famciclovir vs. aciclovir in immunocompetent patients with recurrent genital herpes infections: a parallel-groups, randomized, double-blind clinical trial. Br J Dermatol 2001; 144 (4): 818–24Google Scholar
  154. 154.
    Sacks SL, Aoki FY, Diaz-Mitoma F, et al. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes: a randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA 1996; 276 (1): 44–9Google Scholar
  155. 155.
    Saiag P, Praindhui D, Chastang C. A double-blind, randomized study assessing the equivalence of valacyclovir 1000mg once daily versus 500mg twice daily in the episodic treatment of recurrent genital herpes. Genival Study Group. J Antimicrob Chemother 1999; 44 (4): 525–31CrossRefGoogle Scholar
  156. 156.
    Spruance SL, Tyring SK, DeGregorio B, et al. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med 1996; 156 (15): 1729–35Google Scholar
  157. 157.
    Strand A, Patel R, Wulf HC, et al. Aborted genital herpes simplex virus lesions: findings from a randomised controlled trial with valaciclovir. Sex Transm Infect 2002; 78 (6): 435–9PubMedCrossRefGoogle Scholar
  158. 158.
    Tyring SK, Douglas Jr JM, Corey L, et al. A randomized, placebo-controlled comparison of oral valacyclovir and acyclovir in immunocompetent patients with recurrent genital herpes infections. The Valaciclovir International Study Group. Arch Dermatol 1998; 134 (2): 185–91Google Scholar
  159. 159.
    Aoki FY, Tyring S, Diaz-Mitoma F, et al. Single-day, patient-initiated famciclovir therapy for recurrent genital herpes: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2006; 42 (1): 8–13PubMedCrossRefGoogle Scholar
  160. 160.
    Goldberg LH, Kaufman R, Kurtz TO, et al. Long-term suppression of recurrent genital herpes with acyclovir: a 5-year benchmark. Acyclovir Study Group. Arch Dermatol 1993; 129 (5): 582–7CrossRefGoogle Scholar
  161. 161.
    Douglas JM, Critchlow C, Benedetti J, et al. A double-blind study of oral acyclovir for suppression of recurrences of genital herpes simplex virus infection. N Engl J Med 1984; 310 (24): 1551–6PubMedCrossRefGoogle Scholar
  162. 162.
    Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002; 51 (RR-6): 1–78Google Scholar
  163. 163.
    Mindel A, Faherty A, Carney O, et al. Dosage and safety of long-term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1988; 1 (8591): 926–8PubMedCrossRefGoogle Scholar
  164. 164.
    Ioannidis JP, Collier AC, Cooper DA, et al. Clinical efficacy of high-dose acyclovir in patients with human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis 1998; 178 (2): 349–59PubMedCrossRefGoogle Scholar
  165. 165. Identifier NCT00076232: a phase III, randomized, double-blind, placebo-controlled trial of acyclovir for the reduction of HIV acquisition among high-risk HSV-2 seropositive, HIV seronegative individuals [online]. Available from URL: [Accessed 2006 Dec 12]
  166. 166. Identifier NCT00194519: phase III randomized placebo-controlled trial of HSV-2 suppression to prevent HIV transmission among HIV-discordant couples [online]. Available from URL: [Accessed 2006 Dec 12]
  167. 167.
    Field HJ. Persistent herpes simplex virus infection and mechanisms of virus drug resistance. Eur J Clin Microbiol Infect Dis 1989; 8 (8): 671–80PubMedCrossRefGoogle Scholar
  168. 168.
    Fife KH, Crumpacker CS, Mertz GJ, et al. Recurrence and resistance patterns of herpes simplex virus following cessation of > or = 6 years of chronic suppression with acyclovir. Acyclovir Study Group. J Infect Dis 1994; 169 (6): 1338–41CrossRefGoogle Scholar
  169. 169.
    Bacon TH, Boon RJ, Schultz M, et al. Surveillance for antiviral-agent-resistant herpes simplex virus in the general population with recurrent herpes labialis. Antimicrob Agents Chemother 2002; 46 (9): 3042–4PubMedCrossRefGoogle Scholar
  170. 170.
    Sande MA, Armstrong D, Corey L, et al. Perspectives on switching oral acyclovir from prescription to over-the-counter status: report of a consensus panel. Clin Infect Dis 1998; 26 (3): 659–63PubMedCrossRefGoogle Scholar
  171. 171.
    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 (1): 242–9PubMedCrossRefGoogle Scholar
  172. 172.
    Boon RJ, Bacon TH, Robey HL, et al. Antiviral susceptibilities of herpes simplex virus from immunocompetent subjects with recurrent herpes labialis: a UK-based survey. J Antimicrob Chemother 2000; 46 (6): 1051PubMedCrossRefGoogle Scholar
  173. 173.
    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 (4): 868–72PubMedGoogle Scholar
  174. 174.
    Nugier F, Colin JN, Aymard M, et al. Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey. J Med Virol 1992; 36 (1): 1–12PubMedCrossRefGoogle Scholar
  175. 175.
    Englund JA, Zimmerman ME, Swierkosz EM, et al. Herpes simplex virus resistant to acyclovir: a study in a tertiary care center. Ann Intern Med 1990; 112 (6): 416–22PubMedGoogle Scholar
  176. 176.
    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 (6): 1246–50PubMedCrossRefGoogle Scholar
  177. 177.
    Keller MJ, Tuyama A, Carlucci MJ, et al. Topical microbicides for the prevention of genital herpes infection. J Antimicrob Chemother 2005; 55 (4): 420–3PubMedCrossRefGoogle Scholar
  178. 178.
    Koelle DM, Corey L. Recent progress in herpes simplex virus immunobiology and vaccine research. Clin Microbiol Rev 2003; 16 (1): 96–113PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Departments of Medicine and PediatricsUniversity of WashingtonSeattleUSA
  2. 2.Departments of Medicine and EpidemiologyUniversity of WashingtonSeattleUSA

Personalised recommendations