Several studies have evaluated the influence of HSV reactivation on plasma HIV-1 RNA. 66 Some have shown a rise in plasma HIV-1 RNA in association with genital lesions, whereas others have not. 67,68 Some studies used genital lesions as a marker of HSV reactivation, which, as discussed here, underestimates the frequency in which mucosal HSV infection occurs by approximately 2-fold and ignores the observation that subclinical HSV-2 reactivation influences mucosal HIV-1 replication. Two recent studies that evaluate subclinical HSV shedding suggest that HSV-2 significantly influences the replication of HIV-1. Gray et al. 67 have shown that in newly infected HIV-1–seropositive men and women in Rakai, HSV-2/HIV-1–coininfected persons have HIV-1 RNA titers that are a half log higher than HSV-2–seronegative HIV-1–seropositive persons. Schacker et al. 68 directly studied the influence of HSV infection on HIV-1 replication in vivo by administering chronic daily therapy with acyclovir to HIV/HSV-2–coinfected persons and measuring plasma HIV-1 RNA levels before and after administration of acyclovir. Acyclovir reduced plasma RNA levels by an average of one-third of a log; a reduction in plasma HIV RNA levels was observed in 11 of 12 persons, and HIV-1 RNA levels returned to previous baseline upon discontinuation of therapy. These studies may provide some explanation of the older studies with zidovudine monotherapy that showed increased survival with concomitant acyclovir use. 69 Whether the addition of daily antiviral therapy for HSV-2 infection would enhance the durability of HIV suppression on HAART therapy is unknown.
Nucleoside analogues for the treatment of HSV have been available for >2 decades. 70 All 3 licensed compounds—acyclovir, famciclovir, valacyclovir—have been shown to be effective for episodic, and, more importantly, chronic daily therapy for HSV-2 infection in HIV-positive men and women. 71–75 The data from these studies are summarized in Table 5 and illustrate the safety and efficacy of all 3 medications for reducing clinical and subclinical reactivation of HSV infection in HIV-infected men and women. Thrombotic microangiopathy was observed in early studies of valacyclovir in doses of 8 g per day for prevention of cytomegalovirus disease in HIV-1–infected patients but has not been observed among patients with HIV-1 treated with lower doses of valacyclovir appropriate for HSV infections (e.g., 1–1.5 g/d). 76 Oral antiviral medications for HSV lack significant drug interactions with antiretroviral therapies.
Decreased susceptibility of HSV isolates to acyclovir was initially described in immunocompromised patients, and acyclovir-resistant HSV became an important management issue early in the HIV-1 epidemic. 77 Three mechanisms of HSV resistance to acyclovir have been described. 78,79 By far, the most common is deficiency of thymidine kinase, which renders acyclovir ineffective as the drug requires viral thymidine kinase for initial phosphorylation. 80 Other, less commonly found mutants, include strains with altered thymidine kinase and DNA polymerase mutations. 81,82 Strains resistant to acyclovir are almost always resistant to penciclovir (the active form of famciclovir). Isolates with in vitro resistance to acyclovir may be found in lesions that respond to therapy. 83–85 In general, poor clinical response to the nucleosides is associated with high-level resistance to acyclovir (>10 μg/mL). Treatment of acyclovir-resistant HSV is beyond the scope of this review; success has been achieved with foscarnet, topical trifluoridine, and topical cidofovir. 86,87 Little is known of antiviral resistance to HSV infections in the developing world and antiviral monitoring of acyclovir resistance among HIV-seropositive persons should be maintained, as nucleoside treatment of genital herpes continues to increase worldwide. 88,89 If increasing chronic suppressive use results in increasing rates of resistance, then recommendations will need to be refocused on select groups at greatest benefit and with the lowest risk of acyclovir-resistant herpes.
The frequency of acyclovir-resistant HSV infection in the United States and Western Europe appears to have stabilized and even decreased, perhaps coincident with the widespread use of HAART. A recent survey of HIV-positive persons attending STD clinics in the United States showed that 3–5% of HIV-infected persons harbored HSV-2 isolates with reduced (>2 μg/mL) susceptibility to acyclovir in vitro, which is only slightly higher than the 1% observed among HIV-negative persons recruited from the same sites 88; none of these persons displayed clinically evident, symptomatic acyclovir-resistant herpes. Anecdotal evidence suggests that frequency of acyclovir-resistant herpes declined with the introduction of HAART.
Despite the data on the clinical utility of these medications on HSV reactivation in HIV-positive populations, definitive guidelines on the use of the nucleoside analogues for HSV are not available. We recommend that genital herpes be treated to reduce the duration and severity of clinical reactivation anogenital herpes. Given the high HSV-2 seroprevalence among HIV-infected persons, treatment of HSV-2 could potentially have a substantial public health impact on HIV trans mission, which has led to intervention studies to determine what degree HSV-2 suppression reduces HIV transmission Similarly, no data are available to indicate whether anti-HSV therapy further prolongs survival among HAART-treated pa tients, as it did with zidovudine monotherapy. 90
What should clinicians do now pending these data? There are no definitive answers and resource allocations appear to drive current practice. We believe the weight of the data support more frequent use of type-specific serologies to identify HIV-infected persons with unrecognized genital herpes and daily anti-HSV therapy for HIV-infected persons. HIV-seropositive persons whose disease is poorly controlled on ART and who have frequent HSV reactivation should be considered for chronic suppressive therapy. In addition, HIV- and HSV-2–coinfected persons who are sexually active should be advised of the association between HSV-2 reactivation and mucosal HIV-1 shedding, and such persons should be considered for daily suppressive anti-HSV therapy.
Studies have indicated that >95% of HSV-2–seropositive persons reactivate HSV-2 on mucosal surfaces and hence provide support for the concept that serologic testing for HSV-2 infection identifies persons at risk for mucosal reactivation. 91 In the United States and Western Europe, 40–80% of HIV-infected persons are coinfected with HSV-2, and, as such, serologic screening for HSV-2 would identify persons at high risk of frequent mucosal HSV-2 reactivation and enhanced shedding of mucosal HIV-1. Type-specific serologic assays for antibodies to HSV-2 have been approved for clinical use by the US Food and Drug Administration and are licensed throughout Europe. These assays detect antibodies to the HSV-1 and HSV-2 glycoproteins gG1 and gG2 and have been used in a wide variety of settings involving HIV-seropositive men and women. Their utility in some areas of central Africa is still being debated, but they have had extensive use in serosurveys and clinical management in the United States and Europe. 91–93 In addition to these serologic assays, laboratory assays such as viral culture, or, preferably, HSV DNA PCR should be used to define the etiology of genital lesions in HIV-seropositive persons. 94,95 Clinical diagnosis of GUD in HIV-seropositive persons is often unreliable, and infection with multiple pathogens is common. 94 HSV DNA PCR is the assay with the greatest sensitivity for detecting HSV in genital lesions. Ballard et al. 23 have shown that the appropriate treatment of genital lesions due to HSV-2 results in reduced amount of HIV-1 shed in such lesions.
In North America and Europe, we believe that data are sufficient to urge routine serologic testing for HSV-2 among persons with HIV-1 infection. Identifying the 50–60% of HIV-infected persons who are HSV-2 seropositive provides important information about the high likelihood of intermittent perianal and genitourinary symptoms from HSV-2 reactivation and the potential that such reactivation may lead to increases in plasma HIV-1 RNA elevations. 68,96 Moreover, such persons should have anti-HSV medications included for the empiric treatment of genital ulcerations or to consider HSV as a likely co-infecting pathogen if other causes of GUD are suspected.
We believe that HSV-2 serologic assays are unlikely to be necessary to define prevalent HSV-2 infection in populations where such coinfection is nearly universal (e.g., commercial sex workers in Africa). Such persons should be considered to be coinfected and increased awareness of the high prevalence of HSV as a sole or copathogen of genital ulcers in such persons is important. More systematic surveys of the prevalence of HSV-2 in African, Caribbean, and Asian HIV-infected people should be performed.
New approaches to reducing the transmission of HSV-2 and HIV-1 are needed. The increasing number of HSV-2– and HIV-1–seropositive persons with CD4 T-cell counts of >350 cells/mm3 who are not on HAART is of concern regarding the influence HSV-2 will continue to play in promulgating the HIV-1 epidemic in North America and Europe. Although use of antivirals for episodic therapy would be less costly and easier to implement as an HIV-1 prevention strategy, episodic treatment is also likely to be less effective in preventing HIV-1 acquisition or transmission than daily suppressive therapy, given the high proportion of subclinical HSV-2 reactivation. Lastly, recent consideration by the World Health Organization to include antiviral therapy for the syndromic treatment of GUD will lead toward providing more appropriate therapy for genital ulcers in the developing world. The tight epidemiologic and clinical association between HSV-2 and HIV-1 also provide an impetus to speed development of a vaccine to prevent HSV-2 acquisition or reactivation. From both clinical and public health perspectives, there is a clear imperative to test different approaches to interrupting the synergistic link between herpes and HIV-1.
1. Wasserheit JN. Epidemiological synergy: interrelationships between human immunodeficiency virus infection and other sexually transmitted diseases. Sex Transm Dis
2. Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med
3. Rompalo AM, Shepherd M, Lawlor JP, et al. Definitions of genital ulcer disease and variation in risk for prevalent human immunodeficiency virus infection. Sex Transm Dis
4. Hook EW 3rd, Cannon RO, Nahmias AJ, et al. Herpes simplex virus infection as a risk factor for human immunodeficiency virus infection in heterosexuals. J Infect Dis
5. Austin H, Macaluso M, Nahmias A, et al. Correlates of herpes simplex virus seroprevalence among women attending a sexually transmitted disease clinic. Sex Transm Dis
6. Nahmias A, Lee F, Beckman-Nahmias S. Sero-epidemiological and sociological patterns of herpes simplex virus infection in the world. Scand J Infect Dis
7. Brown ZA, Selke SA, Zeh JE, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med
8. Sullender W, Yasukawa L, Schwartz M, et al. Type-specific antibodies to herpes simplex virus type 2 (HSV-2) glycoprotein G in pregnant women, infants exposed to maternal HSV-2 infection at delivery, and infants with neonatal herpes. J Infect Dis
9. Armstrong GL, Schillinger J, Markowitz L, et al. Incidence of herpes simplex virus type 2 infection in the United States. Am J Epidemiol
10. Siegel D, Golden E, Washington AE, et al. Prevalence and correlates of herpes simplex infections: the population-based AIDS in Multiethnic Neighborhoods Study. JAMA
11. Rosenthal SL, Stanberry LR, Biro FM, et al. Seroprevalence of herpes simplex virus types 1 and 2 and cytomegalovirus in adolescents. Clin Infect Dis
12. Oberle MW, Rosero-Bixby L, Lee FK, et al. Herpes simplex virus type 2 antibodies: high prevalence in monogamous women in Costa Rica. Am J Trop Med Hyg.
13. Carvalho M, de Carvalho S, Pannuti CS, et al. Prevalence of herpes simplex type 2 antibodies and a clinical history of herpes in three different populations in Campinas City, Brazil. Int J Infect Dis
14. Sanchez JL, Volquez C, Totten PA, et al. The etiology and management of genital ulcers in the Dominican Republic and Peru. Sex Transm Dis
15. Auvert B, Ballard R, Campbell C, et al. HIV infection among youth in a South African mining town is associated with herpes simplex virus-2 seropositivity and sexual behaviour. AIDS
16. Mbizvo MT, Mashu A, Chipato T, et al. Trends in HIV-1 and HIV-2 prevalence and risk factors in pregnant women in Harare, Zimbabwe. Cent Afr J Med.
17. Greenblatt RM, Lukehart SA, Plummer FA, et al. Genital ulceration as a risk factor for human immunodeficiency virus infection. AIDS
18. Mostad SB, Kreiss JK, Ryncarz AJ, et al. Cervical shedding of herpes simplex virus in human immunodeficiency virus-infected women: effects of hormonal contraception, pregnancy, and vitamin A deficiency. J Infect Dis
19. 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
20. Chen CY, Ballard RC, Beck-Sague CM, et al. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection [see comments]. Sex Transm Dis
21. Ahmed IIJ, 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.
22. Morse SA. Etiology of genital ulcer disease and its relationship to HIV infection. Sex Transm Dis
23. Ballard R, Htun Y, Dangor Y, et al. HIV and genital ulcer disease: determinants of HIV shedding from lesions and consequences of therapy. Paper presented at: International Society for Sexually Transmitted Disease Research; July 11–14, 1999;Denver, CO. Abstract #055.
24. Mbengeranwa O. Trends and management of STDs in Harare, Zimbabwe. WHO/UNAIDS/LSHTM Workshop on HSV-2: Programmatic and Research Priorities in Developing Countries; February 14–16, 2001; London.
25. Beyrer C, Jitwatcharanan K, Natpratan C, et al. Molecular methods for the diagnosis of genital ulcer disease in a sexually transmitted disease clinic population in northern Thailand: predominance of herpes simplex virus infection. J Infect Dis
26. Risbud A, Chan-Tack K, Gadkari D, et al. The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India. Sex Transm Dis
27. Morse SA, Trees DL, Htun Y, et al. Comparison of clinical diagnosis and standard laboratory and molecular methods for the diagnosis of genital ulcer disease in Lesotho: association with human immunodeficiency virus infection. J Infect Dis
28. Wald A, Corey L, Cone R, et al. Frequent genital HSV-2 shedding in immunocompetent women. J Clin Invest
29. Wald A, Link K. Risk of human immunodeficiency virus infection in herpes simplex virus type 2-seropositive persons: a meta-analysis. J Infect Dis
30. Buve A, Carael M, Hayes RJ, et al. Multicentre study on factors determining differences in rate of spread of HIV in sub-Saharan Africa: methods and prevalence of HIV infection. AIDS
. 2001;15(suppl 4):S5–14.
31. Weiss HA, Buve A, Robinson NJ, et al. The epidemiology of HSV-2 infection and its association with HIV infection in four urban African populations. AIDS
. 2001;15(suppl 4):S97–108.
32. del Mar Pujades Rodriguez M, Obasi A, Mosha F, et al. Herpes simplex virus type 2 infection increases HIV incidence: a prospective study in rural Tanzania. AIDS
33. Reynolds SJ, Risbud AR, Shepherd ME, et al. Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India. J Infect Dis
34. Sanchez JL, Whittington WLH, Zuckerman RA, et al. Bacterial STDs and HSV-2 acquisition among MSM HIV seroconverters in Peru. Paper presented at: Conf HIV Pathog Treatment; Buenos Aires, Argentina; February 4–8, 2001:187.
35. Renzi C, Douglas JM Jr, Foster M, et al. Herpes simplex virus type 2 infection as a risk factor for human immunodeficiency virus acquisition in men who have sex with men. J Infect Dis
36. Wald A, Zeh JE, Selke SA, et al. Virologic characteristics of subclinical and symptomatic genital herpes
infections. N Engl J Med
37. Benedetti JK, Zeh J, Corey L. Clinical reactivation of genital herpes
simplex virus infection decreases in frequency over time. Ann Intern Med
38. Wawer MJ, Sewankambo NK, Serwadda D, et al. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Rakai Project Study Group. Lancet
39. Grosskurth H, Gray RH, Hayes R, et al. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. Lancet
40. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med
41. 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
42. Korenromp EL, Bakker R, de Vlas SJ, et al. HIV dynamics and behaviour change as determinants of the impact of sexually transmitted disease treatment on HIV transmission in the context of the Rakai trial. AIDS
43. Baba TW, Trichel AM, An L, et al. Infection and AIDS in adult macaques after nontraumatic oral exposure to cell-free SIV. Science
44. Cunningham AL, Turner RR, Miller AC, et al. Evolution of recurrent herpes simplex lesions: an immunohistologic study. J Clin Invest
45. Koelle DM, Abbo H, Peck A, et al. Direct recovery of herpes simplex virus (HSV)-specific T lymphocyte clones from recurrent genital HSV-2 lesions. J Infect Dis
46. Mosca JD, Bednarik DP, Raj NB, et al. Herpes simplex virus type-1 can reactivate transcription of latent human immunodeficiency virus. Nature
47. Margolis DM, Rabson AB, Straus SE, et al. Transactivation of the HIV-1 LTR by HSV-1 immediate-early genes. Virology
48. Margolis D, Ostrove J, Straus S. HSV-1 activation of HIV-1 transcription is augmented by a cellular protein that binds near the initiator element. Virology.
49. 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
50. Kucera LS, Leake E, Iyer N, et al. Human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 2 (HSV-2) can coinfect and simultaneously replicate in the same human CD4+ cell: effect of coinfection on infectious HSV-2 and HIV-1 replication. AIDS Res Hum Retroviruses
51. Moriuchi M, Moriuchi H, Williams R, et al. Herpes simplex virus infection induces replication of human immunodeficiency virus type 1. Virology
52. Heng MC, Heng SY, Allen SG. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. Lancet
53. Schacker TW, Ryncarz AJ, Goddard J, et al. Frequent recovery of HIV-1 from genital herpes
simplex virus lesions in HIV-1–infected men. JAMA
54. Gadkari DA, Quinn TC, Gangakhedkar RR, et al. HIV-1 DNA shedding in genital ulcers and its associated risk factors in Pune, India. J Acquir Immune Defic Syndr Hum Retrovirol
55. Corey L, Wald A. Genital herpes
. In: Holmes K, Sparling P, PA M, et al., eds. Sexually Transmitted Diseases
ed. New York: McGraw-Hill; 1999.
56. Mbopi Keou FX, Gresenguet G, Mayaud P. et al. Genital herpes
simplex virus type 2 shedding is increased in HIV-infected women in Africa. Letter. AIDS
57. McClelland RS, Wang CC, Overbaugh J, et al. Association between cervical shedding of herpes simplex virus and HIV-1. AIDS
58. Gray RH, Mawer MJ, Brookmeyer R, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet
59. Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes
. N Engl J Med.
60. 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
61. Kamali A, Nunn AJ, Mulder DW, et al. Seroprevalence and incidence of genital ulcer infections in a rural Ugandan population. Sex Transm Infect
62. 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
63. Schacker TW, Zeh JE, Hu HL, et al. Frequency of symptomatic and asymptomatic herpes simplex virus type 2 reactivations among human immunodeficiency virus-infected men. J Infect Dis
64. Augenbraun M, Corey L, Reichelderfer P, et al. The effect of herpes simplex virus shedding on plasma HIV RNA levels in coinfected women. Clin Infect Dis.
65. Posavad CM, Wald A, Kuntz S, et al. No influence of HAART on local containment of HSV in HIV-infected individuals: containment of HSV correlates with HSV-specific CD8+ T cells. JAMA.
(In press, 2004).
66. Serwadda D, Gray RH, Scwankambo 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.
67. Gray R, Chen M, Serwadda D, et al. HIV acquisition associated with genital ulcer disease and herpes simplex virus type 2: a nested case control study in Rakai, Uganda. Paper presented at: International Conference on Sexually Transmitted Disease Research; Ottawa, Canada; 2003:178.
68. Schacker T, Zeh J, Hu H, et al. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis
69. Ioannidis JPA, 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
70. Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med
71. Sexually transmitted diseases treatment guidelines 2002. Centers for Disease Control and Prevention. MMWR Recomm Rep.
72. Schacker TW, 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
73. 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
74. 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
75. Schacker T, Wald A, DeJesus E, et al. Valacyclovir for the suppression of ano-genital herpes
simplex virus infection in HIV-infected persons. IDSA 2002, Chicago, IL.
76. Bell W, Chulay J, Feinberg J. Manifestations resembling thrombotic microangiopathy in patients with advanced HIV disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore)
77. Erlich K, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections
in patients with the acquired immunodeficiency syndrome. N Engl J Med.
78. Balfour H, Benson C, Braun J, et al. Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections. J Acquir Immune Defic Syndr
79. Barry DW, Lehrman SN, Ellis MN. Clinical and laboratory experience with acyclovir-resistant herpes viruses. J Antimicrob Chemother.
80. McLaren C, Chen MS, Ghazzouli I, et al. Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir. Antimicrob Agents Chemother
81. Kost RG, Hill EL, Tigges M, Straus SE. Recurrent acyclovir-resistant genital herpes
in an immunocompetent patient. NEJM
82. Sacks S, Wanklin R, Reece D, et al. Progressive esophagitis from acyclovir-resistant herpes simplex: clinical roles for DNA polymerase mutants and viral heterogeneity. Ann Intern Med
83. Reyes M, Suberdar NS, Graber JM, et al. Prevalence of acyclovir resistance among patients with genital herpes simplex virus infections
. Arch Intern Med
. In press.
84. 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.
85. 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
86. Safrin S, Assaykeen T, Follansbee S, et al. Foscarnet therapy for acyclovir-resistant mucocutaneous herpes simplex virus infection in 26 AIDS patients: preliminary data. J Infect Dis
87. 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
88. 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
89. Bacon TH, Levin MJ, Leary JJ, et al. Herpes simplex virus resistance to acyclovir and penciclovir after two decades of antiviral therapy. Clin Microbiol Rev
90. Ioannidis J, Collier A, Cooper D, et al. Clinical efficacy of high dose acyclovir in human immunodeficiency virus infection: a meta-analysis of randomized individual patient data. J Infect Dis
91. Gupta R, Wald A, Krantz E, et al. Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis
92. Ashley RL. Sorting out the new HSV type specific antibody tests. Sex Transm Infect
93. Hogrefe W, Su X, Song J, et al. Detection of herpes simplex virus type 2-specific immunoglobulin G antibodies in African sera by using recombinant gG2, Western blotting, and gG2 inhibition. J Clin Microbiol
94. DiCarlo RP, Martin DH. The clinical diagnosis of genital ulcer disease in men. Clin Infect Dis
95. 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
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