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.
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