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Changes in Plasma Human Immunodeficiency Virus Type 1 RNA Associated with Herpes Simplex Virus Reactivation and Suppression
  abstract: In early trials of antiretroviral therapy, acyclovir was associated with increased survival by an unknown mechanism. The hypothesis that subclinical herpes simplex virus (HSV) reactivation was associated, in vivo, with increased plasma human immunodeficiency virus (HIV) RNA and suppression with a reduced plasma HIV RNA load was investigated. HSV cultures were performed daily on HSV-2positive/HIV-positive patients, and plasma HIV-1 RNA loads were measured at regular intervals. A subset of patients prior to, during, and after HSV suppression with high-dose acyclovir was measured to determine whether HSV suppression was associated with a decrease in HIV replication. Most (25/27 HSV-2positive/HIV-positive persons) reactivated HSV. Total HSV shedding rate was strongly correlated with plasma HIV-1 RNA load (R = 0.54; P = .004), and the plasma HIV-1 RNA level at a given CD4 cell count was 48% lower when treated with acyclovir. These data indicate that frequent mucosal HSV reactivation influences HIV replication in vivo and daily HSV suppression may be important in the management of HSV-positive/HIV-positive persons. The Journal of Infectious Diseases 2002;186:1718-1725. Schacker et al.
Our data indicate that HSV reactivation (including HSV-1 but predominantly HSV-2 in these patients) markedly influences HIV plasma viremia. Suppression of HSV with acyclovir was associated with a reduction in plasma HIV RNA. Because 40% of HSV shedding was subclinical and acyclovir was even more effective in reducing HSV shedding than in reducing lesions, our results suggest that subclinical as well as clinical HSV reactivation influences plasma HIV RNA. Of note, 10 Study 2 patients experienced subclinical shedding before and after the period when acyclovir was given, but only 3 showed shedding during suppression. The reduction in median plasma HIV-1 RNA load was >5000 copies/mL. Although our study was not designed to define the duration in which acyclovir could reduce plasma HIV-1 RNA levels, if one extrapolates the level of HIV-1 RNA suppression over time, it approaches those that are associated with a measurable survival benefit [42] and would account for the reduced hazard ratio for acyclovir seen in meta-analyses [21]. Our data thus provide some biological understanding beyond the clinical studies indicating a survival benefit on acyclovir among patients on monotherapy and double combination therapy [1721].
Daily acyclovir therapy has not been embraced by most HIV care providers and has not been recommended by the recent Centers for Disease Control and Prevention Guidelines [43], which do not even recommend serologic testing for HSV-2 among HIV positive persons. Our data indicate this inattention to HSV-2 reactivation should be reevaluated. Frequent HSV reactivation influences HIV-1 plasma RNA levels, and our data indicate this occurs with sufficient regularity to quantitatively affect plasma HIV-1 levels in vivo. One intriguing aspect of our data is that they may provide an explanation for the fluctuations that people have recorded in HIV-1 RNA levels on and off therapy [42, 44]. These "blips" may not be measurement errors in the plasma HIV-1 RNA assays, but may be related to true in vivo "microblasts" of HIV-1 replication associated with HSV reactivation. As HSV shedding rates are higher in persons with low CD4 T cell counts, the addition of acyclovir to "salvage therapy" should be studied.
In summary, our data have several clinical implications for the management of HIV-infected persons. Because HSV-2 reactivation, especially frequent reactivation, influences HIV replication, testing for HSV specific antibodies should be considered for HIV-infected persons, even if they do not report a history of HSV infection. Second, defining the frequency of HSV reactivation, especially among those who are not on effective antiretroviral therapy and those who have low CD4 T cell counts, appears to be warranted. Further studies in women, patients shedding predominantly HSV-1, and those receiving HAART appear warranted to evaluate the role HSV plays in plasma HIV RNA load elevation or HIV-1 transmission, and whether acyclovir suppression offers benefit to such persons.
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