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Changes in Plasma Human Immunodeficiency Virus Type 1 RNA Associated with
Herpes Simplex Virus Reactivation and Suppression
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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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