Herpes simplex virus (HSV) is a common cause of recurrent
mucocutaneous and, less often, visceral infection.Foscarnet and cidofovir act by inhibiting the viral polymerase
independent of the viral thymidine kinase, while continuous
infusion acyclovir relies on the limited amount of
2 o OFID o Hammond et al
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initial acyclovir phosphorylation performed by cellular kinases
in the absence of normal viral thymidine kinase activity [7].Acyclovir's antiviral activity hinges on initial phosphorylation
by the HSV viral thymidine kinase enzyme; cellular kinases
then phosphorylate the drug further and acyclovir-
triphosphate then interferes with viral replication by inhibiting
the viral polymerase.Typically immunocompromised patients who develop
acyclovir-resistant or refractory HSV infection have had previous
repeated or prolonged exposure to acyclovir or other similar antiviral
nucleoside analogues for prophylaxis or treatment of HSV
[6].Acyclovir-resistant HSV infection is a rare clinical problem
typically seen in the immunocompromised population, where
it can cause painful protracted mucocutaneous disease associated
with significant morbidity and mortality [3-5].The
need for frequent intravenous delivery and hydration, coupled
with the electrolyte monitoring and repletion requirements of
foscarnet, typically require hospitalization for initiation, which
can be prolonged for some individuals.Thus, resistance is typically mediated
through alterations in the viral thymidine kinase, but can also
be mediated through alterations in the viral polymerase that
can confer cross-resistance to other antiviral therapies.In contrast, as
novel immunosuppressive therapies for the management of hematologic
malignancy grow, patients with hematologic malignancy
remain a large at-risk population with substantial exposure to
prophylactic anti-HSV antivirals.Acyclovir, a nucleoside analogue developed >40 years ago
for the treatment of HSV and other herpesviruses, and the closely
related prodrug valacyclovir, have been the mainstay of treatment
and prevention of HSV infection and recurrence.Systemic treatment options for acyclovir-resistant HSV infection
are limited and include intravenous foscarnet, intravenous
cidofovir, and high-dose or continuous infusion acyclovir
[7, 8].Last, continuous infusion acyclovir is infrequently chosen
for treatment of acyclovir-resistant HSV, and requires
careful monitoring given the potential for acyclovir to cause
crystal nephropathy in patients who are not adequately
hydrated.To avoid the toxicities and other burdens of systemic therapy,
compounded topical cidofovir and intralesional cidofovir
are sometimes used for treatment of localized disease, though
limited data suggest the topical approach alone may result in
complete resolution as infrequently as 30% of the time [12].A case series derived from a phase 2 study of this
drug for treatment of mucocutaneous acyclovir-resistant HSV
infection in immunocompromised patients showed that the
drug was well tolerated, and 19 of 23 participants (83%) had
complete resolution of HSV lesions by 28 days [15].All 3 systemic treatment options are associated with significant
toxicities and require careful monitoring.