Lakhasly

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 Downloaded from https://academic.oup.com/ofid/article/11/3/ofae046/7600571 by guest on 15 March 2024 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.

Herpes simplex virus (HSV) is a common cause of recurrent
mucocutaneous and, less often, visceral infection.
Immunocompromised individuals, including people with human
immunodeficiency virus (PWH), transplant recipients, and patients
with hematologic malignancy, are at particularly high
risk for recurrent HSV infection. In 1 study, 70% of hematopoietic
cell transplant (HCT) recipients developed HSV infection
during transplantation in the absence of antiviral prophylaxis
[1]. 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.
However, early in the development of acyclovir, before systemic
acyclovir was commercially available, reports of resistance
emerged in the immunocompromised population [2].
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].
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. 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.
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]. Although historically PWH were at significant risk for resistant
HSV infection, risk is seemingly lower in this patient population
with contemporary antiretroviral therapy. 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-refractory HSV infection
is a clinical diagnosis that requires attention to host
type, previous antiviral exposure, and response to standard acyclovir
therapy. Definitive diagnosis of acyclovir-resistant HSV is
made by phenotypic testing that can take several weeks to result
[6]. Genotypic testing for acyclovir-resistant in clinical HSV isolates
is not commercially available in the United States (US).
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]. 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 • OFID • Hammond et al
Downloaded from https://academic.oup.com/ofid/article/11/3/ofae046/7600571 by guest on 15 March 2024
initial acyclovir phosphorylation performed by cellular kinases
in the absence of normal viral thymidine kinase activity [7].
All 3 systemic treatment options are associated with significant
toxicities and require careful monitoring. Foscarnet, the
treatment of choice for acyclovir-resistant HSV disease according
to US guidelines [9], is given intravenously multiple times
per day with concurrent hydration. Foscarnet carries a risk of
kidney dysfunction and profound electrolyte disturbances including
hypocalcemia that can lead to seizures. Less often, foscarnet
can also cause noninfectious genital ulcers [10]. 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. Some foscarnet toxicities
are dose-dependent, so the fact that lower doses of foscarnet
are needed to treat HSV than cytomegalovirus can mean
the drug may be better tolerated in patients being treated
for HSV infection. Systemic cidofovir is given intravenously
intermittently, so this can obviate the need for initial hospitalization.
However, cidofovir also carries a risk of nephrotoxicity,
and less often uveitis. Because of its prolonged half-life,
cidofovir cannot be cleared quickly when toxicity develops
[11]. 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].
More effective and less toxic oral options for the treatment of
acyclovir-resistant HSV disease are needed.
Pritelivir is a novel oral antiviral agent in development for
treatment of HSV infection that inhibits the viral helicase primase
[13, 14]. 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].
Treatment success with pritelivir given in an expanded access
program has also been reported in several cases of resistant
HSV infection [16–18]. A phase 3 study of pritelivir for treatment
of mucocutaneous-resistant HSV in immunocompromised
individuals is ongoing.
Literature describing the clinical outcomes and toxicities of
treatment for resistant HSV infection with currently available
therapy, particularly with the first-line choice, foscarnet, is
lacking. Furthermore, currently available literature is largely
limited to case reports and series that tend to describe treatment
successes. Larger studies are needed to reduce this type
of success bias. Last, understanding the utility of foscarnet for
treatment of resistant HSV is important to help define treatment
differences with novel therapies. We undertook this multicenter
retrospective study in order to provide a more detailed
description of the clinical outcomes and toxicities of foscarnet
when used to treat resistant HSV infection.