Countermeasures
The systemic antiviral treatment options with the most available data
against MPXV include tecovirimat (TPOXX®), cidofovir, brincidofovir, and
Vaccinia Immune Globulin (VIGIV). Of these options, tecovirimat has
recently seen the broadest utilization, given its oral administration
and strong safety profile. Tecovirimat targets the MPXV p37 protein,
disrupting envelope development and mature virion formation. The CDC has
made tecovirmat available through an Expanded Access New Investigational
Drug protocol (EA-IND). There is currently no high quality clinical data
on tecovirimat’s effectiveness against mpox; however, a human clinical
trial for effectiveness is ongoing, and the drug has been demonstrated
to be safe and well tolerated in humans. The manufacturer recommends a
14-day treatment course based on the development of humoral immunity,
however severe mpox cases in immunosuppressed patients often require
much longer courses.
Cidofovir and brincidofovir inhibit viral DNA polymerase. The FDA
originally approved cidofovir for the treatment of CMV retinitis, butin vitro data suggests it possesses antiviral activity against a
wide number of viruses to include Orthopoxviruses . Similarly,
brincidofovir is an oral prodrug of cidofovir and approved for the
treatment of smallpox. It is currently only available through an
FDA-authorized emergency use-IND. The clinical effectiveness data for
these drugs against human MPXV infection is limited to case reports and
cohort studies. Importantly, usage of these drugs may be limited by
their toxicities: cidofovir is a known potent nephrotoxin and
brincidofovir has been associated with significant hepatotoxicity.
VIGIV is prepared from serum of patients vaccinated against smallpox and
is available from the CDC through an expanded access protocol for mpox.
Like the other countermeasures, its effectiveness against poxviruses is
limited to case reports.
Animal models suggest that delayed administration and host
immunosuppression diminish the effectiveness of cidofovir and
tecovirimat. Animal data has also shown that tecovirimat has a low
barrier to resistance with only a single amino acid substitution of p37
required for reduced antiviral activity to develop. While rare, the
current outbreak has seen the rise of resistant MPXV isolates obtained
from immunosuppressed hosts on long courses of tecovirimat. Notably,
tecovirimat and brincidofovir have been found to have synergistic
activity in vitro and in vivo against poxviruses. While we
concede that it is difficult to draw conclusions based these limited
data, we support the immediate initiation of combination antiviral
therapy with tecovirimat, cidofovir or brincidofovir and VIGIV in
addition to rapid initiation of ART to maximally inhibit viral
replication in the absence of effective cell-mediate immunity, optimize
the potential for antiviral synergy, and shield against the development
of resistance.