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.