Antivirals With Activity Against Mpox: A Clinically Oriented Review

Abstract

Mpox virus is an emergent human pathogen. While it is less lethal than smallpox, it can still cause significant morbidity and mortality. In this review, we explore 3 antiviral agents with activity against mpox and other orthopoxviruses: cidofovir, brincidofovir, and tecovirimat. Cidofovir, and its prodrug brincidofovir, are inhibitors of DNA replication with a broad spectrum of activity against multiple families of double-stranded DNA viruses. Tecovirimat has more specific activity against orthopoxviruses and inhibits the formation of the extracellular enveloped virus necessary for cell-to-cell transmission. For each agent, we review basic pharmacology, data from animal models, and reported experience in human patients.

Keywords: brincidofovir; cidofovir; mpox; tecovirimat.

Conflict of interest statement

Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Poxviruses known to infect humans within the Poxviridae family; 4 genera include the species that are most commonly known to infect humans. While not characterized as human pathogens, additional orthopoxviruses, such as mousepox and rabbitpox, serve as the infectious agent in animal models that most closely replicate human infections with other orthopoxviruses such as smallpox (variola). Figure created with BioRender.com.

Figure 2.

Natural history and clinical manifestations of human mpox infection after initial exposure. The virus replicates at the initial infection site, resulting in a local inflammatory response. The virus then spreads to the regional lymph nodes and via the bloodstream (primary viremia) to lymphoid organs, which explains the signs and symptoms seen during the prodrome phase, including lymphadenopathies. The virus spreads again to the bloodstream (secondary viremia), leading to the end-organ involvement with the skin rash and other complications. Fever starts during the prodrome phase and resolves within 3 days of rash onset. Lymphadenopathy is a specific manifestation of mpox, differentiating it from smallpox and varicella. The skin lesions evolve from macules, to papules, to vesicles and pustules, and finally to crusts and scabs, each phase taking about 2 days on average. The skin lesions then resolve, often with pitted scarring. Additional complications can occur from secondary bacterial infection or viral spread to other organs and could lead to death. The frequency of these complications is reported based on a description of cases from the 1981–1986 outbreak in the Democratic Republic of Congo and might not reflect the severity of other outbreaks caused by a different clade of the virus. Specific characteristics of the 2022 outbreak are highlighted. Figure created with BioRender.com.

Figure 3.

Mpox life cycle and mechanisms of action of antivirals. This simplified diagram describes the life cycle of mpox virus inside human cells. Notably, mpox virus undergoes its entire life cycle inside the cytoplasm since it carries all the enzymes it needs for DNA replication and protein synthesis, thus obviating the need for an intranuclear stage. Viral particles are assembled into intracellular mature viruses, then released as extracellular enveloped viruses during cell lysis. Cidofovir and its prodrug brincidofovir inhibit DNA synthesis by incorporation of cidofovir diphosphate into the growing DNA strand. Tecovirimat inhibits membrane protein p37, which is essential for the formation of the extracellular enveloped virus upon cell lysis. Figure adapted from “Generic Viral Life Cycle” by BioRender.com (2022); publication and licensing rights obtained from BioRender. Retrieved from https://app.biorender.com/biorender-templates.