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TPOXX Resistance Risk ? Guidance for Tecovirimat Use Under Expanded Access Investigational New Drug Protocol during 2022 U.S. Monkeypox Outbreak
  Updated September 15, 2022
Tecovirimat should be considered for use in people who have the following clinical manifestations:
Tecovirimat should also be considered for use in people who are at high risk for severe disease:
People currently experiencing severe immunocompromise due to conditions such as advanced or poorly controlled human immunodeficiency virus (HIV), leukemia, lymphoma, generalized malignancy, solid organ transplantation, therapy with alkylating agents, antimetabolites, radiation, tumor necrosis factor inhibitors, or high-dose corticosteroids, being a recipient of a hematopoietic stem cell transplant <24 months post-transplant or ≥24 months but with graft-versus-host disease or disease relapse, or having autoimmune disease with immunodeficiency as a clinical component1
People with a condition affecting skin integrity - conditions such as atopic dermatitis, eczema, burns, impetigo, varicella zoster virus infection, herpes simplex virus infection, severe acne, severe diaper dermatitis with extensive areas of denuded skin, psoriasis, or Darier disease (keratosis follicularis)
Risk of Viral Resistance to TPOXX:
Viruses can change over time. Sometimes these changes make antiviral drugs less effective at combating the virus they are targeting, meaning those drugs won’t work as well or might not work at all.
TPOXX works by inhibiting a viral protein, called VP37, that all orthopoxviruses (e.g., smallpox virus, monkeypox virus, vaccinia virus) share. However, as noted in the drug label, TPOXX has a low barrier to viral resistance. This means small changes to the VP37 protein could have a large impact on the antiviral activity of TPOXX.
CDC scientists are actively monitoring for changes in the monkeypox virus that could make the virus less susceptible to TPOXX. Because of the potential for the virus to become resistant to TPOXX, it is important the drug be used in a judicious manner.
Patients should enroll in NIAID’s randomized, controlled clinical trial when feasible to facilitate assessment of the safety, efficacy, and resistance profile of TPOXX. For patients for whom enrollment in a randomized clinical trial is not feasible (e.g., a clinical trial site is not geographically accessible), use of TPOXX under CDC’s expanded access protocol should be consistent with applicable guidelines for TPOXX use.
Information for the Scientific Community:
On September 12, 2022, the FDA released additional information in publicly posted reviews supporting approval of the new drug application for tecovirimat to describe specific changes in the VP37 proteins of orthopoxviruses (e.g., vaccinia virus and monkeypox virus) that are associated with tecovirimat drug resistance.
As described in the FDA reviews, multiple independent studies characterized tecovirimat resistance development in orthopoxviruses in cell culture studies, in animal studies, and in an anecdotal human case of progressive vaccinia. These studies identified several genetic pathways for orthopoxviruses to become resistant to tecovirimat, which involves the emergence of amino acid substitutions in the viral VP37 drug target (see Table below). Many of the resistance pathways require only a single amino acid change in VP37 to cause a substantial reduction in tecovirimat antiviral activity.
Collectively, these studies indicate tecovirimat has a low barrier to resistance, and this must be considered in the context of the current monkeypox public health emergency because there is a risk that tecovirimat resistant virus could emerge and possibly spread.
The FDA is releasing this information to aid the scientific community’s genomic sequencing efforts to support national surveillance of the current monkeypox virus outbreak in the U.S. The FDA believes releasing this additional information will further facilitate the ability to monitor for the development and spread of tecovirimat-resistant virus and therefore is important in promoting public health

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