11/17/2022 | Press release | Distributed by Public on 11/17/2022 18:34
Distributed via the CDC Health Alert Network
November 17, 2022, 7:00 PM ET
Monkeypox cases have declined since mid-August 2022 in the United States; however, new cases-including clinically severe cases-continue to occur. While there are currently no treatments specifically approved for monkeypox, therapeutics developed for patients with smallpox have been deployed during the current outbreak. This Health Alert Network (HAN) Health Update provides clinicians and public health officials with new information about managing monkeypox in patients requiring therapeutics.
Specifically, this Health Update
Tecovirimat is a virostatic agent that targets a major envelope protein conserved across orthopoxviruses (VP37 in monkeypox virus). While naturally circulating tecovirimat-resistant monkeypox viruses have not been observed, previous cell culture experiments performed during drug development and independent studies performed prior to the current outbreak have demonstrated induction of resistance following tecovirimat exposure. Furthermore, experimental data have highlighted a relatively low barrier to resistance, with single amino acid substitutions at various locations in the F13L gene coding VP37 conferring substantial reductions in tecovirimat's antiviral activity.1
For most patients with intact immune systems, monkeypox is a self-limited illness that does not require anti-viral treatment to clear disease. For those who do require tecovirimat treatment, disease usually resolves during a 14-day course of oral tecovirimat. Most patients with indications for tecovirimat do not require treatment with any additional therapeutics.
Identification of Tecovirimat Resistance
Since the start of the current monkeypox virus outbreak and as part of routine surveillance activities, the Centers for Disease Control and Prevention (CDC) and other laboratories have evaluated clinical monkeypox specimens from patients receiving tecovirimat and those not receiving tecovirimat. The evaluation has included a focus on the presence of F13L mutations that might indicate tecovirimat resistance. Specifically, CDC has been evaluating suspect cases (identified either by F13L sequencing efforts or by suspicion based on clinical course) for phenotypic resistance.
CDC has confirmed the presence of tecovirimat-resistant viruses in two patients. CDC was notified of one patient with persistent monkeypox whose viral isolates demonstrated tecovirimat resistance. Isolates from this patient, sequenced by the state laboratory, demonstrated genotypic changes in F13L associated with tecovirimat resistance. In addition, CDC confirmed phenotypic resistance to tecovirimat in cell culture. CDC also confirmed tecovirimat resistance in another patient who was tested due to poor response to tecovirimat treatment; genotypic and phenotypic testing subsequently confirmed resistance.
Both patients had severe immunocompromising conditions with disseminated and progressive monkeypox infection despite prolonged treatment (>14 days) with tecovirimat. Both patients required inpatient treatment. These are the first known cases of monkeypox with laboratory-confirmed tecovirimat resistance in the United States.
CDC has analyzed sequences from more than 4,000 specimens from across the world, and only 13 changes in the F13L protein were found, including the two cases included in this HAN Update. Isolates from the other 11 cases were sensitive to tecovirimat in cell culture. These 4,000 specimens in which the F13L gene was analyzed are from CDC surveillance efforts and include isolates from individuals receiving and not receiving tecovirimat.
Orthopoxvirus resistance to tecovirimat had been observed previously in a person with progressive vaccinia following vaccination with ACAM2000.2 This patient was severely immunocompromised from chemotherapy, and tecovirimat resistance developed late in disease after prolonged treatment during which levels of tecovirimat below target concentrations were intermittently observed. The patient recovered after receiving brincidofovir and VIGIV as concurrent therapies with tecovirimat.
Tecovirimat resistance testing is an important part of ongoing public health surveillance during the current outbreak. For patients with suspected resistance, ideally both resistance testing and pharmacokinetic testing should be performed to determine if any cases of confirmed resistance are associated with drug levels below target concentrations. However, neither tecovirimat resistance nor pharmacokinetic test results are available to inform patient treatment because neither are approved as Clinical Laboratory Improvement Amendments (CLIA) regulated procedures, and culture-based resistance testing requires multiple viral propagation steps and takes weeks to perform. Therefore, management of patients for whom resistance is suspected will need to be guided by the patient's clinical status and may warrant consideration of additional therapeutics as outlined below.
Other Therapeutics for Managing Monkeypox
In patients who have severe disease or certain patients who are at high risk for progression to severe disease, such as patients with HIV and CD4 counts <350 cells/mm3 or other severely immunocompromising conditions, the use of two or more therapeutics should be considered based on the individual clinical situation. In addition to tecovirimat (oral and intravenous), available therapeutics include cidofovir (intravenous), brincidofovir (oral), and VIGIV. Cidofovir is commercially available; intravenous tecovirimat, brincidofovir, and VIGIV are only available via CDC or FDA approval for release from the Strategic National Stockpile (SNS).
For any patients who may benefit from multiple therapeutics, consultation with CDC as well as infectious disease specialists and other experts is encouraged. For CDC consultation, contact the CDC Emergency Operations Center (EOC) at 770-488-7100.
Cidofovir and Brincidofovir
Cidofovir is a commercially available antiviral medication that is approved by the FDA for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). It has been shown to be effective against orthopoxviruses in in vitro and animal studies. As of October 31, 2022, brincidofovir, an oral prodrug of cidofovir, is available from the SNS to treat monkeypox infections through an FDA-authorized single-patient emergency use Investigational New Drug protocol (IND) upon clinician-request (submitted to FDA). Serious renal toxicity or other adverse events have not been observed during treatment of cytomegalovirus infections with brincidofovir as compared to treatment using cidofovir. Cidofovir should not be used simultaneously with brincidofovir.
Brincidofovir is available for people with positive test results for orthopoxvirus or monkeypox virus who:
In deciding whether to request and administer brincidofovir, clinicians should be aware of its side effect profile. Clinicians who would like to treat their patients with brincidofovir should submit an e-IND request to FDA by email ([email protected]) or call (301-796-3400 or 1-855-543-3784) during normal business hours (8:00 am-4:30 pm ET Mondays-Fridays). After hours, call the FDA Emergency Coordinator at 1-866-300-4374 or 301-796-8240, or email [email protected], and call the CDER Emergency Coordinator at 301-796-9900.
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