CDC's 2023 Interim Considerations for Treating Severe Mpox

This page describes interim guidance published in February 2023. Check CDC's current mpox treatment information before acting on it.

Mpox is caused by Monkeypox virus, an orthopoxvirus in the same genus as Variola virus, which causes smallpox. In 2022 a global outbreak of clade IIb mpox was recognized, mainly among gay, bisexual and other men who have sex with men. Most patients had healthy immune systems and 10 or fewer rash lesions, and CDC recommended supportive care including pain control. But some developed severe disease: eye lesions, neurologic complications, myopericarditis, complications of lesions on the mouth, rectum, genitals or urethra, and uncontrolled spread of the virus in people with moderate or severe immunocompromise, particularly advanced HIV.

The drugs used for severe cases were medical countermeasures — FDA-regulated drugs and biologics stockpiled mainly by the federal government for smallpox or shown to work against other orthopoxviruses. From May 2022 to January 2023, CDC gave more than 250 mpox consultations to U.S. clinicians. This MMWR report pulled together animal studies, past human use against related orthopoxviruses such as vaccinia and cowpox, unpublished data, advice from experts in infectious diseases, immunology, neurology, ophthalmology, dermatology and emergency response, and the consultations themselves. It was meant to support decisions, not to be a prescriptive guideline, while randomized trials were awaited.

The countermeasures

• Tecovirimat, brincidofovir and VIGIV (vaccinia immune globulin intravenous) were recommended on the strength of animal studies against several orthopoxviruses — though those animals were exposed through the airways, not through the close skin and mucosal contact driving the outbreak.
• Cidofovir and trifluridine eye drops were recommended because they had worked against other viral infections, and cidofovir also because of data on brincidofovir.

All four antivirals had occasionally been used for severe orthopoxvirus infections before 2022, and VIGIV had treated complications of live smallpox vaccines such as Dryvax and ACAM2000, and smallpox itself before its eradication in 1980. Whether any of them actually changed outcomes was unknown.

As of February 2023, tecovirimat and VIGIV were available through CDC-sponsored expanded-access protocols, brincidofovir through FDA emergency single-patient authorization, and cidofovir and trifluridine commercially. No data yet showed that any of them helped, even for pain, and most people recovered with supportive care alone. Using them — tecovirimat especially — without close monitoring risked low drug levels and resistance, so CDC strongly encouraged enrolling patients in trials such as the NIH-funded STOMP study of tecovirimat.

Who should be considered for treatment

Severe mpox can mean hemorrhagic disease, many merging or necrotic lesions, severe necrotizing or obstructive lymphadenopathy (for example in the upper airway), obstructive edema (for example of the gastrointestinal tract), disease beyond the skin (pulmonary nodules, encephalitis, myopericarditis, ocular infection) and sepsis. Countermeasures were to be considered, whatever the patient's immune status, for people with severe disease and for those at risk of it because of moderate or severe immunocompromise or lesions in places such as the foreskin, urethral opening or vulva that could lead to strictures or swelling needing catheterization, colostomy or surgical debridement.

Children under 18 and pregnant people made up under 0.3% of U.S. cases and had mild illness, but because young children historically fared worse with clade I mpox and outcomes in pregnancy were not yet known, treatment for them was to be weighed case by case. So was treatment for people with atopic dermatitis or eczema, or with extensive breaks in the skin from burns, impetigo, varicella zoster or herpes simplex virus infections, severe acne, severe diaper dermatitis, psoriasis or Darier disease.

CDC's approach to treating patients with severe mpox or at risk for it, February 2023. CDC figure.

How to use them

Every patient with suspected mpox was to be checked for immunocompromising conditions and tested for HIV, with coinfections such as syphilis, herpes, varicella zoster or molluscum considered. None of the antivirals kills the virus outright; recovery depends on the immune system. So restoring immune function as early as possible — pausing or lowering chemotherapy and immunomodulating drugs, and promptly starting antiretroviral treatment for HIV — was critical. Since August 2022 many consultations had involved people with HIV and low CD4 counts.

Tecovirimat was the first choice if only one drug was used: taken two or three times a day depending on weight, usually for 2 weeks, with a fatty meal, which gives drug levels comparable to the intravenous form. Scarce IV tecovirimat was reserved for patients who could not take pills or fatty meals, had diarrhea or other gut problems that could hinder absorption, or had widespread disease. Severely immunocompromised patients with new or worsening lesions might get extended courses in short increments of 3–7 days, with close monitoring. Resistance had appeared in a few patients with advanced HIV treated for weeks to months, and can also arise from low drug levels, so resistance testing was encouraged for new lesions after 7 or more days of treatment.

Brincidofovir or cidofovir could be added for severe disease, usually once a week for 2 weeks; one animal study suggested brincidofovir works synergistically with tecovirimat. Neither was to be used alone unless tecovirimat could not be, and never together or within a week of each other, since both produce the same long-acting active compound. Both carry FDA boxed warnings, and brincidofovir commonly causes diarrhea, which can impair absorption of oral tecovirimat. Resistance to them is less likely than to tecovirimat.

VIGIV, a single dose of antibodies against vaccinia that may cross-protect against mpox, was recommended for patients unable to clear the virus, such as those with HIV and CD4 counts under 350 or after organ transplant. It was in short supply and used with caution for eye disease involving the cornea, after an animal study linked it to lasting corneal scarring; repeat doses were decided case by case with CDC.

Trifluridine eye drops, effective against vaccinia eye infections in animals and humans, were not to be used continuously beyond 4 weeks because of possible damage to the cornea.

Severe complications

• Eye infections: blepharitis, conjunctivitis, lesions on the conjunctiva, keratitis and vision loss, usually from the patient spreading virus to the eye or from nearby lesions.
• Neurologic complications: encephalitis and myelitis, rarely reported but seen in people with normal immunity even as skin lesions healed; the cause is unknown.
• Myopericarditis: reported in people with normal immunity, from uncertain mechanisms.
• Mucosal lesions: strictures that make eating, bowel movements or urination painful or obstruct the airway.
• Uncontrolled spread: in people with advanced HIV or organ transplants, widespread lesions involving multiple organs, sometimes fatal.

Other considerations

• Some patients with advanced HIV who had just started antiretrovirals developed worsening lesions resembling immune reconstitution inflammatory syndrome. Steroids and other immunomodulators were to be used cautiously, since steroids worsened orthopoxvirus disease in animals.
• PCR tests stay positive until lesions heal, so repeat testing helps only for new or worsening lesions; patients remain infectious until all scabs have fallen off and healthy skin is visible.
• New lesions despite treatment called for testing for other infections and other causes, and viral culture, available from laboratories such as CDC's poxvirus laboratory, could show whether live virus remained.

Gaps

Randomized trials were needed. CDC and NIH were studying immune dysregulation in people with advanced HIV (the VIRISMAP study), laboratories were sequencing the tecovirimat target gene, F13L, to track resistance, and CDC was measuring antibody levels to guide VIGIV redosing. Clinicians giving countermeasures under the expanded-access programs were asked to submit data forms.

Sources

• Rao AK, Schrodt CA, Minhaj FS, et al. "Interim Clinical Treatment Considerations for Severe Manifestations of Mpox — United States, February 2023." MMWR 2023;72(9). The imported text is the corrected version of the report. It spells tecovirimat "tecovorimat" once; this is corrected here.