Consideration |
Medical countermeasures |
Tecovirimat (Tpoxx or ST-246) |
Brincidofovir (Tembexa or CMX001) |
Cidofovir (Vistide) |
VIGIV |
Trifluridine (Viroptic) |
Description |
An OPXV-specific antiviral with limited activity against unrelated RNA or DNA viruses |
Lipid-conjugated analog of cidofovir with different properties compared with cidofovir |
Monophosphate nucleotide analog used to treat viral infections including cytomegalovirus |
Solvent- or detergent-treated, filtered sterile solution of purified immune globulin from human plasma of persons with antibodies to vaccinia virus |
Nucleoside analog used to treat ocular viral infections including herpes simplex virus keratitis |
Mechanism of action against OPXVs |
Inhibits association of VP37 (a protein encoded by and highly conserved across the OPXV genus) with a cellular protein, preventing formation of egress-competent envelope virions necessary for cell-to-cell dissemination of virus |
Once inside cells, the lipid ester linkage is cleaved to form cidofovir, which is then converted to CDP, which selectively inhibits OPXV DNA polymerase. |
Intracellularly converted to CDP which selectively inhibits OPXV DNA polymerase |
Provides passive antibody which might have cross-reactivity across the OPXV genus |
Thymidine analog that interferes with DNA synthesis in cultured mammalian cells with selective toxicity to viral replication of OPXVs |
Dose |
600 mg† |
200 mg§ |
5 mg/kg |
6,000–9,000 units/kg¶ |
One drop into affected eyes |
Route |
Oral (capsules) or IV** |
Oral (tablets or suspension) |
IV |
IV |
Topical |
Frequency |
Twice daily (40 kg to <120 kg) Three times daily (>120 kg) |
Once weekly |
Once weekly |
Single dose but can be repeated depending on duration of illness and severity of immunocompromise |
Every 2 hrs when awake for the first 2 wks (maximum nine drops per eye per day) Then, four times daily for an additional 2 wks |
Duration |
2 wks unless indication to prolong†† |
2 wks unless indication to prolong†† |
2 wks unless indication to prolong†† |
NA |
>4 wks |
Potential adverse events |
Headache, nausea, diarrhea, itching, and abdominal pain; labeled contraindication for IV administration when creatinine clearance is <30 mL/min§§ |
Abdominal pain, diarrhea, nausea, vomiting, and elevated liver enzymes |
Nephrotoxicity, nausea, vomiting, and acidosis |
Adverse events associated with infusion of immunoglobulins (e.g., headache, diaphoresis, erythema, anaphylaxis, thrombosis, acute kidney injury, and volume overload) |
Adverse events associated with topical use (e.g., burning, stinging, or eyelid edema) |
Warnings |
Other warnings: Clearance of hydroxypropyl-β-cyclodextrin is dependent on glomerular filtration, and caution is advised in patients with mild to moderate renal impairment, and in pediatric patients <2 yrs. |
BBW: Increased mortality seen in a 24-wk placebo-controlled trial for CMV prophylaxis in hematopoietic stem-cell transplant recipients. Prolonging therapy beyond 2 wks should be considered with caution, and currently requires FDA authorization on an individual patient basis through an emergency IND request. Other warnings: Neutropenia Potential human carcinogen, teratogen, and causing hypospermia |
BBW: Severe nephrotoxicity resulting in dialysis or contributing to death. IV prehydration and administration of probenecid must be used with each infusion. Neutropenia Potential human carcinogen, teratogen, and causing hypospermia Other warnings: Decreased intraocular pressure, metabolic acidosis |
Other warnings: Hypersensitivity, renal dysfunction, interference with blood glucose testing, thrombotic events, aseptic meningitis syndrome, hemolysis, transfusion-related acute lung injury, and transmission of infectious agents from human plasma |
Other warnings: Continuous administration beyond the recommended duration might cause corneal epithelial toxicity. |
Drug interactions |
Might reduce levels of NNRTI rilpivirine Might increase concentration of blood glucose-lowering agent repaglinide Decrease concentration of midazolam |
Protease inhibitors, cobicistat, and fostemsavir might increase brincidofovir concentration. |
Cidofovir has limited interactions; however, it necessitates coadministration with probenecid which has numerous interactions (e.g., zidovudine, beta-lactam antimicrobials, diuretics, NSAIDs, and ACEi) that need to be monitored. |
Vaccination with live virus vaccines (e.g., varicella measles, mumps, and rubella) should be deferred for 3 mos after use. |
NA |
Data gleaned from selected animal studies ¶¶ |
Cynomolgus macaques were lethally challenged IV with MPXV and treated on day 4, 5, and 6 postchallenge. Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given starting at day 6 postchallenge. |
In a lethal rabbitpox and mousepox (ectromelia) model of infection, treatment with brincidofovir resulted in statistically significant improvement in survival relative to placebo, except when given starting at day 6 postchallenge in the mousepox study. |
In a lethal dormouse model of MPXV, cidofovir-treated mice reduced mortality from 100% to 19%. |
In a mouse-tail lesion model, VIGIV exerted a protective effect against vaccinia infection when compared with a negative control. |
In a study of 56 rabbits with vaccinia keratitis, trifluridine significantly reduced clinical disease and viral culture positivity. |
Data gleaned from use in humans before and during the 2022 outbreak |
Of 255 patients treated during the current outbreak,*** the median interval to first subjective improvement was 3 days with limited adverse events reported. |
Limited use as monotherapy; used (unsuccessfully) alternating with cidofovir for severe cowpox infection in a kidney transplant recipient |
Limited use as a sole agent; used for ocular cowpox infection with unclear benefit and once (unsuccessfully) alternating with brincidofovir for severe cowpox infection in a transplant recipient |
Evidence for smallpox prevention when given to high-risk contacts Mixed evidence for efficacy for treatment of progressive vaccinia |
Used successfully off-label for ocular complications of vaccinia virus vaccination |
Pregnancy, breastfeeding, and fertility considerations |
Likely safe in pregnancy and breastfeeding without affecting fertility |
Not recommended for pregnancy or breastfeeding Might cause irreversible infertility in males |
Not recommended for pregnancy or breastfeeding Might cause irreversible infertility in males |
Likely safe in pregnancy and breastfeeding without affecting fertility |
Negligible systemic absorption when administered into the eye; likely safe in pregnancy and breastfeeding without affecting fertility |
CNS considerations ††† |
Penetrates well |
Penetrates to uncertain degree |
Penetrates to limited degree |
Penetrates to limited degree |
NA |
Resistance considerations |
Single point mutation can confer resistance.§§§ |
Single point mutation can confer minor resistance; however, multiple mutations are needed for high-level resistance and the resultant virus becomes less virulent. |
Single point mutation can confer minor resistance; however, multiple mutations are needed for high-level resistance and the resultant virus becomes less virulent. |
NA |
Although in vitro resistance has not been reported, the possibility of resistance exists. |
Miscellaneous considerations |
High-fat (approximately 600 calories and 25g fat) meal required with each oral dose IV administration should be considered in those who are unable to take oral therapy, unable to consume high-fat meal, have impaired gastrointestinal absorption (e.g., gastric bypass, diarrhea, or evidence of other gastrointestinal disfunction that might negatively affect drug absorption), or fail to improve on approximately 7 days of oral therapy. |
Must be taken on an empty stomach or with a low-fat meal (approximately 400 calories with 25% of calories from fat) Might have superior antiviral activity to that of cidofovir because of increased cellular uptake Should not be administered within 1 wk of cidofovir because both form the same active metabolite (CDP), which has a prolonged duration of action |
Must be given with probenecid to minimize nephrotoxicity Probenecid might have substantial drug interactions and consultation with a pharmacist is advised. Should not be administered within 1 wk of brincidofovir because both form the same active metabolite (CDP), which has a prolonged duration of action |
Vaccinia-specific antibody, which might cross-react with MPXV Might interfere with endogenous antibody production and IgG antibody testing When used to treat vaccinia keratitis in rabbits, VIGIV resulted in prolonged scarring and stromal edema. |
Can cause permanent limbal stem cell deficiency with prolonged use |