Monkeypox infection conventionally exhibits mild clinical manifestations and the majority of patients can recuperate without any treatment. As per the CDC guidelines, no definitive treatment is currently known for monkeypox infection, symptomatic management and prevention of complications are the key therapeutic goals. Treatment options should only be considered for high-risk groups; these include immunocompromised or people having comorbidities, elderly, pregnant or breastfeeding individuals, children younger than 8 years of age, people having skin conditions that cause breach in mucocutaneous barriers, and patients experiencing severe symptoms for monkeypox infection that may or may not require hospitalization. Treatment options for monkeypox is an area that still requires extensive research, the utility of certain antiviral medications in treating monkeypox infection is still controversial and debatable. The evidence available in the literature is preclinical with an insignificant amount of data available on human disease models. (70). Literature proves effectiveness of smallpox vaccination for pre and post-exposure prophylaxis; antiviral drugs (Tecovirimat and Brincidofovir), and Vaccinia Immune Globulin (VIG) have shown promising results in active infections. Tecovirimat and Brincidofovir, are licensed by the United States Food and Drug Administration (FDA) for treatment of smallpox, meanwhile cidofovir is FDA approved for the treatment of CMV retinitis in patients with AIDS. These antivirals are now being explored as possible treatment options for monkeypox infection.(37) (45) (56)
Tecovirimat, a 4-trifluoromethyl phenol derivative antiviral (also known as ST-246 or TPOXX®®), has now been approved by the European Medicines Agency (EMA) for treatment of monkeypox. Although a variety of animal species models have demonstrated therapeutic effectiveness of Tecovirimat against all orthopox virus infections, no significant data is available in the literature to establish its efficacy in humans; however, a clinical trial called STOMP is currently under progress to assess it. (70) (71) The drug by targeting the orthopox virus F13L gene that encodes VP37 membrane protein, prevents enveloping of intracellular mature viral particles that would otherwise disseminate outside the infected cell into the host’s body. (72) (73) Tecovirimat shows an established safety profile in humans at an oral dosage of 600 mg twice daily, headache and nausea are the two most commonly reported adverse effects. (71) Non-human primate models show that Tecovirimat reduces morbidity and mortality in monkeypox infection, and its maximum effect is seen when administered within 5 days of the infection. In real scenarios, the symptoms appear much later following the onset of infection, and this suggests a decrease in the effectiveness of tecovirimat in treating symptomatically active monkeypox infection than when given as post-exposure prophylaxis. Smallpox vaccine alone was not found to be much effective for post-exposure prophylaxis, as it only reduces the disease severity but does not prevent it, but its combination with oral tecovirimat or oral administration of tecovirimat alone was found to be 100% protective against the infection. (74) (75) (76) (77) Apart from NPH models, certain studies provide the evidence of effectiveness of tecovirimat in human models too. A case series of monkeypox infected humans from Massachusetts, USA, reported markedly reduced disease severity and resolution of symptoms around day 5, 9, or 14 when they were administered tecovirimat 600 mg, orally, every 12 hours for 2 weeks during active symptomatic phase of the infection. (78)
Tecovirimat can be administered either orally or intravenously. Fecal elimination is the major clearance route, and no fetal risks have been reported with gestational usage in animal models. Some major adverse reactions reportedly include headache, gastrointestinal upset, xerostomia, and hypersensitivity reactions. The recommended dosage regimen for monkeypox treatment is 14 days in animal models, 21 days in safety data, while further clinical trials are still ongoing to explore 28 days regimens.
Daily oral dosage for tecovirimat is as follows:
“13 kg–24 kg: 200 mg 12 hourly;
25 kg–39 kg: 400 mg 12 hourly;
40 kg–119 kg: 600 mg 12 hourly;
120 kg or above: 600 mg 12 hourly.”
In contrast, the IV dosage of tecovirimat is recommended as follows:
“3 kg–34 kg: 6 mg/kg 12 hourly, over 6 hours;
35 kg–119 kg: 200 mg 12 hourly, over 6 hours;
120 kg and above: 300 mg 12 hourly, over 6 hours.” (79)
Table 2
Weight-adjusted daily dosage for oral and intravenous (IV) Tecovirimat.
| Body weight | Strength | Dosing |
Oral Tecovirimat | 13–24 kg | 200mg | 12 hourly |
Oral Tecovirimat | 25–39 kg | 400 mg | 12 hourly |
Oral Tecovirimat | 40–119 kg | 600 mg | 12 hourly |
Oral Tecovirimat | ≥ 120 kg | 600 mg | 8 hourly |
Intravenous (IV) Tecovirimat | 3–34 kg | 6 mg/kg, over hours | 12 hourly |
Intravenous (IV) Tecovirimat | 35–119 kg | 200 mg, over 6 hours | 12 hourly |
Intravenous (IV) Tecovirimat | ≥ 120 kg | 300 mg, over 6 hours | 12 hourly |
The table is the authors' own creation, based on the data available in literature (79)
An acyclic nucleoside phosphate, Cidofovir, and its lipid conjugated prodrug, Brincidofovir (also known as CMX001) are antivirals that block viral DNA synthesis of orthopoxviruses, including monkeypox virus, by inhibiting the viral DNA polymerase. Cidofovir is a monophosphate nucleotide and needs to be phosphorylated by intracellular kinases to get activated. In contrast, Brincidofovir is cleaved following its intracellular uptake to release the phosphorylated cidofovir molecule already present in the drug. This explains brincidofovir’s higher cellular toxicity and stronger antiviral activity, greater selective index, and 25-fold efficacy than cidofovir against monkeypox, vaccinia, variola and cowpox virus. (72) Brincidofovir has exhibited antiviral activity against monkeypox in animal models. (80) (81)
Brincidofovir is available in oral formulation only. 51% of the drug undergoes urinary clearance while 50% of it is excreted in feces. Risk of teratogenicity has been reported in animal models, partners should use contraception during and after the treatment till at least 4 months after the last dose. Nausea, vomiting, diarrhea, abdominal pain, and elevation of liver enzymes are the major known adverse effects.
Brincidofovir is recommended to be taken as 2 doses, 1 week apart (day 1 and 8), with following weight-adjusted dosage:
“<10 kg: 6 mg/kg (suspension);
10 kg to < 48 kg: 4 mg/kg (suspension);
48 kg and above: 200 mg (20 mL or 1 tablet).” (79)
Cidofovir is available in IV formulation only. It is known to be teratogenic, hence not recommended in pregnant patients. Up to 75–80% of the drug undergoes renal clearance. Adverse effects include neutropenia, decreased ocular pressure, and nephrotoxicity. Limited data is available on its dosage regimen but the available literature recommends a single dose of 5 mg/kg. About 2 gm Probenecid is given 3 hours prior to cidofovir to prevent potential nephrotoxicity, followed by 1 L 0.9% NS prior to administration of 5 mg/kg cidofovir, diluted in 100 ml NS, infused IV over 1 hour. If further volume can be tolerated, an additional 1 L NS can be given over 1–3 hours, started with cidofovir infusion. Finally, 1 g probenecid should be repeated 2 and 8 hours post cidofovir infusion. The goal is to reduce the nephrotoxic potential of cidofovir by administration of probenecid to reduce tubular secretion of the antiviral along with good IV hydration to reduce the renal contact time. (79) (82)
Among the aforementioned three antiviral drugs, tecovirimat is considered as the first-line and the best treatment option for monkeypox infection because of an established safety profile in humans, great antiviral response in both prophylactic and therapeutic terms, broad antiviral spectrum, and a more tolerable adverse effects profile. (74) (83) Vaccinia Immune Globulin (VIG) can treat complications of vaccinia/smallpox vaccination such as eczema vaccinium, severe generalized vaccinia etc. when given intravenously. However, it is neither approved by CDC or EMA. No significant literary evidence exists to demonstrate efficacy of VIG in monkeypox infection. However, a healthcare provider may decide to administer it to severely immunocompromised individuals with impaired T cell responses, conditions which contraindicate the usage of smallpox vaccination for post-exposure prophylaxis to monkeypox. (70)