A double-stranded DNA virus of the Orthopoxvirus family, mpox (formerly monkeypox), continues to infect people daily, following the 2022 global outbreak.¹ Two clades (clade 1 and clade 2) have been identified, with the 2022 outbreak caused by a subclade of clade 2, referred to as clade 2b.² Comparatively, clade 1 leads to a more severe disease state and greater risk of death.^3,4 A majority of clade 2 mpox cases do not cause any serious illness; however, immunosuppressed individuals may be at risk of serious infection, such as those with HIV/AIDS, patients with cancer undergoing chemotherapy and organ transplant recipients, who are at increased risk of severe mpox. Their impaired immune responses increase their susceptibility to prolonged and severe infection, necessitating treatment beyond supportive therapy.

Ideally, vaccines are provided for close contacts or high-risk individuals. JYNNEOS^® (licensed internationally as IMVAMUNE or IMVANEX; Bavarian Nordic, Inc., Durham, NC, USA) and ACAM2000 (Emergent BioSolutions, Rockville, MD, USA) are currently available in the USA for mpox prevention.⁵ ACAM2000 is a live vaccinia virus and, as such, is contraindicated in immunocompromised individuals.⁶ JYNNEOS/IMVAMUNE/IMVANEX, a smallpox vaccine (i.e. modified vaccinia Ankara–Bavarian Nordic) was recently shown to be 58% effective against mpox and could prove a valuable addition to preventive mpox measures.⁷ The treatment option that should be used depends on patient, virus and drug factors such as disease severity, risk of complications, underlying medical conditions and drug–drug interactions. To date, treatment options consist of three antivirals (tecovirimat, brincidofovir and cidofovir) and one immunoglobulin (vaccinia immunoglobulin [VGIV]) in addition to supportive therapy (Table 1).^6,8–13 All three antivirals were developed or stockpiled for the treatment or prophylaxis of smallpox; however, their use against mpox is supported by varying levels of evidence from in vitro studies, animal models and human case reports.¹³ A topical agent, trifluridine, may be considered for the treatment of mpox ocular infection.¹⁴

Cidofovir

Cidofovir has a wide range of activities against DNA viruses; currently, cidofovir is only approved for the treatment of cytomegalovirus (CMV).^9,15 Cidofovir is transformed into its active form once phosphorylated inside the host cell. This active form competes with endogenous nucleotides to be incorporated into the viral DNA, which slows down DNA synthesis and inhibits viral replication.⁹ While efficacy data for mpox treatment in humans are minimal, a study with macaques showed promising results; while 100% of untreated macaques receiving a lethal dose of mpox perished, only 1 out of 11 macaques did not survive when treated with multiple doses of cidofovir.¹⁶ Additionally, it is believed that for cidofovir to be effective against human mpox, treatment may be needed to be initiated before the appearance of the skin rash.¹⁷ This would necessitate early diagnosis and detection of viral DNA in blood samples during the prodromal phase. Cidofovir has a long half-life and is removed from the plasma by the kidneys, and it is contraindicatory in patients with low creatinine clearance (<55 mL/min), ≥2+ proteinuria (equivalent to urine protein ≥100 mg/dL) or renal impairment, as nephrotoxicity is a major concern.⁴ Damage to the proximal tubule resulting from cidofovir’s slow excretion into the lumen of the kidney is thought to be responsible for the nephrotoxicity associated with cidofovir.¹⁸ Careful patient selection, appropriate dosing and the use of prophylactic measures such as probenecid and intravenous (IV) hydration can help minimize the risk. Any potential concomitant nephrotoxic agents should be discontinued 7 days prior to starting cidofovir. Other considerations with cidofovir include avoidance during pregnancy and the potential impairment of fertility in males.¹⁹ While not considered first-line, IV cidofovir may be a treatment option for severe mpox, particularly in cases where tecovirimat is unable to be used and brincidofovir is unavailable. Of note, intralesional cidofovir provides an option for refractory verrucae, offering a safer alternative to systemic cidofovir.²⁰

Brincidofovir

A cidofovir analogue, brincidofovir, possesses activity against several DNA viruses and has been granted orphan drug status for the treatment of smallpox.^10,21 As a lipid-conjugated form of cidofovir, brincidofovir possesses a longer half-life and greater bioavailability. Brincidofovir also has decreased accumulation in the kidneys, resulting in less nephrotoxicity than cidofovir. Though less likely, cases of reversible nephrotoxicity have been reported with brincidofovir.²² The most common side effects seen with brincidofovir are gastrointestinal (GI)-related issues such as abdominal pain, diarrhoea and nausea/vomiting.¹⁰ In one cohort, a reported 40% of patients experienced diarrhoea (compared with 25% in the placebo group) when taking brincidofovir. Patients experiencing such GI effects should be closely monitored for dehydration, especially in patients with additional comorbidities. Additionally, liver function should be monitored for potential hepatotoxicity. Brincidofovir should be discontinued if alanine aminotransferase levels increase and remain >10 times the upper limit of normal or if signs and symptoms are seen with an increase in alkaline phosphatase, bilirubin or the International Normalized Ratio (INR).²³ Finally, brincidofovir has a black box warning when used for an extended duration due to increased mortality observed in hematopoietic cell transplant patients receiving brincidofovir for prophylaxis for treating CMV.¹⁰ The possibility highlights the importance of carefully considering the risks and benefits of brincidofovir treatment, especially in immunocompromised individuals. In regard to drug interactions, brincidofovir is an OATP1B1 and OATP1B3 substrate; therefore, caution is necessary when brincidofovir is co-administered with inducers or inhibitors of these transporters. For example, clarithromycin is a potent organic anion transporting polypeptide (OATP) inhibitor and might be prescribed for a concomitant bacterial infection, more commonly seen with immunosuppression.²⁴

Tecovirimat

Tecovirimat was considered a first-line but still investigational, antiviral for mpox.²⁵ Available orally or intravenously, tecovirimat is an FDA-approved treatment for smallpox and inhibits orthopoxvirus transmission, including mpox.²⁶ Resistance to tecovirimat is low, but cases can occur not only in patients previously exposed to tecovirimat but also among persons with no previous exposure.²⁷ Prolonged viral shedding in immunocompromised persons combined with low drug concentrations could prompt prolonged treatment, which increases the risk of drug resistance.¹⁹ The use of tecovirimat for treatment is extrapolated from efficacy against other poxviruses and/or is based on in vitro/animal data. Data from the PALM007 (A randomized, placebo-controlled, double-blinded trial of the safety and efficacy of tecovirimat for the treatment of adult and pediatric patients with monkeypox virus disease; ClinicalTrials.gov identifier: NCT05559099) trial indicate that tecovirimat is not effective against clade 1 mpox, despite its lower overall mortality of 1.7% compared with the mpox mortality of 3.6% reported in all cases in the region.²⁸ The study randomly assigned participants to receive tecovirimat or placebo while being admitted to the hospital for 14 days. Ultimately, no significant difference was found between participants who received tecovirimat compared with those who received a placebo.²⁹

A small pharmacokinetic (PK) study of 14 subjects diagnosed with mpox (clade 2) showed lower tecovirimat concentrations in persons living with HIV (PLWH) compared with those without concomitant HIV.³⁰ Despite the comparatively lower concentrations, all concentration time points remained above the in vitro IC90, and all patients recovered clinically. The reason behind the lower concentrations is unclear. When administered with a meal, tecovirimat concentrations are approximately 40% higher than fasting. Meal intake was not recorded in the study, so it is unknown what impact food had on drug concentrations. An intensive PK study of 12 patients by Wei et al. showed similar results, with tecovirimat concentrations of the subjects being lower in persons with mpox compared with healthy volunteers.³¹ Although subjects in this PK subset had concentrations higher than the minimally effective Cmin in non-human primate studies, currently, no clear clinical threshold exists that tecovirimat should exceed, which is associated with efficacy. More importantly, interim results from the STOMP (ACTG 5418; A randomized, placebo-controlled, double-blinded trial of the safety and efficacy of tecovirimat for the treatment of human mpox virus disease; ClinicalTrials.gov identifier: NCT05534984) trial showed that tecovirimat was not effective in reducing pain in persons with mpox, nor did it reduce the time to resolution of symptoms compared with those receiving a placebo.^32–34 The randomized, blinded study enrolled adult subjects, in a two:one ratio (tecovirimat/placebo), with mild-to-moderate mpox at low risk for severe symptoms. Based on these results, the study has stopped enrolment; enrolment was also stopped in a study arm, enrolling only those at risk or having severe disease. Of note, approximately 75% of subjects enrolled in the STOMP trial received tecovirimat for more than 5 days following symptom onset.^32,33 The future role of tecovirimat in mpox treatment is unclear.

Vaccinia immunoglobulin

Vaccinia immunoglobulin is derived from the antibodies of people who have been vaccinated against smallpox.¹² Smallpox and mpox are closely related and share similar antigenic properties; therefore, those who have received the smallpox vaccine are thought to produce antibodies that are cross-reactive to mpox.³⁵ VGIV is administered intravenously based on patient weight as a single dose.³⁶ The Centers for Disease Control and Prevention recommends considering VGIV for patients with mpox who are unable to mount a robust immune response, such as PLWH with CD4 count below 350 or those who have undergone solid organ transplantation.³⁷ One safety concern is the potential for corneal scarring, though this is limited to data from a mouse study; otherwise, VGIV has an overall favourable safety profile.¹³

Emerging challenges and future directions

Tecovirimat is the most used treatment modality at the moment; however, results from the PALM007 and STOMP trials raise concerns regarding tecovirimat’s efficacy in mild-to-moderate clade 1 and 2 infections.^29,31,32 Many antivirals require initiation early in treatment to prevent disease.³⁸ The optimal time to initiate tecovirimat – if there is one – has not been identified. Additionally, there are no data regarding tecovirimat’s use as a synergistic agent in a combination regimen. It is thought that combination regimens may increase the odds of successful treatment, i.e. tecovirimat with brincidofovir/cidofovir. If available, brincidofovir’s side effect profile is superior to that of cidofovir. Cidofovir may be best used topically or intralesionally for severe cases.^16,39 Finally, if available, VGIV should be considered in patients who are immunocompromised or with severe infections.⁴⁰

Overall, the aforementioned antivirals may offer potential therapeutic benefits. Issues such as drug resistance, toxicity and the complexities of treatment, especially in immunocompromised individuals, must be carefully managed. On-going research, clinical trials and the development of future therapies are essential to optimize treatment outcomes and address the evolving landscape of mpox management. Two novel antiviral agents that have shown activity against orthopoxviruses in preclinical studies include nucleoside analogues N-methanocarbathymidine and KAY-2-41.⁴¹ In addition, researchers are focusing on repurposing current agents that have displayed activity against mpox, including nitroxoline, an antibiotic for urinary tract infections.^42,43 As with many emerging diseases, until new treatment options are available, a multi-pronged approach to prevention and judicious use of current antivirals will be necessary to limit mpox’s spread.