Antiviral Treatment against Monkeypox: A Scoping Review

During the COVID-19 pandemic, the increase in reports of human monkeypox virus infection cases spreading in many countries outside Africa is a major cause for concern. Therefore, this study aimed to explore the evidence of antiviral pharmacotherapy available for the treatment of adult patients with monkeypox. A scoping review of the literature was conducted using PubMed, Scopus, Web of Science, Embase, and CENTRAL databases until 12 September 2022. The key search terms used were “monkeypox” and “treatment”. A total of 1927 articles were retrieved using the search strategy. After removing duplicates (n = 1007) and examining by title, abstract, and full text, 11 studies reporting case reports of monkeypox with antiviral treatment were included, detailing the number of monkeypox cases, clinical manifestations, number of participants with antiviral treatment, history of sexually transmitted diseases, method of diagnosis, location of skin lesions, drugs used in antiviral treatment, route of administration, and outcome. A total of 1281 confirmed cases of monkeypox have been reported, of which 65 monkeypox cases had antiviral treatment distributed most frequently in the United States (n = 30), the United Kingdom (n = 6), and Spain (n = 6). Of the total cases, 1269 (99.1%) were male with an age range of 18 to 76 years, and 1226 (95.7%) had a sexual behavior of being men who have sex with men. All confirmed cases of monkeypox were diagnosed by reverse transcriptase polymerase chain reaction (RT-PCR). The most frequent clinical manifestations were skin lesions, fever, lymphadenopathy, headache, fatigue, and myalgia. The most frequent locations of the lesions were perianal, genital, facial, and upper and lower extremities. The most commonly used drugs for antiviral treatment of monkeypox were: tecovirimat, cidofovir, and brincidofovir. All patients had a complete recovery. According to current evidence, the efficacy and safety of antiviral drugs against monkeypox is of low quality and scarce.


Introduction
During the COVID-19 pandemic, increased reporting of human monkeypox virus infection cases spreading in many countries outside of Africa is a major cause for concern [1]. MPX is a zoonotic viral disease caused by the monkeypox virus (MPXV) [3]. MPXV is a double-stranded DNA virus of the genus Orthopoxvirus of the family Poxviridae known for more than half a century but geographically restricted to a limited number of endemic countries in Central and West Africa [4].
The transmission of MPX to humans occurs mainly through contact with body fluids, skin lesions, or respiratory droplets from animals infected directly or indirectly through contaminated fomites [5]. The symptoms are similar to those of the disease known as smallpox, with MPX usually involving fever, a skin rash that is more common on the face and extremities than on the trunk, and lymphadenopathy, which is a characteristic feature of MPX [6], with an incubation period varying from 5 to 21 days [7].
MPXV has two distinct genetic clades: the Central African clade (Congo Basin) and the West African clade [8]. The West African clade is known to have a more favorable prognosis, with a case fatality rate of less than 1%. On the other hand, the Central Basin clade (Central African clade) is more lethal, with a case fatality rate of up to 10% in unvaccinated children [9].
At present, there is no authoritative treatment or adequate evidence-based guideline for the treatment of MPX. Thus, clinical management aims to provide symptomatic treatment, manage complications, and prevent long-term sequelae [4]. Although MPX is usually self-limiting and does not require medical treatment, there are some antiviral treatment alternatives, such as tecovirimat, brincidofovir (BCV), and cidofovir, which have been approved in animal models, but their efficacy has not been measured in humans [10,11]. However, the United States has recommended a licensed vaccine, JYNNEOS (Smallpox and MPX Vaccine, Live, Nonreplicating) for the vaccination of persons at risk of occupational exposure to Orthopoxviruses [12].
Although current vaccines offer cross-protection against MPX, they are not specific against the disease-causing MPXV, and their efficacy has not yet been proven in light of recent outbreaks in several countries [13]. Moreover, as a consequence of the eradication and cessation of smallpox vaccination for four decades, MPXV found an opportunity to re-emerge, but with different characteristics [14].
The objective of the present scoping review is to explore the evidence on antiviral pharmacotherapy available for the treatment of adult patients with MPX.

Protocol and Registration
The recommendations of the Preferred Reporting Items for Systematic and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) [15] and the methodological criteria of the Joana Briggs Institute were followed in the present scoping review [16]. The protocol was previously registered in the Figshare platform (https://doi.org/10.6084/m9.figshare. 20577312.v1) (accessed on 31 August 2022).

Eligibility Criteria
We included primary research articles on patients over the age of 18 who had a serological diagnosis, Polymerase Chain Reaction (PCR), electron microscopy, or immunohistochemical findings positive for MPX and who received some type of pharmacological treatment with an antiviral mechanism of action. The types of studies included in the present review were case reports, case series, observational studies (cohort, cross-sectional, case-control), and clinical trials (randomized and non-randomized). No language limit was established for the articles, and publications were included until 12 September 2022. Scoping reviews, systematic reviews, narrative reviews, letters to the editor without original results, and conference proceedings and abstracts were excluded.

Study Selection
The authors (A.S., L.A.C.C., D.K.B.-A., and A.J.R.-M.) reviewed the full-text reports and analyzed the inclusion criteria to reach a decision.

Outcomes
The primary outcome was to report on the antiviral drug therapy available for the treatment of adult patients with MPX.

Data Collection Process and Data Items
Three investigators independently extracted data from the selected studies into a Microsoft Excel spreadsheet. The following data were extracted from the selected studies: First author, country, year of publication, study design, number of patients, age, sex, method of MPX diagnosis, clinical signs, comorbidities, period of illness, antiviral treatment, dose, mode of administration, discharge, and death. A fourth investigator checked the list of articles and data extractions to ensure that there were no duplicate articles or duplicate information and resolved discrepancies about study inclusion. The results are summarized in narrative form and tables.

Study Selection
A total of 1927 articles were retrieved using the search strategy. The selection strategy is shown in the prism flow chart (Preferred Reporting Items for Systematic and Meta-Analysis Extension for Scoping Reviews). After the removal of duplicates (n = 920), 1007 articles were screened by the reviewers. After filtering the titles and reading the abstracts, 48 articles were selected for full-text reading, and 11 were considered eligible for inclusion in this Scoping Review ( Figure 1) [1,[18][19][20][21][22][23][24][25][26][27].

Data Collection Process and Data Items
Three investigators independently extracted data from the selected studies into a Microsoft Excel spreadsheet. The following data were extracted from the selected studies: First author, country, year of publication, study design, number of patients, age, sex, method of MPX diagnosis, clinical signs, comorbidities, period of illness, antiviral treatment, dose, mode of administration, discharge, and death. A fourth investigator checked the list of articles and data extractions to ensure that there were no duplicate articles or duplicate information and resolved discrepancies about study inclusion. The results are summarized in narrative form and tables.

Study Selection
A total of 1927 articles were retrieved using the search strategy. The selection strategy is shown in the prism flow chart (Preferred Reporting Items for Systematic and Meta-Analysis Extension for Scoping Reviews). After the removal of duplicates (n = 920), 1007 articles were screened by the reviewers. After filtering the titles and reading the abstracts, 48 articles were selected for full-text reading, and 11 were considered eligible for inclusion in this Scoping Review ( Figure 1) [1,[18][19][20][21][22][23][24][25][26][27].

Oral
None Full recovery NR: No report.

Discussion
There is currently no approved treatment specifically for MPXV infections [28]. However, antivirals developed for use in smallpox patients may be beneficial against MPX, therefore the objective of the present scoping review is to explore the evidence on antiviral pharmacotherapy available for the treatment of adult patients with MPX. It is important to know the correct management of these patients to help mitigate the disease process in order to avoid possible sequelae and even death.
In total, we included 11 studies involving 1281 patients, with the United Kingdom being the country with the most reported patients. All confirmed cases of MPX were diagnosed by RT-PCR. Most of the patients were male and stated that they had the sexual behavior of being men who have sex with men. This would indicate the importance of the sexual transmission mechanism in the spread of MPX. In addition, 35.7% of patients tested positive for HIV, which could predispose them to a more aggressive development of MPX disease.
According to the World Health Organization, reports that current epidemiological statistics indicate that young males are disproportionately affected, with 98.2% (20,138/ 20,500) of patients with gender information being male and a median age of 36 years (interquartile range: 30-43 years). A total of 95.8% (9484/9899) of patients with reported sexual orientation were identified as males who have intercourse with men [29].
It was reported that only 5% of patients received antiviral treatment against MPX, most often with tecovirimat or cidofovir. Although there is a lack of information on these substances' efficacy in humans, animal research and case studies imply that they may be effective [30].
Tecovirimat (ST-246) is an antiviral drug that was approved by the Food and Drug Administration (FDA) for the treatment of smallpox disease. Tecovirimat has activity against orthopoxviruses but no notable activity against other dsDNA viruses [31]. One of the main targets of tecovirimat is the palmitoylated phospholipase F13 or p37. F13 is located in the viral envelope and membrane and is involved in the formation of the extracellular enveloped virus (EVV). EVV is hypothesized to be a major contributor to viral entry, cell-tocell transmission, and transmission through the bloodstream to distant tissues [31][32][33]. In the present review, 41 participants received tecovirimat at a dose of 600 mg twice daily for pharmacokinetics of tecovirimat [34,35]. In general, adverse effects were mild and did not leave sequelae, the most frequent being headache and nausea [30]. The efficacy of tecovirimat was previously demonstrated in animal models [30,36], but no data are yet available in humans. A multicenter Phase 2 clinical trial evaluated the safety, tolerability, and pharmacokinetics of tecovirimat when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in adult volunteers 18 to 74 years of age and found it to be safe and well tolerated, with no deaths or serious adverse events [35]. Two Phase III clinical trials are currently underway to evaluate the efficacy of tecovirimat for the treatment of MPX (NCT05534984, NCT05534165), both with tentative completion dates of 2023.
Cidofovir is a drug used to treat poxviruses; however, the FDA has only approved its usage in Acquired Immune Deficiency Syndrome (AIDS) patients for cytomegalovirus retinitis. Cidofovir diphosphate (CDV-pp), a prodrug that enters cells and is phosphorylated to its active form by cellular enzymes, has the effect of integrating into the developing DNA strand and slowing DNA synthesis. It can also decrease DNA polymerase's 3 -5 exonuclease activity [31]. It has been demonstrated to be effective in treating molluscum contagiosum lesions in individuals with AIDS-related CMV retinitis [37]. It is also effective against bovine smallpox and Tecovirimat-associated eczema [38,39]. There is inadequate clinical evidence to support the efficacy of cidofovir against MPX in humans. However, its in vitro efficacy has been demonstrated on MPX infections in animals [10,40,41]. A clinical trial evaluated the synthesis and in vitro and in vivo activity of cidofovir against a variety of orthopoxviruses, it was found to be a broad-spectrum antiviral with potent activity against orthopoxviruses [42].
BCV is another treatment that was approved by the FDA to treat smallpox in 2021. This drug has shown efficacy in treating other orthopoxviruses. BCV, a lipid conjugate of cidofovir, is an acyclic lipid nucleoside phosphonate that is available orally. Unlike cidofovir, BCV provides fewer toxic effects, such as nephrotoxicity, which has been demonstrated after intravenous (IV) dosing in animals and humans and has benefits such as oral use [31,43]. BCV shows activity against several DNA viruses, mainly the poxviruses as the MPXV [44]. It was evidenced in a study in which 3 MPX patients were treated with a weekly BCV dose of 200 mg, that it demonstrated a reduction of the viral load; however, none of the patients completed the treatment because they reported elevations of hepatic enzymes, without observing other hematological alterations [18]. A clinical trial evaluated the safety of brincidofovir against orthopoxvirus in healthy adult subjects and found it to be safe and well tolerated, with no serious or life-threatening adverse reactions [45]. In addition, a Phase II clinical trial evaluating the use of BCV IV in patients with adenovirus infection is currently underway (NCT04706923). Importantly, clinical trials are still needed to evaluate the efficacy and safety of BCV in MPX.
The situation of this re-emerging zoonotic disease is very worrying and deserves further study on the antiviral treatments that can be used against this disease that is currently affecting several continents and with possible new routes of transmission, even during the COVID-19 pandemic that has not yet ended. Key interventions to prevent MPX outbreaks include a high index of suspicion, early identification, isolation, barrier nursing, and strict infection prevention practices by healthcare workers [46].

Limitations and Strengths
Among the limitations of this scoping review is the small number of eligible participants who received antiviral therapy against MPX. In addition, most of the studies corresponded to case reports and case series, where there was no control group with which to compare the effectiveness of the antiviral drugs used. Therefore, with the current evidence, it is not possible to provide a conclusion regarding the efficacy of antiviral drugs. Future randomized clinical studies with appropriate methods are required to assess the effectiveness of tecovirimat, BCV, cidofovir, and other drugs, particularly in populations thought to be at risk, such as HIV patients. In addition, another limitation is that we did not identify articles from the gray literature. In terms of strengths, the present study has a rigor-ous methodology since it was conducted by the JBI and PRISMA-ScR guidelines. Likewise, all the processes carried out for the selection of studies were performed independently by two or more authors.

Conclusions
MPX has spread rapidly throughout the world, and there is less information on the effectiveness of antiviral drugs in treating this disease. However, because smallpox and MPXV are genetically related, antiviral drugs developed to protect against smallpox could also be used to treat MPXV infections. Patients with compromised immune systems and those who are more likely to develop the severe disease may be advised to take antivirals, such as tecovirimat. According to current studies, symptoms usually resolve with or without treatment; however, future randomized clinical trials are needed to determine the efficacy and safety of tecovirimat, cidofovir and BCV against MPX.