ORIGINAL RESEARCH
Microbes, Infection and Chemotherapy ISSN: 2789 - 4274 https://doi.org/10.54034/mic.e1963
Antiviral Drugs for Treatment of Human Monkeypox: A Systematic Review/Meta-analysis
Ahmed Mohamed Abdelghany1,*, Fathy Fathy Ghaly2, Mohamed Farouk Allam1,3,#
1Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, October 6 University, Cairo, Egypt.
2Menouf Fever Hospital, Menoufia, Egypt.
3Department of Family Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Corresponding author: E-mail:farouk.allam@med.asu.edu.eg
Orcid ID: *https://orcid.org/0009-0002-3924-4507, #https://orcid.org/0000-0001-5954-8909
Submitted: september 09, 2023
Reviewed: december 17, 2023
Approved: march 05, 2024
Abstract
Background. On 23 July 2022, the World Health Organization declared a Public Health Emergency of International Concern. Monkeypox is a zoonotic viral disease caused by the monkeypox virus that is transmitted from animals to humans or from human to human. To date, treatment for human monkeypox is mostly symptomatic, as there is no specific standard antiviral treatment. Persons with severe symptoms and signs, immunocompromised patients, children younger than 8 years, and pregnant individuals should be considered for specific antiviral treatment. Objective. This study aims to assess effectiveness of antiviral drugs in treatment of human monkeypox. Methodology. Published clinical trials and cohort studies on the role of antivirals in the management of human monkeypox that were identified through a comprehensive search of electronic databases up to April 1, 2023. The patients included were children and adults confirmed with monkeypox. The diagnosis was based on PCR or clinical symptoms. The intervention was antivirals administration in human monkeypox patients, versus supportive treatment/placebo. Outcome measured include the duration of monkeypox until recovery, need for hospitalization, and ICU admission. Results. We included four completed studies with 195 participants assessing the safety, pharmacokinetics, and efficacy of antiviral treatments for human monkeypox compared to placebo. Three studies investigated Tecovirimat (st-246), and one investigated Brincidofovir. Both drugs were safe, tolerable, and effective with no serious adverse effects. The other 5 studies were not completed and are ongoing. Conclusion. There are currently no approved antivirals for the treatment of monkeypox; some medications could be authorized for outbreak use and are now under investigation, such as Tecovirimat, Cidofovir, and Brincidofovir.
Keyword: monkeypox, tecovirimat, cidofovir, brincidofovir, meta-analysis, systematic review.
Introduction
Monkeypox is a zoonotic viral disease caused by the monkeypox virus; there are 2 genetic clades of monkeypox virus: clade I, in Central Africa, and clade II, in West Africa. It is a double-stranded DNA virus belongs to the Orthopoxvirus genus in the Poxviridae family that can be transmitted from animals to humans and from humans to humans (1), with an incubation period ranging from 5 to 21 days. Symptoms include rash, fever, and swollen lymph nodes. Although usually self-limiting, monkeypox can be severe or even fatal, especially in young children and immunosuppressed individuals (2).
Monkeypox virus was first discovered in laboratory monkeys in Denmark in the late 1950s. Thereafter, it is identified as a cause of disease in humans in the Democratic Republic of Congo in the 1970s when a 9-year-old boy developed smallpox like illness, which was eventually confirmed as human monkeypox by the World Health Organization. Since then, it has occurred sporadically in Central, East Africa and West Africa. In 2003, an outbreak in the US was linked to imported wild animals from Africa. Thousands of suspected cases have been reported annually in the Democratic Republic of Congo since 2005. In 2017, monkeypox re-emerged as a public health issue in Nigeria, spreading locally and among international travelers. Between 2018 and 2021, cases were confirmed in six African countries: Cameroon, Central African Republic, Congo, Nigeria, Democratic Republic of Congo, and Sierra Leone. In May 2022, a new multinational outbreak, affected over 87,000 people in 110 countries with 112 deaths, primarily affecting gay and bisexual (3).
Antiviral drugs previously tested for the treatment of human monkeypox include:
1) Tecovirimat (TPOXX or ST-246) was approved by the FDA in July 2018 for the treatment of human smallpox (4). It targets and inhibits the activity of the orthopoxvirus VP37 protein and blocks its interaction with cellular Ras-related protein Rab-9A guanosine triphosphate (Rab9 GTPase) and tail-interacting protein of 47 kDa (TIP47), which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus (5). Tecovirimat is also approved by the European Medicine Agency (EMA) for the treatment of orthopoxvirus disease (smallpox, monkeypox, cowpox) and vaccinia complications. It is available as an immediate-release oral capsule administered twice daily for 14 days. The US FDA approved an intravenous formulation on May 19, 2022 (6). It has been shown to reduce morbidity and mortality even when treatment is initiated after the onset of clinical signs ). Common side effects include headache, nausea, and abdominal pain (7). NIOCH-14 is a synthetic Tecovirimat analog developed by the State Research Center of Virology and Biotechnology Vector in 2001. Owing to the small number of patients treated, the clinical efficacy of this therapeutic for monkeypox is uncertain (8).
(2) Cidofovir (vistide) was approved by the FDA in June 1996 for the treatment of cytomegalovirus (CMV) retinitis in patients with (AIDS) (9). Data on the effectiveness of Cidofovir in the treatment of monkeypox virus infection in humans are not available. However, it has been shown to be effective against orthopoxviruses in in-vitro and animal studies (10).
Cidofovir is a monophosphate nucleotide analog that is phosphorylated to the diphosphate form, which competitively inhibits the incorporation of deoxycytidine triphosphate (dCTP) into viral. DNA by viral DNA polymerase. The incorporation of the drug disrupts further chain elongation (11). It is associated with nephrotoxicity, which can be minimized by concomitant oral administration of probenecid and intravenous saline hydration (12).
(3) Brincidofovir (Tembexa or CMX001) is a prodrug of Cidofovir approved by the FDA in June 2021 for the treatment of human smallpox (13). It is a lipid conjugate that is converted intracellularly to Cidofovir, with greater bioavailability and less nephrotoxicity (14,15). Reported side effects of this medication include elevation of hepatic transaminases, diarrhea, nausea, vomiting, and abdominal pain (16). Brincidofovir is not recommended for pregnant women because of the risk of embryo-fetal toxicity (17).
Till date, there is limited consensus on the optimal treatment strategy for human monkeypox. The aim of this systematic review was to assess the evidence of antiviral drugs' effectiveness in human monkeypox treatment.
Methodology
Criteria for considering the studies in this review
Types of studies: clinical Trials and Cohort Studies.
Participants: participants were child and adult patients diagnosed with human monkeypox. Patients were considered to have a definite diagnosis of human monkeypox if they were laboratory-confirmed using reverse transcription polymerase chain reaction (RT-PCR) and/or clinical symptoms with anti-orthopoxvirus IgM. All healthcare settings (community/primary care, hospital outpatient, or long-stay institution) were considered eligible.
Types of interventions: antiviral administration in human monkeypox patients versus supportive treatment/placebo.
Types of outcome measures: At least one of these outcome measures was considered:
1) Duration of human monkeypox till recovery.
2) Need for hospitalization.
3) Need for ICU admission.
4) Fatal prognosis.
Search strategy for identification of studies
Published studies and abstracts on the role of antivirals in the management of human monkeypox were identified through a comprehensive search of electronic databases.
We searched the following databases up to 1 April 2023: PubMed (https://pubmed.ncbi.nlm.nih.gov/ ), ScienceDirect (www.sciencedirect.com), Scirus (www.scirus.com/srsapp), ISI Web of Knowledge (http://www.isiwebofknowledge.com), and CENTRAL Cochrane Central Register of Controlled Trials (http://www.mrw.interscience.wiley.com/cochrane/cochrane_clcentral_articles_fs.htm), using a combination of the following keywords: "Human Monkeypox, Antivirals, ST-246, Tecovirimat, Brincidofovir, Cidofovir, NIOCH-14, Clinical Trail, Cohort Study".
This study was limited to articles published in Arabic, English, French, and Spanish.
Screening and evaluation of articles
The following screening was used to screen the articles yielded by reviewing the literature after ranking the articles according to the authors and journal of publication. Only articles that fulfilled the inclusion criteria were included for further data collection, analysis, and reporting.
Sociodemographic information
Sociodemographic information included age, sex, and skin color/race. Patients < 10 years old were considered children and those between 10 and 18 years old were considered adolescents, on criteria set by the World Health Organization.
Inclusion criteria:
Inclusion criteria for this study encompass cohort studies and randomized controlled trials conducted on adult human subjects diagnosed with human monkeypox, confirmed through positive reverse transcription polymerase chain reaction (RT-PCR) results and/or clinical symptoms with anti-orthopoxvirus IgM. Additionally, eligible studies are those conducted in all healthcare settings (community/primary care, hospital outpatient, or long-stay institutions), and published in Arabic, English, French, or Spanish.
Exclusion criteria:
Exclusion criteria include review and opinion studies, case series, animal studies, and studies published in languages other than Arabic, English, French, or Spanish.
Data extraction:
A copy of each identified study was obtained, and relevant data were abstracted by the first author for a quantitative overview.
The type of risk estimate (i.e., relative risk or number needed to treat) and the country where the study was carried out were also ascertained. In case of discrepancies, or when the information presented in a study was unclear, abstraction by a second reviewer was sought to resolve the discrepancy.
Ethical Considerations: systematic reviews and meta-analysis are exempted from Ethical Committees Approvals.
Results
After a comprehensive search using the keywords “Monkeypox AND Antiviral,” only 18 studies were identified. These studies were published between 2000 and 2023.
Table 1 lists the studies identified after the comprehensive search and before excluding studies that did not fulfill the inclusion criteria.
Table 1. Studies identified through database searching (PubMed, ScienceDirect, Scirus, ISI Web of Knowledge, and CENTRAL) using the keywords “Monkeypox AND Antiviral”
| N | Authors | Title | Year | Journal |
|---|---|---|---|---|
| 1 | Douglas W Grosenbach, et al (18). | Oral Tecovirimat for the Treatment of Smallpox. | 2018 | N Engl J Med 2018;379(1):44-53. |
| 2 | Robert Jordan, et al (19). | ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification. | 2009 | Antimicrob Agents Chemother 2009;53(5):1817-22. |
| 3 | Jarasvech Chinsangaram, et al (20). . | Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers. | 2012 | Antimicrob Agents Chemother 2012;56(9):4900-5. |
| 4 | Jarasvech Chinsangaram, et al (21). | Pharmacokinetic comparison of a single oral dose of polymorph form i versus form V capsules of the antiorthopoxvirus compound ST-246 in human volunteers. | 2012 | Antimicrob Agents Chemother 2012;56(7):3582-6. |
| 5 | Robert Jordan, et al (22). | Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor. | 2008 | Antimicrob Agents Chemother 2008;52(5):1721-7. |
| 6 | Greg Chittick, et al (23). | Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox. | 2017 | Antiviral Res 2017;143:269-77. |
| 7 | Wendy Painter, et al (24). | First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. | 2012 | Antimicrob Agents Chemother 2012;56(5):2726-34. |
| 8 | D Calista (25). | Topical cidofovir for severe cutaneous human papillomavirus and molluscum contagiosum infections in patients with HIV/AIDS. A pilot study. | 2000 | J Eur Acad Dermatol Venereol 2000;14(6):484-8. |
| 9 | O Yu Mazurkov, et al (26). | Estimation of Absolute Bioavailability of the Chemical Substance of the Anti-Smallpox Preparation NIOCH-14 in Mice. | 2020 | Bull Exp Biol Med 2020;170(2):207-210. |
| 10 | Oleg Yu Mazurkov, et al (8). | New effective chemically synthesized anti-smallpox compound NIOCH-14. | 2016 | J Gen Virol 2016;97(5):1229-39. |
| 11 | Ksenya A Titova, et al (27). | Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy. | 2015 | J Gen Virol 2015;96(9):2832-43. |
| 12 | Al A Sergeev, et al (28). | The Possibility of Using the ICR Mouse as an Animal Model to Assess Antimonkeypox Drug Efficacy. | 2016 | Transbound Emerg Dis 2016;63(5):e419-30. |
| 13 | A S Kabanov, et al (29). | A comparative study of the antiviral activity of chemical compounds concerning the orthopoxviruses experiments in vivo. | 2013 | Vopr Virusol 2013;58(4):39-43. Russian. |
There are five ongoing trials (NCT05559099, NCT05534984, NCT05534165, NCT05597735 and ISRCTN17461766) investigating the efficacy and safety of Tecovirimat for monkeypox treatment; these studies are conducted in Congo, USA, Canada, Brazil, Switzerland, and UK respectively. Four of these RCTS are Phase III and one is Phase II (Congo). Upon the availability of outcomes from the five ongoing randomized controlled trials (RCTs), it will be possible to compare the safety and effectiveness of Tecovirimat versus placebo for the treatment of monkeypox (30-34).
Of these 18 studies, only 9 studies examined the safety and/or pharmacokinetics of systemic antiviral drugs in human monkeypox.
Four of the included 9 studies conducted on humans were Phase III, randomized controlled clinical trials. Two were Phase II clinical trials and three were Phase I clinical trials.
Figure 1 summarizes the reasons for excluding 9 of the 18 studies identified after database searching.
Figure 1 Flow Diagram Highlighting the Process of Study Selection for each Step of the Systematic Review
Table 2 Summary of Published clinical trials using systemic antiviral for the treatment of human monkeypox
| N | Short Summary of the clinical trial |
|---|---|
| 1 | Title of the study: Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers. |
| Clinical Trial Phase: Phase II | |
| Summary: A double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study (20). | |
| 2 | Title of the study: Pharmacokinetic comparison of a single oral dose of polymorph form I versus form V capsules of the antiorthopoxvirus compound ST-246 in human volunteers. |
| Clinical Trial Phase: Phase I | |
| Summary: A double-blind, randomized, crossover, exploratory study was conducted to compare the pharmacokinetics of a single daily 400-mg oral dose of ST-246 polymorph form I (test drug) versus polymorph form V (reference drug) administered to fed, healthy human volunteers. Both forms appeared to be well tolerated, with no serious adverse events. It was found that ST-246 form I is safe and more stable than form V (21). | |
| 3 | Title of the study: Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor. |
| Clinical Trial Phase: Phase I | |
| Summary: A double-blind, randomized, placebo-controlled single ascending dose study was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was safe and well tolerated when administered orally as a single dose to healthy human volunteers in a fasting state (500 to 2,000 mg) or nonfasting state (1,000 mg) (22). | |
| 4 | Title of the study: First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. |
| Clinical Trial Phase: Phase I | |
| Summary: A randomized, double-blind, placebo-controlled, parallel group, dose-escalating study in healthy volunteers. The objectives of the study were to evaluate the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. CMX001 was well tolerated at all doses, with no dose-limiting toxicity especially nephrotoxicity (24) | |
| 5 | Title of the study: 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. |
| Clinical Trial Phase: Phase II | |
| Summary: This study tests the antiviral drug Tecovirimat for the treatment of adults and children with laboratory-confirmed monkeypox disease in the Democratic Republic of Congo. 450 participants will be randomized to receive either oral Tecovirimat or placebo, each administered in the hospital with standard-of-care (SOC) treatment for 14 days. Participants will be followed for 28 days with an optional visit at Day 59 for long-term assessment.(31). | |
| 6 | Title of the study: 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. |
| Clinical Trial Phase: Phase III | |
| Summary: In this study, 530 eligible participants will be randomized to receive either Tecovirimat or placebo for 14 days. Participants will self-monitor their skin and mucosal lesions daily for 29 days or until resolution. Weekly assessments through day 29 will be conducted to monitor monkeypox disease. A final assessment will be conducted on day 57 to check for potential infection recurrence (32). | |
| 7 | Title of the study: Placebo-controlled Randomized Trial of Tecovirimat in Non-hospitalized Patients with Monkeypox: Canadian Feasibility Study (PLATINUM-CAN). |
| Clinical Trial Phase: Phase III | |
| Summary: PLATINUM-CAN is a parallel collaborative trial linked with the sister trial PLATINUM led by Oxford University. PLATINUM-CAN is a multi-centre, randomized, placebo-controlled trial of Tecovirimat in non-hospitalized patients with PCR confirmed monkeypox infection. The study will test the efficacy and safety of Tecovirimat for patients infected with monkeypox and determines the feasibility of conducting interventional monkeypox trials in Canada (34). | |
| 8 | Title of the study: A Phase III, Multi-country, Randomized, Placebo-controlled, Double-blinded Trial to Assess the Efficacy and Safety of Tecovirimat Antiviral Treatment for Patients With Monkeypox Virus Disease. |
| Clinical Trial Phase: Phase III | |
| Summary: The overall purpose of this study is to evaluate whether Tecovirimat is an efficient and safe antiviral in the treatment of monkeypox in adults and adolescents (14 years old and older).The primary objective is to evaluate the clinical efficacy, as assessed by time to all visible lesion(s) resolution, of Tecovirimat treatment + Standard of Care (SOC) compared to placebo + SOC for patients with monkeypox.The secondary objective is to evaluate the clinical efficacy, as assessed by mortality, hospitalization, complications, duration of symptoms and virological shedding, and the safety of Tecovirimat treatment + SOC compared to placebo + SOC in patients with monkeypox (30). | |
| 9 | Title of the study: Placebo-controlled randomized trial of tecovirimat in non-hospitalized monkeypox patients (PLATINUM) |
| Clinical Trial Phase: Phase III | |
| Summary: it is a double blind randomized parallel group placebo-controlled trial that enroll 500 participants with monkeypox in the UK. Randomized 2:1 to Tecovirimat or placebo for 14 days. Severe or high-risk cases receive open label Tecovirimat. Participants self-monitor for 28 days. The primary endpoint is time to resolution of all lesions. To achieve full study power, results will be combined with the sister study, PLATINUM -CAN, a similar Canadian study, in a meta-analysis (33). |
Discussion
Many studies discussed the prevalence, symptoms, diagnosis, treatment, and prognosis of poxvirus, especially after its emerging attacks in the last decade.
In this systematic review, we try to identify clinical trials for the treatment of poxvirus, and we focused on treatment for human monkeypox. Only 18 studies were localized, of which 9 were conducted on humans and the other 9 studies were conducted on animals or in-vitro, thus were excluded.
Jordan and collaborators conducted the first clinical trial on humans for the treatment of monkeypox. The authors evaluated and examined the safety and tolerability of ST-246. The single-dose plasma pharmacokinetics of ST-246 in fasting subjects showed dose proportionality over the dose levels of 500 and 1,000 mg. ST-246 was safe and well tolerated when administered orally as a single dose to healthy human volunteers in a fasting state (500 to 2,000 mg) or non-fasting state (1,000 mg). The single-dose plasma pharmacokinetics of ST-246 in fasting subjects showed dose proportionality over the dose levels of 500 and 1,000 mg, with saturation of exposure occurring above the 2,000-mg dose level. About 15.8% reported at least one treatment-emergent adverse event (22).
The second clinical trial was conducted by Chinsangaram and collaborators to determine ST-246 polymorphic forms with high bioavailability against monkeypox. The primary objective of this phase I, randomized, double-blind, crossover study of fed, healthy subjects was to compare the pharmacokinetics of a single oral dose (400 mg) of ST-246 polymorph form I (test drug) versus ST-246 polymorph form V (reference drug). The authors found that both forms exhibited comparable plasma concentration versus time profiles. Complete bioequivalence between the two forms was not found, but both forms of the drug provided adequate plasma exposure in humans at a 400-mg dose, which is much higher than that needed for efficacy in animals. The extent of absorption (as defined by AUC0-∞) of form I was 11.7% lower than that of form V. ST-246 form I is safe and more stable than form V (21).
The third clinical trial was conducted by the same authors as the second one, as a continuation of their research on ST-246. The authors conducted a phase 2, double-blind, randomized, placebo-controlled, multicenter trial. ST-246 was found to be safe, well tolerated, and predictable when administered as a single daily oral dose of 400 or 600 mg for 14 days to 18- to 74-year-old fed volunteers. This clinical trial reported that the 400- and 600-mg dose proportionality analysis showed that the ratios of dose-normalized maximum drug concentration and area under plasma concentration‐time curve to the end of dosing interval values ranged from 80% to 85%. The most reported treatment-emergent adverse events were mild nausea and headache. There were no remarkable or clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or ECGs. No deaths or serious adverse events occurred during this study (20).
The fourth clinical trial evaluated the safety and pharmacokinetic parameters of CMX001 after single and multiple doses. The authors reported that CMX001 was well-tolerated when administered as a single dose of up to 2 mg/kg or as 3 doses of up to 1 mg/kg given once every 6 days against multiple double-stranded DNA viruses. No adverse events were detected based on physical examinations(24).
Clinical trial numbers from 5 to 9 are in progress in Congo, USA, Canada, Brazil, Switzerland, and UK.
Limitations of this study include a small number of included clinical trials investigating monkeypox treatment with a limited number of patients. Furthermore, this systematic review focuses solely on systemic antivirals and does not encompass topical treatments. Additionally, up to the present time, no antiviral has been found to be FDA approved for the treatment of monkeypox.
Conclusion
There are currently no approved antivirals for the treatment of monkeypox; some medications could be authorized for outbreak use and are now under investigation, such as Tecovirimat, Cidofovir, and Brincidofovir, these drugs were found to be safe, tolerable, and effective with no serious adverse effects. New randomized controlled clinical trials to assess the effectiveness of antiviral drugs in the management of human monkeypox are strongly and urgently needed.
Authors' contributions
Ahmed Mohamed Abdelghany: study design, analysis and interpretation of data, manuscript writing, collection of data, critical revision. Fathy Fathy Ghaly: study design, analysis and interpretation of data, collection of data. Mohamed Farouk Allam: study design, manuscript writing, critical revision.
Ethics statement
Systematic reviews and Meta-analysis are exempted from Ethical Committees Approvals.
Funding
None.
Conflict of interest
None.
Availability of data
The datasets generated and /or analyzed during current study available from the corresponding author on reasonable request.
References
1. Bunge EM, Hoet B, Chen L, Lienert F, Weidenthaler H, Baer LR, et al. The changing epidemiology of human monkeypox-A potential threat? A systematic review. PLoS Negl Trop Dis 2022;16(2):e0010141.
2. CDC. Centers for Disease Control and Prevention. 2023 [cited 2024 Mar 1]. Mpox in the U.S. Available from: https://www.cdc.gov/poxvirus/mpox/symptoms/index.html
3. Mpox (monkeypox) [Internet]. [cited 2024 Mar 1]. Available from: https://www.who.int/news-room/questions-and-answers/item/monkeypox
4. Commissioner O of the. FDA. FDA; 2020 [cited 2024 Mar 1]. FDA approves the first drug with an indication for treatment of smallpox. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-indication-treatment-smallpox
5. Grosenbach DW, Jordan R, Hruby DE. Development of the small-molecule antiviral ST-246® as a smallpox therapeutic. Future Virol 2011;6(5):653–71.
6. Tecovirimat SIGA | European Medicines Agency [Internet]. [cited 2024 Mar 1]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/tecovirimat-siga
7. Russo AT, Grosenbach DW, Chinsangaram J, Honeychurch KM, Long PG, Lovejoy C, et al. An overview of tecovirimat for smallpox treatment and expanded anti-orthopoxvirus applications. Expert Rev Anti Infect Ther 2021;19(3):331–44.
8. Mazurkov OY, Kabanov AS, Shishkina LN, Sergeev AA, Skarnovich MO, Bormotov NI, et al. New effective chemically synthesized anti-smallpox compound NIOCH-14. J Gen Virol. 2016;97(5):1229–39.
9. FDA approves cidofovir for treatment of CMV retinitis. Food and Drug Administration. J Int Assoc Physicians AIDS Care 1996;2(8):30.
10. Treatment Information for Healthcare Professionals | Mpox | Poxvirus | CDC [Internet]. 2023 [cited 2024 Mar 3]. Available from: https://www.cdc.gov/poxvirus/mpox/clinicians/treatment.html
11. Lea AP, Bryson HM. Cidofovir. Drugs 1996;52(2):225–30; discussion 231.
12. Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives DV, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med 1997;126(4):257–63.
13. Research C for DE and. FDA approves drug to treat smallpox. FDA [Internet]. 2021 Sep 30 [cited 2024 Mar 1]; Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-smallpox
14. Chan-Tack K, Harrington P, Bensman T, Choi SY, Donaldson E, O'Rear J, et al. Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration's Evaluation. Antiviral Res 2021;195:105182.
15. Hutson CL, Kondas AV, Mauldin MR, Doty JB, Grossi IM, Morgan CN, et al. Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model. mSphere 2021;6(1):e00927-20.
16. McCollum AM, Damon IK. Human monkeypox. Clin Infect Dis 2014;58(2):260–7.
17. Adler H, Gould S, Hine P, Snell LB, Wong W, Houlihan CF, et al. Clinical features and management of human monkeypox: a retrospective observational study in the UK. Lancet Infect Dis 2022;22(8):1153–62.
18. Grosenbach DW, Honeychurch K, Rose EA, Chinsangaram J, Frimm A, Maiti B, et al. Oral Tecovirimat for the Treatment of Smallpox. N Engl J Med 2018;379(1):44–53.
19. Jordan R, Goff A, Frimm A, Corrado ML, Hensley LE, Byrd CM, et al. ST-246 Antiviral Efficacy in a Nonhuman Primate Monkeypox Model: Determination of the Minimal Effective Dose and Human Dose Justification. Antimicrob Agents Chemother 2009;53(5):1817–22.
20. Chinsangaram J, Honeychurch KM, Tyavanagimatt SR, Leeds JM, Bolken TC, Jones KF, et al. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers. Antimicrob Agents Chemother 2012;56(9):4900–5.
21. Chinsangaram J, Honeychurch KM, Tyavanagimatt SR, Bolken TC, Jordan R, Jones KF, et al. Pharmacokinetic comparison of a single oral dose of polymorph form i versus form V capsules of the antiorthopoxvirus compound ST-246 in human volunteers. Antimicrob Agents Chemother 2012;56(7):3582–6.
22. Jordan R, Tien D, Bolken TC, Jones KF, Tyavanagimatt SR, Strasser J, et al. Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor. Antimicrob Agents Chemother 2008;52(5):1721–7.
23. Chittick G, Morrison M, Brundage T, Nichols WG. Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox. Antiviral Res 2017;143:269–77.
24. Painter W, Robertson A, Trost LC, Godkin S, Lampert B, Painter G. First pharmacokinetic and safety study in humans of the novel lipid antiviral conjugate CMX001, a broad-spectrum oral drug active against double-stranded DNA viruses. Antimicrob Agents Chemother 2012;56(5):2726–34.
25. Calista D. Topical cidofovir for severe cutaneous human papillomavirus and molluscum contagiosum infections in patients with HIV/AIDS. A pilot study. J Eur Acad Dermatol Venereol 2000;14(6):484–8.
26. Mazurkov OY, Shishkina LN, Bormotov NI, Skarnovich MO, Serova OA, Mazurkova NA, et al. Estimation of Absolute Bioavailability of the Chemical Substance of the Anti-Smallpox Preparation NIOCH-14 in Mice. Bull Exp Biol Med 2020;170(2):207–10.
27. Titova KA, Sergeev AA, Zamedyanskaya AS, Galahova DO, Kabanov AS, Morozova AA, et al. Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy. J Gen Virol 2015;96(9):2832–43.
28. Sergeev AA, Kabanov AS, Bulychev LE, Sergeev AA, Pyankov OV, Bodnev SA, et al. The Possibility of Using the ICR Mouse as an Animal Model to Assess Antimonkeypox Drug Efficacy. Transbound Emerg Dis 2016;63(5):e419-430.
29. Kabanov AS, Sergeev AA, Shishkina LN, Bulychev LE, Skarnovich MO, Sergeev AA, et al. [A comparative study of the antiviral activity of chemical compounds concerning the orthopoxviruses experiments in vivo]. Vopr Virusol 2013;58(4):39–43.
30. Alexandra C. A Phase III, Multi-country, Randomized, Placebo-controlled, Double-blinded Trial to Assess the Efficacy and Safety of Tecovirimat Antiviral Treatment for Patients With Monkeypox Virus Disease [Internet]. clinicaltrials.gov; 2023 Oct [cited 2024 Jan 1]. Report No.: NCT05597735. Available from: https://clinicaltrials.gov/study/NCT05597735
31. National Institute of Allergy and Infectious Diseases (NIAID). 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 [Internet]. clinicaltrials.gov; 2024 Feb [cited 2024 Jan 1]. Report No.: NCT05559099. Available from: https://clinicaltrials.gov/study/NCT05559099
32. National Institute of Allergy and Infectious Diseases (NIAID). A Randomized, Placebo-Controlled, Double-Blinded Trial of the Safety and Efficacy of Tecovirimat for the Treatment of Human Monkeypox Virus Disease [Internet]. clinicaltrials.gov; 2024 Feb [cited 2024 Jan 1]. Report No.: NCT05534984. Available from: https://clinicaltrials.gov/study/NCT05534984
33. ISRCTN - ISRCTN17461766: Antiviral treatment with tecovirimat for patients managed at home with mpox [Internet]. [cited 2024 Mar 3]. Available from: https://www.isrctn.com/ISRCTN17461766
34. Klein M. Placebo-controlled Randomized Trial of Tecovirimat in Non-hospitalized Patients With Monkeypox: Canadian Feasibility Study (PLATINUM-CAN) [Internet]. clinicaltrials.gov; 2024 Feb [cited 2024 Jan 1]. Report No.: NCT05534165. Available from: https://clinicaltrials.gov/study/NCT05534165
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