What is the aim of this review?
There are no drugs licenced specifically for treating mpox, but some drugs that are licenced for treating similar viral infections, such as smallpox, are authorized for treating mpox during an outbreak. The effects of these drugs have not yet been studied in randomized trials in people with mpox. Randomized trials include at least two treatment groups, such as one receiving the drug and one receiving a placebo, where the people recruited for the trial are randomly allocated to either group. This review summarizes evidence on the safety and effectiveness of treatments for mpox in humans, which was completed in two parts: a review of evidence from randomized controlled trials (RCTs) and a review of safety data from non-randomized studies.
Randomized controlled trials review
We searched for RCTs on both the safety and effectiveness of treatments for mpox.
Non-randomized studies review
We searched for non-randomized studies on the safety of treatments for mpox only.
Key messages
Randomized controlled trials review
When their results become available, data from five ongoing RCTs will allow us to compare safety and effectiveness outcomes between people who receive treatment for mpox and those who do not. We will be able to compare patient-important outcomes for different treatment options.
Non-randomized studies review
Tecovirimat, an oral anti-viral drug, is safe and well tolerated in individuals with mpox, based on evidence from non-randomized studies. Three people treated with brincidofovir, another oral anti-viral drug, experienced a sudden increase in one liver enzyme called alanine transaminase (ALT), and their treatment was discontinued as a result. This result may indicate mild liver injury caused by the drug. More severe forms of drug-induced liver injury can cause serious liver damage and even liver failure, so this should be closely monitored in people with mpox who are treated with brincidofovir.
What was studied in the review?
Randomized controlled trials review
This review identified five ongoing clinical trials assessing tecovirimat for treating people with mpox. They aim to recruit a total of 1750 people in the USA, Canada, Brazil, Switzerland, UK, and Democratic Republic of Congo.
Non-randomized studies review
This review identified three non-randomized studies conducted in the Central African Republic, UK and USA. A total of 355 people received tecovirimat, and three received brincidofovir as their treatment drug.
What are the main results of the review?
Randomized controlled trials review
There is currently no evidence from RCTs available, but the five ongoing trials identified will be assessed in future updates of this review.
Non-randomized studies review
Three non-randomized studies assessed safety in 358 people treated for mpox (355 received tecovirimat, 3 received brincidofovir). Very few of the people who received tecovirimat reported unwanted or harmful effects (16 out of 355 people). These included 11 mild unwanted or harmful effects, two mental health outcomes, and one case of increased liver enzymes. There was also one death and one case of anaemia, but neither of these was thought to be related to the study drug.
All three people who received brincidofovir reported an increase in alanine transaminase (ALT; a liver enzyme released by liver cells when they are damaged) which led to discontinuation of their treatment. In at least two of the cases treated with brincidofovir, their increased alanine transaminase level may indicate mild drug-induced liver injury. We do not know whether this would have progressed to become more serious if treatment had not been discontinued. Liver enzymes should be carefully monitored in individuals receiving this drug.
What are the limitations of the evidence?
Randomized controlled trials review
There is currently no evidence from RCTs available.
Non-randomized studies review
People included in the studies all received the treatment, so we are unable to compare these results against people with a placebo or no treatment. The study investigating brincidofovir was also very small.
How up to date is this review?
Randomized controlled trials review
The review authors searched for studies available up to 25 January 2023.
Non-randomized studies review
The review authors searched for studies available up to 22 September 2022.
Randomized controlled trials review
This review found no evidence from randomized controlled trials concerning the efficacy and safety of therapeutics in humans with mpox.
Non-randomized studies review
Very low-certainty evidence from non-randomized studies indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection. In contrast, very low-certainty evidence raises a safety signal that brincidofovir may cause liver injury. This is also suggested by indirect evidence from brincidofovir use in smallpox. This warrants further investigation and monitoring.
This Cochrane Review will be updated as new evidence becomes available to assist policymakers, health professionals, and consumers in making appropriate decisions for the treatment of mpox.
Mpox was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) on 23 July 2022, following the identification of thousands of cases in several non-endemic countries in previous months. There are currently no licenced therapeutics for treating mpox; however, some medications may be authorized for use in an outbreak. The efficacy and safety of possible therapeutic options has not been studied in humans with mpox. There is a need to investigate the evidence on safety and effectiveness of treatments for mpox in humans; should any therapeutic option be efficacious and safe, it may be approved for use around the world.
There are two parts to this Cochrane Review: a review of evidence from randomized controlled trials (RCTs), and a narrative review of safety data from non-randomized studies.
Randomized controlled trials review
To systematically review the existing evidence on the effectiveness of therapeutics for mpox infection in humans compared to:
a) another different therapeutic for mpox, or
b) placebo, or
c) supportive care, defined as the treatment of physical and psychological symptoms arising from the disease.
Non-randomized studies review
To assess the safety of therapeutics for mpox infection from non-randomized studies (NRS).
Randomized controlled trials review
We searched the following databases up to 25 January 2023: MEDLINE (OVID), Embase (OVID), Biosis previews (Web of Science), CAB Abstracts (Web of science), and Cochrane CENTRAL (Issue 1 2023). We conducted a search of trial registries (Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP)) on 25 January 2023. There were no date or language limits placed on the search. We undertook a call to experts in the field for relevant studies or ongoing trials to be considered for inclusion in the review.
Non-randomized studies review
We searched the following databases on 22 September 2022: Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9 of 12, 2022), published in the Cochrane Library; MEDLINE (Ovid); Embase (Ovid); and Scopus (Elsevier). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress.
For the RCT review and the narrative review, any therapeutic for the treatment of mpox in humans was eligible for inclusion, including tecovirimat, brincidofovir, cidofovir, NIOCH-14, immunomodulators, and vaccine immune globulin.
Randomized controlled trials review
Studies were eligible for the main review if they were of randomized controlled design and investigated the effectiveness or safety of therapeutics in human mpox infection.
Non-randomized studies review
Studies were eligible for inclusion in the review of non-randomized studies if they were of non-randomized design and contained data concerning the safety of any therapeutic in human mpox infection.
Randomized controlled trials review
Two review authors independently applied study inclusion criteria to identify eligible studies. If we had identified any eligible studies, we planned to assess the risk of bias, and report results with 95% confidence intervals (CI). The critical outcomes were serious adverse events, development of disease-related complications, admission to hospital for non-hospitalized participants, pain as judged by any visual or numerical pain scale, level of virus detected in clinical samples, time to healing of all skin lesions, and mortality.
We planned to perform subgroup analysis to explore whether the effect of the therapeutic on the planned outcomes was modified by disease severity and days from symptom onset to therapeutic administration. We also intended to explore the following subgroups of absolute effects: immunosuppression, age, and pre-existing skin disease.
Non-randomized studies review
One review author applied study inclusion criteria to identify eligible studies and extracted data. Studies of a non-randomized design containing data on the safety of therapeutics could not be meta-analyzed due to the absence of a comparator; we summarized these data narratively in an appendix.
Randomized controlled trials review
We did not identify any completed RCTs investigating the effectiveness of therapeutics for treating mpox for the main review. We identified five ongoing trials that plan to assess the effectiveness of one therapeutic option, tecovirimat, for treating mpox in adults and children. One of these ongoing trials intends to include populations with, or at greater risk of, severe disease, which will allow an assessment of safety in more vulnerable populations.
Non-randomized studies review
Three non-randomized studies met the inclusion criteria for the narrative review, concerning data on the safety of therapeutics in mpox. Very low-certainty evidence from non-randomized studies of small numbers of people indicates no serious safety signals emerging for the use of tecovirimat in people with mpox infection, but a possible safety signal for brincidofovir. All three participants who received brincidofovir had raised alanine aminotransferase (ALT), but not bilirubin, suggesting mild liver injury. No study reported severe drug‐induced liver injury with brincidofovir.