Clinical Use of Tecovirimat (Tpoxx) for Treatment of Monkeypox Under an Investigational New Drug Protocol — United States, May–August 2022

Currently, no Food and Drug Administration (FDA)-approved treatments for human monkeypox are available. Tecovirimat (Tpoxx), however, is an antiviral drug that has demonstrated efficacy in animal studies and is FDA-approved for treating smallpox. Use of tecovirimat for treatment of monkeypox in the United States is permitted only through an FDA-regulated Expanded Access Investigational New Drug (EA-IND) mechanism. CDC holds a nonresearch EA-IND protocol that facilitates access to and use of tecovirimat for treatment of monkeypox.§ The protocol includes patient treatment and adverse event reporting forms to monitor safety and ensure intended clinical use in accordance with FDA EA-IND requirements. The current multinational monkeypox outbreak, first detected in a country where Monkeypox virus infection is not endemic in May 2022, has predominantly affected gay, bisexual, and other men who have sex with men (MSM) (1,2). To describe characteristics of persons treated with tecovirimat for Monkeypox virus infection, demographic and clinical data abstracted from available tecovirimat EA-IND treatment forms were analyzed. As of August 20, 2022, intake and outcome forms were available for 549 and 369 patients, respectively; 97.7% of patients were men, with a median age of 36.5 years. Among patients with available data, 38.8% were reported to be non-Hispanic White (White) persons, 99.8% were prescribed oral tecovirimat, and 93.1% were not hospitalized. Approximately one half of patients with Monkeypox virus infection who received tecovirimat were living with HIV infection. The median interval from initiation of tecovirimat to subjective improvement was 3 days and did not differ by HIV infection status. Adverse events were reported in 3.5% of patients; all but one adverse event were nonserious. These data support the continued access to and treatment with tecovirimat for patients with or at risk for severe disease in the ongoing monkeypox outbreak.

Tecovirimat ¶ is an antiviral drug developed as a medical countermeasure to treat smallpox, a serious and life-threatening infection caused by Variola virus, of genus Orthopoxvirus; Monkeypox virus belongs to the same genus but typically causes less severe disease.** Global eradication of smallpox was declared by the World Health Assembly in 1980. † † Because opportunities to develop clinical trials in countries where Monkeypox virus infection is considered endemic have been limited, the efficacy of tecovirimat to treat monkeypox has not been fully evaluated in humans. Instead, efficacy data that supported FDA approval of tecovirimat for smallpox were based on nonhuman primate and rabbit studies § § (3); efficacy studies were also conducted in macaque monkeys and prairie dogs (4,5).
During May 2022, a multinational monkeypox virus outbreak (Clade II) was first reported, principally affecting MSM (1,2). Interim CDC guidance currently recommends that tecovirimat be considered in patients with severe disease, those at high risk for severe disease, or those with aberrant infections. ¶ ¶ This report describes the available demographic and clinical characteristics, clinical indications for use, clinical outcomes, and adverse events reported among some of the first known recipients of tecovirimat treatment under the EA-IND protocol for Monkeypox virus infection in the United States.
During May 29-July 20, 2022, the EA-IND protocol required patient assessment forms at the start of treatment and once during three follow-up time points (assessment A: day 1-7, assessment B: day 8-14, and assessment C: posttreatment). Initially, the protocol's eligibility criteria included laboratory confirmation of   * The initial intake form captured sex without any other qualification, and the revised version of the form captured sex as "sex assigned at birth." These two variables were combined to form the variable "sex"; therefore, some patients might have been misclassified. † HHS region 2 = New Jersey and New York; region 3 = District of Columbia, Maryland, Pennsylvania, and Virginia; region 4 = Alabama, Florida, Georgia, North Carolina, South Carolina, and Tennessee; region 5 = Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin; region 9 = Arizona, California, Hawaii, and Nevada; other regions combined = HHS region 1 (Connecticut, Massachusetts, and Rhode Island), HHS Region 6 (Arkansas, Louisiana, and Texas), HHS region 7 (Iowa, Kansas, Missouri, and Nebraska), HHS region 8 (Colorado), and HHS region 10 (Idaho, Oregon, and Washington). § Vaccination status was assessed by medical record and patient questionnaire, not by physical exam, so those unaware of vaccination status, even those with a scar from Dryvax, might have been missed. ¶ Clinical indication was only captured on the revised intake form; therefore, the denominator is reduced (240 revised intake forms with nonmissing data). ** Lesions in anatomic areas that might result in serious sequelae (e.g., eye, genitals, and oral mucosa) were not described in the form but reported based on the treating clinician's assessment based on the phrase "lesions in sensitive anatomical areas. " † † Includes receipt of immunosuppressive therapies and the following categories collected from the investigational new drug protocol paperwork: Among 369 patients with outcome forms, data on hospitalization status was available for 331; among these, 23 (6.9%) were hospitalized after symptom onset (Table 2), and the median duration of hospitalization was 4 days (IQR = 1-5 days). Among 255 patients with available data, the median time to subjective improvement after starting treatment was 3 days (IQR = 2-4 days). ¶ ¶ ¶ Among 317 patients with available outcome information, 230 (72.6%) recovered with or without sequelae**** by or before completion of the posttreatment assessment; 87 (27.4%) patients were reported by clinicians to be not yet recovered, 78 of whom had not yet completed the standard 14-day tecovirimat treatment course. Adverse events were reported for 12 (3.5%) of 340 patients with information on adverse events; these included headache (three), nausea (two), visual disturbance (two), weakness (two), and hospitalization for psychiatric reasons (one). † † † † At the time of the posttreatment follow-up visit, three (2.2%) of 137 persons with information available had developed new lesions compared with 25 (13.1%) who had developed new lesions during the first week of treatment. Most (119, 89.5%) patients reported that all lesions were crusted and healing with a new layer of skin under the scab following treatment. Among 174 patients with available data, the interval to subjective improvement did not differ between HIV-positive persons (42; median = 3 days) and persons without documentation of HIV positive status (64; median = 3 days) with available data (p = 0.83).

Discussion
The data in this report support the continued availability of tecovirimat in the current monkeypox outbreak for U.S. patients with laboratory-confirmed or clinically diagnosed monkeypox. Initial findings indicate that tecovirimat is likely well tolerated; among reported adverse events, most were not serious, and it is not known whether tecovirimat caused the adverse events reported. The preliminary safety reporting with tecovirimat use under the EA-IND is consistent with data from the healthy human tecovirimat safety studies (SIGA-246-001). § § § § Two other investigational treatments for orthopoxviruses, cidofovir and brincidofovir, have demonstrated substantial toxicity with limited efficacy data (6).
For patients treated under the EA-IND protocol and included in this report, the median time to subjective improvement was 3 days after receiving tecovirimat. However, no control group ¶ ¶ ¶ Time to first observed (including patient-reported) improvement. **** Per clinical judgment of the treating provider. † † † † All adverse events included headache (three), nausea (two), visual disturbance (two), weakness (two), vomiting (one), asymptomatic elevated liver function tests (one), depression with suicidality (one), rash (one), hives (one), numbness (one), fatigue (one), and dizziness (one). § § § § https://www.clinicaltrials.gov/ct2/show/NCT02474589 was available for comparison; therefore, no conclusions can be drawn regarding the effectiveness of tecovirimat to treat monkeypox based on these data. Time to improvement did not differ significantly with HIV infection status. A report from Nigeria suggested that HIV-positive patients might have prolonged illness; however, illness severity could be affected by HIV viral suppression, which was not reported in the current evaluation (7). Three of 137 patients (2.2%) with posttreatment follow-up and available data developed new lesions after completing treatment. A retrospective study in the United Kingdom reported one patient treated with tecovirimat had a shorter duration of illness compared with six patients (8), and another report of a small U.S. cohort treated with tecovirimat (also under the EA-IND) demonstrated complete resolution of lesions by day 21 in 23 (92%) of 25 patients (9). This report illustrated that many patients were prescribed tecovirimat for lesions in anatomic areas that might result in serious sequelae, and nearly all received tecovirimat as outpatients, suggesting that severe disease was uncommon. The demographic characteristics of patients who received tecovirimat are similar to those with monkeypox: as described recently by CDC: the first 3,000 reported monkeypox infections in the United States occurred almost exclusively (99%) in men, with a median age of 35 years; approximately 40% were in White persons; and 41% of patients were living with HIV infection (1). Approximately one half of patients described in the EA-IND data did not have laboratory confirmation of Monkeypox virus infection and received tecovirimat empirically; because it is currently not known which patients benefit most from tecovirimat treatment, clinical judgment is important. Although this report could not evaluate efficacy, clinicians are encouraged to continue following CDC guidelines for tecovirimat use in patients with severe disease or at risk for severe disease. Because there is the potential for false-positive test results, tecovirimat should be considered only in those with a high pretest probability of being infected with Monkeypox virus to avoid unnecessary treatment or implementation of

Summary
What is already known about this topic? Tecovirimat (Tpoxx) was approved by the Food and Drug Administration for treatment of smallpox based on data obtained from animal models; there are no safety or efficacy data regarding its use in patients with Monkeypox virus infection.
What is added by this report?
Among 549 patients with Monkeypox virus infection treated with tecovirimat under an Expanded Access Investigational New Drug protocol, 99.8% received it orally as an outpatient. Among 369 patients, few adverse events were reported.
What are the implications for public health practice?
Tecovirimat is generally well tolerated, and these data support continued access to treatment with tecovirimat during the current monkeypox outbreak.  * Hospitalized at any time after symptom onset. Among 23 patients hospitalized, two patients were admitted to the intensive care unit. † At latest follow-up visit, which might have been during treatment or posttreatment. Recovery status was defined by clinical judgment of the treating provider. § Time to first observed (including patient-reported) improvement. ¶ All adverse events included headache (three), nausea (two), visual disturbance (two), weakness (two), vomiting (one), asymptomatic elevated liver function tests (one), hospitalization for psychiatric reasons (one), rash (one), hives (one), numbness (one), fatigue (one), and dizziness (one). ** Nonmissing data.
other public health measures (10). Inappropriate uses could potentially lead to resistance (3). Continued prescribing guidance updates on administering tecovirimat to those who would benefit the most from its use will be crucial as more is learned about effectiveness, viral resistance, and adverse events.
The findings in this report are subject to at least six limitations. First, only patients whose EA-IND forms were submitted to CDC were included in this report, representing a fraction of those treated to date ¶ ¶ ¶ ¶ ; this limitation could lead to convenience sample bias that might not be representative of all patients treated with tecovirimat. Second, to lessen the regulatory burden on prescribers, the EA-IND forms were streamlined during the data collection process, leading to inconsistent variable collection. Third, some variables were collected as free text; therefore, absent data might not necessarily indicate absence of conditions. Fourth, the profile of patients might differ across assessment time points; for example, those with worse initial symptoms might have been more likely to receive follow-up assessments, making true time to resolution or improvement difficult to ascertain. Fifth, it is not known whether the outcomes described for patients who received tecovirimat differ from those of patients who do not receive tecovirimat because no control group was included. Finally, CD4 count and viral load, markers of unsuppressed HIV infection, were not collected, limiting the evaluation of treatment outcomes for persons living with HIV infection.
Ongoing monitoring is essential to assess the safety of tecovirimat in patients with Monkeypox virus infection under the EA-IND during the current monkeypox outbreak. CDC is continuing to review additional data as they become available. Currently, there are no human data demonstrating the efficacy of tecovirimat, and clinical trials are necessary to elucidate clinical efficacy in patients with Monkeypox virus infection, indications for treatment, and ideal duration of treatment.