This cohort study examines whether staring tecovirimat within 7 days of mpox symptom onset is associated with a lower rate of mpox disease progression among people with HIV.
Key Points
Question
Is use of tecovirimat within 7 days of mpox symptom onset associated with lower rates of mpox disease progression among people with HIV (PWH)?
Findings
In this cohort study including 112 PWH after propensity matching, those treated with tecovirimat within 7 days of mpox symptom onset compared with those who were treated after 7 days or who did not receive tecovirimat were 13 times less likely to progress to severe mpox disease.
Meaning
The findings of this study support the use of tecovirimat in all PWH as soon as mpox is suspected.
Abstract
Importance
Despite a lack of effectiveness data in humans, tecovirimat was widely prescribed to people with HIV (PWH) with mpox during the 2022 mpox epidemic, particularly PWH with low CD4+ T-cell counts or severe mpox clinical manifestations.
Objective
To evaluate if PWH with mpox who were treated with tecovirimat within 7 days of symptom onset were less likely to have mpox disease progression.
Design, Setting, and Participants
This cohort study included PWH diagnosed with mpox at 4 hospitals in Atlanta, Georgia, between June 1 and October 7, 2022. Patients were grouped according to whether they were treated with tecovirimat within 7 days of mpox symptom onset (early tecovirimat cohort) or they did not receive tecovirimat or received the drug 7 or more days after symptom onset (late or no tecovirimat cohort). Multivariable logistic regression models were used to identify factors associated with progression of mpox disease. The 2 cohorts were then matched 1:1 using propensity scores based on the identified factors, and mpox disease progression was compared.
Exposures
Treatment with tecovirimat within 7 days of mpox symptom onset.
Main Outcome and Measures
Progression of mpox disease, defined as the development of at least 1 severe mpox criterion established by the US Centers for Disease Control and Prevention, after symptom day 7.
Results
After propensity score matching, a total of 112 PWH were included in the analysis; 56 received tecovirimat within 7 days of mpox symptom onset (early tecovirimat group) and 56 were either treated later or did not receive tecovirimat (late or no tecovirimat group). In the early tecovirimat group, the median (IQR) age was 35 (30-42) years; 54 individuals (96.4%) were cisgender men, 46 (82.1%) were Black individuals, and 10 (17.9%) were individuals of other races (American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or White) or unknown race. In the late or no tecovirimat group, the median (IQR) age was 36 (32-43) years; 54 (96.4%) were cisgender men, 49 (87.5%) were Black individuals, and 7 (12.5%) were individuals of other races or unknown race. Mpox disease progression occurred in 3 PWH (5.4%) in the early tecovirimat group and in 15 PWH (26.8%) in the late or no tecovirimat group (paired odds ratio, 13.00 [95% CI, 1.71-99.40]; P = .002).
Conclusion and Relevance
Results of this cohort study support starting tecovirimat in all PWH as soon as an mpox diagnosis is suspected. Additional research is warranted to confirm these findings.
Introduction
The 2022 global mpox outbreak disproportionately affected people with HIV (PWH).1,2 This population may develop more severe mpox disease manifestations and worse clinical outcomes,3,4 especially individuals with lower CD4+ T-cell counts5 and nonsuppressed HIV viremia,6 highlighting the urgent need for effective therapeutic agents for this population.
Tecovirimat (ST-246), an antiviral agent developed to treat smallpox, has antiviral activity against other orthopoxviruses, including mpox virus. In animal models, tecovirimat was shown to prevent morbidity and mortality associated with mpox, especially when started within 5 days of mpox inoculation.7,8,9
Based on these data, the US Food and Drug Administration approved tecovirimat for mpox treatment using expanded access for an investigational new drug. Data showing the effectiveness of tecovirimat for treating mpox disease in humans are lacking.10,11 Meeting enrollment goals for a randomized controlled trial assessing the efficacy of tecovirimat for mpox infection (the STOMP [Study of Tecovirimat for Human Monkeypox Virus] trial12) has been challenging due to declining number of mpox cases. We aimed to perform a matched cohort analysis to examine the association between early tecovirimat treatment (started within 7 days of mpox symptom onset) and progression of mpox disease among PWH.
Methods
Study Design and Population
Individuals diagnosed with mpox infection were identified at 4 academic medical centers in Atlanta, Georgia, between June 1 and October 7, 2022. An mpox case was diagnosed using specimens collected via a swab from any anatomical site that tested positive for monkeypox or orthopoxvirus via polymerase chain reaction. Data were manually collected from electronic medical records using a standardized data abstraction tool (Research Electronic Data Capture [REDCap], version 13.8.1; Vanderbilt University). Each medical record review extended through the conclusion of the individual’s mpox disease course (ie, recovery or death). This retrospective cohort study was reviewed by the Emory University Institutional Review Board and determined to be exempt from review and the informed consent requirement because deidentified data were used. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
The study population included PWH with mpox infection whose HIV viral load (VL) at the time of mpox diagnosis was known. Individuals were excluded if there was no HIV VL detectable within 6 months before mpox diagnosis to 1 month after diagnosis. We built 2 matched cohorts differentiated by the exposure of interest, namely, being prescribed tecovirimat within 7 days of mpox symptom onset. The exposed cohort (early tecovirimat group) and unexposed cohort (late or no tecovirimat group) were matched at a 1:1 ratio. Individuals in the late or no tecovirimat group included those who were not prescribed tecovirimat and those who were prescribed tecovirimat treatment after symptom day 7.
Outcome
The outcome was progression of mpox disease after day 7 of symptom onset until the time the mpox infection was deemed resolved or death occurred. This was a composite outcome of PWH who first met severe mpox disease criteria after 7 days of symptoms and those with severe mpox disease prior to 7 days after symptom onset who had progression of disease with any new manifestation of severe mpox disease after day 7. Severe mpox disease was defined in accordance with the US Centers for Disease Control and Prevention (CDC) criteria13 (eMethods in Supplement 1).
Propensity Score Matching
Candidate variables examined to inform estimated propensity scores included demographics (age, gender, and race and ethnicity), CD4+ T-cell count, HIV VL, mpox vaccination status, number of mucosal sites involved at presentation, and hospitalization at 7 days after symptom onset. Self-reported race and ethnicity were obtained from medical records and were categorized as Black or other (including American Indian or Alaska Native, Asian, Native Hawaiian or Pacific Islander, White, and individuals with unknown race or ethnicity); data for other races and ethnicity were collapsed because the number of individuals other than Black were inadequate for statistical comparisons. Ethnicity was categorized as Hispanic/Latinx or non-Hispanic/Latinx. Data on race were collected because Black individuals bore an increased burden of mpox disease morbidity and mortality during the 2022 mpox outbreak, especially in the Southeastern US.4,14 Two logistic regression models were initially fit using these variables (one with severe mpox as the outcome, the other with early tecovirimat treatment as the outcome). Variables retained in either or both models based on stepwise selection with entry and retention significance at P < .25 were included in a final logistic model to estimate the probability of exposure to early tecovirimat treatment. The initial logistic regression models retained race as a variable to be included in the propensity score matching. However, these models did not show any association between ethnicity and the outcome (ie, development of severe mpox) or the exposure (ie, being prescribed tecovirimat prior to symptom day 7). Greedy nearest-neighbor 1-1 propensity score matching was implemented using the SAS psmatch procedure (SAS/STAT, version 15.1; SAS Institute Inc), seeking (regardless of the outcome) to assign 1 matched participant among the late or no tecovirimat cohort to each member of the early tecovirimat cohort (eFigure in Supplement 1).
Statistical Analysis
Covariate balance between the 2 matched cohorts was assessed using standardized mean differences. P values were calculated using a Mann-Whitney U test for continuous variables and a Fisher exact test for categorical variables. Propensity score–based analysis was conducted using the McNemar test for comparing binary proportions on pair-matched data.15 A corresponding exact binomial test was conducted in conjunction with a paired databased odds ratio (OR) estimate and 95% CI.16 The prespecified cutoff for statistical significance was P < .05. Data analysis was performed using SAS/STAT.
Results
Of a total of 262 PWH with mpox infection, 65 individuals met criteria to be included in the early tecovirimat cohort and 197 individuals met criteria for inclusion in the late or no tecovirimat cohort. In the initial logistic regression model, HIV VL nonsuppression and involvement of at least 1 mucosal site had the strongest association with increased odds of severe mpox disease.
After applying exclusion criteria, 56 PWH in the early tecovirimat cohort (median [IQR] age, 35 [30-42] years; 54 cisgender men [96.4%]; 46 Black individuals [82.1%], 10 individuals of other races [American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, or White] or unknown race [17.9%]) were matched with 56 PWH who did not receive early tecovirimat treatment (median [IQR] age, 36 [32-43] years; 54 cisgender men [96.4%]; 49 Black individuals [87.5%] and 7 individuals of other races or unknown race [12.5%]), forming the 2 analyzed cohorts (Figure). Factors selected for inclusion in the final propensity score estimation model included age, race, HIV VL suppression, involvement of any mucosal site, and hospitalization on day 7. Characteristics of the 2 cohorts are outlined in Table. Although not a variable considered in matching, the median (IQR) CD4+ T-cell count was lower in the early tecovirimat cohort (314 [201-496] cells/μL vs 433 [266-576] cells/μL]). Fourteen PWH (25.0%) in the early tecovirimat cohort had a CD4+ T-cell count of 200 cells/μL or less compared with 9 PWH (16.1%) in the late or no tecovirimat cohort. In the late or no tecovirimat cohort, 20 PWH (35.7%) eventually received tecovirimat after symptom day 7, with tecovirimat started on a median (IQR) of 10 (9-15) days after mpox symptom onset.
Figure. Flowchart of Matched Cohort Analysis.
Individuals were excluded if there was no HIV viral load within 6 months before mpox diagnosis to 1 month after diagnosis.
Table. Matched Cohorts of Persons With HIV and Mpox Who Received Early Tecovirimat vs Late or No Tecovirimat.
| Covariate or exposure | No. (%) | P valuea | |
|---|---|---|---|
| Early tecovirimat cohort (n = 56) | Late or no tecovirimat cohort (n = 56) | ||
| Demographics | |||
| Age, median (IQR), y | 35 (30-42) | 36 (32-43) | .60 |
| Gender | |||
| Cisgender men | 54 (96.4) | 54 (96.4) | >.99 |
| Otherb | 2 (3.6) | 2 (3.6) | |
| Race | |||
| Black | 46 (82.1) | 49 (87.5) | .60 |
| Otherc | 10 (17.9) | 7 (12.5) | |
| HIV indices | |||
| HIV viral load, cells/mL | |||
| <200 | 33 (58.9) | 34 (60.7) | >.99 |
| >200 | 23 (41.1) | 22 (39.3) | |
| Mpox symptoms and clinical course | |||
| Mucosal involvement at presentation | |||
| None | 21 (37.5) | 22 (39.3) | >.99 |
| ≥1 Site | 35 (62.5) | 34 (60.7) | |
| Hospitalized at day 7 after symptom onset | |||
| Yes | 15 (26.8) | 15 (26.8) | >.99 |
| No | 41 (73.2) | 41 (73.2) | |
| Exposure to tecovirimat | |||
| Received tecovirimat | 56 (100) | 20 (35.7) | NA |
| Received tecovirimat on or before day 7 after symptom onset | 56 (100) | 0 | NA |
| If treated: days of symptoms prior to starting tecovirimat, median (IQR) | 4 (3-6) | 10 (9-15) | NA |
Abbreviation: NA, not applicable.
Calculated using a Mann-Whitney U test for continuous variables and a Fisher exact test for categorical variables.
Other gender includes transgender women.
Other race includes American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, and White individuals and individuals with unknown race.
Progression of mpox disease occurred in 3 PWH (5.4%) in the early tecovirimat cohort and 15 PWH (26.8%) in the late or no tecovirimat cohort. There were 14 matched pairs in which 1 individual experienced the primary outcome and the other did not; in 13 of these pairs, the PWH with severe mpox disease progression was in the late or no treatment group (P = .002). The corresponding paired-data OR estimate was 13.00 (95% CI, 1.71-99.40), indicating higher odds of severe mpox disease progression in the late or no tecovirimat cohort. The median (IQR) time after exposure stratification (ie, symptom day 7) to mpox disease progression was 22 (4-57) days in the early tecovirimat cohort and 4 (2-13) days in the late or no tecovirimat cohort.
In the early tecovirimat cohort, the median (IQR) time from symptom onset to initiation of tecovirimat was 4 (3-6) days. The 3 PWH who received early tecovirimat and went on to develop severe mpox disease started treatment 4, 7, and 7 days after symptom onset.
In the early tecovirimat cohort, 51 of 56 PWH (91.1%) met CDC guidance for use of tecovirimat at the time of their tecovirimat prescription. In the late or no tecovirimat group, 44 PWH (78.6%) presented prior to 7 days after symptom onset and, of these individuals, 37 PWH (84.1%) had met CDC interim guidance criteria for use of tecovirimat at the time of their presentation to medical care (eTable in Supplement 1).
Discussion
In this prospective matched cohort analysis, PWH with mpox disease who were prescribed tecovirimat within 7 days of symptom onset were significantly less likely to have progression of mpox disease compared with PWH who were not prescribed tecovirimat within 7 days of symptom onset. Results of the present study suggest that tecovirimat treatment should be started early at the time of suspected mpox diagnosis in all PWH, especially in those with nonsuppressed HIV viremia or mucosal site involvement.
Limitations
This study has limitations. First, it is possible that unmatched confounding variables could have contributed to fewer cases of severe mpox disease being observed in the early tecovirimat cohort. Second, this study has a small sample size and is inadequately powered to examine specific mpox complications or mortality. Third, most of our population (84.8%) were Black individuals, which reflected the population affected by the 2022 mpox outbreak in Atlanta but may limit generalizability to populations with different races and ethnicities. Fourth, the timing of tecovirimat initiation was determined based only on the time that the tecovirimat prescription was written, and we could not confirm if individuals took the medication or for how long. Fifth, we did not evaluate adverse events associated with tecovirimat. A large cohort study previously reported that tecovirimat is well tolerated.11
Conclusions
To our knowledge, this cohort study represents the first controlled analysis of tecovirimat for the treatment of mpox disease in PWH. The findings support starting tecovirimat in all PWH as soon as an mpox diagnosis is suspected. Additional research is needed to confirm these findings.
eMethods
eFigure. Standardized Mean Differences Plot of Matched Variables
eTable. Indications for Tecovirimat Treatment Prior to Symptom Day 7
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods
eFigure. Standardized Mean Differences Plot of Matched Variables
eTable. Indications for Tecovirimat Treatment Prior to Symptom Day 7
Data Sharing Statement
