Severe Mpox Among People With Advanced Human Immunodeficiency Virus Receiving Prolonged Tecovirimat in New York City

Abstract Severe mpox has been observed in people with advanced human immunodeficiency virus (HIV). We describe clinical outcomes of 13 patients with advanced HIV (CD4 <200 cells/μL), severe mpox, and multiorgan involvement. Despite extended tecovirimat courses and additional agents, including vaccinia immune globulin, cidofovir, and brincidofovir, this group experienced prolonged hospitalizations and high mortality.

During the 2022 mpox outbreak, 44% of mpox cases in New York City (NYC) from mid-May to mid-August were among people living with human immunodeficiency virus (HIV) (unpublished data).People with advanced HIV have required extended hospitalization for severe mpox manifestations, resulting in significant morbidity and mortality, especially among Black non-Hispanic men [1,2].A global case series reported 25% mortality among people with HIV (PWH) with low CD4 counts (CD4 <350 cells/μL) who were hospitalized with mpox [3].
Tecovirimat is approved by the US Food and Drug Administration to treat smallpox and can be used for mpox under an expanded-access Investigational New Drug protocol.Additional mpox investigational agents, including vaccinia immune globulin intravenous (VIG), brincidofovir, cidofovir, and trifluridine, have been used along with tecovirimat as combination therapy for severe mpox.To better inform clinical management, we describe the mpox clinical outcomes among NYC residents living with advanced immunosuppression due to HIV (CD4 <200 cells/μL) receiving prolonged courses of tecovirimat.

METHODS
This is a retrospective study.Patients with an HIV status known to providers who were living in NYC were included if they had a positive non-variola orthopoxvirus or mpox test, CD4 count <200 cells/μL, and a limited response to tecovirimat (characterized by slow-healing or complex lesions requiring a treatment course >14 days).Cases were collected when healthcare providers contacted the NYC Department of Health and Mental Hygiene (DOHMH) or the Centers for Disease Control and Prevention's (CDC) clinical team for consultation between 2 August 2022 and 16 December 2022.
We analyzed and reviewed DOHMH mpox surveillance for demographic information, any documented clinical information during consultations, and a data collection tool completed by providers.We cross-matched cases by name and date of birth with DOHMH HIV surveillance for CD4 and viral load and NYC Department of Social Services surveillance for housing status.For specimens submitted to the DOHMH Public Health Laboratory with low enough polymerase chain reaction cycle thresholds, whole genome sequencing (WGS) was performed.
The data collection tool included demographic, laboratory, and clinical data, as well as parameters from the Mpox Severity Scoring System (MPOX-SSS) [4], a scoring system designed during the 2022 mpox outbreak to provide a standard measure of mpox disease severity between groups and evaluate treatment response through quantitative standardization.The proposed MPOX-SSS tool dated November 2022 was used for data collection, which has slight variations from the current tool dated June 2023.

RESULTS
We identified 14 eligible patients; providers returned data tools for 13 patients (Table 1).All patients identified as men; median Open Forum Infectious Diseases B R I E F R E P O R T age was 38 years (range, 26-63 years).Ten (77%) identified as Black, African American, or Afro-Caribbean, 2 (15%) as Hispanic/Latino, and 4 (31%) as other race/ethnicity (providers were able to select all applicable race and ethnicity categories, so percentages add up to >100%).Five (38%) experienced unstable housing in the last year, defined as residing in a shelter, transitional single-room occupancy, or congregate residential housing.Eleven (85%) were reported as not taking antiretroviral therapy (ART) at mpox diagnosis (providers reported if patients were on ART, but no additional adherence data were collected).Median CD4 at the time closest to mpox diagnosis was 32 cells/μL (range, 2-149 cells/μL); 10 (77%) had CD4 counts <50 cells/μL.Two (15%) had received 1 dose of JYNNEOS vaccine, both of whom were diagnosed with mpox within 5 days of vaccination.
hepatotoxicity following brincidofovir administration.All patients received ART during hospitalization.One patient (8%) was treated as an outpatient and had lesion resolution.Twelve patients (92%) were hospitalized with severe mpox manifestations; the median length of hospitalization was 56 days (range, 8-203 days).Severe manifestations included necrotic facial lesions, bacterial superinfection of the eye, ocular collapse, cavitary pulmonary lesions, airway edema requiring intubation and tracheostomy, esophageal ulcers, and uncontrollable rectal bleeding.Reasons for hospitalization, other infectious disease manifestations, and other complications are listed in Table 1.Among hospitalized patients, 6 patients (46%) died, and 6 were discharged (46%).
MPOX-SSS scores could be calculated for 9 patients (69%).The median severity score at initial presentation was 12 (range, 8-17), and the median final severity score upon discharge or death was 10 (range, 1-22).Among 4 patients who died, the median initial severity score was 16 (range, 9-17), and the median final severity score was 21 (range, 17-22).Among 5 patients whose lesions resolved, the median initial severity score was 12 (range, 8-17), and the median final severity score was 3 (range, 1-10) (Supplementary Figure 1).Specimens from 11 (85%) patients were submitted to the Public Health Laboratory for analysis.Specimens were sequenced for 9 of these patients; specimens for 2 patients failed to meet quality endpoints required for WGS.Of these 9 specimens, 4 (44%) had a mutation in the F13L gene associated with tecovirimat resistance.

DISCUSSION
This group of patients living with advanced HIV and mpox experienced prolonged hospitalization and high mortality, which is consistent with previous literature [1,3,[5][6][7].Nearly half of the patients in this case series died.Most identified as Black, were unstably housed, and were disengaged from HIV care.Notable manifestations of severe mpox included ocular involvement culminating in globe collapse, gastrointestinal hemorrhage, and disfiguring necrotic facial lesions.All received extended tecovirimat treatment courses.Tecovirimat is not viricidal, and effective immune responses are required to clear mpox infection [8].Early initiation of ART in these patients, and rapid and multipronged mpox treatment approach, including tecovirimat in combination with VIG, cidofovir, and/or brincidofovir, may improve clinical outcomes [9][10][11].Studies to assess the efficacy of tecovirimat for mpox are underway, but additional data are needed to understand the impact of combination therapy.
Broader access to tecovirimat resistance testing is needed to guide clinical decision making in this population.Four percent of CDC-sequenced specimens had F13L mutations that may indicate resistance [9], with almost 60% of those having confirmed phenotypic resistance, all found in PWH [12].In our case series, which was limited to patients who received extended tecovirimat courses, 9 patients had specimens that underwent sequencing, of which 4 (44%) specimens had F13L genotypic mutations; however, without paired phenotypic results, these data are not conclusive for resistance.There may be an increased risk of tecovirimat resistance in this population due to severe immunocompromised status and extended treatment duration, as well as oral absorption concerns that may lead to subtherapeutic concentrations [13].In the absence of resistance testing, we suggest a low threshold to switch to intravenous tecovirimat to increase bioavailability, and early combination therapy with other antivirals [9].
Previous case series highlighting mpox severe outcomes and death have raised concerns for immune reconstitution inflammatory syndrome (IRIS) [3].IRIS was generally not suspected by clinicians in this case series due to sustained low CD4 counts and continued immunosuppression despite initiation of ART during hospitalization for most patients, with severe outcomes possibly resulting from progression of mpox and overwhelming and unchecked viral replication [8].Prompt ART initiation in PWH not on treatment at the time of mpox diagnosis is a critical component of mpox treatment, as optimized immune responses are essential to clear viral infection [8,9,14].
This case series applies the MPOX-SSS to severe cases.While data were only available for 69% of patients, patients who died had a higher median initial severity score that increased over time, compared to lower initial severity scores that improved over time in those who survived.While additional validation is needed, these trends suggest that MPOX-SSS could be a useful tool in triaging severe mpox cases and assist in decision making around medical countermeasures.
This group faced intersectional barriers to HIV care and mpox prevention, as well as delays in presentation to care following mpox symptom onset, which may lead to mpox progression [15].Strategies to engage and retain PWH in care require mitigation of structural barriers to accessing and sustaining engagement in care, including linkage to social support services such as housing, as well as proactive outreach to PWH disengaged from care [16][17][18][19][20]. Mpox vaccination and preventive care efforts should ensure that structural racism and institutional inequities are addressed [21][22][23].
Detailed clinical courses for several patients in this case series have been published [24,25].Strengths of this case series include cross-matching clinical data with NYC public health surveillance and social service data systems, reporting of WGS results, and use of the MPOX-SSS to characterize severe mpox manifestations.Potential limitations include dependence on provider reporting to identify cases based upon requests for VIG and other medical countermeasures; convenience sampling that may not be representative of all severe mpox cases in NYC or among people with advanced HIV with CD4 counts <200 cells/μL; and lack of phenotypic resistance testing results.

CONCLUSIONS
These mpox patients with advanced HIV experienced high social vulnerability, severe mpox manifestations, and high mortality.Factors associated with poor HIV outcomes may contribute to severe mpox outcomes, necessitating proactive outreach, vaccination, and other preventive measures for this population.ART for HIV, as well as early and extended tecovirimat with coadministration of other mpox treatments, is essential to improving clinical outcomes from mpox.Findings of severe disease and high mortality highlight the urgency of mitigating deep social inequities and the need for research to optimize mpox prevention and care among PWH.

Table 1 . Continued
a Tecovirimat course >14 days.bMultiple categories could be selected; percentages may add up to >100%.cUnstably housed defined as shelter, transitional single room occupancy, or congregate residential housing.d