Surveillance of Complicated Mpox Cases Unresponsive to Oral Tecovirimat in Los Angeles County, 2022

Abstract

The Los Angeles County Department of Public Health established a surveillance system to identify complicated (advanced human immunodeficiency virus [HIV] or hospitalized) mpox cases. From 1 August to 30 November 2022, we identified 1581 mpox cases, of which 134 (8.5%) were complicated. A subset of 8 cases did not recover after either initiating or completing a course of oral tecovirimat. All 8 patients were HIV positive and had advanced HIV (CD4 count <200 cells/μL). We identified 8 distinct mutations previously associated with tecovirimat resistance in specimens collected from 6 patients. Ongoing surveillance of viral evolution requires close coordination between health departments and frontline providers.

Mpox (formerly recognized as monkeypox) is an orthopoxvirus that primarily had occurred from sporadic zoonotic spillovers in West and Central Africa [1]. Aside from a large outbreak in 2003 in the United States (US) from imported small mammals from West Africa and in cases of returned travelers, the disease was rarely seen elsewhere prior to the 2022 mpox virus (MPXV) outbreak. Transmission between humans is primarily through close skin-to-skin contact, while treatment was limited to supportive care prior to the recent outbreak. Scientists had predicted a potential mpox epidemic given the end of routine smallpox vaccination in the 1980s, which was thought to provide cross-protective serologic immunity. The 2022 MPXV outbreak was the first time this disease caused a pandemic and one of the first outbreaks in which sexual contact was implicated as the primary mode of spread [2].

During the 2022 MPXV outbreak, cases were largely confined to men who have sex with men, a population with high rates of sexually transmitted infections (STIs) including human immunodeficiency virus (HIV)/AIDS [2]. Of all US states, California reported the highest case count at 5800 cases as of July 2023 [3]. Within California, Los Angeles County reported the highest burden with 2488 cases, including 2 mpox deaths, both occurring among patients with poorly controlled HIV/AIDS [4, 5].

Currently, there are no approved treatments for mpox. However, the US Food and Drug Administration and Centers for Disease Control and Prevention (CDC) have provided medical countermeasures under expanded-access Investigational New Drug (IND) protocols for smallpox treatments. These include tecovirimat and brincidofovir, as well as intravenous vaccinia immunoglobulin (VIGIV), and mpox vaccinations [6].

Tecovirimat is an antiviral compound that targets VP37, a highly conserved envelope protein used for extracellular virus particle formation [6–8]. By inhibiting VP37, the drug slows viral replication and dissemination, although it is not viricidal. In vitro data suggest that tecovirimat is efficacious at stopping replication of the 2022 MPXV clade IIb strain [7]. However, in vitro studies also suggest that tecovirimat has a low barrier to antiviral resistance [7]. Resistance mutations to tecovirimat have previously been described in MPXV and other orthopoxviruses, including the current outbreak where phenotypic resistance was confirmed [5, 8, 9].

In patient populations that are immunocompromised, such as those with poorly controlled HIV, viral clearance may be delayed, presenting a greater risk for the development of mpox mutations conferring antiviral resistance. In addition, patients with poorly controlled HIV often face comorbid mental health issues, substance abuse disorder, and housing instability, which can contribute to challenges with medication adherence. Given the spread of mpox in populations with advanced HIV during this outbreak, antiviral resistance represents an urgent concern [10].

OBJECTIVES

The Los Angeles County Department of Public Health (LACDPH) implemented a supplementary surveillance system for complicated mpox cases in August 2022. Complicated cases were defined as MPXV infections in patients with HIV and CD4 counts <200 cells/μL, and all cases hospitalized for MPXV infection. We describe a subset of cases identified through this surveillance who completed partial or full courses of oral tecovirimat without complete recovery. We describe the development of our surveillance system, characterize clinical and social factors common among this case subset, identify challenges in both surveillance and clinical management, and summarize key lessons that can inform future surveillance efforts for mpox outbreaks.

METHODS

Our target population in this study was all reported mpox cases in Los Angeles County. Our study population was composed of complicated cases among all confirmed MPXV infections reported to LACDPH during 1 August–30 November 2022. The study sample included a subset of complicated cases with persistent lesions who had been prescribed a full course of tecovirimat, regardless of adherence.

A confirmed mpox case was defined using the CDC case definition: demonstration of the presence of MPXV DNA by polymerase chain reaction testing or next-generation sequencing of a clinical specimen or isolation of MPXV in culture from a clinical specimen [9, 11].

Los Angeles County Public Health Surveillance

LACDPH began supplemental monitoring of all complicated cases of mpox in August 2022, after the first severe case of mpox with antiviral resistance had been identified in a patient with advanced HIV who ultimately died [5]. The goal was to identify patients with a higher risk of progression to severe disease who may need further investigation and consultation for treatment options.

All identified mpox cases were matched to an HIV case registry maintained by the LACDPH Division of HIV and Sexually Transmitted Diseases multiple times per week to identify patients with concurrent mpox, HIV, and CD4 count <200 cells/μL. All hospitalized cases were identified through provider or facility report to the health department, or self-report by the case during initial interview or follow-up contacts.

We reviewed public health nursing notes for all mpox cases with low CD4 counts and all mpox cases who were hospitalized to identify cases. We also attempted to contact the providers of all hospitalized cases who had not been discharged. Among hospitalized cases, we discussed case details and conducted clinical chart reviews. We provided clinical consultation to providers managing complicated cases and facilitated CDC consultation when needed.

For cases whose lesions worsened or failed to improve despite initiating or completing treatment with tecovirimat, we either collected or obtained multiple lesion swabs and performed whole genome sequencing in the LACDPH laboratories over the course of treatment. Detailed methods and findings from genomic investigation are available in a separate publication [9].

Approvals

This study was deemed not to constitute human subjects research by the LACDPH institutional review board.

RESULTS

Surveillance

Between 1 August and 30 November 2022, we identified 1581 confirmed mpox cases (Figure 1). Of these, 739 had HIV coinfection and 60 had low CD4 count (<200 cells/μL). Ninety-five cases were hospitalized. Among confirmed cases, 134 were complicated cases (ie, hospitalized and/or low CD4 count).

Figure 1.

Flowchart of mpox cases in Los Angeles County, 2022. Abbreviation: HIV, human immunodeficiency virus.

Of the hospitalized cases, 71 had HIV coinfection, and 21 had low CD4 counts. Of complicated cases, 8 cases met the inclusion criteria of persistent lesions despite initiation or completion of tecovirimat for the subset of interest. A summary of the clinical characteristics and treatment challenges of these cases is presented in Table 1.

Table 1.

Patient Clinical Background, Treatment and Challenges, and Outcomes

Case	Age, y, Gender	Medical History	CD4 Count, Cells/μL	HIV Viral Load, Copies/mL	Treatment	Treatment Challenges	Clinical Outcomes
1	30, Transgender female	HIV/AIDS, methamphetamine use disorder, late latent syphilis	<35	130 565	Tecovirimat (PO, IV), VIGIV, ART	Did not complete full oral courses; refused IV access; left against medical advice before completing treatment	Deceased
2	43, male	HIV/AIDS	73	<20	Tecovirimat (PO, IV), VIGIV, brincidofovir, ART	Difficulty with swallowing due to oral pain	Recovering at discharge; lost to follow-up, seen in emergency room without mpox lesions noted (7 mo postdischarge)
3	34, Male	HIV/AIDS (new diagnosis), HSV-2, Shigella bacteremia	136	178 982	Tecovirimat (PO, IV), VIGIV, ART	Bloody diarrhea during follow-up hospital course; unclear PO dosing during initial tecovirimat treatment course	Followed up in outpatient clinic with ongoing lesions (3 wk postdischarge)
4	32, Male	HIV/AIDS	<35	26 724	Tecovirimat (PO, IV)	Difficulty with oral administration due to pain; agitated and combative with staff	Full resolution of skin lesions with reepithelialization (10 wk postdischarge)
5	41, Male	HIV/AIDS, neurosyphilis, ulcerative colitis, CMV viremia	96	2620	Tecovirimat (PO, IV), cidofovir; VIGIV, ART	Presumed ulcerative colitis flare with diarrhea	Followed up in outpatient ID clinic with full resolution of mpox lesions (4 mo postdischarge)
6	36, Male	HIV/AIDS	191	606	Tecovirimat (PO), ART	Refused brincidofovir and VIGIV	Ongoing skin lesions without full recovery and with fungating appearance (11 mo postdischarge)
7	40, Male	HIV/AIDS, cryptococcal meningitis, gonorrhea, chlamydia, syphilis, HSV-2, Enterococcus faecalis bacteremia	<35	113 944	Tecovirimat (PO, IV), ART	Inconsistent outpatient oral tecovirimat adherence	Followed up in ID clinic with most lesions healed and no new lesions (4 wk postdischarge)
8	54, Transgender female	HIV/AIDS, late latent syphilis, Cryptosporidium	54	485 298	Tecovirimat (PO, IV), ART	Profuse watery diarrhea (Cryptosporidium positive); left against medical advice before completing treatment; refused treatment and IV lines during admissions	Ongoing skin lesions without full recovery (7 wk postdischarge)

Abbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; HIV, human immunodeficiency virus; HSV-2, herpes simplex virus type 2; ID, infectious disease; IV, intravenous; PO, oral; VIGIV, intravenous vaccinia immunoglobulin.

Description of Cases of Interest

The median age was 38 years (range, 30–54 years); 6 identified as male and 2 as transgender females; all patients had HIV, and median CD4 count was 63.5 cells/μL.

Five of 8 patients had 1 or more concurrent comorbidities including STIs (syphilis, gonorrhea, chlamydia), substance use disorders, or psychiatric disorders and/or were experiencing homelessness. Extended courses of tecovirimat were given in all cases, and 4 patients received additional therapeutics including VIGIV, cidofovir, and brincidofovir. Antiretroviral therapy (ART) was restarted in 7 of 8 cases. One case died, 3 had full recovery, and 4 had ongoing lesions at last follow-up with varying degrees of improvement.

A detailed description of cases can be found in the Supplementary Material. A detailed description of tecovirimat resistance mutations identified through our surveillance system can be found in the Supplementary Material and Garrigues et al [9], including all GenBank, sequence read archive, and global initiative on sharing all influenza data identification numbers for the relevant sequences. These cases of interest were not known to be epidemiologically linked to each other based on case interviews.

DISCUSSION

We describe a surveillance system for complicated mpox cases. Surveillance of complicated mpox cases required close coordination between health departments and their providers. Through this effort we defined and identified complicated patients; facilitated appropriate clinical care, including provision of IND therapeutics; and ensured that isolates with high pretest probability for resistance were further evaluated.

Many infections during the 2022 outbreak occurred in immunocompromised hosts, especially those living with HIV, in whom viral clearance can be more difficult, increasing the risk of developing drug resistance. The emergence of and ability to detect new mutations associated with resistance depends on numerous factors, including the size and density of sexual networks, distributions of immunocompromised hosts, the mutation rate of the strain, and drug selection pressure. We targeted our resources by focusing sequencing efforts on isolates with a higher pretest probability such as mpox cases not responding to oral tecovirimat.

We identified multiple single-amino-acid substitutions that have been previously noted to confer high-level phenotypic resistance against tecovirimat in other orthopoxviruses in 6 of the 8 identified cases (full results available in Garrigues et al [9]). In 1 case, resistance mutations were identified after tecovirimat exposure but not before, suggesting that resistance developed during treatment [9]. The mutations identified may have resulted from a combination of selection pressure due to inadequate levels secondary to adherence or malabsorption and host immunosuppression.

Continued sequencing of MPXV specimens will be important to monitor the evolution of circulating strains, including recently reported reinfections [12]. Plasticity of the genomic termini in orthopoxviruses allows for host adaptation via gene deletion [13]. Through whole genome sequencing, identification of gene deletions that impacted accuracy of diagnostic assays were identified during this outbreak [14]. Phylogenetic analysis early in the outbreak found multiple-fold more single-nucleotide polymorphism differences between observed strains versus what would be expected compared to genomes of circulating strains from the Nigerian 2018–2019 outbreak, suggesting potentially accelerated evolution or ongoing, cryptic transmission for several years [15].

In the subset of cases who did not recover despite initiation of tecovirimat, we helped assess the appropriateness of additional therapeutics with distinct viral targets (brincidofovir, VIGIV) based on experience, first principles, and interim treatment guidelines when available [6]. While a recent case series identifying immune reconstitution inflammatory syndrome (IRIS) in a high proportion of mpox cases with advanced HIV has been reported, we have not observed this phenomenon in our review of complicated cases [10]. Regardless of the risk of IRIS, immune reconstitution is critical for clearing the virus in patients with advanced HIV, and ART should be initiated early. Although the role of steroids is still unclear, there have been case reports in which steroid use has reportedly been associated with recovery from inflammatory pathogenesis [16].

In our case series, patient adherence to full courses of oral tecovirimat was often inconsistent due to psychosocial challenges, including lack of housing, mental health issues, and lack of regular access to food, consistent with findings from larger case series [2, 10]. In multiple hospitalized cases, we found that patient adherence to therapies posed challenges, especially without adequate intravenous access. In 1 patient, this was likely a contributing factor in the patient's death as we were unable to initiate therapies against the patient's will. In some cases, even provision of housing facilitated by our health department did not lead to complete medication adherence. In cases where tecovirimat adherence is challenging in both oral and intravenous formulations, the weekly administration of brincidofovir, an oral prodrug of cidofovir that targets viral DNA polymerase, may be particularly helpful.

The same factors that are associated with incomplete adherence to ART regimens also serve as obstacles to adherence for mpox antiviral regimens. These overlapping challenges have contributed to difficulties with completing full 14-day courses of tecovirimat, which requires coadministration with a high-fat meal for optimal absorption and at least 2 weeks of twice-daily medication administration [6, 8]. For patients who are experiencing homelessness, regular daily meals are not always available. Ensuring that these cases have safe discharge plans, including attention to social and structural challenges that they may face outside of the hospital, will be essential in complete recovery.

While resistance mutations were identified in our subset of cases and in the first US mpox death reported from our department, we do not know the prevalence of these mutations among all mpox patients with advanced HIV [5]. Other reports of tecovirimat resistance testing, including isolates from patients with HIV, have not described associated mutations [17].

CONCLUSIONS

During the 2022 mpox outbreak, active public health surveillance identified complicated mpox cases. Among these complicated cases, selective sequencing of at-risk cases successfully identified tecovirimat-resistant isolates from patients with advanced HIV. Among cases with resistance including the first US death, fatality was high (2/7). Close monitoring in immunocompromised patients is essential, and coordination between public health departments and clinicians can improve surveillance for resistance as well as care coordination for patients facing psychosocial challenges that may impede adherence to HIV and mpox therapeutics.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Notes

Disclaimer. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention.

Financial support. A. K. is supported by the National Institutes of Health (grant number 2T32AI052073-16A1, Global Infectious Disease Epidemiology Training Grant, Stanford University). This publication was supported by the Centers for Disease Control and Prevention (grant/cooperative agreement number 6 NU50CK000498-04-03).

Supplement sponsorship. This article appears as part of the supplement “Mpox: Challenges and Opportunities Following the Global 2022 Outbreak,” sponsored by the Centers for Disease Control and Prevention (Atlanta, GA).