Clinical Considerations for Mpox in Immunocompromised People

Overview

People who are severely immunocompromised or have certain skin conditions are at risk of developing protracted or life-threatening manifestations of mpox regardless of disease severity at presentation. A March 3, 2023, MMWR provides clinical treatment considerations about using therapeutics to treat severe mpox cases, including ocular infections, neurologic complications, myopericarditis, complications associated with mucosal lesions, and complications from uncontrolled viral spread.

These considerations are based upon limited evidence available to date about mpox in people who are immunocompromised. The approaches outlined below are intentionally cautious until additional evidence becomes available.

Immunosuppressive conditions and agents considered for this report

Moderate and severe immunocompromising conditions and treatments include but are not limited to:

• HIV infection, particularly in the presence of a low CD4 count (<200 cells/mm³)
• Moderate or severe primary immunodeficiency (e.g., phagocyte disorders, agammaglobulinemia, common variable immunodeficiency disease, severe combined immunodeficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, or any other immunodeficiency with immune dysregulation)
• Active treatment for a solid tumor or hematologic malignancy
• Immunosuppressive therapy for solid-organ or islet transplant
• Active treatment with high-dose corticosteroids (i.e., 20 or more mg of prednisone or equivalent per day when administered for 2 or more weeks), an alkylating agent, antimetabolite, transplant-related immunosuppressive drug, cancer chemotherapeutic agent classified as severely immunosuppressive, tumor necrosis factor (TNF) blocker, or other biologic agent that is immunosuppressive or immunomodulatory
• Receipt of chimeric antigen receptor (CAR)-T-cell therapy or hematopoietic cell transplant (within 2 years of transplantation or taking immunosuppressive therapy)

Factors to consider when assessing the level of immune competence in a patient include underlying disease severity, duration, clinical stability, complications, comorbidities, and any potentially immune-suppressing treatment. For additional information about the degree of immune suppression associated with different medical conditions and treatments, providers can consult ACIP's General Best Practices for Vaccination of People with Altered Immunocompetence, the 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host, and the AAP Red Book.

Mpox in people who are immunocompromised

Most patients, including those with well-controlled HIV, experience self-limiting disease and recover with supportive care alone. However, people who are significantly immunocompromised, most commonly from advanced HIV (CD4 T lymphocyte [CD4] cell count <200 cells/mm³ and especially <50 cells/mm³), have experienced more severe infections, including increased likelihood of hospitalization and disseminated disease, likely because their weakened immune systems are unable to clear the virus.

Although they may have a higher risk of infection and severe illness, severe outcomes are not universally seen in people who are immunocompromised: one study from the 2003 outbreak of mpox in the United States noted recovery without severe disease in one patient with lupus nephritis and another patient with prior bone marrow transplant.¹ A case series published in 2023 reported 11 cases of mpox among persons with solid organ transplantation, including 1 mpox-related death in the cohort. Despite noting a high burden of skin lesions and systemic symptoms, most resolved their infection within 30 days of treatment. It is important to note that differences in disease severity may also be affected by the route of transmission, host susceptibility, and the quantity of MPXV inoculated.²

Mpox in people with HIV

Available summary surveillance data from the European Union^{3, 4, 5}, England⁶, and the United States⁷ indicate that among gay, bisexual, and other men who have sex with men (MSM) with mpox for whom HIV status is known, 28%–51% have HIV infection. However, it is currently unknown whether an HIV infection increases a person's risk of developing mpox after exposure.

The available data indicate that people with advanced and uncontrolled HIV can be at a higher risk of protracted or life-threatening manifestations of mpox:

• In a 2017–18 case series of 122 Nigerian patients with mpox, 4 of the 7 deaths occurred among people with untreated advanced HIV; however, data about the overall proportion of patients who had HIV were lacking.⁸
• A second 2017–18 case series, also reported from Nigeria, included 9 people with HIV for whom clinical data relevant to HIV status were provided: CD4 cell counts ranged from 20–357 cells/mm³, indicating immunosuppression. Compared with other patients, those with HIV had higher rates of secondary bacterial infections, more prolonged illnesses (and thereby also longer period of infectiousness), as well as a greater likelihood of a confluent or partially confluent rash, rather than discrete lesions.⁹
• In published reports from the ongoing global clade II outbreak, mpox among people with advanced or untreated HIV has been associated with hospitalization, severe disease, including progressive or disseminated rash, protracted course, and complications including sepsis, ocular disease, encephalitis, and death.^{2, 10-12}

For additional information see Severe Mpox in Hospitalized Patients—United States, August 10–October 10, 2022 | MMWR (cdc.gov) and Health Alert Network (HAN) 00475: Severe Manifestations of Mpox among People who are Immunocompromised Due to HIV or Other Conditions.

Incubation

It is not known whether the incubation of mpox differs between people who are immunocompromised and those who are immunocompetent.

Diagnosis

Clinical picture

Fever and other prodromal symptoms such as chills, lymphadenopathy, malaise, myalgias, and headache may precede or follow the rash or be absent. It is not known whether the prodromal phase of mpox differs between people who are immunocompromised and those who are immunocompetent.

People who are immunocompromised may present with an atypical rash, including a disseminated rash, which may make diagnosis more challenging. In one study, people with poorly controlled HIV were more likely to have genital lesions and a confluent or partially confluent rash, as opposed to discrete lesions.⁹ Rash presentations in people who are immunocompromised can also have coalescing or necrotic lesions. Additionally, people in this study with poorly controlled HIV were more likely to have prolonged illness.

See also Severe Mpox in Hospitalized Patients — United States, August 10–October 10, 2022 | MMWR (cdc.gov) and HAN 00475: Severe Manifestations of Mpox among People who are Immunocompromised Due to HIV or Other Conditions.

Signs and symptoms

In people who are immunocompromised, the signs and symptoms of mpox may be either similar (i.e., rash, fever, and lymphadenopathy) or dissimilar to those observed in people who are immunocompetent. In people who are immunocompromised, mpox may present with atypical manifestations or more severe illness (e.g., sepsis, disseminated rash, hemorrhagic disease, numerous confluent lesions, necrotic lesions, severe lymphadenopathy that can be obstructing, ocular or periorbital infections, pulmonary involvement, encephalitis, myocarditis or other conditions requiring hospitalization).¹²

For more information on severe disease caused by mpox see Severe Mpox in Hospitalized Patients — United States, August 10–October 10, 2022 | MMWR (cdc.gov) and HAN 00475: Severe Manifestations of Mpox among People who are Immunocompromised Due to HIV or Other Conditions.

Differential diagnosis

In people who are immunocompromised, mpox should be considered as a possible etiology of rash illness. Other etiologies to consider include herpes zoster (shingles), scabies, molluscum contagiosum, herpes simplex, enteroviral infection (hand-foot-and-mouth disease), syphilis, chancroid, lymphogranuloma venereum, and other infections which can cause cutaneous manifestations in immunocompromised hosts (e.g., endemic fungi, non-tuberculous mycobacteria), allergic skin rashes, and drug eruptions. Mpox can be confused with disseminated herpes zoster or herpes simplex virus infections. These herpes virus infections, and especially disseminated herpes zoster, most commonly affect people with immunocompromising conditions. Therefore, to establish a diagnosis for immunocompromised people who present with a rash, clinicians should elicit a medical history that includes a detailed sexual health history (i.e., partner number, frequency, activities), perform a complete physical examination, and order appropriate laboratory testing.

Coinfections

Mpox coinfections with STIs have been reported. In a September 2022 MMWR, among 1,969 people with mpox in eight U.S. jurisdictions, 38% had HIV infection, and 41% had an STI in the preceding year. Therefore, people being evaluated for mpox should also be tested, and treated as indicated, for HIV and other STIs.^{13, 14}

Laboratory Confirmation

For details on specimen collection and handling, please see Guidelines for Collecting and Handling Specimens for Mpox Testing.

Treatment

Mpox in people who are immunocompetent tends to be a mild illness that resolves spontaneously. For such patients, supportive care, pain management, skin care, and wound care that is implemented early in the course of illness is usually sufficient. However, prognosis depends on multiple factors, including initial health status, concurrent illnesses, previous vaccination history, and comorbidities. People who are severely immunocompromised from HIV (i.e., CD4 cell count <200 cells/mm³) or other conditions or from immunosuppressive therapy may be at increased risk of protracted or life-threatening infection.

Early optimization of immune function (e.g., by temporarily delaying or decreasing doses of chemotherapy and immunomodulatory therapies and by promptly initiating effective HIV antiretrovirals) is critical to favorable outcomes. Prompt initiation of tecovirimat (potentially the intravenous formulation), and possible combination with either cidofovir or brincidofovir, and VIGIV, should be considered in this population, depending on the severity of immunocompromise and uncontrolled viral replication.

Decisions on whether and when to use medical countermeasures must be made individually for each person and can depend on a variety of clinical and other parameters.¹⁵The decision whether to treat and monitor a person who is immunocompromised in their home or in an inpatient setting should also be individualized. If the patient fails to improve with a usual course (i.e., 14 days) of oral tecovirimat, consideration may be given to both extending the duration of therapy, additional therapeutics, and changing the route of tecovirimat administration from oral to IV. Such considerations should be made on a case-by-case basis, taking into account the patient's condition, other comorbidities, ability to absorb oral medications, and ability to take a full, fatty meal.

A March 3, 2023, MMWR provides updated clinical treatment considerations about using therapeutics to treat severe mpox cases, including ocular infections, neurologic complications, myopericarditis, complications associated with mucosal lesions, and complications from uncontrolled viral spread.

In severe cases of mpox or for patients with mpox and immunocompromising conditions that put them at risk for developing severe disease, consider consultation with infectious disease, public health experts, or CDC. The CDC clinical consultation service for patient management questions may be accessed by emailing poxvirus@cdc.gov or for urgent requests, calling the CDC Emergency Operations Center (EOC) at (770) 488-7100.

Managing HIV in people with mpox and HIV

ART and opportunistic infection prophylaxis should be continued in all people with HIV who develop mpox. ART interruption may lead to rebound viremia that could complicate the management of mpox (for example, worsen the severity of illness). People without HIV who are taking ART for HIV pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) should also continue taking these medications.

People diagnosed with mpox who have HIV (even if newly diagnosed) who are not on ART should be started on ART as soon as possible in consultation with an expert in HIV medicine if needed.¹⁶

Clinicians using antivirals for mpox should be alert for drug-drug interactions with any antiretrovirals used to prevent^{17, 18} or treat¹⁹ HIV infection as well as with any other medications used to prevent or treat HIV-related opportunistic infections.¹⁶ Key critical interactions are discussed below for each mpox antiviral. Any potential drug-drug interactions not noted below can be assessed using the interactive University of Liverpool HIV Drug Interactions database.

Special considerations for medical countermeasures

Tecovirimat

• Tecovirimat might reduce the levels of the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine. Therefore:
  • Long-acting cabotegravir/rilpivirine should not be started during tecovirimat therapy and for 2 weeks after the conclusion of tecovirimat.
  • For individuals who have recently received their initial dose of long-acting rilpivirine/cabotegravir IM, consider adding oral rilpivirine 25 mg once daily during tecovirimat treatment and for 2 weeks after the end of treatment.
• Although the tecovirimat eIND mentions drug interactions between tecovirimat and both doravirine and maraviroc, neither requires dose-adjustments when co-administered with tecovirimat.
• Although few interactions are expected between standard immunosuppressive medications and tecovirimat,^[1] tecovirimat may reduce serum concentrations for tacrolimus and sirolimus. Close monitoring of tacrolimus and sirolimus levels are recommended, as dose increases may be required.
• For additional resources to determine drug interactions and potential dosing modifications, please see: University of Liverpool HIV Drug Interactions database and Drug-Drug Interactions: ARVs and Treatments for Severe Mpox – AIDS Institute Clinical Guidelines (hivguidelines.org).

Cidofovir

• Dose-dependent nephrotoxicity is a concern with cidofovir, and it is contraindicated in patients with serum creatinine >1.5 mg/dL.
• Cidofovir should not be used simultaneously with brincidofovir.
• Co-administration of cidofovir with tenofovir disoproxil fumarate (TDF) is not recommended. If concomitant use of TDF and nephrotoxic agents is unavoidable, renal function should be monitored closely.
• Cidofovir is typically co-administered with probenecid to reduce nephrotoxicity and boost its effectiveness. Probenecid substantially increases zidovudine plasma levels; if co-administered, zidovudine should either be temporarily discontinued or decreased by 50% on the day of cidofovir-probenecid administration to avoid zidovudine-induced hematological toxicity.
• No drug interactions are anticipated between cidofovir and standard immunosuppressive medications.
• Cidofovir has interactions, including contraindications for use, with other medications that should be assessed by the clinical team.

Brincidofovir

• Brincidofovir should not be used simultaneously with cidofovir. In contrast to cidofovir (which is associated with dose-dependent nephrotoxicity), serious renal toxicity or other adverse events have not been observed during treatment of cytomegalovirus infections with brincidofovir.
• Brincidofovir has clinically relevant drug interactions with protease inhibitors (PIs), cobicistat, and fostemsavir that may require modification of therapy. If PIs, cobicistat, or fostemsavir are co-administered with brincidofovir, clinicians should monitor closely for adverse reactions (for example, elevations in transaminase levels), and dosing of ART should be delayed for at least 3 hours after brincidofovir administration.
• Brincidofovir has interactions, including contraindications for use, with other medications that should be assessed by the clinical team.

Vaccinia Immune Globulin Intravenous (VIGIV)

• Glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase method (monitor and test strips) must not be used for blood glucose testing in patients receiving VIGIV, since maltose in IGIV products has been shown to give falsely high blood glucose levels in these testing systems. Instead, blood glucose measurement in patients receiving VIGIV must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose contained in VIGIV.
• VIGIV is contraindicated in individuals with
  • a history of anaphylaxis or prior severe systemic reaction associated with the parenteral administration of this or other human immune globulin preparations.
  • Immunoglobulin A (IgA) deficiency with antibodies against IgA and a history of IgA hypersensitivity.

Vaccination with live virus vaccines (for example, varicella, measles, mumps, and rubella) should be deferred for 3 months after use of VIGIV.

• Mpox can cause keratitis. Caution should be exercised when using VIGIV in the treatment of people with active keratitis, as increased corneal scarring was observed in an animal model of vaccinia keratitis. This finding, however, has not been noted in other studies. Therapeutic considerations for ocular mpox are included in the guidance on management of ocular mpox.
• There are no specific contraindications for use of VIGIV among people who are immunocompromised, including with HIV. There are no known or anticipated interactions with ART or immunosuppressive medications.

Vaccination

Vaccination prior to exposure to MPXV

Mpox vaccination should be offered to people with high risk for exposure to mpox.

The JYNNEOS vaccine may be given to people with congenital or acquired immune deficiency disorders, including those taking immunosuppressive medications and people living with HIV (regardless of immune status). JYNNEOS is considered safe in persons with HIV infection, although effectiveness may be lower among severely immunocompromised individuals.

Postexposure prophylaxis

Vaccination after known or presumed exposure to monkeypox virus.

Postexposure prophylaxis (PEP) vaccination for mpox should be offered to people who are immunocompromised, including from HIV as indicated. The benefits and potential adverse effects of PEP vaccination should be discussed with the person using shared decision-making. Although the efficacy of these therapies for mpox PEP is unknown,

• early use of vaccination (within 4 days from exposure) could prevent mpox, later use (5 days or more after exposure) may decrease the severity of mpox if infection does occur.
• in a person who is severely immunocompromised with a known high-risk exposure (who is at risk for severe mpox), the benefits of vaccination more than 14 days after exposure may still outweigh risks.

Other therapies, including the antiviral medication tecovirimat and VIGIV, may be considered for mpox PEP on a case-by-case basis in consultation with CDC in an exposed person with severe immunodeficiency in T-cell function. Factors to consider include known high-risk exposure to a confirmed or probable case of infection and clinical conditions that necessitate an alternative option to PEP vaccination.

Timing of vaccination

Vaccines for PEP should not be delayed, regardless of whether patients are taking immunosuppressive therapies. Vaccinations administered prior to exposure to MPXV should ideally be timed taking into consideration current or planned immunosuppressive therapies, optimization of both the person's medical condition and anticipated response to vaccination, and individual benefits and risks.

Ideally, orthopoxvirus vaccines should be administered at least 2 weeks before initiation or resumption of immunosuppressive therapies when administered prior to exposure to MPXV. For patients who receive B-cell-depleting therapies on a continuing basis, vaccines should be administered approximately 4 weeks before the next scheduled therapy.

The utility of serologic testing, cellular immune testing, or B-cell quantification to assess immune response to vaccination and guide clinical care has not been established. Such testing outside of the context of research studies is not recommended at this time.

Vaccine safety and efficacy

JYNNEOS

JYNNEOS is a two-dose nonreplicating live virus vaccine.²⁰ It is licensed by FDA for prevention of both smallpox and mpox disease in adults 18 years of age and older. Because JYNNEOS is replication-deficient, it poses no risk for

• progressive vaccinia
• autoinoculation (i.e., transfer of vaccinia virus from one part of the body to another)
• inoculation of others who come into contact with the vaccination site.

Therefore, JYNNEOS can be administered to people who are in contact with household members who are immunocompromised.

Available human data on JYNNEOS administered to people who are immunocompromised are insufficient to determine efficacy. JYNNEOS is considered safe for people with immunocompromising conditions; however, people who are immunocompromised may be less likely to mount an effective immune response after vaccination. There are limited data available regarding safety and efficacy of JYNNEOS in people who are immunocompromised except for studies regarding people with HIV. Specifically, one study enrolled people with a prior diagnosis of AIDS who were virologically suppressed and had CD4 counts between 100 and 500 and found no serious safety concerns; two doses produced neutralizing antibodies in 100% of people who were immunocompromised.^{21, 22}

Studies regarding safety and efficacy of JYNNEOS in people who are immunocompromised are also limited. JYNNEOS was studied in an immunocompromised macaque animal model as a potential vaccine vector without any substantial safety concerns.²³ Another study evaluated the safety and immunogenicity of JYNNEOS in a small number of people with prior hematopoietic stem cell transplant and found that JYNNEOS was safe and immunogenic in this population.²⁴

Although an intradermal route of administration has been shown to be immunologically noninferior to a subcutaneous route in people who are immunocompetent, no data are available comparing safety and immunogenicity of these two routes in people who are immunocompromised. However, the risk for serious adverse events with either route is expected to be low. People who are immunocompromised may be vaccinated using either subcutaneous or intradermal route of administration.