Optimal management of severe mpox in patients with uncontrolled human immunodeficiency virus

In May 2022, a cluster of nontravel‐related cases of human mpox were reported in the United Kingdom. The outbreak has since spread worldwide infecting over 85 000 patients and causing over 100 deaths. Recent data clearly suggest that patients infected with human immunodeficiency virus (HIV) with CD4 counts less than 200 cells per mm3 suffer significantly worse outcomes than immunocompetent patients. The available countermeasures lack robust clinical data and are deployed based on in vitro and animal studies as well as extrapolations from use against other poxviruses. In many cases, despite administration of these available treatments, initiation of antiretroviral therapy (ART), and management of suspected immune reconstitution inflammatory syndrome after initiating ART, patients die. This review summarizes available data, identifies knowledge gaps and proposes recommendations on the management of severe mpox in people living with HIV.


| INTRODUCTION
Mpox virus (MPXV) is a large double-stranded DNA virus that causes a febrile illness with rash in humans. 1 Until recently, MPXV caused sporadic zoonotic outbreaks primarily in Africa.However, in May 2022, a cluster of nontravel-related cases of human mpox were reported in the United Kingdom. 2 Since those initial infections, the outbreak has spread world-wide infecting over 85 000 patients and causing over 100 deaths. 3Early outbreak data suggested no significant difference in outcome among people living with human immunodeficiency virus (PLWH, HIV) and those without HIV. 4However, subsequent data have shown the majority of severe and fatal cases of human mpox infection occur in those with advanced HIV. 5,6 It is now clear that advanced HIV is a significant risk factor for severe mpox and death, and that immune reconstitution inflammatory syndrome (IRIS) may play a role in these outcomes. 5,7ile the number of new mpox cases has dropped significantly since the outbreak began, recent case clusters suggest ongoing community transmission. 8,9This continued circulation poses an ongoing threat to susceptible hosts.Risk factors for progression of disease other than advanced HIV, natural progression of disease, and optimal management remain undefined.While the STOMP Trial and VIRISMAP are actively enrolling patients to address these questions, the decline in cases worldwide (a positive development overall) has stymied hopes of rapid answers.Given the rare occurrence of this infection in the outbreak's current phase, and the absence of clinical trial data to address treatment for the most severe cases, optimal management will require vigilant multidisciplinary collaboration between the specialties involved in the care of these patients.This review summarizes the pathogenesis of mpox, available clinical data, identifies knowledge gaps and proposes recommendations on the management of these most severe cases among patients with advanced HIV with an emphasis on early combination antivirals and longitudinal wound care.

| PATHOGENESIS OF MPOX
The available data describing the pathogenesis of MPXV infection is limited.Present understanding of MPXV pathogenesis extrapolates from what is known about smallpox virus infection and animal data (Figure 1). 1 MPXV enters the body via infection of mucosal epithelial cells or skin cells. 1,10,11Viral proteins attach to host cells, facilitating membrane fusion and entry. 12The human proteins to which poxviruses bind include heparans, chondroitin, and laminin which are widely expressed among human cell lines and likely accounts for the virus' ability to infect a wide range of cells. 124][15] Notably, there has been significant variability in the clinical presentations during the most recent mpox outbreak, so it is possible lymphoid infection does not always occur.Immunohistochemical evaluations suggest that fibroblasts and dendritic cells are the primary targets of MPXV infection within lymphoid tissue. 10Infected macrophages then enter the bloodstream producing a cell-associated viremia. 1,10,11,13From the bloodstream, MPXV disseminates to the skin and other organs. 1,10,11,13opsied lesions from human MPXV infections reveal eosinophilic cytoplasmic inclusions called Guarnieri bodies which are diagnostic of poxvirus infections. 16[18] The interplay between MPXV and the immune system, and specifically T lymphocytes is complex.Early animal data suggest that while MPXV infects and disseminates in macrophages, it did not appear to infect lymphocytes. 10However, levels of circulating CD4+ T cells, CD8+ T cells, NK cells and B cells all significantly decline in the days following MPXV infection and do not return to normal levels until 10 days after infection. 11Recent human data also suggest an initial decrease in CD4 lymphocytes in early MPXV infection followed by a clonal expansion. 19MPXV appears to evade antiviral CD4+ and CD8+ T cell responses by directly suppressing T cell activation. 20Notably, Vaccinia virus appears to preferentially bind antigen presenting cells (APCs) and activated T cells, but not resting T cells. 21It is unclear if MPXV possesses a similar tropism.
Importantly, CD4+ T cells appear to play a critical role in protection against MPXV.Despite vaccination, SIV-infected macaques with CD4+ T cell counts <300 cells mm −3 were unable to mount an immune response and died when challenged with MPXV. 22is vulnerability has clearly borne out clinically in the recent 2022 outbreak, with PLWH comprising greater than 80% of the severe cases. 23Therefore, reconstitution of the immune system appears critical to recovery and clearance of the infection (Figure 2).
F I G U R E 1 Pathogenesis of mpox.The virus replicates in the cytoplasm of host cells at the site of inoculation.The virus then can spread to local lymph nodes, although it is not clear if this is a necessary step in its pathogenesis.Infected macrophages then enter the bloodstream producing a cellassociated viremia.From the bloodstream, mpox virus (MPXV) disseminates to the skin and other organs.Data from mpox cases before the 2022 outbreak suggested that patients with HIV complicated by AIDS are at risk for more severe disease. 24,25As the 2022 outbreak progressed, the CDC reported that the majority of severe mpox cases occurred in PLWH, particularly in those with low CD4+ T Cell counts. 23,268][29][30][31][32][33][34][35][36][37] Many develop bacterial superinfection, sepsis and acute respiratory distress syndrome (ARDS). 5,7,29Reports suggest that initiation of ART is often delayed for weeks after presentation. 5,7,29Among the largest cohorts, mortality rates in patients with advanced HIV range from 15% to 40%. 5,7Death occurs many weeks to months after the initial presentation. 5,7,23,27,29,30,34,36ese reports also highlight the phenomenon of IRIS, described as an acute worsening or spreading of a patient's lesions and clinical deterioration approximately 2 weeks after initiation of ART. 5,27,29,36 this time, it is not clear if these cases represent true IRIS, or simply the natural progression of mpox in severely immunosuppressed patients.Notably, IRIS has been described previously with other poxvirus infections. 38Additionally, as of the writing of this manuscript, there are no established criteria for defining severe mpox.Among the literature describing these severe cases, severity is generally determined based on clinical course and outcomes, and the World Health Organization describes severe cases to include cases with severe pain, respiratory, gastrointestinal, neurologic, ocular, or cardiac involvement, severe dehydration, progressive lesions, and cases with >100 lesions. 39

| COUNTERMEASURES
The systemic antiviral treatment options with the most available data against MPXV include tecovirimat (TPOXX ® ), cidofovir, brincidofovir, and vaccinia Immune Globulin (VIGIV).Of these options, tecovirimat has recently seen the broadest utilization, given its oral administration and strong safety profile. 40Tecovirimat targets the MPXV p37 protein, disrupting envelope development and mature virion formation. 41The CDC has made tecovirmat available through an expanded access new investigational drug protocol (EA-IND). 40There is currently no high quality clinical data on tecovirimat's effectiveness against mpox; however, a human clinical trial for effectiveness is ongoing, and the drug has been demonstrated to be safe and well tolerated in humans. 42,43The manufacturer recommends a 14-day treatment course based on the development of humoral immunity, however severe mpox cases in immunosuppressed patients often require much longer courses. 29,41dofovir and brincidofovir inhibit viral DNA polymerase.The FDA originally approved cidofovir for the treatment of CMV retinitis, but in vitro data suggests it possesses antiviral activity against a wide number of viruses to include Orthopoxviruses. 44Similarly, brincidofovir is an oral prodrug of cidofovir and approved for the treatment of smallpox. 45,46It is currently only available through an FDAauthorized emergency use-IND. 47The clinical effectiveness data for these drugs against human MPXV infection is limited to case reports and cohort studies. 48Importantly, usage of these drugs may be limited by their toxicities: cidofovir is a known potent nephrotoxin and brincidofovir has been associated with significant hepatotoxicity. 46GIV is prepared from serum of patients vaccinated against smallpox and is available from the CDC through an expanded access protocol for mpox. 49Like the other countermeasures, its effectiveness against poxviruses is limited to case reports. 48I G U R E 2 Depiction of the progression of severe mpox in uncontrolled human immunodeficiency virus (HIV) patients and proposed management strategy.Clinical events are represented over time.Immune reconstitution starts with initiation of antiretroviral therapy (ART) while combination antiviral agents against mpox virus (MPXV) are administered.All agents are continued to bridge the immune system to the point at which is recovers and is able to clear the virus.Notably-not all cases will take a similar time course.1][52] Animal data has also shown that tecovirimat has a low barrier to resistance with only a single amino acid substitution of p37 required for reduced antiviral activity to develop. 41,53While rare, the current outbreak has seen the rise of resistant MPXV isolates obtained from immunosuppressed hosts on long courses of tecovirimat. 26,54Notably, tecovirimat and brincidofovir have been found to have synergistic activity in vitro and in vivo against poxviruses. 55While we concede that it is difficult to draw conclusions based on these limited data, we support the immediate initiation of combination antiviral therapy with tecovirimat, cidofovir brincidofovir and VIGIV in addition to rapid initiation of ART to maximally inhibit viral replication in the absence of effective cell-mediate immunity, optimize the potential for antiviral synergy, and shield against the development of resistance.
For uninfected patients, vaccination is a critical component of preventative care.The severe reactions caused by the live virus smallpox vaccines limited their widespread use.However, the novel nonreplicating JYNNEOS vaccine has become the standard of care and early data suggest that it can prevent and attenuate the severity of mpox infection. 56

| WOUND CARE
The most severe cases of mpox evolve over weeks to months.Patients develop multiple necrotic lesions that progress and become secondarily infected until the immune system reconstitutes sufficiently to clear the virus.Therefore, in addition to systemic antiviral therapy and rapid ART, high-quality longitudinal wound care provided by a specialist becomes a critical component of management of the severe mpox patient.
In patients with skin and tissue loss resulting in fat, muscle, or bone exposure, advanced wound care principles following the DIME method (devitalized tissue/debridement, infection/inflammation, moisture management, edge); addressing devitalized tissue or debridement can be done with autolytic, enzymatic (collagenase), ultrasonic, or surgical/sharp debridement. 57,58The method of debridement that is appropriate is dependent on the patient's pain and ability to tolerate procedures.
Bacterial superinfection is common in the most severe mpox cases. 59All suspected infections should be cultured, either with biopsy or using the Levine technique, before initiation of antibiotic therapy. 60The ulcers should be cleansed with hypochlorous acid solution, wound cleanser, or mild soap such as baby shampoo.Other chemical cleansers such as sodium hypochlorite solutions, chlorhexadine, alcohol-containing solutions, povodine iodine, and hydrogen peroxide should be avoided as they are cytotoxic with a lower therapeutic index than hypochlorous acid. 58,61isture management in the ulcers and periwound skin is also Scar formation is also reduced. 62Moisture can be added to the base of the wound, if needed, by applying hydrogels, hydropolymer, or hydrocolloid dressings.Excess moisture, or heavy exudate, can be managed with alginate, hydrofiber, foam, or superabsorbent dressings.
Despite severe wounds with full thickness necrosis, severe mpox cases can recover complete tissue regeneration with quality wound care (Figure 3).

| OPTIMAL MANAGEMENT
The optimal management of these severe cases in PLWH remains unknown.However, based on the available published data summarized above, recommendations from the CDC and our institutional experience, we make the following recommendations on the management of severe mpox in PLWH (Figure 4). 3. ART should be initiated as soon as feasible, and in accordance with other HIV management guidance.While data are scarce, there appears to be no benefit to delaying ART to attenuate possible IRIS. 5,27,29,36 Patients should be evaluated for alternative etiologies of their disease, as well as concomitant sexually transmitted infections and opportunistic infections as recommended by other HIV management guidance.
5. Providers should perform a thorough history and physical examination to identify all possible organ systems that may be affected but may not be immediately apparent; these include musculoskeletal, ocular, central nervous system, gastrointestinal, pulmonary, and cardiovascular systems.represents the natural course of the disease in severely immunosuppressed hosts, or if there is a true development of IRIS.In the limited data available, there does not appear to be a significant difference in outcome among those who received IRIS treatment and those who did not; nor does there appear to be any benefit to delaying ART initiation. 5,27,29Therapies targeted at IRIS include corticosteroids and may be considered at the provider's discretion.into the STOMP trial and VIRISMAP to further define the natural course of this disease and clarify optimal management strategies.
Figure created with BioRender.com.
Figure created with BioRender.com.T A B L E 1 Select publications providing data on severe mpox outcomes and management in PLWH.

1 .
Upon identification of severe mpox in PLWH, we recommend consultation with CDC and local health departments, and immediate initiation of tecovirimat in combination with VIGIV and either cidofovir or brincidofivor if these agents are available and not contraindicated.While CDC guidance makes the addition of multiple agents a consideration, we feel strongly that a combination of agents should be employed to maximally inhibit viral replication while the immune system regains the ability to clear the virus.63None of the available agents is viricidal, and therefore management should aim for maximal inhibition, effectively 'bridging' the host into a reconstituted state.This strategy also employs the theoretical benefits of protecting against resistance that may result from active viral replication in the presence of a single inhibitor, as well as antiviral synergy.These agents should be continued at least until lesions stop progressing and begin healing, which may take several weeks to months.2.Eligible patients should be encouraged to enroll the STOMP Trial and VIRISMAP, as combination antivirals against mpox does not exclude patients from these studies.

6 .
In patients with suspected bacterial infection, providers should obtain appropriate cultures and then provide empiric antibiotics.The duration of empiric antibacterial therapy should be no longer than what would be given for the specific diagnosis that is suspected (ie SSTI or bacteremia) if the suspected diagnosis cannot be ruled out.Antibiotics should not be given indefinitely.While bacterial superinfection of mpox patients is low in the general population, patients with uncontrolled HIV and severe disease have higher incidence of bacterial superinfection. 59Bacterial infection resulting in sepsis can also be a significant cause of death in these patients, particularly those with anogenital and gastrointestinal lesions. 29,647. Patients should be closely reassessed longitudinally over the full course of their recovery.As these severe mpox patients progress, F I G U R E 3 Progression of lesions in a patient with severe mpox.The days refer to days after diagnosis with mpox.they often develop fevers, leukocytosis, progression of lesions and new symptoms over the course of their management.Based on the heterogeneity of published cases, it is not clear if this progression

8 .
Care should be provided with a multidisciplinary approach to comprehensively and longitudinally address the multiple complex issues that stem from severe MPXV infection as well as any potential barriers to treatment adherence upon discharge.Specialties likely to be involved include: Infectious Disease, Internal Medicine, Pharmacy, Nursing, Wound Care, Pain and Palliative Care, Neurology, General Surgery, Orthopedic Surgery, Podiatry, Urology, Plastic Surgery, Ophthalmology, Dermatology, OBGYN, Psychiatry and Social Work.Quality wound care provided by a specialist is a critical component to this longitudinal care.

7 |
CONCLUSIONThe rapid global expansion of mpox cases during the 2022 outbreak demonstrated how a zoonotic infection effectively transformed into a sexually transmitted disease in the modern era.65It is now clear that PLWH who are poorly controlled are at significantly increased risk of severe disease and death.Sporadic case clusters suggest ongoing community transmission, though it remains to be seen if mpox will ultimately become truly endemic.The natural progression of disease in these severe cases, to include possible IRIS and risk factors for progression other than low CD4 T Cell count, must be further clarified, and optimal management remains undefined.While the STOMP trial and VIRISMAP are actively attempting to answer these questions, low case counts have slowed enrollment.Therefore, until further data are available, we advise that the most severe cases should be treated in consultation with the CDC, with combination antiviral therapy, rapid initiation of ART and followed by a multidisciplinary team to include a wound care specialist over the prolonged course of the recovery.Those at risk should be vaccinated with Jynneos.We also strongly encourage providers to enroll patients F I G U R E 4 Proposed flowchart of management of severe mpox.SHISHIDO and STREET | 7 of 9