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\begin{document}

\title{Optimal Management of Severe Mpox in Patients with Uncontrolled HIV}



\author[1]{Akira  Shishido}%
\author[1]{Stacy Street}%
\affil[1]{Virginia Commonwealth University}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
In May 2022, a cluster of non-travel-related cases of human mpox were
reported in the UK. The outbreak has since spread world-wide 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 mm \textsuperscript{3} suffer
significantly worse outcomes than immunocompetent patients. The
available countermeasures lack robust clinical data and are deployed
based on \emph{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, and
management of Immune Reconstitution Inflammatory Syndrome (IRIS),
patients die. This review summarizes available data, identifies
knowledge gaps and proposes recommendations on the management of severe
mpox in PLWH.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Mpox virus (MPXV) is a large double-stranded DNA virus that causes a
febrile illness with rash in humans. Until recently, MPXV caused
sporadic zoonotic outbreaks primarily in Africa. However, in May 2022, a
cluster of non-travel-related cases of human mpox were reported in the
United Kingdom. Since those initial infections, the outbreak has spread
world-wide infecting over 85,000 patients and causing over 100 deaths.
Early outbreak data suggested no significant difference in outcome among
people living with Human Immunodeficiency Virus (PLWH, HIV) and those
without HIV. However, subsequent data have shown the majority of severe
and fatal cases of human mpox infection occur in those with advanced
HIV. 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.

While the number of new mpox cases has dropped significantly since the
outbreak began, recent case clusters suggest ongoing community
transmission. This 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.

\textbf{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).
MPXV enters the body via infection of mucosal epithelial cells or skin
cells. Viral proteins attach to host cells, facilitating membrane fusion
and entry. The 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. The virus replicates in the cytoplasm of host cells at the
site of inoculation and spreads to local lymph nodes.
Immunohistochemical evaluations suggest that fibroblasts and dendritic
cells are the primary targets of MPXV infection within lymphoid tissue.
Infected macrophages then enter the bloodstream producing a
cell-associated viremia. From the bloodstream, MPXV disseminates to the
skin and other organs. Biopsied lesions from human MPXV infections
reveal eosinophilic cytoplasmic inclusions called Guarnieri bodies which
are diagnostic of poxvirus infections. In early-stage lesions,
keratinocytes exhibit balloon-cell degradation with a mixed inflammatory
infiltrate composed of neutrophils and lymphocytes. Advanced lesions
reveal full thickness epidermal necrosis with surrounding inflammatory
infiltrate composed of lymphocytes, neutrophils and eosinophils.

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. However, 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. Recent human data also suggest an initial decrease in CD4
lymphocytes in early MPXV infection followed by a clonal expansion. MPXV
appears to evade antiviral CD4+ and CD8+T cell responses by directly
suppressing T cell activation. Notably, Vaccinia virus appears to
preferentially bind antigen presenting cells (APCs) and activated T
cells, but not resting T cells. It 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 \textless{}300 cells mm-3 were unable to mount an immune
response and died when challenged with MPXV. This vulnerability has
clearly borne out clinically in the recent 2022 outbreak, with PLWH
comprising greater than 80\% of the severe cases. Therefore,
reconstitution of the immune system appears critical to recovery and
clearance of the infection (Figure 2).

\textbf{Severe mpox in PLWH}

Data from mpox cases prior to the 2022 outbreak suggested that patients
with HIV complicated by AIDS are at risk for more severe disease. As 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. This growing body of data suggests PLWH with CD4+ T Cell counts
less than 200 cells/mm\textsuperscript{3} are at significantly increased
risk for fatal outcome (Table 1). Of the most severe cases reported,
patients often present with vast necrotizing skin lesions and to develop
multiorgan involvement to include the pulmonary, gastrointestinal,
musculoskeletal, and central nervous systems. Many develop bacterial
superinfection, sepsis and acute respiratory distress syndrome (ARDS).
Reports suggest that initiation of ART is often delayed for weeks after
presentation. Among the largest cohorts, mortality rates in patients
with advanced HIV range from 15 to 40\%. Death occurs many weeks to
months after the initial presentation. These 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. At 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.

\textbf{Countermeasures}

The systemic antiviral treatment options with the most available data
against MPXV include tecovirimat (TPOXX\selectlanguage{ngerman}®), 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. Tecovirimat targets the MPXV p37 protein,
disrupting envelope development and mature virion formation. The CDC has
made tecovirmat available through an Expanded Access New Investigational
Drug protocol (EA-IND). There 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. The 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.

Cidofovir and brincidofovir inhibit viral DNA polymerase. The FDA
originally approved cidofovir for the treatment of CMV retinitis,
but\emph{in vitro} data suggests it possesses antiviral activity against
a wide number of viruses to include O\emph{rthopoxviruses} . Similarly,
brincidofovir is an oral prodrug of cidofovir and approved for the
treatment of smallpox. It is currently only available through an
FDA-authorized emergency use-IND. The clinical effectiveness data for
these drugs against human MPXV infection is limited to case reports and
cohort studies. Importantly, usage of these drugs may be limited by
their toxicities: cidofovir is a known potent nephrotoxin and
brincidofovir has been associated with significant hepatotoxicity.

VIGIV is prepared from serum of patients vaccinated against smallpox and
is available from the CDC through an expanded access protocol for mpox.
Like the other countermeasures, its effectiveness against poxviruses is
limited to case reports.

Animal models suggest that delayed administration and host
immunosuppression diminish the effectiveness of cidofovir and
tecovirimat. 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. While rare, the
current outbreak has seen the rise of resistant MPXV isolates obtained
from immunosuppressed hosts on long courses of tecovirimat. Notably,
tecovirimat and brincidofovir have been found to have synergistic
activity \emph{in vitro} and \emph{in vivo} against poxviruses. While we
concede that it is difficult to draw conclusions based these limited
data, we support the immediate initiation of combination antiviral
therapy with tecovirimat, cidofovir or 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.

\textbf{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. The method of debridement that is
appropriate is dependent on the patient's pain and ability to tolerate
procedures.

Bacterial superinfection is common in these most severe mpox cases. All
suspected infections should be cultured, either with biopsy or using the
Levine technique, prior to initiation of antibiotic therapy. The 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.

Moisture management in the ulcers and periwound skin is also essential
for healing. The base of the wound requires enough moisture to promote
healing without causing maceration of the periwound. A moist wound
environment reduces pain, promotes autolytic debridement, collagen
formation and epithelialization. Scar formation is also reduced.
Moisture 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).

\textbf{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.

\begin{enumerate}
\tightlist
\item
  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. None 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.
\item
  Eligible patients should be encouraged to enroll the STOMP Trial and
  VIRISMAP, as combination antivirals against mpox does not exclude
  patients from these studies.
\item
  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.
\item
  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.
\item
  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.
\item
  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. Bacterial infection resulting
  in sepsis can also be a significant cause of death in these patients,
  particularly those with anogenital and gastrointestinal lesions.
\item
  Patients should be closely reassessed longitudinally over the full
  course of their recovery. As these severe mpox patients progress, 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
  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.
\item
  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, 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.
\end{enumerate}

\textbf{Conclusion}

The 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. It 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
into the STOMP trial and VIRISMAP to further define the natural course
of this disease and clarify optimal management strategies.

\textbf{References}

Table 1. Select publications providing data on severe MPOX outcomes and
management in PLWH.\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Author}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Cases with CD4 \textless{} 200 (\% of total PLWH in
study)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Severe Manifestations}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Suspected IRIS (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Time to initiation of ART (median days)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Mortality among PLWH CD4 \textless{} 200 (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Median Days to death after diagnosis}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Notes}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mitja et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
179 (85\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing Skin Lesions, lung involvement, CNS involvement, GI
involvement, secondary infections, sepsis\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21 (25\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
21\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27 (15\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
57\% mortality rate of those with suspected IRIS.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Triana-Gonzalez et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10 (15.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Intestinal obstruction/peritonitis, lung involvement/ARDS,\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4 (40\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Risk factors for mortality: CD4 \textless{} 100, absence of ART,
\textgreater{}50 lesions at presentation.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Miller et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
40 (93\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing Skin lesions, lung involvement, CNS involvement,\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Advocates combining anti-MPXV therapies with progression.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Riser et al\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24 (89\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Necrotizing skin lesions\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24 (89\%)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
24 (100\%) *Only included deceased\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
68\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
23 of the 27 HIV+ patients had CD4 counts \textless{} 50\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hermanussen et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, deep soft tissue abscess/myositis, GI
involvement, CNS involvement\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
All patients treated with tecovirimat. Those with CD4 \textless{} 200
hospitalized \textgreater{} 2 weeks.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Warner et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, CNS involvement, septic arthritis, secondary
infections, sepsis\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
33\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1 (50\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
68\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Both patients with suspected IRIS.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Pettit et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, GI involvement, pulmonary involvement,
bacterial superinfection\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
35\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Both patients with suspected IRIS, treated with steroids and pausing of
ART.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Filippov et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, lung involvement, ocular involvement\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Never on ART\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Never on ART\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
74\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patient declined ART, was treated with cidofovir, tecovirimat and
VIGIV.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Stafford et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin and oral lesions\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
immediate\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patient treated with ART, tecovirimat and cidofovir.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Viguier et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
47\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Thet et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, GI involvement, bacterial superinfection\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
immediate\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patient treated with ART, tecovirimat, and VIGIV. Recovery did not begin
until after VIGIV administration.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Caria et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Necrotizing skin lesions, GI involvement, lung involvement, CNS
involvement\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1 (100\%)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
107\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patient treated with ART, tecovirimat, and cidofovir.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Martinez et al\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
0 *Case had CD4 count of 218 cells/mm\textsuperscript{3}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Necrotizing skin lesions, GI involvement, rectal abscess, bacterial
superinfection\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Not provided\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NA\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Patient treated with ART, tecovirimat, cidofovir and VIGIV.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Legend: ART -- antiretroviral therapy; CD4 -- cluster of differentiation
4 T cells; CNS -- central nervous system; GI -- gastrointestinal system;
IRIS -- immune reconstitution inflammatory syndrome; PLWH -- people
living with HIV; VIGIV -- Intravenous Vaccinia Immunoglobulin.

Figure 1. Pathogenesis of mpox.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 2. Depiction of the progression of severe mpox in uncontrolled
HIV patients and proposed management strategy.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 3. Progression of lesions in a patient with severe mpox. The days
refer to days after diagnosis with mpox.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/mpox-lesions-progression/mpox-lesions-progression}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/mpox-path/mpox-path}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/mpox-progression/mpox-progression}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

