The frequency of EM in HIV-positive patients has increased and these patients present with atypical symptoms and persistent skin lesions. Most cases of EM are associated with viral infections, particularly herpes simplex virus (HSV), Epstein-Barr virus (EBV), and HIV [
4,
5]. HIV infection plays direct and indirect roles in triggering EM. The indirect role of HIV infection in the development of EM can be attributed to the immune system’s response to HIV infection, synergistic interactions with other infections (such as
Mycoplasma pneumoniae, Mycobacterium tuberculosis (TB), Treponema pallidum, and histoplasmosis), drugs (such as nonsteroidal anti-inflammatory agents, sulfonamides, and barbiturates), food additives (such as benzoates), and certain industrial chemicals [
6,
10,
11]. The possible reason for this may be due to the dysregulation of CD8 + T cells seen in HIV infection and the direct interaction between HIV and epithelial cells.
Hyperactivation of CD8 + T cells
HIV infection results in a dysfunctional immune response with disrupted T cell homeostasis, marked by a decreased CD4+:CD8 + T cell ratio [
3]. Progression of HIV infection is characterized by a gradual decline in CD4 + T cells and rapid expansion and activation of CD8 + T-cells at the onset and during the chronic phase of HIV infection [
3]. The low CD4+:CD8 + T-cell ratio increases the risk of hypersensitivity drug reactions due to the hyperactivation of CD8 + T cells [
3,
12‐
15]. Interestingly, EM has been reported as a sign and symptom of acute HIV infection as part of a seroconversion illness [
16‐
18], a time when there is rapid expansion and activation of CD8 + T cells. The expansion and activation of CD8 + T-cells is also observed after HIV rebounds, with an increase in viral load following a period of viral suppression, due to factors including interruption of ART [
13] or reinfection. The interruption of ART is expected to result in an increase in viral load and a low CD4+:CD8 + T-cell ratio. Discontinuation of ART and a low CD4+: CD8 + T-cell ratio have been associated with EM due to the expansion and activation of CD8 + T cells [
1,
19].
The declining CD4 + T cells have a significant influence on the way HIV infection is managed, with a focus on decreasing the viral load and reconstituting CD4 + T cells [
3,
14,
20]. The latter is used as a surrogate marker for immune reconstitution, with little or no attention given to the consequence of increased dysfunctional and dysregulated CD8 + T cells [
3,
14,
15]. This is despite the fact that hyperactivation of CD8 + T cells is considered a hallmark of chronic HIV infection and HIV rebound [
13]. The activation of these CD8 + T cells involves nonspecific mechanisms, which include cross-reactivity and antigen-independent cytokine activation, given the propensity of these cells to stimulate cytokines [
13]. The T cells involved are mainly non-HIV-specific CD8 + T cells because of the so-called bystander activation [
13,
21].
The persistent increase and activation of CD8 + T cells is reported to correlate proportionally with an increased risk of non-AIDS-related morbidity and mortality, which is linked to inflammation despite reconstitution of CD4 + T cells with antiretroviral therapy [
14,
20]. The non-AIDS related conditions are linked to activation of non-HIV specific CD8 + T cells directed against non-persistent and persistent antigens derived from new or latent viral and bacterial infections [
13,
14,
20]. Viruses inducing CD8 + T cell activation include HSV, CMV, EBV, Influenza virus, and adenovirus, leading to non-AIDS-related events [
3,
13,
21]. These viruses are common in HIV-infected individuals. This corroborates the increased risk of EM among HIV-infected individuals, since the viruses mentioned are also triggers of EM [
22,
23]. Bacteria and their by-products can also promote non-HIV-specific CD8 + T cell activation when translocated to an injured site [
20]. The bacterial products found to be associated with hyperactivation include lipopolysaccharides (LPS) [
13], which are important antigens for periodontal pathogens. Thus, anaerobic bacteria producing LPS found in dental biofilms could be a potential culprit in the development of EM. Poor oral hygiene can predispose HIV-infected individuals to EM.
The hyperactivation of CD8 + T cells may explain the link between HIV infection and EM. Exposure to HIV and ART in susceptible individuals triggers a dysregulated CD8 + T cell-mediated immune reaction in keratinocytes. Dysregulated CD8 + T cells against persistent and non-persistent antigens are fertile grounds for EM development. This is further supported by the fact that in the subset of non-HIV-specific CD8 + T cells, memory cells are activated more efficiently than naïve cells [
24], indicating a more robust response leading to the destruction of keratinocytes seen in EM. There is also potential cross-reactivity of non-HIV CD8 + T cells directed against other infectious agents for HIV virions on infected keratinocytes or that of HIV-specific CD8 + T cells for infectious antigens other than HIV infection [
24]. The potential role of HIV infection in triggering EM could be seen as both a direct and indirect mechanism, given the known immunological response, which involves hyperactivation of CD8 + T cells [
13].
Although data on the prevalence of EM among HIV-infected individuals are scarce, it can be presumed that individuals who are HIV-positive and on ART have an increased risk for EM. Hence, EM and its more severe counterparts, Steven Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are increasingly being observed among HIV-positive individuals [
19]. Underreporting and misdiagnosis of EM among HIV-infected individuals may be a significant contributing factor to the lack of data on the prevalence of EM among HIV-infected individuals. Moreover, the fact that the condition is acute and self-limiting, resolving within weeks without any significant sequelae, means that it can go unnoticed and unreported [
10,
16]. The absence of a universally accepted distinction between EM and conditions such as SJS adds to the underreporting of EM incidence in HIV-infected individuals [
25].
Direct tissue damage: HIV-epithelial cell interaction
HIV-epithelial cell interactions significantly influence the pathogenesis of HIV-related diseases. HIV can interact with epithelial cells in the genital and oral mucosa during both its initial encounter and the spread of systemic HIV infection [
26]. Independent of CD4, HIV is known to infect and bind to epithelial cells through alternative HIV-associated receptors, including C-X chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), galactosylceramide (GalCer), heparan sulfate proteoglycans (HSPG), mannose receptors, and T cell immunoglobulin and mucin domain 1 (TIM-1) [
7,
26]. When HIV comes into contact with epithelial cells, the integrity of the barrier is compromised, leading to the internalization of the virus [
26].
We postulate that comparable mechanisms could amplify EM in the context of both local and systemic immunoinflammatory reactions targeting HIV-infected epithelial cells. Furthermore, HIV interaction with epithelial cells results in an increased expression of the cytokines tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) [
26], which is believed to play a role in the pathogenesis of EM.
Presence of opportunistic infections
Individuals with HIV are more likely to develop opportunistic infections owing to a gradual decline in CD4 + T cells. These include infectious agents that are also implicated in EM, including HSV, Epstein-Barr virus (EBV), varicella zoster virus (VZV), hepatitis C virus, cytomegalovirus (CMV), streptococcal, Mycobacterial tuberculosis, Treponema pallidum, and histoplasmosis [
10,
11,
19,
27‐
29]. Despite the significant decline in the incidence of these types of infections since the advent of ART, they continue to occur in a considerable number of HIV-infected patients. The activation of a subset of non-HIV-specific CD8 + T memory cells against epithelial cells is more robust and efficient in the presence of these infectious agents than in their naïve counterparts [
24]. HIV and these infectious agents have a synergistic interaction within the epithelia, which can accelerate the development of EM. This interaction involves disruption of the epithelial barrier caused by HIV’s interaction of HIV with epithelial cells, which facilitates the acquisition and/or activation of opportunistic infections. This leads to an inflammatory response that induces the release of HIV virions from infected epithelial cells and a resulting CD8 + T cell response that is implicated in the development of EM. This vicious cycle created by this synergistic interaction could be one of the reasons for the increased incidence and persistence of EM among HIV-infected individuals.
Adverse reaction to antiretrovirals
Adverse drug reactions (ARDs) are defined as harmful and unintended responses to medication at typical therapeutic doses. These reactions can manifest as side effects, allergic reactions, or other adverse events [
30]. Erythema multiforme (EM) is a short-term adverse effect that may go unnoticed in HIV-infected individuals but can become more pronounced when ART is introduced [
9,
31]. EM is reported to be a common cutaneous adverse drug reaction in HIV-infected individuals, with drugs triggering approximately 50% of cases [
32]. In HIV-infected patients, the prevalence of EM is even higher and has a more severe clinical presentation [
9]. The use of ART for the treatment of HIV infection is associated with a range of ARDs, from mild discomfort to severe life-threatening side effects [
9,
33,
34]. Antiretroviral drugs known to cause EM include zidovudine, abacavir, efavirenz, nevirapine, protease inhibitors, etravirine, tenofovir, and new antiretrovirals [
8,
9,
34,
35]. Concurrent use of these drugs with other medications that can trigger EM, such as penicillin’s, cephalosporins, macrolides, sulphonamides, antipyretics, cotrimoxazole, isoniazid, nonsteroidal anti-inflammatory drugs (NSAIDs), and herbal remedies, can exacerbate the condition [
1,
4,
9,
22,
36].
The risk of hypersensitivity drug reactions increases when the CD4+:CD8 + T-cell ratio is low, leading to the hyperactivation of CD8 + T-cells, which is important in delayed hypersensitivity reactions involved in the pathogenesis of EM [
10,
16,
24]. The reaction towards certain ART metabolites triggers a dysregulated T cell response against epithelial cells expressing antigens from infectious agents and drug haptens, resulting in an influx of CD8 + T cells, macrophages, and neutrophils that release a range of cytokines [
9,
36]. These cytokines, along with those released by targeted epithelial cells, mediate inflammation [
4,
9,
10]. The resulting inflammation leads to epithelial cell death, sometimes accompanied by sub- and intra-epithelial vesiculation, and ultimately results in the blistering, erosion, and ulceration seen in EM [
4,
8,
37].
Considering the complex array of medications that most HIV-positive patients typically take, it can be challenging to accurately confirm adverse drug reactions (ADR). One such ADR is a reaction with eosinophilia and systemic symptoms (DRESS), a delayed-type hypersensitivity reaction that presents with symptoms such as pruritic maculopapular rash, eosinophilia, lymphadenopathy, and potentially life-threatening conditions like hepatitis, nephritis, and pneumonitis [
34,
38]. DRESS is a form of drug-induced hypersensitivity reaction developing within one– six weeks of exposure to the offending drug [
34]. In some cases, EM may be mistaken for DRESS because of the similar symptoms. Biopsies are often not performed in these patients, and the diagnosis is typically based on clinical and serological findings. It is possible that some cases initially believed to be DRESS may actually have EM with DRESS-like features. Therefore, EM should be considered in the differential diagnosis of DRESS in HIV-positive patients.