Page 5 of 11

DR11.2 | Dermatologic Reactions to ART Drugs — SDL Guide (Part 2)

Differential Diagnosis and Severity Grading

A multi-panel diagram grades HIV-related cutaneous drug reactions by warning signs, SJS-TEN body surface area detachment, and differentiation from DRESS and IRIS. — **Panel A:** Severity triage pathway showing mild rash versus severe warning signs: mucosal involvement, painful or dusky skin, blistering, positive Nikolsky sign, fever, systemic upset.. **Panel B:** Stevens-Johnson syndrome with less than 10% body surface area epidermal detachment.. **Panel C:** SJS-TEN overlap with 10-30% body surface area epidermal detachment and confluent erosions.. **Panel D:** Toxic epidermal necrolysis with more than 30% body surface area epidermal detachment.. **Panel E:** DRESS versus IRIS comparison showing timing, clinical features, eosinophilia, liver involvement, ART timing, and investigation support..

Once a cutaneous reaction is identified, the decisive step is to grade its severity, because this determines whether the drug can be continued or must be stopped. The most important severity framework is the Stevens-Johnson syndrome / toxic epidermal necrolysis spectrum, defined by the body surface area (BSA) of epidermal detachment: Stevens-Johnson syndrome involves less than 10% BSA, the SJS-TEN overlap involves 10–30% BSA, and toxic epidermal necrolysis involves more than 30% BSA. Warning signs that a rash is becoming severe include mucosal involvement, painful or dusky skin, blistering, a positive Nikolsky sign (epidermis shears with lateral pressure), fever, and systemic upset. A second severe reaction to distinguish is DRESS, which presents with a latency of roughly two to eight weeks, fever, facial oedema, lymphadenopathy, eosinophilia, and internal organ involvement (especially the liver). Crucially, both must be separated from IRIS, which is timed to the start of ART and represents a flare of existing infection rather than a drug allergy, and therefore does not call for stopping ART. Investigations support the grading: a full blood count detects the eosinophilia of DRESS, and liver function tests detect the hepatotoxicity that may accompany a nevirapine reaction.

Three-panel comparison diagram classifying SJS, SJS-TEN overlap, and TEN by percentage of epidermal detachment, morphology, clinical signs, and mortality. — **Panel A:** Stevens-Johnson syndrome: <10% BSA epidermal detachment, mucosal erosions, dusky targetoid lesions, small blisters and erosions, immediate drug withdrawal, mortality ~1-5%.. **Panel B:** SJS-TEN overlap: 10-30% BSA epidermal detachment, confluent erosions, mucosal involvement, positive Nikolsky sign, urgent supportive care, mortality ~10-15%.. **Panel C:** Toxic epidermal necrolysis: >30% BSA epidermal detachment, widespread epidermal necrosis, large flaccid bullae, sheet-like denudation, multisite mucosal erosions, mortality ~25-35%..

SELF-CHECK

A patient on nevirapine has epidermal detachment affecting an estimated 8% of body surface area with mucosal erosions. According to the BSA-based classification, what is this, and what does it imply?

A. Toxic epidermal necrolysis (>30% BSA); a benign self-limiting reaction

B. Stevens-Johnson syndrome (<10% BSA); a severe reaction requiring immediate nevirapine withdrawal

C. A simple morbilliform rash; continue nevirapine with antihistamines

D. DRESS; continue the drug and add an antihistamine

Reveal Answer

Answer: B. Stevens-Johnson syndrome (<10% BSA); a severe reaction requiring immediate nevirapine withdrawal

Epidermal detachment of less than 10% BSA with mucosal involvement defines Stevens-Johnson syndrome. (The SJS-TEN overlap is 10–30% and TEN is greater than 30% BSA.) This is a severe cutaneous adverse reaction: nevirapine must be stopped immediately and never rechallenged, and the patient needs urgent supportive care.

Primary Management and Drug Decisions

Severity-based management diagram for ART-related cutaneous reactions, contrasting mild morbilliform rash with severe SCAR and drug-specific decisions. — **Panel A:** Severity triage pathway showing mild isolated morbilliform rash versus severe warning signs, with continue ART versus stop drug and urgent referral decisions.. **Panel B:** Mild morbilliform ART rash showing intact mucosa, no blisters, antihistamines, emollients, close observation, and continued ART.. **Panel C:** Severe cutaneous adverse reaction showing mucosal erosions, blistering, dusky painful skin, epidermal detachment, fever/systemic upset, stop culprit drug, never rechallenge, and ICU/burns care.. **Panel D:** Drug-specific management matrix for DRESS, abacavir hypersensitivity, zidovudine hyperpigmentation, and IRIS..

The management of an ART cutaneous reaction follows directly from its severity grade, and the single most important judgement is whether to continue or to stop the offending drug. A mild, isolated morbilliform rash without systemic features or mucosal involvement can often be managed by continuing the drug under close observation, with antihistamines for itch and emollients — many such rashes settle. By contrast, any reaction with mucosal involvement, blistering, dusky or painful skin, a positive Nikolsky sign, fever, or systemic upset signals a severe cutaneous adverse reaction: the offending drug — most often nevirapine — must be stopped immediately and never rechallenged, and the patient referred urgently. Stevens-Johnson syndrome and toxic epidermal necrolysis require management akin to a burn — admission to an intensive care or burns unit, meticulous fluid and electrolyte support, wound care, and supportive treatment (the role of adjuncts such as systemic corticosteroids, IVIG, or cyclosporin is debated and is a specialist decision). DRESS requires drug withdrawal and systemic corticosteroids. Abacavir hypersensitivity mandates permanent withdrawal, because rechallenge can be fatal. Zidovudine hyperpigmentation needs only reassurance, with a switch if the patient is distressed. IRIS is managed by continuing ART, treating the underlying infection, and adding corticosteroids for severe flares — it is not a reason to stop ART. When nevirapine is stopped for a reaction, an alternative agent such as efavirenz or a protease inhibitor is substituted under specialist guidance (confirm current substitution choices against NACO guidance).

Key management points:

Mild morbilliform rash, no systemic/mucosal signs: continue under observation + antihistamines
Severe signs (mucosa, blistering, Nikolsky+, fever): STOP the drug (usually nevirapine) immediately, never rechallenge, refer urgently
SJS/TEN: ICU/burns-unit-level supportive care (fluids, wound care); adjuncts are a specialist decision
DRESS: withdraw drug + systemic corticosteroids
Abacavir hypersensitivity: permanent withdrawal — rechallenge can be fatal
Zidovudine hyperpigmentation: reassure; switch only if distressing
IRIS: continue ART, treat the infection, add steroids for severe flares

Self-Assessment: ART Drug Reactions

A five-panel infographic summarizes ART drug reaction assessment, including rash triage, SJS/TEN BSA thresholds, nevirapine DRESS, abacavir HLA-B*57:01 testing, and drug reaction versus IRIS differentiation. — **Panel A:** Clinical decision pathway: patient on ART with rash, likely offending drug, severity grading, warning signs, continue versus stop and refer.. **Panel B:** SJS/TEN classification silhouettes labelled SJS <10% BSA, SJS-TEN overlap 10-30% BSA, and TEN >30% BSA.. **Panel C:** Nevirapine-associated DRESS showing fever, facial oedema, lymphadenopathy, eosinophilia, delayed onset 2-8 weeks, stop offending drug and refer.. **Panel D:** Abacavir hypersensitivity pathway showing HLA-B*57:01 testing, avoid if positive, permanently discontinue if hypersensitivity occurs, no rechallenge.. **Panel E:** Comparison of nevirapine drug reaction versus IRIS after ART initiation, contrasting drug hypersensitivity signs with immune recovery inflammatory flare..

Having mapped the spectrum of ART cutaneous reactions, their mechanisms, drug-specific patterns, severity grading, and management, it is time to consolidate the decision-making that ties them together. The central competency you should now hold is the ability to take a patient on a known ART regimen, identify the likely offending drug from the reaction pattern, grade the severity using body-surface-area cut-offs and warning signs, and decide whether to reassure and continue or to stop the drug permanently and refer. Reason through the prompts below as clinical decisions rather than as recall items, and where a prompt concerns drug substitution or thresholds, remember to confirm specifics against current NACO antiretroviral therapy guidance. If any answer is unclear, return to the relevant section above and re-trace the link from mechanism to severity to management decision.

Work through these self-check questions:

State the body-surface-area cut-offs that separate Stevens-Johnson syndrome, SJS-TEN overlap, and toxic epidermal necrolysis.
A patient develops fever, facial oedema, lymphadenopathy, and eosinophilia six weeks after starting nevirapine — name the reaction and outline its management.
Explain the significance of HLA-B*57:01 testing before starting abacavir, and the action required if hypersensitivity occurs.
Differentiate a nevirapine drug reaction from IRIS occurring after ART initiation, and state how the management differs.
For a mild morbilliform rash with no systemic features, justify why the drug may be continued under observation.

CLINICAL PEARL

For ART rashes, the decision rule is simple: look for the red flags, and if any are present, stop and never rechallenge. The red flags that turn a benign rash into an emergency are mucosal involvement, blistering, dusky or painful skin, a positive Nikolsky sign, fever, and systemic upset. Nevirapine is the ART drug most likely to cause Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS, and abacavir hypersensitivity (HLA-B*57:01) is the reaction where rechallenge can kill. Conversely, do not over-react: a mild morbilliform rash without red flags, or zidovudine hyperpigmentation, does not warrant abandoning a working regimen. Knowing which way to jump — continue or stop forever — is the whole of DR11.2.