Can non‑nucleoside reverse transcriptase inhibitors (NNRTIs) cause Stevens‑Johnson syndrome?

NNRTIs and Stevens-Johnson Syndrome

Yes, NNRTIs definitively cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), with nevirapine carrying the highest risk among this drug class and requiring immediate permanent discontinuation when these severe reactions occur. 1, 2

Evidence of Association

Skin rash is a class-adverse reaction of NNRTIs, with more serious cutaneous manifestations including SJS and TEN documented across multiple guidelines and clinical studies. 1

Nevirapine: Highest Risk NNRTI

• Nevirapine causes SJS in approximately 0.37% of patients, a rate markedly higher than other antiretroviral agents. 3
• In a multinational case-control study of 18 HIV-infected patients with SJS/TEN, 15 of 18 (83%) were receiving nevirapine, demonstrating strong epidemiologic association. 1
• The median time from nevirapine initiation to severe cutaneous eruption is 11 days, with two-thirds of cases occurring during the initial dosing period, though reactions can occur from 10 days up to 240 days after starting therapy. 1, 3
• A large European case-control study (EuroSCAR) documented a relative risk exceeding 22 for nevirapine-associated SJS/TEN. 4

Efavirenz: Lower but Notable Risk

• Efavirenz causes rash in 10-17% of patients, though the incidence of severe reactions (SJS/TEN) is considerably lower than with nevirapine. 3
• Case reports document efavirenz-induced SJS, including a documented case where a patient who developed gynecomastia on efavirenz subsequently developed SJS when switched to nevirapine. 5

High-Risk Populations

Female patients face up to a seven-fold increased risk of developing grade 3 or 4 skin rashes compared with male patients when treated with nevirapine. 1, 3

Critical Management Principles

Immediate Actions Required

• Promptly and permanently discontinue the NNRTI when SJS or TEN is suspected—delay in stopping treatment after rash onset may result in more serious reactions. 1, 2
• Assess immediately for mucosal involvement, skin detachment/epidermal sloughing, and fever >39°C, which indicate severe hypersensitivity requiring hospitalization. 3, 6
• Measure transaminases immediately if nevirapine-associated rash is suspected, as hepatotoxicity may accompany severe cutaneous reactions. 2

Cross-Reactivity Considerations

• The majority of experienced clinicians do not recommend using another NNRTI in patients who experienced SJS or TEN with one NNRTI, though the exact incidence of cross-hypersensitivity is unknown. 1
• Limited reports suggest patients with prior nevirapine-associated rash may tolerate efavirenz without increased cutaneous reactions, but this should not be extrapolated to patients with prior SJS/TEN. 1

Prophylaxis: What NOT to Do

Prophylactic corticosteroids or antihistamines at nevirapine initiation are strongly discouraged—these strategies have not prevented SJS/TEN and may actually increase rash incidence. 1, 3, 2

Risk Mitigation Strategies

• The 14-day lead-in period with nevirapine 200 mg daily dosing reduces the frequency of rash and must not exceed 28 days total duration. 2
• Do not increase nevirapine dose if mild to moderate rash occurs during the lead-in period until the rash has resolved. 2
• The total duration of once-daily lead-in dosing must not exceed 28 days, at which point an alternative regimen should be sought. 2

Common Pitfalls to Avoid

• Never rechallenge with nevirapine after a severe hypersensitivity reaction—subsequent reactions are typically more rapid and severe, potentially fatal. 3, 7, 2
• Do not continue NNRTI therapy if severe rash or any rash accompanied by constitutional findings develops. 2
• Avoid using prednisone to prevent nevirapine-associated rash, as a clinical trial showed this increased both incidence and severity of rash during the first 6 weeks. 2

Comparative Context

While NNRTIs carry the highest risk for severe cutaneous reactions among antiretroviral classes, other agents can also cause SJS/TEN:

• Abacavir (an NRTI) causes hypersensitivity reactions that may include rash and requires permanent discontinuation without rechallenge. 1, 3
• Amprenavir (a protease inhibitor) causes rash in ≤27% of patients in clinical trials. 1

The evidence consistently demonstrates that NNRTIs, particularly nevirapine, are established causes of SJS and TEN, with clear documentation in FDA labeling 2, multiple clinical guidelines 1, and high-quality epidemiologic studies 4.