skip to content

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

  •   Table of Contents

Download Guidelines

Management of Medication Toxicity or Intolerance

Rash and Hypersensitivity Reactions

Last Updated: March 1, 2016; Last Reviewed: March 1, 2016

Table 12l. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Rash and Hypersensitivity Reactions
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring  Management
Rash Any ARV can cause rash. Onset:
  • First few days to weeks after starting therapy
  • Most rashes are mild-to-moderate, diffuse maculopapular eruptions.
Note: Some rashes are the initial manifestation of systemic hypersensitivity (see Systemic HSR, SJS/TEN/EM Major).
Common (>10% Adults and/or Children):
Less Common (5% to 10%):
Unusual (2% to 4%):
  • LPV/r, RAL, MVC, RPV
  • Sulfonamide allergy is a risk factor for rash with PIs containing a sulfonamide moiety (FPV, DRV, and TPV).
  • Possible association of polymorphisms in CYP2B6 and multiple HLA loci with rash with NVP.
When Starting NVP or Restarting After Interruptions >14 Days:
  • Once-daily dosing (50% of total daily dose) for 2 weeks, then escalation to target dose with twice-daily dosing is associated with fewer rashes.a
  • Avoid the use of systemic corticosteroids during NVP dose escalation.
  • Assess patient for rash severity, mucosal involvement, and other signs of systemic reaction.
  • Consider concomitant medications and illnesses that cause rash.
Mild-to-Moderate Maculopapular Rash Without Systemic or Mucosal Involvement:
  • Most will resolve without intervention; ARVs can be continued while monitoring.a
  • Antihistamines may provide some relief.
Severe Rash (e.g., Blisters, Bullae, Ulcers, Skin Necrosis) and/or Rash Accompanied by Systemic Symptoms (e.g., Fever, Arthralgias, Edema) and/or Rash Accompanied by Mucous Membrane Involvement (e.g., Conjunctivitis):
  • Manage as SJS/TEN/EM major (see below).
Rash in Patients Receiving NVP:
  • Given elevated risk of HSR, measure hepatic transaminases.
  • If hepatic transaminases are elevated, NVP should be discontinued and not restarted (see HSR-NVP).
ENF Onset:
  • First few days to weeks after starting therapy
  • Local injection site reactions with pain, erythema, induration, nodules and cysts, pruritus, ecchymosis. Often multiple reactions at the same time.
Adults and Children:
  • >90%
  • Routinely assess patient for local reactions.
  • Rotate injection sites.
  • Massage area after injection.
  • Continue the agent as tolerated by the patient.
  • Ensure patient is injecting as per instructions.
  • Rotate injection sites.
SJS/TEN/EM Major Many ARVs, especially NNRTIs (see frequency column) Onset:
  • First few days to weeks after initiating therapy
  • Initial rash may be mild, but often becomes painful, evolving to blister/bulla formation with necrosis in severe cases. Usually involves mucous membrane ulceration and/or conjunctivitis. Systemic symptoms may include fever, tachycardia, malaise, myalgia, and arthralgia.
  • NVP (0.3%), EFV (0.1%), ETR (<0.1%)
Case Reports:
  • Female gender
  • Race/ethnicity (black, Asian, Hispanic)
To Lower the Risk of Reactions to NVP when Starting or Restarting after Interruptions >14 Days:
  • Utilize once-daily dosing (50% of total daily dose) for 2 weeks, then escalate to target dose with twice-daily dosing, which is associated with fewer rashes.a
  • Counsel families to report symptoms as soon as they appear.
  • Discontinue all ARVs and other possible causative agents such as cotrimoxazole.
  • Provide intensive supportive care, IV hydration, aggressive wound care, pain management, antipyretics, parenteral nutrition, and antibiotics as needed in case of superinfection.
  • Corticosteroids and/or IVIG are sometimes used, but use of each is controversial.
  • Do not reintroduce the offending medication.
  • In case of SJS/TEN/EM major with one NNRTI, many experts would avoid use of other NNRTIs.
  • 1–8 weeks
  • Fever
  • lymphadenopathy
  • facial swelling
  • a morbilliform to polymorphous rash
  • peripheral eosinophilia
  • atypical circulating lymphocytes
  • internal organ involvement (particularly liver and/or renal)
Rare Unknown
  • Obtain CBC, AST, ALT and creatinine in patient presenting with suggestive symptoms.
  • Discontinue all ARVs and other possible causative agents such as cotrimoxazole.
  • Role for steroids unclear; suggest consultation with specialist.
  • Supportive care for end-organ disease
  • Do not reintroduce the offending medication.
Systemic HSR
With or without skin involvement and excluding SJS/TEN
ABC Onset
With First Use:
  • Within first 6 weeks
With Re-Introduction:
  • Within hours
  • Symptoms include high fever, diffuse skin rash, malaise, nausea, headache, myalgia, arthralgia, diarrhea, vomiting, abdominal pain, pharyngitis, respiratory symptoms (e.g., dyspnea).
  • Symptoms worsen to include hypotension and vascular collapse with continuation. With re-challenge, symptoms can mimic anaphylaxis.
2.3% to 9% (varies by racial/ethnic group).
  • HLA-B*5701 (HSR very uncommon in people who are HLA-B*5701-negative); also HLA-DR7, HLA-DQ3.
  • HSR risk is higher in those of white race compared to those of black or East Asian race.
  • Screening for HLA-B*5701. ABC should not be prescribed if HLA-B*5701 is positive. The medical record should clearly indicate that ABC is contraindicated.
  • When starting ABC, counsel patients and families about the signs and symptoms of HSR to ensure prompt reporting of reactions.
  • Discontinue ARVs and investigate for other causes of the symptoms (e.g., a concurrent viral illness).
  • Treat symptoms as necessary.
  • Most symptoms resolve within 48 hours after discontinuation of ABC.
  • Do not rechallenge with ABC even if the patient is HLA-B*5701-negative.
NVP Onset:
  • Most frequent in the first few weeks of therapy but can occur through 18 weeks.
  • Flu-like symptoms (including nausea, vomiting, myalgia, fatigue, fever, abdominal pain, jaundice) with or without skin rash that may progress to hepatic failure with encephalopathy.
4% (2.5% to 11%) Adults:
  • Treatment-naive with higher CD4 count (>250 cells/mm3 in women; >400 cells/mm3 in men).
  • Female gender (risk is 3-fold higher in females compared with males).
  • NVP hepatotoxicity and HSR are less common in pre-pubertal children than in adults. The PREDICT Study showed a 2.65 times higher risk of overall NVP toxicity (rash, hepatotoxicity, hypersensitivity) in children with CD4 ≥15% compared to children with CD4 <15%.
When Starting NVP or Restarting After Interruptions >14 Days:
  • 2-week lead-in period with once-daily dosing then dose escalation to twice daily as recommended may reduce risk of reaction.a
  • Counsel families about signs and symptoms of HSR to ensure prompt reporting of reactions.
  • Obtain AST and ALT in patients with rash. Obtain AST and ALT at baseline, before dose escalation, 2 weeks post-dose escalation, and thereafter at 3-month intervals.
  • Avoid NVP use in women with CD4 counts >250 cells/mm3 and in men with CD4 counts >400 cells/mm3 unless benefits outweigh risks.
  • Do not use NVP in PEP.
  • Discontinue ARVs.
  • Consider other causes for hepatitis and discontinue all hepatotoxic medications.
  • Provide supportive care as indicated and monitor patient closely.
  • Do not re-introduce NVP. The safety of other NNRTIs is unknown following symptomatic hepatitis due to NVP, and many experts would avoid the NNRTI drug class when restarting treatment.
ENF, ETR Onset:
  • Any time during therapy.
  • Symptoms may include rash, constitutional findings, and sometimes organ dysfunction including hepatic failure.
Rare Unknown Evaluate for hypersensitivity if the patient is symptomatic. Discontinue ARVs.

Rechallenge with ENF or ETR is not recommended.
MVC Rash preceding hepatotoxicity Rare Unknown Obtain AST and ALT in patients with rash or other symptoms of hypersensitivity. Discontinue all ARVs.

Rechallenge with MVC is not recommended.
DTG Rash with hepatic dysfunction Rare Unknown Obtain AST and ALT in patients with rash or other symptoms of hypersensitivity. Discontinue all ARVs.

Rechallenge with DTG is contraindicated
a The prescribing information for NVP states that patients experiencing rash during the 14-day lead-in period should not have the NVP dose increased until the rash has resolved. However, prolonging the lead-in phase beyond 14 days may increase risk of NVP resistance because of sub-therapeutic drug levels. Management of children who have persistent mild or moderate rash after the lead-in period should be individualized and consultation with an expert in HIV care should be obtained. NVP should be stopped and not restarted if the rash is severe or is worsening or progressing.

Key to Acronyms: ABC = abacavir; ALT = alanine transaminase; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CBC = complete blood count; CD4 = CD4 T lymphocyte cell; ddI = didanosine; DRESS = drug rash with eosinophilia and systemic symptoms; DRV = darunavir; EFV = efavirenz; EM = erythema multiforme; ENF = enfuvirtide; ETR = etravirine; FPV = fosamprenavir; FTC = emtricitabine; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IDV = indinavir; IV = intravenous; IVIG = intravenous immune globulin; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PEP = post-exposure prophylaxis; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; SJS = Stevens-Johnson syndrome; TDF = tenofovir disoproxil fumarate; TEN = toxic epidermal necrolysis; TPV = tipranavir; ZDV = zidovudine


  1. Borras-Blasco J, Navarro-Ruiz A, Borras C, Castera E. Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection. J Antimicrob Chemother. 2008;62(5):879-888. Available at
  2. Davis CM, Shearer WT. Diagnosis and management of HIV drug hypersensitivity. J Allergy Clin Immunol. 2008;121(4):826-832 e825. Available at
  3. Kea C, Puthanakit T, Apornpong T, al. e. Incidence and risk factors for nevirapine related toxicities among HIV-infected Asian children randomized to starting ART at different CD4%. Abstract MOPE240. 6th International AIDS Society Conferene on HIV Pathogenesis and Treatment and Prevention; July, 2011, 2011; Rome, Italy.
  4. Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727-732. Available at
  5. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579. Available at
  6. Mirochnick M, Clarke DF, Dorenbaum A. Nevirapine: pharmacokinetic considerations in children and pregnant women. Clinical Pharmacokinetics. 2000;39(4):281-293. Available at
  7. Puthanakit T, Bunupuradah T, Kosalaraksa P, et al. Prevalence of human leukocyte antigen-B*5701 among HIV-infected children in Thailand and Cambodia: implications for abacavir use. Pediatr Infect Dis J. 2013;32(3):252-253. Available at
  8. Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. 2003;34 Suppl 1(Suppl 1):S21-33. Available at
  9. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at
  10. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): an update. Dermatology. 2003;206(4):353-356. Available at
  11. Trottier B, Walmsley S, Reynes J, et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. J Acquir Immune Defic Syndr. 2005;40(4):413-421. Available at
  12. Vitezica ZG, Milpied B, Lonjou C, et al. HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. AIDS. 2008;22(4):540-541. Available at
  13. Yuan J, Guo S, Hall D, et al. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS. 2011;25(10):1271-1280. Available at
  14. Dziuban EJ, Hughey AB, Stewart DA, et al. Stevens-Johnson syndrome and HIV in children in Swaziland. Pediatr Infect Dis J. 2013;32(12):1354-1358. Available at
  15. Rutstein RM, Samson, P., Fenton, T., Fletcher, C.V., Kiser, J.J., Mofenson, L.M., Smith, E,. Graham, B., Mathew, M., Aldrovani, G.; for the PACTG 1020A Study Team. Long-Term Safety and Efficacy of Atazanavir-Based Therapy in HIV-Infected Infants, Children and Adolescents: The Pediatric AIDS Clinical Trials Group Protocol 1020A. Pediatr Infect Dis J. 2015;34:162-167. Available at
  16. Perry ME, Almaani N, Desai N, Larbalestier N, Fox J, Chilton D. Raltegravir-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome - implications for clinical practice and patient safety. Int J STD AIDS. 2013;24(8):639-642. Available at
  17. Bourezane Y, Salard D, Hoen B, Vandel S, Drobacheff C, Laurent R. DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy. Clin Infect Dis. 1998;27(5):1321-1322. Available at
  18. Ripamonti D, Benatti SV, Di Filippo E, Ravasio V, Rizzi M. Drug reaction with eosinophilia and systemic symptoms associated with raltegravir use: case report and review of the literature. AIDS. 2014;28(7):1077-1079. Available at
  19. Noguera-Morel L, Hernandez-Martin A, Torrelo A. Cutaneous drug reactions in the pediatric population. Pediatric Clinics of North America. 2014;61(2):403-426. Available at
  20. Bossi P, Colin D, Bricaire F, Caumes E. Hypersensitivity syndrome associated with efavirenz therapy. Clin Infect Dis. 2000;30(1):227-228. Available at
  21. Prezista [package insert]. Food and Drug Administration. 2015. Available at,202895s013lbl.pdf. 2015. Accessed January 13, 2016.
  22. Complera (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration. 2015. Available at,202895s013lbl.pdf.
  23. Tivicay (dolutegravir) [package insert]. Food and Drug Administration. n.p. Available at

Download Guidelines