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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Rash and Hypersensitivity Reactions

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

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Table 11l. 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
Presentation:
  • Most rashes are mild-to-moderate, diffuse maculopapular eruptions.
Note: Some rashes are the initial manifestation of systemic hypersensitivity (see HSR, SJS/TEN/EM major).

Common
(>10% Adults and/or Children)
:
  • NVP, EFV, ETR, FPV, ATV, FTC
Less Common
(5%–10%)
:
  • ABC, DRV, TPV, TDF
Unusual
(2%–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.
  • Avoid the use of 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 Mucus 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
Presentation
  • Local injection site reactions with pain, erythema, induration, nodules and cysts, pruritis, ecchymosis. Often multiple reactions at the same time.
Adults and Children:
  • >90%

Unknown
  • During routine visits, assess patient for local reactions.
  • Rotate injection sites.
  • Massage area after injection.
  • Continue the agent as tolerated by the patient.
  • Adjust injection technique.
  • Rotate injection sites.
SJS/TEN/EM Major Many ARVs, especially NNRTIs (see frequency column) Onset
  • First few days to weeks after initiating therapy
Presentation
  • 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.
Infrequent:
  • NVP (0.3%), EFV (0.1%), ETR (<0.1%)
Case Reports:
  • FPV, ABC, DRV, ZDV, ddI, IDV, LPV/r, ATV, RAL
Adults:
  • Female gender
  • Race/ethnicity (black, Asian, Hispanic)
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
  • 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.
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.
Presentation
  • 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%–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 re-challenge 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.
Presentation
  • 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.
  • DRESS syndrome has also been described.
4% (2.5%–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).
Children
  • 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 reintroduce 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.
Presentation
  • 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.
RAL DRESS syndrome Case report Unknown Evaluate for hypersensitivity if the patient is symptomatic. Discontinue all ARVs.

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

Rechallenge with MVC is not recommended.
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; 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; 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

References

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