Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Management of Medication Toxicity or Intolerance
Rash and Hypersensitivity Reactions
Last Updated: April 14, 2020; Last Reviewed: April 14, 2020
|Adverse Effects||Associated ARVs||Onset/Clinical Manifestations||Estimated Frequency||Risk Factors||Prevention/Monitoring||Management|
|Rash||Any ARV drug can cause rash.||Onset:
||Sulfonamide allergy is a risk factor for rash in patients who are taking PIs that contain a sulfonamide moiety (i.e., DRV).
Polymorphisms in CYP2B6 and multiple HLA loci are associated with an increased risk of rash in patients who are taking NVP.
|When Starting NVP or Restarting NVP After Interruptions of >14 Days:
||Mild-to-Moderate Maculopapular Rash Without Systemic or Mucosal Involvement:
|SJS/TEN/EM Major||Many ARV drugs, especially NNRTIs (see the Estimated Frequency column)||Onset:
||When Starting NVP or Restarting NVP After Interruptions of >14 Days:
||Discontinue all ARV drugs and other possible causative agents (e.g., TMP-SMX).
Provide intensive supportive care including, IV hydration, aggressive wound care, eye care, labial adhesion preventative care, pain management, and antipyretics. Parenteral nutrition and antibiotics may also be necessary.
Corticosteroids and/or IVIG are sometimes used, but the use of these interventions is controversial.
Do not reintroduce the offending medication.
In cases where a patient experiences SJS/TEN/EM major while taking an NNRTI, many experts would avoid using other NNRTIs when restarting ART.
|DRESS||DRV, DTG, EFV, ETR, NVP, RAL, RPV||Onset:
||Rare||Unknown||Obtain a CBC and AST, ALT, and creatinine levels from patients who present with suggestive symptoms.||Discontinue all ARV drugs and other possible causative agents (e.g., TMP-SMX).
The role of systemic steroids in treatment is unclear; consultation with a specialist is recommended.
Provide supportive care for end-organ disease.
Do not reintroduce the offending medication.
With or without skin involvement and excluding SJS/TEN
With First Use:
|<1% to 9% (varies by ethnicity)||HLA-B*5701 (HSR is very uncommon in people who are HLA-B*5701 negative).
The risk of HSR is higher in patients who are white than in patients who are black or East Asian.
|Screen for HLA-B*5701. ABC should not be prescribed if HLA-B*5701 is present. The medical record should clearly indicate that ABC is contraindicated in these patients.
When starting ABC, counsel patients and families about the signs and symptoms of HSR to ensure prompt reporting of reactions.
|Discontinue all ARV drugs and investigate other causes of the symptoms (e.g., a concurrent viral illness).
Provide symptomatic treatment.
Most symptoms resolve within 48 hours after discontinuing ABC.
Do not rechallenge with ABC even if the patient is HLA-B*5701 negative.
||Occurs in 4% of patients on average, with a range of 2.5% to 11%||Adults:
||When Starting NVP or Restarting NVP After Interruptions of >14 Days:
||Discontinue all ARV drugs.
Consider other causes for hepatitis and discontinue all hepatotoxic medications.
Provide supportive care as indicated and monitor the patient closely.
Do not reintroduce NVP. It is unclear whether it is safe to use other NNRTIs after a patient experiences symptomatic hepatitis due to NVP, and many experts would avoid the NNRTI drug class when restarting treatment.
||Rare||Unknown||Evaluate for hypersensitivity if the patient is symptomatic.||Discontinue all ARV drugs.
Rechallenge with ETR is not recommended.
|MVC||Rash preceding hepatotoxicity||Rare||Unknown||Obtain AST and ALT levels from patients with rash or other symptoms of hypersensitivity.||Discontinue all ARV drugs.
Rechallenge with MVC is not recommended.
|DTG||Rash with hepatic dysfunction||Rare||Unknown||Obtain AST and ALT levels from patients with rash or other symptoms of hypersensitivity.||Discontinue all ARV drugs.
Rechallenge with DTG is contraindicated.
a The prescribing information for NVP states that patients who experience 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 the risk of NVP resistance because of subtherapeutic drug levels. Children who have persistent mild or moderate rash after the lead-in period should receive individualized care. Consult an expert in HIV care when managing these patients. NVP should be stopped and not restarted if the rash is severe or progressing. See the Nevirapine section of the Drug Appendix.
b Lead-in dosing is not recommended when using NVP for either empiric or definitive HIV therapy in newborns with perinatal HIV exposure or perinatal HIV infection. See the Nevirapine section of the Drug Appendix and Table 12.
Key: ABC = abacavir; ALT = alanine transaminase; ART = antiretroviral therapy; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CBC = complete blood count; CD4 = CD4 T lymphocyte; CYP = cytochrome P; DRESS = drug reaction (or rash) with eosinophilia and systemic symptoms; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; EM = erythema multiforme; ETR = etravirine; FTC = emtricitabine; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; 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; TMP-SMX = trimethoprim-sulfamethoxazole; ZDV = zidovudine
- 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: http://www.ncbi.nlm.nih.gov/pubmed/18653488.
- Davis CM, Shearer WT. Diagnosis and management of HIV drug hypersensitivity. J Allergy Clin Immunol. 2008;121(4):826-832 e825. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18190954.
- Kea C, Puthanakit T, Apornpong T, et al. Incidence and risk factors for nevirapine related toxicities among HIV-infected Asian children randomized to starting ART at different CD4%. Abstract MOPE240. Presented at: 6th International AIDS Society Conferene on HIV Pathogenesis and Treatment and Prevention. 2011. Rome, Italy.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/18256392.
- Mirochnick M, Clarke DF, Dorenbaum A. Nevirapine: pharmacokinetic considerations in children and pregnant women. Clin Pharmacokinet. 2000;39(4):281-293. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11069214.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/22986704.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/14562855.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/23343913.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/12771485.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/16280695.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/18301070.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/21505298.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/23743542.
- Rutstein RM, Samson P, Fenton T, et al. 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: https://www.ncbi.nlm.nih.gov/pubmed/25232777.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/23970584.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/9827291.
- 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: http://www.ncbi.nlm.nih.gov/pubmed/24685746.
- Noguera-Morel L, Hernandez-Martin A, Torrelo A. Cutaneous drug reactions in the pediatric population. Pediatr Clin North Am. 2014;61(2):403-426. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24636653.
- Bossi P, Colin D, Bricaire F, Caumes E. Hypersensitivity syndrome associated with efavirenz therapy. Clin Infect Dis. 2000;30(1):227-228. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10619772.
- Prasertvit P, Chareonyingwattana A, Wattanakrai P. Nevirapine patch testing in Thai human immunodeficiency virus infected patients with nevirapine drug hypersensitivity. Contact Dermatitis. 2017;77(6):379-384. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28782122.
- Shah R, Nabiswa H, Okinda N, Revathi G, Hawken M, Nelson M. Prevalence of HLA-B*5701 in a Kenyan population with HIV infection. J Infect. 2018;76(2):212-214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28919349.
- Martin C, Payen MC, De Wit S. Dolutegravir as a trigger for DRESS syndrome? Int J STD AIDS. 2018;29(10):1036-1038. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29621952.
- Fillekes Q, Mulenga V, Kabamba D, et al. Is nevirapine dose escalation appropriate in young, african, HIV-infected children? AIDS. 2013. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23595153.
- Nishijima T, Gatanaga H, Teruya K, et al. Skin rash induced by ritonavir-boosted darunavir is common, but generally tolerable in an observational setting. J Infect Chemother. 2014;20(4):285-287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24507978.
- Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24589294.
- Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30527329.
- Mounzer K, Hsu R, Fusco JS, et al. HLA-B*57:01 screening and hypersensitivity reaction to abacavir between 1999 and 2016 in the OPERA((R)) observational database: a cohort study. AIDS Res Ther. 2019;16(1):1. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30651100.