|Rating of Recommendations: A = Strong; B = Moderate; C = Optional|
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents but not studies limited to postpubertal adolescents
Medication Toxicity or Intolerance
The overall benefits of viral suppression and improved immune function because of effective antiretroviral therapy (ART) far outweigh the risks associated with the adverse effects (AEs) of some antiretroviral (ARV) drugs. AEs have been reported, however, with the use of all ARV drugs. Currently recommended ARV regimens are associated with fewer serious and intolerable AEs than regimens used in the past. In the mid-1990s when combination ART was introduced, AEs were among the most common reasons for switching or discontinuing therapy and for medication nonadherence1-3 (see Adverse Effects of Antiretroviral Agents in the Adult and Adolescent Antiretroviral Guidelines). In recent clinical trials, however, <10% of ARV-treated patients had treatment-limiting AEs.4-14
The incidence of some longer-term complications of ART (e.g., bone or renal toxicity, dyslipidemia, accelerated cardiovascular disease) might be underestimated, because most clinical trials enroll a select group of patients based on highly specific inclusion criteria and the duration of participant follow-up is relatively short.6,7,15-17 To achieve sustained viral suppression during a child’s lifetime, both short- and long-term ART toxicities must be anticipated. The clinician must consider potential AEs and issues with medication palatability when selecting an ARV regimen, as well as the individual child’s comorbidities, concomitant medications, and history of drug intolerance or viral resistance.
The AEs caused by ARV drugs can vary from mild, more common symptoms (e.g., gastrointestinal intolerance, fatigue) to infrequent but severe and life-threatening, illness. Drug-related toxicity can be acute (i.e., occurring soon after a drug has been administered), subacute (i.e., occurring within 1 day to 2 days after administration), or late (i.e., occurring after prolonged drug administration). For a few ARV medications, pharmacogenetic markers associated with the risk of early toxicity have been identified; however, the only marker that is routinely screened for is HLA-B*5701, a marker for abacavir (ABC) hypersensitivity.18 For selected children aged <3 years who require treatment with efavirenz (EFV), an additional pharmacogenetic marker, cytochrome P450 (CYP) 2B6 genotype, should be assessed in an attempt to prevent toxicity18-22 (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information). For agents such as EFV, therapeutic ranges for plasma concentrations, as determined by therapeutic drug monitoring (TDM), may indicate the need for dose reduction or modification of ART in patients who experience central nervous system (CNS) AEs.
The most common acute and chronic AEs that are associated with currently recommended ARV drugs or drug classes are presented in Tables 1a–1k, which are listed below. These tables include information on common causative drugs, estimated frequency of occurrence, timing of symptoms, risk factors, potential preventive measures, and suggested clinical management strategies. The tables also include selected references that provide further information about these toxicities in pediatric patients.
LDL-C 130 mg/dL = 3.4 mmol/L
LDL-C 250mg/dL = 6.5mmol/L
TG >100 mg/dL = 1.1 mmol/L in children <10years, TG >130 mg/dL (1.5mmol/L) in children >10years
TC >200mg/dL (5.2 mmol/L)
HDL-C <409mg/dL (1.0mmol/L)
Consider referral to a paediatric gastroenterologist for co-management of viral hepatitis.
Blood sugar level 7.0 mmol/L or random 11.1mmol/L.
Blood sugar level 61-6.9 mmol/L
Impaired glucose tolerance if 2 hour blood sugar level 7.8-11mmol/L.
Consider referral to a paediatric endocrinologist for insulin resistance and/or asymptomatic hyperglycaemia in children with HIV receiving ART in Australia.
ART-associated AEs can range from acute and potentially life threatening, to chronic and insidious. Serious life-threatening events (e.g., hypersensitivity reaction [HSR] due to ABC, symptomatic hepatotoxicity, severe cutaneous reactions) require the immediate discontinuation of all ARV drugs and re-initiation of an alternative regimen without overlapping toxicity. Toxicities that are not life threatening (e.g., urolithiasis caused by atazanavir, renal tubulopathy caused by tenofovir disoproxil fumarate) usually can be managed by substituting another ARV agent for the presumed causative agent without interrupting ART. Other chronic, non–life-threatening AEs (e.g., dyslipidemia) can be addressed either by switching the potentially causative agent for another agent or by managing the AE with additional pharmacological or nonpharmacological interventions, such as lifestyle modification.
Management strategies must be individualized for each child, taking into account the severity of the toxicity, the child’s viral suppression status, and the available ARV options. Clinicians should anticipate the appearance of common, self-limited AEs and reassure patients that many AEs will resolve after the first few weeks of ART. For example, when initiating therapy with boosted protease inhibitors (PIs), many patients experience gastrointestinal AEs, such as nausea, vomiting, diarrhea, and abdominal pain.
Instructing patients to take PIs with food may help minimize these AEs. Some patients may require antiemetic and antidiarrheal agents for symptom management. CNS AEs are encountered commonly when initiating therapy with EFV. Symptoms can include dizziness, drowsiness, vivid dreams, or insomnia. Patients should be instructed to take EFV-containing regimens at bedtime and on an empty stomach to help minimize these AEs. Patients should be advised that these AEs usually diminish within 2 to 4 weeks of initiating therapy in most people; however, they may persist for months in some patients and may require a medication change.23 In addition, mild rash can be ameliorated with drugs, such as antihistamines. Addressing AEs is essential, because continued use of an ARV agent that a patient finds intolerable may lead the patient to stop their treatment, risking viral rebound and the development of drug resistance.
In patients who experience intolerable AEs from ART, every attempt should be made to identify the offending agent and to replace the drug with another effective agent as soon as possible.9,24 For mild-to- moderate toxicities, changing to a drug with a different toxicity profile might be sufficient, and discontinuation of all therapy might not be required. When interrupting a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, many experts will stop the NNRTI for 7 to 14 days before stopping the dual nucleoside analogue reverse transcriptase backbone, because of the long half- life of NNRTI drugs. However, patients who have a severe or life-threatening toxicity (e.g., HSR—see Table 1k. Rash and Hypersensitivity Reactions) should stop all components of the drug regimen simultaneously, regardless of drug half-life. Once the offending drug or alternative cause for the AE has been determined, planning can begin for—
- Resuming therapy with a new ARV regimen that does not contain the offending drug, or
- Resuming therapy with the original regimen if the event is attributable to another
All drugs in the ARV regimen should then be started simultaneously, rather than one at a time, while observing the patient for AEs.
When therapy is changed because of toxicity or intolerance in a patient with virologic suppression, agents with different toxicity and AE profiles should be chosen, when possible.25-28 Clinicians should have comprehensive knowledge of the toxicity profile of each agent before selecting a new regimen. In the event of drug intolerance, changing a single drug in a multidrug regimen is permissible only for patients whose viral loads are undetectable.
In general, dose reduction is not a recommended strategy for toxicity management, because inadequate ARV drug levels may lead to decreased virologic efficacy TDM is recommended; however, it may be in the management for a child with mild or moderate toxicity if the toxicity is thought to be the result of a drug concentration exceeding the normal therapeutic range29-31 An expert in the management of pediatric HIV should be consulted when considering dose reduction based on the results of TDM. Dose reduction after TDM has been studied most extensively with EFV, because increased CNS toxicity has clearly been associated with higher levels of EFV (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).
To summarize, management strategies for drug intolerance include the following:
- Symptomatic treatment of mild-to-moderate, transient
- Switching one drug for another drug that is active against a patient’s virus (e.g., changing to ABC for zidovudine-related anemia or to a PI or integrase strand transfer inhibitor for EFV-related CNS symptoms) (see Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression on Antiretroviral Therapy).
- Using dose reduction, guided by TDM, after consulting with an expert in pediatric
- Desta Z, Gammal RS, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2B6 and efavirenz-containing antiretroviral therapy. Clin Pharmacol Ther. 2019;106(4):726-733. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31006110.
- Szpak R, Lombardi NF, Dias FA, Borba HHL, Pontarolo R, Wiens A. Safety of antiretroviral therapy in the treatment of HIV/AIDS in children: systematic review and meta-analysis. AIDS Rev. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34082441.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents adults and adolescents with HIV. 2022. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/whats-new-guidelines
- Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr. 2012;59(3):274-280. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22126740.
- Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013;381(9875):1391- 1403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23473847.
- Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and treatment of perinatally HIV-infected children and adolescents. J Int AIDS Soc. 2013;16(1):18600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23782481.
- Purswani M, Patel K, Kopp JB, et al. Tenofovir treatment duration predicts proteinuria in a multiethnic United States cohort of children and adolescents with perinatal HIV-1 infection. Pediatr Infect Dis J. 2013;32(5):495-500. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23249917.
- 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: https://www.ncbi.nlm.nih.gov/pubmed/23343913.
- Fortuin-de Smidt M, de Waal R, Cohen K, et al. First-line antiretroviral drug discontinuations in children. PLoS One. 2017;12(2):e0169762. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28192529.
- Nachman S, Alvero C, Acosta EP, et al. Pharmacokinetics and 48-week safety and efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children 4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4(4):e76-83. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26582887.
- Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015;34(11):1207-1213. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26244832.
- Levy ME, Griffith C, Ellenberger N, et al. Outcomes of integrase inhibitor-based antiretroviral therapy in a clinical cohort of treatment-experienced children, adolescents and young adults with HIV infection. Pediatr Infect Dis J. 2020;39(5):421-428. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32176183.
- Abo YN, Refsum E, Mackie N, Lyall H, Tudor-Williams G, Foster C. Paediatric integrase inhibitor use in a real-life setting: a single-centre cohort experience 2009–2018. Clin Drug Investig. 2019;39(6):585-590. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30976998.
- Ciccullo A, Baldin G, Putaggio C, Di Giambenedetto S, Borghetti A. Comparative safety review of recommended, first-line single-tablet regimens in patients with HIV. Expert Opin Drug Saf. 2021;20(11):1317-1332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34018892.
- Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad. 2018;4(2):72-79. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29682298.
- Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV. 2018;5(6):e291-e300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29731407.
- Aurpibul L, Namwongprom S, Sudjaritruk T, Ounjaijean S. Metabolic syndrome, biochemical markers, and body composition in youth living with perinatal HIV infection on antiretroviral treatment. PLoS One. 2020;15(3):e0230707. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32226033.
- Asensi V, Collazos J, Valle-Garay E. Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics. World J Virol. 2015;4(3):169-177. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26279978.
- Sinxadi PZ, Leger PD, McIlleron HM, et al. Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa. Br J Clin Pharmacol. 2015;80(1):146-Available at: https://www.ncbi.nlm.nih.gov/pubmed/25611810.
- Bolton Moore C, Capparelli EV, Samson P, et al. CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 months with HIV infection. AIDS. 2017;31(8):1129-1136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28323755.
- Gallien S, Journot V, Loriot MA, et al. Cytochrome 2B6 polymorphism and efavirenz- induced central nervous system symptoms : a substudy of the ANRS ALIZE trial. HIV Med. 2017;18(8):537-545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28145050.
- Soeria-Atmadja S, Osterberg E, Gustafsson LL, et al. Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin. PLoS One. 2017;12(9):e0181316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28886044.
- Wynberg E, Williams E, Tudor-Williams G, Lyall H, Foster C. Discontinuation of efavirenz in paediatric patients: why do children switch? Clin Drug Investig. 2018;38(3):231-238. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29181714.
- Strehlau R, Shiau S, Arpadi S, et al. Substituting abacavir for stavudine in children who are virally suppressed without lipodystrophy: randomized clinical trial in Johannesburg, South Africa. J Pediatric Infect Dis Soc. 2018;7(3):e70-e77. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29373687.
- Valantin MA, Bittar R, de Truchis P, et al. Switching the nucleoside reverse transcriptase inhibitor backbone to tenofovir disoproxil fumarate + emtricitabine promptly improves triglycerides and low-density lipoprotein cholesterol in dyslipidaemic patients. J Antimicrob Chemother. 2010;65(3):556-561. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20053692.
- Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on ritonavir-boosted lopinavir in HIV-infected children exposed to nevirapine: long-term outcomes of a randomized trial. Clin Infect Dis. 2017;65(3):477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28419200.
- Raffi F, Esser S, Nunnari G, Perez-Valero I, Waters L. Switching regimens in virologically suppressed HIV-1-infected patients: evidence base and rationale for integrase strand transfer inhibitor (INSTI)-containing regimens. HIV Med. 2016;17 Suppl 5:3-16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27714978.
- Jao J, Yu W, Patel K, et al. Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study. HIV Med. 2018;19(3):175-183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29159965.
- Vo TT, Varghese Gupta S. Role of cytochrome P450 2B6 pharmacogenomics in determining efavirenz-mediated central nervous system toxicity, Treatment outcomes, and dosage adjustments in patients with human immunodeficiency virus infection. Pharmacotherapy. 2016;36(12):1245-1254. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27779789.
- Engelbrecht AE, Wiesner L, Norman J, Rabie H, Decloedt EH. Pediatric antiretroviral therapeutic drug monitoring: a five and a half year experience from a South African tertiary hospital. J Trop Pediatr. 2020;66(4):385-394. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31754710.
- Senneker T, Tseng A. An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors. Curr Opin HIV AIDS. 2021;16(6):309-320. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34475342.