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.

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Management of Medication Toxicity or Intolerance

Overview

Last Updated: May 22, 2018; Last Reviewed: May 22, 2018

Panel's Recommendations Regarding Management of Medication Toxicity or Intolerance
Panel's Recommendations
  • In children who have severe or life-threatening toxicity (e.g., a hypersensitivity reaction), all antiretroviral (ARV) drugs should be stopped immediately (AIII). Once symptoms of toxicity have resolved, antiretroviral therapy should be resumed with substitution of a different ARV drug or drugs for the offending agent(s) (AII*).
  • When modifying therapy because of toxicity or intolerance to a specific drug in children with virologic suppression, changing one drug in a multidrug regimen is permissible; if possible, an agent with a different toxicity and side-effect profile should be chosen (AI*).
  • The toxicity and the medication presumed responsible should be documented in the medical record and the caregiver and patient should be advised of the drug-related toxicity (AIII).
  • In general, dose reduction is not a recommended option for management of ARV toxicity (AII*).
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 post-pubertal adolescents

Medication Toxicity or Intolerance

The overall benefits of viral suppression and improved immune function as a result of effective antiretroviral therapy (ART) far outweigh the risks associated with the adverse effects (AEs) of some antiretroviral (ARV) drugs. However, AEs have been reported with the use of all ARV drugs and—in the mid-1990s when combination ART was introduced—were among the most common reasons for switching or discontinuing therapy and for medication nonadherence (see The Adult and Adolescent Guidelines).1

Fortunately, currently recommended ARV regimens are associated with fewer serious and intolerable AEs than regimens used in the past. Generally, <10% of ART-naive patients enrolled in randomized trials have treatment-limiting AEs.2-11 Some longer-term complications of ART (e.g., bone or renal toxicity, dyslipidemia, accelerated cardiovascular disease) may 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. To achieve sustained viral suppression over a child’s lifetime, both short-term 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 prior history of drug intolerance or viral resistance.

ARV drug-related AEs 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 (occurring soon after a drug has been administered), subacute (occurring within 1 to 2 days of administration), or late (occurring after prolonged drug administration). For a few ARV medications, pharmacogenetic markers associated with risk of early toxicity have been identified, but the only such screen in routine clinical use is HLA-B*5701 as a marker for abacavir hypersensitivity.12-14 For selected children aged <3 years who require treatment with efavirenz, an additional pharmacogenetic marker, CYP2B6 genotype, should be assessed in an attempt to prevent toxicity (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).13-17 For agents such as efavirenz, 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 experiencing central nervous system (CNS) AEs (see below).

The most common acute and chronic AEs associated with ARV drugs or drug classes are presented in the Management of Medication Toxicity or Intolerance tables. The 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 provide selected references regarding these toxicities in pediatric patients.

Management

ART-associated AEs can range from acute and potentially life-threatening to chronic and insidious. Serious life-threatening events (e.g., hy persensitivity reaction [HSR] due to abacavir, symptomatic hepatotoxicity, or severe cutaneous reactions) require the immediate discontinuation of all ARV drugs and reinitiation 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) can usually 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. 

Management strategies must be individualized for each child, taking into account the severity of the toxicity, viral suppression status, and 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 antiemetics and antidiarrheal agents for symptom management. CNS AEs are commonly encountered when initiating therapy with efavirenz. Symptoms can include dizziness, drowsiness, vivid dreams, or insomnia. Patients should be instructed to take efavirenz-containing regimens at bedtime, on an empty stomach, to help minimize these AEs. Patients should be advised that these AEs usually diminish in general within 2 to 4 weeks of initiating therapy in most people, but may persist for months in some, and may require a medication change.18-20 In addition, mild rash can be ameliorated with drugs such as antihistamines. Addressing AEs is essential, as continued use of an ARV that a patient finds intolerable may lead the patient to stop their treatment, risking viral rebound and the development of resistance.

In patients who experience unacceptable 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.21,22 For mild to moderate toxicities, changing to a drug with a different toxicity profile may be sufficient, and discontinuation of all therapy may not be required. When interrupting a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, many experts will stop the NNRTI 7 to 14 days before stopping the dual nucleoside analogue reverse transcriptase backbone, due to the long half-life of NNRTI drugs. However, patients who have a severe or life-threatening toxicity (e.g., HSR—see Hypersensitivity Reaction, Table 15l)  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 cause. 

All drugs in the ARV regimen should then be started simultaneously, rather than one at a time, with observation for AEs. 

When therapy is changed because of toxicity or intolerance in a patient with virologic suppression, agents with different toxicity and side-effect profiles should be chosen, when possible.23-27 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 for patients whose viral loads are undetectable. However, substitution of a single active agent for a single drug in a failing multidrug regimen (e.g., a patient with virologic failure) is generally not recommended because of concern for development of resistance (see Recognizing and Managing Antiretroviral Treatment Failure in Management of Children Receiving Antiretroviral Therapy).

In general, dose-reduction is not recommended for toxicity management, as inadequate ARV drug levels may lead to decreased virologic efficacy. Although TDM is not routinely recommended, it may be used in the management of a child with mild or moderate toxicity if the toxicity is thought to be the result of a drug concentration exceeding the normal therapeutic range.28,29 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 the most data for efavirenz, where increased CNS toxicity has clearly been associated with higher drug levels (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).

To summarize, management strategies for drug intolerance include:

  • Symptomatic treatment of mild to moderate transient AEs.
  • Switching one drug for another drug that is active against a patient’s virus (e.g., changing to abacavir for zidovudine-related anemia or to a PI or integrase strand transfer inhibitor [INSTI] for efavirenz-related CNS symptoms).
  • Using dose reduction as guided by TDM in consultation with an expert in pediatric HIV. 

References

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 2016. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
  2. 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 http://www.ncbi.nlm.nih.gov/pubmed/22126740.
  3. Arpadi S, Shiau S, Strehlau R, et al. Metabolic abnormalities and body composition of HIV-infected children on lopinavir or nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98(4):258-264. Available at http://www.ncbi.nlm.nih.gov/pubmed/23220209.
  4. 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 http://www.ncbi.nlm.nih.gov/pubmed/23473847.
  5. 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;16:18600. Available at http://www.ncbi.nlm.nih.gov/pubmed/23782481.
  6. Cohen S, Smit C, van Rossum AM, et al. Long-term response to combination antiretroviral therapy in HIV-infected children in the Netherlands registered from 1996 to 2012. AIDS. 2013;27(16):2567-2575. Available at http://www.ncbi.nlm.nih.gov/pubmed/23842124.
  7. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS. 2013;27(5):781-785. Available at http://www.ncbi.nlm.nih.gov/pubmed/23169331.
  8. Prendergast AJ. Complications of long-term antiretroviral therapy in HIV-infected children. Arch Dis Child. 2013;98(4):245-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/23413313.
  9. 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 http://www.ncbi.nlm.nih.gov/pubmed/23249917.
  10. 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.
  11. 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.
  12. Lubomirov R, Colombo S, di Iulio J, et al. Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. J Infect Dis. 2011;203(2):246-257. Available at http://www.ncbi.nlm.nih.gov/pubmed/21288825.
  13. Aceti A, Gianserra L, Lambiase L, Pennica A, Teti E. Pharmacogenetics as a tool to tailor antiretroviral therapy: A review. World J Virol. 2015;4(3):198-208. Available at http://www.ncbi.nlm.nih.gov/pubmed/26279982.
  14. 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 http://www.ncbi.nlm.nih.gov/pubmed/26279978.
  15. 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):146-156. Available at http://www.ncbi.nlm.nih.gov/pubmed/25611810.
  16. 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.
  17. 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. Available at https://www.ncbi.nlm.nih.gov/pubmed/28145050.
  18. Gazzard B, Duvivier C, Zagler C, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48-week results. AIDS. 2011;25(18):2249-2258. Available at http://www.ncbi.nlm.nih.gov/pubmed/21881478.
  19. Nelson M, Stellbrink HJ, Podzamczer D, et al. A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. AIDS. 2011;25(3):335-340. Available at http://www.ncbi.nlm.nih.gov/pubmed/21150563.
  20. Leutscher PD, Stecher C, Storgaard M, Larsen CS. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse effects. Scand J Infect Dis. 2013;45(8):645-651. Available at http://www.ncbi.nlm.nih.gov/pubmed/23427878.
  21. Elzi L, Marzolini C, Furrer H, et al. Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008. Arch Intern Med. 2010;170(1):57-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/20065200.
  22. Davidson I, Beardsell H, Smith B, et al. The frequency and reasons for antiretroviral switching with specific antiretroviral associations: the SWITCH study. Antiviral Res. 2010;86(2):227-229. Available at http://www.ncbi.nlm.nih.gov/pubmed/20211651.
  23. Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697-1707. Available at http://www.ncbi.nlm.nih.gov/pubmed/20467288.
  24. Viergever RF, ten Berg MJ, van Solinge WW, Hoepelman AI, Gisolf EH. Changes in hematological parameters after switching treatment of HIV-infected patients from zidovudine to abacavir or tenofovir DF. HIV Clin Trials. 2009;10(2):125-128. Available at http://www.ncbi.nlm.nih.gov/pubmed/19487183.
  25. 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 http://www.ncbi.nlm.nih.gov/pubmed/20053692.
  26. Mallolas J, Podzamczer D, Milinkovic A, et al. Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study. J Acquir Immune Defic Syndr. 2009;51(1):29-36. Available at http://www.ncbi.nlm.nih.gov/pubmed/19390327.
  27. 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. Available at https://www.ncbi.nlm.nih.gov/pubmed/28419200.
  28. Pretorius E, Klinker H, Rosenkranz B. The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection. Ther Drug Monit. 2011;33(3):265-274. Available at http://www.ncbi.nlm.nih.gov/pubmed/21566505.
  29. 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.

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