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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Management of Medication Toxicity or Intolerance
(Last updated: February 12, 2014; last reviewed: February 12, 2014)
In children who have severe or life-threatening toxicity, all antiretroviral (ARV) drugs should be stopped immediately (AIII). Once symptoms of toxicity have resolved, ARV 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 advised of the drug-related toxicity (AIII).
Dose reduction is not a recommended option for management of ARV toxicity, except when therapeutic drug monitoring indicates a drug concentration above the normal therapeutic range (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 postpubertal adolescents
Medication Toxicity or Intolerace
The goals of combination antiretroviral therapy (cART) include achieving and maintaining viral suppression and improving immune function, with a regimen that is not only effective but also as tolerable and safe as possible. This requires consideration of the toxicity potential of a cART regimen, as well as the individual child’s underlying conditions, concomitant medications, and prior history of drug intolerances or viral resistance.
Adverse effects have been reported with use of all antiretroviral (ARV) drugs, and are among the most common reasons for switching or discontinuing therapy, and for medication nonadherence. However, rates of treatment-limiting adverse events in ARV-naive patients enrolled in randomized trials or large observational cohorts appear to be declining with increased availability of better-tolerated and less toxic cART regimens and are generally less than 10%.1-4 In general, the overall benefits of cART outweigh its risks, and the risk of some abnormal laboratory findings (e.g., anemia, renal impairment) may be lower with cART than in its absence.
ARV drug-related adverse events can vary in severity from mild to severe and life-threatening. 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 some 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.5 For selected children aged <3 years who require treatment with efavirenz, an additional pharmacogentic marker, CYP2B6 genotype, should be assessed (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).6
The most common acute and chronic adverse effects 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 and provide selected references regarding these toxicities in pediatric patients.
Management of medication-related toxicity should take into account its severity, the relative need for viral suppression, and the available ARV options. In general, mild and moderate toxicities do not require discontinuation of therapy or drug substitution. However, even mild adverse effects may have a negative impact on medication adherence and should be discussed before therapy is initiated, at regular provider visits, and at onset of any adverse effects. Common, self-limited adverse effects should be anticipated, and reassurance provided that many adverse effects will resolve after the first few weeks of cART. For example, when initiating therapy with boosted protease inhibitors (PIs) many patients experience gastrointestinal adverse effects such as nausea, vomiting, diarrhea, and abdominal pain. Instructing patients to take PIs with food may help minimize these side effects. Some patients may require antiemetics and antidiarrheal agents for symptom management. Central nervous system (CNS) adverse effects 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 to help minimize these adverse effects and be advised that these side effects should diminish or disappear within 2 to 4 weeks of initiating therapy in most people. In addition, mild rash can be ameliorated with drugs such as antihistamines. For some moderate toxicities, using a drug in the same class as the one causing toxicity but with a different toxicity profile may be sufficient and discontinuation of all therapy may not be required.
In patients who experience an unacceptable adverse effect from cART, every attempt should be made to identify the offending agent and replace the drug with another effective agent as soon as possible.1,7 Although many experts will stagger a planned interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based cART regimen, stopping the NNRTI first and the dual nucleoside analogue reverse transcriptase backbone 7-14 days later because of the long half-life of NNRTI drugs , in patients who have a severe or life-threatening toxicity, all components of the drug regimen should be stopped simultaneously, regardless of drug half-life. Once the offending drug or alternative cause for the adverse event has been determined, planning can begin for resumption of therapy with a new ARV regimen that does not contain the offending drug or 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 adverse effects.
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.8-12 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 virololgic 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).
Therapeutic drug monitoring (TDM) may be used in the management of the child with mild or moderate toxicity if the toxicity is thought to be the result of a drug concentration exceeding the normal therapeutic range13,14 (see Role of Therapeutic Drug Monitoring). This is the only setting in which dose reduction would be considered appropriate management of drug toxicity, and even then, it should be used with caution; an expert in the management of pediatric HIV infection should be consulted.
To summarize, management strategies for drug intolerance include:
Symptomatic treatment of mild-to-moderate transient side effects.
If necessary, change from one drug to another drug to which a patient’s virus is sensitive (such as changing to abacavir for zidovudine-related anemia or to nevirapine for efavirenz-related CNS symptoms).
Change drug class, if necessary (such as from a PI to a non-nucleoside reverse transcriptase inhibitor or vice versa) and if a patient’s virus is sensitive to a drug in that class
Dose reduction only when drug levels are determined excessive.
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. Jan 11 2010;170(1):57-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/20065200.
Sauvageot D, Schaefer M, Olson D, Pujades-Rodriguez M, O'Brien DP. Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children <5 years of age. Pediatrics. May 2010;125(5):e1039-1047. Available at http://www.ncbi.nlm.nih.gov/pubmed/20385636.
Buck WC, Kabue MM, Kazembe PN, Kline MW. Discontinuation of standard first-line antiretroviral therapy in a cohort of 1434 Malawian children. J Int AIDS Soc. 2010;13:31. Available at http://www.ncbi.nlm.nih.gov/pubmed/20691049.
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. Mar 1 2012;59(3):274-280. Available at http://www.ncbi.nlm.nih.gov/pubmed/22126740.
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. Jan 15 2011;203(2):246-257. Available at http://www.ncbi.nlm.nih.gov/pubmed/21288825.
Bolton C, Samson P, Capparelli E, et al. Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in HIV+ children <3 years of age and implications for dosing. CROI Paper #981. Paper presented at: Conference on Retrovirueses and Opportunistic Infections; 2012; Seattle, Washington.
Davidson I, Beardsell H, Smith B, et al. The frequency and reasons for antiretroviral switching with specific antiretroviral associations: the SWITCH study. Antiviral Res. May 2010;86(2):227-229. Available at http://www.ncbi.nlm.nih.gov/pubmed/20211651.
Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. Jul 17 2010;24(11):1697-1707. Available at http://www.ncbi.nlm.nih.gov/pubmed/20467288.
McComsey G, Bhumbra N, Ma JF, Rathore M, Alvarez A, First Pediatric Switch S. Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study. Pediatrics. Mar 2003;111(3):e275-281. Available at http://www.ncbi.nlm.nih.gov/pubmed/12612284.
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. Mar-Apr 2009;10(2):125-128. Available at http://www.ncbi.nlm.nih.gov/pubmed/19487183.
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. Mar 2010;65(3):556-561. Available at http://www.ncbi.nlm.nih.gov/pubmed/20053692.
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. May 1 2009;51(1):29-36. Available at http://www.ncbi.nlm.nih.gov/pubmed/19390327.
van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. Oct 1 2009;52(2):240-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/19593159.
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. Jun 2011;33(3):265-274. Available at http://www.ncbi.nlm.nih.gov/pubmed/21566505.