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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Management of Medication Toxicity or Intolerance
(Last updated: March 1, 2016; last reviewed: March 1, 2016)
Panel's Recommendations Regarding Management of Medication Toxicity or Intolerance
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 advised of the drug-related toxicity (AIII).
Dose reduction is not a recommended option for management of ARV toxicity, except for those few ARV drugs (e.g., efavirenz) for which a therapeutic range of plasma concentrations detected by therapeutic drug monitoring correlates with 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 goals of antiretroviral therapy (ART) 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 ART regimen, as well as the individual child’s underlying conditions, concomitant medications, and prior history of drug intolerance or viral resistance.
Adverse effects (AEs) 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 AEs 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 ART regimens and are generally less than 10%.1-11 In general, the overall benefits of ART outweigh its risks, and the risk of some abnormal laboratory findings (e.g., anemia, renal impairment) may be lower with ART than in its absence during HIV infection.
ARV drug-related AEs 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.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).13-16 For a few other ARV drugs, known 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 AEs (see below and Role of Therapeutic Drug Monitoring in Management of Pediatric HIV Infection).
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 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 AEs 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 AEs. Common, self-limited AEs should be anticipated, and reassurance provided 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. Central nervous system 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. They 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.17-19 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 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.20,21 Many experts will stagger a planned interruption of a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, stopping the NNRTI first and the dual nucleoside analogue reverse transcriptase backbone 7 to 14 days later because of the long half-life of NNRTI drugs. For patients who have a severe or life-threatening toxicity (e.g., hypersensitivity reaction—see Hypersensitivity Reaction, Table 12l), however, all components of the drug regimen should be stopped simultaneously, regardless of drug half-life. Once the offending drug or alternative cause for the AE 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 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.22-26 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).
TDM 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 range27,28 (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 susceptible (such as changing to abacavir for zidovudine-related anemia or to a PI or integrase strand transfer inhibitor (INSTI) for efavirenz-related central nervous system symptoms).
Change drug class, if necessary (e.g., from a PI to an INSTI or a NNRTI or vice versa) and if a patient’s virus is susceptible to a drug in that class.
Dose reduction only when drug concentrations are determined to be above the therapeutic range.
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