Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Management of Medication Toxicity or Intolerance
(Last updated:11/1/2012; last reviewed:11/1/2012)
- In children who have severe or life-threatening toxicity, all components of their drug regimen should be stopped immediately (AIII). Once symptoms of toxicity have resolved, antiretroviral therapy (ART) should be resumed with substitution of a different antiretroviral (ARV) drug or drugs for the offending agent(s) (AII*).
- When modifying therapy because of toxicity or intolerance to a specific drug in children in whom virus has been suppressed, 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 to facilitate future medication choices if care is transferred (AIII).
- Dose reduction is not a recommended option in the setting of ARV toxicity, except when therapeutic drug monitoring (TDM) 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
Side effects from or intolerance to antiretroviral (ARV) agents are common in children and should prompt a re-evaluation of the ARV regimen. 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 treatment discontinuation because of toxicity have been identified, but the only such screen in clinical use is HLA B*5701 as a marker for abacavir hypersensitivity.1 The differential diagnosis of drug toxicity includes toxicity due to HIV infection or other infections or conditions, bone marrow suppression with disseminated Mycobacterium avium complex (MAC) infection, and anemia due to blood loss from cytomegalovirus colitis. ARV drug-related adverse events can vary in severity from mild to severe and life threatening (see Tables 17a–17l. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations).
Identification of the responsible agent may allow for substitution of a similar agent that recent HIV drug-resistance testing predicts will be active against a patient’s virus. Knowledge of a patient’s ARV history and viral resistance profile before the current course of antiretroviral therapy (ART) is essential. Any new agent used should be assessed for likely effectiveness against a patient’s virus and for possible interactions with other medications the patient will take.
Experience with ARV drugs has led to the recognition of several types of distinct adverse drug effects that may be most common with certain ARV drugs or drug classes (see Tables 17a–17l. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations).
Physicians, patients, and caregivers should discuss the response to medication-related toxicity, taking 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. For example, when initiating therapy with boosted protease inhibitors (PIs) many patients experience gastrointestinal (GI) 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 addition, mild rash can be treated 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. Severe, life-threatening toxicity requires discontinuation of all ARV drugs and the initiation of appropriate supportive therapy (depending on the type of toxicity). Once the patient is stable and toxicity has resolved, another drug can be substituted for the drug associated with the toxicity.
In patients who experience an unacceptable adverse effect from ART, every attempt should be made to identify the offending agent and replace the drug with another effective agent as soon as possible.2,3 For example, if therapy needs to be stopped because of a severe or life-threatening side effect, all ARV drugs should be stopped at the same time. 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. Many experts recommend stopping efavirenz, etravirine, or nevirapine before stopping other drugs, if possible, because these drugs have significantly longer half-lives than nucleoside reverse transcriptase inhibitors (see Discontinuation or Interruption of Therapy section). However, 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.
When therapy is changed because of toxicity or intolerance in the context of virologic suppression, agents with different toxicity and side-effect profiles should be chosen, when possible.4-8 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 a permissible for patients whose viral loads are undetectable. However, substitution of a single active agent for a single drug in a failing multidrug regimen is generally not recommended because of concern for development of resistance (see Approach to the Management of Antiretroviral Treatment Failure).
Therapeutic drug monitoring (TDM) is not available on a routine basis to most clinicians, and the settings in which it is useful are unclear, especially in children. One such setting, however, may be in the context of the child with mild or moderate toxicity possibly attributable to a particular ARV agent (see Role of Therapeutic Drug Monitoring in Management of Treatment Failure). In this situation, it is reasonable for a clinician to use TDM (if available) to determine if the toxicity is result of a drug concentration exceeding the normal therapeutic range.9,10 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.
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.
Tables 17a–17l. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations describe specific adverse drug effects observed in children, including lactic acidosis, hepatic toxicity, renal toxicity, fat maldistribution and body habitus changes, hyperlipidemia, hyperglycemia, osteopenia, hematological complications, GI adverse effects, CNS adverse effects, peripheral neuropathy, hypersensitivity reactions, and skin rashes. 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.
- 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 athttp://www.ncbi.nlm.nih.gov/pubmed/21288825.
- 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 athttp://www.ncbi.nlm.nih.gov/pubmed/20065200.
- 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 athttp://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 athttp://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 athttp://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 athttp://www.ncbi.nlm.nih.gov/pubmed/21566505.