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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
(Last updated: March 5, 2015; last reviewed: March 5, 2015)
Ritonavir is used as a PK enhancer of other protease inhibitors (PIs) and of an integrase inhibitor (elvitegravir) when elvitegravir is included in a boosted protease-containing regimen. The recommended dose of ritonavir varies and is specific to the drug combination selected. See dosing information for specific PIs and for elvitegravir.
* Ritonavir has antiretroviral activity but is no longer recommended for use as an antiviral agent (see text).
Possible increased bleeding episodes in patients with hemophilia
Toxic epidermal necrolysis and Stevens-Johnson syndrome
Administer ritonavir with food to increase absorption and reduce GI adverse effects.
Do not administer ritonavir with cobicistat or drugs that contain cobicistat (Stribild).
If ritonavir is prescribed with didanosine, administer the drugs 2 hours apart.
Refrigerate ritonavir capsules only if the capsules will not be used within 30 days or cannot be stored below 77° F (25° C). Ritonavir tablets are heat stable.
Do not refrigerate ritonavir oral solution; store at room temperature (68° F to 77° F or 20° C to 25° C). Shake the solution well before use.
Ritonavir oral solution has limited shelf life; use within 6 months.
Patients who have persistent or significant nausea with the capsule may benefit from switching to the tablet. Also, the tablet is smaller than the capsule and thus easier to swallow.
To Increase Tolerability of Ritonavir Oral Solution in Children:
Mix solution with milk, chocolate milk, or vanilla or chocolate pudding or ice cream.
Before administration, give a child ice chips, a Popsicle, or spoonfuls of partially frozen orange or grape juice concentrate to dull the taste buds, or give peanut butter to coat the mouth.
After administration, give a child strong-tasting foods such as maple syrup or cheese.
Check food allergy history before making these recommendations.
Cytochrome P (CYP) 3A4 and CYP2D6 inhibitor; CYP3A4 and CYP1A2 inducer.
Dosing of ritonavir in patients with hepatic impairment: Ritonavir is primarily metabolized by the liver. No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. Data are unavailable on ritonavir dosing for adult or pediatric patients with severe hepatic impairment. Use caution when administering ritonavir to patients with moderate-to-severe hepatic impairment.
Metabolism: Ritonavir is extensively metabolized by and is one of the most potent inhibitors of hepatic cytochrome P450 3A (CYP3A). There is potential for multiple drug interactions with ritonavir.
Before ritonavir is administered, a patient’s medication profile should be carefully reviewed for potential interactions with ritonavir and overlapping toxicities with other drugs.
Ritonavir and cobicistat are not interchangeable and may result in different drug interactions.
Avoid concomitant use of intranasal or inhaled fluticasone because of reports of adrenal insufficiency.1 Use caution when prescribing ritonavir with other inhaled steroids; limited data suggest that beclomethasone may be a suitable alternative to fluticasone when an inhaled/intranasal corticosteroid is required for a patient who is taking ritonavir.2,3
Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution
Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis, and hepatitis (life-threatening in rare cases). Allergic reactions, including bronchospasm, urticaria, and angioedema. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.4
Resistance to ritonavir is not clinically relevant when the drug is used as a pharmacokinetic (PK) enhancer of other antiretroviral (ARV) medications.
Ritonavir has been approved by the Food and Drug Administration for use in the pediatric population.
Efficacy: Effectiveness in Practice
Use of ritonavir as the sole protease inhibitor (PI) in combination antiretroviral therapy in children is not recommended. Although ritonavir has been well studied in children as an ARV agent, it is no longer used as a sole PI for therapy because ritonavir is associated with a higher incidence of gastrointestinal toxicity and has a greater potential for drug-drug interactions than other PIs. Also, ritonavir as a sole PI was associated with a higher risk of virologic failure than efavirenz or ritonavir-boosted lopinavir, and children who developed virologic failure while receiving ritonavir as a sole PI had a high prevalence of major PI and multiclass mutations.5-9 In addition, poor palatability of the liquid preparation and large pill burden with the capsules (adult dose is six capsules or tablets twice daily) limit its use as a sole PI. Concentrations are highly variable in children younger than 2 years, and doses of 350 to 450 mg/m2 twice daily may not be sufficient for long-term suppression of viral replication in this age group.10-18 However, in both children and adults, ritonavir is recommended as a PK enhancer for use with other PIs or, in adults, with the integrase inhibitor elvitegravir when used in combination with another PI. Ritonavir is a CYP3A4 inhibitor and functions as a PK enhancer by slowing the metabolism of elvitegravir and of the PIs.
Pediatric dosing regimens including boosted fosamprenavir, tipranavir, darunavir, atazanavir and a PI co-formulation, ritonavir-boosted lopinavir, are available (see individual PIs for more specific information). Dosing of ritonavir when used as a PK enhancer of elvitegravir in a boosted PI regimen is available for adults (see elvitegravir section).
Full-dose ritonavir has been shown to prolong the PR interval in a study of healthy adults who were given ritonavir at 400 mg twice daily.4 Potentially life-threatening arrhythmias in premature newborn infants treated with ritonavir-boosted lopinavir have been reported; thus, ritonavir-boosted lopinavir should not be used in this group of patients.19,20 Co-administration of ritonavir with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone) should be undertaken with caution because it is unknown how co-administering any of these drugs with ritonavir will affect the PR interval. In addition, ritonavir should be used with caution in patients who may be at increased risk of developing cardiac conduction abnormalities, such as those with underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or cardiomyopathy.
Bernecker C, West TB, Mansmann G, Scherbaum WA, Willenberg HS. Hypercortisolism caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid therapy. 2 case reports and a review of the literature. Exp Clin Endocrinol Diabetes. 2012;120(3):125-127. Available at http://www.ncbi.nlm.nih.gov/pubmed/22328106.
Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361. Available at http://www.ncbi.nlm.nih.gov/pubmed/23535292.
Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013;14(9):519-529. Available at http://www.ncbi.nlm.nih.gov/pubmed/23590676.
Davies MA, Moultrie H, Eley B, et al. Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration. J Acquir Immune Defic Syndr. 2011;56(3):270-278. Available at http://www.ncbi.nlm.nih.gov/pubmed/21107266.
van Zyl GU, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South African children with virologic failure. Pediatr Infect Dis J. 2009;28(12):1125-1127. Available at http://www.ncbi.nlm.nih.gov/pubmed/19779394.
Taylor BS, Hunt G, Abrams EJ, et al. Rapid development of antiretroviral drug resistance mutations in HIV-infected children less than two years of age initiating protease inhibitor-based therapy in South Africa. AIDS Res Hum Retroviruses. 2011;27(9):945-956. Available at http://www.ncbi.nlm.nih.gov/pubmed/21345162.
Feucht UD, Rossouw T, Van Dyk G, Forsyth B, Kruger M. Consequences of prior use of full-dose ritonavir as single protease inhibitor as part of combination antiretroviral regimens on the future therapy choices in HIV-1-infected children. Pediatr Infect Dis J. 2014;33(2):e53-59. Available at http://www.ncbi.nlm.nih.gov/pubmed/23958813.
Orrell C, Levison J, Ciaranello A, et al. Resistance in pediatric patients experiencing virologic failure with first-line and second-line antiretroviral therapy. Pediatr Infect Dis J. 2013;32(6):644-647. Available at http://www.ncbi.nlm.nih.gov/pubmed/23303240.
Thuret I, Michel G, Chambost H, et al. Combination antiretroviral therapy including ritonavir in children infected with human immunodeficiency. AIDS. 1999;13(1):81-87. Available at http://www.ncbi.nlm.nih.gov/pubmed/10207548.
Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum Retroviruses. 2000;16(12):1113-1121. Available at http://www.ncbi.nlm.nih.gov/pubmed/10954886.
Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children. Scand J Infect Dis. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
Yogev R, Lee S, Wiznia A, et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J. 2002;21(2):119-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/11840078.
Fletcher CV, Yogev R, Nachman SA, et al. Pharmacokinetic characteristics of ritonavir, zidovudine, lamivudine, and stavudine in children with human immunodeficiency virus infection. Pharmacotherapy. 2004;24(4):453-459. Available at http://www.ncbi.nlm.nih.gov/pubmed/15098798.
Chadwick EG, Rodman JH, Britto P, et al. Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age. Pediatr Infect Dis J. 2005;24(9):793-800. Available at http://www.ncbi.nlm.nih.gov/pubmed/16148846.
King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: pediatric AIDS clinical trials group protocol 403. Pediatr Infect Dis J. 2005;24(10):880-885. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220085.
Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins with cardiomyopathy and complete heart block born to an HIV-infected mother treated with HAART. AIDS. 2007;21(18):2564-2565. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025905.
McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J. 2009;28(12):1127-1129. Available at http://www.ncbi.nlm.nih.gov/pubmed/19820426.