Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Pharmacokinetic Enhancers

Ritonavir

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Ritonavir (RTV) is extensively metabolized by (and is one of the most potent inhibitors of) hepatic cytochrome P450 (CYP) 3A. Also, RTV is a CYP2D6 inhibitor and a CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. RTV inhibits the intestinal transporter P-glycoprotein. There is potential for multiple drug interactions with RTV.
• Before RTV is administered, a patient’s medication profile should be reviewed carefully for potential interactions with RTV and overlapping toxicities with other drugs.
• RTV and cobicistat are not interchangeable. The potential drug interactions for these drugs are different.²
• Avoid concomitant use of corticosteroids, including intranasal or inhaled fluticasone or inhaled budesonide. Reduced elimination of steroids can increase steroid effects, leading to adrenal insufficiency.^3,4 Use caution when prescribing RTV with other inhaled steroids. Limited data suggest that beclomethasone may be a suitable alternative to fluticasone when a patient who is taking RTV requires an inhaled or intranasal corticosteroid.^5,6 Iatrogenic Cushing’s syndrome and suppression of the hypothalamic-pituitary axis secondary to the drug interaction between RTV and local injection of triamcinolone has occurred.^7,8 See Drug Interactions Between Protease Inhibitors and Other Drugs in the Adult and Adolescent Antiretroviral Guidelines for additional information.

Major Toxicities

• More common: Nausea, vomiting, diarrhea, headache, abdominal pain, anorexia, circumoral paresthesia, abnormal lipid levels
• Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis. Cases of hepatitis, including life-threatening cases, have been reported. Allergic reactions, including bronchospasm, urticaria, and angioedema have occurred. Toxic epidermal necrolysis and Stevens-Johnson syndrome have occurred.⁹

Resistance

Resistance to RTV is not clinically relevant when the drug is used as a pharmacokinetic (PK) enhancer of other antiretroviral (ARV) medications.

Pediatric Use

Approval

RTV has been approved by the U.S. Food and Drug Administration for use in the pediatric population.

Effectiveness in Practice

Use of RTV as the sole protease inhibitor (PI) in ARV therapy in children is not recommended. In both children and adults, RTV is recommended as a PK enhancer for use with other PIs. RTV is a CYP3A inhibitor and functions as a PK enhancer by slowing the metabolism of the PI.

Dosing

Dosing regimens for RTV-boosted darunavir and atazanavir and coformulated lopinavir/ritonavir (LPV/r) are available for pediatric patients. For more information about individual PIs, see other sections of Appendix A: Pediatric Antiretroviral Drug Information.

Toxicity

Full-dose RTV has been shown to prolong the PR interval in a study of healthy adults who were given RTV 400 mg twice daily.⁹ Potentially life-threatening arrhythmias have been reported in premature infants who were treated with LPV/r; therefore, the use of LPV/r is generally not recommended before a gestational age of 42 weeks (see Lopinavir/Ritonavir).^10,11 Coadministration of RTV with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone) should be undertaken with caution because it is unknown how coadministering any of these drugs with RTV will affect the PR interval. In addition, RTV should be used with caution in patients who may be at increased risk of developing cardiac conduction abnormalities, such as patients who have underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or cardiomyopathy.

References

1. Morris JB, Tisi DA, Tan DCT, Worthington JH. Development and palatability assessment of norvir (ritonavir) 100 mg powder for pediatric population. Int J Mol Sci. 2019;20(7):1718. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30959935.
2. Marzolini C, Gibbons S, Khoo S, Back D. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. J Antimicrob Chemother. 2016;71(7):1755-1758. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26945713.
3. 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: https://www.ncbi.nlm.nih.gov/pubmed/22328106.
4. Peyro-Saint-Paul L, Besnier P, Demessine L, et al. Cushing’s syndrome due to interaction between ritonavir or cobicistat and corticosteroids: a case-control study in the French Pharmacovigilance Database. J Antimicrob Chemother. 2019;74(11):3291-3294. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31369085.
5. 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: https://www.ncbi.nlm.nih.gov/pubmed/23535292.
6. 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: https://www.ncbi.nlm.nih.gov/pubmed/23590676.
7. Dubrocq G, Estrada A, Kelly S, Rakhmanina N. Acute development of cushing syndrome in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0076. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29118985.
8. Noe S, Jaeger H, Heldwein S. Adrenal insufficiency due to ritonavir-triamcinolone drug-drug interaction without preceding Cushing’s syndrome. Int J STD AIDS. 2018;29(11):1136-1139. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29749880.
9. Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18924248.
10. 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: https://www.ncbi.nlm.nih.gov/pubmed/18025905.
11. 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: https://www.ncbi.nlm.nih.gov/pubmed/19820426.