Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Drug Interactions

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

• Metabolism: Atazanavir (ATV) is both a substrate and an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme system and has significant interactions with drugs that are highly dependent on CYP3A4 for metabolism. ATV also competitively inhibits CYP1A2 and CYP2C9. ATV is a weak inhibitor of CYP2C8. ATV inhibits the glucuronidation enzyme uridine diphosphate glucuronosyl transferase (UGT1A1). Because of the potential for multiple drug interactions with ATV, a patient’s medication profile should be carefully reviewed for potential drug interactions before administering ATV.
• Nucleoside reverse transcriptase inhibitors (NRTIs): Tenofovir disoproxil fumarate (TDF) decreases ATV plasma concentrations. Only atazanavir/ritonavir (ATV/r) or atazanavir/cobicistat (ATV/c) should be used in combination with TDF. The effect of tenofovir alafenamide (TAF) on unboosted ATV is unknown; thus, only ATV/r or ATV/c should be used with TAF.
• Non-nucleoside reverse transcriptase inhibitors: Efavirenz (EFV), etravirine (ETR), and nevirapine (NVP) decrease ATV plasma concentrations significantly. NVP and ETR should not be administered to patients who are receiving ATV (with or without a booster). Although the combination of EFV and ATV/r is not commonly used in clinical practice, EFV may be used in combination with ritonavir (RTV)-boosted ATV 400 mg in antiretroviral therapy (ART)-naive patients. ATV/r should be taken with food, and EFV should be taken on an empty stomach, preferably at bedtime. Coadministering ATV/r and EFV in ART-experienced patients is not recommended, because this combination is expected to result in suboptimal ATV exposure in these patients.
• Integrase strand transfer inhibitors: ATV is an inhibitor of UGT1A1 and may increase plasma concentrations of raltegravir (RAL). This interaction may not be clinically significant.
• Absorption: ATV absorption is dependent on low gastric pH. The dose for ATV should be adjusted when it is administered with medications that increase gastric pH. Guidelines for the appropriate doses of ATV to use with antacids, H2 receptor antagonists, and proton-pump inhibitors in adults are complex and can be found in the package insert for ATV. No information is available on the appropriate doses of ATV to use in children when the drug is coadministered with medications that increase gastric pH.
• Coadministering cobicistat (COBI)—a CYP3A4 inhibitor—and medications that are metabolized by CYP3A4 may increase the plasma concentrations of these medications. This may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions) that are associated with the concomitant medications. Coadministration of COBI, ATV, and CYP3A4 inducers may lead to lower exposures of COBI and ATV, a loss of efficacy of ATV, and possible development of resistance.¹ Coadministering COBI and ATV with some antiretroviral (ARV) agents (e.g., with ETR, with EFV in ART-experienced patients, or with another ARV drug that requires pharmacokinetic [PK] enhancement, such as another protease inhibitor [PI] or elvitegravir) may result in decreased plasma concentrations of that agent, leading to loss of therapeutic effect and the development of resistance.

Major Toxicities

• More common: Indirect hyperbilirubinemia that can result in jaundice or icterus but is not a marker of hepatic toxicity. Headache, fever, arthralgia, depression, insomnia, dizziness, nausea, vomiting, diarrhea, and paresthesia.
• Less common: Prolongation of the electrocardiogram PR interval. Abnormalities in atrioventricular (AV) conduction are generally limited to first-degree AV block, but second-degree AV block has been reported. Rash is generally mild or moderate, but in rare cases includes life-threatening Stevens-Johnson syndrome. Fat maldistribution and lipid abnormalities may be less common than with other PIs. The use of ATV/r is associated with lipid abnormalities, but to a lesser extent than with other boosted PIs.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, spontaneous bleeding in hemophiliacs, and elevation in serum transaminases. Chronic kidney disease, including biopsy-proven cases of granulomatous interstitial nephritis that were associated with the deposition of ATV drug crystals in the renal parenchyma have occurred. Nephrolithiasis and cholelithiasis have been reported. Hepatotoxicity (patients with hepatitis B virus or hepatitis C virus infections are at increased risk of hepatotoxicity).

Resistance

The International Antiviral Society–USA maintains a list of updated resistance mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

ATV is approved by the U.S. Food and Drug Administration (FDA) for use in infants (aged ≥3 months and weighing ≥5 kg), children, and adolescents. Because RTV oral solution is no longer commercially available, use of ATV/r is limited to children weighing ≥15 kg who can use the RTV 100 mg powder packet or 100 mg tablet. ATV coformulated with COBI (as Evotaz) has been approved by the FDA for use in pediatric patients weighing ≥35 kg.

Efficacy

Studies in ART-naive adults have shown that ATV/r is as effective as EFV and lopinavir/ritonavir (LPV/r) when these drugs are administered with two NRTIs.^2-5 In AIDS Clinical Trials Group (ACTG) A5257, ATV/r was compared to darunavir/ritonavir (DRV/r) or RAL, each administered with a TDF/emtricitabine backbone. Although all three regimens had equal virologic efficacy, the regimen that contained ATV/r was discontinued more frequently than the other regimens because of toxicity but most often because of hyperbilirubinemia or gastrointestinal complaints.⁶

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT)/Pediatric AIDS Clinical Trials Group (PACTG) P1020 enrolled 195 ART-naive and ART-experienced patients with HIV aged 3 months to 21 years. Capsule and powder formulations of ATV given with and without RTV boosting were investigated in this open-label study; area under the curve (AUC) targeting was used to direct dose finding. Of the 195 patients enrolled, 142 patients received ATV-based treatment at the final recommended dose. Among these patients, 58% were ART-naive. At Week 48, 69.5% of the ART-naive patients and 43.3% of the ART-experienced patients had HIV viral loads ≤400 copies/mL.^7,8 (Kiser, Fletcher et al. 2008, Kiser, Rutstein et al. 2011)

Two open-label clinical trials in infants and children, PRINCE-1 and PRINCE-2, studied a powder formulation of ATV that was administered once daily and boosted with liquid RTV.^9-11 In total, 134 infants and children aged ≥3 months and weighing between 5 kg and 35 kg were evaluated. Using a modified intent-to-treat analysis, 28 of 52 ARV-naive patients (54%) and 41 of 82 ART-experienced patients (50%) had HIV RNA <50 copies/mL at Week 48. The median increase from baseline in absolute CD4 T lymphocyte cell count at 48 weeks of therapy was 215 cells/mm³ (a 6% increase) in ARV-naive patients and 133 cells/mm³ (a 4% increase) in ARV-experienced patients.

Pharmacokinetics and Dosing

Oral Capsule

The results of the IMPAACT/PACTG 1020A trial in children and adolescents indicate that, in the absence of RTV boosting, ATV can achieve protocol-defined PK targets—but only when used at higher doses (on a mg per kg body weight or mg per m² of body surface area basis) than the doses that are currently recommended in adults. In IMPAACT/PACTG 1020A, children aged >6 years to <13 years required a dose of 520 mg per m² of body surface area per day of the ATV capsule formulation to achieve PK targets.⁸ Unboosted ATV at this dose was well tolerated in those aged <13 years who were able to swallow capsules.¹² The approved dose for adults is ATV 400 mg once daily without RTV boosting; however, adolescents aged >13 years required a dose of ATV 620 mg per m² of body surface area per day.⁸ In this study, the AUCs for the unboosted arms were similar to those seen in the ATV/r arms, but the maximum plasma concentration (C_max) was higher and the minimum plasma concentration (C_min) was lower in the unboosted arms. Median doses of ATV, both with and without RTV boosting, from IMPAACT/PACTG 1020A are outlined in Table A below. When administering unboosted ATV to pediatric patients, therapeutic drug monitoring is recommended to ensure that adequate ATV plasma concentrations have been achieved. A minimum target trough concentration for ATV is 150 ng/mL.¹³ Higher target trough concentrations may be required in PI-experienced patients. IMPAACT P1058, a study of unboosted ATV PKs in ART-experienced children, concluded that once-daily ATV 400 mg provided suboptimal exposure and that administering higher, unboosted doses or splitting the daily dose into twice-daily doses warranted investigation in ART-experienced children, adolescents, and young adults.¹⁴

In the report of the IMPAACT/PACTG P1020A data, ATV satisfied PK criteria at a dose of 205 mg per m² of body surface area in pediatric subjects when administered with RTV.¹² A study of a model-based approach that used ATV concentration-time data from three adult studies and one pediatric study (P1020A),¹⁵ along with subsequent additional adjusted modeling,¹⁶ informed the use of the following weight-based ATV/r doses that are listed in the current FDA-approved product label for children aged ≥6 years to <18 years:

• Weighing 15 kg to <35 kg: ATV/r 200 mg/100 mg
• Weighing ≥35 kg: ATV/r 300 mg/100 mg

Cobicistat as a Pharmacokinetic Enhancer

COBI (as Tybost) is approved by the FDA at the 150-mg dose for use with ATV 300 mg in children and adolescents weighing ≥35 kg. A study of 14 adolescents, aged 12 to 18 years, showed that COBI is a safe and effective PK enhancer when used in combination with ATV and two NRTIs in adolescent patients.¹⁷ PK findings from this study are summarized in Table B below.

Oral Powder

The unboosted ATV powder arms in IMPAACT/PACTG P1020A were closed, because participants were unable to achieve target exposures. For the IMPAACT/PACTG P1020A trial, AUC targets (30,000 ng·hr/mL to 90,000 ng·hr/mL) were established based on exposures in adults in early studies of unboosted ATV. In IMPAACT/PACTG P1020A, children aged 3 months to 2 years who were in the boosted ATV powder cohorts and who received a daily dose of ATV 310 mg per m² of body surface area achieved average ATV exposures that approached, but did not meet, protocol targets. Variability in exposures was high, especially among the very young children of 3 months to 2 years in this study.⁸

Assessment of the PKs, safety, tolerability, and virologic response of ATV oral powder for FDA approval was based on data from two open-label, multicenter clinical trials:

• PRINCE-1, which enrolled pediatric patients aged 3 months to <6 years⁹ 
• PRINCE-2, which enrolled pediatric patients aged 3 months to <11 years.¹⁰

In total, 134 treated patients (weighing 5 kg to <35 kg) from both studies were evaluated during the FDA approval process. All patients in the PRINCE trials were treated with boosted ATV and two NRTIs. Children received an oral solution that contained ATV and RTV. Doses were assigned according to the child’s weight:

• Weighing 5 kg to <10 kg: ATV 150 mg or ATV 200 mg and RTV 80 mg
• Weighing 10 kg to <15 kg: ATV 200 mg and RTV 80 mg
• Weighing 15 kg to <25 kg: ATV 250 mg and RTV 80 mg
• Weighing 25 kg to <35 kg: ATV 300 mg and RTV 100 mg

No new safety concerns were identified during these trials. Table C lists the PK parameters that were measured during the PRINCE trials, including mean AUC, for the weight ranges that correspond to the recommended doses.

In these PK studies, although the PK targets were met in all patients using ATV powder except those who received ATV/r 150 mg/80 mg in the 5 kg to <10 kg weight band, the coefficients of variation were large, especially among the youngest patients.

Transitioning from Powder to Capsules

For children who reach a weight ≥25 kg while taking the powder, ATV 300 mg powder (six packets) plus RTV 100 mg oral solution, both administered once daily with food, may be used. ATV capsules should be used for children who can swallow pills. Bioavailability is higher for the capsules than for the powder; therefore, a lower mg/kg dose is recommended when using capsules. Opened capsules have not been studied and should not be used.

Toxicity

In the IMPAACT/PACTG 1020A trial, 9% of patients enrolled had a total bilirubin ≥5.1 times the upper limit of normal,¹² whereas 9% of patients enrolled in the PRINCE studies had a total bilirubin ≥2.6 times the upper limit of normal.^9,11 The most common laboratory abnormality during the PRINCE trials was elevated amylase levels, which occurred in 33% of patients.¹⁰ Three children (2%) had treatment-related cardiac disorders during the PRINCE trials; one child discontinued therapy because of QT corrected for heart rate (QTc) prolongation, and two experienced first-degree AV block.^9,11 In IMPAACT/PACTG P1020A, three children (3%) had QTc prolongations >470 msec; two of these children came off the study, and all were asymptomatic.

References

1. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.
2. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36(5):1011-1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15247553.
3. Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr. 2008;47(2):161-167. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17971713.
4. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-655. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18722869.
5. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53(3):323-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20032785.
6. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161(7):461-471. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25285539.
7. Kiser JJ, Fletcher CV, Flynn PM, et al. Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection. Antimicrob Agents Chemother. 2008;52(2):631-637. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18025112.
8. Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):1489-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21610486.
9. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26066346.
10. Reyataz (Atazanavir) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021567s044,206352s008lbl.pdf.
11. Cotton MF, Liberty A, Torres-Escobar I, et al. Safety and efficacy of atazanavir powder and ritonavir in HIV-1-infected infants and children from 3 months to <11 years of age: the PRINCE-2 study. Pediatr Infect Dis J. 2018;37(6):e149-e156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29206747.
12. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the pediatric AIDS clinical trials group protocol 1020A. Pediatr Infect Dis J. 2015;34(2):162-167. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25232777.
13. Gonzalez de Requena D, Bonora S, Canta F, et al. Atazanavir Ctrough is associated with efficacy and safety at 24 weeks: definition of therapeutic range. Abstract 60. Presented at: 6th International Workshop on Clinical Pharmacology of HIV Therapy; 2005. Quebec City, Canada. Available at: https://www.researchgate.net/profile/Maria_Grazia_Milia2/publication/267256045_Atazanavir_Ctrough_is_associated_with_efficacy_and_safety_definition_of_therapeutic_range/links/560106c808ae07629e52b5e1/Atazanavir-Ctrough-is-associated-with-efficacy-and-safety-definition-of-therapeutic-range.pdf?origin=publication_detail.
14. Cressey TR, Hazra R, Wiznia A, et al. Pharmacokinetics of unboosted atazanavir in treatment-experienced HIV-infected children, adolescents and young adults. Pediatr Infect Dis J. 2016;35(12):1333-1335. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27583590.
15. Hong Y, Kowalski KG, Zhang J, et al. Model-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents Chemother. 2011;55(12):5746-5752. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21930880.
16. Sevinsky H, Cirincione B, Raybon J. Challenges in developing a population PK model describing the PK of atazanavir and supporting dose selection in HIV infected pediatric subjects. Presented at: The Seventh American Conference on Pharmacometrics 2016. Bellevue, WA.
17. McFarland EJ, Heresi GP, Batra J, et al. Pharmacokinetics, safety, and efficacy of ATV or DRV with COBI in adolescents. Presented at: Conference on Retroviruses and Opportunistic Infections; 2017. Seattle, WA.