Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Protease Inhibitors (PIs)
Last Updated: May 22, 2018; Last Reviewed: May 22, 2018
|Atazanavir (ATV, Reyataz)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
|Powder Packet: 50 mg/packet
Capsules: 150 mg, 200 mg, and 300 mg
Fixed-Dose Combination Tablets:
Capsules: 150 mg, 200 mg, 300 mg
Capsules and powder packets are not interchangeable.
|Dosing Recommendations||Selected Adverse Events|
For Treatment-Naive Pediatric Patients Who Do Not Tolerate Ritonavir:
|a mg/kg dosing is higher for the powder packets than for the capsules. Bioavailability was higher for the capsules than for the powder when studied in adults.
b For a child weighing ≥25 kg who cannot swallow atazanavir capsules, atazanavir 300 mg (6 packets) oral powder plus ritonavir 100 mg oral solution, both once daily with food, may be used.
c Either ritonavir capsules or ritonavir oral solution can be used.
d For adult patients who cannot swallow capsules, atazanavir oral powder is taken once daily with food at the same adult dose as the capsules, along with ritonavir.
e See cobicistat section for important information about toxicity, drug interactions, and monitoring of patients who receive cobicistat and the combination of cobicistat and TDF.
- Metabolism: Atazanavir is both a substrate and an inhibitor of the cytochrome P (CYP) 3A4 enzyme system and has significant interactions with drugs highly dependent on CYP3A4 for metabolism. Atazanavir also competitively inhibits CYP1A2 and CYP2C9. Atazanavir is a weak inhibitor of CYP2C8. Atazanavir inhibits the glucuronidation enzyme uridine diphosphate glucuronosyltransferase (UGT1A1). Because there is potential for multiple drug interactions with atazanavir, a patient’s medication profile should be carefully reviewed for potential drug interactions before atazanavir is administered.
- Nucleoside reverse transcriptase inhibitors (NRTIs): Tenofovir disoproxil fumarate (TDF) decreases atazanavir plasma concentrations. Only atazanavir/ritonavir (ATV/r) should be used in combination with TDF.
- Non-nucleoside reverse transcriptase inhibitors: Efavirenz, etravirine, and nevirapine decrease atazanavir plasma concentrations significantly. Nevirapine and etravirine should not be co-administered to patients receiving atazanavir (with or without ritonavir). Efavirenz should not be co-administered with atazanavir in treatment-experienced patients, but may be used in combination with atazanavir 400 mg plus ritonavir boosting in treatment-naive adults.
- Integrase inhibitors: Atazanavir is an inhibitor of UGT1A1 and may increase plasma concentrations of raltegravir. This interaction may not be clinically significant.
- Absorption: Atazanavir absorption is dependent on low gastric pH. Atazanavir dosage should be adjusted when it is administered with medications that alter gastric pH. Guidelines for dosing atazanavir with antacids, H2 receptor antagonists, and proton-pump inhibitors in adults are complex and can be found on the package insert for atazanavir. No information is available on dosing atazanavir in children when the drug is co-administered with medications that alter gastric pH.
- Co-administering cobicistat, a CYP3A4 inhibitor, and medications metabolized by CYP3A4 may increase plasma concentrations of these medications. This may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions) associated with the concomitant medications. Co-administration of cobicistat with atazanavir in combination with CYP3A4 inducers may lead to lower exposure of cobicistat and atazanavir, loss of efficacy of atazanavir, and possible development of resistance.1 Co-administration of cobicistat and atazanavir with some antiretroviral (ARV) agents (e.g., with etravirine, with efavirenz in treatment-experienced patients, with another ARV 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 development of resistance.
- 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 PR interval of electrocardiogram (ECG). Abnormalities in atrioventricular (AV) conduction are generally limited to first-degree AV block, but with rare reports of second-degree AV block. Rash, 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 addition of ritonavir to atazanavir is associated with lipid abnormalities, but to a lesser extent than with other boosted PIs.
- Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, and elevation in serum transaminases. Chronic kidney disease including biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma, nephrolithiasis. Hepatotoxicity (patients with hepatitis B virus or hepatitis C virus infections are at increased risk).
Atazanavir is Food and Drug Administration (FDA)-approved for use in infants (aged >3 months and weighing ≥5 kg), children, and adolescents.
ATV/r has efficacy equivalent to efavirenz-based and lopinavir/ritonavir (LPV/r)-based combination therapy when given in combination with two NRTIs in treatment-naive adults.2-5 In ACTG A5257, ATV/r was compared to darunavir/ritonavir (DRV/r) or raltegravir, each administered with a TDF/emtricitabine backbone. Although all three regimens had equal virologic efficacy, ATV/r was discontinued more frequently than the other regimens due to toxicity, most often hyperbilirubinemia or gastrointestinal complaints.6
P1020 enrolled 195 antiretroviral therapy (ART)-naive and ART-experienced patients with HIV aged 3 months to 21 years. Capsule and powder formulations and boosted and unboosted regimens 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 atazanavir-based treatment at the final recommended dose. Among them, 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
Two open-label clinical trials, PRINCE I and PRINCE II, studied a powder formulation of atazanavir administered once daily and boosted with liquid ritonavir in infants and children aged ≥3 months and weighing ≥5 kg.9,10 One hundred and thirty-four infants and children weighing between 5 kg and 35 kg were evaluated. Using a modified intent-to-treat analysis, overall proportions of ARV-naive and ARV-experienced patients with HIV RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively. The median increase from baseline in absolute CD4 T lymphocyte count (percent) at 48 weeks of therapy was 215 cells/mm3 (6%) in ARV-naive patients and 133 cells/mm3 (4%) in ARV-experienced patients.
Pharmacokinetics and Dosing
The results of the IMPAACT/PACTG 1020A trial in children and adolescents indicate that, in the absence of ritonavir boosting, atazanavir can achieve protocol-defined PK targets—but only when used at higher doses of atazanavir (on a mg/kg body weight or mg/m2 body surface area basis) than doses currently recommended in adults. In IMPAACT/PACTG 1020A, children aged >6 to <13 years required atazanavir dosing of 520 mg/m2 per day of atazanavir capsule formulation to achieve PK targets.8 Unboosted atazanavir at this dose was well tolerated in those aged <13 years who were able to swallow capsules.11 Doses required for older adolescents were greater than the approved dose for adults of atazanavir 400 mg given without ritonavir boosting once daily; adolescents aged >13 years required atazanavir dosing of 620 mg/m2 per day.8 In this study, the AUCs for the unboosted arms were similar to the ATV/r groups but the maximum plasma concentration (Cmax) was higher and the minimum plasma concentration (Cmin) was lower for the unboosted arms. Median doses of atazanavir in mg/m2 both with and without ritonavir boosting from IMPAACT/PACTG 1020A are outlined in the following table. When dosing unboosted atazanavir in pediatric patients, therapeutic drug monitoring is recommended to ensure that adequate atazanavir plasma concentrations have been achieved. A minimum target trough concentration for atazanavir is 150 ng/mL.12 Higher target trough concentrations may be required in PI-experienced patients. IMPAACT P1058, a study of unboosted atazanavir PKs in treatment-experienced children, concluded that once-daily atazanavir 400 mg provided suboptimal exposure and that administering higher unboosted doses or splitting the daily dose into twice-daily doses warranted investigation in treatment-experienced children, adolescents, and young adults.13
|Age Range (Years)||ATV Given with RTV||ATV Median Dose (mg/m2)a||ATV Median Dose (mg*)|
|a Dose satisfied protocol-defined AUC/PK parameters and met all acceptable safety targets. These doses differ from those recommended by the manufacturer. TDM was used to determine patient-specific dosing in this trial.
Key to acronyms: AUC = area under the curve; ATV = atazanavir; PK = pharmacokinetic; RTV = ritonavir; TDM = therapeutic drug monitoring
In the report of the P1020A data, atazanavir satisfied PK criteria at a dose of 205 mg/m2 in pediatric subjects when dosed with ritonavir.14 A study of a model-based approach using atazanavir concentration-time data from 3 adult studies and 1 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 to <18 years:
- 200/100 mg (15 kg to <35 kg)
- 300/100 mg (≥35 kg)
Cobicistat as a Pharmacokinetic Enhancer
A study of 14 adolescents, aged 12 years to 18 years, suggests that cobicistat is a safe and effective PK enhancer when used in combination with atazanavir in adolescent patients.17
The unboosted atazanavir powder cohorts in IMPAACT/ PACTG P1020A were closed based on the inability to achieve target exposures. For the IMPAACT/PACTG P1020A trial, AUC targets were established based on exposures in adults in early studies of unboosted atazanavir. For that study, target AUC range was 30,000 to 90,000 ng*hr/mL. Boosted atazanavir powder cohorts in IMPAACT/PACTG P1020A in children aged 3 months to 2 years, using a dose of 310 mg/m2 daily, achieved average atazanavir exposures that approached but did not meet protocol targets. Variability in exposures was greater, especially among the very young children in this age range.8
Assessment of the PK, safety, tolerability, and virologic response of atazanavir oral powder for FDA approval was based on data from 2 open-label, multicenter clinical trials:
- PRINCE I: In pediatric patients aged 3 months to <6 years9
- PRINCE II: In pediatric patients aged 3 months to <11 years10
One hundred and thirty-four treated patients (weighing 5 kg to <35 kg) from both studies were evaluated. All patients in the PRINCE trials were treated with boosted atazanavir and two NRTIs. Patients weighing 5 kg to <10 kg received either 150 mg or 200 mg atazanavir and 80 mg ritonavir oral solution, 10 kg to <15 kg received 200 mg atazanavir and 80 mg ritonavir oral solution, 15 kg to < 25 kg received 250 mg atazanavir and 80 mg ritonavir oral solution, and 25 kg to <35 kg received 300 mg atazanavir and 100 mg ritonavir oral solution. No new safety concerns were identified in these trials. The FDA label includes the following PK parameters measured in the PRINCE trials, including mean AUC, for the weight ranges that correspond to the recommended doses:
|PK Parameters||PRINCE Triala ATV/r||PRINCE Triala ATV/r||PRINCE Triala ATV/r||PRINCE Triala ATV/r||PRINCE Triala ATV/r||Young Adult Studyb||Adult Studya|
|Dose 150/80 (mg)||Dose 200/80 (mg)||Dose 200/80 (mg)||Dose 250/80 (mg)||Dose 300/100 (mg)|
|Body Weight (kg) 5 to <10||Body Weight (kg) 5 to <10||Body Weight (kg) 10 to <15||Body Weight (kg) 15 to <25||Body Weight (kg) ≥25 to <35|
(CV% or 95% CI)
(CV% or 95% CI)
|a Reyataz package insert.10
b The young adults were also receiving TDF.7
c Means are geometric means.
Key to Acronyms: ATV/r = atazanavir/ritonavir; AUC = area under the curve; CI = confidence interval; CV = coefficient of variation; PK = pharmacokinetic; TDF = tenofovir disoproxil fumarate
While the PK targets were met in these PK studies of atazanavir powder in all but the ATV/r 150/80 mg dose in the 5 kg to <10 kg weight band, there were large coefficients of variation (CV)%, especially in the youngest patients.
Transitioning from Powder to Capsules
For children who reach a weight ≥25 kg while taking the powder, atazanavir 300 mg (6 packets) powder plus ritonavir oral solution 100 mg, both once daily with food, may be used. Atazanavir capsules should be used for children who can swallow pills. Bioavailability was higher for the capsules than for the powder when studied in adults; therefore, a lower mg/kg dose is recommended. Opened capsules have not been studied and should not be used.
Nine percent of patients enrolled in the IMPAACT/PACTG 1020A trial had a bilirubin ≥5.1 times the upper limit of normal.11 Asymptomatic ECG abnormalities were observed in a small number of patients: Grade 3 QTC prolongation in one patient, Grade 2 PR or HR changes in nine patients, and Grade 3 PR prolongations in three patients. No significant changes in serum cholesterol or triglycerides were observed during 48 weeks of therapy in 63 children receiving unboosted atazanavir in combination with two NRTIs.10
- Cobicistat [package insert]. Food and Drug Administration. 2014. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/15247553.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/17971713.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/18722869.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/20032785.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/25285539.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/18025112.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/21610486.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/26066346.
- Atazanavir [package insert]. Food and Drug Administration. 2016. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021567s039,206352s004lbl.pdf#page=25.
- Rutstein RM, Samson P, Fenton T, Fletche CV, Kiser JJ, Mofenson LM, et al. for the PACTG 1020A Study Team. 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;34:162-167. Available at
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 2016. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
- 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.
- 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.
- 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 http://www.ncbi.nlm.nih.gov/pubmed/21930880.
- 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.
- 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.