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: April 16, 2019; Last Reviewed: April 16, 2019
|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
Capsules: 150 mg, 200 mg, 300 mg
Fixed-Dose Combination Tablets:
|Dosing Recommendations||Selected Adverse Events|
For Treatment-Naive Children and Adolescents Who Do Not Tolerate Ritonavir:
Child and Adolescent Dose:
|a mg/kg dosing is higher for the powder packets than for the capsules. In P1020A, children of similar age and size taking atazanavir powder had lower exposures compared with those taking atazanavir capsules.
b Children who weigh ≥25 kg and who cannot swallow atazanavir capsules may receive atazanavir 300 mg (six packets) oral powder plus ritonavir 100 mg oral solution, both administered once daily with food.
c Either ritonavir capsules or ritonavir oral solution can be used.
d Adult patients who cannot swallow capsules may take atazanavir oral powder once daily with food at the same adult dose as the capsules, along with ritonavir.
e See the 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 P450 (CYP) 3A4 enzyme system and has significant interactions with drugs that are 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 glucuronyl transferase (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. The effect of tenofovir alafenamide (TAF) on unboosted atazanavir is unknown; thus, only ATV/r should be used with TAF.
- Non-nucleoside reverse transcriptase inhibitors: Efavirenz, etravirine, and nevirapine decrease atazanavir plasma concentrations significantly. Nevirapine and etravirine should not be coadministered to patients who are receiving atazanavir (with or without ritonavir). Efavirenz should not be coadministered with atazanavir in antiretroviral therapy (ART)-experienced patients, but this drug may be used in combination with ritonavir-boosted atazanavir 400 mg in ART-naive adults. Although ATV/r should be taken with food, efavirenz should be taken on an empty stomach, preferably at bedtime.
- 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. The dosage for atazanavir should be adjusted when it is administered with medications that alter gastric pH. Guidelines for the appropriate doses of atazanavir to use 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 the appropriate doses of atazanavir to use in children when the drug is coadministered with medications that alter gastric pH.
- Coadministering cobicistat, 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 cobicistat, atazanavir, and CYP3A4 inducers may lead to lower exposures of cobicistat and atazanavir, a loss of efficacy of atazanavir, and possible development of resistance.1 Coadministering cobicistat and atazanavir with some antiretroviral (ARV) agents (e.g., with etravirine, with efavirenz in ART-experienced patients, or 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 the 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 the PR interval. Abnormalities in atrioventricular (AV) conduction are generally limited to first-degree AV block, but there have been 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 that were associated with the deposition of atazanavir 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).
Atazanavir is approved by the Food and Drug Administration (FDA) for use in infants (aged ≥3 months and weighing ≥5 kg), children, and adolescents.
Studies in treatment-naive adults have shown that ATV/r is as effective as efavirenz and lopinavir/ritonavir (LPV/r) when these drugs are administered with two NRTIs.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 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 in infants and children, PRINCE I and PRINCE II, studied a powder formulation of atazanavir that was administered once daily and boosted with liquid ritonavir.9-11 One hundred and thirty-four 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 ARV-experienced patients (50%) had HIV RNA <50 copies/mL at Week 48.The median increase from baseline in absolute CD4 T lymphocyte 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
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 (on a mg/kg body weight or mg/m2 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 520 mg/m2 per day of the 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.12 The approved dose of atazanavir for adults is 400 mg once daily without ritonavir boosting; however, adolescents aged >13 years required a dose of atazanavir 620 mg/m2 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 (Cmax) was higher and the minimum plasma concentration (Cmin) was lower in the unboosted arms. Median doses of atazanavir, both with and without ritonavir boosting, from IMPAACT/PACTG 1020A are outlined in the table below. When administering unboosted atazanavir to 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.13 Higher target trough concentrations may be required in PI-experienced patients. IMPAACT P1058, a study of unboosted atazanavir PKs in ART-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 ART-experienced children, adolescents, and young adults.14
|Age Range||ATV Given with RTV||ATV Median Dose (mg/m2)a||ATV Median Dose (mg)|
|a These doses 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.
Source: Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):1489-96.
Key to Acronyms: AUC = area under the curve; ATV = atazanavir; PK = pharmacokinetic; RTV = ritonavir; TDM = therapeutic drug monitoring
In the report of the IMPAACT/ PACTG P1020A data, atazanavir satisfied PK criteria at a dose of 205 mg/m2 in pediatric subjects when administered with ritonavir.15 A study of a model-based approach that used atazanavir concentration-time data from three adult studies and one pediatric study (P1020A),16 along with subsequent additional adjusted modeling,17 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
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.18
The unboosted atazanavir 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 to 90,000 ng*hr/mL) were established based on exposures in adults in early studies of unboosted atazanavir. In IMPAACT/PACTG P1020A, children aged 3 months to 2 years who were in the boosted atazanavir powder cohorts and who received a daily dose of atazanavir 310 mg/m2 achieved average atazanavir exposures that approached, but did not meet, protocol targets. Variability in exposures was high, especially among the very young children in this age range.8
Assessment of the PKs, safety, tolerability, and virologic response of atazanavir oral powder for FDA approval was based on data from two open-label, multicenter clinical trials:
- PRINCE I, which enrolled pediatric patients aged 3 months to <6 years;9 and
- PRINCE II, which enrolled pediatric patients aged 3 months to <11 years.10
One hundred and thirty-four 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 atazanavir and two NRTIs. Children received an oral solution that contained atazanavir and ritonavir. Doses were assigned according to the child’s weight:
- Weighing 5 kg to <10 kg: Atazanavir 150 mg or atazanavir 200 mg and ritonavir 80 mg
- Weighing 10 kg to <15 kg: Atazanavir 200 mg and ritonavir 80 mg
- Weighing 15 kg to <25 kg: Atazanavir 250 mg and ritonavir 80 mg
- Weighing 25 kg to <35 kg: Atazanavir 300 mg and ritonavir 100 mg
No new safety concerns were identified during these trials. The FDA label includes the following PK parameters that were measured during the PRINCE trials, including mean AUC, for the weight ranges that correspond to the recommended doses:
Table B. Pharmacokinetic Parameters for Atazanavir Powder in Children (PRINCE I and II)a versus Capsules in Young Adultsa and Adultsb
|PK Parameters||PRINCE Trialb ATV/r
Dose: 150 mg/80 mg
Weighing: 5 kg to <10 kg
|PRINCE Trialb ATV/r
Dose: 200 mg/80 mg
Weighing: 5 kg to <10 kg
|PRINCE Trialb ATV/r
Dose: 200 mg/80 mg
Weighing: 10 kg to <15 kg
|PRINCE Trialb ATV/r
Dose: 250 mg/80 mg
Weighing: 15 kg to <25 kg
|PRINCE Trialb ATV/r
Dose: 300 mg/100 mg
Weighing: ≥25 kg to <35 kg
|Young Adult Studya||Adult Studyb|
Meanc (CV% or 95% CI) [N]
|32,503 (61%) ||39,519 (54%) ||50,305 (67%) ||55,525 (46%) ||44,329 (63%) ||35,971 (30,853–41,898) ||46,073 (66%) |
Meanc (CV% or 95% CI) [N]
|336 (76%) ||550 (60%) ||572 (111%) ||678 (69%) ||468 (104%) ||578 (474–704) ||636 (97%) |
|a The young adults were also receiving TDF.7
b This information comes from the Reyataz package insert.10
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 patients except those who received ATV/r 150 mg/80 mg in the 5 kg to <10 kg weight band, there were large coefficients of variation, especially among the youngest patients.
Transitioning from Powder to Capsules
For children who reach a weight ≥25 kg while taking the powder, atazanavir 300 mg powder (six packets) plus ritonavir 100 mg oral solution, both administered once daily with food, may be used. Atazanavir 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.
Nine percent of patients enrolled in the IMPAACT/PACTG 1020A trial had a bilirubin ≥5.1 times the upper limit of normal.12 Nine percent 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 due to 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 study, and all were asymptomatic.
- Cobicistat [package insert]. Food and Drug Administration. 2018. 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. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021567s042,206352s007lbl.pdf.
- 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.
- 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;34:162-167.
- 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.
- 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.