Johns Hopkins ABX Guide
Atazanavir
INDICATIONS
FDA
- Treatment of HIV infection in combination with other ARVs.
FORMS
brand name | preparation | manufacturer | route | form | dosage^ | cost* |
Reyataz | Atazanavir (ATV) | Bristol-Myers Squibb | oral | capsule | 150 mg; 200 mg; 300 mg | $25.59 per 150 mg or 200 mg cap, $50.69 per 300 mg |
oral | oral powder | 50 mg per packet | $7.90 per packet | |||
Evotaz | Atazanavir/cobicistat (ATV/c) | Bristol-Myers Squibb | oral | tablet | 300 mg (ATV)/150 mg (COBI) | $56.15 per tablet |
*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.
USUAL ADULT DOSING
Pill burden: 1-2 caps/day PO (either ATV 400 mg once-daily [2 pills] OR ATV/r 300/100 mg once-daily [2 pills] OR ATV/c 300/150 mg once daily [1 pill]).
- ATV 400 mg once-daily w/ food (FDA-approved dose for treatment-naive pts).
- ATV/r 300/100 mg once-daily w/ food (FDA-approved dose for treatment-experienced pts, but preferred dose for treatment-naive pts as well).
- ATV/c 300 mg/150 mg once-daily with food.
- Combination specific recommendations:
- ddI + either FTC or 3TC: avoid with unboosted ATV (poor clinical response).
- DRV: ATV 300 mg once-daily + DRV/r 600/100 mg twice-daily.
- DTG:ATV/r 300/100 mg once-daily + DTG 50 mg once-daily (or DTG 50 mg twice daily for INSTI-experienced patients with certain INSTI-associated resistance mutations-see DTGfor list of mutations)
- EFV: ATV/r 400/100 mg once-daily + EFV 600 mg qhs (consider TDM; co-administration not recommended in pts w/ PI resistance). Co-administration with ATV/c not recommended.
- ETR: co-administration not recommended by manufacturer, but clinical significance unclear. Consider ATV/r 300/100 mg once-daily + ETR 200 mg twice-daily with TDM. Co-administration with ATV/c not recommended.
- EVG: ATV/r 300/100 mg once daily + EVG 85 mg once daily
- EVG/cobi/TDF/FTC: co-administration not recommended with other ARVs.
- FPV: insufficient data; avoid or consider TDM (studied regimen FPV 1400 mg once-daily + ATV 400 mg once-daily).
- LPV/r: ATV 300 mg once-daily + LPV/r 400/100 mg twice-daily.
- MVC: ATV/r 300/100 mg once-daily + MVC 150 mg twice-daily. In PI-naive pts, unboosted ATV can also be considered with MVC.
- No dosing recommendation with co-administration of other PIs (IDV, NFV).
- NVP: avoid co-administration.
- RAL: ATV/r 300/100 mg once-daily + RAL 400 mg twice-daily.
- SQV: ATV 400 mg + SQV 1200 mg once-daily (did not perform well in trials) or consider ATV/r 300/100 mg + SQV 1500-2000 mg daily (limited data).
- TDF: ATV/r 300/100 mg once-daily + TDF 300 mg daily.
- TPV: ATV may be significantly decreased. Avoid co-administration.
- Dose in pregnancy: ATV/r 300/100 mg. Use higher doses (ATV/r 400/100 mg) if also taking H2-receptor antagonist or TDF. Do not use ATV/c during second and third trimester if also taking H2-receptor antagonist and/or tenofovir DF.
PEDIATRIC DOSING
USUAL PEDIATRIC DOSING
- Neonates/infants: NOT approved for use due to risks associated with hyperbilirubinemia.
- Pediatrics (≥ 3 months and weight 10 to < 25 kg only): dosing using oral powder (each packet contains 50 mg of ATV)
- 10 to < 15 kg: ATV 200 mg (4 packets) PLUS RTV 80 mg PO once daily
- 15 to < 25 kg: ATV 250 mg (5 packets) PLUS RTV 80 mg PO once daily
- ≥ 25 kg: powder NOT recommended
- Pediatrics (≥ 6 to 18 years): dosing using oral capsules
- < 15 kg: capsules NOT recommended
- 15 to < 20 kg: ATV/r 150/100 mg PO once daily with food
- 20 to < 40 kg: ATV/r 200/100 mg PO once daily with food (note: some experts increase ATV to 300 mg at ≥35kg to avoid under-dosing, especially when co-administered with TDF)
- ≥40 kg: ATV/r 300/100 mg PO once daily with food
- >13 y.o. and > 40 kg who are unable to tolerate RTV: ATV 400 mg once daily
- NOTE: unboosted ATV is NOT recommended in children < 13 years
Acknowledgement: Pediatric dosing information authored by Alice Jenh Hsu Pharm.D. BCPS
PEDIATRIC RENAL DOSING
- No renal dosage adjustment required. Serum concentrations may be lower with HD.
OTHER PEDIATRIC INFORMATION
- 100 mg capsules no longer manufactured, therefore 250mg dose previously recommended for 35 to < 40 kg weight group no longer achievable.
- Some experts would increase ATV to 300 mg at ≥35 kg to avoid under-dosing, especially when co-administered with tenofovir.
- ATV powder should be mixed preferentially with at least one tablespoon of soft food (apple sauce, yogurt); after administration, add one additional tablespoon of soft food to container to feed the residual mixture. ATV can also be mixed with at least 30 mL of a beverage (milk, infant formula, or water); after administration, add additional 15 mL to container to feed residual mixture. If using dosing syringe in younger infants, mix with and draw up 10 mL of liquid; after administration, add additional 10 mL to container and draw up to feed residual mixture.
RENAL DOSING
DOSING FOR GLOMERULAR FILTRATION OF 50-80
No data. Usual dose likely.
DOSING FOR GLOMERULAR FILTRATION OF 10-50
No data. Usual dose likely.
DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN
No data. Usual dose likely.
DOSING IN HEMODIALYSIS
- Serum concentrations may be lower (25-43%) in HD pts.
- Unboosted ATV should be avoided.
- Manufacturer does not recommend ATV/r or ATV/c in treatment experienced patients on HD; however, ATV/r 300/100 mg or ATV/c 300/150 mg once-daily can be considered if no ATV associated mutations.
- Consider TDM.
DOSING IN PERITONEAL DIALYSIS
No data. Unboosted ATV should be avoided; use ATV/r 300/100 mg or ATV/c 300/150 mg once-daily. Consider TDM.
DOSING IN HEMOFILTRATION
No data. Unboosted ATV should be avoided; use ATV/r 300/100 mg or ATV/c 300/150 mg once-daily. Consider TDM.
ADVERSE DRUG REACTIONS
GENERAL
- Adverse effects with ATV/c did not differ significantly in a randomized, double-blind, active-controlled study comparing ATV/r to ATV/c, both in combination with TDF/FTC.
COMMON
- Reversible indirect hyperbilirubinemia, with grade 3-4 (>2.6 x UNL) occurring in 35-47% of pts.
- Clinically benign: does not indicate liver disease and does not require discontinuation.
- Trough >0.85 mcg/mL associated higher incidence of hyperbilirubinemia.
- COBI inhibits tubular secretion of serum creatinine resulting in an early 10-15% reduction in creatine-based estimates of creatinine clearance (e.g. Cockcroft-Gault); does not affect true GFR.
OCCASIONAL
- Jaundice with scleral icterus in up to 7-8% of pts.
- In comparison of ATV vs. ATV/r, grade 2-4 jaundice seen in < 1% on ATV, 3% on ATV/r. Reversible with discontinuation.
- GI side effects: less common than with LPV/r but more common than with DRV/r
- Mild transaminase elevation (unrelated to phase II conjugation UGT 1A1 inhibition)
- Rash
- Headache
- Diabetes, hyperlipidemia: minimal or no effect on lipid profile or insulin resistance. Lipids slightly higher with RTV or COBI boosting.
- Lipodystrophy listed, but unboosted ATV unlikely to cause fat accumulation.
RARE
- Dose dependent QTc and PR interval prolongation.
- Use with caution in pts with baseline altered cardiac conduction and with drugs that can alter cardiac conduction (e.g., diltiazem and clarithromycin; see drug-drug interaction section for dosing recommendation).
- Studies with ATV/r 300/100 mg once-daily showed slight but not significant increases in PR interval averaging 3 msec and no change at 1 month.
- 2nd and 3rd degree AV block and left bundle branch block have been reported.
- Nephrolithiasis secondary to precipitation of ATV (30 cases reported to FDA from Dec 2002- Jan 2007)
- Interstitial nephritis (case report)
- Cholestasis, cholelithiasis, and cholecystitis
- Hepatitis
- Severe rash (Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported). Mention nephrotoxicity per D:A:D study
DRUG INTERACTIONS
- Substrate and inhibitor of CYP3A4.
- Weak inhibitor of CYP1A2 and CYP2C9 in vitro but clinical significance unknown.
- Inhibitor of phase II conjugation (UGT1A1).
- CYP3A4 inhibitors may increase ATV levels.
- CYP3A4 inducers may decrease ATV levels.
- ATV may increase levels of CYP3A4 substrates.
- NRTI levels generally not affected by ATV.
- COBI is a potent inhibitor of CYP3A4 and P-glycoprotein and BCRP drug transporters. Unlike RTV, COBI has weaker activity against 2D6 and no 2C8 inhibitory actiivty. Drug interaction data is limited for COBI given differing effects on CYP enzymes, data from RTV cannot be extrapolated to COBI for all medications. Known differences are noted below.
Drug | Effect of Interaction | Recommendations/Comments |
ABC plasma concentration decreased by 17%. | Unknown mechanisms and clinical implications. | |
Alfuzosin | May significantly increase alfuzolin serum concentrations resulting in hypotension. | Avoid co-administration. |
May increase serum level of alprazolam. | Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, oxazepam, or temazepam). | |
Amiodarone | May significantly increase amiodarone serum level. | Applies to all PIs: Data limited to case report of increased amiodarone levels with IDV co-administration. ATV not recommended to be co-administered with amiodarone. If co-administration can not be avoided, monitor for amiodarone ADR (PFTs, TSH). Consider monitoring serum level of amiodarone, but its long half-life may make titration difficult. |
Amlodipine | May increase serum level of amlodipine. | Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (this led to PR interval prolongation). All PIs have the potential for prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with a low dose and slowly titrated with close monitoring of BP and pulse. |
Antacids | May significantly decrease ATV serum levels. | Avoid co-administration. Separate administration time, ATV 2 hrs before AC or 1 hr after buffered ddI or antacid administration. |
Apixaban | May result in significantly increased apixaban concentrations | Avoid co-administration. Warfarin is preferred oral anticoagulant in patients on PI. Manufacturer of apixaban suggests a dose reduction to 2.5 mg twice daily in select patients on ritonavir (< 80 years, >60 kg and/or SCr < 1.5 mg/dL), however no reversal agents currently available for this novel anticoagulant. Author advises caution with this combination. |
Artemether (artemisinin) | May increase serum level of artemether. | Applies to All PIs: Close monitoring for artemether toxicity (bone marrow suppression, bradycardia and seizure). |
Astemizole | May significantly increase astemizole serum level. | Contraindicated due to potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine. |
Atenolol | Atenolol AUC increased by 25%; Cmin: no significant change. ATV not affected. | No effect on PR or QTc interval with co-administration. Start with low dose atenolol with slow dose titration. |
Atorvastatin | May increase atorvastatin serum concentrations. | Start with atorvastatin 10 mg/d, then titrate to therapeutic effect. |
Azathioprine | Interaction unlikely. | Applies to all PIs and NNRTI: use standard dose. |
Avanafil | May significantly increase avanafil concentrations. | Avoid co-administration. |
BOC AUC and Cmin decreased 5% and 18%, respectively. ATV AUC and Cmin decreased 33% and 49%, respectively. | Avoid co-administration. | |
Bepridil | May significantly increase bepridil serum level. | The manufacturer of ATV does not recommend bepridil co-administration; this contraindication should extend to all PIs since a significant increase in bepridil serum level can result in pro-arrhythmic events such as VT, PVC, and VFib. |
Bosentan | May significantly increase bosentan serum concentrations. | Co-administer bosentan only after RTV or COBI dosing has reached steady-state. In patients on RTV or COBI >10 days: start bosentan at 62.5 mg once daily or every other day. In patients already on bosentan: discontinue bosentan for at least 36 hrs prior to initiation of RTV or COBI-boosted PIs and restart bosentan at 62.5 mg once daily or every other day after RTV or COBI have reached steady-state (after 10 days). |
Budesonide | ATV/r results in increased serum concentrations of budesonide. | Avoid co-administratrion unless benefits of treatment outweight risks of effects of systemic corticosteriods. At least one case report of Cushing’s syndrome in a patient on ATV/r and oral budesonide has been reported. |
Buprenorphine | ATV/r increases AUC of buprenorphine (66%) and its active metabolite norbuprenorphine (105%). Buprenorphine decreases concentrations of ATV. | Do not co-administer unboosted ATV. A dose reduction of buprenorphine may be necessary with ATV/r. Monitor for sedation and cognititive effects. |
Carbamazepine | May decrease serum levels of ATV. RTV decreases carbamazepine levels. | Consider alternative anticonvulsants (e.g., valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider TDM of ATV. Co-administration of unboosted ATV is not recommended. Monitor carbamazepine concentrations with ATV/r or ATV/c. |
Chlordiazepoxide | May increase serum level of chlordiazepoxide. | Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, temazepam, or oxazepam). |
Cisapride | May significantly increase cisapride serum level. | Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide. |
ATV AUC increased by 28%. Clarithromycin AUC increased by 94%. 14-hydroxyclarithromycin metabolite AUC decreased by 70%. | QTc prolongation observed with co-administration. 50% of clarithromycin dose recommended. Consider azithromycin. | |
Clorazepate | May increase serum level of clorazepate. | Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, temazepam, or oxazepam). |
Colchicine | Results in increased concentrations of colchicine. | Co-administration in patients with renal or hepatic impairment is not recommended. Treatment of gout flares: 0.6 mg x 1, followed by 0.3 mg 1 hr later. Do not repeat for 3 days. Prophylaxis of gout flares: decrease dose by 75% (ex. if on 0.6 mg twice daily, give 0.3 mg once daily) |
Cyclophosphamide | May increase serum level of cyclophosphamide. | Applies to all PIs: data limited to an interaction study conducted with IDV resulting in a 50% increase in cyclophosphamide serum level. Since all PIs have potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity recommended. |
Cyclosporine | May significantly increase serum level of cyclosporine. | Applies to all PIs: monitor serum level of cyclosporine closely with co-administration. Cyclosporine dose may need to be decreased. |
Dabigatran | RTV may result in increased dabigatran concentrations. | ATV/r or ATV/c: Use caution in patients with CrCl >50 mL/min. Avoid co-administration in patients with CrCl < 50 mL/min. No interaction expected with ATV. |
ATV/r significantly increases serum concentrations of daclatasvir | With ATV/r or ATV/c, reduce dose to 30 mg daily. | |
No significant interaction | Dose: darunavir 600/100 mg twice-daily plus ATV 300 mg once-daily | |
Dexamethasone | ATV/r may increase dexamethasone concentrations. Dexamethasone may decrease ATV concentrations. | Avoid long term co-administratrion unless benefits of treatment outweight risks of effects of systemic corticosteriods. Dexamethasone may also decrease ATV concentrations. |
Diazepam | May increase levels of diazepam. | Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, oxazepam, or temazepam). |
Didanosine (ddI) (buffered) | No effect on ddI serum level. ATV AUC decreased by 87%, Cmin decreased by 84% (single dose study ATV 400 mg x1 with ddI buffered 200 mg x1). | Administer ATV 400 mg one hr after ddI (buffered) administration. Consider ddI EC. The combination of ddI, FTC, and unboosted ATV did not perform well in a randomized ACTG trial. |
Digoxin | Digoxin AUC may be increased with ATV/r co-administration | Monitoring of digoxin concentration closely. Digoxin dose may need to be reduced. |
Diltiazem | Diltiazem AUC increased by 125%. Desacetyl diltiazem (active metabolite) AUC increased by 165%. ATV not affected. | PR interval prolongation observed. Start with 50% of diltiazem dose and titrate slowly with close monitoring of BP and pulse. |
Disopyramide | May increase disopyramide serum levels. | Applies to all PIs: No data. Monitor disopyramide serum level (target: 2.8 to 7.5 mcg/mL). |
Docetaxel | May increase serum level of docetaxel. | Case reports of severe haematological and cutaneous toxicity when coadministered with RTV. Avoid coadministration with ATV/r if possible. Docetaxel manufacturer recommends 50% dose reduction of docetaxel if co-administration is necessary. |
Dofetilide | May significantly increase serum level of dofetilide. | Applies to all PIs: No data. Use with caution. Monitor QTc closely and adjust dofetilide dosing based on QTc prolongation and renal function. Consider an alternative class III antiarrhythmic such as bretylium or ibutilide. |
Dolutegravir | DTG AUC decreased 62% and 91% with ATV/r and ATV co-administration, respectively. No change in ATV concentrations based on historical control comparison. | Use Standard dose. |
Echinacea | May decrease ATV serum level. Echinacea (400 mg 4xd) decreased CYP3A4 substrate (midazolam) by 23%. | Applies to all PIs and NNRTIs. Clinical significance unknown but should avoided until the safety of this combination is further evaluated. |
ATV AUC decreased by 74%, Cmax decreased by 59%, Cmin decreased by 93%. | Co-administration of ATV as a sole PI with EFV not recommended. Boosting ATV 400 mg + RTV 100 mg daily recommended with co-administration of standard dose of EFV. Avoid co-administration in pts with PI resistance. Co-administration with ATV/c is not recommended. | |
Ergot Alkaloid | May significantly increase serum level of ergotamine resulting in acute ergot toxicity. | Contraindicated. Consider alternative agent for migraine such as sumatriptan (but not eletriptan since it is a CYP3A4 substrate and significant drug-drug interaction occurred with a CYP3A4 inhibitor). |
May increase serum level of estazolam. | Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, temazepam, or oxazepam). | |
Ethinyl estradiol and norethindrone | Norethindrone Cmax: increased 67%; AUC: increased 110%; Cmin: increased 262%; Ethinyl estradiol AUC: increased 48%; Cmax: no significant change; Cmin: increased 91% (with unboosted ATV). | Clinical significance unknown. Dose: with unboosted ATV co-administration, do not exceed EE 30 mcg/d . Monitor for OC adverse drug reaction. With ATV/r co-administration, use at least EE 35 mcg/d. Consider an additional barrier form of contraception. |
Ethosuximide | May increase serum levels of ethosuximide. | Applies to all PIs: consider switching to valproic acid for the treatment of absence seizure. |
Etoposide | May increase serum level of etoposide. | Applies to all PIs: No data. Close monitoring of chemotherapy induced toxicity recommended. |
With unboosted ATV: ETV AUC increased by 50%, but ATV Cmin decreased by 47%. With ATV/r: ETV AUC increased by 30% and ATV AUC and Cmin decreased by 14% and 38%, respectively. | Avoid with unboosted ATV with ETR co-administration. Unclear clinical significance with ATV/r, but the manufacturer recommends avoiding co-administration. Consider ATV/r 300/100 mg once-daily + ETR 200 mg twice-daily with TDM. Co-administration with ATV/c not recommended. | |
Everolimus | Significant increases in everolimus expected | Consider empiric dose reduction and monitor everolimus levels closely. Interaction with ATV/r has not been studied therefore a specific empiric dose reduction cannot be recommended. |
Felodipine | May increase serum level of felodipine. | Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (this led PR interval prolongation). All PIs have potential of prolonging PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with low dose and slowly titrated with close monitoring of BP and pulse. |
Fentanyl | May significantly increase fentanyl serum level. | Use with caution. Consider morphine. |
Flecainide | May increase antiarrhythmic serum level. | Applies to all PIs: Avoid co-administration; if necessary, monitor flecainide trough level with co-administration. Target: 200-1000 ng/mL. Toxicity frequent with trough serum levels above 1000 ng/mL. |
No significant interaction | Use standard dose | |
Flurazepam | May increase serum level of flurazepam. | Applies to All PIs: Consider alternative benzodiazepines (e.g., lorazepam, temazepam, or oxazepam). |
Fluticasone | May significantly increase systemic corticosteroid exposure. | Avoid long-term co-administration. Consider beclomethasone. |
Food (light meal) | ATV AUC increased by 70%. | ATV should be administered with food. |
ATV AUC decreased by 33%. APV AUC increased by 78%. (Dose studied: FPV 1400 mg daily + ATV 400 mg daily) | Insufficient data; clinical significance unknown. Avoid or consider TDM in PI-experienced patients. | |
Garlic supplement | No data. | Studies only done with SQV resulting in SQV serum level reduction. No data with other PIs or NNRTIs. Avoid co-administration. |
Granisetron | May increase serum level of granisetron. | Applies to all PIs: Due to the large therapeutic index of granisetron, potential interaction unlikely to be clinically significant. |
H2 blocker | ATV/r + famotidine: Cmin decreased by 28% (but comparable to ATV/r Cmin when co-administered with TDF) | Avoid co-administration if possible. If ATV/r (300/100 mg) is co-administered with famotidine, the max recommended dose for ARV-naive pts is famotidine 40 mg twice-daily. Max dose for ARV-experienced pts is famotidine 20 mg twice-daily with ATV/r co-administration. Administer ATV 2 hrs before or 10 hrs after H2 blocker is preferred. If co-administered with TDF + famotidine 20 mg twice-daily, increase ATV/r to 400/100 mg once-daily (consider TDM).. |
Heroin (Diamorphine) | Drug interactions unlikely. | Applies to PIs and NNRTIs: Interaction unlikely but illicit drug use should be avoided for obvious reasons. |
Ifosfamide | May increase serum level of ifosfamide. | Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended. Consider changing to non-PI based regimen. |
Irinotecan | May increase irinotecan serum level. | Applies to all PIs: |
CYP3A4 inhibitor and substrate - potential for bidirectional inhibition with increase levels of PIs and itraconazole. | Except for IDV, there are no recommendations for dose adjustment for other PIs or NNRTIs. Doses of itraconazole >200 mg/day is not recommended without TDM. | |
TV unaffected. Ketoconazole not studied. | Standard dose ATV with ketoconazole co-administration. Doses >200 mg with ATV/r not recommended. | |
Ledipasvir/sofosbuvir (LDV/SOF) | May increase serum levels of LDV | No dosage adjustment necessary. Regimens containing RTV, LDV/SOF and TDF may lead to increased concentrations of TDF. Monitor for TDF-toxicity if co-administer. |
Lidocaine | May increase antiarrhythmic serum levels. | Applies to all PIs: No data. Use with caution, monitor lidocaine serum level (target: 1.5 to 6 mcg/mL) with co-administration. |
ATV geometric mean Cmin increased by 45% with LPV/r 400/100 mg twice-daily co-administration (compared to ATV/r 300/100 mg daily). LPV PK comparable to historical data. | Dose: ATV 300 mg daily + LPV/r 400/100 mg twice-daily. | |
Serum levels of lovastatin may be significantly increased. | Contraindicated. Recommended alternatives include pravastatin, rosuvastatin, and fluvastatin (and possibly atorvastatin- start with 10 mg/day). Monitor for adverse effect due to limited clinical data. | |
MVC AUC increased 388% | Dose: ATV/r 300/100 mg once-daily + MVC 150 mg twice-daily. In PI-naive pts, unboosted ATV can also be considered with MVC. | |
Mefloquine | Effect on mefloquine level unclear. May result in decreased RTV levels. | Use with caution. |
No data. | Interaction unlikely but should monitor for sedation with co-administration. | |
Mexiletine | May increase antiarrhythmic serum levels. | Applies to all PIs: No data. Use with caution. Monitor EKG and serum level. Serum levels exceeding 1.5 to 2 mcg/mL have been associated with an increased risk of toxicity. |
May significantly increase midazolam concentrations. | Concurrent administration of oral midazolam is contraindicated. IV midazolam may be considered with close monitoring. Consider alternative benzodiazepines (temazepam, oxazepam, or lorazepam). | |
Milk thistle | No data. | Data limited to an interaction study with milk thistle and IDV. IDV AUC: unchanged; IDV Cmin: decreased by 47% Clinical significance unknown. Unknown effect of the metabolism of other PIs or NNRTIs. Avoid co-administration with PIs and NNRTIs until it can be further evaluated. |
Mirtazapine | May increase serum level of mirtazapine. | Applies to all PIs: Use with caution. Consider an alternative antidepressant (e.g., SSRIs including escitalopram, citalopram, sertraline, or fluoxetine). |
Mycophenolate | Interaction unlikely. | Applies to all PIs and NNRTIs: Use standard dose. |
Nefazodone | May increase serum level of nefazodone. | Applies to all PIs: Use with caution. Consider an alternative antidepressant (e.g., SSRIs including escitalopram, citalopram, sertraline, or fluoxetine). |
Unboosted ATV Cmin was significantly lower with NVP co-administration. | NVP Cmin increased 46% and ATV Cmin decreased 41%. Avoid co-administration. | |
Nifedipine | May increase serum level of nifedipine. | Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (this led to PR interval prolongation). All PIs have potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started at low dose and slowly titrated with close monitoring of BP and pulse. |
Nisoldipine | May increase serum level of nisoldipine. | Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (this led to PR interval prolongation). All PIs have potential of prolonging the PR interval with Ca channel blockers co-administration. Ca channel blockers should be started at low dose and slowly titrated with close monitoring of BP and pulse. |
ATV may increase paclitaxel serum concentrations. | Avoid co-administration with ATV/r or ATV/c. Monitor closely for toxicity if co-administer with unboosted ATV. | |
Paritaprevir/ ritonavir/ombitasvir plus dasabuvir (PrOD) | Serum concentrations of PrOD increased, but no dose adjustment needed | Co-administer with ATV 300 mg. No additional RTV dose needed. Do not co-administer with ATV/c. |
PCP | May significantly increase serum level of PCP. | Applies to all PIs: Avoid PCP use with PIs (and all illicit drug use for obvious reasons). |
Phenobarbital | May decrease serum levels of ATV. | Consider alternative anticonvulsants (e.g., valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider TDM of ATV. Do not co-administer with unboosted ATV. |
Phenytoin | May decrease serum levels of ATV. | Consider alternative anticonvulsants (e.g., valproic acid, lamotrigine, levetiracetam, or topiramate). With co-administration, monitor anticonvulsants level and consider TDM of ATV. Do not co-administer with unboosted ATV. |
Pimozide | May significantly increase pimozide serum level resulting in QTc prolongation. | Contraindicated. Consider alternative: olanzapine. |
Pitavastatin | Pitavastatin AUC increased 31% | Use standard dose. |
ATV AUC increased 2.5-fold. Posaconazole AUC increased 3.7-fold. | Monitor for potential increase in adverse drug reactions. | |
PPI (omeprazole, rabeprazole, esomeprazole, lansoprazole, and pantoprazole) | ATV Cmin decreased by 78%. Cmin decreased by 46% if separated by 12 hours. | Co-administration of PPI and ATV is contraindicated in ARV-experienced pts. In ARV-naive pts, ATV/r (300/100mg) + omeprazole (20 mg (max) separated by 12 hours) may be considered, but not recommended by author. PPI equivalence: omeprazole (Prilosec) 20 mg = rabeprazole (Aciphex) 20 mg ~ esomeprazole (Nexium) 20 mg = lansoprazole (Prevacid) 30 mg = pantoprazole (Protonix) 40 mg |
Propafenone | May increase antiarrhythmic serum levels. | Applies to all PIs: No data. Co-administration should be avoided. Serum levels are not routinely recommended due to the poor correlation with efficacy and toxicity. |
Quetiapine | May increase serum levels of quetiapine | Initiate quetiapine at lowest dose and titrate as needed. Monitor QTc. |
Quinidine | May increase antiarrhythmic serum levels. | Applies to all PIs: No data. Contraindicated with RTV. With all PIs and NNRTIs co-administration, monitor EKG (QTc) and serum level: Target: 2 to 5 mcg/mL. |
RAL AUC increased 41% | Dose: ATV/r 300/100 mg once-daily + RAL 400 mg twice-daily. | |
Ranolazine | May significantly increase ranolazine serum concentrations. | Contraindicated. May increase risk of QTc prolongation. |
Repaglinide | ATV may increase repaglinide serum concentrations. | Monitor blood glucose closely with co-administration. |
ATV/r may increase serum concentrations of rifabutin. | In HIV-negative patients, ATV/r was shown to increase rifabutin AUC by 8-fold. In HIV/TB co-infected patients on ATV/r, rifabutin 150 mg every other day led to trough concentrations lower than the MIC for M. tuberculosis. CDC guidelines/DHHS guidelines now recommend rifabutin 150 mg daily with RTV-boosted protease inhibitors. Monitor for uveitis and neutropenia. | |
Rifampin | ATV may be significantly decreased. | Co-administration with rifampin not recommended. Rifabutin may be safer alternative. Dose: ATV 400 mg daily + rifabutin 150 mg 3x/week. |
Rifapentine | ATV serum levels may be significantly decreased. | Avoid co-administration. Consider using rifabutin. |
ATV AUC increased by 238%, Cmin increased by 1089% (Dose: ATV 300 mg + RTV 100 mg once-daily). | Boosting ATV 300 mg with 100 mg RTV results in better PK profile (doubles total ATV exposure and increases ATV trough by 10-fold), which may be preferred in PI-experienced pts. | |
Rivaroxaban | May significantly increase rivaroxaban serum levels | Avoid co-administration. Warfarin is preferred oral anticoagulant in patients on PI. |
Rosuvastatin AUC increased 213%. | Start with rosuvastatin 5 mg/day and titrate. Do not exceed 10mg/d. Close monitoring recommended due to limited clinical data. | |
Salmeterol | May increase salmeterol serum concentrations. | Avoid co-administration with boosted ATV. Consider formoterol |
SQV AUC increased by 449% (SQV dosed at 1200 mg once-daily with ATV 400 mg once-daily) ATV not measured. | Beneficial PK interactions which allows daily administration of SQV, but combination was inferior to LPV/r. ATV 400 mg + SQV 1200 mg once-daily (did not perform well in trials). Consider ATV 300 mg + RTV 100 mg + SQV 1500-2000 mg once-daily (limited data). | |
Sildenafil | May increase sildenafil serum level. | Applies to all PIs: Use with close monitoring. Do not exceed 25 mg in a 48 hr period. Contraindicated for pulmonary arterial hypertension. |
Simeprevir (SIM) | May significantly increase SIM serum levels. | Co-administration is not recommended. |
May significantly increase simvastatin levels. | Contraindicated. Alternative that may be used include atorvastatin, pravastatin, rosuvastatin, fluvastatin. Monitor for adverse effect due to limited clinical data. | |
Sirolimus | May significantly increase serum level of sirolimus. | Applies to all PIs: Dose sirolimus based on serum level. A significantly reduction of sirolimus dose with co-administration of all PIs is highly likely. |
St. John’s wort | May significantly decrease ATV serum level. | Contraindicated. Studies only done with IDV but St John’s wort may affect the metabolism of other PIs and NNRTIs. Use an alternative (more effective) antidepressant. |
Suvorexant | Increased serum levels of suvorexant expected | Co-administration not recommended. |
Tacrolimus | May significantly increase serum level of tacrolimus. | Applies to all PIs: Dose tacrolimus based on serum level. A significantly reduction of tacrolimus dose with all PIs co-administration is recommended. |
Tadalafil | May increase serum level of tadalafil. | Erectile dysfunction: Start with 5 mg. Do not exceed 10 mg in 72 hrs. Consider sildenafil due to more clinical data and shorter half-life allowing for easier titration. Benign prostatic hyperplasia: Maximum recommended dose is 2.5 mg/day PAH: Start with 20 mg daily in patients on PI-therapy. Can titrate to 40 mg daily based on tolerability. For patients on tadalafil and swithing to PI-therapy, stop tadalfil for >24 hours before PI initiation and restart tadalafil 7 days later at 20 mg once daily. |
Tamoxifen | ATV may increase concentrations of tamoxifen. RTV may decrease serum level of endoxifen (active metabolite). | ATV may lead to increased concentrations of tamoxifen. Monitor for toxicity. ATV/r may result in decreased efficacy of tamoxifen by reducing concentrations of active metabolite, endoxifen, by RTV. Consider alternatives. |
Teniposide | May increase serum level of teniposide. | Applies to all PIs: No data. Close monitoring of teniposide-induced toxicity recommended. |
ATV AUC decreased by 28% (compared to boosted ATV 300 mg/ RTV100 mg), but still significantly (200%) higher than unboosted ATV. TDF not measured. | Interaction unlikely to be significant when ATV is boosted due to high ATV concentrations achieved with additional RTV (100 mg). Avoid use of TDF with unboosted ATV. If co-administered with TDF + famotidine 20 mg twice-daily, increase ATV/r to 400/100 mg) once-daily. | |
Terfenadine | May significantly increase terfenadine serum level. | Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine. |
THC | Applies to PIs and NNRTIs: Interactions are unlikely. | |
Ticagrelor | May significantly increase serum levels of ticagrelor | Avoid co-administration |
ATV may be significantly decreased | Avoid co-administration | |
May increase serum level of trazadone. | Applies to all PIs: Use with caution. Consider alternative antidepressant (e.g., SSRIs including escitalopram, citalopram, sertraline, or fluoxetine). | |
Triazolam | May significantly increase triazolam serum level. | Contraindicated. Consider alternative benzodiazepines (temazepam, oxazepam, or lorazepam). |
Vardenafil | May significantly increase serum level of vardenafil. | Applies to all PIs: Do not exceed vardenafil 2.5 mg in 72 hrs (with RTV) or 2.5 mg in 24 hrs (with other PIs). Consider sildenafil due to more clinical data and less pronounced interaction. |
Verapamil | May increase serum level of verapamil. | Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse. |
Vinblastine | ATV/r increased vinblastine AUC 131% and Cmax 25% | Monitor closely for developement of toxicity (autonomic and peripheral neuropathy and myelosuppression) |
Vincristine | May increase serum level of vincristine. | Monitor closely for developement of toxicity (autonomic and peripheral neuropathy and myelosuppression) |
Vitamin C | No data. | Data limited to interaction study with IDV and vitamin C (1 g/d) resulting in IDV AUC decreased by 14% and Cmin by 32%. Avoid co-administration until more data available. |
May decrease voriconazole AUC. Voriconazole may increase co-administered ATV. | Low dose RTV boosting (200 mg/d) decreased voriconazole AUC by 39%; co-administration should be avoided or should be used with caution. In severe cases of invasive aspergillosis the addition or substitution of voriconazole with ambisome or an echinocandin should be considered. Monitor voriconazole serum concentrations (target Cmin >2mcg/mL). | |
AZT and 3TC AUC unaffected, but AZT trough decreased 30% (intracellular concentrations not measured). ATV not studied. | ||
Zolpidem | May increase serum level of zolpidem | Initiate zolpidem at lowest dose and monitor. |
RESISTANCE
- No resistance seen with failure of ATV/r or ATV/c when used for initial therapy in patients without PI resistance
- I50L: unique primary ATV mutation, selected by unboosted ATV. Results in intermediate resistance to ATV but susceptibility (or hypersusceptibility) to other PIs. Typically followed by A71V (in 40% of pts). Limited data suggest that PI resistance less common with failure of ATV/r as initial PI.
- L10Y/F, I50L, L63P, A71V, N88S, V32I, M46I, I84V, and L89M: 4-5 of the following mutations resulted in >90-fold resistance to ATV in vitro.
- PI mutations (L33F, 82A/F/T/S, 84V/A/C, 90M, 46I/L) and (L10I/F/V, K20R/M/I, L24I, V32I, M36I/L/V, I50L, I54V, L63P, A71V, G73C/S/T/A) ≥4 mutations: decreased potency of ATV (post-hoc analysis of 045 study).
- ATV mutation score: 10F/I/V, 16E, 33F/I/V, 46I/L, 60E, I84V, 85V, and 90M. Response: 0-1 mutation=100%; 2 mutation=80%; 3 mutations=42%; 4 mutations=0%.
PHARMACOLOGY
MECHANISM
Inhibition of HIV protease, which results in nonfunctional, immature and non-infectious virions.
PHARMACOKINETIC PARAMETERS
Absorption
Well absorbed with food.
Metabolism and Excretion
CYP 3A4 substrate and inhibitor. Metabolized to 2 inactive metabolites and excreted primarily via biliary excretion. 13% of ATV and/or its metabolites are excreted in the urine.
Protein Binding
86%
Cmax, Cmin, and AUC
Mean Cmax=3.152 mcg/mL; Cmin=0.273 mcg/mL; AUC = 22.3 mcg hr/mL (ATV 400 mg once-daily at steady-state). Cmin 0.15-0.85 mcg/mL associated with good response.
T1/2
6.5 hrs
Distribution
Highly variable and poor CNS penetration. Poor seminal fluid penetration.
DOSING FOR DECREASED HEPATIC FUNCTION
ATV AUC increased by 45% with mild to moderate hepatic insufficiency. Consider decreasing dose to ATV to 300mg daily, but no clinical data.
PREGNANCY RISK
Category B. No human data. In animal studies, ATV did not result in embryonic or fetal toxicity when given maternally toxic doses. In the Pediatric HIV/AIDS Cohort Study, ATV exposure in the first trimester was associated with an increased risk of birth defects (adjusted OR 1.93), primarily skin and musculoskeletal defects. However, the Antiretroviral Pregnancy Registry reports no increase in birth defects with ATV exposure during the first trimester (prevalence 2.2%).
Can consider increased dose during the second and third trimester for all patients (ATV/r 400/100 mg). Lower plasma concentrations have been observed with standard dosing during the second and third trimester, but no difference in virologic efficacy has been noted. The pharmacokinetics of cobicistat during pregnancy have not been evaluated, therefore ATV/c during pregnancy is not recommended.
BREAST FEEDING COMPATIBILITY
No data.
COMMENTS
- Pro:
- Cons:
- Classified as alternative in DHHS guidelines because of superior efficacy of DRV/r due to better tolerability
- Potential for jaundice or scleral icterus
- Potential for nephrotoxicity, nephrolithiasis
- Potential for cholelithiasis
- Drug interactions with PPIs, H2 blocker, and antacids
- Food requirement.
- RTV or COBI-boosting improves potency, but with slight increase in lipids and jaundice vs. unboosted ATV.
References
- 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):461-71. [PMID:25285539]
Comment: Comparison of RAL, ATV/r and DRV/r with regards to virologic efficacy and tolerability over 96 weeks. ATV/r resulted in higher incidence of tolerability discontinuation than RAL and DRV/r. All three regimens resulted in equivalent rates of virologic suppression. In a composite endpoint of virologic efficacy and tolerability, RAL was found to be superior to ATV/r and DRV/r and DRV/r was found to be superior to ATV/r.
- Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis. 2013;208(1):32-9. [PMID:23532097]
Comment: Comparison of COBI-boosted ATV to RTV-boosted ATV, both in combination with FTC/TDF, in treatment-naive patients. COBI was found to be non-inferior to RTV with comparable rates of virologic suppression (85.2% vs 87.4%, respectively) and tolerability.
- Daar ES, Tierney C, Fischl MA, et al. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154(7):445-56. [PMID:21320923]
Comment: ACTG 5202 randomized ARV-naïve patients to ATV/r (n=463) or EFV (n=465), both with ABC/3TC or TDF/FTC. At 96 wks, virologic response rates were similar between ATV/r and EFV treated patients.
- 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):323-32. [PMID:20032785]
Comment: CASTLE compared ATV/r 300/100 mg daily vs LPV/r 400/100 mg (caps) twice-daily both combined with TDF/FTC in 883 treatment-naive pts. 96-wk results showed comparable rates of VL suppression (74% for ATV/r vs 68% for LPV/r100K; however, lower rate of virologic suppression in LPV/r-treated pts with lower baseline CD4 count (80% with CD4 >200 vs 63% with CD4
- Squires KE, Young B, Dejesus E, et al. Similar efficacy and tolerability of atazanavir compared with atazanavir/ritonavir, each with abacavir/lamivudine after initial suppression with abacavir/lamivudine plus ritonavir-boosted atazanavir in HIV-infected patients. AIDS. 2010;24(13):2019-27. [PMID:20613461]
Comment: ARIES randomized 419 treatment-naive pts who VL ABC/3TC to either continue ATV/r or switch to unboosted ATV plus ABC/3TC. At 48 wks, 86% taking ATV had VL100,000. Hyperbilirubinemia, cholesterol, and TG elevation lower in pts who switched to ATV.
- Cohen C, Nieto-Cisneros L, Zala C, et al. Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin. 2005;21(10):1683-92. [PMID:16238909]
Comment: Phase III trial that compared ATV (400 mg once-daily) with LPV/r (400/100 mg twice-daily), each in combination with 2 NRTIs, in 300 treatment-experienced pts with virologic failure following a single PI-based regimen. At 24 wks LPV/r showed a better virologic response: 75% vs 54% with VL<400 and 50% vs 34% with VL<50. Unboosted ATV is inferior to LPV/r and should not be used in PI-experienced pts.
- Johnson M, Grinsztejn B, Rodriguez C, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS. 2005;19(7):685-94. [PMID:15821394]
Comment: 358 pts who had failed at least 2 HAART regimens containing at least 1 PI, NNRTI, and NRTI randomized to ATV/ RTV300/100 mg once-daily, ATV/ SQV400/1200 mg once-daily, or LPV/r400 mg100 mg twice-daily each combined with TDF plus 1 NRTI. At 48 wks, 58% vs 56% achieved VL <400 in LPV/r and ATV/ RTV arm, respectively. Trend favoring LPV/r, with 46% vs 38% achieving VL endpoint of <50, but not statistically significant. ATV/ SQV arm did not perform as well as other 2 groups. Note that not all pts in this trial were heavily PI-experienced. Only 33% of the ATV/ RTV arm and 37% of the LPV/r arm had >4 PI mutations (10, 20, 24, 32, 33, 36, 46, 50, 54, 63, 71, 73, 82, 84, 90). In a post-hoc analysis of these pts with >4 PI mutations at baseline, LPV/r regimen demonstrated greater decline in VL compared to the ATV/ RTV arm (1.47 log and 1.38, respectively). The limitation of this genotypic analysis is that the percent of critical PI mutation (i.e 32, 33, 54, 82, 84, and 90) in each group is not known. In addition, only 1/3 of pts were on a PI-containing regimen at the time of the genotype analysis. The post-hoc analysis of the more heavily PI-experienced pts was under powered to show difference between 2 groups. For the mean time it is safe to say that boosted-ATV is non-inferior to LPV/r in moderately PI-experienced pts, and these data can probably be extrapolated to PI-naive pts as well.
- Wood R, Phanuphak P, Cahn P, et al. Long-term efficacy and safety of atazanavir with stavudine and lamivudine in patients previously treated with nelfinavir or atazanavir. J Acquir Immune Defic Syndr. 2004;36(2):684-92. [PMID:15167287]
Comment: Switch study in which NFV recipients in BMS 008 (ATV vs. NFV) were offered ATV at 72 wks. The 63 participants who selected switch option showed sustained antiviral effect and a significantly better lipid profile with mean decreases in total and LDL cholesterol at 24 wks of 31 mg/dL and 33 mg/dL, respectively. Of the total 346 pts who received ATV, only 2% discontinued due to adverse events (with avg. follow-up of 108 wks).
- 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):1011-9. [PMID:15247553]
Comment: BMS 034, which compared EFV and ATV each with ZDV and 3TC. Results at 48 wks showed comparable outcomes (VL <50in 37% of EFV pts and 32% of ATV pts). Low % achieving VL<50 at 48 wks in both arms inconsistent with results from other EFV trials and felt to be due preservative used in specimens submitted for VL determination.
- Haas DW, Zala C, Schrader S, et al. Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS. 2003;17(9):1339-49. [PMID:12799555]
Comment: Compared ATV/ SQV (400/1200 mg once-daily), ATV/ SQV (600/1200 mg once-daily) and SQV/ RTV (400/400 mg twice-daily), each with 2 NRTIs in pts with virologic failure on PI-based HAART regimens. At 48 wks, comparable efficacy across groups with mean VLL decreases of 1.44, 1.19 and 1.66 logs (p = NS). VL <400 achieved in 41, 29 and 35% (p = NS), respectively. Pts receiving ATV had significantly better post-therapy lipid profiles and fewer GI side effects. Obvious limitation of this trial is the comparison to a PI combination ( SQV400/ RTV400 mg twice-daily) that is no longer routinely used.
- Malan DR, Krantz E, David N, et al. 96-week efficacy and safety of atazanavir, with and without ritonavir, in a HAART regimen in treatment-naive patients. J Int Assoc Physicians AIDS Care (Chic Ill). 2010;9(1):34-42. [PMID:20071596]
Comment: 200 ARV-naive pts randomized to ATV/r 300/100 mg (n=95) or ATV 400 mg (n=105), both in combination with 3TC and d4T XR, all daily. At 96-wks, response rates comparable between ATV/r and ATV (75% and 70% had VL <50 by ITT analysis, respectively). However, study not powered to determine non-inferiority of ATV vs. ATV/r, and there were numerically more virologic failures in ATV arm, with more apparent PI and NRTI resistance. Jaundice more common in ATV/r arm, and lipids somewhat higher, though few pts required lipid-lowering therapy.
- Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed (04/23/14) [pages O-62 to O-66]Comment: DHHS guideline dosing recommendations for atazanavir in pediatric patients.
