Atazanavir

Paul G. Auwaerter, M.D., Janessa M. Smith, Pharm.D., BCPS

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

200 mg

300 mg

$29.27 per cap

$57.98 per cap

oral

oral powder

50 mg per packet

$9.04 per packet

Atazanavir (ATV)

generic

oral

capsule

150 mg

200 mg

300 mg

$25.05-27.80 per cap

$25.05-27.80 per cap

$50.09-55.08 per cap

Evotaz

Atazanavir/cobicistat

(ATV/c)

Bristol-Myers Squibb

oral

tablet

300 mg (ATV)/150 mg (COBI)

$64.22 per tablet

*Prices represent the specified cost per unit and the "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • Important: boosted atazanavir + abacavir and lamivudine should not be used in patients with pre-ART HIV RNA ≥100,000 copies/mL (HHS Guidelines, 2022).
    • Drug should be taken with food to enhance absorption.
    • Capsules and power are not interchangeable.
    • ATV may be less well absorbed in non-acidic gastric environments.
  • ART-naive, unable to tolerate ritonavir (not a recommended regimen by the HIV Guideline panel)
    • ATV 400 mg once-daily w/ food (FDA-approved dose for treatment-naive pts).
    • Consider ATV/r 300/100 mg once daily due to superior PK.
    • ATV 400 mg daily (without RTV) is not recommended with TDF, EFV, ddI, and NVP co-administration.
  • ART-naive and ART-experienced
    • ATV/r 300/100 mg once-daily w/ food (FDA-approved dose for treatment-experienced pts, but preferred dose for treatment-naive pts).
  • Atazanavir/cobicistat:
    • ATV/c 300 mg/150 mg once daily with food.

ADULT RENAL DOSING

DOSING IN HEMODIALYSIS

  • Serum concentrations may be lower (25-43%) in HD pts.
  • Unboosted ATV should be avoided.
  • The manufacturer does not recommend ATV/r or ATV/c in treating experienced patients on HD; however, ATV/r 300/100 mg or ATV/c 300/150 mg once daily can be considered if there are 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 RENAL REPLACEMENT THERAPY

  • No data. Unboosted ATV should be avoided; use ATV/r 300/100 mg or ATV/c 300/150 mg once daily. Consider TDM.

Other Adult Renal Dosing

  • GFR < 10 - 80 ml/min: No data. The usual dose is likely.

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

Important:

  • ATV oral powder should be mixed, e.g., 1 tablespoon of soft food (e.g., applesauce, yogurt).
    • Oral powder mixed with a beverage (at least 30 mL of milk or water) may be used for older infants who can drink from a cup.
    • For young infants (< 6 months) who cannot eat solid food or drink from a cup, the oral powder should be mixed with at least 10 mL of infant formula and administered using an oral dosing syringe.
  • Administer RTV immediately following powder administration.
  • Administer the entire dose of oral powder within 1 hour of preparation.
  • 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)
    • 5 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 < 35 kg: ATV/r 200/100 mg PO once daily with food
    • >35 kg: ATV/r 300/100 mg PO once daily with food
    • NOTE: unboosted ATV is NOT recommended in children < 13 years

PEDIATRIC RENAL DOSING

  • No renal dosage adjustment is required. Serum concentrations may be lower with HD.

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, combined 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 is 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); it does not affect true GFR.

OCCASIONAL

  • Jaundice with scleral icterus in up to 7-8% of pts.
    • In comparing ATV vs. ATV/r, grade 2-4, jaundice was seen in < 1% on ATV and 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 are slightly higher with RTV or COBI boosting.
  • Lipodystrophy is listed, but unboosted ATV is unlikely to cause fat accumulation.

RARE

  • Dose-dependent QTc and PR interval prolongation.
    • Use caution in patients with baseline altered cardiac conduction and drugs that can alter cardiac conduction (e.g., diltiazem and clarithromycin; see drug-drug interaction section for the dosing recommendation).
    • Studies with ATV/r 300/100 mg once-daily showed slight but insignificant increases in PR interval averaging 3 msec and no change at 1 month.
    • Second- and third-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).

DRUG INTERACTIONS

Use a drug interaction checker, as the list below is not all-inclusive.

  • 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 are 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 activity. 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-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

Abacavir

ABC plasma concentration decreased by 17%.

Unknown mechanisms and clinical implications.

Alfuzosin

It may significantly increase alfuzosin serum concentrations resulting in hypotension.

Avoid co-administration.

Alprazolam

It may increase the serum level of alprazolam.

Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, oxazepam, or temazepam).

Amiodarone

It may significantly increase amiodarone serum levels.

Applies to all PIs: Data limited to case reports of increased amiodarone levels with IDV co-administration. ATV is not recommended to be co-administered with amiodarone. If co-administration can not be avoided, monitor for amiodarone ADR (PFTs, TSH). Consider monitoring the serum level of amiodarone, but its long half-life may make titration difficult.

Amlodipine

It may increase the serum level of amlodipine.

Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem resulted in a doubling of diltiazem serum level (this led to PR interval prolongation). All PIs can potentially prolong 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

It 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

This may result in significantly increased apixaban concentrations.

Avoid co-administration. Warfarin is the preferred oral anticoagulant in patients with PI. The 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 are currently available for this novel anticoagulant. The author advises caution with this combination.

Artemether (artemisinin)

It may increase the serum level of artemether.

Applies to All PIs: Close monitoring for artemether toxicity (bone marrow suppression, bradycardia and seizure).

Astemizole

It may significantly increase the astemizole serum level.

Contraindicated due to potential for cardiac arrhythmias. Recommended alternative antihistamines: loratadine, fexofenadine, desloratadine, or cetirizine.

Atenolol

Atenolol AUC increased by 25%; Cmin: no significant change. ATV is not affected.

No effect on PR or QTc interval with co-administration. Start with low-dose atenolol with slow-dose titration.

Atorvastatin

It may increase atorvastatin serum concentrations.

Start with atorvastatin 10 mg/d, then titrate to therapeutic effect.

Azathioprine

Interaction is unlikely.

Applies to all PIs and NNRTI: use a standard dose.

Avanafil

It may significantly increase avanafil concentrations.

Avoid co-administration.

Boceprevir

BOC AUC and Cmin decreased by 5% and 18%, respectively.

ATV AUC and Cmin decreased by 33% and 49%, respectively.

Avoid co-administration.

Bepridil

It may significantly increase bepridil serum levels.

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

It may significantly increase bosentan serum concentrations.

Co-administer bosentan only after RTV or COBI dosing has reached a 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 before 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-administration unless the benefits of treatment outweigh the risks of the effects of systemic corticosteroids. 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 the 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 cognitive effects.

Carbamazepine

It 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

It may increase the serum level of chlordiazepoxide.

Applies to all PIs: Consider alternative benzodiazepines (e.g., lorazepam, temazepam, or oxazepam).

Cisapride

It may significantly increase cisapride serum levels.

Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.

Clarithromycin

ATV AUC increased by 28%. Clarithromycin AUC increased by 94%. 14-hydroxy clarithromycin metabolite AUC decreased by 70%.

QTc prolongation was observed with co-administration. 50% of clarithromycin dose recommended. Consider azithromycin.

Clorazepate

It may increase the 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

It may increase the 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 the potential to increase cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.

Cyclosporine

It may significantly increase the 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 is expected with ATV.

Daclatasvir

ATV/r significantly increases serum concentrations of daclatasvir

With ATV/r or ATV/c, reduce the dose to 30 mg daily.

Darunavir

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-administration unless the benefits of treatment outweigh the risks of the effects of systemic corticosteroids. Dexamethasone may also decrease ATV concentrations.

Diazepam

It 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%, and 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 is not affected.

PR interval prolongation observed. Start with 50% of the diltiazem dose and titrate slowly, closely monitoring BP and pulse.

Disopyramide

It may increase disopyramide serum levels.

Applies to all PIs: No data. Monitor disopyramide serum level (target: 2.8 to 7.5 mcg/mL).

Docetaxel

It may increase the serum level of docetaxel.

Case reports of severe hematological and cutaneous toxicity when coadministered with RTV. Avoid coadministration with ATV/r if possible. Docetaxel manufacturer recommends a 50% dose reduction if co-administration is necessary.

Dofetilide

It may significantly increase the 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 by 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

It may decrease ATV serum levels. Echinacea (400 mg 4xd) decreased the CYP3A4 substrate (midazolam) by 23%.

Applies to all PIs and NNRTIs. Clinical significance is unknown but should be avoided until this combination’s safety is further evaluated.

Efavirenz (EFV)

ATV AUC decreased by 74%, Cmax by 59%, and Cmin by 93%.

Co-administration of ATV as a sole PI with EFV is not recommended. Boosting ATV 400 mg + RTV 100 mg daily is recommended with co-administration of a standard dose of EFV. Avoid co-administration in pts with PI resistance. Co-administration with ATV/c is not recommended.

Ergot alkaloid

It may significantly increase the serum level of ergotamine resulting in acute ergot toxicity.

Contraindicated. Consider alternative agents for migraine such as sumatriptan (but not eletriptan since it is a CYP3A4 substrate and significant drug-drug interaction occurred with a CYP3A4 inhibitor).

Estazolam

It may increase the 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 is 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

It may increase serum levels of ethosuximide.

Applies to all PIs: consider switching to valproic acid to treat absence seizure.

Etoposide

It may increase the serum level of etoposide.

Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity is recommended.

Etravirine

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 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 is not recommended.

Everolimus

Significant increases in everolimus are 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

It may increase the serum level of felodipine.

Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem resulted in a doubling of diltiazem serum level (this led to PR interval prolongation). All PIs can potentially prolong 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.

Fentanyl

It may significantly increase fentanyl serum levels.

Use with caution. Consider morphine.

Flecainide

It may increase antiarrhythmic serum levels.

Applies to all PIs: Avoid co-administration; if necessary, monitor flecainide trough level with co-administration. Target: 200-1000 ng/mL. Toxicity is frequent with trough serum levels above 1000 ng/mL.

Fluconazole

No significant interaction

Use standard dose

Flurazepam

It may increase the 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.

Fosamprenavir

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 resulted in SQV serum level reduction—no data with other PIs or NNRTIs. Avoid co-administration.

Granisetron

It may increase the serum level of granisetron.

Applies to all PIs: Due to the large therapeutic index of granisetron, potential interaction is 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. The 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 are unlikely.

Applies to PIs and NNRTIs: Interaction is unlikely, but illicit drug use should be avoided for obvious reasons.

Ifosfamide

It may increase the serum level of ifosfamide.

Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity is recommended. Consider changing to non-PI-based regimen.

Irinotecan

It may increase irinotecan serum levels.

Applies to all PIs:
Co-administration of ATV is contraindicated by the manufacturer.

Itraconazole

CYP3A4 inhibitor and substrate - potential for bidirectional inhibition with increased 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.

Ketoconazole

Ketoconazole not studied.

Standard dose ATV with ketoconazole co-administration. Doses >200 mg with ATV/r are not recommended.

Ledipasvir/sofosbuvir

(LDV/SOF)

May increase serum levels of LDV

No dosage adjustment is necessary. Regimens containing RTV, LDV/SOF and TDF may lead to increased concentrations of TDF. Monitor for TDF toxicity if co-administer.

Lidocaine

It 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.

Lopinavir/ ritonavir (LPV/r)

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 is comparable to historical data.

Dose: ATV 300 mg daily + LPV/r 400/100 mg twice daily.

Lovastatin

Serum levels of lovastatin may be significantly increased.

Contraindicated. Recommended alternatives include pravastatin, rosuvastatin, fluvastatin (and possibly atorvastatin- starting with 10 mg/day). Monitor for adverse effects due to limited clinical data.

Maraviroc

MVC AUC increased by 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. This may result in decreased RTV levels.

Use with caution.

Methadone

No data.

Interaction is unlikely but should monitor for sedation with co-administration.

Mexiletine

It may increase antiarrhythmic serum levels.

Applies to all PIs: No data. Use with caution. Monitor EKG and serum levels. Serum levels exceeding 1.5 to 2 mcg/mL have been associated with an increased risk of toxicity.

Midazolam

It 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 is 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

It may increase the 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 is unlikely.

Applies to all PIs and NNRTIs: Use standard dose.

Nefazodone

It may increase the serum level of nefazodone.

Applies to all PIs: Use with caution. Consider an alternative antidepressant (e.g., SSRIs including escitalopram, citalopram, sertraline, or fluoxetine).

Nevirapine (NVP)

Unboosted ATV Cmin was significantly lower with NVP co-administration.

NVP Cmin increased by 46%, and ATV Cmin decreased by 41%. Avoid co-administration.

Nifedipine

It may increase the serum level of nifedipine.

Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem resulted in a doubling of diltiazem serum level (this led to PR interval prolongation). All PIs can potentially prolong the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started at a low dose and slowly titrated with close monitoring of BP and pulse.

Nisoldipine

It may increase the serum level of nisoldipine.

Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem resulted in a doubling of diltiazem serum level (this led to PR interval prolongation). All PIs can potentially prolong the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started at a low dose and slowly titrated with close monitoring of BP and pulse.

Paclitaxel

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 is needed.

Co-administer with ATV 300 mg. No additional RTV dose is needed. Do not co-administer with ATV/c.

PCP

It may significantly increase the serum level of PCP.

Applies to all PIs: Avoid PCP use with PIs (and all illicit drug use for obvious reasons).

Phenobarbital

It 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

It 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

It may significantly increase pimozide serum level resulting in QTc prolongation.

Contraindicated. Consider alternative: olanzapine.

Pitavastatin

Pitavastatin AUC increased by 31%

Use standard dose.

Posaconazole

ATV AUC increased 2.5-fold. Posaconazole AUC increased 3.7-fold.

Monitor for the 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 the author. PPI equivalence: omeprazole (Prilosec) 20 mg = rabeprazole (Aciphex) 20 mg ~ esomeprazole (Nexium) 20 mg = lansoprazole (Prevacid) 30 mg = pantoprazole (Protonix) 40 mg

Propafenone

It 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 between efficacy and toxicity.

Quetiapine

It may increase serum levels of quetiapine

Initiate quetiapine at the lowest dose and titrate as needed. Monitor QTc.

Quinidine

It 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.

Raltegravir

RAL AUC increased by 41%

Dose: ATV/r 300/100 mg once daily + RAL 400 mg twice daily.

Ranolazine

It may significantly increase ranolazine serum concentrations.

Contraindicated. It may increase the risk of QTc prolongation.

Repaglinide

ATV may increase repaglinide serum concentrations.

Monitor blood glucose closely with co-administration.

Rifabutin

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 is not recommended. Rifabutin may be a 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.

Ritonavir(RTV)

ATV AUC increased by 238%, and Cmin increased by 1089% (Dose: ATV 300 mg + RTV 100 mg once daily).

Boosting ATV 300 mg with 100 mg RTV results in a 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 the preferred oral anticoagulant in patients with PI.

Rosuvastatin

Rosuvastatin AUC increased by 213%.

Start with rosuvastatin 5 mg/day and titrate. Do not exceed 10mg/d—close monitoring is recommended due to limited clinical data.

Salmeterol

It may increase salmeterol serum concentrations.

Avoid co-administration with boosted ATV. Consider formoterol

Saquinavir(SQV)

SQV AUC increased by 449% (SQV dosed at 1200 mg once daily with ATV 400 mg once daily). ATV not measured.

Beneficial PK interactions allow daily administration of SQV, but the 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)

It may significantly increase SIM serum levels.

Co-administration is not recommended.

Simvastatin

It may significantly increase simvastatin levels.

Contraindicated. Alternatives that may be used include atorvastatin, pravastatin, rosuvastatin, and fluvastatin. Monitor for adverse effects due to limited clinical data.

Sirolimus

It may significantly increase the serum level of sirolimus.

Applies to all PIs: Dose sirolimus based on serum level. A significant reduction of sirolimus dose with co-administration of all PIs is highly likely.

St. John’s wort

It may significantly decrease ATV serum levels.

Contraindicated. Studies have only been 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 is not recommended.

Tacrolimus

It may significantly increase the serum level of tacrolimus.

Applies to all PIs: Dose tacrolimus based on serum level. A significant reduction of tacrolimus dose with all PIs co-administration is recommended.

Tadalafil

It may increase the 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: The 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 switching to PI therapy, stop tadalafil 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 the serum level of endoxifen (active metabolite).

ATV may lead to increased concentrations of tamoxifen. Monitor for toxicity. ATV/r may decrease tamoxifen’s efficacy by reducing concentrations of the active metabolite, endoxifen, by RTV. Consider alternatives.

Teniposide

It may increase the serum level of teniposide.

Applies to all PIs: No data. Close monitoring of teniposide-induced toxicity is recommended.

Tenofovir (TDF)

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 is unlikely to be significant when ATV is boosted due to high ATV concentrations achieved with additional RTV (100 mg). Avoid the 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

It may significantly increase terfenadine serum levels.

Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamines: loratadine, fexofenadine, desloratadine, or cetirizine.

THC

Based on data with NFV and IDV, interactions are unlikely.

Applies to PIs and NNRTIs: Interactions are unlikely.

Ticagrelor

It may significantly increase serum levels of ticagrelor

Avoid co-administration

Tipranavir

ATV may be significantly decreased

Avoid co-administration

Trazadone

It may increase the serum level of trazodone.

Applies to all PIs: Use with caution. Consider alternative antidepressants (e.g., SSRIs including escitalopram, citalopram, sertraline, or fluoxetine).

Triazolam

It may significantly increase triazolam serum levels.

Contraindicated. Consider alternative benzodiazepines (temazepam, oxazepam, or lorazepam).

Vardenafil

It may significantly increase the 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

It may increase the serum level of verapamil.

Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem resulted in a doubling of diltiazem serum level (this led to PR interval prolongation). All PIs can potentially prolong 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 the development of toxicity (autonomic and peripheral neuropathy and myelosuppression)

Vincristine

It may increase the serum level of vincristine.

Monitor closely for the development 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 is available.

Voriconazole

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 used cautiously. In severe cases of invasive aspergillosis, adding or substituting voriconazole with liposomal amphotericin should be considered. Monitor voriconazole serum concentrations (target Cmin >2mcg/mL).

Zidovudine (AZT) /Lamivudine (3TC)

AZT and 3TC AUC were unaffected, but AZT trough decreased by 30% (intracellular concentrations not measured). ATV not studied.

Standard dose AZT/ 3TC with ATV.

Zolpidem

May increase the serum level of zolpidem

Initiate zolpidem at the lowest dose and monitor.

RESISTANCE

  • When used for initial therapy in patients without PI resistance, no resistance was seen with the failure of ATV/r or ATV/c.
  • 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 is less common with failure of ATV/r as initial PI.
  • L10Y/F, I50L, L63P, A71V, N88S, V32I, M46I, I84V, and L89M: 4-5 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 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 the dose of ATV to 300mg daily, but no clinical data.

PREGNANCY RISK

  • Category B. No human data. In animal studies, ATV did not produce 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 trimesters for all patients (ATV/r 400/100 mg). Lower plasma concentrations have been observed with standard dosing during the second and third trimesters, but no difference in virologic efficacy has been noted. The pharmacokinetics of cobicistat during pregnancy has not been evaluated. Therefore ATV/c during pregnancy is not recommended.

BREASTFEEDING COMPATIBILITY

No data.

COMMENTS

  • ATV/r is not recommended for HIV-infected if HIV RNA is >100,000 copies/mL. Therefore now has a limited role in the treatment of HIV.
    • HHS panel Panel classifies ATV/r and ATV/c plus (TAF or TDF) with (FTC or 3TC) (BI) as Recommended Initial Regimens in Certain Clinical Situations.
    • ATV/c plus TDF/FTC is not recommended for patients with CrCl < 70 mL/min, and ATV/c plus TAF/FTC is not recommended for patients with CrCl < 30 mL/min.
    • COBI should be avoided in pregnancy because COBI and its boosted drugs have lower levels in the second and third trimesters. However, frequent viral load monitoring is recommended if pregnant women with the suppressed virus on ATV/c elect to continue the drug.

Basis for recommendation

  1. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/protease-inhibitor-based-regimens... (last updated 6/2/21 for Protease-based regimens, accessed 6/28/23)

    Comment:
    ATV treatment is no longer recommended, and ATV/r has limited indications.

  2. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/pediatric-arv/guidelines-pediatric-arv.pdf (accessed 6/28/23)

    Comment: DHHS guideline dosing recommendations for atazanavir in pediatric patients.

References

  1. Antunes F. Atazanavir sulfate + cobicistat for the treatment of HIV infection. Expert Rev Anti Infect Ther. 2017;15(6):569-576.  [PMID:28443391]

    Comment: Dual therapy in one pill offers an easier option compared to boosted ATV/r.

  2. 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 regarding virologic efficacy and tolerability over 96 weeks. ATV/r resulted in a 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 superior to ATV/r and DRV/r, and DRV/r was superior to ATV/r.

  3. 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, combined 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.

  4. 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) with ABC/3TC or TDF/FTC. At 96 wks, virologic response rates were similar between ATV/r and EFV-treated patients.

  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):323-32.  [PMID:20032785]

    Comment: CASTLE compared ATV/r 300/100 mg daily vs. LPV/r 400/100 mg (caps) twice-daily 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, a lower rate of virologic suppression in LPV/r-treated pts with lower baseline CD4 count (80% with CD4 >200 vs. 63% with CD4.

  6. 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.

  7. 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), combined 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.

  8. 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 arms, 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 the 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, the LPV/r regimen demonstrated a greater decline in VL than 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 unknown. In addition, only 1/3 of pts were on a PI-containing regimen at the genotype analysis. The post-hoc analysis of the more heavily PI-experienced pts was underpowered to show the difference between the 2 groups. In the meantime, 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.

  9. 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 the 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).

  10. 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 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). The low percentage achieving VL< 50 at 48 wks in both arms was inconsistent with results from other EFV trials and felt due to preservatives used in specimens submitted for VL determination.

  11. 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 was achieved in 41, 29 and 35% (p = NS). Pts receiving ATV had significantly better post-therapy lipid profiles and fewer GI side effects. An obvious limitation of this trial is the comparison to a PI combination ( SQV400/ RTV400 mg twice daily) that is no longer routinely used.

  12. 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). 2010;9(1):34-42.  [PMID:20071596]

    Comment: 200 ARV-naive pts were randomized to ATV/r 300/100 mg (n=95) or ATV 400 mg (n=105), combined with 3TC and d4T XR, all daily. At 96 weeks, response rates were comparable between ATV/r and ATV (75% and 70% had VL < 50 by ITT analysis, respectively). However, the study was not powered to determine the non-inferiority of ATV vs. ATV/r, and there were numerically more virologic failures in the ATV arm, with more apparent PI and NRTI resistance. Jaundice was more common in the ATV/r arm, and lipids were somewhat higher, though few pts required lipid-lowering therapy.

Last updated: August 8, 2023