Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

When Given Simultaneously

• ↓ ATV expected

H2RA dose should not exceed a dose equivalent to famotidine 40 mg twice daily in ART-naive patients or famotidine 20 mg twice daily in ART-experienced patients.

Give ATV 300 mg (plus COBI 150 mg or RTV 100 mg) with food simultaneously with and/or ≥10 hours after the dose of H2RA.

If using TDF and H2RA in ART-experienced patients, administer ATV 400 mg plus RTV 100 mg with food simultaneously with and/or ≥10 hours after the dose of H2RA.

Do not coadminister ATV/c with TDF and H2RA in ART-experienced patients.

With Ranitidine

• ↔ DRV/r

With Omeprazole 40 mg

• ATV AUC ↓ 76%

When Omeprazole 20 mg Is Given 12 Hours Before ATV/c or ATV/r

• ATV AUC ↓ 42%

PPI dose should not exceed a dose equivalent to omeprazole 20 mg daily in PI-naive patients.

PPIs should be administered at least 12 hours before ATV/c or ATV/r.

Do not coadminister in PI-experienced patients.

↔ DRV/r

Omeprazole AUC ↓ 42%

• ↑ bedaquiline possible

Compared With Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Once Daily) Plus ATV/r

• Rifabutin AUC ↑ 110% and metabolite AUC ↑ 2,101%

Recommended dose is rifabutin 150 mg once daily.

Monitor for antimycobacterial activity and consider therapeutic drug monitoring. Monitor for rifabutin-related adverse events, including neutropenia and uveitis.

PK data in this table are results from healthy volunteer studies. Lower rifabutin exposure has been reported in patients with HIV than in healthy study participants.

Compared With Rifabutin (300 mg Once Daily) Alone, Rifabutin (150 mg Every Other Day) Plus DRV/r

• ↔ rifabutin AUC and metabolite AUC ↑ 881%

↑ rifabutin expected

↓ COBI expected

Daily and Weekly Dosing

• ↓ PI expected

↑ clarithromycin expected 

↑ ATV/r and PI/c expected

DRV/r ↑ clarithromycin AUC 57%

RTV 500 mg twice daily ↑ clarithromycin 77%

Consider alternative ARV or azithromycin.

If use of clarithromycin is necessary in a patient with impaired renal function, reduce clarithromycin dose by 50% in patients with CrCl 30 to 60 mL/min. In patients with CrCl <30 mL/min, reduce clarithromycin dose by 75%.

Monitor for clarithromycin-related adverse events, including QTc prolongation.

↑ erythromycin expected

↑ PI expected

Do not coadminister in patients who require apixaban 2.5 mg twice daily.

In Patients Requiring Apixaban 5 mg or 10 mg Twice Daily

• Reduce apixaban dose by 50%.

With COBI 150 mg Alone

• Dabigatran AUC ↑ 110% to 127%

With ATV/r

• ↑ dabigatran expected

Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation in Adult Patients

• CrCl >30 mL/min: no dose adjustment needed
• CrCl ≤30 mL/min: do not coadminister.

Treatment and Reduction in the Risk of Recurrence of DVT and PE or Prophylaxis of DVT and PE Following Hip Replacement Surgery in Adult Patients

• CrCl ≥50 mL/min: no dose adjustment needed
• CrCl <50 mL/min: do not coadminister.

With DRV/c

• Single dose DRV/c: dabigatran AUC ↑ 164%
• After 14 days of DRV/c: dabigatran AUC ↑ 88%

With DRV/r

• Single dose DRV/r: dabigatran AUC ↑ 72%
• After 14 days of daily DRV/r: dabigatran AUC ↑ 18%

Treatment of Nonvalvular Atrial Fibrillation

• No dose adjustment needed

Treatment of DVT and PE

• Reduce edoxaban dose to 30 mg once daily.

Treatment of Nonvalvular Atrial Fibrillation

• No dose adjustment needed

Treatment of DVT and PE

• No dose adjustment needed

Monitor INR closely when stopping or starting PI/c or PI/r and adjust warfarin dose accordingly.

If switching between RTV and COBI, the effect of COBI on warfarin is not expected to be equivalent to RTV’s effect on warfarin.

↑ nefazodone expected

↑ PI possible

Selective Serotonin Reuptake Inhibitors

(e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine)

Paroxetine AUC ↓ 39%

Sertraline AUC ↓ 49%

RTV 200 mg twice daily (for 2 days)

• Trazodone ↑ AUC 240%

Tricyclic Antidepressants 

(e.g., amitriptyline, doxepin, nortriptyline)

Starting Cariprazine in a Patient Who Is Already Receiving a PI

• Administer cariprazine 1.5 mg on Day 1 and Day 3, with no dose given on Day 2. From Day 4 onward, administer cariprazine 1.5 mg daily. Dose can be increased to a maximum of cariprazine 3 mg daily. If the PI is withdrawn, cariprazine dose may need to be increased.

Starting a PI in a Patient Who Is Already Receiving Cariprazine

• For patients receiving cariprazine 3 mg or cariprazine 6 mg daily, reduce the dose by half. For patients taking cariprazine 4.5 mg daily, the dose should be reduced to cariprazine 1.5 mg or cariprazine 3 mg daily. For patients taking cariprazine 1.5 mg daily, change to cariprazine 1.5 mg every other day. If PI is withdrawn, the cariprazine dose may need to be increased.

↔ olanzapine expected

↑ samidorphan possible

Starting Quetiapine in a Patient Receiving a PI

• Initiate quetiapine at the lowest dose and titrate up as needed. Monitor for quetiapine effectiveness and adverse events, including QTc prolongation.

Starting a PI in a Patient Receiving a Stable Dose of Quetiapine

• Consider alternative ARV. If coadministered, reduce quetiapine dose to 1/6 of the current dose. Closely monitor for quetiapine effectiveness and adverse events, including QTc prolongation.

Chronic migraine: Do not coadminister.

Episodic migraine: Administer atogepant at a dose of 10 mg once daily.

↔ PI expected

↔ fluconazole expected

↑ isavuconazole expected

↓ PI possible

↑ isavuconazole expected

↓ PI possible

↑ itraconazole expected

↑ PI expected

ATV AUC ↑ 146%

↔ posaconazole possible

↑ PI expected

↔ posaconazole possible

RTV 100 mg twice daily

↓ voriconazole AUC 39%

↑ lumefantrine expected

↑ artemether possible

↔ artemether expected

↔ DHA^a expected

Lumefantrine AUC ↑ 175%

↔ DRV

With ATV/r

• Atovaquone AUC
  ↓ 46%
• Proguanil AUC
  ↓ 41%

With DRV/r

• ↓ atovaquone/proguanil possible

With RTV 200 mg Twice Daily

• RTV AUC ↓ 31% and C_min ↓ 43%
• ↔ mefloquine

With ATV (Unboosted), PI/c, or PI/r

• ↑ mefloquine possible

↑ carbamazepine possible

May ↓ PI concentrations substantially

Carbamazepine AUC ↑ 45%

↔ DRV

↑ carbamazepine possible

↓ COBI expected

↓ PI expected

↓ phenobarbital possible

↓ PI possible

↓ COBI expected

↓ PI expected

↓ phenytoin possible

↓ PI possible

↓ COBI expected

↓ PI expected

Elbasvir AUC ↑ 4.8-fold

Grazoprevir AUC ↑ 10.6-fold

Elbasvir ↔ ATV

Grazoprevir ↑ ATV AUC 43%

Contraindicated

May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations caused by OATP1B1/3 inhibition.

Elbasvir AUC ↑ 66%

Grazoprevir AUC ↑ 7.5-fold

↔ DRV

With (ATV 300 mg plus RTV 100 mg) Once Daily

• Glecaprevir AUC ↑ 6.5-fold
• Pibrentasvir AUC ↑ 64%

With (DRV 800 mg plus RTV 100 mg) Once Daily

• Glecaprevir AUC ↑ fivefold
• ↔ pibrentasvir

ATV AUC ↑ 33%

Ledipasvir AUC ↑ 113%

↔ sofosbuvir

No dose adjustment needed

Coadministration of ledipasvir/sofosbuvir with TDF and a PI/r results in increased exposure to TDF. The safety of the increased TDF exposure has not been established. Consider alternative HCV or ARV drugs to avoid increased risk of TDF toxicities. If coadministration is necessary, monitor for TDF-related adverse events.

↔ PI expected

↔ ledipasvir and sofosbuvir

↔ DRV/r

Sofosbuvir AUC ↓ 28%

↔ velpatasvir

With ATV/r

• Voxilaprevir AUC ↑ 4.3-fold
• Velpatasvir AUC ↑ 93%
• Sofosbuvir AUC ↑ 40%

With DRV/r

• Voxilaprevir AUC ↑ 2.4-fold
• ↔ DRV/r, velpatasvir, and sofosbuvir

↑ PI expected

↑ ritonavir-boosted nirmatrelvir expected

With RTV 300 mg Twice Daily

• Indacaterol AUC ↑ 1.7-fold

↑ amiodarone possible

↑ PI possible

↑ amiodarone possible

↑ PI possible

RTV 200 mg twice daily ↑ digoxin AUC 29% and ↑ half-life 43%

DRV/r ↑ digoxin AUC 36%

COBI ↑ digoxin C_max 41% and ↔ AUC

May need to decrease beta-blocker dose; adjust dose based on clinical response.

Consider using beta-blockers that are not metabolized by CYP2D6 enzymes (e.g., atenolol, labetalol, nadolol).

↑ dihydropyridine possible

↑ verapamil possible

Unboosted ATV ↑ diltiazem AUC 125%

Greater ↑ of diltiazem AUC is likely with ATV/c or ATV/r

With ATV (Unboosted)

• ↓ ATV expected

With PI/r or PI/c

• ↑ bosentan expected

Do not coadminister bosentan and unboosted ATV.

In Patients on a PI (Other Than Unboosted ATV) >10 Days

• Start bosentan at 62.5 mg once daily or every other day.

In Patients on Bosentan Who Require a PI (Other Than Unboosted ATV)

• Stop bosentan ≥36 hours before PI initiation and restart bosentan 10 days after PI initiation at 62.5 mg once daily or every other day.

When Switching Between COBI and RTV

• Maintain same bosentan dose.

↔ 17-BMP (active metabolite) AUC

RTV 100 mg twice daily ↑ 17-BMP AUC 2-fold

↑ glucocorticoids possible

RTV 100 mg twice daily ↑ fluticasone AUC 350-fold

↑ glucocorticoids possible

↓ PI possible

If a patient is already tolerating canagliflozin 100 mg daily, increase canagliflozin dose to 200 mg daily.

If a patient is already tolerating canagliflozin 200 mg daily and requires additional glycemic control, management strategy is based on renal function.

In Patients With eGFR ≥60 mL/min/1.73 m²

• Canagliflozin dose may be increased to 300 mg daily.

In Patients With eGFR <60 mL/min/1.73 m²

• Consider adding another antihyperglycemic agent.

↔ ethinyl estradiol AUC and C_min ↓ 25%

↔ levonorgestrel

Ethinyl estradiol AUC ↓ 19% and C_min ↓ 37%

Norgestimate AUC ↑ 85%

Norethindrone AUC ↑ 51% and C_min ↑ 67%

↑ drospirenone expected

↔ estetrol

Drospirenone AUC ↑ 58%

Ethinyl estradiol AUC ↓ 30%

Ethinyl estradiol AUC ↓ 44% and C_min ↓ 62%

Norethindrone AUC ↓ 14% and C_min ↓ 30%

When Used for Contraception

• Consider alternative ARV or contraceptive methods. If combined, consider using an oral contraceptive with at least 35 mcg of ethinyl estradiol.

When Used for Other Clinical Indications (e.g., Acne, Menstrual Cycle Regulation)

• Monitor for clinical effectiveness of hormonal therapy.

↓ ethinyl estradiol possible with ritonavir

↑ ethinyl estradiol possible with cobicistat

↑ norelgestromin, levonorgestrel possible

Ethinyl estradiol AUC ↓ 26%

Etonogestrel AUC ↑ 79%

No dose adjustment needed with etonogestrel/ethinyl estradiol vaginal rings.

Use alternative ARV or contraceptive methods with segesterone/ethinyl estradiol vaginal rings.

↓ ethinyl estradiol possible with ritonavir

↑ ethinyl estradiol possible with cobicistat

↑ dutasteride possible

↑ finasteride possible

↑ drospirenone possible

↑ MPA

↑ micronized progesterone

See the Hormonal Therapies—Contraceptives section for other progestin-PI interactions.

With ATV/r

• ↔ pitavastatin expected
• ↔ ATV/r expected

With DRV/r

• ↓ pitavastatin AUC 26%
• ↔ DRV/r

With DRV/r

• Pravastatin AUC ↑ 81% following single dose of pravastatin
• Pravastatin AUC ↑ 23% at steady state

Buprenorphine AUC ↑ 66%

Norbuprenorphine (active metabolite) AUC ↑ 105%

↔ buprenorphine

Norbuprenorphine (active metabolite) AUC ↑ 46% and C_min ↑ 71%

↑ tramadol expected

↓ M1 (active metabolite) possible

For Treatment of Erectile Dysfunction

• Start with sildenafil 25 mg every 48 hours and monitor for sildenafil-related adverse events.

Contraindicated for treatment of PAH.

For Treatment of Erectile Dysfunction

As-Needed Use

• Start with tadalafil 5 mg and do not exceed a single dose of tadalafil 10 mg every 72 hours. Monitor for tadalafil-related adverse events.

Once-Daily Use

• Do not exceed tadalafil 2.5 mg once daily. Monitor for tadalafil-related adverse events.

For Treatment of PAH

In Patients on a PI >7 Days

• Start with tadalafil 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.

In Patients on Tadalafil Who Require a PI

• Stop tadalafil ≥24 hours before PI initiation. Seven days after PI initiation, restart tadalafil at 20 mg once daily and increase to tadalafil 40 mg once daily based on tolerability.

In Patients Switching Between COBI and RTV

• Maintain tadalafil dose.

For Treatment of Benign Prostatic Hyperplasia

• Maximum recommended daily dose is tadalafil 2.5 mg per day. Monitor for tadalafil-related adverse events.

↑ benzodiazepine possible

RTV 200 mg twice daily (for 2 days) ↑ alprazolam half-life 222% and ↑ AUC 248%

Oral midazolam is contraindicated with PIs.

Parenteral midazolam can be used with caution when given in a monitored situation with appropriate medical management available in case of respiratory sedation and/or prolonged sedation. Consider dose reduction, especially if more than a single dose of midazolam is administered. 

↑ triazolam expected

RTV 200 mg twice daily ↑ triazolam half-life 1,200% and ↑ AUC 2,000%

RTV 100 mg twice daily ↑ colchicine AUC 296% and C_max ↑ 184%

Significant ↑ colchicine expected with all PIs, with or without COBI or RTV

For Treatment of Gout Flares

• Administer a single dose of colchicine 0.6 mg, followed by colchicine 0.3 mg 1 hour later. Do not repeat dose for at least 3 days.

For Prophylaxis of Gout Flares

• If original dose was colchicine 0.6 mg twice daily, decrease to colchicine 0.3 mg once daily. If dose was 0.6 mg once daily, decrease to 0.3 mg every other day.

For Treatment of Familial Mediterranean Fever

• Do not exceed colchicine 0.6 mg once daily or colchicine 0.3 mg twice daily.

Contraindicated in patients with hepatic (Child-Pugh Score A, B, or C) or renal impairment (CrCl <60 mL/min)