Appendix B: Characteristics of Protease Inhibitors

Generic Name (Abbreviation) Trade Name	Formulations	Dosing Recommendations^a	Elimination/ Metabolic Pathway	Serum Half-Life	Adverse Events^b
Atazanavir (ATV) Reyataz (ATV/c) Evotaz Note: Generic products of ATV are available.	Reyataz 200-mg, and 300-mg capsules 50-mg oral powder/packet Generic 200-mg, and 300‑mg capsules Evotaz ATV 300-mg/COBI 150-mg tablet	Reyataz In People Without Prior ARV Treatment (ATV 300 mg plus RTV 100 mg) PO once daily with food; or ATV 400 mg PO once daily with food. With TDF or in ARV-Experienced People (ATV 300 mg plus RTV 100 mg) PO once daily with food. Unboosted ATV is not recommended. With EFV in People Without Prior ARV Treatment (ATV 400 mg plus RTV 100 mg) PO once daily with food. Evotaz One tablet PO once daily with food. The use of ATV/c is not recommended for patients who are taking TDF and who have baseline CrCl <70 mL/min (see Appendix B, Table 12 for the equation for calculating CrCl). For dosing recommendations for patients who also are receiving H2 antagonists and PPIs, refer to Table 24a.	ATV CYP3A4 inhibitor and substrate Weak CYP2C8 inhibitor UGT1A1 inhibitor COBI CYP3A inhibitor and substrate CYP2D6 inhibitor Dose adjustment is recommended in patients with hepatic insufficiency (see Appendix B, Table 12).	7 hours	Indirect hyperbilirubinemia Cholelithiasis Nephrolithiasis Renal insufficiency Serum transaminase elevations Hyperlipidemia (especially with RTV boosting) Skin rash Hyperglycemia Lipodystrophy An increase in serum creatinine may occur when ATV is administered with COBI. PR interval prolongation: First-degree symptomatic AV block has been reported. Use with caution in patients who have underlying conduction defects or who are on concomitant medications that can cause PR prolongation.
Darunavir (DRV) Prezista (DRV/c) Prezcobix	Prezista 600-mg, and 800‑mg tablets 100-mg/mL oral suspension Prezcobix DRV 800-mg/COBI 150-mg tablet Also available as part of the STR Symtuza (DRV/c/TAF/FTC)	Prezista In People Without Prior ARV Treatment or ARV-Experienced Treatment With No DRV Mutations (DRV 800 mg plus RTV 100 mg) PO once daily with food. In ARV-Experienced People With One or More DRV Resistance Mutations (DRV 600 mg plus RTV 100 mg) PO twice daily with food. Unboosted DRV is not recommended. Prezcobix One tablet PO once daily with food. Not recommended for patients with one or more DRV resistance-associated mutations. Coadministering Prezcobix and TDF is not recommended for patients with baseline CrCl <70 mL/min (see Appendix B, Table 12 for the equation for calculating CrCl). See Appendix B, Table 1 for dosing information for Symtuza.	DRV CYP3A4 inhibitor and substrate CYP2C9 inducer COBI CYP3A inhibitor and substrate CYP2D6 inhibitor	15 hours when combined with RTV 7 hours when combined with COBI	Hepatotoxicity Diarrhea, nausea Headache Hyperlipidemia Serum transaminase elevation Hyperglycemia Fat maldistribution An increase in serum creatinine may occur when DRV is administered with COBI. Skin rash: DRV has a sulfonamide moiety; however, incidence and severity of rash are similar in those with or without a sulfonamide allergy—Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme have been reported.
Ritonavir (RTV) Norvir Note: Generic is available. RTV was initially developed as a PI for HIV treatment but is now primarily used at a lower dose of 100 mg once or twice daily as a PK enhancer to increase the concentrations of other PIs.	Norvir 100-mg tablet 100-mg single packet oral powder Also available as part of the FDC tablet Kaletra (LPV/r)	As a PK Booster (or Enhancer) for Other PIs RTV 100–200 mg PO per day in one or two divided doses (refer to other PIs for specific dosing recommendations) with food.	CYP3A4 > 2D6 substrate Potent CYP3A4 and 2D6 inhibitor Inducer of UGT1A1 and CYPs 1A2, 2C8, 2C9, and 2C19	3–5 hours	GI intolerance, nausea, vomiting, diarrhea Paresthesia (circumoral and extremities) Hyperlipidemia (especially hypertriglyceridemia) Hepatitis Asthenia Dysgeusia Hyperglycemia Fat maldistribution
^a For dose adjustments in patients with hepatic insufficiency, see Appendix B, Table 12. ^b Also see Table 20. Key: ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; AV = atrioventricular; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DRV = darunavir; DRV/c = darunavir/cobicistat; EFV = efavirenz; FDC = fixed-dose combination; FTC = emtricitabine; GI = gastrointestinal; H2 = histamine H2 receptor; LPV/r = lopinavir/ritonavir; PI = protease inhibitor; PK = pharmacokinetic; PO = orally; PPI = proton pump inhibitor; RTV = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; UGT1 = uridine diphosphate glucuronyl transferase 1 family

Generic Name
(Abbreviation)
Trade Name

Formulations

Dosing Recommendations^a

Elimination/ Metabolic Pathway

Serum Half-Life

Adverse Events^b

Atazanavir
(ATV)
Reyataz

(ATV/c)
Evotaz

Note: Generic products of ATV are available.

Reyataz

200-mg, and 300-mg capsules
50-mg oral powder/packet

Generic

200-mg, and 300‑mg capsules

Evotaz

ATV 300-mg/COBI 150-mg tablet

Reyataz

In People Without Prior ARV Treatment

(ATV 300 mg plus RTV 100 mg) PO once daily with food; or
ATV 400 mg PO once daily with food.

With TDF or in ARV-Experienced People

(ATV 300 mg plus RTV 100 mg) PO once daily with food.
Unboosted ATV is not recommended.

With EFV in People Without Prior ARV Treatment

(ATV 400 mg plus RTV 100 mg) PO once daily with food.

Evotaz

One tablet PO once daily with food.
The use of ATV/c is not recommended for patients who are taking TDF and who have baseline CrCl <70 mL/min (see Appendix B, Table 12 for the equation for calculating CrCl).

For dosing recommendations for patients who also are receiving H2 antagonists and PPIs, refer to Table 24a.

ATV

CYP3A4 inhibitor and substrate
Weak CYP2C8 inhibitor
UGT1A1 inhibitor

COBI

CYP3A inhibitor and substrate
CYP2D6 inhibitor

Dose adjustment is recommended in patients with hepatic insufficiency (see Appendix B, Table 12).

7 hours

Indirect hyperbilirubinemia

Cholelithiasis

Nephrolithiasis

Renal insufficiency

Serum transaminase elevations

Hyperlipidemia (especially with RTV boosting)

Skin rash

Hyperglycemia

Lipodystrophy

An increase in serum creatinine may occur when ATV is administered with COBI.

PR interval prolongation: First-degree symptomatic AV block has been reported. Use with caution in patients who have underlying conduction defects or who are on concomitant medications that can cause PR prolongation.

Darunavir
(DRV)
Prezista

(DRV/c)
Prezcobix

Prezista

600-mg, and 800‑mg tablets
100-mg/mL oral suspension

Prezcobix

DRV 800-mg/COBI 150-mg tablet

Also available as part of the STR Symtuza (DRV/c/TAF/FTC)

Prezista

In People Without Prior ARV Treatment or ARV-Experienced Treatment With No DRV Mutations

(DRV 800 mg plus RTV 100 mg) PO once daily with food.

In ARV-Experienced People With One or More DRV Resistance Mutations

(DRV 600 mg plus RTV 100 mg) PO twice daily with food.

Unboosted DRV is not recommended.

Prezcobix

One tablet PO once daily with food.
Not recommended for patients with one or more DRV resistance-associated mutations.
Coadministering Prezcobix and TDF is not recommended for patients with baseline CrCl <70 mL/min (see Appendix B, Table 12 for the equation for calculating CrCl).

See Appendix B, Table 1 for dosing information for Symtuza.

DRV

CYP3A4 inhibitor and substrate
CYP2C9 inducer

COBI

CYP3A inhibitor and substrate
CYP2D6 inhibitor

15 hours when combined with RTV

7 hours when combined with COBI

Hepatotoxicity

Diarrhea, nausea

Headache

Hyperlipidemia

Serum transaminase elevation

Hyperglycemia

Fat maldistribution

An increase in serum creatinine may occur when DRV is administered with COBI.

Skin rash: DRV has a sulfonamide moiety; however, incidence and severity of rash are similar in those with or without a sulfonamide allergy—Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme have been reported.

Ritonavir
(RTV)
Norvir

Note: Generic is available.

RTV was initially developed as a PI for HIV treatment but is now primarily used at a lower dose of 100 mg once or twice daily as a PK enhancer to increase the concentrations of other PIs.

Norvir

100-mg tablet
100-mg single packet oral powder

Also available as part of the FDC tablet Kaletra (LPV/r)

As a PK Booster (or Enhancer) for Other PIs

RTV 100–200 mg PO per day in one or two divided doses (refer to other PIs for specific dosing recommendations) with food.

CYP3A4 > 2D6 substrate

Potent CYP3A4 and 2D6 inhibitor

Inducer of UGT1A1 and CYPs 1A2, 2C8, 2C9, and 2C19

3–5 hours

GI intolerance, nausea, vomiting, diarrhea

Paresthesia (circumoral and extremities)

Hyperlipidemia (especially hypertriglyceridemia)

Hepatitis

Asthenia

Dysgeusia

Hyperglycemia

Fat maldistribution

^a For dose adjustments in patients with hepatic insufficiency, see Appendix B, Table 12.

^b Also see Table 20.

Key: ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; AV = atrioventricular; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DRV = darunavir; DRV/c = darunavir/cobicistat; EFV = efavirenz; FDC = fixed-dose combination; FTC = emtricitabine; GI = gastrointestinal; H2 = histamine H2 receptor; LPV/r = lopinavir/ritonavir; PI = protease inhibitor; PK = pharmacokinetic; PO = orally; PPI = proton pump inhibitor; RTV = ritonavir; STR = single-tablet regimen; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; UGT1 = uridine diphosphate glucuronyl transferase 1 family

Back to Appendix B

Appendix B, Table 5. Characteristics of Protease Inhibitors