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The Protease Inhibitors (PIs)

Key Management Information



Direct Links to PI Info
Key Points
Generic Brand
nelfinavir Viracept
indinavir Crixivan
ritonavir Norvir
saquinavir Fortovase
amprenavir Agenerase
lopinavir / ritonavir Kaletra
atazanavir Reyataz
tipranavir / ritonavir Aptivus
fosamprenavir Lexiva
darunavir Prezista
Protease Inhibitor Summary Information
Boosted Protease Inhibitor Regimens



To insure future usefulness of protease inhibitors, AVOID prescribing patterns that may yield multidrug-resistant (MDR) HIV.

Protease inhibitors (PIs) are considered by many to be the most potent antiretroviral drugs in general.

a    Recent studies, however, point to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) as extremely potent, durable, pharmacokinetically-suited, easier to adhere to, and possibly less toxic alternatives to PIs. 

b    Recent advances in protease inhibitors (e.g. atazanavir, fosamprenavir, boosting) seem to even out the adherence issues and make PI-based regimens the best choice for many patients including naïve and experienced subpopulations.

2 All PIs undergo hepatic metabolism and have potential liver toxicity and multiple drug interactions, but so long as liver function is normal, they may be used despite renal insufficiency.   Atazanavir and indinavir are associated with usually asymptomatic hyperbilirubinemia.  Consider dose adjustment of PIs for hepatic insufficiency.  Consult reference material, a computer, or a personal digital assistant (PDA) when prescribing protease inhibitors to elucidate all possible drug-drug interactions especially when using rifampicins, anticoagulants, anticonvulsants, hypnotics, antidepressants, statins, and drugs for erectile dysfunction.  Unanticipated drug interactions may result in considerable loss of therapeutic effect or toxicity which may be severe.  Avoid using protease inhibitors in situations where drug-drug interaction information is not available or only very preliminary.

PIs are associated with mild to severe hyperlipidemias, fat redistribution, and type 2 diabetes.

a     These problems seem to be accentuated by combination ritonavir and stavudine therapy. 

b     Severe hyperlipidemias may occur especially with boosted PI regimens, and they may be refractory to diet, exercise, and hypolipidemic drugs. 

c     Substitution of atazanavir, fosamprenavir, or other highly active drugs such as NNRTIs may be beneficial.

d     Atorvastatin and pravastatin are the preferred drugs for use in treatment of hyperlipidemias associated with protease inhibitors


Protease inhibitor resistance issues can be summarized as follows:

a     Resistance occurs in the setting of the following:

1)      Monotherapy with a protease inhibitor (except in very special circumstances, e.g. lopinavir/ritonavir where that is the only option)

2)      Inadequate dosing

3)      Subtherapeutic drug levels (drug interactions, malabsorption, poor compartmental penetration, etc.)

4)      Poor dosing adherence for whatever reason

5)      Adding one antiretroviral to a failing combination regimen (equivalent to monotherapy)

6)      Incomplete viral suppression for whatever reason

b    Most PIs (excluding nelfinavir) require multiple mutations which occur relatively slowly over time. While NNRTI resistance can develop quickly in the setting of low serum levels, PI resistance occurs much more slowly.  This is referred to as a “high barrier to resistance.”  See PI Summary Chart for more detailed resistance information.


Proper management of protease inhibitor therapy includes the following:

a    There are many reasons that HAART may fail including nonadherence, malabsorption of antiretrovirals, drug interactions which lower antiretroviral drug levels, and transmission of drug resistant virus.   Resistance analysis may be helpful especially when performed while on the drugs in question.

b    If side effects are too great, consider stopping the offending drug or drugs and replacing that drug(s) only. If toxicity is severe, and the cause is unclear, stop all antiretrovirals simultaneously.

c    Never add a PI (or any single antiretroviral) to a failing regimen.

d    If the selected regimen is not tolerated by patient, the patient should inform provider immediately!

e    Never lower antiretroviral dosage unless dictated by pharmacokinetics (e.g. 3TC/ddC/d4T/AZT/ddI in renal failure or amprenavir in hepatic failure)

f     Frequent lab monitoring for efficacy and toxicity should be performed.  This includes virologic (viral load) and immunologic testing (CD4-lymphocytes) as well as liver and lipid testing.

g    Clinical and lab monitoring should be performed at 2-4 weeks after initiation and at 1-3 month intervals thereafter.

h    The metabolism of most protease inhibitors is inhibited by concomitant ritonavir used at low dosage.  The strategy of adding low dose ritonavir is called "protease inhibitor boosting."  Ritonavir is not an active antiretroviral drug in this situation; it serves as an inhibitor of the metabolic pathways of the active protease inhibitor.  Boosting increases PI drug levels and lowers dosing frequency, pill burden, and meal dependence.  The possibility for other drug reactions and lipodsytrophy may be increased.  Boosting is generally recommended whenever use of protease inhibitors is considered.   Kaletra consists of lopinavir and ritonavir coformulated into tablets.  When PI boosting is considered, darunavir and Kaletra may be the drugs of choice.  Drug interactions in this setting can be multiple, uncertain, and/or dangerous.  Some other proven boosting regimens include the following: atazanavir plus ritonavir, saquinavir plus ritonavir, indinavir plus ritonavir, lopinavir/ritonavir plus indinavir, and fosamprenavir plus ritonavir.  There is some data to suggest that saquinavir is boosted by atazanavir, but more information is needed.

i     Atazanavir and indinavir should not be used together due to the possibility of severe hyperbilirubinemia.


Strategic planning is important to consider when prescribing protease inhibitors

a    Nelfinavir : consider the need for food ingestion and prescribing antidiarrheal medication at initiation; bathroom availability must be considered

b    Indinavir:  plan with the patient regarding adequate fluid consumption with climactic modification.  Also consider the need for an empty stomach if using a nonboosted regimen.

c    Lopinavir/ritonavir: plan on medication ingestion prior to and after work if associated with diarrhea and abdominal pain and consider antidiarrheal therapy prescription.  Also consider need for refrigeration for the gelatin capsule form.  Bathroom availability must be considered.

d    Fortovase: consider need for food ingestion, antidiarrheal medication and refrigeration.  Also bathroom availability must be considered

e    Atazanavir, tipranavir, darunavir: consider need for food

7 Certain protease inhibitors have only been fully studied in treatment-experienced patients.  Tipranavir/ritonavir should only be used in this population until further information is available regarding treatment-naive patients.



Protease Inhibitor Summary Information
Generic (Nomenclature)
Pill Burden
Per Day
Dose Frequency
Per Day
GI Lipo Meal
Other High Level Resistance Mutations
Fortovase or
16-18 9-12 2-3 1-2 Diarrhea,
+++ Meal Meal Refrigerated & large soft gel caps
Both forms almost always boosted with ritonavir
Hard gel caps must be boosted with ritonavir
48, I84V, L90M
NA 4 NA 1-2
6 6-8 3 2 Abdominal
++++ Empty None Nephrolithiasis V82F/L/T, I84V
4-10 ? 2-3 NA Diarrhea ++ Meal NA Boosting generally not useful D30N, I84V, L90M


12 NA 2 NA Abdominal
 pain, diarrhea, nausea
++++ Meal NA Nearly unusable as single PI V82F/L/T, I84V
16 8/2 2 1-2 Nausea ++ Not high fat meal Not high fat meal Large soft gel caps, rash
Largely replaced by fosamprenavir
lopinavir / ritonavir
4-8 6/2 2 2 Abdominal
diarrhea, nausea
++++ gel caps: meal
film coated tabs: with or without meal
Meal Gel caps: refrigerated, large soft gel caps V82F/L/T, I84V, L90M
2 2/1 1 1 jaundice + Meal Meal Use boosted regimen in antiretroviral-experienced pt I50L, I84V
4 2/2 2 1-2   ++ None None Avoid use of
single daily dosing in ARV-experienced pt
Contains a sulfonamide component
50, I84V
tipranavir / ritonavir
NA 8 NA 2 Abdominal
diarrhea, nausea
NA Meal This drug appears very similar to lopinavir / ritonavir.  May retain activity in the presence of multiple UPAMs*
Contains a sulfonamide component
Relatively high incidence of hepatitis, rash
Indicated only for treatment-experienced patients
V82F/L/T, I84V, L90M
darunavir /
NA 3-4 NA 1-2 diarrhea,
++ NA Meal This drug appears to have significant activity against PI-resistant virus.  


NB = nonboosted regimen

B = ritonavir-boosted regimen
NA = not applicable


Boosting protease inhibitors increases the risk of hepatitis, hyperlipidemia, fat redistribution

Lipo = fat redistribution, hyperlipidemia, risk of Type 2 diabetes mellitus in nonboosted regimen
UPAM = universal protease associated mutations (I84V, V82F/L/T, L90M)



Protease Inhibitor Boosting

Optimizing Protease Inhibitor Therapy: Improved Drug Levels and Improved Adherence





Saquinavir boosted with ritonavir 

8 x 200 mg saquinavir hard-gel capsule
100 mg ritonavir

both once a day with food

2 x 500  mg saquinavir hard-gel capsule
100 mg ritonavir,

both twice a day with food


3.  5 x 200  mg saquinavir hard-gel capsule
100 mg ritonavir,

both twice a day with food

 2 x 200  mg saquinavir hard-gel capsule
4x100 mg ritonavir

both twice a day with food

Hyperlipidemia, hepatitis, fat redistribution, diarrhea, abdominal pain, diarrhea

Higher doses of ritonavir may be associated with increasing hyperlipidemia, GI intolerance, hepatitis, perioral paresthesia, and increased drug interactions


Twice daily boosted saquinavir is FDA-approved

boosted with

2 x 400 mg indinavir twice a day

1-2 x 100 mg ritonavir twice a day

with or without food

Hyperlipidemia, hepatitis, fat redistribution, diarrhea, abdominal pain, chapped lips, nephrolithiasis

Hydration with at least 48-64 oz of fluid per day is necessary.

boosted with

2 x 500 mg saquinavir hard-gel caps twice a day
3 caps lopinavir/ritonavir twice a day

both with food

Hyperlipidemia, hepatitis, fat redistribution, diarrhea, abdominal pain, diarrhea

boosted with

2 film-coated tablets twice a day OR
3 caps lopinavir/ritonavir twice a day
1 x 100 mg ritonavir twice a day

dose with food

Hyperlipidemia, hepatitis, fat redistribution, diarrhea, abdominal pain, diarrhea

boosted with

2 x 150 mg atazanavir
1 x 100 mg ritonavir

both once a day


Atazanavir should always be boosted in antiretroviral-experienced patients

boosted with


2 x 700 mg fosamprenavir
2 x 100 mg ritonavir

both once a day with food


1 x 700 mg fosamprenavir
1 x 100 mg ritonavir
both twice a day

Nausea, headache, rash, diarrhea

Newest PI with least experience

Boosted once-a-day dosing is not recommended for antiretroviral-experienced patients.



Protease Inhibitor Combination Therapy That Is NOT RECOMMENDED
(Two Active Protease Inhibitors)
Generic Rationale for AVOIDANCE

combined with

Antagonistic in vitro
combined with
Antagonistic in vitro

combined with


Subtherapeutic levels of lopinavir


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Links to Antiretroviral Sections (click on anything)
Nucleoside & Nucleotide Reverse Transcriptase Inhibitors (NRTI)
AZT  |  ddC  |  ddI  |  d4T  |  3TC  |  ABC  |  FTC  |  TDF  |  Combivir  |  Trizivir  |  Epzicom  |  Truvada  |  Atripla
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI)
efavirenz  |  nevirapine  |  delavirdine
Protease Inhibitors (PI)  |  Boosted Protease Inhibitors
saquinavir  indinavir  |  ritonavir  |  nelfinavir  |  amprenavir  |  lopinavir + ritonavir  |  atazanavir  |  fosamprenavir  | tipranavir  |  darunavir
Fusion Inhibitors


Quick Menu / Table of Contents
Introduction Principles Management NRTI Info NNRTI Info
PI Info Fusion Inhibitors Drug Summary Investigational Adherence
Lab Evaluation Resistance Tests PEP Antiretroviral Tables OI Prevention
Vaccinations TB Therapy Hepatitis Therapy OI Diagnosis OI Therapy
Bibliography Links Palliative Therapy


Updated 6.24.2011