The Protease Inhibitors (PIs)

Key Information

August 2005

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.

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 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 gel caps; therefore, when PI boosting is considered, Kaletra may be the drug 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, fosamprenavir plus ritonavir, and amprenavir 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.  Bathroom availability must be considered.

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

e    Atazanavir: consider need for food

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