What Is a Protease Inhibitor?

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Protease inhibitors (PI) are a class of HIV antiviral drugs (AVRs) that break down the structural proteins necessary for the assembly and morphogenesis of virus particles. Protease is an enzyme needed to break down larger viral particles into smaller ones used to form a full-fledged HIV particle. This step in the formation of viral particles is vital to replication. By blocking this step, the virus cannot replicate. If protease inhibitors are used in combination with other antiviral drugs HIV particles can be reduced to undetectable levels, which:

  • Prevents disease progression
  • Limits symptoms
  • Keeps the immune system intact

The U.S. Food and Drug Administration (FDA) has approved 26 medications in six drug classes for the treatment of HIV. Each drug type works in a different way. While there is no cure for HIV, the use of protease inhibitors in combination with other AVRs have helped to control the disease.

couple discussing HIV treatment

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How Protease Inhibitors Work

Protease is an essential element for viral maturation in the life cycle of HIV. Protease inhibitors (PIs) block the activity of the protease enzyme, which HIV uses to clip larger viral proteins into small ones required for assembly of new viral particles. The uncleaved particles are immature and unable to infect new cells. 

The specific protease that is blocked is HIV-1 protease, which cleaves the Gag and Gag-Pol polyprotein at nine different processing sites to produce mature active proteins. Protease inhibitors block HIV-1 protease by occupying the active site of the protein, rendering it unable to attach to the processing sites of the larger protein that it wants to cleave into mature viral particles. 

Types of Protease Inhibitors 

Of the 26 drugs approved by the FDA for treatment of HIV, 10 are protease inhibitors.
Protease inhibitors usually end in -avir. There are two classes of protease inhibitors: first-generation and second-generation inhibitors. The first-generation protease inhibitors include:

  • Indinavir
  • Ritonavir
  • Nelfinavir
  • Saquinavir

The HIV virus developed mutations to avoid the action of these protease inhibitors prompting scientists to create a new class of drug that could treat HIV-resistant cases.

These second-generation protease inhibitors—that are now widely and more commonly used in combination AVR therapy—include:

  • Atazanavir, which may be marketed under the name Reyataz, or Evotaz if it is prescribed in a combination tablet. 
  • Darunavir, which may be marketed under the name Prezista, or Rezolsta and Symtuza if it is prescribed in a combination tablet. 
  • Lopinavir, which is only available in the combination tablet Kaletra.

The complete list of the ten FDA approved protease inhibitors are:

  • Saquinavir: Generic name, Invirase and FDA approved December 6, 1995
  • Ritonavir: Generic name, Norvir and FDA approved March 1, 1996
  • Indinavir: Generic name, Crixivan and FDA approved March 1, 1996
  • Nelfinavir: Generic name, Viracept and FDa approved April 30, 2003
  • Amprenavir: Generic name, Agenerase and FDA approved April 15, 1999
  • Lopinavir: Commonly found in combination with ritonavir as th generic, Kaletra FDA approved September 15, 2000
  • Atazanavir: Generic name, Reyataz and FDA approved June 20, 2003.
  • Fosamprenavir: Generic name, Lexiva and FDA approved October 20, 2003
  • Tipranavir: Generic name, Aptivus and FDA approved June 22, 2005
  • Darunavir: Generic name, Prezista and FDA approved June 23, 2006

Side Effects

The use of protease inhibitors as a singular treatment has ceased for many reasons, including greater efficacy as part of combination treatment and side effects. Most of the inhibitors are accompanied by side effects in long-term treatment; the most significant being a condition called HIV protease inhibitor-induced metabolic syndrome, which results in:

  • Irregularities in fat distribution throughout the body (dyslipidemia and lipodystrophy)
  • Insulin-resistance
  • Increased risk of developing cardiovascular or cerebrovascular disease

Other side effects include:

  • Nausea
  • Vomiting
  • Diarrhea 
  • Increased blood sugar levels.
  • Increased cholesterol or triglyceride levels
  • Rash
  • Liver problems

While side effects are more likely to occur with longer use or use of first-generation PIs, they can occur at any time and with any class of the drug. If you are experiencing any side effects consult a healthcare provider immediately.

Protease inhibitors should not be taken if you experience an allergic reaction and should be taken cautiously if you have liver disease, hemophilia, or diabetes. 

Protease inhibitors may also interfere with certain drugs such as:

  • Blood thinners
  • Anti-seizure medication (anticonvulsants) 
  • Antidepressants
  • Anxiolytic medication
  • Beta-blockers
  • Antacids
  • Some antibiotics
  • Diabetes medication
  • Antifungals
  • Antiplatelet
  • Cardiac Medications

Of note, the use of Aptivus is contraindicated if you have a co-infection with HBV or HCV.

Drug Interactions

Protease inhibitors have many drug-drug interactions that can heighten or diminish its effectiveness or the effectiveness of another drug. The amount of PIs in our blood needs to stay within a narrow therapeutic window in order for it to work as intended.

When PI levels decrease in the blood they are less effective, but if they increase in the blood PIs may not work as expected or stay in the blood for too long, increasing the risk of interacting with other drugs in your system.

The effectiveness of many protease inhibitors is based on how it is metabolized by the body. Protease inhibitors should always be started under the supervision of a healthcare professional.

Recommendations for managing a particular drug interaction may differ depending on whether a new ARV drug is being initiated in a patient on a stable concomitant medication or whether a new concomitant medication is being initiated in a patient on a stable ARV regimen.

Of note, the magnitude and extent of PI drug interaction are difficult to predict, especially in those who are on many medications, so your doctor may formulate a personalized medication regimen that is best for you. 

This table provides information on some of the more common interactions between PIs and non-ARV drugs.

Drug PI Interaction Effect Recommendation
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)  All PIs May decrease PI levels PIs are not co-administered or contraindicated depending on PI used and medical condition
Antihypertensive-Dihydropyridine Calcium channel blockers (e.g. verapamil, diltiazem) All PIs Increases CCB level Decrease CCB dose and titrate slowly
Antihypertensive - Beta Blockers (e.g. metoprolol, timolol) RTV, EFV Blood level of beta blocker may increase with RTV, but decrease with EFV Clinical monitoring advised
Antiplatelet (clopidogrel, ticagrelor, prasugrel) All PIs Antiplatelet drug levels in blood tend to decrease making them less effective Do not coadminister
Antiplatelet (Warfarin) All PIs Variable effects on Warfarin Monitor INR and adjust warfarin dose when initiating/ discontinuing PI or NNRTI
Antacids All PIs Blood level of PIs increases Administer PI ≥2h before/2h after antacid
Cardiac Medications (amiodarone, flecainide, propafenone, quinidine, eplerenone, all beta blockers, all calcium channel blockers) All PI’s except TPV Variable reactions to be discussed with doctor Contraindicated unless otherwise specified by a licensed healthcare professional
Corticosteroids (Fluticasone, Prednisone, Dexamethasone) All PIs Dexamethasone can decrease PI levels.
All corticosteroids may increase the risk of bone damage in HIV-infected patients
Do not coadminister unless doctor deems that the benefits outweigh the risk of adverse event
Statins (simvastatin, atorvastatin, lovastatin, lomitapide)  All PIs The amount of statin in your blood may increase to an unsafe level. **Contraindicated (exceptions often made on a per case basis)
Selective Serotonin Reuptake Inhibitors
(e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)
All PIs May increase PI levels  Titrate SSRI dose based on clinical response.
Proton Pump Inhibitors (PPIs) All PIs AVR levels may decrease Avoid concomitant use unless otherwise specified by a healthcare professional

This list is not exhaustive and you should always consult a healthcare professional prior to use. 

A Word From VeryWell

HIV has gradually become a chronic, controllable disease but still, only 49% of people achieve an undetectable viral load. To give yourself the best chance of achieving this milestone it is important to take your AVR medication as prescribed.

Newer classes of PIs have lower side effect profiles and work more effectively than older classes of drugs and that’s why they are still so commonly used in combination therapy. Still, lingering side effects may occur especially if you are on drug treatment for a long time.

Monitor how you feel and let a healthcare provider know if anything has changed. Fortunately, recent medical advancements have made it possible for most people to manage their HIV and live a happy and healthy life.

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