Protease Inhibitors

What are protease inhibitors?

Protease inhibitors (PIs) are medications that treat viral infections. They work by preventing a virus from making more copies of itself. They’re most commonly used as an antiretroviral to manage HIV/AIDS. They can also be used to treat hepatitis C and COVID-19.

Some protease (pronounced “PRO-tee-ayz”) inhibitors can be taken on their own (monotherapy), but many are used in combination with other antiviral medications. When they’re used to help another medication be more effective, they’re called a “booster.”

What conditions do protease inhibitors treat?

Protease inhibitors are only approved to treat specific viral infections. Protease inhibitors can be used as part of treatments for:

• HIV/AIDS. Providers can use protease inhibitors on their own or as part of a “cocktail” of several drugs to treat HIV. The combination of drugs used to treat HIV is called antiretroviral therapy, or ART. They’re also sometimes used to prevent an HIV infection after you’ve been exposed to the virus (post-exposure prophylaxis).
• Hepatitis C. Protease inhibitors are used in combination with other antiviral medications to treat or cure hepatitis C.
• COVID-19. Providers sometimes prescribe a medication that’s a combination of two protease inhibitors to reduce your risk of getting severely ill with COVID-19.

How do protease inhibitors work (mechanism of action)?

Proteases break long chains of proteins into smaller ones. This activates the smaller proteins to perform certain functions.

In viruses, the smaller proteins go on to create more copies of the virus. Protease inhibitors block protease so it can’t cut proteins into their active pieces. This prevents viruses from making more copies of themselves that infect your cells.

What drugs are protease inhibitors?

Since each virus has its own protease, different types of PIs are used to treat HIV, hepatitis C and COVID-19. You can recognize protease inhibitors by how their names end: drugs ending in “-navir” treat HIV and those ending in “-previr” treat hepatitis C.

HIV protease inhibitors

These are examples of antiretroviral protease inhibitors for HIV treatment. These PIs block HIV-PR, the protease HIV uses to make more copies of itself:

• Amprenavir.
• Atazanavir.
• Darunavir.
• Indinavir.
• Fosamprenavir.
• Lopinavir.
• Nelfinavir.
• Ritonavir.
• Saquinavir.
• Tipranavir.

Hepatitis C protease inhibitors

These are examples of antiviral protease inhibitors for hepatitis C treatment. These PIs block NS3/4A serine protease (this is what the hepatitis C virus uses to make more copies of itself):

• Boceprevir.
• Glecaprevir.
• Grazoprevir.
• Paritaprevir.
• Simeprevir.
• Telaprevir.

COVID-19 protease inhibitors

Paxlovid® is a combination of protease inhibitors (nirmatrelvir and ritonavir) that treats COVID-19. Nirmatrelvir is a 3C-like (3CL) protease inhibitor. 3CL is the protease that SARS-CoV-2, the virus that causes COVID-19, uses to make more copies of itself.

Which protease inhibitor should I be on?

Your provider will select protease inhibitors based on:

• Your specific viral infection.
• Your health and any additional health conditions.
• Potential interactions with other medications you’re taking.
• Whether you’ve taken other medications for your condition before.
• How effective your provider expects them to be, in your case. This can depend on the subtype (strain) of virus you have or other factors.
• Potential side effects or complications (toxicity).

Make sure to tell your provider about any other medications you’re taking and any other conditions you have. This can reduce your risk of serious interactions or complications.

What are the potential benefits of protease inhibitors?

Benefits of protease inhibitors include:

• They can keep levels of HIV undetectable as part of ART treatment.
• They can help cure hepatitis C infections.
• They can help prevent a COVID-19 infection from becoming severe.

What are the side effects or complications of protease inhibitors?

Protease inhibitor side effects and complications vary depending on which one you’re taking, what other medications you’re taking and your overall health.

Not all types have the same risk of complications. Talk to your healthcare provider about the risks and side effects of taking protease inhibitors so you know what to expect.

Common side effects of protease inhibitors

• Abdominal pain.
• Nausea and vomiting.
• Diarrhea.
• Rash.
• Cough.
• Fatigue.
• Kidney stones.
• Redistribution of fat on your body (lipodystrophy).
• Bad taste in your mouth.

Serious side effects and complications of protease inhibitors

• Liver damage.
• Internal bleeding. This includes intracranial bleeding, or bleeding inside your skull.
• Stevens-Johnson syndrome. This causes a painful, blistering rash.
• High blood sugar (hyperglycemia), a serious issue in people with diabetes.
• High cholesterol (hyperlipidemia, hypercholesterolemia).
• Hemolytic anemia. A condition where your blood cells are destroyed faster than your body can replace them.
• Heart attack (myocardial infarction).
• Problems with your heart’s electrical system, including long QT syndrome.

How long will I need to be on a protease inhibitor?

How long you need to be on a protease inhibitor depends on what kind of viral infection you’re treating:

• HIV. There’s no cure for HIV, so you’ll need to treat it for the rest of your life. You may use many combinations of treatment over time, including different kinds of protease inhibitors. Sometimes treatments stop working or become less effective. Your provider will adjust what medications you’re on as needed.
• Hepatitis C. Hepatitis can usually be cured with a combination of antivirals, including protease inhibitors. This can take several weeks or months.
• COVID-19. You take antiviral treatments for COVID-19 for five days. But it may take longer to feel better.

Is there anything I can do to make this treatment easier on me?

Ask your provider about reducing your risk of complications or side effects. You may be able to avoid some side effects by:

• Taking your medications as directed by your provider.
• Drinking plenty of water.
• Avoiding any medications that interact with your protease inhibitor.
• Eating certain foods when you take your medication.

Why are protease inhibitors taken with food?

Eating a meal with fat increases your body’s absorption of some protease inhibitors. This allows them to work better. Ask your provider if you should take your PI with food and what kind of food to take it with.

When should I call my healthcare provider?

Call your healthcare provider if you have unexpected side effects or concerns about your treatment. Seek medical attention immediately if you have signs of severe side effects, including:

• Fever.
• Confusion or mental changes.
• Yellowing of your skin or eyes (jaundice).
• Blistering, painful or widespread rash.
• Severe abdominal pain.
• Severe vomiting.

A note from Cleveland Clinic

Protease inhibitors are an important part of treatment plans for chronic viral illnesses. They can keep HIV undetectable and help cure hepatitis C. Talk to your provider about any concerns you have about treatment with protease inhibitors. Together, you can work on a treatment plan that works best for you.