Protease inhibitors: Uses, common brands, and safety info

Protease inhibitors are medications primarily used to treat human immunodeficiency virus (HIV), although they’re also used to treat hepatitis C. As effective antiretroviral drugs, protease inhibitors have improved the outlook for individuals living with HIV and hepatitis C. Protease inhibitors work by reducing viral load, or the amount of viruses, in the blood, which helps treat HIV symptoms, slow the progression of HIV into acquired immune deficiency syndrome (AIDS), and prevent transmission of the virus. 

Continue reading to learn more about protease inhibitors, their uses, and their side effects.

Other protease inhibitors

• Incivek (telaprevir)

• Olysio (simeprevir)

• Victrelis (boceprevir)

• Fortovase (saquinavir)

• Agenerase (amprenavir)

What are protease inhibitors?

Antiretroviral drugs target different stages of the HIV life cycle to prevent the virus from replicating or reproducing, in the body. Protease inhibitors are antiretroviral drugs that target the HIV-1 protease enzyme and interrupt the virus’s replication process. These medications are effective and powerful for treating HIV, although they’re often used in combination with other HIV drugs.

The standard, initial treatment for HIV consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus another antiviral drug, such as an integrase strand inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) boosted with ritonavir or cobicistat. The use of multiple antiviral drugs for the treatment of HIV is known as highly active antiretroviral therapy, or HAART. This combination of drugs blocks specific stages of the HIV life cycle in order to reduce viral load and prevent viral resistance against a single medication.

Protease inhibitors are usually prescribed with a booster medication, such as ritonavir or cobicistat. Ritonavir is a protease inhibitor that can help treat HIV, but it is primarily used to help increase the absorption of other protease inhibitors. Cobicistat is a structural analogue of ritonavir that is used in a similar way. Both ritonavir and cobicistat work as pharmacokinetic enhancers that block the CYP3A4 enzyme, which results in increased blood levels of protease inhibitors.

How do protease inhibitors work?

The HIV-1 protease enzyme is involved with the replication process of the virus. Protease enzymes break down proteins into smaller protein fragments known as peptides, and these peptides are broken down further into amino acids. The smaller protein fragments are necessary to build the virus parts so they can infect other cells. Without the protease enzyme, there is no replication and maturation of the virus. 

Protease inhibitors block the protease enzyme from functioning. They work by binding to the active site of the protease enzyme, which blocks the cleavage of viral peptides and prevents the maturation of the virus. While protease inhibitors do not cure HIV/AIDS, they can reduce the viral load to undetectable levels. At an undetectable level, HIV is less likely to be passed on to sexual partners. 

On the other hand, protease inhibitors can help cure hepatitis C infections. Protease inhibitors interfere with hepatitis C virus replication by blocking the enzyme NS3/4A serine protease. Without a functioning protease enzyme, there is no replication of the hepatitis C virus. 

What are protease inhibitors used for?

Protease inhibitors are FDA-approved to treat specific viral infections caused by retroviruses. 

• HIV

• Hepatitis C

• Exposure to HIV

Types of protease inhibitors

There are two types of protease inhibitors. One type is specific to HIV and the other for HCV. Inhibition of the enzyme pathway used to replicate the particular virus results in a decrease in viral load. 

HIV Protease Inhibitors

The following medications are FDA-approved to treat HIV:

• Aptivus (tipranavir)

• Crixivan (indinavir)

• Invirase (saquinavir)

• Kaletra (lopinavir/ritonavir)

• Lexiva (fosamprenavir)

• Norvir (ritonavir) 

• Prezista (darunavir)

• Reyataz (atazanavir)

• Viracept (nelfinavir)

HIV protease inhibitors can also be classified as first-generation or second-generation protease inhibitors. The first-generation protease inhibitors were previously effective for treating HIV but have been met with growing viral resistance due to mutations in the active site of the HIV protease enzyme. First-generation protease inhibitors include saquinavir, ritonavir, nelfinavir, indinavir, and amprenavir. Second-generation protease inhibitors have greater potency against HIV infection and include lopinavir, fosamprenavir, and atazanavir. 

HCV Protease Inhibitors 

The following medications are FDA-approved to treat HCV:

• Olysio (simeprevir)

• Victrelis (boceprevir)

• Incivek (telaprevir)

• Viekira Pak (dasabuvir/ombitasvir/paritaprevir/ritonavir)

• Technivie (ombitasvir/paritaprevir and ritonavir)

Who can take protease inhibitors?

Adults

Adults with HIV may be treated with a drug regimen that includes protease inhibitors. Treatment for HIV/AIDS will consist of a multi-drug regimen. Combination therapy is required because HIV can become resistant to a single drug. Adults with HIV should tell their healthcare provider about any past history of medical conditions or medications before starting treatment with a protease inhibitor. 

Children

Several protease inhibitors are FDA-approved for use in children. As with adults, protease inhibitors will be part of a multi-drug regimen. Many protease inhibitor drugs are available in liquid form for ease of administering to children. The dosing of protease inhibitors for children is typically calculated based on weight. 

The following protease inhibitors are FDA approved for children:

• Viracept (nelfinavir)

• Kaletra (lopinavir/ritonavir)

• Norvir (ritonavir)

• Reyataz (atazanavir)

• Prezista (darunavir)

• Lexiva (fosamprenavir)

• Aptivus (tipranavir)

• Invirase (saquinavir)

• Crixivan (indinavir)

Seniors

Seniors may take protease inhibitors; however, treatment will be based on current medical conditions the individual may have or other medications the individual may be taking. Seniors often have other health conditions, such as kidney or liver problems, cardiovascular problems, and low bone mineral density, that may be affected by the use of antiretroviral agents like protease inhibitors. For instance, protease inhibitors have been linked to an increased risk of bone loss, or osteoporosis, in older patients. Patients with a history of osteoporosis may need to be put on an alternative treatment regimen. 

Decreased liver and kidney function in older people can also affect the clearance of protease inhibitors. Therefore, seniors may need close monitoring to avoid complications of drug accumulation or build-up. 

Can you take protease inhibitors while pregnant or breastfeeding?

Some protease inhibitors can be taken while pregnant. The preferred protease inhibitor medications during pregnancy are atazanavir/ritonavir and darunavir/ritonavir. 

The following protease inhibitors are not recommended during pregnancy:

• Lopinavir/ritonavir

• Darunavir/cobicistat

• Atazanavir/cobicistat

If a woman already taking antiretroviral drugs becomes pregnant, it is recommended to continue the current therapy and not change medications. 

Antiretroviral treatment may significantly reduce the risk of HIV transmission while breastfeeding. However, according to clinical trials, the use of antiretroviral drugs while breastfeeding does not eliminate the risk of HIV transmission. Therefore, breastfeeding is not recommended for women who are HIV positive. 

Are protease inhibitors safe?

In general, protease inhibitors are safe. Patients with other medical conditions will need to be monitored for potential side effects. Tell your healthcare provider about any medications and supplements you are taking before starting a protease inhibitor. 

Black box warnings

Aptivus (tipranavir) carries a black box warning for liver toxicity and intracranial bleeding, or hemorrhage. Death resulting from liver disease or worsening liver function has been reported with Aptivus. Intracranial hemorrhage, both fatal and non-fatal, has also been reported with Aptivus. 

Norvir (ritonavir) carries a black box warning regarding drug interactions. Severe reactions can occur if Norvir is given with drugs like sedative-hypnotics, antiarrhythmics, and ergot alkaloid medications.

Olysio (simeprevir) carries a black box warning to test for hepatitis B infection before administration. Hepatitis B infection can be reactivated by the use of Olysio.

Refer to the drug labels of protease inhibitors to determine if they carry a possible black box warning. Discuss the potential for serious adverse effects with a healthcare professional before starting treatment with a protease inhibitor. 

Recalls

There are no current recalls for specific protease inhibitors.

Restrictions

Protease inhibitors are contraindicated in those with a known hypersensitivity reaction to any ingredients in protease inhibitors. Protease inhibitors should also be used with caution in those who have liver disease, hemophilia, or diabetes. Consult a healthcare provider for other possible warnings and precautions before starting treatment with a protease inhibitor. 

Are protease inhibitors controlled substances?

No, protease inhibitors are not controlled substances. 

Common protease inhibitors side effects

The most common side effects of protease inhibitors include:

• Nausea 

• Vomiting

• Diarrhea

• Rash or dry skin

• Insomnia

• Development of gallstones or kidney stones

• Changes in taste perception

• Elevations in liver enzymes

• Insulin resistance

• Hyperglycemia

• Elevated cholesterol levels

More severe but rare side effects of protease inhibitors include:

• Skin reactions

• Liver failure

• Seizures

• Pancreatitis

This list of side effects is not comprehensive. Certain adverse effects may be more common with certain protease inhibitors, so it’s important to evaluate the risk of side effects based on the protease inhibitor prescribed. Speaking with a healthcare professional is also the best way to get a complete list of side effects and determine whether taking protease inhibitors is suitable for you.

Drug interactions

Tell your healthcare provider about all medications you are currently taking so they can check for any interactions with protease inhibitors. All protease inhibitors are substrates of the CYP3A4 enzyme, a common enzyme that metabolizes, or processes, many medications in the body. Protease inhibitors act as CYP3A4 inhibitors and can interact with medications that are metabolized by the CYP3A4 enzyme. For example, protease inhibitors can increase blood levels of corticosteroids and increase the risk of Cushing syndrome. The following drugs are known to interact with protease inhibitors:

• Warfarin

• Benzodiazepines

• Anticonvulsants

• Corticosteroids 

• Statins 

• Calcium channel blockers

• Azole antifungals

How much do protease inhibitors cost?

Protease inhibitors vary in price but tend to be moderate to high priced. Protease inhibitors are typically included in a multi-drug regimen that consists of multiple tablets or a single-tablet form. Insurance coverage will vary based on your provider. Using a prescription discount card from SingleCare may help reduce the cost of protease inhibitors.