Protease inhibitors

background

Protease inhibitors (PIs) disrupt the replication of HIV (human immunodeficiency virus). These drugs interfere with the protease enzyme that HIV uses to produce infectious viral particles. When protease is blocked, the new copies of HIV are not formed properly, and they are unable to infect new cells.
The U.S. Food and Drug Administration (FDA) has approved 10 protease inhibitors, including Agenerase®, Aptivus®, Crixivan®, Invirase®, Kaletra®, Lexiva®, Norvir®, Prezista®, Reyataz®, and Viracept®.
Since HIV primarily targets the body's CD4 T-cells, which are white blood cells that help coordinate the immune system's response to infections and diseases, HIV patients are vulnerable to opportunistic infections (OIs). Opportunistic infections occur in patients who have weakened immune systems. Although antiretrovirals are not curative, they are able to suppress HIV subsequently boosting the patient's immune system. These drugs have also shown to dramatically slow the progression of OIs.
HIV patients typically receive a combination of antiretroviral drugs because, as the virus reproduces, different strains emerge, and some are resistant to certain drugs. This happens less often when patients adhere to their medication regimens. Therefore, highly active antiretroviral therapy (HAART), which is a combination of drugs from at least two different classes, is recommended.
Currently, the FDA has approved 28 antiretroviral drugs to treat HIV patients. These drugs fall into four major classes: fusion inhibitors, protein inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Related Terms

Antiretroviral therapy, antiretrovirals, ART, fusion inhibitors, HAART, highly active antiretroviral therapy, HIV, HIV protease enzyme, human immunodeficiency syndrome, immune defense system, immune system, immunocompromised, immunodeficiency, infection, inhibitor, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, OI, opportunistic infections, polyprotein, protease, protease enzyme, reverse transcriptase inhibitors, virion, virus.

function

Once HIV infects a human cell, the virus copies its own genetic makeup into the cell's DNA. This programs the human cell to produce new copies of HIV. The infected cell makes a long strand of genetic material that must be cut up and put back together in order to form new copies of HIV. The protease enzyme is responsible for "cutting up" these strands. Without the protease enzyme, the virus cannot replicate.
Protease inhibitors (PIs) prevent the protease enzyme from doing its job. Like a key fitting into a lock, PIs inhibit the activity of the protease enzyme. When protease is blocked, HIV makes copies of itself that are unable to infect new cells. Studies have shown that protease inhibitors can reduce the amount of virus in the blood and increase CD4 cell counts. These drugs have shown to effectively increase CD4 cell counts, even when counts are extremely low.

types of protease inhibitors

Amprenavir (Agenerase®) :
Amprenavir (Agenerase®) was approved by the U.S. Food and Drug Administration (FDA) on April 15, 1999. It is available in an oral gel capsule or oral solution.
Amprenavir is typically taken along with ritonavir (Norvir®). Patients typically take 1,200 milligrams of amprenavir along with 200 milligrams of ritonavir once a day. Alternatively, patients may take 600 milligrams of amprenavir with 100 milligrams of ritonavir twice a day. Adolescents ages 13-16 typically take 1,200 milligrams of amprenavir twice a day. The recommended dosages for children ages four to 12 or adolescents ages 13-16 who weigh less than 110 pounds, vary depending on the patient's weight. Patients should take medications exactly as prescribed by their healthcare providers. Patients should not switch formulations of amprenavir without first consulting their healthcare providers.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. Patients who take blood-thinning drugs (warfarin) or have low levels of vitamin K, should consult their healthcare providers to determine if the vitamin E in amprenavir interferes with treatment. Vitamin E supplements are not recommended in patients taking amprenavir because recent evidence suggests that regular use of high-doses of vitamin E may increase the risk of death (from "all causes") by a small amount.
Patients who are taking sildenafil (Viagra®) should consult their healthcare providers because amprenavir may increase the risk of Viagra®-related side effects, including low blood pressure, changes in vision, or penile erection lasting more than four hours.
Use cautiously with diabetes medications because amprenavir may increase blood sugar. Amprenavir may cause a serious skin rash or hemolytic anemia (low levels of red blood cells).
Other more common side effects may include nausea, vomiting, diarrhea, numbness of the hands or feet, and a tingling sensation around the mouth. These side effects generally subside or disappear as the mediation is continued.
Avoid in patients who are pregnant or trying to become pregnant because amprenavir may cause birth defects if taken during pregnancy.
Tipranavir (Aptivus®) :
Tipranavir (Aptivus®), also called TPV, was approved by the U.S. Food and Drug Administration (FDA) on June 22, 2005. Tipranavir is available in a 250 milligrams oral capsule. The drug must be taken at the same time as ritonavir (Norvir®). Tipranavir should be taken with food.
Patients typically take 500 milligrams of tipranavir, along with 200 milligrams (or 2.5 milliliters of solution) of ritonavir twice daily. Some patients may require alternative doses. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. For instance, tipranavir has been shown to interact with migraine medicines (ergot alkaloids), triazolam (Halcion®), astemizole (Hismanal®), pimozide (Orap®), cisapride (Propulsid®), quinidine (Quinaglute®), midazolam (Versed®), terfenadine (Seldane®), amiodarone (Pacerone®), bepridil (Vascor®), propafenone (Rythmol®), or flecainide (Tambocor®).
Some patients who are taking tipranavir with 200 milligrams ritonavir may develop severe liver disease that may lead to death. Patients should undergo regular blood tests to monitor liver function during treatment. Patients with liver diseases such as Hepatitis B and Hepatitis C may experience a worsening of their liver disease. Symptoms of severe liver disease may include tiredness, flu-like symptoms, loss of appetite, nausea, jaundice (yellowing of the skin and eyes), dark urine, pale stools, and pain or sensitivity on the right side below the ribs. Patients who experience these symptoms should consult their healthcare providers.
An estimated 10% of patients who take tipranavir develop mild to moderate rashes or sensitivity to sunlight. Limiting skin exposure to sunlight and wearing sunscreen may help reduce symptoms associated with sunlight sensitivity. Some patients who develop rashes also experience joint pain or stiffness, throat tightness, or generalized itching.
Hemophilic patients may experience an increase in bleeding.
Tipranavir may increase blood sugar levels and potentially lead to diabetes in some patients. Patients with diabetes before starting treatment may experience a worsening of symptoms, such as increased thirst and urination, flu-like symptoms, sores that heal slowly, swollen or tender gums and weight loss or weight gain. Some patients will need to change their current diabetes treatments.
Throughout treatment, a qualified healthcare provider should regularly monitor the patient's triglycerides and cholesterol (amount of fat in the blood) because some patients may experience dramatic increases in these levels. It is currently unknown whether tipranavir increases the likelihood of heart attack or stroke.
Changes in body fat may also occur in some patients. Tipranavir may cause fat to accumulate on the upper back and neck ("buffalo hump"), as well as in the breast, chest, and stomach area. Other patients may experience a loss of fat in the arms, legs, and/or face. The exact cause and long-term effects of these conditions remain unknown.
Common side effects include diarrhea, nausea, vomiting, stomach pain, tiredness, and headache. Women who are taking birth control pills have an increased risk of developing a skin rash.
Indinavir (Crixivan®) :
Indinavir (Crixivan®) was approved by the U.S. Food and Drug Administration (FDA) on March 13, 1996 for the treatment of HIV in adults in combination with other antiretrovirals. Indinavir is an oral capsule, which is available in 100 milligram, 200 milligram, 333 milligrams, and 400 milligram strengths.
Indinavir should be taken on an empty stomach, either one hour before or two hours after eating a meal. This allows for better absorption of the drug in the intestine. Adults typically take 800 milligrams of indinavir every eight hours. Some patients, including those with liver disease, may require different doses. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. For instance, patients should not take indinavir if they are taking amiodarone (Cordarone®), ergot medications (Wigraine®, Cafergot®, Migranal®, Ergotrate®, or Methergine®), triazolam (Halcion®), astemizole (Hismanal®), lovastatin (Mevacor®), pimozide (Orap®), cisapride (Propulsid®), or simvastatin (Zocor® or Vytorin®).
Some patients may develop kidney stones, which can potentially lead to more severe kidney problems such as kidney failure, inflammation of the kidneys, or kidney infection. Drinking at least six, eight-ounce glasses of liquid each day may help reduce the likelihood of developing kidney stones.
Some patients experience hemolytic anemia (low levels of red blood cells in the body), which in some cases may be severe and even result in death. Patients may also experience severe liver problems, which may lead to liver failure or even death.
Indinavir may increase blood sugar levels and potentially lead to diabetes in some patients. Patients who have diabetes before starting treatment may experience a worsening of symptoms, and they may need to change their current diabetic medications.
Patients with hemophilia have an increased risk of bleeding.
Severe muscle pain and weakness have been reported in patients taking indinavir, along with cholesterol-lowering medicines called "statins," such as atorvastatin (Lipitor® or Torvast®) or fluvastatin (Lescol®).
Because some patients may experience dramatic increases in the levels of triglycerides and cholesterol (fat) in the blood, regular blood tests should be performed during treatment. It remains unknown whether indinavir increases the likelihood of heart attack or stroke.
Increases in bilirubin (yellow-red pigment of human bile in the liver) have occurred in about 14% of patients. In rare cases, this may lead to jaundice (yellowing of the skin and eyes).
Less serious side effects include change in sense of taste, diarrhea, nausea, vomiting, dizziness, drowsiness, fatigue, headache, stomach pain, and trouble sleeping. These symptoms generally subside or disappear as the medication is continued.
Saquinavir mesylate (Invirase®) :
Saquinavir mesylate (Invirase®) was approved by the U.S. Food and Drug Administration (FDA) on November 7, 1997 for the treatment of HIV in combination with other antiretrovirals.
Saquinavir mesylate is available as a tablet and capsule, and it should be taken with food. It must be taken along with ritonavir (Norvir®), according to the FDA. Patients typically receive 1,000 milligrams of squinavir mesylate in combination with 100 milligrams of ritonavir twice daily. Some patients may require alternative doses. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other medications (prescription or over-the-counter), herbs, or supplements because they may interact with treatment.
Common side effects include diarrhea, abdominal pain or discomfort, nausea, loss of appetite, ulcers in the mouth, dizziness, numbness of the hands or feet, headache, musculoskeletal pain, muscle pain, nausea, abnormal sensation (like burning or prickling on the skin), peripheral neuropathy (nerve disorder), itchy skin, and rash.
Rare side effects include confusion, loss of muscle coordination, muscle weakness, acute myeloblastic leukemia, hemolytic anemia (low levels of red blood cells), Stevens-Johnson syndrome, seizures, severe skin reaction associated with increased liver function tests, isolated elevation of transaminases, thrombophlebitis (inflammation of a vein that occurs when blood clots), headache, thrombocytopenia, worsening of chronic liver disease, jaundice (yellowing of the skin and eyes), fluid in the abdomen, drug fever, blisters, polyarthritis (inflammation of many joints), pancreatitis (inflammation of the pancreas), kidney stones, internal bleeding of the brain, peripheral vasoconstriction, high blood pressure, and intestinal obstruction.
Protease inhibitors may increase the risk of bleeding in hemophilic patients.
Because some patients may experience dramatic increases in the levels of triglycerides and cholesterol in the blood, regular blood tests should be performed during treatment. It remains unknown whether saquinavir mesylate increases the likelihood of heart attack or stroke.
Lopinavir/ritonavir (Kaletra®) :
Lopinavir/ritonavir (Kaletra®) is a combination pill made from two protease inhibitors. The drug was approved by the U.S. Food and Drug Administration (FDA) on September 15, 2000. This combination pill was developed because lopinavir breaks down too quickly in the body if it is taken alone. Ritonavir prolongs the amount of time it takes to break down the pill, allowing for complete absorption of the drug.
Lopinavir/ritonavir is available as a tablet or oral solution. The tablets contain 200 milligrams of lopinavir and 50 milligrams of ritonavir. Every 5 milliliters of lopinavir/ritonavir oral solution contains 400 milligrams of lopinavir and 100 milligrams of ritonavir. Adults who have taken antiretroviral drugs before typically take two tablets or 5 milliliters of oral solution twice daily. Patients who have never received antiretroviral therapy before typically take four tablets once daily. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. If lopinavir/ritonavir is taken once daily, certain antiretrovirals, including amprenavir (Agenerase®), efavirenz (Sustiva®), nelfinavir (Viracept®), nevirapine (Viramune®), and phenytoin (Dilantin®), should be avoided. Lopinavir/ritonavir should not be taken with dihydroergotamine (D.H.E. 45®), ergonovine (Ergotrate®), ergotamine (Cafergot®, Ercaf®), triazolam (Halcion®), astemizole (Hismanal®), pimozide (Orap®), cisapride (Propulsid®), terfenadine (Seldane®), midazolam (Versed®), rifampin (Rimactane®, Rifadin®, Rifater®, or Rifamate®), fluticasone (Flonase®), lovastatin (Mevacor®), simvastatin (Zocor®), phenobarbital (Luminal® Sodium), carbamazepine (Tegretol®), or products containing the herb St. John's wort (Hypericum perforatum).
Use cautiously with sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®) because lopinavir/ritonavir may increase the risk of developing side effects associated with these drugs.
Pancreatitis (inflammation of the pancreas) and liver problems, which can be fatal, have been reported in patients taking lopinavir/ritonavir.
The most commonly reported side effects of moderate severity include abdominal pain, abnormal bowel movements, diarrhea, fatigue, headache, and nausea. Children are more susceptible to side effects and have an increased risk of developing a skin rash.
Because some patients may experience dramatic increases in the levels of triglycerides and cholesterol in the blood, regular blood tests should be performed during treatment. It remains unknown whether lopinavir and ritonavir increase the likelihood of heart attack or stroke.
Fosamprenavir calcium (Lexiva®) :
The U.S. Food and Drug Administration approved fosamprenavir calcium (Lexiva®) on October 20, 2003. Fosamprenavir calcium is available as a 700 milligrams oral tablet. This drug should not be taken with amprenavir (Agenerase®).
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. For instance, patients taking fosamprenavir calcium should not take triazolam (Halcion®), ergot medications (Cafergot®, Migranal® or D.H.E. 45®), cisapride (Propulsid®), midazolam (Versed®), pimozide (Orap®), simvastatin (Zocor®), lovastatin (Mevacor®), rifampin (Rifadin®), delavirdine mesylate (Rescriptor®), or any products containing the herb St. John's wort (Hypericum perforatum). Fosamprenavir calcium should not be taken with hormonal contraceptives (birth control pills) because it may reduce their safety and effectiveness.
Life-threatening drug interactions may occur if patients take medications, such as amiodarone (Cordarone®), intravenous lidocaine, amitriptyline HCl (Elavil®), imipramine pamoate (Tofranil®), tricyclic antidepressants, or quinidine (Quinaglute®), with fosamprenavir calcium.
Use cautiously with sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®) because fosamprenavir calcium may increase the risk of developing side effects associated with these drugs.
Fosamprenavir calcium may increase blood sugar levels and can potentially lead to diabetes in some patients. Patients who are diagnosed with diabetes before starting antiretroviral therapy may experience a worsening of symptoms, and they may require changes in their current diabetic medications.
The most common side effects include diarrhea, headache, nausea, rash, and vomiting.
Ritonavir (Norvir®) :
The U.S. Food and Drug Administration (FDA) approved ritonavir (Norvir®) on March 1, 1996 for the treatment of HIV in adults and children older than two years old.
Ritonavir is available as 800 milligrams/milliliter oral solution or 100 milligrams oral capsule. Both forms should be taken with food. Adults typically take 600 milligrams of ritonavir twice daily. The recommended doses for children vary, depending on the patient's weight. Pediatric doses should not exceed 600 milligrams twice a day. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment.
Pancreatitis (severe inflammation of the pancreas) is a serious side effect that may cause stomach pain, nausea, or vomiting. Other serious side effects may include changes in body fat distribution, increased bleeding in hemophilia patients, increased blood sugar levels (which may lead to the onset or worsening of diabetes symptoms), and increased triglyceride and cholesterol levels in the blood.
Other less serious side effects may include fatigue, burning or prickling sensation in the hands and/or feet, stomach pain, diarrhea, constipation, indigestion, gas, nausea, vomiting, loss of appetite, change in sense of taste, headache, dizziness, drowsiness, insomnia, fever, skin rash, sore throat, and increased sweating.
Darunavir (Prezista®) :
The U.S. Food and Drug Administration (FDA) approved darunavir (Prezista®) on June 23, 2006 for the treatment of HIV in adults.
Darunavir is available as a 300 milligrams oral tablet. Adults typically take 600 milligrams of darunavir in combination with 100 milligrams of ritonavir (Norvir®) twice daily. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. Darunavir may interact with estrogen-based contraceptives (birth control pills), antiarrhythmics (used to treat irregular heart beat), anticoagulants (blood thinners), anticonvulsants (anti-seizure drugs), anti-depressants, anti-infectives (drugs that treat bacterial infections), antifungals (drugs that treat fungal infections), antimycobacterials (drugs that treat bacterial infections), corticosteroids (drugs that treat inflammation or asthma), HMG-CoA reductase inhibitors (drugs that lower cholesterol), immunosuppressants, narcotic analgesics, PDE-5 inhibitors (drugs that treat erectile dysfunction), and selective serotonin reuptake inhibitors (drugs that treat depression, anxiety, or panic disorder). Avoid with antihistamines (used to treat allergy symptoms), migraine medications, gastrointestinal motility agents, psychiatric drugs, or drugs that treat sleeping disorders because they may cause serious side effects.
In some patients, darunavir has caused severe or life-threatening rashes. Patients should contact their healthcare providers if a rash develops.
Other serious side effects may include changes in body fat distribution, increased bleeding in hemophilia patients, increased blood sugar levels (that may lead to the onset or worsening of diabetes symptoms), and increased triglyceride and cholesterol levels in the blood.
Patients with advanced HIV infection who have had opportunistic infections may develop symptoms of inflammation from previous infections soon after antiretroviral therapy is started. These symptoms are thought to be a sign that the body's immune system is improving because the body is now able to fight against infections.
The most common side effects include diarrhea, nausea, headache, sore throat, and common cold.
Atazanavir sulfate (Reyataz®) :
The U.S. Food and Drug Administration (FDA) approved atazanavir sulfate (Reyataz®) on June 20, 2003 for the treatment of HIV in adults.
Atazanavir sulfate is available as an oral capsule in 100 milligram, 150 milligram, 200 milligram, and 300 milligram strengths. Adults who have received antiretrovirals before typically take 300 milligrams in combination with 100 milligrams of ritonavir (Norvir®) once daily. Adults who have never received antiretrovirals before typically take 400 milligrams of atazanavir sulfate once daily. Patients should always take medications exactly as prescribed. Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment.
Serious side effects may include jaundice (yellowing of the skin or eyes), irregular heartbeat, increased blood sugar levels (that may lead to the onset or worsening of diabetes symptoms), diarrhea, increased risk of bleeding in hemophilic patients, changes in body fat distribution, blood in the urine, and nausea. Patients who have liver diseases, such as hepatitis B or C, may experience a worsening of symptoms when taking atazanavir sulfate.
Other, less severe, side effects may include headache, stomach pain, skin rash, vomiting, depression, cough, difficulty sleeping, fatigue, back pain, joint pain as well as numbness, tingling, or burning of the hands or feet.
Some patients taking atazanavir sulfate in combination with other antiretrovirals called nucleoside analogues may develop lactic acidosis syndrome. This life-threatening condition is a severe buildup of acid in the blood. Lactic acidosis syndrome is a medical emergency that must be treated in the hospital. Symptoms of lactic acidosis syndrome include nausea, vomiting, or unexpected stomach discomfort, fatigue, and difficulty breathing.
Nelfinavir mesylate (Viracept®) :
The U.S. Food and Drug Administration (FDA) approved nelfinavir mesylate (Viracept®) on March 14, 1997 for the treatment of HIV and for the prevention of HIV infection in individuals who have been exposed to the virus.
Nelfinavir mesylate is available as a 500 milligram oral suspension (powder) and 250 milligram, or 625 milligram oral tablets. Adults typically take 1,250 milligrams twice daily or 750 milligrams three times a day. The recommended dose for children ages two years and older varies depending on their weight. Patients should always take medications exactly as prescribed.
Patients should tell their healthcare providers if they are taking any other drugs (prescription or over-the-counter), herbs, or supplements because they may interact with treatment. For instance, nelfinavir mesylate should not be taken with amiodarone (Cordarone®), triazolam (Halcion®), midazolam (Versed®), pimozide (Orap®), rifampin (Rifadin®), simvastatin (Zocor®), lovastatin (Mevacor®), ergot medicines (D.H.E. 45®), or products containing the herb St John's wort.
Serious side effects may include changes in body fat distribution, increased bleeding in hemophilia patients, increased blood sugar levels (that may lead to the onset or worsening of diabetes symptoms), and increased triglyceride and cholesterol levels in the blood.
Other less serious side effects may include gas, diarrhea (mild to moderate), nausea, and skin rash. These symptoms generally subside or disappear as treatment continues.