Protease is an enzyme HIV needs at a later stage in its reproductive cycle. Protease inhibitors are a class of anti-HIV drugs that work by inhibiting (slowing down or blocking) the action of protease. When this enzyme can't do its work, HIV makes defective copies of itself that cannot infect other cells. Like reverse transcriptase inhibitors, protease inhibitors may reduce the amount of HIV that can be measured in your blood, which in turn may raise CD4 cell counts. Protease inhibitors work best when combined with two or more reverse transcriptase inhibitors.
In addition to the specific adverse effects listed for the individual protease inhibitors, they all may potentially lead to changes in fat distribution (loss of fat in the arms, buttocks, and thighs; increased fat in the abdomen, and the back of the neck). They may also cause increases in triglyceride and cholesterol (types of fat in your blood), and glucose (blood sugar). You may or may not notice any symptoms from increases in triglyceride and cholesterol. However, your doctor will routinely check for elevations in your blood. Too high triglycerides may place you at risk of pancreatitis, in which case, you may notice pain around the abdomen, nausea and vomiting. Symptoms of elevated glucose may include increased urination, hunger and/or thirst, or numbing/tingling of the feet.
Protease inhibitors (especially ritonavir) may affect the way your body breaks down other drugs that pass through the liver. For this reason, there are many potential drug interactions with protease inhibitors. Therefore, it is very important to let your health care providers know exactly which medications you are taking (i.e. prescription, over-the-counter, herbals and street drugs), and plan on taking. By doing this, potential harmful drug interactions may be avoided.
Saquinavir (Fortovase™, Invirase™)
Saquinavir was the first protease inhibitor developed. Originally it was formulated as a hard gel capsule (Invirase™). However, due to its poor oral absorption, the formulation was changed to a soft gel capsule (Fortovase™). To further improve the amount of saquinavir available to the body, it is often used in combination with ritonavir (see below). More recent studies have shown that combining Irvirase with (Norvir™) actually provides higher drug levels compared to (Fortovase™) with (Norvir™). (Invirase™) with (Norvir™) is now the recommended choice when choosing saquinavir.
Usual Dose:
1200 mg three times daily (Fortovase™) [Dosage is lower if used with ritonavir].
600 mg three times daily (Invirase™) [Dosage is lower if used with ritonavir].
Availability: 200 mg capsules Dietary Restrictions: Should be taken with food/meals. Storage: Pharmacies will store Fortovase in the refrigerator prior to dispensing. Once it is brought to room temperature, the capsules should be used with in 3 months. Adverse Effects: diarrhea, abdominal discomfort, nausea, increases in triglyceride, cholesterol or glucose, changes in fat distribution, increases in liver enzymes.
Ritonavir (Norvir™)
In addition to blocking protease, ritonavir also blocks the break down of some medications that the body eliminates through the liver. Since all the current protease inhibitors pass through the liver, ritonavir is often combined with another protease inhibitor to improve its effect. When given in this way this is called "boosting." The dose of both medications are reduced and given less frequently. Examples of dual protease combinations that are used are listed below.
Usual Dose: 600 mg twice daily (start at 300 mg twice daily and increase at 2 to 3 day intervals by 100 mg twice daily up to 600 mg twice daily). Availability: 100 mg capsules, 80 mg/ml liquid syrup [bottles of 240 ml] Dietary Restrictions:Should be taken with food. Storage Requirements: Refrigeration of Norvir soft gelatin capsules is recommended, but not required if used within 30 days and stored below 77oF. Pharmacies will store Norvircapsules in the refrigerator prior to dispensing. Adverse Effects: nausea, vomiting, diarrhea, feeling weak or tired, loss of appetite, abdominal pain, taste disturbances, tingling sensation or numbness in the hands, feet or around the lips, headache, dizziness, increases in triglycerides and cholesterol, increases in blood sugar, fat redistribution, increases in liver enzymes.
Examples of commonly used ritonavir based dual protease inhibitor combinations are listed below:
Usual Dose: 800 mg every 8 hours Availability: 200 and 400 mg capsules Dietary Restrictions: Take on empty stomach with plenty of liquids (1.5 liters/day) - water, coffee, juice, tea, skim milk is okay. If nausea is a problem, take with a light meal low in protein and fat (e.g dry toast with jelly, corn flakes with skim milk and sugar.) If indinavir is combined with ritonavir, there are no food restrictions. Storage Requirements: The capsules are sensitive to moisture, therefore, keep stored in original container. Adverse Effects: kidney stones (symptoms may include pain in the back, blood in urine) [Note: It is very important to drink plenty of fluids to help prevent kidney stones.], nausea, vomiting, diarrhea, abdominal pain, increases in liver enzymes, glucose (blood sugar), triglycerides and cholesterol, changes in body fat distribution.
Nelfinavir (Viracept™)
Usual Dose: 750 mg three times daily, 1250 mg twice daily Availability: 250 mg tablets, and 50 mg/g powder Dietary Restrictions: Take with food/meals Adverse Effects: diarrhea, nausea, rash, fatigue, increases in liver enzymes, triglycerides/cholesterol and/or glucose, changes in body fat distribution
Amprenavir (Agenerase™)
Amprenavir is the most recent protease inhibitor approved for use in HIV disease.
Usual Dose: 1200 mg twice daily Availability: 50, 150 mg capsules, 15 mg/ml liquid syrup [bottles of 240 ml] Dietary Restrictions: Take with food/meals. Each 150 mg capsule contains 159 IU of Vit E. Therefore, avoid any additional vitamin E supplements. Adverse Effects: nausea, vomiting, rash, headache, diarrhea, increases in liver enzymes, triglycerides/cholesterol, and glucose, may causes changes in body fat distribution.
Fosamprenavir Calcium (Lexiva™)
Fosamprenavir Calcium is a new formulation of amprenavir. Fosamprenavir is rapidly converted to amprenavir once absorbed into the body. Fosamprenavir is available in tablet form and requires less pills per dose compared to amprenavir. Eventually amprenavir will be discontinued by the drug maker and all patients taking amprenavir will be switched to fosamprenavir calcium. Fosamprenavir may be given once daily with ritonavir if patients have not taken a protease inhibitor previous to starting fosamprenavir. Fosamprenavir may also be prescribed as twice daily either alone or in combination with ritonavir. If a patient has taken a different protease inhibitor prior to starting fosamprenavir then fosamprenavir must be taken twice daily with ritonavir.
Usual Dose:
Fosamprenavir 1400 mg once daily + Ritonavir 200 mg once daily for patients who have never took a protease inhibitor
Fosamprenavir 700 mg twice daily + Ritonavir 100 mg twice daily for patients who have never took a protease inhibitor
Fosamprenavir 1400 mg twice daily for patients who have never took a protease inhibitor
Fosamprenavir 700 mg twice daily + Ritonavir 100 mg twice daily for patients who have taken a protease inhibitor previously
Availability: 700 mg tablets Dietary Restrictions: No food or fluid restrictions. Adverse Effects: Most common side effects were diarrhea, headache, nausea, vomiting, fatigue and rash. The drug is generally well tolerated. Long term adverse effects may include increases in glucose, triglyceride, cholesterol and may cause changes in body fat distribution.
Lopinavir/Ritonavir (Kaletra™)
In addition to blocking protease, ritonavir also blocks the break down of some medications that the body eliminates through the liver. Since all the current protease inhibitors pass through the liver, ritonavir is often combined with another protease inhibitor to improve its effect. When given in this way, the dose of both medications are reduced and given less frequently. Examples of dual protease combinations that are used are listed below.
Usual Dose: The recommended adult dosage of KALETRA™ is 400/100 mg (3 capsules or 5.0 mL) twice daily. A dose increase of KALETRA™ to 533/133mg (4 capsules or 6.5 mL) twice daily when used in combination with efavirenz (Sustiva™) or nevirapine (Viramune™).
Availability: Kaletra™ capsules are available as 133.3mg lopinavir/33.3 mg ritonavir capsules (bottles of 180 capsules each or packages of 120 unit dose blisters).
Kaletra oral solution contain 400 mg lopinavir/100 mg ritonavir per 5 mL (80mg lopinavir/20mg ritonavir per mL) packaged with a marked dosing cup in a 160 mL bottle.
Dietary Restrictions: Should be taken with food.
Storage Requirements: Refrigeration of Kaletra™ soft gelatin capsules is recommended, but not required if used within 30 days and stored below 77oF (25 oC). Pharmacies will store Kaletra™ capsules in the refrigerator prior to dispensing.
Adverse Effects: The most common adverse event associated with Kaletra™ therapy was diarrhea, which was generally of mild to moderate severity. Possible side effects include nausea, rash, weakness, headache, vomiting, elevations in liver enzymes, triglycerides, or cholesterol, or hyperlipemia (excess fat in the blood). Side effects common to all protease inhibitors are diabetes and high blood sugar, high fat levels in the blood, liver problems, weight gain, thinning of face, arms, and legs, with fat added to stomach, breasts, and upper back (lipodystrophy). Refer to Ritonavir for other adverse effects.
Atazanavir Sulfate (Reyataz™)
Atazanavir is the latest protease inhibitor to be approved for use in combination HIV therapy. An important advantage is once daily dosing and less long term side effects. Unlike the other protease inhibitors, atazanavir appears not to affect glucose, triglyceride and cholesterol levels.
Usual Dose: 400 mg once daily or 300 mg once daily + 100 mg Ritonavir Availability: 100 mg capsules, 150 mg capsules and 200 mg capsules Dietary Restrictions: Take with food. Reyataz™ without ritonavir should not be coadministered with efavirenz. Reyataz™ should be administered 2 hours before or 1 hour after ddI buffered formulations. Coadministration with indinavir not recommended. Coadminstration with tenofovir may lead to decreased levels of atazanavir. Adverse Effects: Most common side effects include nausea, vomiting, abdominal pain, headache, diarrhea, peripheral neuropathy and rash. Most patients taking Reyataz? experience increases in the substance called bilirubin. When bilirubin accumulates to very high concentrations it may cause jaundice. The jaundice seen in patients taking atazanvir is painless and is reversible when the drug is discontinued. Alternative antiretroviral therapy to Reyataz™ may be considered if janudice or “yellow eyes” becomes a cosmetic concern.
