Protease inhibitors block an enzyme called HIV protease, which prevents infected cells from producing more HIV. There are 11 U.S. FDA-approved protease inhibitors used to treat HIV. The use of two protease inhibitors in dual protease-inhibitor regimens is popular because of drug interactions that increase potency, reduce dose frequency, require fewer food restrictions, and lower the cost. Long term effects of dual protease-inhibitor regimens are unknown.
Blood levels of protease inhibitors drop significantly shortly after being taken. This makes frequent dosing necessary to maintain a level of the medication in the blood to destroy the virus. Missed doses lead to low blood levels of drug, allowing the virus to multiply, mutate, and develop resistance. Much of the focus of current studies is to develop new medications and new ways of taking medications that maintain proper drug levels, prevent resistance, and overcome the need for frequent dosing.
Protease inhibitors have been associated with new onset diabetes mellitus and may worsen pre-existing diabetes. All patients who are on antiretroviral therapy must be followed closely by a health care professional for treatment-related side effects. PIs can cause elevations in blood levels of sugar, as well as cholesterol and other fats and have been associated with lipodystrophy.
Protease inhibitors approved to treat HIV include the following:
- Saquinavir mesylate (Invirase, Fortovase)
Saquinavir was first approved for use in the United States in 1995. It was first known by the brand name Invirase and is no longer marketed as Fortovase. The usual dose is six 200 mg pills three times daily or eight 200 mg pills twice daily. This drug is prescribed with ritonavir, which can boost saquinavir levels more than 10 times. Patients usually take 1 ritonavir pill with 2 Invirase pills twice daily.
Side effects include diarrhea, nausea, and upset stomach. Patients may also experience headaches and fatigue.
- Ritonavir (Norvir)
Ritonavir was the second protease inhibitor approved for use in the United States. Ritonavir has many side effects and interacts with many drugs. The fact that it interacts so readily with other drugs can be used advantageously, if combined with the right drugs. Low doses of ritonavir are now routinely used with saquinavir, indinavir, and amprenavir to boost their levels, increase their potency, and decrease the number of daily doses required. These interactions can also be dangerous leading to unintentional overdoses of prescription medications or illegal drugs.
When taken as the only protease inhibitor, the usual dose is four to six 100 mg pills twice daily. If ritonavir is being used to boost another protease inhibitor, the usual dose is one or two 100 mg pills twice daily.
Ritonavir can cause numbness and tingling of the face and mouth, nausea, diarrhea, belly pain, headaches, and fatigue. Side effects are minimized if the dose of ritonavir is slowly increased over 1 to 2 weeks.
The interaction of ritonavir with other drugs can lead to life-threatening situations. Patients should tell their doctors about all drug use, legal and illegal, to avoid adverse effects resulting from a drug interaction.
- Indinavir (Crixivan)
Indinavir was approved for use in the United States in 1996. Until recently, the dose of indinavir was two 400 mg pills every eight hours on an empty stomach. If not taken on time or on an empty stomach, blood levels readily drop below what is necessary to kill the virus.
Many HIV specialists now give indinavir along with norvir to overcome this problem. Norvir raises the levels of indinavir in the blood enough to decrease the dosing to every 12 hours instead of every 8. A commonly prescribed dose of indinavir is two 400 mg pills with 100 or 200 mg of norvir twice daily. When taken with norvir, it can be taken with food.
Side effects include kidney stones, belly pain, diarrhea, and dry skin and mouth. Patients who take indinavir should drink plenty of water to prevent or minimize side effects.
- Nelfinavir (Viracept)
Nelfinavir, which was the fourth protease inhibitor approved for use in the United States, received FDA approval in March 1997. The usual dose is five 250 mg pills or two 625 mg pills twice daily, taken with food.
The main side effect is diarrhea, which occurs in 10–30 percent of patients. This condition is usually treatable and only about 5 percent of patients stop taking nelfinavir because of diarrhea. Other side effects include poor concentration, intermittent headaches, and moderate hypertension (high blood pressure).
- Amprenavir (Agenerase)
Amprenavir was the fifth protease inhibitor to be approved for HIV treatment. The FDA-approved dose is eight 150 mg pills twice daily. Current studies show that taking ritonavir simultaneously boosts the level of amprenavir. Some HIV specialists now prescribe 100 to 200 mg of ritonavir with three or four 150 mg amprenavir pills twice daily.
The main side effects are skin rash and gastrointestinal complications, including nausea, vomiting, and diarrhea. The skin rash, which usually is mild to moderate but can be life threatening, occurs in more than 25 percent of all patients.
Amprenavir interacts with many other drugs, including antacids, so patients should tell their doctors about all drug use, legal and illegal, to prevent adverse effects resulting from drug interaction.
- Lopinavir and ritonavir (Kaletra)
Lopinavir and ritonavir, also known as Kaletra, was approved for use by the FDA in September of 2000. Kaletra is a combination of 133 mg of Lopinavir and 33mg of Ritonavir. The usual dose is three pills twice a day. Ritonavir gives Lopinavir levels that are 20-30 times higher than those necessary to kill usual HIV. These high levels of drug may also make Kaletra helpful against resistant HIV.
The most common side effects are diarrhea, nausea and vomiting. Some patients also experience rash, fatigue and headache. Because Kaletra contains ritonavir, it should never be taken with other medications unless the medications have been reviewed by a physician or pharmacist who is an expert in the treatment of HIV. Ritonavir can raise blood levels of many medications to dangerous levels.
- Atazanavir sulfate (ATV, Reyataz)
This protease inhibitor was approved by the FDA in June 2003. It is approved for use in adults and should be taken with food. Reyataz is taken as a tablet once per day and the dosage depends on whether the patient is just beginning antiretroviral therapy or is changing medications.
Reyataz reacts with a number of other drugs, and patient should notify their doctor of all over-the-counter medications (including herbal remedies) and prescription drugs they are taking before beginning treatment. Side effects include kidney stones, headache, dizziness, nausea, and tingling in the arms and legs. Liver damage may also occur.
- Fosamprenavir calcium (Lexiva)
Lexiva received FDA approval in October 2003. This drug is used to treat HIV infection in adults and can be taken either once or twice per day.
Common side effects include nausea and vomiting, diarrhea, headache, and skin rash. In some cases, this drug has been shown to worsen diabetes and cause high blood sugar.
- Tipranavir (TPV, Aptivus)
In 2005, the Food and Drug Administration approved this drug, which must be taken with ritonavir (Norvir), to treat HIV in adults. It is available as a capsule that must be swallowed and not chewed, and is taken twice per day. Aptivus and Norvir are used in combination with other medications.
Side effects include diarrhea, stomach pain, headache, and fatigue. This drug can also cause liver damage and increase bleeding in patients who have hemophilia.
- Darunavir (Prezista)
Prezista is a protease inhibitor that was approved in June 2006. It also is taken with Norvir and is used in combination with other antiretrovirals. Long term effects of this medication are not yet known. It is not approved for use in adults who are just beginning antiretroviral therapy or in children.
Prezista may cause diarrhea, headache, and the common cold. In some cases, it worsens diabetes, results in liver problems, and causes mild-to-severe skin rash.
- Raltegravir (Isentress)
In October 2007, the FDA approved the HIV integrase strand transfer inhibitor raltegravir (Isentress) to treat HIV infection. This drug is approved for use in adult patients who are already on antiretroviral therapy. It is used in combination with other medications.
Side effects include nausea, diarrhea, and headache. Raltegravir may increase the risk for serious conditions, such as muscle disorders (myopathy) and the destruction of skeletal muscle (called rhabdomyolysis).
- Dolutegravir (Tivicay)
In August 2013, dolutegravir (Tivicay) was approved to treat HIV-1 infection. According to the FDA, dolutegravir is an integrase strand transfer inhibitor that interferes with one of the enzymes needed for HIV to multiply. This drug is approved for use in adults with HIV who have never taken antiretrovirals, adults who have previously been on antiretroviral therapyincluding other integrase strand transfer inhibitors, and children over the age of 12 who weigh at least 88 pounds who have never taken an integrase strand transfer inhibitor.
Side effects include trouble sleeping and headache. Serious side effects include hypersensitivity and abnormal liver function in patients with hepatitis B or hepatitis C. Patients taking dolutegravir should be monitored for serious side effects.
In December 2012, the FDA approved the first medication to treat diarrhea in people with HIV who are on antiretroviral therapy. This botanical drugcrofelemer (Fulyzaq)is taken twice a day to control diarrhea that is not caused by a viral or bacterial infection, a parasite, or GI condition. Common side effects include upper respiratory infection, cough and elevated levels of the liver enzyme bilirubin.