AIDS Committee of Windsor: HIV Treatment Information

Summary
Indinavir is a type of anti-HIV drug called a protease inhibitor. The most common side effects are nausea, headache, diarrhea, vomiting, and weakness. Indinavir can also cause kidney stones, but drinking at least 1.5 extra litres of water daily can help reduce the risk. Indinavir is taken every 8 hours on an empty stomach (either one hour before or two hours after a meal).

What is it?
Indinavir, sold under the brand name Crixivan, is a type of antiretroviral drug called a protease inhibitor. Antiretroviral drugs fight HIV infection by interfering with the life cycle of the virus. At each stage of this cycle, chemical messengers called enzymes help the virus makes copies of itself. Some drugs can inhibit (slow down or stop) the actions of these enzymes. When these enzymes can't perform effectively, virus does not replicate as efficiently, and this slows the progression of HIV disease.

How does indinavir work?
HIV infects cells and then replicates with the help of its own enzymes. Protease (or proteinase) is one of the enzymes that allow HIV to make copies of itself. Indinavir blocks the action of protease and causes HIV to make defective copies that can't infect new cells.

Using indinavir in combination with reverse transcriptase inhibitors interferes with two different stages of the viral life cycle. For many people, a drug cocktail containing a protease inhibitor with two or more other antiretrovirals can improve CD4+ counts and viral load measures, and reduce opportunistic infections.

Resistance and cross-resistance
Over time, as HIV makes copies of itself, the virus can change its structure. These changes or mutations can allow HIV to resist the effects of antiretroviral drugs. Combining indinavir with at least two other drugs may delay the development of drug resistance. To limit the risk of resistance, all anti-HIV drugs should be taken every day, exactly as prescribed. The very strict schedule for taking indinavir is necessary because resistant virus can develop if the level of drug in the blood drops. This may happen if doses are delayed or skipped.

Research has shown that all currently available protease inhibitors may be cross-resistant. This means that, if HIV becomes resistant to one protease inhibitor, it may also be able to resist the effects of other protease inhibitors. In other words, if the virus has become resistant to indinavir, it will probably be resistant to saquinavir, ritonavir and nelfinavir. Cross-resistance can limit the choices of antiretroviral treatment.

Side effects
The most common side effects include nausea, vomiting, abdominal pain, headache, diarrhea, fatigue or weakness, and insomnia.

The most dangerous side effect is kidney stones (nephrolithiasis). Pain in the lower back and sides (flanks), with or without blood in the urine, is a symptom of kidney stones. These symptoms should be reported to your doctor immediately. To reduce the risk of developing kidney stones, people using indinavir should drink an extra 1.5 to 2.0 litres of liquids every day.

Lab tests may show higher than normal blood levels of bilirubin, a substance produced by the liver. Bilirubin levels often return to normal after a few months, but they should be monitored. High levels of bilirubin can sometimes cause the skin to darken slightly, giving the appearance of a tan or mild sunburn.

Dry skin, dry or cracked lips, and ingrown toenails have also been reported by indinavir users. These symptoms are sometimes referred to as ectodermal dysplasia.

Hemophiliacs may experience spontaneous bleeding episodes, including bruising and bleeding into joints. It is not clear if, or how, protease inhibitors cause bleeding. Any such episodes should be closely monitored.

With longer-term use, protease inhibitors (including indinavir) may cause increased blood sugar levels and diabetes. Although the risk of developing diabetes is very low, symptoms that may be related to diabetes (increased thirst, increased urination, unexplained weight loss, fatigue and dry, itchy skin) should be discussed with a doctor.

Lipodystrophy syndrome
Lipodystrophy syndrome is the term used to describe a range of symptoms that may be associated with the use of protease inhibitors. These symptoms can include physical changes in the body, such as:

1. Loss of fat from the face, arms and legs.
2. Thickening of the waist ("protease paunch").
3. Fat pads at the back of the neck ("buffalo hump") or around the base of the neck ("horse collar").
4. Increased breast size.
5. "Moon" face.
6. Bulging or visible veins in the arms and/or legs due to the loss of subcutaneous fat.

Along with these changes in appearance, there may be metabolic changes signalled by blood tests that show:

1. Increased levels of triglycerides (fats).

2. Decreased levels of high-density lipoprotein (HDL) or "good" cholesterol.

3. Increased levels of low-density lipoprotein (LDL) or "bad" cholesterol.

4. Increased levels of insulin.

5. Insulin resistance or reduced sensitivity to insulin.

The exact cause of lipodystrophy is not known, although many researchers, doctors and patients believe this syndrome is a side effect of protease inhibitors. Other researchers have observed the body shape changes and high blood fats before protease inhibitors became available. They suggest that lipodystrophy syndrome may be related to HIV itself rather than to antiretroviral drugs. Lipodystrophy syndrome is most likely caused by several different factors, which may include protease inhibitors, different chemicals or proteins in the body, and the virus itself.

Drug interactions
Indinavir, like many drugs, is metabolized (broken down and processed) by the liver through the actions of the p450 cytochrome enzymes. Taking indinavir with other drugs that are metabolized the same way can change blood levels of each drug. As a result of these drug interactions, blood levels of some drugs may drop too low to be of benefit, or they may rise so high they cause serious side effects. Dosages of other drugs may therefore have to be raised or lowered, or some drugs may have to be changed.

Drugs that should not be taken with indinavir include rifampin, Prepulsid (cisapride), Halcion (triazolam), Versed (midazolam) and the antihistamines Seldane and Hismanal.

If rifabutin (Mycobutin) is used while taking indinavir, the manufacturer recommends reducing the rifabutin dosage by one half. If ketoconazole is used while taking indinavir, the dosage of indinavir should be reduced to 600 milligrams (mg) every 8 hours.

Indinavir and other protease inhibitors
A small Australian study has shown that indinavir and ritonavir (Norvir) may be a useful combination. Other trials are underway to confirm those results and to study different doses. The Australian study used 400 milligrams (mg) of each drug taken twice daily with meals and without the extra one or two litres of water indinavir users are advised to drink daily.

Dosage
The recommended dose of indinavir is 800 mg every eight hours. For the best absorption, indinavir should be taken with water on an empty stomach, that is, either one hour before or two hours after a meal. Alternatively, it can be taken with a light meal: corn flakes with sugar and skim milk, or dry toast with jam, juice, and coffee, for example. Fats and proteins decrease the amount of indinavir that can be absorbed and used by the body.

Availability
Indinavir is available by prescription and is covered by all provincial formularies.

This information was provided by the Community AIDS Treatment Information Exchange (CATIE). For more information, contact CATIE at 1-800-263-1638.