AIDS Committee of Windsor: HIV Treatment Information

Summary
Ritonavir is a type of anti-HIV drug called a protease inhibitor. The most common side effects associated with the drug are nausea, vomiting, diarrhea, and unusual taste. Less common side effects include headaches, loss of appetite, and a burning or tingling sensation around the mouth. Taking ritonavir with food, especially fatty food, can help reduce side effects.

What is ritonavir?
Ritonavir, sold under the brand name Norvir, 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 make copies of itself. Some drugs can inhibit (slow down or stop) the actions of these enzymes. When these enzymes can't perform effectively, the virus does not replicate as efficiently, and this slows the progression of HIV disease.

How does ritonavir 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. Ritonavir blocks the action of protease and causes HIV to make defective copies that can't infect new cells.

Using ritonavir 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 ritonavir with at least two other drugs may delay the development of drug resistance. To limit the risk of developing drug resistance, all anti-HIV drugs should be taken every day, exactly as prescribed. The strict schedule for taking ritonavir 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 ritonavir, it will probably be resistant to saquinavir, indinavir and nelfinavir. Cross-resistance can limit the choices of antiretroviral treatment.

Side effects
The most common side effects are nausea, vomiting, diarrhea, loss of appetite, fatigue, a numbness or tingling sensation around the mouth (circumoral parasthesiae), abdominal pain, headache and dizziness.

To help prevent or minimize side effects, the manufacturer recommends taking ritonavir with food. "Dosing up" to the recommended level may also help. Start at half the prescribed dose: for example, take 300 milligrams (mg) ritonavir twice daily for three days. Then take 400 mg twice daily for four days, 500 mg twice daily for five days, then 600 mg twice daily.

Because ritonavir is metabolized (processed and broken down) by the liver, blood tests may show increased levels of liver enzymes.

Women may experience heavier menstrual periods. A recent article in the medical journal The Lancet reported that four women using ritonavir developed anemia after one or two very heavy periods.

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 ritonavir) 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 the base of the neck ("horse collar").
4. Increased breast size in women (several bra sizes).
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 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 these 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
Ritonavir, like many drugs, is metabolized (broken down and processed) by the liver through the actions of the p450 cytochrome enzymes. Taking ritonavir 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 ritonavir include some birth control pills, codeine, Demerol, Darvon, rifabutin, rifampin, ketaconozole, Tagamet, Paxil, Xanax, Valium, Halcion and the antihistamines Seldane, Hismanal and Claritin. Abbott Laboratories have compiled a list of about 200 drugs that may interact with ritonavir. Check with your doctor or pharmacist about possible interactions with any other drugs you may be using.

Ritonavir and other protease inhibitors
Ritonavir's ability to increase the effects of other drugs has led to the use of powerful double protease inhibitor combinations that can often mean fewer pills to take and easier dosing schedules.

Ritonavir plus saquinavir (Invirase): This combination became popular because it increases the amount of saquinavir (Invirase) that the body can use. The most common dose is 400 milligrams (mg) of each drug taken twice daily.

Ritonavir plus indinavir (Crixivan): A small Australian study has shown that this may be a useful combination. Other trials are underway to confirm those results and to study different doses. The Australian study used 400 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 each day.

Dosages
In July 1998, Abbott Laboratories (the makers of ritonavir) reported a serious problem with the production of ritonavir capsules. Abbott discovered the sudden appearance of a new crystalline form of ritonavir that did not permit the capsules to dissolve properly. The crystal form is not well absorbed by the body. Although the company examined, cleaned, and replaced their manufacturing equipment, Abbott has been unable to prevent the development of the crystalline ritonavir. As a result, production of ritonavir capsules has been stopped, and the liquid form of ritonavir has been substituted.

For some time, Abbott has been working on a soft elastic capsule (SEC) that would allow the capsules to be stored at room temperature. Development of this new capsule has been stepped up, and the company hopes it will be approved for sale in Canada before the end of the year.

To convert from 100 mg capsules to liquid dose
6 capsules = 7.5 ml of liquid
5 capsules = 6.25 ml of liquid
4 capsules = 5 ml of liquid
3 capsules = 3.75 ml of liquid

Ritonavir liquid comes with a measured dosing cup that shows the amount of liquid to be taken for the two most common doses. Ritonavir liquid has an unpleasant taste. Drinking chocolate milk, or eating peanut butter, Peanut Butter Cups, or Nutella (a chocolate and hazelnut spread) may help.

Storage
Ritonavir liquid should not be refrigerated. It should be stored at room temperature (between 20 and 25°C) and used within 30 days (check the expiration date on the label). It must be shaken well before each use to prevent crystals from forming.

Availability
Ritonavir is available with a 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.