AIDS Committee of Windsor: HIV Treatment Information

Summary
Saquinavir (Fortovase) is a type of anti-HIV drug called a protease inhibitor. The most common side effects associated with the drug are nausea, diarrhoea, abdominal discomfort, and farting. Saquinavir (as Invirase) was the first protease inhibitor approved for sale. In November 1998, a new formulation of saquinavir, called Fortovase, was approved for sale in Canada.

What is saquinavir?
Saquinavir, sold under the brand names Invirase and Fortovase, 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 (replicate). 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 quickly, and this slows the progression of HIV disease.

The original version of saquinavir, Invirase, was not well absorbed by the body: only about 4% of the drug swallowed actually went to work to fight HIV. Fortovase is an improved form of saquinavir in a soft-gel capsule that allows the body to use much more of the drug.

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

Using saquinavir 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 improved 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 saquinavir 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 saquinavir is necessary because of the possibility that drug-resistant virus may evolve even between doses.

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 saquinavir, it will probably be resistant to indinavir, ritonavir and nelfinavir. Cross-resistance will limit the choices of antiretroviral treatment.

Side effects
The most common side effects of saquinavir are gastrointestinal, including nausea, diarrhoea, abdominal discomfort or pain, farting and heartburn. Less common side effects include fatigue, headaches, insomnia and altered taste.

Because saquinavir is metabolized (processed and broken down) by the liver, lab tests may show increased blood levels of liver enzymes. By regularly testing blood levels of liver enzymes, doctors can monitor how saquinavir affects the liver.
Haemophiliacs 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 saquinavir) 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 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
Saquinavir, like many drugs, is metabolized (broken down and processed) by the liver through the actions of the p450 cytochrome enzymes. Taking saquinavir 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.

Fortovase should not be used with Seldane (terfenadine), Hismanal (astemizole), Prepulsid (cisapride), triazolam (Halcion), midazolam (Versed) or migraine drugs that are ergot derivatives (like Cafergot, Ergotamine, etc.).

Rifabutin and rifampin should not be used with saquinavir (both Invirase and Fortovase).

Antiretroviral drugs that can raise blood levels of saquinavir include delavirdine (Rescriptor), indinavir (Crixivan), ritonavir (Norvir) and nelfinavir (Viracept). Nevirapine can lower blood levels of saquinavir.

Saquinavir and other protease inhibitors
Ritonavir (Norvir) can increase the amount of Invirase that the body can use. The most common dose is 400 milligrams (mg) of each drug taken twice daily. This combination means fewer pills to take and an easier dosing schedule.

Fortovase and nelfinavir (Viracept): This combination does not seem to show any special benefit. In clinical trials, this double protease inhibitor combination plus two nucleoside analogues (nukes) had about the same effect as one protease inhibitor plus two nukes.

Dosage
In November 1998, Fortovase, the new formulation of saquinavir in a soft-gel capsule, was approved for sale in Canada. The recommended dose of Fortovase is 1200 mg taken three times a day with food, or up to two hours after a meal.

Early results from a continuing clinical trial, the TIDBID study, suggest that taking 1600 mg Fortovase twice a day may be as effective as taking 1200 mg three times a day.

Availability
Invirase was approved for sale in Canada in March 1996. Fortovase was approved for sale in November 1998. Both drugs are available with a prescription. Invirase is covered by all provincial formularies. The manufacturer is negotiating with provincial health ministries to have Fortovase placed on their drug formularies.

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