AIDS Committee of Windsor: HIV Treatment Information

Summary
Nelfinavir is a type of anti-HIV drug called a protease inhibitor. The most common side effect associated with this drug is mild to moderate diarrhoea, which often can be controlled with over-the-counter medicines. Nelfinavir is taken three times daily with food.

What is nelfinavir?
Nelfinavir, sold under the brand name Viracept, 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 efficiently, and this slows the progression of HIV disease.

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

Using nelfinavir 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 nelfinavir 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. This strict schedule 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 indinavir. Cross-resistance can limit the choices of antiretroviral treatment.

Side effects
The most common side effect of nelfinavir is diarrhoea, which can often be controlled with over-the-counter anti-diarrhoea treatments. Other side effects reported include abdominal pain, nausea, vomiting, farting and rash.

Because nelfinavir 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 nelfinavir 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.

There have been reports of some people experiencing hypersensitivity and developing hives (urticaria) in reaction to nelfinavir. Dr. Pascal Demoly and his colleagues have developed a method to desensitize patients to nelfinavir. They gave three patients very small amounts of the drug and gradually increased the dosage until the patients' tolerance improved. One patient could not tolerate the treatment, but the other two were successfully desensitized and were able to continue using nelfinavir.

With longer-term use, protease inhibitors (including nelfinavir) 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
Nelfinavir, like many drugs, is metabolized (broken down and processed) by the liver through the actions of the p450 cytochrome enzymes. Taking nelfinavir 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 nelfinavir include Seldane, Hismanal, Prepulsid (cisapride), rifampin, Versed (midazolam), Halcion (triazolam), Cordarone (amiodarone) and quinidine. Migraine drugs that are ergot derivatives (such as Cafergot, Ergodryl, Gravergol, etc.) should not be taken with nelfinavir.

The daily rifabutin (Mycobutin) dose should be cut in half if it is taken with nelfinavir.

Nelfinavir may lower blood levels of certain brands of birth control pills, making them less effective. It may be necessary to use alternative forms of contraceptives.

Nevirapine (Viramune), phenobarbital, Dilantin (phenytoin), and Tegretol (carbamazepine) can lower blood levels of nelfinavir, which may make it less effective.

Nelfinavir and other protease inhibitors
Nelfinavir can raise blood levels of soft-gel saquinavir (Fortovase) up to five times the normal level. This may increase the side effects of Fortovase and a change in dose may be necessary.

Interaction studies with indinavir and ritonavir were done with HIV-negative volunteers. Nelfinavir raised indinavir levels somewhat but had little effect on ritonavir levels. However, indinavir caused a significant increase in nelfinavir levels, and ritonavir raised nelfinavir levels even higher. These interactions may require changes in dosage if nelfinavir is used with ritonavir or indinavir.

Dosage
The recommended dose of nelfinavir is 750 milligrams (mg) taken three times a day with food. Early results from a continuing two-year clinical trial suggest that 1,250 mg nelfinavir taken twice a day may be equally effective as the approved dose.

Availability
Nelfinavir is available with a prescription. Drug plan coverage may not yet be in place in every province and territory.

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