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Drugs! Drugs! Drugs!
An Overview of the Approved Anti-HIV Medications

Sustiva (Efavirenz, EFV)

Fall 2003/Winter 2004

Its FDA approval in September 1998 made Sustiva the third available NNRTI. Since then, it has become one of the most popular antiretrovirals and is often recommended for a person's first regimen because of its effectiveness and once-a-day dosing. While its nervous system side effects can be a problem, many people have found them to be temporary or at least manageable.


Background

Sustiva might be called the "little drug that could." After the less-than-impressive results seen with the first two NNRTIs, Viramune (nevirapine) and Rescriptor (delavirdine), few people expected Sustiva to perform any better. But DuPont Pharma, the company that first developed the drug, had different ideas -- they had the nerve to pit Sustiva against Crixivan (indinavir), the protease inhibitor that was then the "gold standard" for treatment.

In 1997, DuPont began the trial (DMP 266-006) that would throw NNRTIs into the spotlight and lead to Sustiva's FDA approval. In the trial, 450 people took either Sustiva or Crixivan, along with Retrovir (AZT) and Epivir (3TC). 80% of the trial participants had never taken antiretrovirals. After 11 months, 64% of those taking Sustiva had viral loads below 50, compared to 43% of those taking Crixivan. Some of this difference was probably due to the difficulty of taking Crixivan (every 8 hours on an empty stomach) compared to Sustiva's once-daily dosing. Still, this result flew in the face of conventional wisdom, which held that it was necessary to hit the virus at different points in its lifecycle. The combination of Sustiva, Retrovir, and Epivir targets the reverse transcriptase enzyme only -- people were surprised to find that this was as effective as combinations that target both the reverse transcriptase and protease enzymes.

Other trials have supported Sustiva's effectiveness. In the FOCUS study that began in 2000, 161 people who had never used anti-HIV drugs took either Sustiva or a combination of the protease inhibitors (PIs) Fortovase (saquinavir) and Norvir (ritonavir), both taken once a day. Everyone also took two nucleosides. Once again, Sustiva outperformed the PIs. After 11 months, 71% of the participants on Sustiva had viral loads below 50, compared to 51% of those taking the PIs. Contributing to Sustiva's success in both of these studies was the fact that more people taking a protease inhibitor dropped out due to side effects.

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A number of studies have shown that people can successfully switch from a protease inhibitor to Sustiva. DMP-049, a study of 346 people who had viral loads below 50 while taking a PI, found that 84% who switched to Sustiva kept that low viral load after 11 months, compared to 73% of those who stayed on their PI. A similar trial (DPC-049) found that 93% of those who switched to Sustiva were able to keep their viral loads below 50, compared to 85% of those who stayed on their PI.

Unfortunately, the news surrounding Sustiva hasn't always been terrific. Shortly after Sustiva was approved, DuPont announced that the price of their drug would be 60% higher than the other NNRTIs -- closer to the more expensive PIs. This was the first non-PI to do so and it led to a long series of loud protests by activists. DuPont never budged. Bristol-Myers Squibb later bought DuPont Pharma and has left the price relatively unchanged.


Side Effects

Sustiva is famous for its effects on the central nervous system, which can result in strange dreams that are experienced by many people. These are usually not nightmares but, rather, as the manufacturer describes them, "vivid dreams" (one person we know dreamt that he was a superhero saving the world every night). No one is sure why Sustiva causes these dreams and other central nervous system side effects. For most people, the dreams subside after a few weeks. For others, however, they can become a chronic problem, along with difficulty sleeping, drowsiness, and trouble concentrating.

The best strategy for lessening these side effects is usually to take Sustiva at bedtime, and on an empty stomach. Taking it with food can raise the amount of drug in the body by up to 51%, increasing the side effects. Combining Sustiva with recreational drugs, particularly marijuana, can also increase the psychological side effects.

About 2% of people taking Sustiva have more severe psychiatric problems, including severe depression, strange thoughts, or angry behavior. Some patients have thoughts of suicide and a few have actually committed suicide. People with a history of mental illness should be especially careful if they start Sustiva.

Rash is also a common side effect, affecting 26% of adults and up to 46% of children. Rashes usually go away in a few weeks, but are serious enough to cause 2% of adults and 9% of children to stop taking Sustiva. Other common side effects include tiredness, upset stomach, vomiting, and diarrhea.

There have been a handful of cases of swelling of the breasts (gynecomastia) reported in men taking Sustiva, but it is not yet known if this is due to Sustiva or something else.


Drug Interactions

Sustiva lowers the levels of the protease inhibitors Reyataz (atazanavir), Crixivan, Agenerase (amprenavir), Fortovase and Invirase, and Kaletra (lopinavir/ritonavir) in the body. Adding low-dose Norvir may help increase PI levels, but it may be best to avoid using these drugs together in a combination.

Some drugs may cause serious and life-threatening side effects when taken with Sustiva including drugs used to treat anxiety, like Versed (midazolam) and triazolam (Halcion, Restoril, Dalmane and others), and the ergotamine drugs (used to treat migraines). These drugs should not be taken with Sustiva.

Sustiva lowers levels of Biaxin (clarithromycin) so these drugs should not be taken together. Sustiva can reduce levels of Mycobutin (rifabutin) by 50%, so the Mycobutin dose should be increased. Sustiva can also lower levels of methadone by up to 57%. If withdrawal symptoms occur, the methadone dose should be increased -- the average increase needed in one study was 21%.

St. John's wort (hypericum) may reduce the levels of all NNRTIs and PIs, so it is best avoided.


When to Consider It

Sustiva's popularity as part of a first regimen is clear, due to its strength, dosing simplicity, and the fact that it lacks the metabolic side effects seen with most of the protease inhibitors. But recent studies have found Viramune to be equally effective, so Viramune's significantly lower price and lack of nervous system side effects could help it challenge Sustiva as "king of the hill."

People also choose to switch to Sustiva, usually for one of two reasons -- to simplify their regimen with its once-daily dosing or to try to improve lipodystrophy. Unfortunately, most studies have found that simply substituting Sustiva for a protease inhibitor does not significantly improve body shape. For example, a study from Spain of 39 people found that while 76% reported body shape improvements, objective measurements (like body mass index) did not back this up. In addition, triglycerides increased from 169 to 201 (not good), but HDL cholesterol (the "good" cholesterol) also increased, from 36 to 50. Other studies have shown that a switch to Viramune has a better effect on cholesterol and triglyceride levels than a switch to Sustiva.


Good to Know

  • Even though less than 5% of Sustiva enters the CSF (cerebrospinal fluid -- the fluid around the brain), it can still inhibit 95% of the HIV in the CSF.

  • Sustiva can cause a false positive test for marijuana if the CEDIA DAU Multi-level TCH immunoassay is used. People taking Sustiva should ask for a gas chromatography test, which will provide accurate results.

  • For children or people who have trouble swallowing pills, Sustiva capsules can be opened and the contents added to liquids or foods. The drug has a strong, unpleasant taste, so it may take a while to find a food or liquid that will disguise the drug's taste.


Pregnancy

Sustiva is classified as an FDA pregnancy category C drug. Pregnant women should not take Sustiva. While there have been over 100 reported cases of infants born without birth defects after being exposed to Sustiva in the womb, there is one report of an infant born with severe birth defects after Sustiva exposure in the womb. It has also caused birth defects in monkeys. Because of these findings, no studies of Sustiva in pregnancy are planned. Women should have a pregnancy test before starting Sustiva, and the manufacturer recommends using a barrier method of contraception in addition to an oral or other hormonal contraceptive.


Dose

600 mg once a day, usually taken as one 600-mg tablet, preferably on an empty stomach. Sustiva also comes in 50, 100, and 200-mg capsules. For children 3 years and older who weigh less than 88 pounds, the dosing is based on body weight. The recommended dose for children weighing 88 pounds or more is the same as that for adults -- 600 mg once a day. Sustiva is available as a strawberry-flavored liquid through an expanded access program. Doctors can call 877-372-7097 to enroll patients.

FDA Approval: 1998

Manufacturer: Bristol-Myers Squibb

Patient Assistance Program: 800-474-2762





  
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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication ACRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.
 

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