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Efavirenz (Sustiva) Approved by FDA-Information on Sustiva


As you may know the FDA approved Sustiva last week. It should have been made available in your pharmacy immediately. That's how it usually works. As soon as the FDA approves a drug it is available immediately in pharmacies. The NATAP web site and newsletter (NATAP Reports) have written extensively about this drug (NNRTI Update- Click here to link to article). I've had several requests about information on Sustiva, so this will be a brief report about the drug.

Discussed below are-

How NNRTIs work. Sustiva is a NNRTI (non-nucleoside reverse transcriptase inhibitor). It work to inhibit the reverse transcriptase (RT) enzyme. This enzyme helps HIV in the reproduction process within a CD4 cell. HIV turns CD4 cells into factories for producing more HIV. A single CD4 cell can produce as many as 10,000 more viruses before the cell dies. HIV is a retrovirus. It enters the CD4 cell in the form of RNA. To reproduce itself it must turn itself into DNA to integrate itself into the reproductive machinery of the CD4 cell. The RT enzyme turns the RNA into DNA. Nucleosides like AZT and NNRTIs like Sustiva work to inhibit that process.

24 week data Sustiva+AZT/3TC. Research in recent years has shown that 3 or 4 drug regimens which includes a protease inhibitor can suppress viral activity below detection in your blood. A protease inhibitor (PI) regimen of 3 or 4 drugs, which includes 2 NRTIs, has been the standard of care used by doctors. At the Intl Geneva AIDS Conference, DuPont Pharmaceuticals reported 24 weeks of data showing that Sustiva+AZT/3TC suppressed--

These are impressive numbers. It' s important to remember, that the study participants have never before taken antiviral treatment for HIV. In individuals with treatment experience, the effect of Susiva and how to use it changes. The 95% figure represents 95% of individuals who stayed on the drug. Individuals who stopped taking Sustiva for any reason were not included in that percentage. The FDA calls this an as-treated analysis of the study. A different statistical and more stringent analysis is called intent-to-treat. If a person did not stay on Sustiva for any reason-side effects, they moved, they died in a car accident-they were still included as a participant in an intent-to-treat analysis. So, the percentage of people lowering their viral load to undetectable will be less than 95%.

For individuals who started the study with viral load above 100,000 copies/ml-

No matter how you measure it Sustiva performed very well in this study. It performed well for 2 reasons: it is potent, it's probably easier to take because it's administered once-a-day. Because it is easier to take people are more likely to adhere or be compliant. It is important to remember that the people in this study are treatment-naïve. All NNRTIs including Sustiva will be used differently for people with prior antiviral experience.

Food Effect. Sustiva has no dietary restrictions except if you eat a high fat meal with Sustiva it may increase blood levels of Sustiva. So, you can take Sustiva with or without food, but DuPont recommends not to take Sustiva with a high fat meal

CSF. Sustiva is taken 600 mg once per day. Sustiva has been found to penetrate the CSF (cerebrospinal fluid) in humans. At this point we don't know how effective it might be in the brain or CSF against viral load and HIV related brain dysfunction, but since it enters the CSF it should have antiviral activity against virus in the CSF. It is generally accepted that if a drug can penetrate the CSF it will penetrate the brain. We are however unable to measure drugs levels in a person's brain.

Durability; Dosing; Resistance. Sustiva comes in 200 mg pills for now so you have to take 3 pills at each dose. Next year it's expected Sustiva may come in 300 or 600 mg pills. The FDA granted accelerated approval based upon this 24 week data (95%). Protease inhibitors have been in studies for 2-3 years. Many individuals remain undetectable after all this time. Being undetectable after 24 weeks is good but it is important to continue following the data to monitor Sustiva's durability. Resistance to a NNRTI is easier to develop than to a protease inhibitor. One or two mutations are enough to cause resistance to develop for a NNRTI. It normally takes several mutations for resistance to develop to a PI. One way to reduce the risk of developing resistance to a Sustiva or any other NNRTI regimen is not to use 3TC in that regimen. Resistance to 3TC is easier to develop than to AZT, d4T or ddI. Resistance to D4T and DDI are probably the most difficult of these 4 NRTIs to develop resistance to followed by AZT and then 3TC. At the ICAAC AIDS meeting in San Diego, where I am now attending, DuPont will present 36 weeks of data. Although I haven't seen the data yet I've been told it is holding up. In coming months DuPont will present 48 weeks of data. If Sustiva holds up at 48 weeks that will be an important milestone. And of course we want to see it continue to hold up as protease inhibitors have out to 2-3 years.

Pregnancy. DuPont gave a specific type of monkey Sustiva during the first trimester of pregnancy, when fetuses are at the greatest risk. Three out of 13 monkeys were born with birth defects. The monkeys received doses equivalent to human doses. It is uncertain of the effect in humans if Sustiva were taken by a pregnant women during the first trimester. But, women are warned not o take Sustiva if pregnant and not to get pregnant if taking Sustiva.

Lipodystrophy. Many doctors are using a Sustiva 3 drug combination instead of a PI combination because-- of the side effects of lipodystrophy that some people think are associated with taking a PI; Sustiva is taken only once a day and a PI regimen is taken 2 or 3 times a day; because Sustiva is potent; protease inhibitors can be difficult to take for a number of reasons (dosing schedule, side effects, dietary restrictions) although nelfinavir (Viracept) and saquinavir (Fortovase) are easier to take than ritonavir and indinavir. So far, there has not been evidence of lipodystrophy (fat redistribution) associated with taking Sustiva or other NNRTIs. But, NNRTIs have not been used as long as PIs. Dr Don Kotler thinks the development of fat redistribution may be associated with the magnitude of viral load reduction rather than PIs. If that is the case we should see lipodystrophy associated with Sustiva therapy after a period of time. Lipodystrophy can take 1 year to develop. However, protease inhibitors have demonstrated durability. That is not to say that Sustiva will not have the same durability. It's just that we have not used the drug that long yet.

Side Effects. All HIV antiviral drugs have side effects. NNRTIs can cause a rash, but so far Sustiva appears to have less of an incidence and severity of rashes than the other 2 NNRTIs-delavirdine and nevirapine. Side effects can emerge moreso after a drug is approved and used more widely. Elevations of liver enzymes can occur using Sustiva but it appears to develop at a low incidence compared to protease inhibitors. 20-35% of people taking Sustiva have reported what is being called CNS (Central Nervous System) related side effects. They've reported dizziness, bad dreams, disorientation, etc. It's been reported that usually these CNS related side effects go away with 2-3 weeks after starting Sustiva. They can occur within several hours after taking a dose but usually go away within several hours. That is why it is recommended to be taken at bedtime. Although these side effects usually go away within a few weeks after starting Sustiva some people have reported continuing to experience these side effects for months. A small number of people have stopped taking Sustiva due to this. However, remember that protease inhibitors and NNRTIs all have some side effects. They are potent drugs and it is expected that you will experience some side effects. But, some of the PIs may be more difficult to tolerate which is why some doctors are prescribing a NNRTI regimen to begin therapy with instead of a PI regimen.

Role in Salvage Therapy. Sustiva can play a role in salvage therapy for individuals who have failed a PI regimen. But only if you have not previously taken a different NNRTI. In all likelihood all NNRTIs are cross-resistant. That is, once you fail 1 NNRTI by developing resistance mutations you may not respond to another NNRTI. If you fail a PI regimen and have not taken a NNRTI before you can use Sustiva in combination with other drugs to suppress your viral load. But, you need to put together a regimen that contains enough potent drugs that you will be sensitive to. The goal of treatment should always be to suppress your viral load to below 50 copies/m.

When considering how to combine Sustiva with protease inhibitors it is important to consider the interactions between Sustiva and protease inhibitors. This info is based on preliminary research and could change as more research is conducted-

Research is being conducted on combining 2 NNRTIs in one regimen. Until we receive initial data from this study we have no guidelines on combining 2 NNRTIs.

Drug Interactions. Do not take Sustiva with-

If you are taking Biaxin (clarithromycin) you may have to change dosing.

Again, DuPont recommends not to take Sustiva with a high fat meal because it may raise Sustive blood levels thereby increasing side effects.

As I stated above, I am currently attending the ICAAC AIDS conference in San Diego. New info on Sustiva will be reported by me. I will try to report highlights on this web site on a daily basis fom San Diego on all important info. When I return to NYC I will start reporting ICAAC data and Geneva data. I have been pre-occupied setting up the NATAP community treatment education program in NY for the past 2 months. That is why I haven't written more treatment info for this web site. However, our treatment ed program is now inplace. So, I will be focusing on writing now. If you have further questions about Sustiva or any other subject you can contact NATAP and me through the email at top of front page on web site or by calling 212 219-0106 or 888-26-NATAP.