AIDS Community Research Initiative of America (ACRIA) - Fall 2003 / Winter 2004

Emtriva (emtricitabine, FTC), the most recently approved nucleoside analog, probably caused less excitement when it was approved in July 2003 than any antiretroviral so far. Many people viewed it simply as a "me-too" drug because its chemical structure and activity are so similar to Epivir (3TC). Even Emtriva's once-a-day dosing had lost its novelty by the time of its approval since a slew of other drugs, including Epivir, had been approved for once-a-day use by then.

Background: Emtriva has had a long development history involving several companies and two publicly announced brand names - Coviracil was the first. Initially discovered at Emory University in Atlanta, the drug was licensed to Triangle Pharmaceuticals in 1996. Triangle, a small company, continued to develop the drug until reaching an agreement with Abbott Laboratories in June 1999 which would have allowed Abbott to bring the drug to market. Three years later, Triangle bought back marketing rights to the drug from Abbott. Then in January 2003, Gilead Sciences purchased Triangle. Throughout all of this corporate drama, clinical trials of Emtriva (fluorocytidine, usually referred to more simply as FTC) continued.

The results of two relatively large clinical trials led to Emtriva's approval. FTC-301 involved 571 people who had never been on antiretroviral treatment before. The trial was designed to compare Emtriva to Zerit, with everyone taking Videx EC and Sustiva as well. It was a double-blind trial, meaning that neither the participants nor the researchers knew who was taking which drug. In July 2002, the Data and Safety Monitoring Board stopped the trial early after finding significantly fewer side effects and better efficacy in the group taking Emtriva. The study was unblinded and all participants were offered Emtriva. A 48 week analysis showed that 78% of the group taking Emtriva had viral loads less than 50 copies compared to only 59% of those taking Zerit. And the average increase in CD4 cells was significantly higher in the Emtriva group (168) compared to the Zerit group (134). Since Videx and Zerit have overlapping toxicities, their combined side effects may have contributed to the poor results in the Zerit arm of the trial and made Emtriva seem particularly impressive.

FTC-303 was designed to compare Emtriva to Epivir in people who had been on three-drug combinations that included Epivir for at least three months and had viral loads below 400. Two-thirds of the 440 study participants switched from Epivir to Emtriva, and the remaining third stayed on their Epivir-containing regimen. All of the combinations included Zerit or AZT and either a protease inhibitor or a non-nucleoside. At the end of 48 weeks, both groups did equally well in terms of side effects (nothing severe) and keeping their viral loads below undetectable levels.

There's almost no information available yet as to how Emtriva might work for people who have experienced virologic failure on a regimen. Emtriva's similarity to Epivir includes its resistance pattern. As with Epivir, Emtriva requires only one change in HIV's reverse transcriptase enzyme (the M184V mutation) to make HIV completely resistant to Emtriva. So if you're resistant to Epivir, Emtriva won't work. Further studies are needed to figure out whether Emtriva offers any real advantage over Epivir.

Side Effects: Emtriva has very few side effects, although more may be discovered as the drug is used in clinical practice. The side effects seen in clinical trials - headaches, diarrhea, nausea, and rash - were no more frequent or severe in people taking Emtriva than in those on other treatment regimens. The only unusual side effect is skin discoloration (extra pigmentation) on the palms of the hands and/or soles of the feet, which occurred primarily in non-Caucasians. Nobody knows the cause.

Drug Interactions: So far, no drug interactions have been identified with Emtriva. Then again, very few interaction studies have been performed. Some interactions may be discovered through further research and real-life experience, but since Emtriva's chemical structure is so similar to that of Epivir, it may be reasonable to expect that Emtriva will have as few drug interactions as Epivir does.

When To Consider It: Emtriva doesn't fill any desperately needed place in the antiretroviral toolbox. Figuring out how and when best to use it will develop as we learn more about the drug's long-term safety and effectiveness. There probably won't be many surprises because of its similarity to Epivir, and most of the same considerations that go into deciding when to use Epivir probably hold true with Emtriva. One significant difference between the two drugs is that Emtriva stays in the blood much longer than Epivir. Because of this, it may take longer for resistance to Emtriva to develop, but there isn't any data from clinical trials to confirm this. The most recent Department of Health and Human Services treatment guidelines don't discuss Emtriva in any detail or include it in any preferred or alternative regimens. That doesn't mean that the drug couldn't be useful in a first combination - it's just that it was approved shortly before the revised guidelines were released.

Good To Know:

• Gilead, which also markets Viread (tenofovir), is developing a Viread/Emtriva combination pill that they hope to release in 2005. That could be a useful combination and, with its once-daily dosing, would give Combivir some stiff competition. People who take it with Sustiva will take just two pills once a day - the most convenient regimen to date.
  
  
• Like Epivir and Viread, Emtriva is also active against chronic hepatitis B (HBV) infection. Studies are underway for Emtriva's use in this disease. People should be tested for chronic HBV before starting Emtriva, since there have been reports of disease flare-ups in people with HBV when they stop the drug.
  
  
• It's recommended that people with severe kidney problems use a lower dose of Emtriva.

Pregnancy: Emtriva is classified as an FDA pregnancy category B drug. Extremely high doses of Emtriva given to pregnant mice and rabbits haven't caused problems to the development of the fetus, but adequate, well-controlled studies of pregnant women haven't been conducted.

Dose: 200 mg a day, taken as one 200-mg capsule, with or without food. Emtriva is not yet approved for pediatric use, although studies in children are ongoing.

FDA Approval: 2003

Manufacturer: Gilead Sciences

Patient Assistance Program: 800-445-3235 #6

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