We’re now in a countdown of days and hours until the U.S. Food and Drug Administration (FDA) approves the first antiretroviral of 2008: Tibotec’s etravirine (also known as TMC125). Scheduled to be approved by the end of this week, etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI)—a “non-nuke”—with a very important twist. It works against HIV strains resistant to Sustiva (efavirenz) and Viramune (nevirapine), effectively becoming the first NNRTI to break the cross-resistance barrier that has long plagued this class of drugs.
Jeff Taylor, a cochair of the AIDS Treatment Activists Coalition (ATAC) drug development committee says, “It’s a non-nuke with a unique resistance profile that will be extremely useful for people with non-nucleoside resistance. And it appears to have a pretty clean safety profile and should be well-tolerated.”
Should the FDA approve etravirine, it will be the third new antiretroviral approved in the last six months. Such a cluster of drug approvals in HIV hasn’t been seen since the first protease inhibitors were approved in 1995 and 1996. And just as the protease inhibitors ushered in an era of hope and health, the string of recent approvals that will soon include etravirine will likely have a significant impact on the lives of thousands of people who are heavily treatment-experienced and in desperate need of new treatment options.
What Makes Etravirine Different?
The NNRTI class of drugs is one of the most popular for use in people who are just starting antiretroviral treatment for the first time. Both Sustiva and Viramune have proven highly effective at achieving and maintaining undetectable viral loads and boosting CD4 counts. Though they both have their unique set of side effects, overall they are considered to be safe; Rescriptor (delavirdine) is less frequently used, largely due to its three-times-daily dosing schedule. Their Achilles’ heel, however, is their vulnerability to drug resistance—the development of genetic changes, or mutations, in HIV that render antiretrovirals less active against the virus.
Unlike most of the protease inhibitors (PI), where the virus needs to acquire several mutations before it can effectively block members of the PI drug class from working, Sustiva and Viramune can lose all potency through the development of a single change in HIV’s reverse transcriptase (RT) enzyme. With Sustiva, the RT mutation dubbed “K103N” lays it low. With Viramune, the RT mutation most commonly seen is called “Y181C.”
An even bigger problem with these two mutations is that they cause cross resistance within the NNRTI class. For example, if the K103N mutation develops, not only does it halt Sustiva from working effectively, it also prevents Viramune and Rescriptor from sequestering the virus. Etravirine is custom made to overpower both K103N and Y181C, making it the first genuine “second generation” NNRTI to offer potential benefits for those with HIV resistance to Sustiva, Viramune and Rescriptor.
Dan Kuritzkes, MD, a director of AIDS research and professor of medicine at Harvard Medical School and a Tibotec research consultant, explains, etravirine “binds to the enzyme in a way that’s different than the other non-nukes, and is still able to bind with the enzyme despite the presence of mutations that make the existing [NNRTIs] ineffective.”
In studies conducted thus far, etravirine handidly conquered virus carrying the K103N mutation. It can also overcome virus with just the Y181C mutation, provided that this is the only NNRTI mutation a person has. Understanding resistance, and who will benefit from etravirine, will take a careful and cautious eye.
How Does NNRTI Resistance Affect Etravirine?
“Because there are clearly identified mutations in reverse transcriptase that predict activity of the drug, it is critical that this drug be used properly,” says Martin Markowitz, MD, the clinical director of the Aaron Diamond AIDS Research Center in New York City and a recipient of Tibotec research funding. This, he explains, requires drug-resistance testing and careful review of the results.
The list of NNRTI mutations associated with a weakened response to etravirine is still being finalized. The K103N mutation isn’t on that list, but the Y181C probably will be. At the end of the day, however, it’s not just the specific mutations that matter, but how many NNRTI mutations are present in a person’s virus. In the clinical trials of etravirine, “If the patients had no mutations they did extremely well,” says Markowitz. “The more mutations patients had, the worse they did.”
Markowitz and Taylor stress that health care providers will need to familiarize themselves with etravirine’s resistance profile, to ensure that is used appropriately. “I just hope that the company will do a good job of educating patients and providers around resistance issues,” Taylor says, “so that they can know how to best use the drug. And in a broader sense, give patients the information they need to figure out how to sequence their drugs, so that they’re not eliminating drugs unwittingly.”
John Baxter, MD, medical director of the early intervention program at Cooper University Hospital in Camden, New Jersey, and a Tibotec study investigator, points out that having an accurate drug-resistance-test result to work from is important. “If you don’t have the genotype results…[from] when [a] non-nuke regimen first failed, it’s important keep in mind that there could be low-level resistance that isn’t showing up using a genotype test [conducted before prescribing etravirine].” He says. “However, as long as a person’s current genotype looked favorably for etravirine, I would still feel comfortable using it, but I would make sure that it was supported by at least two active agents.”
How Potent Is Etravirine?
So far, Tibotec has publicly presented 24-week data from two phase III studies of etravirine. Both studies involved HIV-positive patients with a lot of treatment experience, including previous NNRTI use. The first study, called DUET-1, pitted 200 mg of etravirine, taken twice daily, plus an optimized background regimen that included 600 mg of Prezista (darunavir) boosted with 100 mg of Norvir (ritonavir) twice a day against a placebo plus an optimized background regimen including Norvir-boosted Prezista. The second study, DUET-2, had an identical design. The use of Fuzeon (efuvirtide) in the background regimen was allowed in both studies.
Approximately 600 patients were in each study; half received etravirine and the other half received a placebo. Most of the participants in both studies were male and Caucasian. The average CD4 count was around 100, and approximately 60 percent had an AIDS diagnosis. Roughly half of the participants had one or fewer active drugs in their background regimen. To enter the study people had to have documented resistance to both NNRTIs and protease inhibitors (PI). Sixty-five to 67 percent of people in the two studies had two or more NNRTI mutations, and 59 to 66 percent of the participants had four or more PI mutations.
When researchers checked the results after 24 weeks of treatment, etravirine clearly showed its potency and potential. In DUET-1, 56 percent of the participants reduced their viral loads to undetectable levels (below 50 copies) after 24 weeks of therapy, compared with just 39 percent of people who received a placebo. Similarly, in DUET-2, 62 percent of those on etravirine had viral loads under 50 copies after six months, compared with 44 percent of those on the placebo. These results were highly statistically significant, meaning that the differences were too great to have happened by chance.
CD4 cell gains were also significant. In DUET-1, people taking etravirine gained an average of 89 CD4 cells, while those on placebo gained 64 cells. In DUET-2, people on etravirine gained an average of 78 cells, compared with 66 cells among those receiving placebo.
When Tibotec combined the data from both trials and performed a secondary analysis asking how well people did based on the number of etravirine-specific NNRTI mutations, the results were informative. Eighty percent of people who had no mutations reached and maintained virus levels below 50 copies for six months. In those with either one or two mutations, roughly 60 percent of the participants had less than 50 copies at six months. In people with three mutations, the percentage of people with less than 50 copies dropped to about 40 percent, with four mutations about 30 percent responded, and with five mutations less than 20 percent of people responded.
According to Kuritzkes, should the FDA approve etravirine based on this data, it will likely be approved only for people who’ve already become resistant to several classes of antiretrovirals. He says, “People should keep in mind that this is not a drug to replace Sustiva as a first-line drug. There are drugs in development for that, and this drug may [eventually] be tested in that setting, but we just don’t have the data on that yet.”
How Safe Is Etravirine?
A relatively small number of people, roughly 5 percent in both studies, discontinued treatment with etravirine due to serious adverse events, and there was no statistically significant difference between the percentage of those taking etravirine who discontinued treatment compared with those taking a placebo. With nearly every type of side effect noted in the study, the proportion who experienced those side effects while on etravirine was no greater than the proportion of people on the placebo. The only exception was the development of a rash, which happened twice as often in people on etravirine compared with those on placebo.
With 14 to 20 percent of people in the two studies reporting a rash, this number is slightly higher than that seen in studies with the older NNRTIs. However, Taylor doesn’t expect this to be a major problem. He says, “It’s got the usual rash, but this is something that patients and clinicians know how to deal with given the existing drugs in the class.”
Aside from rash, other commonly reported side effects included nausea, diarrhea and headache. Nervous system disorders, which are a common side effect of Sustiva, occurred at a rate of approximately 17 percent in all the groups, however, there was actually a trend toward fewer people on etravirine experiencing such side effects compared with those taking the placebo.
Increases in cholesterol and triglycerides, a concern with most of the protease inhibitors and a potential risk factor for heart disease, were not seen with etravirine. An equal percentage of people on etravirine compared to people on placebo developed increases in triglycerides or cholesterol, and overall, the proportion of people developing serious increases was relatively low and averaged about 5 percent in all groups.
If there’s one aspect that will be a concern for people living with HIV, it’s the rather long list of drugs with which etravirine can interact. “The drug does have a number of interactions with other drugs, antiretroviral drugs and non-antiretroviral drugs,” says Kuritzkes, “So if adding etravirine to a regimen, it would be important that a patient’s clinician was aware of those interactions, or had looked carefully through a list of the medications that a patient might be on to make sure that there won’t be any significant interactions that could compromise treatment with one of the other agents. The most important example in the HIV category is an interaction with Aptivus (tipranavir); those two drugs can’t be given together because of the interaction.”
If the FDA does approve the drug, the prescribing information will likely include instructions about the drugs that can’t be used with etravirine or where a dose adjustment will be necessary. When asked whether these instructions will cover most of the drugs used by people living with HIV, Kuritzkes says, “I believe that [Tibotec has] done drug–drug interaction studies, though I don’t have a list at my finger tips, with the major kinds of drugs that people would be concerned about, such as oral contraceptives, rifampin, which is an oral TB drug, and methadone.”
A Care Revolution for Treatment-Experienced Patients?
As potent and safe as etravirine may be, the timing of its approval may turn out to be its most significant selling point. Its arrival comes on the heels of a newly revised set of federal HIV treatment guidelines, which carry a substantially different approach to antiretroviral therapy in people who are heavily treatment-experienced.
Whereas older versions of the guidelines encouraged physicians to use at least one other active drug and to strive for significant viral load reductions, the new guidelines urge doctors to accept nothing less now than an undetectable viral load and good CD4 gains, using combinations of newly approved agents, no matter how treatment-experienced their patients may be.
The change in the guidelines occurred not because doctors didn’t know how to best use antiretrovirals in the past, but because there were so few options for treatment-experienced patients. “If you think back over what’s happened over the last seven or eight years, when we had the introduction of Kaletra, the first of the salvage drugs, people were adding Kaletra to a regimen or substituting Kaletra with another failing protease inhibitor, very often in a situation when there was no other drug to use along with Kaletra,” says Kuritzkes. “Then when Fuzeon (enfuvirtide) was developed it was much the same story.”
With the series of new drugs for treatment-experienced patients, including the approvals of Pfizer’s Selzentry (maraviroc) in August and Merck’s Isentress (raltegravir) in October, it is now possible to do far better. The two DUET studies demonstrate this well. In those studies, people who had two or more active drugs in their background regimen faired particularly well, and had success rates approaching what is seen in studies of drugs in people who’ve never taken antiretrovirals before.
Kuritzkes concurs, saying, “Over the last year and a half or so, the most common advice that I was giving…was to hold off until there were enough drugs that could be combined for that particular patient to fully suppress the virus, rather than adding one drug at a time as it became available.”
This means that there is a whole new paradigm for people who’ve been struggling for years with detectable virus and single- or double-digit CD4 cell numbers. And that is certainly reason for renewed hope.
When asked if he thought that the roster of new drugs will mean a lot more people will render their viral loads undetectable, Taylor says, “Absolutely, if people have been savvy enough to hold off and not construct regimens with incomplete efficacy that they’re in a position to really benefit from all of these drugs that have just been approved. I think we’re going to see a lot fewer salvage patients in really dire straights.”Kuritzkes concludes by saying, “Just as with initial therapy where we use three drugs to fully suppress the virus, we now have the opportunity to take exactly the same approach with heavily treated patients. And that’s really unique in the history of HIV drug development.”