One Sustiva Plus One Truvada Might Equal One Pill Once-A-Day
by Chael Needle
LifeGuide [Treatment Horizons]
As a result of a U.S.-based joint venture forged in late December 2004, Bristol-Myers Squibb Company (BMS) and Gilead Sciences, Inc., have announced the submission of a New Drug Application to the FDA for approval of a product that combines BMS’s Sustiva (efavirenz) and Gilead’s Truvada (a single once-daily tablet containing emtricitabine, or Emtriva, and tenofovir disoproxil fumarate, or Viread) in a once-daily single tablet regimen. If approved, the yet-unnamed coformulation will become the first-ever product containing a complete HAART regimen in a single once-daily tablet. The product candidate could be used alone or in combination with other antiretrovirals, depending on the needs of the patient. Only one prescription would be needed; the drugs will continue to be sold separately as well.
“We hope that this partnership will set the standard for future collaborations between companies, not just in HIV but also in other fields where patients can benefit from new treatments developed by these types of collaborative partnerships. This combination may be the first single tablet regimen, but it is our goal that it not be the last,” says Dr. Norbert Bischofberger, executive vice president of R&D at Gilead. “The partnership between Gilead and BMS was born from our shared commitment to making treatment simpler for HIV patients. Gilead’s goal has always been the simplification of therapy for patients, starting with the introduction of our first once-daily antiretroviral, Viread, in 2001, followed by the introduction of Emtriva and the subsequent combination of the two into the fixed-dose tablet Truvada. Sustiva, also a once-daily treatment, has a profile that aligns well with that of Truvada.” Indeed, the U.S. Department of Health and Human Services (DHHS) lists the combination of tenofovir, embricitabine, and efavirenz as one of the preferred NNRTI-based treatment regimens for first-line therapy for treatment-naive patients.
Activists and researchers alike, reminds treatment educator Nelson Vergel, have long been urging pharmaceutical companies to put competition aside and work together. This teaming was perhaps a bit easier to facilitate as Sustiva and Truvada are different classes of anti-HIV medications, and so are not in direct competition with one another. And while the new product will be profitable for both companies, Vergel is heartened by the bridging of research: “...For the first time we’re seeing collaboration that’s actually going to lead to a coformulation. Companies are going to start talking to each other because it makes sense to minimize pill burden, market one single [coformulation]...this is the beginning of something else.” Vergel hopes other companies get the message; he mentions Abbott Laboratories’ Norvir as a viable candidate for coformulation as it is often paired with other protease inhibitors. “Maybe [the teaming of Gilead and BMS] will shift the paradigm [away from the notion that] companies can never work together because they’re competitors.”
The science of the coformulation builds, of course, on past studies of Sustiva and Truvada, whose three active ingredients work by blocking the enzyme reverse transcriptase, but an ongoing study is testing the safety and efficacy of the new therapy. Study 934, a three-year randomized study in treatment-naive patients, compares tenofovir, embricitabine, and efavirenz with Combivir and efavirenz, “which has been the gold standard therapy for some time now,” says Dr. Joel Gallant, principal investigator of the study as well as an HIV physician and researcher at Johns Hopkins.
“At one year [the study] showed the superiority of the once-a-day regimen, primarily because of a greater dropout rate due to side effects—mainly due to anemia—in the Combivir/efavirenz arm.” After forty-eight weeks, eighty-four percent of those participants who were given tenofovir, embricitabine, and efavirenz showed a reduced viral load compared with seventy-three percent in the other group. The Sustiva/Truvada coformulation was better tolerated in general, specifically in terms of anemia and with fewer gastrointestinal side effects and fatigue to some degree than the other arm. Retrospective baseline resistance testing “found that there were a substantial number of people who had had baseline NNRTI resistance and those people did not do well on the study,” says Dr. Gallant, who expressed confidence that the coformulation will become the default regimen for everyone, with the following exceptions: “women who either intend to become pregnant or are not using reliable birth control (because of the potential birth defects from efavirenz); people who have preexisting renal dysfunction—decreased kidney function—who should probably not be taking tenofovir if they have other alternatives; [and] people who have preexisting resistance, especially NNRTI resistance.”
He adds, “A handful of people will not tolerate efavirenz and not be willing to put up with it long enough to get used to the side effects or will have persistent side effects despite continued use, and those people will have to switch from efavirenz to something else.” Says Vergel: “Sustiva does have some problems ten days to two weeks at the beginning; people tend to have nightmares, and not sleep well, and they feel a little dizzy and disoriented. Doctors can manage, I hope, counseling patients [that] once a day is very convenient yet you are going to experience for the next two weeks or so some changes in your mental status [but] don’t freak out because most people get over that.” Vergel does not anticipate any “surprise” side effects, unless the future holds some discovery of long-term effects of use. Though he suggests that more research needs to be done in patient populations involving women and African-Americans, “in general doctors feel comfortable with prescribing this combo because they’ve had enough [positive efficacy data] for so many years.”
Prime candidates for the once-a-day, single dose would also seem to be those on HAART, who for whatever reason, are nonadherent or find adherence challenging because of forgetfulness, substance abuse, depression, or an aversion due to side effects, among other reasons. Suggests Dr. Gallant, “Adherence is better with once-a-day, so those are exactly the type of people we should be prescribing it to. Given the long half-lives of the combination in that particular regimen of tenofovir, embricitabine, and efavirenz, patients who miss the occasional dose are probably not going to get into as much trouble as they might with drugs that have shorter half-lives because the drug levels will persist in the blood even with a missed dose....On the other hand, somebody who stops their medicine abruptly and goes away for a couple of weeks and doesn’t take any at all—that actually could be problematic because the half-lives are long and so the drug levels in the blood [will persist] and that could increase the risk of resistance. So it really depends on what their pattern of nonadherence is, in terms of what they would be better off taking. Somebody who interrupts therapy for long periods of time would probably be better off on a protease inhibitor-based regimen rather than an NNRTI like efavirenz.”
HIVers, especially those who are newly diagnosed and concerned about pill burden, will probably welcome the news of a once-a-day, single dose, says Vergel. When he lectures around the country, he hears the same questions: How long can I prolong not taking my first meds? Can I take a vitamin or supplement that would make me not need my meds for a while? The Sustiva/Truvada coformulation “is actually the easiest, and most convenient [regimen] that we’ve ever had in almost twenty-five years of HIV,” says Vergel. This new coformulation, he believes, will be an easier pill to swallow—mentally.
Dependent on whether the companies involved in the joint venture provide a “good prize” and compassionate pricing, Vergel suggests that outreach might be easier to the thirty-six or so million out of forty million who are not taking HIV meds, especially those in the developing world. As for developing countries, Dr. Bischofberger says, “A single tablet regimen represents an important tool for treatment in resource-limited settings. We are in active discussions with a third pharmaceutical company, Merck, to develop an agreement that would make the single tablet regimen available outside the United States. Merck holds the rights to distribute Sustiva (under the brand name Stocrin) in Africa and other developing regions. We hope to announce an agreement for developing world access to the single tablet regimen in the near future.” Here in the U.S., attests Dr. Bischofberger, “Gilead and BMS will also work with state health authorities to negotiate discounted prices for the single tablet regimen under Medicaid and AIDS Drug Assistance Programs.”
But the shift in perception might also allay the fears of the newly diagnosed, says Vergel, who describes the difference between two pills (Sustiva and Truvada) once-a-day and one pill once-a-day as more significant than one might think. “It’s not a big deal, right? But it is—in terms of perception. A small shift from two to one can make a huge shift mentally to somebody who just got diagnosed. I can’t really describe it beyond that.” One pill once-a-day perhaps seems less like being on an anti-HIV regimen and more like taking a routine once-a-day vitamin, which Vergel has often suggested to those who are newly diagnosed to help them acclimate to the “complete lifestyle change” that often comes with treating HIV.
Vergel, who has been positive for twenty-three years, cautions that trumpeting a reduction of pill burden could give those at-risk for HIV the false impression that HIV disease is easily managed for everyone. “We’re already fighting here two misconceptions in the United States—the fact that people think we have a cure, and that [HIV] is not a big deal anymore. The huge wave of unsafe sex, especially in the younger gay male population” might continue. “The twenty-something generation of gay men have never seen death. I’m forty-seven and I’ve seen forty-two of my friends die. They haven’t really seen how nasty AIDS can be, and it’s really not cured. People have side effects, long-term effects, and thirty percent of us don’t respond,” he says, referring to those like himself who have multidrug resistance and cannot benefit from this potential reality of one pill once-a-day but must continue to revise and supplement their regimens. But urging people to get tested and to test early might be facilitated, he says, with the promise of catching HIV before it becomes AIDS as well as knowing about the availability of this simplified regimen, when it becomes approved.
June marks the twenty-fifth anniversary of the CDC’s first reporting of what would become known as AIDS, a time when no known treatments existed. Says Dr. Bischofberger: “We have made great strides in improving treatment for physicians and patients since the advent of HAART over a decade ago. This is an incremental step that raises the bar for the future of HIV care.”
Chael Needle wrote about a study investigating the relationship between liver injury and HAART for the May issue.
June 2006
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