2010 & Beyond
BY Benjamin Ryan
November 18 2010 4:00 AM ET
While drugmakers have produced 30 individual or combination antiretrovirals since 1987 (28 of which are still on the market) the federal Food and Drug Administration hasn’t approved any new medications since the nonnucleoside analog Intelence (etravirine) in 2008. Although output from the new-drug pipeline has slowed, manufacturers are still looking for medications that have fewer side effects, are better at fighting resistance, and reduce pill burden. Companies are racing to develop a once-a-day combo pill for treatment-naive HIVers that is as effective or more effective than Atripla but that has fewer side effects, providing an alternative for people who are troubled in particular by Atripla’s tendency to cause vivid dreams -- a side effect attributed to its Sustiva (efavirenz) component.
But even though there has been no new antiretroviral released to the market for almost two years, there are a dozen or so anti-HIV candidates currently in advanced clinical studies (Phase II and III). If they make it through these stages, at least six compounds could be submitted for Food and Drug Administration approval in the next few years.
> Bevirimat, a maturation inhibitor being developed by Panacos and purchased by Myriad Genetics, showed mixed results in Phase IIb trials in 2007, working in only 60% of HIVers studied because of mutations in their respective viral populations.
> Elvitegravir is an integrase inhibitor being developed by Gllead; it’s in Phase III.
> GSK-572 is an integrase inhibitor being developed by ViiV Healthcare, the combined antiretroviral development units of GlaxoSmithKline and Pfizer. Promising results from its Phase IIa trials were released in July 2009. If ultimately successful, this med could become an alternative to Atripla when combined in a daily dose with Ziagen (abacavir) and Epivir (3TC). Although there is an effective screening test to rule out those who would not tolerate the drug, the allergic reaction some HIVers have to Ziagen remains a barrier.
> The “Quad” is a once-a-day combo pill from Gilead that combines forthcoming integrase inhibitor elvitegravir, Truvada (Viread and Emtriva), and a new boosting agent that researchers hope will be better-tolerated than Norvir (ritonavir). Currently being studied in treatment-naive patients, with good results in Phase II trials, it could also become an alternative to Atripla.
> Rilpivirine (TMC278) is a second-generation nonnucleoside analog from Tibotec that entered Phase III trials in April 2008; study completion is expected in January. If successful, the new nonnuke may challenge Atripla if studies show it is as potent when combined in a single pill with Truvada.
> Vicriviroc is a CCR5 antagonist, being developed by Merck, that did not show promise for treatment-experienced HIVers; but Phase II/III studies are ongoing for people who have not previously been on treatment. A previous CCR5 inhibitor, Selzentry (maraviroc), was approved in 2007.
While none of these specific drugs promises to revolutionize treatment, over the coming decade, experts and pharmaceutical representatives say they anticipate even more combination pills will hit the market -- and not just formulations aimed mostly at treatment-naive HIVers. Otherwise, there are many other scientific endeavors still in their infancy that could one day drastically change how HIV is treated and possibly even lead to a cure. We may not see such total ground shift by the end of the decade, but there should at least be a better idea of where we’re headed by then.
Long gone are the days when scientists believed extended suppression of HIV through highly active antiretroviral therapy could permanently eradicate the virus from the body. Elusive viral reservoirs continue to harbor small amounts of HIV and evade medications. Now, as new-drug development slows and researchers look to the next big thing, some of the more enterprising among them are trying to better understand these reservoirs -- what they are and how they manage to remain mostly untouched by treatment -- in order to one day perhaps purge those last remaining HIV cells from the body.
“Ten years from now I think we’ll have made progress toward eradication,” says Steven Deeks, an HIV researcher at the University of California, San Francisco. “I don’t think anyone will have been cured. Hopefully by that time we’ll be actively involved in clinical trials to try and cure HIV.”
David Margolis, a professor of medicine, microbiology, and immunology at the University of North Carolina at Chapel Hill’s school of medicine, whose research lab has been studying viral reservoirs for the past decade, says, “Progress has been very exciting in the past year or two because more groups are seriously looking at these questions of [whether it is] possible to eradicate infection or to treat someone in such a way that they don’t have to be on chronic suppressive therapy.”
The reservoir can mean different things to different scientists. In part, it is made up of resting memory T cells, which for some reason will stop replicating the virus and go into a kind of extended hibernation. During this time, antiretrovirals do not recognize that these T cells are infected with HIV. The challenge for researchers like Margolis is to provoke these cells to express the virus again.
“You could imagine a cure pack -- where you get diagnosed, and you go on antiretrovirals for six months to knock down your viral load to zero,” says Bob Huff, a member of the Drug Development Committee at the AIDS Treatment Activists Coalition. “Then you take another series of pills to express all the residual HIV. Next, you stop that and follow up with a few more months of [antiretrovirals], and then you stop and see if it ever comes back or not. That counts as a revolution. That would be awesome.”
There may be an additional type of cell -- or more than one -- that quietly harbors HIV, but researchers have yet to figure out this mystery. Also, HIV may hide from antiretrovirals in tissues that are inaccessible to the medications, such as the testes, brain, or lymph tissues.
AmfAR, the Foundation for AIDS Research, which prides itself on adopting maverick causes, has now put its weight behind cure research, making the cause the cornerstone of its research program with an initial $1.2 million round of funding. Rowena Johnston, vice president of research at amfAR, says that a “functional cure,” in which a person still has HIV in the body but is able to control the infection without the use of ongoing drug therapy, could come from better understanding what are known as “elite controllers,” the rare HIV-positive people who are somehow able to produce this effect on their own, without the aid of treatment.
Koronis Pharmaceuticals, a biotech company in Redmond, Wash., is working on a therapy that randomly inserts genetic errors into HIV’s DNA as it replicates itself. If successful, this treatment, currently in Phase II clinical trials, would eventually lead to a “viral collapse,” in which the entire HIV population is so riddled with errors that it is no longer able to infect new cells or pass from person to person. Jeff Parkins, vice president of clinical development at Koronis, says that as the reservoir turns over with time, the end result of the therapy could be a cure. Unfortunately, he adds, it’s anybody’s guess as to how long this would take. Ask one scientist the life cycle of the reservoir and he’ll say six months. Ask another: six years. And even another: 60 years.
Other hope for the so-called functional cure comes from the many labs currently researching genetic therapies that would train the body to better fight off HIV. After harvesting a patient’s T cells or stem cells that produce T cells, scientists are inserting genes that, for example, lack the expression for the CCR5 coreceptor that most HIV cells need in order to latch onto the T cells. They then return the cells to the body and hope that these HIV-resistant T cells will flourish and become the dominant aspect of the immune system. A major consideration of this line of therapy is the price tag -- since the process, still in its infancy, costs tens of thousands of dollars. However, if it were needed only twice a year, the savings in comparison to daily medications could tip the balance in its favor.
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