March 17, 2011
Nelson Vergel, B.S.Ch.E., M.B.A., is a leading HIV treatment advocate, author and founder of the Body Positive Wellness Center in Houston, Texas.
We live in parallel worlds rife with contradictions. As we fear more and more budget cuts; AIDS Drug Assistance Program (ADAP) problems; slow, or lack of, global access to HIV medications; and other concerns that keep popping up when attempting to control this epidemic, there are rays of hope that emerge, and motivate many of us working in treatment and research advocacy to keep moving forward.
After attending the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) in Boston, Mass., and following different areas of research, I decided to write down a list of advancements that really thrill and energize me as an educator and research advocate. Keep in mind that this is a very limited list that excludes many advances in pre-exposure prophylaxis (PrEP), microbicide gels and HIV treatment-related research areas.
I remember a few years ago when Marty Delaney -- one of the U.S.'s best-known treatment activists, who died two years ago -- would raise his hand in meetings and ask: "What about spending funds on searching for a cure?" People would turn and look at him as if he was crazy or just plain dreaming. Marty believed that we need to spend more funds on strengthening the immune system instead of finding more and more drugs to take. I wish he was alive today. He would have sat through the different presentations about gene therapies and other approaches during this last CROI, amazed and amused that his wishes were coming true. A shift in perception toward the belief that a cure is possible is the first step to take, and I think we are there now. As an HIV-infected man who has lived with multidrug resistance for most of my 25 years of infection, I have been looking forward to the day that renewed hope for a cure would arrive. Even if it takes years, the word "cure" is no longer a four-letter word in meetings.
Almost four years ago, a young doctor in Berlin decided to think outside the box, which resulted in the first report of a cured HIV-infected patient. The patient, who had leukemia, got a donation of stem cells from a person with the delta32 mutation that confers resistance to HIV. Although this cure may not be accessible to most due to costs and risks, we are now starting to get a glimpse of how this case can be replicated in a more practical way with the use of zinc finger nucleases that can manipulate a gene to force CD4 cells to have this delta32 mutation. Studies in HIV treatment-naive and treatment-experienced patients with or without leukemia are underway, with some exciting pilot data.
Other researchers are devoting their energies to finding safe compounds that can help flush latent HIV out of dormant cells. This flushing could be used in conjunction with other approaches to achieve a functional cure.
The challenge now is to find ways to encourage collaboration between research groups; and to advocate for funding for new immune-based approaches while supporting researchers who are thinking outside the box. As the AIDS Policy Project has reported, only 3% of U.S. National Institutes of Health (NIH) funding goes toward researching HIV cure approaches. There is a lot of work ahead of us.
If all the relevant studies go forward without yielding any surprisingly negative data, we may have three once-daily single pill combos approved during the next three years. The Quad pill and a combo of rilpivirine (TMC278) plus tenofovir/emtricitabine (Truvada) will probably be the next two options approved. (The Quad pill is a combination of tenofovir/emtricitabine plus two as-yet unapproved drugs [elvitegravir, an integrase inhibitor, and cobicistat, a novel booster drug] from Gilead Sciences, Inc. Rilpivirine is an experimental non-nucleoside reverse transcriptase inhibitor [NNRTI] from Tibotec Therapeutics.) A year or two after that, the combo pill 572-Trii will probably be approved. (572-Trii consists of GlaxoSmithKline's experimental integrase inhibitor dolutegravir [also known as S/GSK1349572 or just "572"] plus abacavir/lamivudine [Epzicom, Kivexa].) Hopefully, these new one-pill combos will cause fewer lipid and central nervous system side effects than efavirenz/tenofovir/emtricitabine (Atripla) and will motivate companies to do a better job at pricing reasonably and providing faster access globally to people who need treatment. I hope I am not dreaming in this expectation.
Despite the impressive effectiveness of these drugs in clinical trials, a subset of patients has exhibited virologic failure with many commercially available drugs. Most failures likely occurred because of the inability to construct a regimen that contained two to three fully effective agents. Adverse events, drug-drug interactions and non-adherence also likely contributed to the inability of these drugs to result in durable viral suppression. As a consequence of these factors, the failure rates in recent phase 2/3 studies such as DUET (etravirine [TMC125, Intelence] and darunavir [TMC114, Prezista]), MOTIVATE (maraviroc [Selzentry, Celsentri]), and BENCHMRK (raltegravir [Isentress]) were in the 27%-40% range. It is assumed that many of the patients who failed these recent studies were subsequently unable to construct a suppressive regimen, although the long-term outcomes of those failing these clinical trials are unknown.
The prevalence of multi-regimen failure in clinical practice is also unknown. In a survey I conducted a year ago, 90 doctors reported having over 250 of these patients. Many have advanced disease (CD4 < 100) and hence may not be able to "wait" for the development and approval of multiple new options.
Given that patients who are unable to construct a background regimen often fail therapy, the U.S Food and Drug Administration (FDA) and other interested groups have advocated that future clinical trials only enroll patients who have one or more active drug for their HIV in their background regimen. Although this is an ethically sound recommendation, one unfortunate consequence is that those patients who have now progressed to multi-regimen "deep" salvage are not able to access experimental drugs via clinical trials.
The possibility of constructing a three-active-agent regimen for this population during the next four years is low, which will diminish the chances for survival in those with lower CD4+ cell counts. Consequently, an early expanded access program that makes available current investigational agents that have progressed beyond phase 2 could provide improved chances of survival for these patients in need. A pilot of this multidrug expanded access program is now being set up to provide access to two new drugs that can help people with multidrug resistance: ibalizumab (a CD4 monoclonal antibody made by TaiMed Biologics; formerly known as TNX-355) and dolutegravir (this second generation integrase inhibitor may help some patients with raltegravir resistance). I will elaborate on this program in future writings.
Although not mentioned in any conference reports yet, there are more and more HIV drugs being developed with long half-lives in the body. Progenics has a once-a-week injectable entry inhibitor; Tibotec may improve the pharmacokinetics of its rilpivirine with nanotechnology to enable the drug to stay active longer; ibalizumab may be effective in once-every-two-week or once-a-month dosing (we're still waiting for data on this); and two more companies may have integrase or entry inhibitors that have a long permanence in the body. The term "nPO" is being bounced around for non-oral, non-daily regimens that may be injected every few weeks. How long it will take to see this approach tested in humans is still unknown, but this is no longer fiction!
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