What Lies Ahead: An Activist's View of Promising HIV Treatment Research
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.
1. The Hope for a Cure
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.
2. New HIV Medication Options
Once-Daily One-Pill Regimens
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.
What About Salvage Patients?
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!
3. Recent Advances in Lipodystrophy
With the recent approval of tesamorelin (Egrifta), the daily injectable growth hormone-releasing factor shown to moderately decrease visceral fat, there may be a renewed interest in a field that has been neglected in the past few years due to a frustrating lack of accessible management options. It is an expensive drug at around $2,000 a month, and requires daily subcutaneous injections to attain a 15%-19% decrease in visceral fat in 26 weeks. It seems well tolerated and it has not been studied in combination with diet and exercise. I am monitoring its insurance reimbursement and patient assistance program now through my online network of patients, and will report about this in future writings. Some companies are starting to deny reimbursement since they consider this to be a cosmetic-related treatment that has not yet been shown to improve clinical outcomes.
We are also pretty certain that there is no regimen visceral fat "friendlier" than another, no matter what effect each regimen has on lipids (we used to believe that more lipid-friendly drugs also meant more body-friendly ones). What we have not proven after 16 years of highly active antiretroviral therapy (HAART) is whether or not starting at higher CD4+ cell counts protects patients against more pronounced visceral fat gains. There is a belief that the lower the CD4+ cell count at baseline, the more the immune reconstitution-related "return to health" gain in weight.
Unlike where we are with fat accumulation, we are now pretty certain that stavudine (d4T, Zerit) and zidovudine (AZT, Retrovir) are the main drugs linked to lipoatrophy. However, access to the two products approved by the FDA to correct facial lipoatrophy, poly-L-lactic acid (Sculptra, New-Fill) and calcium hydroxylapatite (Radiesse, Radiance), is still very limited. Over a year ago, Medicare approved reimbursement for facial reconstruction of HIV-infected patients with lipoatrophy-related depression. However, this decision has not helped access since it pays a very low fee for doctors to inject the products (an average of three to six initial sessions and yearly touch-ups are required for each since they are not permanent). The companies' patient assistance programs have also started to cut back with the belief that the approval by Medicare would take care of many patients who lacked access before. There is still no permanent option for HIV lipoatrophy treatment in the U.S., although we have one approved for cosmetic purposes (Artefill) that is cost prohibitive in the volumes required for facial lipoatrophy correction.
Buttock lipoatrophy is an unchartered market that is already attracting foreign companies that carry permanent products such as polymethyl-methacrylate (PMMA) for studies in the U.S. PMMA has also been used successfully as a permanent option for facial lipoatrophy for several years in Latin America and Europe.
So progress has been slow, but promising. A lot of patient advocacy is still needed in this area. You can learn more on the Web site FacialWasting.org.
4. Aging Research: New Data on Therapeutics Needed
We have spent the last few years reviewing cohorts for incidence data on bone loss, vitamin D deficiency, cognitive dysfunction, immune system aging, and other aging-related issues. But little to no intervention data have been generated to date. When searching for aging-related studies at ClinicalTrials.gov, there are only eight that are enrolling. None of the studies uses any therapies.
This is probably the hottest vitamin in HIV research at present. It is made by the body after our skin is exposed to sufficient amounts of sunshine, but the liver and kidneys need to transform it into the "active" form, known as 25-OH vitamin D, which is the form that helps our bones and immune system.
Vitamin D may be involved in increasing the ability of immune cells to kill invaders in our bodies. It also seems to help those with tuberculosis have less severe disease symptoms and progression. It can also mediate inflammation by decreasing tumor necrosis factor alpha levels. In addition, in a review of seven past studies in HIV-uninfected people, five of the studies found a correlation between low vitamin D levels and higher cardiovascular risk (although the studies were not very similar, so it is difficult to compare apples and oranges).
The general population commonly suffers from vitamin D deficiencies, especially now that most of us try to avoid the sun to minimize skin cancer risk. People with darker skin, those who live in northern latitudes, those in winter time and the elderly tend to have more vitamin D deficiency. And HIV in itself, as well as the medications used to treat it, seem to also be risk factors.
It is not completely clear if low vitamin D in HIV-infected people is due to inflammatory responses caused by HIV. Emerging data point to the likelihood that HIV-infected people using efavirenz (Sustiva, Stocrin) may have lower vitamin D levels due to this drug's acceleration of the degradation of the vitamin in the liver (it lowered vitamin D levels by 4.5% in 26 weeks). Other small studies have shown that tenofovir (Viread) may also affect the metabolism of vitamin D into its active metabolite in the kidneys.
There is a large study looking at the long-term effects of vitamin D plus fish oils in 20,000 HIV-uninfected people to see if fractures and other health issues are improved by these supplements. However, results will not be available until five years from now.
The CHARTER cohort in the U.S. included HIV-infected people with an average of 43 years of age (relatively young) and found that almost half of them had some sort of mild cognitive decline. In a conference call with private investigators, I asked them how this compares with a similar HIV-uninfected population. They said that mild cognitive declines would be expected to be present in 10%-20% of HIV-uninfected people, so HIV almost doubles the rate. It seems that CD4+ nadir was one of the strongest predictors of cognitive decline.
The Multicenter AIDS Cohort Study (MACS) showed that after adjusting for most important factors, frailty was higher in HIV-infected men compared to HIV-uninfected men. In fact, it was reported that the frailty of a 55-year-old HIV-infected man may be similar to that of a 65-year-old HIV-uninfected man.
Treatment Studies Needed
So, as a patient and research advocate, I have generated a list of treatment studies that could be considered for those looking for research ideas that may attract patient enrollment:
- effect of donepezil (Aricept) on cognitive function in HIV-infected patients with HIV-associated neurocognitive disorder (HAND)
- effect of vitamin D supplementation on inflammatory and activation markers in HIV disease
- effect of vitamin supplementation on blood levels of HIV antiretrovirals
- assessment of incidence of early-onset menopause in HIV-infected women
- use of leptin on visceral fat and inflammatory markers in HIV-infected people
- effect of armodafinil (Nuvigil) on fatigue, cognitive function and depression scores in aging HIV-infected patients
- effect of acyclovir (Zovirax) on immune activation and inflammatory markers
- effect of coenzyme Q10/carnitine on mitochondrial DNA/function and fatigue
- effect of exercise on inflammatory markers and frailty scores in HIV-infected patients over 50 years of age
- effect of a Mediterranean diet on inflammatory markers, body composition and lipids in HIV-infected patients with a body mass index (BMI) greater than 25
- effect of testosterone replacement on bone density in HIV-infected males with hypogonadism and osteopenia/osteoporosis
- interaction studies of cardiovascular medications and HIV antiretrovirals
Aging and Cure Activism
HIV activists with the Coalition for HIV and Aging Research and Policy Advocacy (CHARPA) are demanding that the U.S. National Institutes of Health (NIH) devote more attention and resources to the issue of aging and HIV. Will the NIH respond, and will it respond in time?
With patient community support and involvement, guidelines geared toward managing aging-related issues in HIV are currently being considered by different groups such as the U.S. Department of Health and Human Services treatment guidelines panel.
The accelerated-aging model that HIV presents in a younger population that is used to clinical study participation may be attractive to experts in gerontology. So, we will definitely see more data on this research area, even if it is slowed down by research budget cuts.
Cure activism is gathering momentum. Advocacy groups such as Treatment Action Group (TAG), Project Inform, amfAR and, last but not least, the AIDS Policy Project are presently trying to initiate community-driven approaches to advocate for more research funding of innovative investigators, researcher collaboration, and community education for study enrollment. The next few years will be exciting and challenging as interest in the cure reaches the predicted tipping point in an era of budget cuts.