CD4 cell manipulation and reinfusion...will they make a difference in long term survival?

Very cool article on Matt's CD4 cell manipulation and reinfusion

Will this be a solution for people whose CD4 cells have remained low even after years of undectectable viral load? Are these "HIV resistant" CD4 cells functional in the long run? Well, Matt thinks his health has improved and he no longer has sinus infections like he used to before he joined the study.  We may soon need all of you to support this new concept, so be ready!

http://www.hivandhepatitis.com/hiv-treatment/hiv-cure/3275-gambling-for-a-cure-for-hiv?ic=700100

The Cure of HIV is Possible- But We Need Your Help

After attending a meeting sponsored by several organizations (TAG, AMFAR, Project Inform, the AIDS Policy Project) in Baltimore on April 20-21 this year, I came to the realization that we needed a video that would wake people up to the challenges ahead of us to get to a cure of HIV that is accessible and practical.  As most of you know, the case of Timothy Brown (aka The Berlin patient), a person who got cured of HIV and leukemia 5 years ago, has jolted a new energy and hope in the search for the cure.  But most people with HIV, policy makers and potential funding sources are not fully aware of this case and what the new movement for a search for a cure are all about.  So, I decided to travel around the country to interview key players in advancing this field to make a short video that could serve as a catalyst for awareness and change. This short video, done with a very low budget with the help of my activist friend Greg Fowler, is only part of a longer, more detailed documentary to be finished before World AIDS Day this year, the 30 year anniversary of the first AIDS cases. Please watch it and forward it to your friends.  Please follow the suggestions made in that video and become part of the cure! Everyone can do something now to raise awareness and funds not only for research but also for advocacy and education in this important new and expanding area.  I hope I can count on you.

Interview with Man Who Got Cured of HIV

This link has a video of an interview with Tim Brown, the man who got cured of HIV (who I refer to as the "Berlin Patient"  in my article below).

http://feedroom.businessweek.com/?fr_story=4a74617791423dc8652dd78d84817c27ba4045aa


From TheBodypro.com

Zinc Fingers and Gene Therapies for HIV: Mimicking the Cured Berlin Patient?

By Nelson Vergel

March 2, 2011

Jay Lalezari, M.D., from the University of California-San Francisco presented first-of-its-kind study data on the use of zinc finger nucleases (ZFNs) to artificially disrupt the CCR5 receptor on the surface of CD4 cells, which HIV uses to infect its human host. The study is an attempt to determine if genetically modifying a patient's own CD4 cells could result in the augmenting of the patient's immune system with lasting, HIV-resistant cells.

Some HIV-infected patients who have an undetectable viral load while taking HIV medications continue to have low CD4+ cell counts. Lalezari et al decided to perform their proof-of-concept study on six of these patients: Each was on HIV antiretrovirals, had an undetectable HIV viral load, had a CD4+ cell count between 200 and 500, and had been HIV infected for more than 20 years. The patients were enrolled in one of two cohorts: in one, 10 billion total cells were modified; in the other, 20 billion. The process involved autologous (i.e., derived from the patient) R5-disrupted T cells that were expanded and modified with ZFNs outside the patients' bodies and then infused into the patients. The patients were followed weekly for one month and then monthly for 11 months post-infusion; blood and rectal mucosa samples were taken.

This novel study construction is the result of a history of groundbreaking findings. CCR5 has long been of interest to HIV researchers because many people who are resistant to HIV infection have a mutation in their CCR5 gene: the delta32 mutation. A minority of people of northern European descent (1% to 2.5%) have this mutation in the CCR5 receptor. After studying these patients, the oral CCR5 inhibitor drug maraviroc (MVC, Selzentry, Celsentri) was developed and ultimately approved in the U.S. in 2007. Fears that blocking the CCR5 receptor would lead to more rapid HIV disease progression or the emergence of other health problems have slowly dissipated since the drug was first given to humans in studies. (That said, there are some known adverse effects of CCR5 receptor blocking, including increased susceptibility to West Nile virus.)

As maraviroc was being developed, companies such as Sangamo BioSciences, Inc., were already trying to block the CCR5 receptor in a more permanent way: by using zinc finger nucleases, which act like scissors that cut the gene that codes for that receptor. But in the past, studies trying to modify CD4 cells in this manner have shown limited persistence of these cells after infusion in patients.
At the same time, some clinicians around the world were also trying to think outside the box on how to block HIV entry into CD4 cells. One such progressive thinker was Gero Hütter, M.D., from the Charité-Universitätsmedizin in Berlin. He had an HIV-infected patient with leukemia; he decided to try to treat both the patient's leukemia and HIV via a stem cell transplant using a donor with the delta32 mutation.

Hütter (and his patient) was lucky to find such a donor. The transplant -- which treats leukemia by essentially rebooting the body's immune system and creating new white blood cells -- also had the benefit of wiping out the HIV infection in the patient. The results of this extraordinary case were presented at CROI 2008 without receiving much excitement from the medical community.

It wasn't until almost two years later -- when it was found that the "Berlin patient" was still free of HIV not only in the blood, but in other compartments as well -- that excitement grew. Now, four years later, the patient remains HIV-free, which suggests he is cured of the disease. This has given companies such as Sangamo even more motivation to pursue a potential functional cure via disruption of the CCR5 receptor.

The data presented by Lalezari about Sangamo's ZFN approach showed several things:

1. The infusion was safe and well tolerated.
2. CD4+ cell count increases were seen in five of the six patients. The patient who did not respond had pre-existing antibodies to the adenovirus vector used to deliver the ZFN into the CD4 cell, so his body destroyed the vector, rendering the ZFN inactive. About 50% of the human population has those same antibodies, so a different vector may be used in future studies.
3. The percentage of CCR5 disruption in the peripheral blood of the five responders was 6%, 3%, 1%, 2%, and 2% (respectively) at day 14 and persisted for the duration of the follow-up. CD4+ cell counts increased in all patients at day 14 (from an average of 35 to 1038 cells/mm³) and were sustained at all time points (with mean increases of 208, 86, 233, 911, 210 cells/mm³, respectively). CCR5-disrupted cells were detected in the rectal mucosa of all patients at all assessed time points, with levels of CCR5 disruption approximating that of peripheral blood when normalized for CD4 cells within each compartment.
4. Three of the five responders had normalization of the CD4/CD8 ratio, which is a hallmark of the health of the immune system.
5. There was a good uptake (grafting) of the modified CD4 cells into the blood of the five responders. In fact, by day 14 these patients had three times the quantity of cells that had been infused, showing that there was a growth of modified cells in their bodies. By day 90, the levels of persistent engraftment had become 6- to 40-fold greater than previously reported. After three months, 6% to 7% of the CD4 cells in the circulating blood had evidence of gene modification, which is over 10-fold higher than achieved by any previous T-cell modification therapy in HIV.
6. Homing of these cells to the gut mucosa was observed in all patients tested, with CCR5 disruption levels similar to that of peripheral blood, suggesting these cells traffic normally. This is important since gut mucosa is the interface between the immune system and HIV.
7. As I noted above, there were two cohorts in dosing: 10 and 20 billion cells. There seemed not to be a response difference between those two cell doses. Cells grafted and expanded during the first two weeks.

This exciting study opens the door to new possibilities, but many questions remain unanswered:

1. What will happen long-term with the newly engrafted CD4 cells? Will they provide a survival or comorbidity benefit in these patients? (Note: Patients in this study will be followed for life.)
2. Will this approach help control HIV replication in patients who stop antiretrovirals after long-term HIV suppression? How can we ethically ask patients to enroll in studies that require a structured treatment interruption? Will institutional review boards be willing to approve these kinds of studies in the future?
3. Do people do better with more than one infusion? What is the best number of cells to ensure optimum immunological response?
4. Will this approach help control HIV replication in treatment-naive patients who have a detectable viral load and who are not taking HIV antiretrovirals? Will these cells still have a survival advantage when challenged with untreated HIV? (Note: Lalezari is currently enrolling a 14-patient study in San Francisco that will attempt to answer these questions.)
5. Will these gene-modified cells have a survival and activity advantage against HIV across the board? Will HIV viral load be controlled well enough for people to stop using antiretrovirals -- or, as stated in the question above, allow them to avoid antiretrovirals entirely?
6. What will the cost of this procedure be?
7. What happens to those with pre-exposure to the adenovirus vector who cannot respond to this type of zinc finger nuclease delivery method?

We should be careful not to overreach with these data. Many people are throwing the "cure" word around when talking about this study, but this is just a very preliminary effort to start answering important questions toward that goal.
At a CROI 2011 press conference, Lalezari and other researchers involved in zinc finger nuclease and HIV gene therapy research discussed their findings and the broader implications of those findings. Click here to read that transcript.

Pipeline Problems

by David Evans

In the past month, two companies shelved their once-promising experimental HIV drugs, citing the challenging nature of bringing a profitable product to market. Has the overwhelming success of modern-day HIV drugs jeopardized the future of new HIV treatment options?

Since Matt Sharp first learned that he was HIV positive in 1988, life has been about trying to stay one step ahead of the virus. Like many, he started each new HIV drug only to have it eventually fail, followed by a wait for the next one to be available through a clinical trial, expanded access program or U.S. Food and Drug Administration (FDA) approval. That’s just the way it was—trying to outrun HIV and to hold on until science and the pharmaceutical industry developed the next best thing. There were no other options.

The last three years, however, have been kinder to Sharp. In the space of about a year and a half, from June 2006 through January 2008, four new antiretroviral (ARV) treatments were approved, all of them with the potential to work against even the most drug-resistant HIV. After Sharp started a regimen with one of these new treatments, his virus became undetectable for the first time ever. His CD4 cells, which had been depressed for years, started to inch back up, and he continues to do well today.

Sharp is not alone in his Lazarus effect. Thousands of people with multidrug resistant virus, many of whom were once quite sick, have been able to push their viral loads to undetectable levels and restore their health with the newest antiretrovirals, often in combination with each other. But what happens if their HIV accumulates additional mutations and breaks through? Unfortunately, the number of promising agents waiting in the wings for people with drug resistant virus is dwindling.

Two companies, Avexa and Myriad Genetics, suspended development of their experimental ARV treatments over the past month. From press statements, it appears that both companies determined that their drugs—apricitabine (a nucleoside reverse transcriptase inhibitor) and bevirimat (a maturation inhibitor)—could not be brought profitably to market. While neither drug was perfect, or had a certain shot at FDA approval, some activists and researchers see their failure as evidence of a paradox—that today’s highly effective drugs are hurting the development of tomorrow’s promising agents.

“The very incentives that got industry involved to develop HIV drugs are now working against us,” says Jay Lalezari, MD, the director of clinical research at Quest Clinical Research in San Francisco, who specializes in the study of drugs for people with multiple drug resistance. “But, you know, money is a driver, and you don’t expect these companies to do it for nothing,” he laments.

“It’s getting harder and harder to hit a homerun with a new HIV drug,” says Bob Huff, a longtime HIV treatment activist from San Diego. “The current drugs are very good, and most doctors and patients are fairly satisfied…. The incentive for companies to invest in developing new HIV drugs is not strong right now.”

“It’s disconcerting,” Sharp agrees. “In terms of practical issues around drug development, we do need to put our heads together and strategize about fixing the things that are broken.”

Sharp is working with Huff and Nelson Vergel, an activist from Houston, to help identify novel ways for people who’ve run out of treatment options to get their hands on multiple experimental agents at one time. The three are also looking at creative ways for companies to get drugs approved that might only benefit treatment-experienced people, a market that is increasingly small and potentially less profitable than ever before.

Sharp, Huff and Vergel express concern about options for people who have already become resistant to current meds. With apricitabine and bevirimat now out of the picture, it only leaves a couple of drugs in an advanced state of development for people with multi-drug-resistant virus. Given the uncertain nature of drug development, however, those drugs could also tank or be delayed, and it could be quite a while before something new is approved.

Sharp is not hopeless, however, and cautions that, “There’s no reason to panic. I definitely don’t think this is the end of the world.”

Lalezari agrees that things are not so bleak, at least not yet. He points out that a number of his patients are still doing well clinically, despite going for many years with very low CD4 counts and detectable virus. He stresses that it is possible to pick a regimen and stick with it for a long time, even if your viral load remains detectable. He encourages people to sit tight on such a regimen and to “try to keep this détente with the virus, and we’ll see if gene therapies or other immune therapies can be brought to bear in the future.”

Vergel is another veteran of the treatment wars and knows what it’s like to face uncertainty. He says that if his current drug regimen fails, he’s not sure what he’ll turn to. He’s not despairing, however, because he feels that he and other activists are making progress with the FDA in figuring out how to make new treatment options available, even when the traditional avenues of approval are a challenge.

In the meantime, he distills his own positive outlook for the many hundreds of people with HIV he interacts with each year through his Internet and public speaking activities. As he sums it up: “You have to give them hope.”
A Good News, Bad News Story

“The bigger picture with HIV therapeutics is a good news, bad news story,” says Paul Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital in Boston. “The good news is that HIV treatment success is so high now. The bad news,” he adds, is that “the motivation to develop new drugs, especially drugs to treat resistant virus, has ironically never been lower. There’s this small group of people who have no options even with those newer drugs, and for them, the situation is very discouraging.”

Treatment success has made developing a new drug targeted toward drug-resistant virus problematic in several ways. First, we can no longer simply pit a new drug against a placebo, with no other active drugs to back it up. A number of studies have found that when people take only one active drug at a time, they quickly develop resistance to that drug. For this reason, federal treatment guidelines recommend waiting to start a new treatment, if possible, until two or three active drugs can be combined into a new regimen.

While combining two or three active agents is good for study participants, it's a headache for trial designers. This is because the difference between an experimental drug and a placebo are much smaller and more difficult to measure if their impact is masked by the potency of other powerful drugs.

Sax points to the failure of the drug vicriviroc to demonstrate efficacy over a placebo in treatment experienced participants as a perfect example of this dynamic at work. “The vicriviroc study had the old study design,” Sax explains, “which was [a background regimen chosen by drug resistance tests] plus or minus the [vicriviroc], and they didn’t see any benefit, unless you [only looked at people taking] one other active drug.”

To detect such slight differences you have to either recruit only people with one or fewer active treatments available or design trials with twice as many people. The first option goes against the grain of treatment guidelines, and Sax thinks that the challenging and slow recruitment for a number of recent studies targeting treatment-experienced patients makes it quite unattractive to the companies. Even more unattractive, however, is the second option which almost doubles the cost of the trial.

Vergel has been working with Lalezari and Steve Deeks, MD, professor of medicine at the University of California at San Francisco, to estimate the number of people in the United States with resistance to all of the existing drugs—the kind of people that Sax says would be a challenge to recruit.

Vergel estimates that there are at least 1,500 such individuals, but that number is not growing rapidly. While this may be good news from a public health perspective, it is bad news for people with highly drug-resistant HIV who are depending on the pharmaceutical industry to develop new treatment options. Corporate board members and shareholders demand the highest profit possible with the least expense. With clinical trials potentially getting more expensive and harder to recruit, and the market size staying small, it’s getting very difficult to meet those demands.

“We’re up against the fact that drug development is about making a profit,” Sharp says, “and unfortunately that’s what we have to deal with.”
What the Future Holds

Sharp, who works frequently with Vergel on treatment advocacy projects, says that there are promising treatments further back in the pipeline, and that still other more innovative types of treatment are finally reaching the point where they can move in to clinical trials designed to prove efficacy and safety. What’s more, Sharp remains devoted to advocacy related to eradication: the elimination of HIV from the body.

Lynda Dee, a veteran treatment activist and the president of AIDS Action Baltimore, confirms Sharp’s experience: “Activists have met with companies over the last year, and some have said that they have internal programs looking at new drugs and eradication,” she says. “I’m hopeful that this discontinuation of the development of [apricitabine and bevirimat] doesn’t mean that all of the industry has turned tail and left the HIV field.”

Lalezari thinks that an entry inhibitor from TaiMed Biologics, an integrase inhibitor from ViiV Healthcare, and an attachment inhibitor from Bristol-Myers Squibb might have a shot further down the road. He’s less sanguine than Sharp or Dee about the prospects for antiretroviral drug development in general, given the challenges involved. “I think we could enter a period where there’s an abrupt end to HIV drug development,” he asserts. “That’s not to say that there aren’t new modalities of interest…but in terms of new direct-acting antivirals, it’s going to be very difficult,” he predicts.
Protecting Your Options

Are we on the verge of returning to the days when the best that a long-term survivor could do was guard against opportunistic infections and pray to survive long enough to benefit from the next drugs to come out of the pipeline?

Perhaps not, according to Lalezari. “The thing about the treatment-experienced population, which is astonishing, is that I have a whole bunch of people that I have been following for a number of years now, who are doing just fine. They have detectable virus, and their [CD4] cells are less than 20, but their health is just great, which is not explained in my understanding of the universe.”

Sax stresses that going off treatment would be a lot worse than staying on a failing regimen. “You know, all attempts of treatment interruptions of people with drug resistant virus met with bad outcomes,” he says, “So one thing for sure, is that people should stay on something. The question of what is more difficult. It’s never been well studied.”

In the end, what’s at stake is whether new drug development can stay ahead of HIV-positive people’s needs for new treatment options. Vergel points out that those who’ve yet to develop drug resistance can preserve their future options by finding a tolerable effective treatment and adhering to it religiously. In this regard, the possibility of a dry spell in new drug approvals could encourage people not to take for granted that new options will inevitably keep coming down the pike. “Fear,” Vergel says, “can be a good motivator” by way of emphasizing the importance of treatment adherence.

For people who’ve run out of new options, there is still reason for hope. It is possible to stay clinically healthy despite a failing ARV regimen, as Sax and Lalezari point out, and there are ways to minimize the risk of developing resistance to the experimental agents that might come later. Vergel tries to remind people of that and tells them “to not come from a place of despair.”

Sax thinks it will be helpful for researchers and health care providers to pool together their knowledge and resources to figure out the best care models for people who’ve run out of treatment options, arguing that since few providers have large numbers of such individuals it is difficult to become an “expert” in treating them. He thinks that activists and groups such as the Forum for Collaborative HIV Research in Washington, DC, can aid in that process.

Despite the challenges involved in developing the next generation of HIV therapies, Sax believes in remaining optimistic, especially with his patients who’ve run out of options. He tells them: “Press on. Drug development has helped us in the past. We hope it does again in the future.”