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October / November 2010
At the End of Your Rope?
by Tim Murphy
Ironically, the success of today’s antiretroviral treatments has hindered the development of new options for longtime survivors with drug-resistant HIV.
Chad Kenney, 56, was always aggressive when it came to his HIV treatment. Shortly after his 1987 diagnosis, the Denver native started a treatment newsletter, Resolute, that quickly became a survival guide for people living with HIV/AIDS in Colorado. He was always game to try to raise his CD4 levels with the latest drug (they’ve never been above the 400s), whether it was Retrovir, the first HIV med; Compound Q, a failed hope; or the very first protease inhibitor. He remembers attending a lecture in the late ’80s given by the late legendary treatment activist Martin Delaney. “[Delaney] asked, ‘If you had a diagnosis of cancer, would you wait and see if it got worse [before] you started to treat it?’” remembers Kenney. “So I decided that I was going to try whatever agent I could find [to fight my HIV].”
But what neither Kenney nor HIV experts knew at the time was that adding just one new drug to a failing HIV regimen is usually not enough to quash viral replication. And, doing so often leads to the rapid development of HIV resistance to one new drug after another.
An accumulation of drug-resistant mutations certainly hasn’t made things easy for Kenney. Despite using a power regimen consisting of Truvada, Isentress and Selzentry, his viral load stayed in the hundreds of thousands.
It was only when he added another new drug, Prezista, that his CD4 cell count rose to 145 and his viral load fell to 69—just above the “undetectable” viral load threshold.
He’s hoping these numbers will stick, if not improve. “I’ve lived with uncertainty for a long, long time,” he says, “so I try not to ride an emotional roller coaster.” But the scary truth is, if his viral load creeps back up, there’s no new HIV drug on the market he can add to his regimen.
Just five years ago, tens of thousands of HIV treatment veterans were in the same boat Kenney finds himself in today. The volume of people facing treatment failure was enough to spur drug companies to develop a new wave of antiretrovirals strong and innovative enough to keep drug-resistant HIV in check. Many of those drugs on the market today—including Aptivus, Fuzeon, Intelence, Isentress, Prezista and Selzentry—have lowered the number of people with HIV who are fully resistant to treatment. Based on most good accounts, there are just a few thousand such people nationwide.
Good news, unless you are a member of this large handful of people—which is expected to grow in size in the future—who still need new options. The number of patients who currently need resistance-busting antiretrovirals is so small that pharmaceutical drug companies have little financial incentive to invest the billions of dollars arguably necessary to develop new drugs, including entirely new classes of compounds.
“HIV drug development is about to come to a halt,” says Jay Lalezari, MD, a San Francisco HIV doc who works on creating new HIV drugs and says that of 1,000 patients in his HIV practice, only about 40 “are waiting for something better to come along.”
Nelson Vergel, a longtime HIV survivor in Houston, only recently got his viral load undetectable, thanks to TaiMed Biologics’ experimental drug ibalizumab (TMB-355). He has devoted his life to finding similarly situated patients and connecting them with the trial drugs they need to suppress their HIV.
During the past 15 years, new options continued to come along for survivors like himself. But today? “They’re in deep shit,” Vergel says. “I’m really angry.”
Why angry? For one thing, the current drugs keeping millions of people alive were tested on the very folks who currently need, or may soon need, new treatment options. “The drug industry owes them a big debt,” says Steven Deeks, MD, another San Francisco HIV doc who works on the issue of drug resistance. “We should not forget this generation of people living with HIV,” he says, adding that we need to provide them with new drugs as soon as possible.
The current pipeline, however, has only a few contenders. Two notable hopefuls: the aforementioned ibalizumab, which blocks a key protein on CD4 cells so HIV can’t bind to it, is gearing up for Phase III studies; and GlaxoSmithKline’s S/GSK-572, which is currently in Phase II studies and shows some promise for folks who’ve developed resistance to Merck’s first-generation integrase inhibitor Isentress.
In recent months, two other experimental HIV drugs—Avexa’s apricitabine and Myriad Genetics’ bevirimat—were shelved. Both were casualties of weak early test results and lack of a profit motive.
In a unique activist-doctor partnership, Vergel, Deeks and Lalezari are working with the developers of TMB-355 and S/GSK-572, as well as with the U.S. Food and Drug Administration, on a program to enable patients who really need new options to go on both drugs simultaneously, before the FDA approves them, to beef up the chance of success. They hope this program will launch by mid-2011.
Kenney, who takes a fistful of meds three times a day, says he’ll only sign up for the new drug program if his current regimen doesn’t hold out, but he’s hoping it does. Meanwhile, life goes on. And though he and others like him may dream of “undetectable,” their lab numbers don’t necessarily reflect how they feel day to day.
Many patients with no options left remain in good health, living functional lives despite low CD4 counts and high viral loads. The trick, it seems, is to stay on the best HIV regimen possible rather than going off HIV meds completely. (See “Safety Nets” on page 18.) Lalezari mentions a patient who’s had one CD4 cell for the past five years. “Somehow the lethality of the virus has been weakened by all the drugs he’s on,” he says, adding that lab CD4 counts are a weak marker of immune health because they detect only CD4s circulating in blood, not in lymph tissues and other compartments.
Kenney hopes to visit his boyfriend this winter in Thailand. For now, he hits the gym daily and eats healthy. And there’s love in his life in Denver. “My brother lives two blocks away, and I have friends that go back more than 20 years,” he says. And at day’s end? “My 7-year-old Lab retriever, Kasandra, sleeps on my bed. She’s very, very affectionate—and incredibly demanding!” Sounds a bit like her owner.
Detectable virus doesn’t mean doom! Here’s how to survive and thrive at the end of your treatment rope while waiting for new options.
DETECTABLE? KEEP TAKING YOUR MEDS!
Research shows that people with multidrug-resistant virus and detectable viral loads do better when they stay on their “failing” HIV meds rather than going off them. Talk to your doctor about finding the best regimen possible. And it’s OK to ask for a second opinion. The indefatigable Nelson Vergel can put you in touch with an expert in your area.
SUPPRESS YOUR HERPES
If you have genital herpes (HSV-2), stick to your anti-herpes meds like acyclovir or talk to your provider about taking it. Research shows these meds also help reduce HIV viral load.
It’s important to use condoms to avoid contracting sexually transmitted infections, because getting STIs can inflame your immune system and make your HIV viral load go up. You’ll also want to protect your partners from drug-resistant HIV.
Eat right, exercise, take quality vitamins and reduce stress with yoga, acupuncture, support groups, a pet—whatever works for you. “Keep a positive outlook,” Vergel says. He should know—he’s had detectable virus most of his 27 years with HIV, and he’s still going strong!
PLUG IN TO FUTURE RESEARCH
Connect with Vergel at salvagetherapies.org or e-mail him directly at firstname.lastname@example.org. He’s your link to the latest resources for folks seeking new options.
Search aidsmeds.com and clinicaltrials.gov for the latest updates on experimental drugs ibalizumab, S/GSK-572 and other agents making their way into clinical trials.
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Today was the start of the first international workshop on Aging and HIV in Baltimore.
The program was started by Dr L. Ferrucci who gave the first presentation on frailty. He works in geriatrics and presented general data from previous studies in the general aging HIV negative population. He presented compelling data that showed that people lose lean body mass (via a syndrome. called age related sarcopenia) and strength in people as they age, and those decreases are correlated to higher mortality. Also, inflammation markers like interleukin 6 increase with age, and levels of over 2.5 pg/ml in the blood have been linked to disability due to loss of muscle strength and mass. He also added that aging related inflammation can decrease brain volume and may be implicated in depression and other health issues.
Dr Joseph Margolick from the MACS Cohort presented previously published frailty data from this cohort that followed 4959 men who have sex with men since 1984 until 2006. Some of these men got infected with HIV and have been followed up before and after infection. A total of 1045 patients with HIV were followed. 75% of them had undetectable HIV viral load.
The frailty related phenotype (FRP) (i.e., the physical characteristics of frailty) was identified using 1 item selected from the questionnaires for each of the following 4 components: weight loss (answer yes to since your last visit, have you had unintentional weight loss of at least 10 pounds), exhaustion [answer yes to during the past 4 weeks, as a result of your physical health, have you had difficulty performing your work or other activities (for example, it took extra effort)?], slowness (answer yes, limited a lot to does your health now limit you in walking several blocks?), and low physical activity level (answer yes, limited a lot to does your health now limit you in vigorous activities, such as running, lifting heavy objects, participating in strenuous sports?). The assessment of weakness (ie, grip strength) was not incorporated into the MACS protocol until October 2005 and therefore could not be used in defining the FRP. A participant was considered as having the FRP at the visit if at least 3 of the 4 components were present. The FRP thus defined had a prevalence of 4.4% among MACS HIV-uninfected men aged 65 years and older, which was similar to the prevalence of frailty observed in the Cardiovascular Health Study for men of similar ages.
Frailty improved with the introduction of HAART. However, after adjusting for most important factors, frailty was still higher in HIV+ men compared to HIV- men. In fact, frailty of a 55 year old HIV+ man may be similar to that of a 65 year old HIV negative man.
Basal metabolic rate has also been found to be higher in HIV+ men compared to HIV- ones.
No therapeutic intervention data was presented to review the effect of exercise, testosterone replacement, and other factors on frailty in HIV+ men.
HIV-resistant cells work in mice. Can they help humans?
California scientists, boosted by stem cell research funding enabled by Proposition 71, are aiming for clinical trials involving gene therapy through bone marrow transplants.
By Rachel Bernstein, Los Angeles Times
6:44 PM PDT, August 21, 2010
Clad in a yellow gown, blue foot covers, hair net, face mask and latex gloves, Paula Cannon pushed open the door to the animal room. “I hate this smell,” she said, wrinkling her nose.
The stink came from scores of little white mice scurrying about in cages. Some of the cages were marked with red biohazard signs, indicating mice that had been injected with HIV.
Yet, in some of the animals — ones with a small genetic change — the virus never took hold.
Like mouse, like man? Maybe so.
In early 2007, a patient in Berlin needed a bone marrow transplant to treat his leukemia. He was also HIV positive, and his doctor had an idea: Why not use the marrow from one of the rare individuals who are naturally resistant to HIV and try to eradicate both diseases at once?
It worked. Sixty-one days after the patient’s transplant, his virus levels were undetectable, and they’ve stayed that way.
Since news of the man’s cure broke, HIV patients have been telephoning doctors to ask for bone marrow transplants. But it’s not that simple. The treatment is too risky and impractical for widespread use.
“A bone marrow transplant — it’s a horrible process you would not wish on your worst enemy unless they needed one to save their life,” said Cannon, a biology professor at USC’s Keck School of Medicine. There are grueling treatments to prepare a patient for transplant; the danger of rejecting the marrow; and the risk of graft-versus-host disease, wherein the marrow attacks the patient.
And that’s assuming the patient can find a matching donor — a difficult proposition in itself — with the right HIV-resistant genetic constitution, which is present in only about 1% of the Caucasian population.
But there could be another way.
Instead of sifting through the sands for a rare donor and then subjecting a patient to the dangers of a bone marrow transplant, Cannon and her colleague Philip Gregory, chief scientific officer at the Richmond, Calif.-based biotech company Sangamo BioSciences, began to think: They could use gene therapy instead, to tweak a patient’s own cells to resistance — and recovery.
The mouse “cure,” they say, suggests they’re on the right track.
Now, with $14.5 million from the California Institute for Regenerative Medicine, the San Francisco-based stem cell research-funding center created by 2004’s Proposition 71, Cannon, Gregory and researchers at the City of Hope cancer center in Duarte are working toward bringing the technique to clinical trials within four years.
Cannon and other HIV researchers insist that, despite cancers and deaths associated with past gene therapy trials, it’s the right way to target the disease. They cite recent successes, including treatments that cured children with the “bubble boy” syndrome and helped blind children regain their vision.
“I don’t think anyone would want to do gene therapy if there were an alternative,” said Caltech biologist David Baltimore, one of the many L.A.-based researchers pursuing gene therapy strategies to prevent or cure HIV. “I think it’s absolutely necessary. Nothing else will work.”
Since AIDS emerged in the early 1980s, development of anti-HIV medications has turned the disease from a virtual death sentence into a chronic, manageable condition.
But the clamor for a cure hasn’t quieted.
Vaccine trials have failed; drug-resistant strains are on the rise; and the meds, which can have uncomfortable side effects such as fatigue, nausea and redistribution of body fat that creates a so-called buffalo hump, cost about $20,000 a year.
A bone marrow transplant is about five times as expensive, but it would have to be done only once.
The question was, could researchers create bone marrow stem cells that — just like the marrow the Berlin patient received — lack the crucial gene, CCR5, that normally lets HIV into the key immune cells it destroys?
In 2006, Gregory asked Cannon if she was interested in testing whether a tool his company developed, called a zinc finger nuclease, could do the trick.
Zinc finger nucleases are genetic scissors, cutting DNA at a specific site — say, in the middle of the CCR5 gene. When the cell glues the gene back together, it usually makes a mistake, resulting in a gene that no longer works.
“It just jumped out at me as, ‘Oh my gosh, that’s actually something that could work,’ ” Cannon said.
The team spent about a year optimizing the procedure for treating delicate stem cells with the CCR5 snippers.
They tested the method using so-called humanized mice — ones engineered to have a human immune system — because HIV doesn’t infect normal mice. When stem cells were treated with the molecular scissors before being injected into mice, the resulting immune system lacked CCR5, exactly as the scientists had hoped.
These mice acted just like the Berlin patient — they fought off the virus.
Ready to make the leap from mouse to man, Gregory found a third leg for the team: researchers at City of Hope, who had extensive bone marrow transplant expertise.
“They brought Paula’s data to us and we said, ‘Wow, this looks fantastic,'” said Dr. John Zaia, City of Hope’s deputy director for clinical research.
Researchers there are now working toward clinical trials, optimizing every element of the treatment for safety, effectiveness and reproducibility.
On a wiltingly hot afternoon in July, lab manager Lucy Brown maneuvered a computer mouse across three screens speckled with red, yellow and green dots.
The computer was hooked to a flow cytometer — a collection of black boxes, green wires and silver knobs that can detect subtle differences between cells and separate them at a rate of 50,000 per second. This is how the scientists will separate stem cells from patients’ blood once trials are underway, to be sure that the genetic fix in the CCR5 gene was made, and kept.
Upstairs, machines with mazes of sterile tubes and pumps stood ready to prepare cells for CCR5-snipping. Here, the scientists will purify the bone marrow stem cells, increasing their numbers first to 5% of total cells, up from a measly 0.1% in the starting mixture, and then to 99%. At this point they can begin testing methods to clip the cells’ DNA.
When all is perfected, the scientists will have a precise recipe for producing batches of engineered stem cells, including exactly how long the cells should be treated, how much of each chemical needs to be added, how pure the cells need to be, and thousands of other details.
“We are literally writing the book on how you do this,” said David DiGiusto, director of City of Hope’s bone marrow stem cell therapy research.
To receive FDA approval for clinical trials — a goal they hope to achieve in three to four years — the researchers must prove that they can safely and reliably prepare the cells. Once they get the green light, the first cases will probably be people like the Berlin patient who need bone marrow transplants to treat AIDS-related lymphoma.
They’ll modify the patients’ cells in the stringently sterile manufacturing lab that DiGiusto designed with details such as cove molding and seamless floors so there are no corners or cracks to collect dust. Anyone who enters must wear a full bunny suit, much like the one Cannon wears in her mouse room, to keep from contaminating the delicate cells.
Some have advertised the effort as a quest for the elusive “C” word, but Cannon doesn’t quite see it that way.
“People say we’re trying to cure HIV,” she said. “I think of it more as, we’re just trying to make the body live quite happily and healthily with a small amount of virus.”