Possible Cure for HIV Discovered

[PoorLepRecon]

http://dsc.discovery.com/news/2009/02/09/hiv-mutation.html

 

 

 

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Feb. 9, 2009 -- HIV is notorious for its ability to mutate and evade drugs designed to destroy it. Now scientists are testing a new drug that actually speeds up that rate of change in the hope that the deadly virus will mutate itself to death.

 

 

 

"The HIV virus is so dependent on mutation that it really lives on the edge of existence," said John Reno, Chief Operating Officer for Koronis Pharmaceuticals, the company developing a drug called KP-1461. "But we figured that if we could increase this mutation rate, [HIV] might finally fall off that edge."

 

 

 

KP-1461 is a mutagen, meaning it encourages mutation, and has been in development for several years by the scientists at Koronis Pharmaceuticals.

 

 

 

When any cell or virus reproduces, there are inevitable mistakes, or mutations, as the four building blocks of DNA pair together into a double helix. Usually, the base adenine pairs up with the base thymine, and one called guanine pairs with cytosine.

 

 

 

That build-up can take time, and could vary depending on the patient and the strain of HIV. The results of the latest Phase Two clinical trial, completed last year with 13 patients, were mixed; some patients saw no drop in their viral load, while others saw a dramatic drop. The scientists are currently working to publish the study results.

 

 

 

What's clear is that KP-1461 does eventually destroy HIV in some patients, unlike the current batch of antiretroviral drugs, which limit the reproduction of the virus but fail to destroy it.

 

 

 

KP-1461 doesn't have any known side effects, but the worry from the Food and Drug Administration is that a drug that induces mutation in a virus could also cause dangerous mutations in the patient's own DNA.

 

 

 

So far it doesn't appear to cause short-term mutations in animal models, but longer-term studies are necessary to eliminate the possibility, said Robert Smith, a professor at the University of Washington who studies other lethal mutagenic drugs.

 

 

 

Mutagenic drugs could be used to fight other diseases as well, such as polio, hepatitis C and influenza. KP-1461 is at the forefront of this new avenue of research.

 

 

 

"Intellectually this is exciting; it's a very creative approach," said Smith. "From a practical perspective, there are still a lot of questions."

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This is a very interesting development in the fight to cure HIV/AIDS. Though it is early on in the process, the results thus far look promising. Much more testing is needed before this could be a viable option for curing HIV, but it is an important step in the right direction.

 

 

 

The process used is very interesting. The scientists took advantage of the HIV virus's high mutation rate, and proceeded to accelerate the rate of mutation so that the HIV virus will mutate itself out of existance. In a few years time we could be looking at an HIV free world.

[mmmcannibalism]

that would be awesome, hopefully it pans out well.

 

 

 

there method is quite ingenious, fight fire with fire and whatnot.

[Kiriyama]

I don't think mutating it more is the best idea.

 

 

 

It could create the deadliest virus the world has ever seen.

[Lenin64]

Ladies and gentlemen, I present to you the zombie apocalypse.

 

 

 

But really, that's fairly interesting. It's like taking them down from the inside.

[RichieMcD]

I'm going to agree with Sworddude on this, if it keeps mutating to essentially avoid combatant by drugs giving it something to further mutate it could be either like pouring a lot of water on a fire, or pouring a lot of petrol on the fire. It could either kill it off, or turn it into the worlds deadliest virus of living times.

[warri0r45]

This is a really interesting approach at killing HIV, thanks for the article.

 

 

 

I suppose the biggest worry is that this drug would cause mutations in human DNA which could lead to cancer, but this article claims that there are no side effects.

 

 

 

Obviously more trials and research is needed before we see this drug available for everyone. Drug trials are very involved and time consuming at the best of times, but it's all for a good reason - so the drugs don't do more harm than good.

[PoorLepRecon]

I don't think mutating it more is the best idea.

 

 

 

It could create the deadliest virus the world has ever seen.

 

 

 

That was the worry the FDA had as well. It makes sense that it might mutate into something much worse, but it could be the cure we are looking for.

 

 

 

Ladies and gentlemen, I present to you the zombie apocalypse.

 

 

 

I Am Legend anyone? (Atleast the movie, never read the book)

[mmmcannibalism]

I don't think mutating it more is the best idea.

 

 

 

It could create the deadliest virus the world has ever seen.

 

 

 

I think the idea is to force the mutation rate so high the virus loses its needed dna. If a human evolved wings a tail a third eye and an extra set of arms all in one generation it would clearly die, they are going with the same plan here.

 

 

 

It does sound like it could cause a problem, the idea is an ingenious approach though

[warri0r45]

I'm going to agree with Sworddude on this, if it keeps mutating to essentially avoid combatant by drugs giving it something to further mutate it could be either like pouring a lot of water on a fire, or pouring a lot of petrol on the fire. It could either kill it off, or turn it into the worlds deadliest virus of living times.

 

 

 

It could, but not necessarily. it's a matter of altering probabilities to our advantage.

 

 

 

At the moment HIV has a high mutation rate and sometimes this produces more virulent strains but most of the time it destroys some vital function of the viral RNA. With n more mutations per generation, we could reduce the risk of increased virulence to be extremely unlikely (stipulate any probability you want, we can work out n statistically). The trick is finding n, and this is where research into evolution and natural selection comes in handy. It's a matter of calculating the risk so we can make this a viable treatment.

 

 

 

Edit: Come to think of it, changing the mutation rate all depends on the drug, so controlling n would be much harder.

[Seraphi]

I think this is going a little bit too far.

 

this is gambling with a deadly virus we're talking about....

 

mutating it more could kill it, or it could create a virus that spreads through air or something *cough* or a zombie apocalypse *cough*

[Zierro]

I don't know about this one. Sometimes I tend to think population controls are actually a good thing.

[meol]

This advancement surely is promising. I really can't wait for more research on this.

 

I don't know about this one. Sometimes I tend to think population controls are actually a good thing.

 

Better focus on sex education, awareness and increased availability of contraceptives are much better and humane ways of controlling population than an illness like AIDS. You can't honestly be saying "AIDS is a good thing because it gets to kill so many people through the whole world", can you? :|

[Zierro]

You're right - of course there are more humane methods, but that doesn't mean they are just as effective. The fact is that millions and millions of people would be here today if AIDs didn't exist. You can't honestly be saying that "having millions and millions more people cramped into this world would be a good thing" either.

[dave0293]

The article seems a little bit behind:

 

http://blogs.poz.com/paul/archives/2008/06/my_journey_with.html

 

[hide=]My journey with KP-1461

 

 

 

The moment I saw the email, I knew something was amiss. It was from Stephen Becker, MD- the medical director for Koronis Pharmaceuticals, a Seattle-based company developing a new HIV drug. The email was addressed to all of the members of their advisory board, which I am a community member, and implored each of us to speak with Stephen (he hates it when I call him Dr. Becker) the next day.

 

 

 

Emails like this are the industry equivalent of your girlfriend or boyfriend saying, we need to talk,- often a sign of trouble ahead. It was.

 

 

 

As I wrote about here http://projectinform.org/news/2008/061208.shtml, Becker was letting us know about a stunning setback for their drug- called KP-1461. The short version is laboratory studies called in to question the drugs viability. Worse still, a look at the results from the ongoing study confirmed these concerns.

 

 

 

Within a few days, the one ongoing study of KP-1461 was halted, I broke the story on our website, and Stephen announced his resignation from Koronis. The future of this product looks bleak at best.

 

 

 

Setbacks are part of the drug development process. The road from discovery to commercialization is indeed fraught with pitfalls, scientific, logistical and economic. In just the past few years, we have seen aplaviroc, T-1249, PL-100, brecanavir and others fail for reasons ranging from formulation problems, to liver toxicity.

 

 

 

Is this just another bump in the road, or something more? I dont know, but it feels significant to me.

 

 

 

My relationship with KP-1461 goes back to my earliest days working on drug development with Project Inform. I was in the office one day, when Marty walked in. Marty works from home, so there is always a reason when he appears at the office. When I asked him why he was in, he told me to meet with a new pharmaceutical company, and I should sit it the meeting.

 

 

 

We sat in our conference room looking with a couple of folks from this Seattle company, I had never heard of. They had a drug they thought held promise for HIV, which worked in a radically new way. It was the radical new way that caught my attention, and piqued my imagination.

 

 

 

KP-1461 was supposed to work in a very count-intuitive way- by encouraging HIV mutation. All other HIV drugs seek to prevent HIV from mutating- a difficult task for sure, but one crucial to the success of ARVs. This drug turned that on its head and proposed that you could actually mutate HIV to death.

 

 

 

I have seen several names for this approach. Koronis website calls it Viral Decay Acceleration. My favorite term is terminal mutigenesis, which I probably like in part because it sounds like a heavy metal band name.

 

 

 

Why in the world would you ever want to encourage HIV to mutate? Doesnt it do that enough on its own? Isnt mutation a bad thing?

 

 

 

In the HIV world we do talk about HIV mutation as a bad thing- and it usually is. HIV is very prone to mutation, making it very adaptable to changing environments. This leads many people to think HIV is clever or wily. Not really.

 

 

 

HIV is sloppy, sometimes to its advantage. It reminds me of the story of Dock Ellis. In 1970, Ellis was a starting pitcher for the Pittsburgh Pirates. Unaware that he was scheduled to start against the San Diego Padres later that day, Ellis and his girlfriend took LSD. Ellis learned later in the day that he was the starting pitcher.

 

 

 

Ellis pitched anyway, throwing what would be the defining game of his career. He allowed no hits, while walking 8 batters and hit one batter. In baseball they call this effectively wild.

 

 

 

HIV is effectively wild. That is, it makes many, many mistakes while replicating. Most of those mistakes are either harmful or neutral. If a person is not taking HIV drugs, the vast majority of mutations go away. When a person is taking HIV drugs, certain mistakes give the virus an advantage- allowing the virus to evade drugs.

 

 

 

We often think of viruses in a science fiction manner, particularly when it comes to mutation. The word itself conjures up images of extra terrestrials and shape shifters, growing ever stronger with each change.

 

 

 

The truth is quite different. Mutation rarely makes a virus stronger. It may provide a survival benefit when one is taking drugs, but is likely to make the virus somewhat weaker on its own. For example, one very common drug resistance associated mutation is called M184V, which often happens when a person is taking either Epivir (3TC) or Emtriva (FTC). While M184V allows HIV to evade these drugs, it also makes it less fit- or able to infect cells and replicate.

 

 

 

(This is why a person might stay on these drugs despite harboring the mutation. If you go off the drug the mutation will sort of go away. It doesnt fully go away, but it will cease to become the dominant viral strain in the body.)

 

 

 

Koronis sought to exploit the reduction in viral fitness by accelerating the rate of mutation. The goal was to make HIV accumulate so many mutations that it would no long be viable- that is it could no longer infect cells and replicate.

 

 

 

Back to the conference room: Marty and I were meeting with Koronis folks to review their pre-clinical data and their development plan. It is fair to say that both Marty and I were fascinated by this idea. At the same time we saw a rocky road ahead. How would such a drug be studied? In whom? How would it be evaluated? What would the FDA have to say about it? Would people with HIV take such a drug?

 

 

 

The drug went ahead. The FDA had concerns, but saw the drugs potential. I was asked by the company to join their scientific advisory committee, to review the research and advise the company on its plans.

 

 

 

The early research was promising. The drug appeared well tolerated- which is the most important factor in early human research. There were signs that the drug was working, but the research was far too preliminary to know with any certainty.

 

 

 

The company received approval to do a phase II trail in the US, and one in Argentina. The US trail was for treatment experienced people and the Argentine for people taking HIV drugs for the first time. Although it was slow to recruit, the US trial was up and running. The Argentine study faced regulatory hurdles, but was recently approved.

 

 

 

I talked with Stephen the day after I got the we should talk email, I expected bad news. I didnt expect his to say what he did.

 

 

 

He explained that the FDA had asked them to repeat a set of tests called, serial passage experiments where HIV is exposed to varying concentrations of a drug in order to force drug resistance to develop. This is a normal part of the drug development process. The FDA required Koronis to repeat their earlier serial passage experiment, because drug resistance did not emerge in the earlier experiments. The idea was to keep the experiment going until resistance did emerge.

 

 

 

It never emerged, because the experiments showed that the drug was having no affect whatsoever on HIV. They went and looked at the results from the US study, and found little to no evidence that the drug was working. Had the clinical data shown the drug working, it would have likely trumped the lab results.

 

 

 

I am both a activist and a journalist. I sat on the story for a few days to make sure that all of the study participants heard from the study, rather than our website. Once I was confident that the information was publically available, I posted the story to the web.

 

 

 

As quoted in our story, Becker said the company was committed to understanding what went wrong. He estimated it would take 2 months to figure it out.

 

 

 

A week ago today, Stephen sent out an email announcing his resignation from Koronis. I was saddened if not surprised. It casts a pall on the future for this drug- most likely it is DOA.

 

 

 

I dont know what led him to resign. Whatever led him to leave Koronis, Stephens acted in a highly ethical and straightforward manner throughout the process. I hope he doesnt stray far from HIV, we need folks like him on our side.

 

Before writing this entry, I went to Koronis website, and there is no mention of either the setback of Beckers resignation. I hope the company does the right thing, invests the resources necessary to figure out what went wrong and continue to follow Stephens example of transparency and forthrightness with community.

 

 

 

This setback feels bigger to me than losing aplaviroc or Beckers last companys CXCR4 inhibitor. The pipeline is both thin and unimpressive. The mechanism of accelerated viral decay is precisely the kind of thing that could lead to true breakthroughs in treatment. We need this kind of creative thinking to move to the next level in HIV.

 

 

 

Posted by Paul Dalton on June 27, 2008 10:58 AM[/hide]

 

 

 

He explained that the FDA had asked them to repeat a set of tests called, serial passage experiments where HIV is exposed to varying concentrations of a drug in order to force drug resistance to develop. This is a normal part of the drug development process. The FDA required Koronis to repeat their earlier serial passage experiment, because drug resistance did not emerge in the earlier experiments. The idea was to keep the experiment going until resistance did emerge.

 

 

 

It never emerged, because the experiments showed that the drug was having no affect whatsoever on HIV. They went and looked at the results from the US study, and found little to no evidence that the drug was working. Had the clinical data shown the drug working, it would have likely trumped the lab results.

 

Something seems a bit weird about this.

 

Furhtermore, on the drug's website it says that the first phase went well, but they suspended the second:

 

Clinical Development

 

Phase 2a Trial

 

 

 

An open label Phase 2a trial of KP-1461 was designed to evaluate the safety, efficacy and tolerability of KP-1461 as a monotherapy in treatment-experienced HIV-infected patients.

 

 

 

The study enrolled 27 of the 32 patients targeted for the trial. Koronis has suspended this trial to investigate a discrepancy in preclinical in vitro data and to examine Phase 2a clinical results. The trial suspension was not requested or required by the FDA and was not related to any safety concerns or adverse events during the trial. Clinical results have demonstated only occasional mild to moderate drug-related adverse events.

 

http://www.koronispharma.com/KP1461forHIV.html

[Mr_Adam]

Oh [cabbage].

 

 

 

I never thought it would come to this, something I created that's been stirring around my school (but apparently it's also shown in South Park). Two Words.

 

 

 

Super-Aids.

 

 

 

I had this predicted before, but now it seems I'll have to delve deeper. I had only gotten so far as to achieve comedic response, but now I'll need to become more serious, with morbidity and such.

 

 

 

At least Super-Aids will become the BEST birth-control.

[Laura]

Morally, I'm almost obligated in this society to say that I'm glad. Though, I digress in the sense that I'm not. HIV/AIDS does far more benefit to the species, rising at the exponential rate that it is, long term, than without it. That said, if I somehow tested positive for AIDS/HIV, I would of course be mad. But I suppose I would find solace in the fact that I'm only a statistic, and that in the modern world I could live my life as normal for a long time.

 

 

 

Great things - all things - come from the smallest of errors, implications, and mistakes. This, no doubt, is no exception. How its used, however, could give rise to devastating effects.

[Skull]

So we get a cure for HIV or a zombie apocalypse? Looks like a win-win to me.

[fastortoise]

So we get a cure for HIV or a zombie apocalypse? Looks like a win-win to me.

 

My thoughts exactly.

[llcoolguy972]

KP-1461 doesn't have any known side effects, but the worry from the Food and Drug Administration is that a drug that induces mutation in a virus could also cause dangerous mutations in the patient's own DNA.

 

Perhaps like X-Men mutations? :o

[Lenin64]

KP-1461 doesn't have any known side effects, but the worry from the Food and Drug Administration is that a drug that induces mutation in a virus could also cause dangerous mutations in the patient's own DNA.

 

Perhaps like X-Men mutations? :o

 

More like Down's Syndrome.

 

 

 

Go Team [developmentally delayed]!

[Flyingjj]

You can't honestly be saying that "having millions and millions more people cramped into this world would be a good thing" either.

 

Yes, yes I can.

[pureprayer]

You cant get AIDS if your not a dumb-[wagon].

[Flyingjj]

You cant get AIDS if your not a dumb-[wagon].

 

May I mention the four letter word that begins with r and ends with the name of one of our simian friends?

[pureprayer]

You cant get AIDS if your not a dumb-[wagon].

 

May I mention the four letter word that begins with r and ends with the name of one of our simian friends?

 

Rape? If your smart it wont happen to you.

[Barihawk]

I don't think mutating it more is the best idea.

 

 

 

It could create the deadliest virus the world has ever seen.

 

 

 

It would obviously be kept in Biohazard Level 5 at the CDC. That place has all the plagues of history sealed in tiny vials, safely.

 

 

 

I like the idea of finally ending AIDS. Hope they come up with something for diabetes soon.