Another brick in the wall

September 25, 2013 5:27 PM

FDA-approved foot cream is found to permanently eradicate HIV from cell cultures.

Selections from the article:

"The persistence of HIV is partially due to the ability of the virus to disable the cell’s altruistic suicide pathway, which is normally activated when a cell becomes infected or damaged."

"[Ciclopirox] works against HIV in two ways: It inhibits the expression of HIV genes and also blocks the essential function of the mitochondria, thereby reactivating the cell’s suicide pathway. Healthy, uninfected cells examined during this study were spared."

The research team has not yet conducted clinical trials on humans to study Ciclopirox as a topical HIV treatment, but the regulatory approval process is likely to be faster because the drug has already been approved by the FDA for other uses.

posted by cairdeas (57 comments total)

This is irresponsible journalism. They always hype these things as cures. You know what else kills HIV in a cell culture? Bleach. Doesn't mean you should start injecting the stuff.

Get back to me after they are done with human trials.
posted by cjorgensen at 5:33 PM on September 25, 2013 [23 favorites]

cjorgensen, I think the difference with bleach is that the drug doesn't damage healthy cells, and is already approved for topical use, which is how it would be used for HIV...

On a different note, here is the journal article, for anyone interested in reading it directly.
posted by cairdeas at 5:35 PM on September 25, 2013 [3 favorites]

But does it moisturize feet?
posted by Ironmouth at 5:36 PM on September 25, 2013 [3 favorites]

...huh.
posted by Sticherbeast at 5:41 PM on September 25, 2013 [1 favorite]

A foot cream.

If I were to strain to make it up, I couldn't come up with something more like a cosmic seltzer bottle blast to the face than repurposed foot cream.

I lost a brother to HIV-related lymphoma a couple of years ago. So many people were gathered around the bed as he passed that the only place I could find to touch him was his feet.

He probably thinks this is hilarious, but he'd think it was funnier if it was Preparation H or something like that.
posted by jquinby at 5:46 PM on September 25, 2013 [122 favorites]

Yes, but so is fire.
posted by Pope Guilty at 5:46 PM on September 25, 2013

jquinby, that is one of the funniest and most heartbreaking things I've ever read. Really sorry for your loss.
posted by letitrain at 5:49 PM on September 25, 2013 [11 favorites]

Okay, it kills HIV without damaging human tissue. So it's substantially better than bleach, or fire, or a handgun.

But what good is a topical cure for HIV?!
posted by Holy Zarquon's Singing Fish at 5:50 PM on September 25, 2013 [2 favorites]

I used to worry that we were living in William Gibson's future, or the future of Neal Stephenson. Now I worry that we're living in Douglas Adams' future.
posted by Slap*Happy at 5:53 PM on September 25, 2013 [45 favorites]

Some of the same authors published related findings in 2009.
posted by beagle at 5:54 PM on September 25, 2013 [1 favorite]

cjorgensen: "You know what else kills HIV in a cell culture? Bleach. Doesn't mean you should start injecting the stuff."

There is another drug, Lamisil (terbinafine hydrochloride) (which also happens to be an antifungal) that has both cream and tablet formulations. You're right that this needs to be tested for systemic toxicity but this might actually be a Real Thing. Which would be awesome.
posted by double block and bleed at 5:56 PM on September 25, 2013 [1 favorite]

But what good is a topical cure for HIV?!

This also confuses me. The Rutgers article says "The utility of Ciclopirox in patients with HIV, for instance after topical application to reduce sexual transmission of the virus, awaits verification in future clinical trials." But what does that mean? You can slather it on your genitals to reduce transmission of HIV? Before or after sex?
posted by yasaman at 5:57 PM on September 25, 2013

This doesn't need to be a panacea to be potentially huge news.
posted by Navelgazer at 5:57 PM on September 25, 2013 [1 favorite]

Problem is these things get reported poorly. I'm all for science, don't pretend to be a scientist, so you probably need someone that is to articulate why this is or isn't exciting. Potentially huge news generally isn't actually even news.
posted by cjorgensen at 5:58 PM on September 25, 2013

About to read the paper, but Rutgers is a reasonable source/research institution and PLOS ONE is a reasonable journal, at the very least.

(Also, note that the cream is "commonly used by dermatologists and gynecologists" according to the first article, so at least someone is applying it to areas other than the foot. Unless you have a terrible gynecologist.)
posted by maryr at 6:07 PM on September 25, 2013 [10 favorites]

(...or some really weird habits, I suppose.)
posted by maryr at 6:07 PM on September 25, 2013 [6 favorites]

jquinby, not to derail my own thread, but what you wrote about your brother reminded me of a passage from one of the books I read as a child that left a deep mark on me:

"Just after dark, Tee and I were sitting in the kitchen when Filene came in. He said, "Ben, you should come." Mama was so white, so still. ... I started to lift the covers. Mama had once said that she would have kept Papa and Guthrie alive by rubbing their feet; that a person needs a comforting hand. They reach out for help. No sooner had I touched the quilt than Filene said, "No, Ben. She's gone loo'ard." The breathing had stopped."
-Teetoncey and Ben O'Neal, 1975

posted by cairdeas at 6:09 PM on September 25, 2013 [5 favorites]

But what does that mean? You can slather it on your genitals to reduce transmission of HIV?

That is my impression; my wild speculation is that one would use it on the testicles.
posted by cairdeas at 6:11 PM on September 25, 2013

But what good is a topical cure for HIV?!

Lube?
posted by bradbane at 6:22 PM on September 25, 2013 [1 favorite]

That is my impression; my wild speculation is that one would use it on the testicles.

No, think of topical steroids... it's absorbed through the skin, passed into the blood stream and then distributed around the body entire. This is how Barry Bonds had huge hulking shoulders by rubbing cream and gel pastes on his thighs.
posted by Slap*Happy at 6:24 PM on September 25, 2013 [3 favorites]

Did they try the medicine drug?
posted by vrakatar at 6:28 PM on September 25, 2013 [10 favorites]

So how long does it take to heel?
posted by hal9k at 6:30 PM on September 25, 2013 [2 favorites]

I've decided to live-tweet my paper reading. Sorry, best friend from high school who apparently follows my Twitter, you're about to get a whole bunch of SCIENCE all up in your phone.
posted by maryr at 6:32 PM on September 25, 2013 [5 favorites]

In case you are too modest to link it, maryr, here is the Twitter feed in question, and your reading is already very interesting to this non-scientist.
posted by cairdeas at 6:42 PM on September 25, 2013 [2 favorites]

Ha ha ha ha... yeah, it's about to slow down DRAMATICALLY now that I have finished reading the abstract.
posted by maryr at 6:44 PM on September 25, 2013 [1 favorite]

Science victorious through de feet.
posted by hal9k at 6:45 PM on September 25, 2013

My family always gets really upset when I explain to them this is how the actual process of science works. You could go slave away for 20 years post PHD at a fancy institution with the finest equipment and just brilliant theories, toil endlessly and get nowhere and die alone, unloved, and most importantly, unpublished whereas some sloppy bastard left his lunch trash next to his bacteria experiment, and some overgrowth from the mold kills his bacteria by accident.... he gets a frickin Nobel and is generally acknowledged to be the medical savior of the free world.

Drugs, we really never know what the hell is going to happen with those. Rogaine was originally tested as a blood pressure drug. Viagra? Originally tested for relieving the pain felt during a heart attack. At that point you have to wonder, is there anything more misleading than calling the known effects of a pharmaceutical a 'side effect'?

So I find it perfectly plausible that a footcream could turn out to be the show stopping AIDS drug because...

SCIENCE, BITCH

/pinkman out
posted by hobo gitano de queretaro at 6:47 PM on September 25, 2013 [20 favorites]

I wouldn't, for a moment, pretend that I have enough knowledge about medicine, HIV, or this subject to comment on it one way or the other. I just stopped by, as someone who lost a wonderful brother-in-law to HIV/AIDS related illness, to encourage everyone to consider their comments carefully. There's room for humor, there always has to be room for humor, but please think about everyone that might read your comment.
posted by HuronBob at 7:01 PM on September 25, 2013 [7 favorites]

This is irresponsible journalism.

This is not irresponsible journalism. It states the results of a study without hype and makes no promises as to a cure, stating simply that trials might proceed apace since the drug is preapproved for human use. Then it talks about Rutgers.
posted by Camofrog at 7:53 PM on September 25, 2013 [7 favorites]

So, I don't really read enough papers to know terrible science... but I'm a good way in to the Methods of the group's previous (2009) paper, and it seems solid so far. I approve of their Western blots, pretty....

I have questions about the results in C, but I haven't read that part yet, so I'm ahead of myself.
posted by maryr at 8:01 PM on September 25, 2013 [2 favorites]

Please be true, be a cure, and be distributed free to anyone who needs it. In this lifetime. Please.
posted by Space Kitty at 10:02 PM on September 25, 2013 [2 favorites]

I'm giving up for tonight - past my bed time and the cat's not really letting me see the keyboard. I finished the 2009 paper and I'm half way through the Results (the description of the experiments) of the 2013 paper that prompted this FPP. The science all seems pretty solid to this lowly BS mol biologist, though I'm not sure how much of it is new to the field and how much is new to me. Of particular note - in the 2013 paper they show no detectable levels of HIV infection after treating chronically infected patient derived lymphocytes, even after stopping treatment, for 12 weeks. And it looks like mice tolerate the foot cream just fine (although I'm not to that part of the paper yet, they just mention it in the abstract).

So I don't know if this is truly a Big Deal and it certainly isn't a cure yet, but it does look promising, at least at a basic science level. And, as noted, since these meds are already FDA approved, trials could be started a lot more quickly and cheaply than they could with a novel compound.
posted by maryr at 10:21 PM on September 25, 2013 [4 favorites]

Fingers (and toes) crossed.
posted by Samizdata at 11:09 PM on September 25, 2013 [1 favorite]

It's a miracle drug, it's an antibiotic too.

I haven't read the article closely enough to pick apart the actual claims, but the lack of robust EC50 curves is odd.
posted by benzenedream at 11:24 PM on September 25, 2013

Before starting into this, I'd like to predict that somewhere they'll reference a cell culture tech with a foot problem and a gritty graduate student who can't let a good problem-source go.
posted by Slackermagee at 4:53 AM on September 26, 2013

Both drugs were identified as candidate inhibitors of protein
hydroxylation by searching drug libraries for structures that fit the
stereochemical parameters of the catalytic mechanism...

Bah, I say. Bah!
posted by Slackermagee at 5:22 AM on September 26, 2013

From reading the first couple of pages of the manuscript, I can't tell if the antifungal would stimulate apoptosis in other cells, which would be....well, catastrophic.

There are a lot of things in cure research that are a LOT further along than this. Also, HIV therapies are so much more tolerable now. In fact, a new drug was just approved last month that is showing fewer side effects than ever, and recently, side effects are becoming less and less problematic in more and more people living with HIV.

We're working on it people. We have 30 people in my group and over 500 at my university working on it every single day.
posted by Sophie1 at 7:18 AM on September 26, 2013 [9 favorites]

It's being tested for leukemia/lymphoma treatment as well. Is there anything this wonder drug can't do? We should all eat a spoonful of foot cream every morning.

Really though, I find it hard to get enthused about these kind of findings. It's a long way from the lab bench to the human subject, and more often than not what works brilliantly on the former is worthless in the latter.
posted by Panjandrum at 7:20 AM on September 26, 2013 [2 favorites]

Sophie1: "From reading the first couple of pages of the manuscript, I can't tell if the antifungal would stimulate apoptosis in other cells, which would be....well, catastrophic. "

As a dangerous layman, the part titled "Lack of apoptosis induction in a murine tissue damage model" seems to address this, but in fairness, much of this is like when, as a Spanish-speaker, I listen to someone speaking Brazilian Portuguese.

I might generally understand that you're discussing the weather, but that's about it.
posted by jquinby at 7:34 AM on September 26, 2013

Ultimately, jquinby, we won't know if it stimulates apoptosis in humans until it is studied in humans. Whether the apoptosis we want or the apoptosis we don't. Also, we won't know if a topical application will help at all or if it is possible to make this antifungal into a bioavailable dose to take orally or by injection. It works in a dish. That's about all they know right now.

I'm not being pessimistic, I have just seen SO many potential cures in my 23 years in HIV research, I have a really hard time getting excited about anything that is approved as a foot cream.
posted by Sophie1 at 7:46 AM on September 26, 2013

Sophie1, from what I read, the foot cream drug induces greater rates of apoptosis in chronically infected cells than in uninfected cells - so the cells that have already triggered apoptosis because Something Has Gone Wrong (viral infection) but are prevented from proceeding by HIV machinery are no longer prevented. FWIW, the enzyme that the antifungal (and the second drug, an iron chelator) seems to work on is active at G1/S and HIV replicates in G2, so they think the time makes sense. The target enzyme is likely an elongation factor - when the drug is present, no HIV RNA fragments larger than like 60bp are created.

I'd imagine there's a risk to cells currently dividing, but we already have a whole class of treatments based on killing rapidly dividing cells. This isn't my field though so I don't know anything about EC50 curves. The 2009 paper was much molecular so I really got a lot out of reading it. The 2013 paper so far involves a lot of skipping graphs, heh.

It is worth noting again that this drug has already been approved for human use, so we do know that it doesn't straight up kill you. And honestly, giving patients with a compromised immune system some extra anti-fungals doesn't seem like the worst drug trial I've ever heard of.

(I'm still impressed by the 2009 paper's pretty Western blots. Apparently that's how you make me like your paper.)
posted by maryr at 8:00 AM on September 26, 2013 [3 favorites]

The leukemia/lymphoma clinical trial that Panjandrum linked to is using an oral formulation of the same drug, so there's reason to believe it's not limited to topical application. That said, topical application does not necessarily prevent systemic absorption. Perhaps someday you'll have your choice of pill or cream to treat HIV.
posted by vytae at 8:22 AM on September 26, 2013 [1 favorite]

I agree with you guys; the work looks pretty solid, and it seems like a good idea on the face of it, but it's too early to get excited. I've never worked on HIV, but I've seen data on a lot of candidate cancer treatments that selectively kill cancer cells in a dish but lose efficacy as soon as you get to animal models.

My understanding is that animal models of HIV aren't great (nice review here). HIV is only good at infecting humans, so the current best bets seem to be SIV in Asian macaques (similar virus, disease progression looks a lot like AIDS) or generating mice with human(ish) immune systems and giving them HIV. I'd guess that their drug should work in either of those models if it's ever going to work in humans, because it's targeting the immune cells' biology rather than the virus', but I'm not enough of an immunologist to be confident of that. Still, you'd expect an HIV lab to have access to whatever model(s) they think most appropriate, so it seems a bit weird to me that they did mouse work but didn't test the treatment. Saving it for the next paper, maybe?

All that aside, they point out in the paper that there are already populations of HIV+ people being treated with DEX or CPX for other conditions, and that there might be something interesting hiding in their data. And, tantalisingly:

At least one case report on a thalassemic patient suggests that DEF displays antiretroviral activity in vivo [204], although the drug had not been prescribed for this purpose.
[...]
DEF shows activity in infected individuals (Saxena et al., unpublished data).

Is this a teaser that they've started looking at that data, and found something interesting? Because that's something I might start getting excited about.
posted by metaBugs at 9:00 AM on September 26, 2013 [1 favorite]

Holy Fucking Moly. First HIV cures Leukemia, now foot-cream cures HIV. Whoever made the Douglas Adams comment above, I am sure he would freakin' love the combination of these two amazing facts! I hope it works, I appreciate people are a little cynical, as the research seems to be at an early stage, but still, as XKCD once said, Science - it works!
posted by marienbad at 9:07 AM on September 26, 2013 [1 favorite]

metaBugs - what about FIV?
posted by maryr at 9:22 AM on September 26, 2013

Huh. For some reason I thought FIV wasn't really useful as a model, but looks like I was wrong.

This section of the review I linked to above says that it has been used quite a bit, particularly in the development of antiretrovirals. But that FIV's genetic similarity to HIV isn't a strong as SIV's, it can infect B lymphocytes and CD8⁺ T lymphocytes in addition to CD4⁺ Ts, and the length of the chronic phase is extremely unpredictable, making it logistically tricky.

That review seems to be pretty well written, and basically concludes that animal models of HIV are a land of contrasts. It doesn't seem to rate any of them as good all-rounders; I think you just have to pick the model deemed to be good at whatever aspect is most important for your test.

As I said though, I'm not an HIV guy. Presumably Sophie1 knows more than me?
posted by metaBugs at 9:41 AM on September 26, 2013

Sorry, I didn't mean the question to imply I had any idea - I just like the idea of FIV as a model because maybe science can save some kitties on our way to saving humans.
posted by maryr at 9:49 AM on September 26, 2013

cairdeas: "cjorgensen, I think the difference with bleach is that the drug doesn't damage healthy cells, and is already approved for topical use, which is how it would be used for HIV..."

If I'm reading the FPP link correctly, it's being suggested as a topical cream for prophylactic use - lube your tube before you enter the Cave of Wonders.

It's potential use to inhibit HIV internally would presumably still require injection, which is a different round of FDA tests. Quicker perhaps than starting from zero with Random Chemical X, but still not assured.
posted by IAmBroom at 9:53 AM on September 26, 2013

Slap*Happy : I used to worry that we were living in William Gibson's future, or the future of Neal Stephenson. Now I worry that we're living in Douglas Adams' future.

I am so stealing this. What a perfect way to describe the utterly amazing and often stupid, stupid future we constantly find ourselves in.
posted by quin at 9:54 AM on September 26, 2013 [1 favorite]

There are a lot of things in cure research that are a LOT further along than this. Also, HIV therapies are so much more tolerable now. In fact, a new drug was just approved last month that is showing fewer side effects than ever, and recently, side effects are becoming less and less problematic in more and more people living with HIV.

We're working on it people. We have 30 people in my group and over 500 at my university working on it every single day.
posted by Sophie1

I, for one, would be fascinated to see an FPP by an HIV research scientist on the current state of cure research in general, if you or someone else ever got the urge to make one.
posted by cairdeas at 10:42 AM on September 26, 2013 [4 favorites]

If I'm reading the FPP link correctly, it's being suggested as a topical cream for prophylactic use - lube your tube before you enter the Cave of Wonders.

I'm pretty certain you're not reading this correctly, which is speaks to my point about why this is suck journalism in particular and science journalism in general blows.

My reading is you don't do anything with the topic cream, since it hasn't been shown to do fuck all about HIV in anything other than a petri dish. The fact that several people, several presumably intelligent people came to this conclusion after reading this article is why I said above it's irresponsible journalism. My reading, is the same as Slap*Happy's, but the larger picture is that there shouldn't be a question. The article should have covered this, but it's a much better headline to say, "HIV Cured!" than to say, "Blip in Research Looks Promising (May Not Be)"

It'''s like when they cure Alzheimer's in mice (that they caused). Maybe great news if you are a mouse with Alzheimer's. A person may or may not (and probably won't) benefit. This isn't an argument against doing science or against covering it. It's an argument toward creating some media literacy and a plea for better science writing for the lay person. This story is not that.
posted by cjorgensen at 1:29 PM on September 26, 2013 [1 favorite]

it's irresponsible journalism ... say, "HIV Cured!" than to say, "Blip in Research Looks Promising (May Not Be)"

Please forgive me, because I don't want to threadsit, but while I don't disagree that this is a problem in science journalism, I honestly don't see how you're getting it at all from this particular article. The article was very clear, both in the body of the piece and the headline itself, that they have so far only looked at cell culture. The article struck me as enthusiastic but measured. The overall gist of the piece, to me, was, "this drug does something interesting in cell culture that may be promising, and it's especially exciting because it will be easier to research in humans since it's already approved for human use." I actually do not see an iota of hyperbole or hype in the article.
posted by cairdeas at 1:40 PM on September 26, 2013

Because I believe you put this out there in good faith, and because I do think it's an interesting post/subject, I'll answer your questions.

Your above objections may hold true for the first link, but the problem is that's an abstract of a scientific paper. It sort of tells you what the paper is about, but if you don't have the training (I don't) to understand the full text of the actual paper then you just have to trust the person writing the abstract. This is fine, but untrained people can come up with whatever reading they like. You've seen that in the comments to this post. A few people think you rub this cream on your penis prior to sex and you're good to go. That abstract does little to actually explain the findings of the paper. This is how you get the second link, and truth be told, if you'd only had the first I probably would have been fine, but the first link allows people like the author of the second to write about shit she obviously doesn't understand.

The CNET article fails from the headline on: Betteridge's law of headlines.

Honestly, the best explanations of the actual paper came from maryr's twitter feed.

I will bang the "I am not a scientist" drum loudly, but I grew up around them, "Laboratory Medicine" was literally (ha!) my bathroom reading material as a child. I read these same articles. I read about the cancer cures, the Alzheimer's cures, the HIV cures, and nearly every time I mention these articles to people who do this for a living I am told why the science is interesting, but that the journalist only wants to hear the exciting story. As someone who spent the last 13 years around professional journalists and editors I've got to understand a lot about media literacy as well. (This is also what I am currently studying and a secondary interest of mine when I was initially an undergrad.) I can give either a breakdown on rhetoric or on ineffective use of actual facts at hand or presentation if you like.

At the end of the day neither link was an informed examination of the underlying paper. Neither were a critique or even a championing of the claim. You have one link repeating the findings of the paper and a second reading tea leaves based on what she thought she'd read.

The human body is a fascinating thing. My prediction after reading your links is that maybe scientists might come up with something that slows or reduces viral loads in people, but this is pretty super fucking far from a cure. There's a better chance than not that this won't even may any difference in HIV. None. Zip.

The things this research has going for it at this point is it worked with cultured cells and since it's a drug already approved for other uses it won't take as long to find out if it does anything. In the mean time, you give people hope, you might suggest there's a cure right around the corner, you make it possible for some people to care less about risk. this is irresponsible to me.

Again, I am not a scientist, so if one wants to come along and say my reading it incorrect I'll be happy to back off.
posted by cjorgensen at 4:33 PM on September 26, 2013

I'm trying to finish up the paper now. Possible info of interest re: drug's effect on healthy cells:

Using the TUNEL assay for DNA fragmentation {note: this is a measure of apoptosis}, less than 10% of cells in infected or uninfected untreated cultures were apoptotic 144 hr after inoculation. This population increased to 24.1% (± 3.2%) of cells in CPX-treated uninfected cultures. By contrast, it rose dramatically to 71.8% (± 8.8%) of CPX-treated cells exposed to HIV-1 (P = 0.009)

That's all expressed in Figure 6 if you want to look at the data, which I can only take their word for as I'm unfamiliar with these tests. I understand this as saying that CPX (err, that's the foot cream) increases the apoptosis 2-3 fold in healthy cells, but it increases death rate in infected cells 7-10 fold and those are the cells that are supposed to die and are ignoring death signals in the original <10%.

OK, finishing the read now for reals, just wanted to pull those numbers out to address the healthy cells being forced into apoptosis issue. That's in a petri dish, but the dish is filled with blood cells taken from an actual human and HIV virus taken from an actual human.
posted by maryr at 8:01 PM on September 26, 2013 [1 favorite]

From the discussion:

In a double-blinded proof-of-concept trial, a one week-course of oral DEF caused an acute zidovudine-like reduction of viral load in individuals who attained the threshold serum level of the drug.... The viral load reduction persisted throughout seven weeks of monitoring after cessation of DEF (Saxena et al., unpublished data).

So, um, when's Saxena's paper coming out then?
posted by maryr at 8:59 PM on September 26, 2013

On the off chance anyone cares, I finished both papers - here's a Storified version of all the tweets. I really flooded my Twitter feed, hah.
posted by maryr at 10:55 PM on September 26, 2013 [6 favorites]

Holy moly maryr. Read your storify - you should do that for a living. Great, great job and actually, after reading the papers and your storify, while I'm not jumping up and down, I am moderately hopeful that "reclaiming apoptotic proficiency" might be a possibility. Also, this may have usefulness as PEP or PrEP depending on how well it's tolerated in humans.

Fun stuff.
posted by Sophie1 at 10:26 AM on September 27, 2013 [3 favorites]