Sometimes I am the worlds worst advocate for my own research.

Yes, its fantastically cool.

Yes, we learn more about the world and how life evolves on it.

But THE REASON I do HIV-1 research is to help ultimately create an HIV-1 vaccine. The only way we are going to beat HIV-1 is to stop new infections, and to stop new infections, we need a vaccine…

Or, everyone could just wear condoms, which reduce HIV-1 transmission ~85%, and we could cut this bastard off at its head in a few generations and I can go do something else.

*blink*

Well, the thing is, things arent that simple. Half the people infected with HIV-1 are women, and the vast majority of them are infected via heterosexual contact. Not every woman has a say in when/where/how she has sex. So not every woman can speak up and say “Yeah, you are so wearing a condom, dude, lol!” Same thing goes for some men.

Ideally, we would like to be able to help the people most at risk of acquiring HIV-1 infection. Put the power in their hands, not the hands attached to the guy not putting on a condom. One way we can do this I talked about a week ago– microbicides. A gel that could be used pre/post sex to help stop HIV-1 transmission.

Weve now got one that works. Kinda.

Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women

They gave a gel containing tenofovir to 445 women, placebo to 444. They were supposed to use it before and after sex, but no more than 2 doses in 24 hours. And they did. There was a very high compliance rate, and the women didnt mind the gel at all– over 97% were totally cool with it.

The gel reduced HIV-1 acquisition by 39% (even higher for women who were really strict about using it properly– 54%).

Thats no 80-90%, but hell, Ill take 40-50% over someone not being able to protect themselves at all.

Also awesome: Applying the drug in small quantities where its needed in a microbicide, instead of giving oral (systemic) antiretrovirals as a prophylactic means you get to avoid a lot of unwanted physical side effects. The ‘worst’ they got with this microbicide? Some people got diarrhea. No renal failure.

What I am actually interested in discussing about this, is the evolutionary aspect. If we put this drug in microbicides, arent we just going to get lots of drug resistant HIV-1 spreading?

NO.


By chance, there are HIV-1 variants in the transmitting sexual partner that are resistant to tenofovir. If that person is not actively on tenofovir, there is no reason to assume resistant variants would be at any higher frequency in the quasispecies than any other random variant of the consensus. Only a fraction of the quasispecies is represented in one particular ejaculation. And that minority variant must be at the right place at the right time to successfully mediate infection in the new host.

So thus far, weve already taken an unlikely event and made it more unlikely-er.

Now, this ‘drug resistant’ variant is in a new host. Once it gets to the lymph node and really gets its claws into this new host, the virus will start rebuilding a new quasispecies. A drug resistant quasispecies? NO. Tenofovir is not at pharmacological concentrations systemically in this new host– its only in the microbicide. When tenofovir is no longer a selective pressure, thus the virus just drifts. Random mutation, drift. It loses tenofovir resistance because it doesnt particularly need it. Worse still, HIV-1 drug resistance almost universally comes at a fitness cost to the virus. It doesnt particularly want the mutation there at all, unless of course, the drug is there, and only the variants with the appropriate mutation survive.

The point at which we all get screwed is when HIV-1 figures out how to be resistant to tenovir… AND maintain high fitness. Chance mutation 1 gives you the resistance and low-level replication. Chance mutation 2 lets it replicate a little faster. Chance mutation number 3 and 4 lets it go a little bit faster. The virus racks up compensatory mutations until ‘wild-type virus’ and ‘drug resistant virus’ are equally fit, whether the drug is there or not.

THAT is when we are screwed.

But that should just happen if the person has a lot of tenofovir around to act as a strong selective pressure. The amount in the microbicide was not enough to actively select for the mutant, because the researchers here couldnt find drug resistant HIV-1 in the people with the tenofovir gel that still got infected.

So right now? This is a fix Im wiling to gamble on, evolutionarily.

… or we could just wear goddamn condoms.

Comments

  1. #1 danmeek
    July 20, 2010

    Great post! Do you wear condoms?

  2. #2 Art
    July 20, 2010

    Good post. Thanks. Hadn’t heard about this.

    And good, if not perfect, stuff.

  3. #3 UberMalark
    July 20, 2010

    I usually do not stray from the physics or science education blogs. But I happened upon this entry (isn’t that one reason SciBlogs is so awesome?) and had to ask:

    Isn’t half of HIV infections occurring to women expected?

  4. #4 Charl
    July 20, 2010

    UberMalark – not necessarily – the highest risk groups in the UK and Europe *used* to be MSM, sex workers and IV drug users (and people who needed frequent blood transfusions, like haemophiliacs, but that’s hopefully not an issue now). If this were still the case, you wouldn’t expect women to contract the disease from their partners. However, enough men in certain cultures have had sex with enough women that it’s now in the heterosexual male population, and they’re happily spreading it to their female partners. And the Pope STILL won’t endorse condoms. Ye gads.

  5. #5 Charl
    July 20, 2010

    Interestingly, I went to some demography lectures that blamed AIDS on European colonialism – apparently annexing half of Africa, encouraging men to move to mining/work camps (where, away from their wives, they started using prostitutes) and then sending them back to their wives (carrying HIV) played a significant role in HIV getting a foot-hold in Africa. But the lecturer who told us all this also refers to Africa quite seriously as Bongo-Bongo Land when he’s talking about immigration to the UK, so take of that what you will.

  6. #6 Joshua Zelinsky
    July 20, 2010

    Is there no worry about a ratcheting effect? I seem to recall that there are examples in bacteria where after the bacteria evolved resistance to some antibiotic that then became fixed as subsequent mutations made having the earlier mutation have higher fitness independent of whether or not the antibiotic was there. Obviously, viruses don’t operate the same way as bacteria, and the relevant mechanisms are very different from what happens with antibiotics but I don’t see why this sort of scenario shouldn’t be that much of a worry. Is it just unlikely? Is there something I’m missing?

  7. #7 heddle
    July 20, 2010

    Fascinating.

  8. #8 UberMalark
    July 20, 2010

    Thanks Charl. I have read about the ban on condoms by the Vatican, it is criminal.

    A gel that helps prevent infection is a good step forward, hopefully there is a vaccine on the horizon.

  9. #9 levi
    July 20, 2010

    Just out of curiosity, where the researchers here who could not find drug resistant HIV-1 in the people with the tenofovir gel that still got infected financially connected or funded by the pharma interests that own/produce tenovir?

    So you are saying that tenovir would have to be found systemically in the patient/user in order to create a selective pressure, and that topical agents will not result in significant drug resistance? Does that apply even if the patient has sex and uses tenovir more than once with the same HIV infected person? No selective pressure?

  10. #10 Perplexed in Peoria
    July 20, 2010

    So, if I understand the numbers in that study correctly, a sexually active 18 year old woman in KwaZulu has a 50% chance of becoming HIV infected by age 30 *if she uses the gel properly*. But if she doesn’t use the gel, then may God (if there is a God) have mercy on her soul.

    I hadn’t realized it was quite that bad. Hope you find a vaccine or cure. Soon.

  11. #11 Prometheus
    July 20, 2010

    “But that should just happen if the person has a lot of tenofovir around to act as a strong selective pressure.”

    Are you saying that this is unlikely because of the present incarnation of CAPRISA 004 is as a user controlled before and after application?

    How likely does your evolutionary pressure scenario become if it is an around the clock proposition like a small doses time release gel?

    I am not finding any information about a contraceptive component to CAPRISA 004 so is the Vatican going to be able to find an angle to condemn it like condoms?

    P.S. FYI: A certain bowl of cabbage soup just hopped the last train to wordpressville and richly deserved obscurity. Pour out half a Dew to your fallen homie.

    I don’t think Bombeck should stand for this. Tell Cankles she should stomp out in a show of solidarity.

  12. #12 theshortearedowl
    July 20, 2010

    @ levi

    The initial infection – yes, there is selective pressure. Resistant strains will be most likely to make it through the gates, so to speak.

    After that, the virus multiplies inside the infected person. Now there’s no selective pressure, since a topical drug will only act at the surface (or in this case – well, you get the picture :). The virus particles that have the resistance gene will replicate at a slower rate than those that do not have it. By the time the viral load is enough to be infectious to the next person, there will be little-to-no difference in drug resistance between that person’s HIV and anyone else’s HIV.

    (This does slightly depend on the relative fitness cost of the gene conferring resistance; but even a fairly minor fitness cost will be a significant burden over a few tens of generations.)

  13. #13 Richard Hendricks
    July 20, 2010

    Levi,
    HIV has relatively poor fidelity as a replicator. Hence “quasi-species”. It’s more like a “cloud of gnats” on a tree-of-life graph than a single branch. Each person has their own “cloud”,with its own mutations. Each cloud starts from a single or small group of gnats, but because of the poor replication fidelity, that cloud slowly expands to cover more “types” of viruses. So even if the initial virus has resistance, once it starts replicating in a drug-free environment, more successful “normal” offspring quickly crowd out the “resistant” offspring.

  14. #14 ERV
    July 20, 2010

    You all have no idea how happy I get when commentors answer other commentors questions, and they are right :)

    I mean, Im happy enough when you all try, but when you are right, I am just so proud :-D

    Joshua– It is always possible something like that happens by chance alone. By chance, there is a variant that has resistance + the 10 other compensatory mutations the virus needs to keep high replicative capacity. I will say, however, that we have not IDed that potential virus yet in laboratory settings, as far as I know. It might not exist. But with HIV-1, really anything is possible.

    Prometheus– Im not sure it is possible to administer enough of the gel to get it at the necessary systemic pharmacologic concentrations for it to be a strong selective pressure. Maybe it would be like coating yourself in benadryl cream to stop anaphylactic shock? BUT, I dont know the pharmacologic profile of this stuff– maybe it is possible.

  15. #15 The Goddess
    July 20, 2010

    What about coconut oil? Haven’t there been studies?

    It keeps my Herpes simplex 1 at bay. If I feel a tingling on my lip I apply it liberally on lips, nose area etc as well as taking it orally and it goes away!

    Nothing else, even prescription meds and l-lysine ever worked like that.

    Also, it’s cheap and already in lubricant form!

  16. #16 Birger Johansson
    July 21, 2010

    With the rapid mutations of HIV, we probably need multiple approaches -this just in at Physorg.com:
    http://www.physorg.com/news198837642.html
    “HIV’s sugar coating offers new vaccine approach”
    (there is an irritating grammar fail in the first paragraph of the article, otherwise I am enthusiastic)

  17. #17 Paul Browne
    July 22, 2010

    Good commentary there Erv. For me the best thing about this news is that it shows that microbicide gels can cut the spread of HIV. An earlier trial with the microbicide PRO 2000 suggested that it could work, but this is the first trial to produce a reliable result. With any luck this result will encourage more investment in microbicide research, so that we can get the reduction closer to the 80-90% that would really help curb the epidemic.

    An underr reported aspect of this advance is the role of research involving monkeys in the development of Tenofovir based prophylaxis and this gel, I’ve taken a look at this at http://speakingofresearch.com/2010/07/21/microbicide-gel-cuts-hiv-infection-rates-thank-the-monkeys/

  18. #18 Grin
    September 20, 2010

    Hi all,

    A couple quick thoughts (yes, I’m know I’m VERY late to this discussion):

    The published resistance analysis consisted of population sequencing about 4 months after the product had stopped being used. Substitutions typically associated with tenofovir resistance (K65R and K70R in the reverse transcriptase protein) are known to negatively affect HIV-1’s replication fitness. In other words, in 4 months time one would expect that wild-type virus would quickly outgrow its slower yet resistant cousins. Also, population sequencing techniques are usually only sensitive enough to detect a subspecies variant that makes up about 20% of the entire viral population. In other words, it’s not too surprising that no resistant variants were detected.

    Selection of resistant viruses may or may not occur within infected women using the gel; that data just hasn’t been reported. The systemic exposure levels—typically measured as plasma concentrations—are low, but given enough time resistant viruses might still be selected. Also, there is a very steep tenofovir concentration gradient at the vaginal epithelium, and HIV-1 infected cells do migrate through that tissue, providing an opportunity for local selection at points of high concentration.

    The clinical significance of tenofovir resistance for microbicides, if any, will have to be assessed as the product gets broader exposure. Keep in mind that the women in these studies are carefully and frequently diagnosed for their HIV-1 infection statuses; women in the real world are not. If a woman in the study becomes infected, she will know it in short order and will stop using the gel, minimizing the opportunity for selection of resistant virus. If the product does become commercially available, it’s very likely that infected women will use the product, perhaps for extended periods of time. It’s also worth noting that this would be a concern even if the gel was 100% effective because it can’t be expected to protect against all routes of challenge (e.g., IV drug use, rectal sex, etc.).

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