The Scientific Activist

A few interesting items have recently come up in the news and in the scientific literature about various methods for preventing the transmission of HIV.

First up is a study (1) published in PLoS Medicine this week that demonstrated the effectiveness of a combination of antiretroviral drugs in preventing viral transmission in a monkey model of HIV. The researchers demonstrated that taking the antiretroviral drug emtricitabine (FTC) orally could reduce the chance that a macaque would become infected. Adding tenofovir-disoproxil fumarate (TDF) increased protection, and injecting both drugs (instead of giving them orally) gave full protection (at least within the small population used in the study). This pre-exposure prophylaxis (PrEP) could offer a promising additional method to protect individuals against acquiring HIV, although–at least in the foreseeable future–it wouldn’t be particularly practical on a large scale. Another study (2) published last month in PLoS Medicine presented a mouse model for studying HIV transmission and also demonstrated the effectiveness of pre-exposure prophylaxis in these mice. Although macaques are genetically much more similar to humans, mice are much easier to work with under controlled conditions, so such a model is still very useful for studying pre-exposure prophylaxis.

Next, I was a little annoyed by a story in yesterday’s New York Times reporting that male circumcision may not be effective at preventing the transmission of HIV from males to females:

A number of studies showing that circumcision among men reduces their risk of infection from the AIDS virus has raised the hope that the procedure would also benefit their female sexual partners.

But the expectations were challenged Sunday by a new study showing that male circumcision conferred no indirect benefit to the female partners and, indeed, increased the risk if the couples resumed sex before the circumcision wound was fully healed, usually in about a month.

Fair enough, but the one-sentence description of the article that appeared in the daily headlines email was “Expectations that circumcision among men would reduce the risk of their female sexual partners becoming infected were refuted by a new study that proved it could immediately increase the risk” (emphasis added). I found this quite misleading, since it must be stressed that any temporary increase in HIV transmission was due to people having sex before the circumcision wounds had healed, against doctors’ orders. There’s nothing intrinsic about being circumcised that increases HIV transmission, and that’s not stressed at all in this article (particularly the point that this increase in transmission is totally irrelevant in regards to infant circumcision).

Issue number two with this press coverage was that, as the story even pointed out, “the findings did not reach statistical significance,” so one certainly can’t read much into these findings. In addition, the study (as far as I know) has not been published anywhere, which is another strike against it.

In the end, it remains to be rigorously demonstrated whether male circumcision affects disease transmission to females, although this study provides evidence that it doesn’t. Regardless, it is still well documented that male circumcision reduces the transmission of a whole host of diseases (including HIV) to males. In the grand scheme of things, I would imagine that cutting down on disease transmission in any one direction should decrease overall disease prevalence.

And, finally, at the very least we can all still agree that one of the most effective methods of preventing the spread of HIV is the use of condoms. Right? Well, not quite. In observance of Super Tuesday, here’s a gem from Republican frontrunner John McCain. From 17 March 2007:

Not that HIV/AIDS is an important issue or anything… but it appears that Republican presidential hopeful John McCain hasn’t been thinking much–or at all–about HIV prevention. The New York Times blog The Caucus reports that when asked about the subject at a recent campaign rally in Iowa, McCain looked completely stumped:

Did he support the distribution of taxpayer-subsidized condoms in Africa to fight the transmission of H.I.V.?

What followed was a long series of awkward pauses, glances up to the ceiling and the image of one of Mr. McCain’s aides, standing off to the back, urgently motioning his press secretary to come to Mr. McCain’s side.

The upshot was that Mr. McCain said he did not know this subject well, did not know his position on it, and relied on the advice of Senator Tom Coburn, a physician and Republican from Oklahoma.

His press secretary, Brian Jones, later reported that Mr. McCain had a record of voting against using government money to finance the distribution of condoms.

Yikes….

Happy voting, everyone!


  1. Garcia-Lerma, J.G., Otten, R.A., Qari, S.H., Jackson, E., Cong, M., Masciotra, S., Luo, W., Kim, C., Adams, D.R., Monsour, M., Lipscomb, J., Johnson, J.A., Delinsky, D., Schinazi, R.F., Janssen, R., Folks, T.M., Heneine, W. (2008). Prevention of Rectal SHIV Transmission in Macaques by Daily or Intermittent Prophylaxis with Emtricitabine and Tenofovir . PLoS Medicine, 5(2), e28. DOI: 10.1371/journal.pmed.0050028
  2. Denton, P.W., Estes, J.D., Sun, Z., Othieno, F.A., Wei, B.L., Wege, A.K., Powell, D.A., Payne, D., Haase, A.T., Garcia, J.V. (2008). Antiretroviral Pre-exposure Prophylaxis Prevents Vaginal Transmission of HIV-1 in Humanized BLT Mice. PLoS Medicine, 5(1), e16. DOI: 10.1371/journal.pmed.0050016

Comments

  1. #1 Sigmund
    February 5, 2008

    “I would imagine that cutting down on disease transmission in any one direction should decrease overall disease prevalence.”
    Would you? You don’t suspect that a proportion of circumcised individuals might think that the circumcision now meant they were protected from HIV risk (isn’t that what a lot of these pro circumcision HIV protection stories are saying?) and would then partake of more risky activities, the end result being the increase in the spread of the disease?
    The benefit of circumcision in terms of HIV protection compared to that of condom use is so insignificant that its surely important as scientists that we don’t portray them in the same equivalent manner.
    And why restrict the study to male circumcision, how about looking at the situation with female circumcision?
    What if we found that circumcised females had similar or even better protection?

  2. #2 Nick Anthis
    February 5, 2008

    I agree that male circumcision should not be portrayed as an effective method alone for preventing the spread of HIV. I’m not aware of any credible sources making such a claim, but if they are, they are certainly sending the wrong message.

    Female circumcision, of course, is a completely different picture. It’s not an analogous procedure to male circumcision, despite the name. A more apt description is genital mutilation, and it has no health benefits to my knowledge.

  3. #3 Paul
    February 5, 2008

    These pre-exposure prophylaxis studies are interesting, but how would it work in practice? The drugs used in this study have side effects in some patients, and while these are often acceptable when treating HIV infection or in post-exposure prophalaxis it seems unlikely that anyone would want to take them on a regular basis as a pre-exposure prophylaxis. Indeed the authors of the study using monkeys mention that the relatively high dose they used might cause side effects in humans (presumably they mean that it would cause unacceptable side effects in a minority of humans on the regime).

    I presume that this pre-exposure method will be improved so as to reduce the possibility of side effects, but I’m still curious to know what scenarios this method is intended for.

  4. #4 MemeGene
    February 5, 2008

    Sigmund, I really hope you were joking about “female circumcision” since that really has no impact on the exposure women get (given that infected fluids go INTO their bodies through that thing called a vagina).

    Nick, one concern I heard was that there is a possibility of infected men getting a circumcision in the hopes of appearing “safe” to future partners. Personally, I am surprised that there would be such objection to condoms that circumcision (especially in adult males) would be considered a more preferable prophylactic option (assuming for a moment that the protection is comparable).

    As far as reducing infection of men impacting the overall transmission of disease, my concern is that in countries where women do not get as much power over partner choice we would not see a significant interruption of disease transmission. There’s a whole other issue of misconceptions by infected men who think that raping a virgin will cure them…

    My optimism about these findings is based less on using circumcision as a prophylactic measure, but more in learning more about HIV transmission and how to prevent it for everyone, preferably without lopping off bits.

  5. #5 Nick Anthis
    February 5, 2008

    It’s not clear to me exactly when pre-exposure prophylaxis would be called for, although clearly it would be horribly impractical to practice it across the board. I would guess that it would be useful for those who know they are going to be habitually exposed to the virus (people with infected partners, sex workers, etc.). The example of anti-malarials is mentioned, a case where pre-exposure prophylaxis is given as a general rule to travelers heading to areas where malaria is endemic. However, I’m not sure if that protocol would really be relevant for HIV, since exposure generally requires some sort of active risk-taking.

  6. #6 Sigmund
    February 5, 2008

    #4 “Sigmund, I really hope you were joking about “female circumcision” since that really has no impact on the exposure women get (given that infected fluids go INTO their bodies through that thing called a vagina).”
    Its a serious point and if you have some figures to back your hand-waving response to the question I would be interested to see them. The question is again, how do the HIV transmission figures look for circumcised women compared to non circumcised women ?(and yes, of course, the apt term is genital mutilation – the same as for the male situation).

  7. #7 MemeGene
    February 5, 2008

    If you are speaking of an anatomically analogous procedure, where part of the foreskin of the clitoris is removed, I am willing to bet that the removal of that relatively small area of mucus membrane has little significant effect on the overall area of mucus membrane and other permeable tissue exposed during vaginal intercourse on a woman, given that infections can be contracted through the urethra and through the vagina.

    If you are speaking of FGM, where some or all of the labia and clitoris are removed, then the amount of permeable tissue is still not significantly changed if there is penile penetration into the vagina, since you have the entire surface area of the inside of the vagina and cervix still available.

    And in the cases where FGM results in a completely closed vaginal opening from scar tissue, my guess would be considerably lower… until the “tamper-evident seal” was broken.

    The male foreskin, on the other hand, in an adult male averages 15 square inches of highly sensitive, permeable mucus-membrane laden tissue. Unless a circumcised male engages in anal intercourse, the only vulnerable skin presented during intercourse would be the opening of the urethra and any open wounds he may have. Thus, we have a significant change in infectable surface area in a circumcised vs. uncircumcized male.

    I doubt there are figures actually measuring differences in infectability of women who have undergone FGM and those who have not due to human rights and other issues.

    For the record, I am not a supporter of genital mutilation or circumcision without consent in either sex.

  8. #8 Walabio
    February 6, 2008

    The Ob/Gyns who make much money through sexual mutilation recently did studies where they took HIV-negative males, mutilated half of them, waited 6 months and then retested. The mutilated males who could not have sex for most of those 6 months had lower rate of HIV.

    Since condoms are so effective at preventing HIV that we do not even know what the failure-rate is,* but if one really wanted to do this pointless study, the way to do it is split up HIV-negative males into 2 groups randomly, mutilate half of them, follow then for a year, remove HIV-positive males from both groups (effectively, this zeros both groups which is important because of group could not have sex for a few months and therefore would have a lower rare of HIV), and then follow the remainder for one year and then test them for the final results of the study.

    * - http://www.cdc.gov/hiv/resources/qa/condom.htm

    Doctors Opposing Circumcision* pointed out the methodological flause in these studies _*BEFORE*_ they began. These studies were done knowing that the results would be useless.

    * - http://doctorsopposingcircumcision.org/

    Because of the profets from sexual mutilation, sexual mutilation is a cure searching for a disease. The fact is that reduction in HIV in the mutilated groups is probably just from forced abstinence during healing. All of the evidence supporting the beneficial effects sexual mutilation on HIV-transmission are cherrypicked:

    It is true that the mutilated Moslems in East Africa have lower rates of HIV than the intact animists. It is also true that significant cultural differences exist between the two groups. This is where the correlation breaks down. Outside of the Moslems of East Africa, one does not find evidence that sexual mutilation protects against HIV:

    South Africa has had > 90% rate of sexual mutilation of males for over a century. It also has > 30% rate of HIV-infection. The United States of America has the highest raters of both sexual mutilation (those OB/Gyns sure work hard) and HIV-infection in the developed world. Africa as a continent has both the highest rate of HIV-infection and sexual mutilation. Frankly, I see no compelling evidence that sexual mutilation protects against HIV.

  9. #9 Randy
    February 6, 2008

    I agree with MemeGene wholeheartedly in regards to the analagous circumcision procedure in females. I also believe the “tamper-evident seal” remark may simultaneously be the most disgusting and hilarious thing I’ve ever read; I don’t know whether to laugh or puke! Anyway, besides having no medically accepted purpose, its absolutely correct that this is really a simple problem of surface area. Cutting off bits of a woman’s genitals reduces the mucous membrane surface area by a tiny percentage compared to the removal of the foreskin in a male. Now, Sigmund, if you mean to bring up the figures on FGM/circumcision to examine whether FGM will increase the risk of a woman (or her partner)contracting HIV, then that’s definately a valid thing to consider. Such figures are probably very difficult to locate due to the nature of the practice (people may not be open to talking about it) and the locales in which it is done. I’m extremely culturally open minded, but an old tribal superstitious/traditional doctrine of FGM is really where I draw the line…that’s right there with the “raping a virgin to cure your HIV infection.” They are irrational, defunct, and in many instances extremely dangerous practices; even if there isn’t a chance of HIV contraction, FGM exposes a woman to massive infection risks, and in an area with lacking medical care, could easily kill her. If there is a risk, if she has open wounds during intercourse (just like the unhealed circumcision wound story) she is even more likely than usual to contract HIV due to the exposure of the vasculature to the virus (the virus can now enter the blood directly rather than have to move across membranes and other anti-pathogenic defenses the body has). HIV is the pansy in the virus community, and dies quickly if it cannot procure a host, so the less exposed surface area where the virus could penetrate, the better. The healthcare community as a whole needs to stomp out things like this and promote condom use both in heavily populated countries and in more remote areas whenever possible. If John McCain is unlearned about this topic, that’s forgivable, and easily remedied. No one can know everything, and perhaps we expect too much sometimes. Now, if he just doesn’t care or thinks there’s something morally wrong with promoting safe sex, then he is an enemy to science and medicine, and no scientific type in their right mind should vote him into office! In regards to the circumcision issue, Russian roulette, although a horrible cliché is a great example. Say you have a revolver with a bullet in five chambers, leaving the sixth chamber empty (but the location is unknown to you, the shooter). Would you put that gun to your head and pull the trigger with an 83% risk of blowing your brains out? Probably not. What if there were only 2 bullets, and 4 chambers empty? Would you then be more likely to play the game, or would you walk away with a 100% chance of not-being-splattered-all-over-your-living-room? Rational people would never even play the game…but some idiot invented it. And so HIV transmission is like RR for your naughty parts. Rational people realize that even a large reduction in the risk still leaves you with a significant risk (33.3% for anyone counting in the example) of extreme bodily harm, and would walk away no matter what. But unfortunately, we all need to realize that most of the human population is NOT rational…especially with sex! People will have unprotected sex, yet be completely oblivious to their partner’s sexual health status, and never even think twice about it. The fact that many hookups like this occur under the influence of drugs or alcohol just dulls that starved, neglected logic nucleus in the brain even more…making it seem like an even better idea to play RR with your health. People thinking with their gut and not using logic view a risk reduction as a ticket for them to safely increase their risky behavior, not comprehending they are ever increasing their chances that the chamber’s loaded (for those of you with a bad sense of humor, I’d like you to think of the phrase “the chamber’s loaded” in reference to someone’s genitals…c’mon, laugh, its funny, we’re not going to judge you). So the bottom line is its irresponsible to print ANYTHING that remotely implies that circumcision is a safe alternative to condom use, or that fails to mention that condom use is imperative in the prevention of the spread of HIV. Sigmund, you hit the nail on the head with that one…yes, circumcision reduces HIV transmission rates to males because it reduces surface area…but a condom covers EVERY bit of surface area…including abrasions you may not realize you had down there, from say, another sexual encounter (with yourself or a partner, its a wound either way) or perhaps even getting your junk snagged in your zipper…it happens (by the way, I say “junk” not because I’m uncomfortable with the word penis, but because saying “penis snagged in your zipper” sounds…well, stuck up). So yes, it’s incredibly important that we in the scientific and healthcare community don’t accidentally mislead people into thinking circumcision and condom use are equivalent in efficacy. Personally, I’m a 4th year Doctor of Pharmacy (yes, I know its not a real PhD dammit!) student, and I work in a community pharmacy back home during breaks (Walgreen’s, to be precise). Since I’ve worked so hard to excel as a student of pharmacy and at my job, I’m trusted by the pharmacist(s) who supervise me to counsel patients on everything from their medication use to sexual health/condom use to drug addiction to giving enemas to infants. Under no circumstances would I ever remotely consider telling someone that circumcision reduces disease transmission rates unless I added the bold disclaimer that its insignificant compared to using a condom or both together…and then I’d make them repeat the disclaimer to make sure they heard and understood me correctly. Now, I don’t know where I’ll end up when I graduate and go into practice…I could be signed with WG, I could be in a hospital, I could be a prison pharmacist. It’s the same everywhere though, because people are the same everywhere…they love to accept the treasured knowledge that comes out of the mysterious vault full of people with white coats…but we who wear the coats have to make sure that in our comfort with scientific vernacular, we don’t inadvertantly give a patient/customer/whatever misleading information that could lead to their harm. As far as PRE-exposure prophylaxis, besides the sex worker industry (and this doesn’t even hold up to argument), I can’t really think of a venue where this would be useful. POST-exposure prophylaxis is very useful for say, a doctor or nurse who is accidentally stuck with a needle contaminated with HIV infected blood. But that’s after the fact. People need to realize that these medications have very nasty side effects even at normal therapeutic doses, so the LAST thing I’d want to do to a patient is expose them to a medication with that kind of side effect profile without a NEED (e.g. definite knowledge of exposure to HIV). For example, the commercial combination of emtricitabine and tenofovir DF is called Truvada (the oral tablet at least). This is a combination of FTC (a synthetic nucleoside analog of cytidine) and tenofovir DF, which is converted in vivo to tenofovir, an acyclic nucleotide analog of adenosine 5′-monophosphate. Both of these drugs are HIV-1 reverse transcriptase inhibitors (i.e. they hinder the way HIV hijacks a cell, more here http://www.rxlist.com/cgi/generic/truvada.htm). The issue is though that RT inhibitors, alone and with other HIV meds, have caused lactic acidosis, liver enlargement, and fat accumulation on the liver, even in the absence of elevated liver enzyme levels on a lab test (this includes fatal cases, primarily in women). Nucleoside analogs can also cause severe acute exacerbation of Hep-B in patients with both diseases, and tenofovir can cause severe renal damage, especially in at-risk patients or patients taking other nephrotoxic drugs. These effects are more common in the obese (a large US demographic) and the longer a patient is on the drug. Finally, not to complain, but does anyone have any idea what a pain in the ass it is to manage HIV drug therapy? Anyone in medicine/pharmacy already knows this, but for those who aren’t, these drugs alter liver metabolic patterns like no other drugs…which means they interact with almost ANY drug you can think of! If you put someone on Truvada for Pre-EP, you would also have to manage ANY other meds they were on (dose adjustments to account for hepatic accumulation, etc), as well as advise them on the use of any OTC, herbal, hormonal, or illicit substances that are metabolized hepatically. In my opinion as a healthcare professional, with a adverse effect profile like that, Pre-EP with Truvada would be the definition of a reckless medical practice, and I would immediately question any doctor who recommended or prescribed it for that purpose. It works well to reduce HIV levels in those already infected, there’s no question about that…the research is solid. But Pre-EP would put uninfected people in unneccessary danger (especially with injection, which comes with exacerbated side effects with the added protection) when condom use would work just as well, with no risk of lethal acidosis or liver failure. Anyone who would rather take a risky and possibly dangerous drug (that could end up doing more damage and killing you faster than HIV could) than put a little rubber balloon on his member has more to worry about than HIV infection…in fact, their risk is likely 0% anyway because insanity tends to drive away potential mates. I know I wrote a LOT here, but this is my first post on this site and frankly, I’m amped I found a scientific site like this…plus, HIV is a big, big issue for EVERYONE in science and healthcare, not to mention the general population. So fellow eggheads out there, do your non-scientific, layman friends a favor…translate for ‘em, teach ‘em some basics if they’re willing to listen a little, and do your part to help keep them safe and healthy. I look forward to anyone who would like to respond to what I’ve said, or who would like to scathingly mock me for writing such an obscenely long post. They don’t put limits on character numbers, and we shouldn’t put limits on our thinking.

    Peace, and be well.
    Randy

  10. #10 Mark Lyndon
    February 6, 2008

    It appears that eight additional women were infected because of this study. Even after the healing time was over, there was still a higher rate of HIV in the partners of circumcised men. Surely it would not be ethical to continue such experiments. Or do we have to wait till there’s a 95% chance that extra woman are being infected before we stop?

    This is not the first time that partner circumcision has been linked with increased risk of HIV in women, and yet the WHO continues to recommend male circumcision. Something is very wrong here. Why are they so keen to promote genital surgery instead of ABC (Abstinence, Being faithful, Condoms)?

  11. #11 truth machine
    February 6, 2008

    Funny that people refer to Obama as an “empty suit” when he’s nothing of the sort, whereas McCain is the real thing. Like Bush, he’s lost without his teleprompter.

  12. #12 MemeGene
    February 6, 2008

    Great post, Randy, and very educational! I completely agree that scientific and medical types need to take an active role in “translating” for laypeople – I’m training to be a bioethicist for that very reason. (and I believe very strongly that people are not Tylenol bottles, but that’s just me)

    Anyone who would rather take a risky and possibly dangerous drug (that could end up doing more damage and killing you faster than HIV could) than put a little rubber balloon on his member has more to worry about than HIV infection…in fact, their risk is likely 0% anyway because insanity tends to drive away potential mates.

    Sadly, that is not true if you look at many in the populace… On a serious note, there is inconsistency in the risk-assessment mechanisms that allows a person to stay in denial when rationalizing why they won’t use a condom but will be first in line to take drugs after being infected.

    And don’t even get me started on where McCain is going now that he looks like the probable nominee and all the anti-science factions will get their claws into him.

    (I love this site – the blogs are awesome)

  13. #13 Mooser
    February 6, 2008

    The male foreskin, on the other hand, in an adult male averages 15 square inches of highly sensitive, permeable mucus-membrane laden tissue.

    Cut it off! Cut it off! Especially since that will expose the remaining nerve-laden skin, and let it dry out and become insensitive. Just what the doctor ordered a little later in life.
    Gee, you don’t think the efficacy of circumcision is related to the religious feelings of the sponsors?

  14. #14 Caledonian
    February 6, 2008

    I would probably be less skeptical about the most recent claimed medical benefits of circumcision if all of the old claimed medical benefits of circumcision hadn’t been garbage.

    Remarkably, just as quickly as it became generally acknowledged that the old claims were wrong, new claims were produced. It’s almost enough to make you think that people were looking for convenient excuse to justify what they’d already decided to do for other reasons.

    Perhaps we’ve finally stumbled upon a true benefit to the practice. Given the history of the procedure, such a claim should be held to a very high standard indeed.

  15. #15 Sigmund
    February 7, 2008

    Whatever about the question of cultural practices, the idea that circumcision is of benefit against the spread of HIV should be treated with a little more skepticism than is currently shown in many recent articles, and is absolutely demonstrated by the tone of the above piece. Using circumcision as an anti-HIV transmission measure is like saying that jumping out a second floor window while holding a cushion is better than jumping out while not holding a cushion – meanwhile not pointing out that there is an alternative of simply walking down the stairs.
    Nick, you might have tagged a little admission of condom use as a good thing at the end of your piece but try reading the piece again to see where you tell us the aspect of the story that annoyed you.
    The circumcision anti-HIV policy is not being actively advocated in places like Europe or Japan (were there is low levels of circumcision) but rather in places like Africa. Why? Is it because of scientific evidence? Or just maybe all the scientific evidence points in one direction (use condoms) and it is the pandering to religious sensitivities that creates a situation where an incredibly minor benefit of circumcision is touted as a reliable anti- HIV measure (or at the very least the equivalent of a proven reliable anti-HIV measure – condom use).

  16. #16 Nick Anthis
    February 7, 2008

    This comments thread is really getting quite out of control. It’s a little absurd to expect that any post about HIV must include a full discussion about the centrality of condom promotion to any anti-HIV strategy. The effectiveness of condoms is so obvious that it (almost) goes without saying. And, I doubt that those misguided individuals who think otherwise are reading this blog.

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