Tuesday, July 17, 2012

Truvada and HIV Pre-exposure Prophylaxis

So the US FDA has finally approved Truvada as an HIV Pre-Exposure Prophylactic (or PrEp if you fancy acronyms). I am not sure what to make of this, to be honest. The proposition here is to prescribe a chemotherapeutic to perfectly healthy people so they can protect themselves against HIV, at a cost of 13900 US$ per annum. What other protections are available? Use condoms. If you've sex with someone who's HIV positive and you want to have unsafe sex, make sure they're on HAART. If they are, the additional protection daily chemotherapy would offer to perfectly health people is close to non-existent and certainly not worth the cost paid. If you live in a society with high HIV prevalence, the odds are that it's a developing country. Your healthcare system should likely not even consider paying for such a prevention strategy, it's simply not cost effective, considering competing health needs in your society.

The drug was tested mostly on folks in high-risk groups who engage in somewhat unusual high-risk behaviour such as having plenty of unprotected sex with folks they do not know or folks they know to be HIV infected (the press release says nothing about the question of whether the latter group included folks who were known by their risk-taking participants to be on HAART), sex workers, etc. So, if you happen to belong to a group of people who engage in high-risk sexual behavior, you likely are disciplined enough to take daily chemotherapeutic drugs to compensate for your risk-taking. Really? This explains probably a 42% efficacy when compared to the placebo control. Adherence might have been a bit of an issue there...  That might also explain why the FDA requires Gilead to keep track of everyone who's (supposedly ) taking Truvada and gets infected anyway. Drug resistance seems a serious concern. Little seems to be known about pregnancy and Truvada, so that's being tested while the drug is being marketed. - Who knows, there might be a market in this high-risk segment of the population, even though it seems unreasonable to me that someone who enjoys such thrills should go on chemotherapy while healthy. Might they might not better wait until they're infected? Equally, in societies where the prevalence of HIV is very high (say, Sub-Saharan Africa), is the proposition to hook large numbers of perfectly health people on these heavy hitting drugs, 'just in case'?

As I said, I'm not sure what to make of this, but I am surprised about the logic of prescribing chemotherapy to healthy individuals as a 'just in case' strategy. Good for the shareholders of Gilead, the maker of Truvada though. You're making money off 'treating' the healthy... To be fair, it is anything but unusual that healthy people are being subjected to treatment in prevention efforts. Just think of flu vaccines, Hep B vaccination and so on and so forth. However, in the case under consideration the proposition is lifelong chemotherapy. That has quite a different ring and quality to it. We should take our time to discuss the pro's and con's of such a prevention strategy carefully, instead of diving headlong into it.

5 comments:

  1. Udo

    I agree with your commentary. The additional factor, which in my mind is also very important, is the long term toxicity of antiviral therapies when used in a prophylactic manner. Although we have come a long way with respect to toxicity, these drugs are not completely benign, and rarely may be associated with severe adverse outcomes such as renal failure. I am not aware that monitoring of such is also being planned.

    Wendy Wobeser

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  2. Hi,

    I think PrEP is best thought of as a additional tool which can reduce risk of acquiring HIV. You mention using condoms and "making sure" that your HIV+ partner is on HAART, but neglect to mention that these are also not entirely straightforward or without problems.

    I would also counter a few of the statements you make about the iPREX study (note this was only done in men who have sex with men and a few trans sex workers). You rightly point out that adherence was significantly associated with protection but without any evidence imply that people who engage in risky sex are unlikely to take pills regularly. One can equally argue that being in a placebo controlled randomised controlled trial where you are told that the medication may or may not work and where there is a 50% chance that you are on a dummy pill is hardly an incentive to high adherence. The missing piece of evidence here is what happens when you tell people that the pill works - this is being addressed in an open label extension of iPREX amongst other studies.
    You also mention resistance but fail to mention that in the studies of PrEP, resistance has rarely been found. This can be explained by the fact that in the high risk groups who adhere well then the risk reduction for HIV seroconversion is > 90%. Those people who got infected were generally not adherent to Truvada and therefore there was no selection pressure on the virus.

    An argument worth considering and with some evidence in gay men, is that 100% condom use is hard to maintain, some gay men don't like them because they interfere with pleasure and some people are at high risk partly because of the characteristics of their sexual network rather than risk behavior per se. PrEP provides an opportunity for these individuals to reduce their risk of HIV in a way that is acceptable to them. There are clearly problems with PrEP in resource poor settings. The argument here should rather be that international donors should support countries to treat their populations AND institute effective prevention measures. If PrEP, perhaps in the form of a vaginal microbicide (see CAPRISA 004) or vaginal ring can be made affordable then this becomes one of the few prevention technologies that can be utilised solely by women.

    You mention treating healthy people to improve population health such as vaccination and cite some examples that benefit both individuals and the population. In the context of HIV however you have not mentioned the ethical implications of treating an individual with HIV infection before that individual actually requires treatment for themselves in order to protect the possible risk to potential future partners.

    With respect to toxicity, the main risks for Truvada relate to renal and bone toxicity. In the studies there did not seem to be any problem with renal function but there was a slightly greater loss of bone mineral density in the treated arm. It is a mistake however to assume that PrEP will be lifelong as this presupposes that individuals never change their behaviour over time. Indeed access to PrEP might be the carrot that we use to engage individuals in other risk reduction interventions or to address issues such as alcohol or drug use. Note that in the studies, individuals were given comprehensive risk reduction counselling and condoms on a regular basis and their risk behaviour reduced over the follow-up period.

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  3. Iain, thanks for your thoughtful comments, and for taking the time... -

    Just a few replies perhaps. It's a bit speculative (I"m probably no better than you on that front!) as to why adherence was seemingly pretty crappy. I'm doubtful that knowledge of the randomisation and placebo control could have made that difference. Would you claim, with a straight face, that you wouldn't notice whether you're on a placebo control or an antiretroviral? That's not exactly supported by the experiences of many folks on ARVs. FWIW, a German language version of our debate is currently taking place on ondamaris.de . This point has been made by a few positive folks there w re to ARVs. I'm also skeptical that folks in the trial wouldn't have cared strongly because of the placebo control, given that they were perfectly healthy to begin with. Clearly they had some incentive to generate the knowledge the trial aimed to generate or else they'd not have participated. - Still, both you and I are speculating here, so it's neither here nor there probably as we don't know what caused the adherence issues.

    You say that resistance has rarely been found. Extrapolate from that rarely to decades of use (I know you're skeptical of this, but there is nothing to suggest folks would not be hooked onto this medication for potentially very long periods of time) and/or population level use as is clearly contemplated by some for high prevalence places like Subsaharan Africa.

    Length of use would likely increase the occurrence of adherence as well as renal issues and bone density issues, so the fact that there were few problems in a relatively short-term study (on the side-effects fronts), to my mind, is nothing to get overly excited about.

    You're spot on about the ethical problem of treating an HIV infected individual with HAART before that's clinical indicated in order to reduce the infection risk for others. I'm surprised nobody has written about this. I have been thinking on and off about this, but I am uncertain where I stand on this. Suggesting that folks who are not even infected should go on such meds seems a different quality tho.

    To my mind, in order to form a sensible view on Truvada, would one not want to know:

    1) how do individuals fare who go on meds after they're infected (ie today, with pretty efficient medication out there) vs folks who go on meds prior in order to prevent an infection. That would have to be done over their lifetimes. If there's a significant survival benefit to going on meds before one is infected you'd have a reason for the treatment recommendations current thrown about, otherwise this doesn't seem to be particularly prudent.

    2) you would also want to know what the long-term health consequences of taking Truvada are for those who would never have got infected (simply monitor someone negative over their lifetime and see how they're doing decades later).

    I appreciate that you think that folks can change behaviours and whatnot, but my impression (in the context of discussions about Truvada in Subsaharan Africa and particular high risk behavior of folks in our neck of the woods), is that there's a tacit understanding that best prevention efforts remain pretty ineffective for a whole bunch of people. I'm the last to pass value judgments on them, but if my interpretation isn't completely off the wall, we really are talking very long term use. Then adherence/resistance as well as side-effects issues matter, given how short-term the current studies are.

    I'm surprised you think PrEP is a carrot that could be dangled in front of folks to counsel them successfully about risk-reduction (as well as implement other interventions). We got PEP already, so isn't the carrot effect more likely a result of the additional attention paid to participants that is a result of trial participation. It wouldn't be replicated in the real world.

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  4. Hey, so truvada is actually a very well tolerated drug. It's not like taking combination treatment for hiv because it only represents 2 of the 3 drugs in standard regimens. Many people with established hiv have experience of past therapy with much worse side effects. In any case in randomised trials you can check this out and in iPrex there was a very small excess of mild nausea in those randomised to drug which only seemed to last for the first month.

    I disagree with you about resistance. This is to some extent down to the biology of the thing. If you don't take drug well enough there is no selection pressure and you either stay negative or get infected with wild type virus. If you do take the drug you don't get infected. Extension of the studies will of course continue to look at this.

    You are neglecting the public health aspects of this in your response. We are not just talking about individual benefit here but about stopping the hiv epidemic. Modelling presented at the recent AIDS conference in Washington suggests that interventions with the biggest impact on the epidemic in gay and bisexual men are those that reduce the intrinsically higher biological risk of transmission for anal sex. Thus, if prep can be done well it significantly reduces the number of new infections, potentially reducing the overall amount of resistance (because there is less hiv around to get resistant and because truvada would have activity against many of the transmitted drug resistant strains.

    I care about people getting infected with hiv so it is not ok with me to wait a lifetime before we use tools to tackle the epidemic which are reasonably safe compared to the excess deaths and illness caused by hiv and the complications of a lifetime of therapy for those diagnosed. This is an infectious disease so if we don't control the epidemic those numbers only continue to grow.

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  5. Wrt pep, I think this is an important issue to compare and contrast as it points to the possible limitations of prep. Pep does not allow for engaging people in other risk reduction because they get 4 weeks of drug and that's it. Prep done well would likely involve continuing to attend for review and testing in order to get more drug. Crucially with pep it depends on people perceiving what they do as risky for hiv. However people often don't make good judgements about this or don't know about pep. (For example there is some evidence that gay men who repeatedly test negative after unprotected sex revise their perceived risk downwards whereas in fact they are just demonstrating the laws of probability.)

    Coverage and people believing that what they do is risky is therefore crucial to success.

    I recognise that in the real world people look to pharmaceutical interventions as wonderdrugs and there is little drive to ask too many questions as long as someone is making a profit. It's also clear that there is a risk that in resource poor settings prep is a distraction and that gay men who are subject to criminal sanction because of their sexuality are not going to benefit. However prep is very likely to happen and can already be prescribed for those rich enough to pay for it. It is likely happening informally already with people sharing pills. The task is not to argue about whether it should happen but to argue for the best possible, most equitable implementation.

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