Much has been going on in the world of HIV, sex and drugs in the last month or so; the US marines recruiting at gay community centers, more mysteriously disappointing study outcomes for PrEP, encouraging news about the effect of microbicide gels against herpes, a new super-easy condom with a brand name that will put off anyone who cares about staying power.

I’ve ignored it all. That’s in part because I’ve discovered a site that really says everything that needs to be said about HIV prevention. Particularly insightful, in this post entitled “usefulness connected realizing hiv indicators”, is this gem:

“For that faculty your body gets very suasible to numerous germ infections and so the indicators are sure not e’er the HIV symptoms. The true unique method to aver that a soul is with HIV is the HIV checking.”

I don’t think I can add to that. Which is my polite way of saying that I’m taking a sabbatical from HIV and epidemiology. I plan to spend the next year or so travelling around Indonesia, eventually writing a book about this wonderful and mad land. Which has it’s own fair share of Bad English, as you can see over at my new blog, Portrait Indonesia.

I’ll be spending a lot of time out of range of wi-fi etc., but will try and post at least weekly. If you’d like to follow my progress, you can sign up here.

For now, on the subject of sex and drugs, it’s over and out. Thanks for taking an interest over the last four years.

Taking anti-HIV pills every day cuts the risk of infection by 63%, said CDC researchers in Botswana. It cuts infection by up to 73%, said University of Washington researchers working in Kenya and Uganda. That’s great news, of course.

Here’s why I’m confused. The larger of these trials was conducted in 4,758 “discordant couples”. [I earlier incorrectly reported that both trials were in discordant couples. The CDC trial in fact recruited 1,200 sexually active uninfected heterosexuals, regardless of their partner status. Full inclusion and exclusion criteria here]. That means researchers in the large discordant couple trial knew that one person was infected and the other uninfected. They chose to give drugs to the uninfected person, to see if it would stop them becoming infected. And it does, in over 60% of cases. But another recent study shows that if we give the drugs to the infected partner, the one who might actually need these same drugs because they have HIV and need it surpressed, it cuts infection by 96%. So in the case of discordant couples, it seems to make much more sense to give the antiretrovirals in question to the infected partner.

That leaves us with the question: who should get PReP? Right now, there are not enough antiretrovirals to go around to treat all the sick people who need treatment. If we’re going to use them selectively for prevention, we should start with the most effective use, which appears to be early treatment of the infected partner in discordant couples. We could also give them to people who aren’t in a couple but who know that they’re likely to get around a bit and might want to stay safe without using condoms. That’s potentially a lot of people; it will stretch our purses. But more than that, it will stretch our political will. Let’s face it, HIV has reached eye-watering levels in many sub-Saharan African countries because both voters and governments have been in deep denial about their own, and their neighbours’, propensity to have sex with someone who is not their single life-time partner. Some people, including influential religious and community leaders, even continue to believe that giving out condoms encourages licentious sex. To them, giving out ARVs will surely mean encouraging licentious unprotected sex (if you’re anti-condom, is that better or worse?).

So who is PReP for? We’ve got a better option for discordant couples. We’re not going to want to give it to randy adolescents. We know it works for gay men, but some of the countries where the trials took place would rather thump or jail gay men than protect their sexual health. We’ve no idea yet if it works for drug users (though a deeply unethical trial by CDC in Thailand will tell us that soon.

Of course PReP will find its niche; when people actually take it it works really well (though not as well as abstinence, when people actually abstain, or condoms, when people actually use condoms). We’ll find out a bit more about just how well at the annual AIDS circus in Rome next week. I’ll look forward to learning what the actual incidence rates in the studies were, and more about sex differentials and adherence. But I think we would be unwise to rush around talking about massive roll-out of PReP before we actually figure out who it works for in the real world.

As an aside, the results have a huge potential impact for Gilead, manufacturer of both Viread (bascially tenofovir, one of the pills that worked in the trial) and Truvada (the tenofovir – emtricitabine combination that was the other). Gilead has come over all generous and has started letting Indian and other developing country companies copy their products. They’ll take a 5% fee; if we really do go for a massive roll-out of PrEP, that will keep drug costs down globally, while giving Gilead extra cash for very little effort. A win-win situation for which they should be congratulated.

A second aside: The CDC trial is confusing in a different way. In December 2009, CDC announced it was terminating the trial of Tenofovir for HIV prevention because they’d had so many drop-outs that the trial would be unlikely to show results even if they doubled the size of it. They kept it going not as an efficacy trial (testing Tenofovir against a placebo) but as a safety and behavioural trial (clocking how good people were at taking their pills, looking for side effects etc.). So it was quite surprising to find them leaping forward with efficacy reults, of which more details here.

Thanks to Eva for pointing out my error.

It’s a huge disappointment to those who were hoping that the pill-a-day-to-avoid-a-pill-a-day solution might drag us out of the despond that we’ve been in as we contemplate 2.7 million new HIV infections this year. That’s the same number as were newly infected when I started in this business 15 years ago. The only real change is in the cost of our failure: that’s increase over 70-fold.

The study, well conducted by my former employers Family Health International in four countries, is at odds with a study released last November, that showed that a daily dose of Truvada, a combination of two antiretorvirals in pill form, cut the risk of infection among gay men by over 40%. The earlier study did show that — surprise surprise — taking pills to prevent HIV doesn’t work unless you actually take your pills. Though virtually everyone said they took their pills, a later analysis of blood samples showed that wasn’t true. We don’t yet have that same analysis for the new trial in women (dubbed FemPrep), so although 95% reported taking their pills, it’s possible that real adherence was much lower. More than possible: likely. All women in the study were taking contraception, but there was a 9% pregnancy rate, apparently much higher in women on the pill than women on injectibles (we don’t yet have the actual numbers). That suggests that some women aren’t all that good at taking one pill a day (I’m one of them; thank God for implants), let alone two.

There’s a real possibility that antiretrovirals taken through the mouth and processed through the digestive tract aren’t as effective at preventing HIV from finding an entry point in the vagina as they are in the rectum, hence the difference between the trials in straight women and gay men. If that’s the case, it ups the ante for putting ARVs directly into your fanny (using fanny in the English sense!). We know from the Caprissa trials that antiretroviral microbicide works vaginally (though not necessarily rectally). But we only know that it works if you “shoot up” both before and after sex; in theory, at least, that is what was being tried. In practice, we know (well, strongly suspect) how unlikely it is that women will actually do that on a long-term basis. We now desperately need trials of a one-shot vaginal microbicide. Because for all the talk of “bio-medical solutions” the confusing results of recent HIV prevention trials remind us that most bio-medical solutions have a very strong behavioural component. Pills that “work” if you take them are no good if they make you feel so sick, so choked, or so fed up that you don’t take them.

One of the things that pleased me greatly about the FemPrep trials was that researchers made sure that the women who volunteered for the research knew about the disappointing results before the press or the scientific community did. There are more details from the study teams about how they interacted with participants on this interesting conference call, arranged by the ever-helpful AVAC network.

This post must end the way these posts seem always to end, with an underlining of the shockingly high rate of new infections in the study overall: five percent of women became infected, despite the fact that they were given female and male condoms, were regularly screened for other sexually transmitted infections and treated as necessary, and counseled up the wazoo. It’s a reminder of how badly suited the tools in our current toolbox are to the job of HIV prevention, and a caution about expecting much more from other behavioural interventions such as the use of pills or gels.

It´s official. Taking antiretroviral drugs when you don´t have HIV cuts the risk that you´ll get infected. It´s exciting news, if not unexpected. But it´s going to be a major headache for politicians.

The results of the iPrEx trial, were published today in the New England Journal of Medicine (with pdf but not the supplementary bits here). The trial was among 2470 gay men and 29 transgendered women in six countries. Everyone took a pill a day; half were randomly assigned to take a combination of tenofovir and emtricitabine (sold by a now very happy Gilead under the brand name Truvada), the other half got a placebo. Neither participants nor researchers knew which was which.

The published headline: people who took Truvada were 44% less likely to contract HIV than people who took the dummy pill — an encouraging result, if not stunning. The real headline: people who actually took Truvada nearly all the time were 73% less likely to get HIV: a huge victory. It´s a smaller protective effect than using a condom all the time, of course. The thing is, we know that people aren´t good at using condoms all the time. And what these study results show us is that people aren´t very good at taking a pill every day, either, though they are keen to tell researchers that they do. One of the most striking things about the results was the mismatch between self-reported pill taking and measured levels of active drugs in people´s bodies.

The researchers cleverly did a study within a study to try and figure out how important it was that people dilligently took their pills. Among people who actually got Truvada, they compared intracellular and plasma drug levels in those who got HIV with a random sample of those on Truvada who didn´t get infected. They found that only 9% of those who got infected had measurable levels of the active drugs in their bodies, compared with 51% of those who didn´t get infected. To put it very bluntly, pre-exposure prophylaxis dosn´t work it you don´t take your pills.

Let´s remember that this was a group of men who were poked, prodded, bled and counselled by study staff every FOUR WEEKS, and they still weren´t taking their pills every day. It´s not all that clear why, though men who got the real drug were more likely than those on the fake pills to report nausea. It´s possible that people were less motivated to take their pills if they weren´t sure that they were actually getting real drugs, or even that if they were, the drugs would actually work as prevention. That may also be why guys in the study didn´t report any rise in risk behaviour (though it´s hard to imagine that they could; 80% of them reported at the start of the study that they´d had unprotected anal sex with someone who might be HIV infected). But it´s a worry; if PrEP goes mainstream for gay men, we´ll need a lot more work on how to get people to take their drugs more diligently.

Another major worry: 10 people who tested negative at the start of the study were actually in the very early stages of HIV infection. Both of the 2 who happened to be assigned to the Truvada group developed resistant forms of the virus, suggesting that giving these drugs in the early stages of infection when the virus is replicating very rapidly may fertilise resistant strains. More shocking to me (though less worrying) was that half of the men who had acute early HIV infection at the start of the study had symptoms of the infection, but none were picked up by the study physicians. This is a pet peeve of mine; bad enough in routine health services but nothing short of a disgrace in a study designed specifically to look at HIV infection in high risk men.

Worries about resistance aside, the news seems pretty good. So why do I say it´s a political nightmare? Because antiretroviral drugs are expensive; a lot of people who need them to prolong their lives can´t get them. Now we´re talking about giving them to gay guys so that they can go out and screw around as much as they like without having to think about using the cheaper and potentially more effective (but generally more bothersome) option of condoms. I´ve been a bit sniffy about this myself in the past, though I did spend about 15 years taking a pill every day so that I could have as much sex as I liked without contracting that long-term, life-changing sexually transmitted condition called pregnancy. But in many countries it is still very hard to give out condoms because it is seen to promote promiscuity. If we could figure out a way to improve adherance, putting ARVs on the public tab will probably save money overall. It´s certainly something we should be trying out in all sorts of different ways. That includes the possibility of “disco dosing” — taking pills only on the days when one has a pretty good idea that one´s going to end up barebacking. But as condoms have taught us, the fact that things work technically doesn´t necessarily mean they work in real life, let alone in politics. Even if we can find a better way to deliver pre exposure prophylaxis (implants? it´s what I do instead of pills these days against that other STD, and I love it) I think it is going to be a hard sell in many countries.

For more, see Roger Tatoud´s reflections on the wisdom of taking a pill every day to avoid taking a pill every day.

Still, for now the news is good. Click on the image at the top of this post, add your own positive Truvada story, and get 5 free mp3 downloads. I think it´s worth celebrating a bit while we can.

The question was raised for me while I am here in Thailand by a comment on an earlier post. It pointed out that US taxpayers, through CDC, are funding a trial among drug injectors in Thailand that withholds the very thing we know will prevent most infections: sterile needles.

CDC, on its website, points out that withholding clean needles is “consistent with Thai government policy”. And yet the agency itself recognises that needle distribution programmes reduce HIV infections. The Helsinki declaration on medical research ethics says that if you’re trying out a new drug or procedure, you’ve got to try it against the best available alternative.
In the past, I’ve argued that it is reasonable for us to read that as “the best alternative feasibly available in the country where the study is being done”. There’s no point trying a drug designed for use in a developing country against a developed-country regimen which is likely to be better, but which couldn’t ever be offered in the study country because it requires too much money, technology or expertise to administer.

The “we’re using the Thai standard of care” argument is very convenient for CDC researchers. After all, they need quite a few people to get infected, so that they can see if significantly fewer people get infected if they’re using the trial drug, tenofivir.* CDC’s other tenofivir trial, among women in Botswana, has just been downgraded, because the research team has realised that it is not getting enough infections in either group for it to be able to measure a difference. That’s in part because of very high drop-out rates — already a red flag for a prevention method that obliges you to take a pill a day for as long as you’re at risk.

We know that an adequate supply of sterile needles, and the freedom to use them without fear of arrest, can cut HIV infections dramatically among injectors. If the CDC study in Thailand gave enough needles to injectors, they probably wouldn’t have enough infections to give them a trial result. And the tenofovir-based prevention method that’s being tried is a method that could be used by other groups too — gay men and sex workers and other heteros at high risk of exposure, for whom we don’t have such easy prevention options. So you can understand why researchers are reluctant to push the envelope on providing decent prevention to study participants. But in this case, the “local standard of care” argument really doesn’t wash. It would be perfectly feasible for Thailand to provide injectors with clean needles. The country has the technology, the money and the health systems to do that. The only block is a political one. It’s bad enough that Thai authorities live with this blind spot in their otherswise quite pragmatic HIV prevention programme. The US has been just as bad at home, although there’s now light at the end of the tunnel for safe injecting programmes in the US. All the more reason that US researchers (and taxpayers) should refuse to compound Thailand’s unethical policy with unethical research.

*Info on the trials: The Thai and Botswana trials aim to investigate whether uninfected people can take a daily dose of antiretroviral drugs to stop themselves getting infected with HIV if they are exposed to the virus through sex or needle-sharing with infected people. It’s know as Pre Exposure Prophylaxis or PrEP, and you can find our a lot more about it here.

The product in question is Pro2000 gel, and the results of the first large trial on more than 3,000 women were reported yesterday at the Conference on Retroviruses and Opportunistic Infections. CROI is all a scientific conference should be (and all the biannual AIDS Circus is not), and you can see and hear every presentation online. The results of the Pro2000 study show that women using the gel were 30% less likely to become infected with HIV than women using a placebo, and a third less likely than women using nothing at all. The reason the researchers are not screaming about it more joyfully is that the results are “not statistically significant”. Meaning, in this particular case, that we can only be between 90 and 94% sure that the difference in infection rates were really the results of the gel, and not the results of pure chance.

This is just silly. If I told you that there was a 94% chance that the red car was a third more likely to crash than the blue car, which would you drive? Yet we’ve managed to establish a norm in the scientific community that only differences that have a 95% probability of not being due to chance can be trusted. For nerds, that means a “p value” of five percent or less is sacrosanct: (p <0.05) has become a talisman of good science. I’m not the first to remark that things can be significant without being statistically significant — economist Tim Hartford wrote a column on statistical significance and Guinness in the FT only last week.

Someone at the conference remarked that “none of us in this audience worship at the alter of the p value of point oh five” but in fact, many of us do. Another thing that researchers at CROI have been bending over backwards to do is to prove that people on ARVs don’t have more risky sex than people not on ARVs. (Aside: this completely misses the point about “behavioural disinhibition” — jargon for “Oh look! HIV won’t kill me! Let’s party!”. What matters is not so much what infected people do once they are on meds, what matters is what uninfected people do because they no longer see any visible connection between unprotected sex and death. Still, people feel the need to show that ARVs don’t make you screw more.) So when a group working in Uganda showed that people on ARVs were 70% more likely to have an extramarital partner than people not on ARVs, they were happy to worship at the alter of the p value of point oh five. In this case, the p value was 0.09 — in other words there was a greater than 90% chance that the differences were real, but researchers were able to say there were “no differences”. We worship from the underside of the alter, too. A larger study looking at ARVs, risky sex and HIV transmission found that unprotected sex was “significantly lower” in those on ARVs. In fact, 17% of those on ARVs reported unprotected sex compared with 19% of those not on ARVs. The difference may have been statistically significant, yes, but does it meet the most important test of significance, the “So What?” test? Almost certainly not.

Epi-rant over. The microbicide trial (and the fact that there is very low transmission from people on antiretrovirals to their partners in the two ARV studies I’ve just ranted about) wasn’t the only good news at CROI today. Giving monkeys antiretrovirals before exposing them to SHIV rectally worked pretty well, too, which bodes well for PrEP in humans. Disappointingly, though, it worked best when the drugs were given between a week and a day before exposure — ARVs taken just a couple of hours before exposure didn’t have much effect. Bang goes my dream of earning millions with an Ecstasy/ Viagra/ Tenofovir combination pill for big nights out. Maybe I’ll just have to settle down and get a real job.

Thanks to Roger for prodding me to spend my day at a virtual conference…

Now we know. “The £15 pill to protect against HIV” was the headline in Metro, the Daily Mail’s give-away version. More muted than I would expect, but Metro is really the Mail Lite. The article, bylined Jo Steele, does indeed seem to have been stolen wholesale from a much more rigorous piece in the New Scientist, headlined Safer Sex in a Pill.

Missing from the headline is a question mark. While the New Scientist piece does point out that we’re not sure that PrEP works, the Metro piece glosses over the uncertainty, saying (wrongly) that Viread and Truvada “have proven successful in human trials involving 19,000 gay men”. Anthony Fauci is quoted as saying “There’s a lot of buzz about PrEP. There’s some cautious optimism this will work”. I see a lot of optimism, not much of it cautious. My favourite example of the glass being half full comes from Bob Grant, from UCSF. He doesn’t think that people who take a pill so that they can have more unprotected sex will actually have more unprotected sex.

“Bob Grant, who researches HIV prevention at the University of California, San Francisco, and helped run the African trial, speculates that some users may even have less unsafe sex. “PrEP might put people in a different frame of mind,” he says. “When people take a pill a day, that reminds them that they are at risk of catching HIV.”

Hmmm. I took pills every day for about two decades so that I could have unprotected sex without catching pregnancy, and I never once thought: ah yes, I took a pill this morning to help avoid pregnancy, and sex can lead to pregnancy so I’d better not have sex.

I’m all for increasing HIV prevention options, especially ones that have been proven to work (if only in some circumstances, some of the time). But I do think we also have to recognise that what works for an individual may not work so well at a population level — we’ve seen this with the roll-out of ARV among gay men in rich countries. Individually, infectivity goes down, but at the population level, new cases are rising. Look out for a paper and commentary along these lines in The Lancet next week. A number of authors from the WHO will argue that testing all adults annually and putting everyone infected on ARVs would essentially wipe out HIV transmission within 10 years. In a commentary, some other authors from the WHO conclude that it would be a good idea, but might be hard to do in practice.

The truth is that what works in a clinical trial (or even on the much thinner ice of a mathematical model) can not always be made to work in practice. There will be a lot of resistance to PrEP at first, not least from the people who already object to giving out condoms. It’s no bad thing to start thinking now about how to deal with that resistance. (IRMA draws our attention to a Congressional briefing on PrEP on December 4th.) But let’s not get too far ahead of ourselves. There’s no point cashing in political capital in favour of PrEP until we’re sure it works.

1) IF a person takes their meds religiously
2) AND IF they are under medical observation
3) AND IF that observation shows their viral load has been undetectable (fewer than 40 viral copies per ml of blood) for six months continuously
4) AND IF they don’t have another sexually transmitted infection
THEN there’s no risk that they will pass on HIV in sex.

You can find the full paper in French here, and an unofficial English translation here. The key references: Quinn et al 2000, Castilla et al 2005, Melo et al 2006, Barreiro et al 2006.

Needless to say, there has been a lot of comment about this here, for example, and here, and here. For my money, the most sensible comment comes from Rex Wockner who points out, quite correctly, that the Swiss usually do their homework pretty thoroughly. So they’re probably right, but should that make anyone throw out the condoms with an untested partner? Of course not. Unless you have some preternatural way of telling that all the IFs are in order. Which none of us do.

The reaction from WHO and UNAIDS is predictably mealy-mouthed. They can’t quite bring themselves to say that the Swiss are right, any more than they can bring themselves to say that the risk of HIV transmission in oral sex for anyone who doesn’t have suppurating mouth wounds is basically zero. The fear is that people might interpret the Swiss statement to mean: if you’re on treatment, you’re not infectious. In other words. they’ll forget about the other IFs. It’s a patronising view: people cannot be trusted to digest the information and make informed choices. As in: “This guy tells me he’s on treatment and he’s good about taking his meds, but then I told him I was on the pill, so…. ”

We’ve been caught out by this many times before. Pretend everything is equally risky, and people will go ahead do dumb things across the board. Let people know exactly what the risks are, and they’ll often choose their dumb things more carefully. If we know that an infected person with good adherence to drugs and excellent medical care can have sex without condoms without endangering their partner, shouldn’t we tell them that? As the Swiss paper says: let the HIV negative partner decide if they want to use extra protection.

It is perhaps worth stressing, though, that all the data they reviewed came from studies in heterosexuals. One exception was a paper from San Fransisco suggesting that HIV incidence was falling among gay men since the initiation of treatment.(Porco st al, 2004) which has sadly since been overtaken by events. In other words, we can’t be quite so sure that a viral load of below 40 copies/ml protects against transmission in anal sex, let alone in injecting, both of which are more efficient than vaginal sex.

There’s something else in the Swiss paper that people haven’t been twittering about, but that I think is really interesting. More here.

Do we really think that HIV negative people will be sufficiently motivated? These brave and honest scientists don’t mention pre-exposure prophylaxis, but their stand on treatment for those already infected would seem to call into question whether it makes sense to give drugs to healthy people.

These results, published in the wonderful, open access Public Library of Science, will encourage those who think we can shut down HIV by doling out drugs to uninfected people before they get exposed to the virus — pre-exposure prophylaxis, or PrEP in the industry jargon. This stratgey is currently being tried in four countries, and you can find out a lot more about it on the very informative Prepwatch site.

A number of mathematical models have shown that this strategy is a good idea from the point of view of public health authorities and taxpayers. The most recent of these, which makes good bedtime reading for higher-order modelling nerds, concludes with this very important sentence: “PrEP can be a cost effective intervention given high efficacy, good adherence and long-term use, especially if sexual disinhibition is prevented.” Which is rather like saying that Elizabeth Pisani can make a fortune as a model, given her height, long blonde hair and great tits, especially if she wears short skirts. The tragedy is that the first three are not given, and the third is so unlikely that you can pretty much discount it. A lot of the reason people don’t use the (cheaper, safer) prevention options already available to them, things like condoms, is not because they can’t (pace Time and others who endlessly reheat the “women are innocent victims” line.) A lot of the people who don’t use condoms don’t use them because they don’t like them, because they are too lazy, or because they are in denial about being at risk. (My husband? He goes to church, he wouldn’t sleep around!). Do we really believe uninfected people are going to do better with toxic drugs than they do with latex?

I confess that I am a bit old-fashioned about spending tax money on expensive, toxic pharmaceuticals to give to people so they can go out and do stupid things for fun. And if I feel that way about it (I who am perfectly happy spend tax money on clean needles and methadone for drug injectors, on free condoms and STI treatment for anyone that needs them), I’ve got a pretty good guess how it will play with the rest of the electorate.