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.

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…