The Wisdom of Whores

Not wanting to be always the purveyor of bad news, I was looking forward to today’s results from the Pro2000 microbicide studies. After hopeful results in an earlier trial, I’d convinced myself the gel would prevent HIV. But it doesn’t.

It’s very depressing news from a huge, well designed and well managed study of over 9,000 women across four countries. I’m fond of saying that if you torture the statistics enough they will confess to anything (as we saw in the recent vaccine trial in northern Thailand.) But however badly you twist the arms of this study, they’re not going to scream success. For the record:

* If you exclude the women who got pregnant or stayed in the trial more than the planned period of one year, there were 130 new infections among those who used the microbicide gel, and 123 in those who used the identical-feeling placebo. Calculated as new infections per 100 woman-years of exposure, that’s 4.5 for the gel and 4.3 for the placebo, making the microbicide 5% more risky. The statisticians are 95% sure that the true effect of the microbicide is somewhere between decreasing risk by18 % or increasing it by 34 %. In other words, we can’t make any claims at all that the product works.

* If you don’t exclude people who got pregnant and look at everyone in the trial for as long as they were enrolled, you get 145 new infections with the microbicide versus 143 without: 4.6 new infections per 100 years of exposure in both. No difference. None. The true effect using this analysis is somewhere between reducing the risk of HIV infection by 21% and increasing it by 26%.

* The researchers also looked at whether women who used the gel consistently were less likely to get infected than those who didn’t. They weren’t.

It is hard to measure consistent use of microbicides in these studies, but researchers compared three sources of information: what all participants reported during study visits, whether all participants brought back used applicators, and what a sub-sample of women recorded in their detailed sex diaries. All point in the same direction: around 90% of women used the gel most of the time. That in itself might be counted a triumph compared to some earlier studies. It means that if we could find something that actually works, women would be quite likely to want to use it. All eyes will now be on the CAPRISA study which is testing a vaginal gel that has antiretorvirals embedded in it.

For my own part, I’m feeling somewhat sheepish as well as disappointed. When the results of an earlier, smaller trial of Pro2000 microbicide showed that it reduced infection by 30%, I was dismissive, bordering on rude, about the tyranny of the statisticians who said the results were “not significant”, and that we needed more research before acting.

I remain impatient with scientists who want to delay any action until we have perfect data. In the field of public health we are often obliged to do the best we can with what we have; as long as policy-makers are prepared to change their approach as the data improve we can save valuable time and lives. But in this case, the caution was well placed. Mea culpa.

Once again, it is worth drawing attention to the most basic fact in this research: 30 years into the epidemic, in a population that had safe sex counselling up the wazoo as well as universal access to condoms and other services such as STI treatment, more than four in 100 women are still getting infected with HIV. Pro2000 may not work, but just urging people to use condoms doesn’t, either. We need to keep looking for something that does.

Finally, some common sense in HIV testing policy in the US. Although you’d be hard pressed to know it from some of the coverage.

Until last Monday, America’s unfathomably illogical health service for the properly poor, Medicaid, refused to pay for HIV testing just as it refuses to pay for all sorts of other screening measures that could allow conditions to be treated early or in some cases prevented enitirely. Now, Medicaid has finally agreed to test its clients for HIV, if they fall into certain categories.

Here’s where the bad reporting comes in. This, for example, from The Goverment Monitor, which reports public sector news:

“The Centers for Medicare & Medicaid Services (CMS) today announced its final decision to cover Human Immunodeficiency Virus (HIV) infection screening for Medicare beneficiaries who are at increased risk for the infection, including women who are pregnant and Medicare beneficiaries of any age who voluntarily request the service.”

So, the two groups that they single out as being “at increased risk” for HIV are pregnant women, and people asking for a test. In fact, of people who have recently had unprotected sex in the United States, pregnant women are among the least likely to be infected with HIV.

The actual decision reads as follows:

CMS will cover both standard and U.S. Food and Drug Administration (FDA)-approved HIV rapid screening tests for:

1. Annual voluntary HIV screening of Medicare beneficiaries at increased risk for HIV infection per USPSTF guidelines:

* Men who have had sex with men after 1975;
* Men and women having unprotected sex with multiple [more than one] partners;
* Past or present injection drug users;
* Men and women who exchange sex for money or drugs, or have sex partners who do;
* Individuals whose past or present sex partners were HIV-infected, bisexual or injection drug users;
* Persons being treated for sexually transmitted diseases;
* Persons with a history of blood transfusion between 1978 and 1985;
* Persons who request an HIV test despite reporting no individual risk factors, since this group is likely to include individuals not willing to disclose high-risk behaviors; and

2. Voluntary HIV screening of pregnant Medicare beneficiaries when the diagnosis of pregnancy is known, during the third trimester, and at labor.

In other words, perfectly sensibly, pregnant women are NOT classified as at high risk for HIV infection, but are offered tests in any case since services to prevent transmission to their babies are available if need be. Now look at the list of those who ARE considered at higher risk. Again, it is mostly perfectly sensible. I’d prefer to see some sort of time stamp on number two — the overwhelming majority of Americans have had more than one partner in their lives, and most will probably have had unprotected sex with at least two of them. But that really doesn’t put them into a “high risk” category unless they are having sex with those multiple partners during overlapping time periods. Because HIV isn’t highly infectious for very long, you’d really like something more precise, such as “unprotected sex with multiple partners in any given three month period”. The biggest group at higher risk missing from the list is “men who have been incarcerated”. I agree that it is not the incarceration but the behaviours while incarcerated that put people at risk for HIV, and those behaviours are covered elsewhere on the list. But many people zone out what happens in jail — they are unlikely to report having sex with other men if it is something that they only do when they are banged up, for example. And yet we know many people in jail are infected with HIV, and we also know that many of them are having anal sex and shooting up drugs, and therefore likely to pass the virus on to other prisoners.

Another piece of good sense: the decision specifically authorises rapid tests. We know that people are far more likely to get their results and to be tied in to the support and care services they may need if they are offered on-the-spot tests, rather than having to come back or call in for results a week later. It would be nice if other countries (with generally better records on preventative medicine) followed this lead. Any Canadians reading this…?

At breakfast in Bangalore this morning, I was greeted by news of Bollywood’s first on-screen gay kiss. When they’re puckerd up like this, wouldn’t you want to? But the Indian censors may not share my enthusiasm. I am Omar will be screening at the Rotterdam film festival. Check it out and see if the kiss is in.

What’s unsustainable about paying fo sex? I guess it depends on what your budget is, and how randy you are. As Copenhagen turns its thoughts green, its mayor Ritt Bjerregaard sent postcards to Copenhagen hotels urging climate conference delegates to: ‘Be sustainable – don’t buy sex’. In response, the city’s sex workers are offering free rides to any delegate who can produce one of the offending cards, according to Speigel.

Unsustainable? Well, there’s latex to dispose of, or worse still, population growth. But on the upside sex warms you up without needing to burn fossil fuels. It’s a renewable resource. And if it’s on offer for free this week in Copenhagen, it might just provide the positive energy to break some of the log-jams in the negotiations.

I’ve followed the build-up to the conference (beautifully dissected by Sam Kinght, writing in Prospect), with some amusement. Way back when I was writing The Wisdom of Whores, a friend from the World Bank was rolling his eyes at every UN agency’s willingness to hook itself to the HIV wagon. I quoted him thus:

““The UN institutions are professional beggars, and beggars go where the money is,” he said. “So you get “culture and AIDS”, “kids and AIDS”, “fish and AIDS”. I’m just waiting for “climate change and AIDS”.”

It wasn’t until months later that I saw the first headlines linking HIV to climate change. Just recently, there’s been a UNFPA report about it, which means it’s now official. As Rasna Warahp pointed out in Kenya’s The Nation, the real link between HIV and global warming will probably be that as more funding goes to the latter less will go to the former.

An aside, since I’m mentioning both development fashion and the World Bank: I am reliably informed that that venerable institution last week headed off a bid to have every loan reviewed for the effect that it has on trafficking of persons (which in the current climate is more or less equated with trafficking of women into the sex indutry). Just sometimes, common sense does prevail.

Thanks to Ron of greencollar for sharing the determination of the Danish with me.

So another World AIDS Day (and this blog’s second birthday) has come and gone. We learned that 2.7 million mothers, lovers, children, school teachers, preachers, husbands and friends became infected with a rather fragile and still potentially fatal virus last year. Each of those prevention failures cost taxpayers about US$ 3,000. Since we’ve known how to prevent HIV for nearly three decades, that’s pretty pathetic. What we need is radical new approaches, and I’m pleased to suggest one.

Pictured above is the miraculous Ceragem massage bed. Promoters of a clinic in South Africa claim that the bed cures AIDS. That’s great news, of course. But why stop there? A truly visionary charlatan would see much greater possibilities. We know that post-exposure prophylaxis works — that taking antiretrovirals very soon after exposure can prevent HIV taking hold in the body. The big HIV news of 2010 is likely to be that pre-exposure prophylaxis works too — we can prevent HIV taking hold by taking antiretorvirals shortly before we do something dumb like have sex without a condom with someone who’s likely to be infected. What’s the obvious gap? Since most HIV infections are contracted in bed, we could run this miracle bed-cure into pending exposure prophylaxis: let’s prevent HIV taking hold at the very moment that people are swapping infected body fluids. Just have sex in one of our massage beds and you’ll never need to think about latex again. I’m looking forward to hearing from the venture capitalists among you…

Thanks to Babe for pointing me in the direction of this great business opportunity.

Epidemiologists don’t often hit the headlines. While forensic scientists are celebrated in endless mini-series, the bug hunters merit just the occasional, mercifully long forgotten film (anyone remember Dustin Hoffman in Outbreak? I thought not). As a job, it’s just not very sexy, and most of us who plod away at it keep our wild sides to ourselves. How delightful, then, to discover that Belle de Jour, a sex icon for our times, is actually a practicing researcher with a PhD in epidemiology.

Needless to say there’s been a big kerfuffle about this. The “all prostitution is explotation crowd” are banging the drum again, anxious to entrench the image of the sex tade as nothing but tawdry. But as Catherine Stephens of the International Union of Sex Workers eloquently points out in this segment on Channel 4 News, those sterotypes are unhelpful.

(For those who are confused by Cath saying she doesn’t think practicing hookers should go public, it’s amazing how Channel 4’s hair and makeup team can nerd a girl down.)

The University of Bristol, where Brooke Magnanti PhD works, has very sensibly said that the way she chose to finance her studies does not have any bearing on the quality of her work. The university doesn’t mention that there are many other similarities between being a hooker and a research scientist. We all provide the services that the people who put down the cash demand, whether they are punters or science funding bodies.

I’ve always been curious to know what a random investigator would make of my in-box. Lots of people find theirs clogged with offers of penis extensions and tireless nights of love; I have the added joy of getting soft-peddalled syphilis diagnostic kits. I also get alerted when medical journals publish papers on a variety of sexual practices. I’ve never thought to restrict the papers to “Humans only” (an option in PubMed). And so it is that I can belatedly bring you the oral sex lives of fruit bats.

The paper, in the (wonderful, open access Public Library of Science), even includes a little cartoon video. Bat porn. In essence, scientists in China have found that a female fruit bat will go down on her partner while he’s taking her from behind. Apparently, the extra stimulation helps him keep it up longer (not a universal observation among females of our species, I venture to guess). The researchers come up with a number of reasons why a lady bat might go to this trouble, among them that it might give his sperm more oomph, might make him less likely to roam, might clean up nasty infections before he passes them to her. But I particularly like their closing shot:

“The behaviour presumably favours the donor, although it may also benefit both partners especially if fertilization success is increased. It is conceivable that the female manipulates the male by increasing sexual stimulation, so that she ultimately benefits.”

I think that’s known as the Pleasure Principle.

Thanks to Klaus for stimulating me to post on this.

As promised, a note on the UK’s latest data on HIV among drug injectors. Some of the US’s battalions of Drug Warriors have been crowing that the new figures show a rise in infection rates among junkies in the UK: clear evidence that the nation’s policy of making sterile needles and injecting equipment available to people who need them doesn’t work.

Unlike the United States, the UK has bothered to track HIV infection among large, representative samples of drug injectors (both current injectors and those in methadone and other treatment programmes) since close to the start of the epidemic. Part of this effort involved testing anonymous samples of left over blood for HIV — the samples were usually taken from treatment or diagnostic purposes and are stripped of all but the most basic demographic and risk information (age, sex, length of time injecting, recent needle sharing) before being tested with HIV. The results, shown separately for London and the rest of England and Wales are shown below.

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Yes, prevalence for the whole of England and Wales (including London — Scotland has its own system and reports separately) has risen by over 77% in the last decade. But still, fewer than one injector in 60 is infected with HIV. If you draw the graph using a normal percentage scale, you’ll see something close to the true level of infection — still too high, of course, but not exactly an overwhelming prevention failure when compared with data from any city or country that doesn’t have needle exchanges. The graph compares what happened in the UK with what happened in Jakarta, just because I happened to have the Indonesian data handy. But it would look just the same with data from Bangkok or Moscow or even New York in the years before the city (with no help from the federal government) began to hand out needles.

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Since I’m just a numbers nerd and obviously don’t have a great visual imagination, perhaps someone could help me out here: how can you conclude from these pictures that safe injecting programmes fail to prevent HIV?

Yesterday the US finally dropped its absolutely senseless law forbidding people with HIV from visiting the Land of the Free. (While Saint Obama is getting patted on the back for ending the ban, he was actually signing off on something that George Bush put in motion last year). That’s unmitigated good news for people with HIV, their lovers, friends and families, as well as for a lot of US employers who can’t import some of the best and the brightest simply because they have a not-very infectious virus that can only be transmitted in a tiny number of well-known ways which we can protect against with safe, cheap technologies.

Does this signal a new wave of common sense in HIV prevention in the United States? That’s certainly what we expected when Obama was elected. During his campaign, for example, he recognised that sterile needle programmes cut HIV infection among injectors, saving lives and money, and pledged to end a ban on funding those programmes from federal coffers. So cities such as his home town of Chicago, pictured in the map below, will now be able to use central money to provide clean needles to the inner city injectors that need them most. As long as they set up in one of the grey spaces. In the cemetary, in other words.

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On this fantastic map, which comes from Yale University’s Dr. Russell Barbour by way of Stop the Drug War, the red areas are the parts of town where it would be illegal to operate a federally funded needle exchange under new rules proposed by Congress. The Drug War Chronicle provides an interesting history of the needle exchange shenannigans. Essentially, Obama did not remove the ban from a budget bill because he thinks policy shouldn’t be made through sub-clauses in budget bills. Democrats on the committee discussing the bill disagreed, and dropped the ban. Then Republicans, not willing to give up the idea that the availability of clean needles would have us all racing to start shooting up smack, decided to protect the innocent by forbidding needle programmes within 1,000 feet of “a public or private day care centre, elementary school, vocational school, secondary school, college, junior college, or university, or any public swimming pool, park, playground, video arcade, or youth centre, or an event sponsored by any such entity”. That’s the red bits on the map of Chicago above. Here’s Dr, Barbour’s map of needle exchange exclusion zones in San Francisco:

This is clearly just a way of pulling the rug from under any effort to increase access to clean needles. We’ve come to expect this kind of implaccable opposition from conservative Drug Warriors in the United States. We used to expect the Brits to be more rational about their drug policy, and the UK has, thank God, held on to its policy of providing clean fits for anyone that needs them. But with the sacking of the government’s independent advisor on drugs David Nutt for repeating his independent advice after the government chose to ignore it, I’m not so sure.

I’m not even going to wade in here about whether or not idependent scientific advisers to government should shut up after their advice is ignored, but I will commend to you a wonderful paper by Dr Nutt on the dangers of Equasy, (pdf) an irrational addiction to horse riding. This has been seized on by many who have not read it as an example of his inappropriate analyses. Irony, where art thou?

The US Drug Warriors also joyously seized on the latest round of anonymous surveillance of HIV among drug injectors in Britain, sending out an e-mail crowing about rising rates of HIV and drawing a link between that and the fact that the UK was the first country in the world to have national injection safety programmes. My next post will put those rather one-eyed claims into perspective.

A month ago, the media got very excited about an HIV vaccine. Study results, released in Thailand with a maximum of fuss and a minimum of detail, showed that the two-step vaccine might protect about a third of the people who get the shots against HIV. Then the doom-mongers weighed in: without more information, we might be overestimating the effects of the jabs. So, is the syringe half full or half empty?

Now more details have been released, we’re still looking at half a glass. Hurrah! said some reports. The vaccine really is protective. Boo hoo, said others. Unless you torture the statistics, they don’t confess to much of an impact. I finally got around to combing through the full report of the trial in the New England Journal of Medicine. Both the optimists and the pessimists are right. It really depends on what your hopes and expectations were. If you are a basic scientist (as most of the people involved in the study were) you’d be pretty thrilled by the results, because they show that vaccines might one day work. If you are a public health boffin such as myself, you’d be pretty disappointed, because the study suggests that that this vaccine doesn’t work for the people who really need it — a point much underplayed in the official reports.

In their full paper the research team reported three sets of results for this study among young men and women in Northern Thailand; only the most optimistic of these was reported to the press in the initial release of results a month ago. Keith Alcorn of Aidsmap has produced a typically sound and balanced summary of the paper if you want more details. But here’s my more opinionated take.

Analysis 1: Real World.
This is technically known as an “intention to treat analysis”. The final analysis includes everyone who was enrolled in the study, regardless of whether or not they followed all the procedures correctly. This is the analysis which is most interesting to public health boffins, because it comes closest to showing how things might happen in the messy reality of life, where people forget to show up for appointments, get given the wrong dose by mistake, etc. In this analysis, people in the vaccinated group were 26.4% less likely than those in the unvaccinated group to get infected with HIV. There was a 92% probability that this difference was not due simply to chance; that means that the difference would not be considered “significant” by those who cleave to the mystical figure of 95% to dictate what is or is not worth considering. Taking into account random differences between the people assigned to the vaccine and the placebo groups, the researchers were 95% sure that the real effect of the vaccine did something between making you 48 percent less likely to contract HIV, and making you four percent more likely to get infected.

Analysis 2: Ideal World.
Known as the “per protocol analysis”, this looks only at the people who got all their shots on time, in the right doses. This is more or less the human equivalent of doing things in lab conditions, and is the sort of analysis that is most useful for basic scientists. Only three quarters of all the study subjects qualified. That in itself is worrying to people like me; if we can’t deliver four doses of vaccine to a quarter of the participants in an incredibly well-organised, well-funded study with hugely well-motivated study staff, how the hell are we going to do it in the real world? More worrying to the basic scientists, I would have thought, is the fact that in this sub-population of people who did everything exactly comme il faut, the vaccine did not have a more pronounced effect (26.2%, with an 16% chance that the effect was due to chance). Because numbers were smaller there was an even wider range that might have reflected the “true” outcome, from increasing infections by 13.3 percent to cutting them by 51.9 percent.

Analysis 3: Tidied-up World
Not a common convention, the “modified intention to treat analysis” essentially reflected the real world with the messiest bits knocked off. In this analysis, the researchers included everyone in the study, except the seven people who it turned out were already infected before their first jab. These people were missed in the initial screening test because they were still in the “window period” during which a person has the virus, but not yet the antibodies which cause a test to show up positive. They were discovered because they had turned positive by their last jab; the team then went back and used a (much more expensive) test for the virus itself on the original screening sample and found that they had already been infected. From a basic science point of view, it makes perfect sense to excluse these people from the analysis; obviously, a vaccine can’t protect people who are already infected. From a public health point of view, it’s debatable whether we should tidy up the data like this. If we put huge national vaccine programmes in place, we’re going to be vaccinating people who are in the window period, especially in the early years, and in groups at highest risk. I’d say we want to take that into account when estimating the potential effect of a vaccine. it was this “tidy” analysis that hit the headlines a month ago, and gave the study its only “significant” result — a 31.2% reduction in HIV infection, with a 96% probability that the effect was not a statistical fluke. This time, we could be 95% sure that the vaccine didn’t make things worse, that it reduced infection by at least 1.1%, and perhaps by as much as 51.2%.

As a public health nerd, I’m most interested in the Real World Analysis. But I’m even more interested in something that’s buried down at the bottom of Table 2.

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Here, the research team looks at the effect of the vaccine on people with different levels of risk behaviour. In a shockingly poor piece of paper writing/ editing, it is not actually possible to tell from the Methods section of this paper how the different levels of risk are defined. But the definition for high risk does seem to include at least some of the usual suspects: needle sharing during drug injection, same sex partners for men, commercial sex etc. And what Table 2 shows is that the vaccine makes no difference at all for those at highest risk. It might cut infection rates by nearly half in that group, or it might increase the chance of getting HIV by nearly three quarters. The best-guess estimate is that it cuts infection rates by under 4% among the people who are most likely to be exposed to the virus. Four percent is as good (or bad) as nothing.

The researchers point out that the study was not designed to look at these differences, but call the results “intriguing”. To an immunologist, they must be. Perhaps the immunity conferred by the vaccine is not strong enough to withstand the repeated assaults suffered by someone who shares needles daily or turns tricks three times a week — I have no idea. But to public health workers, it is not intriguing, it is devastating. If a vaccine doesn’t work for the people who need it most, what’s the point? It depends on costs, of course. But would we really develop something that we could give to people who have a very low probability of exposure, while leaving those who are likely to be at risk for HIV unprotected?

It’s a false dichotomy, of course. This trial is a triumph for basic science, because it gives us something positive to work with. It is very far from being a triumph for public health, and it is not helpful that in the early rush of euphoria it was presented as such. I’d even be wary of the language used by the authors of the NEJM paper: in their headline result, they reported quite wrongly that the study showed that “there was a trend toward the prevention of HIV-1 infection among the vaccine recipients”. A trend is something that develops over time. If anything, the data suggest that the effect of the vaccine was weakened over time, so the trend was away from protection, not towards it. But I’m splitting hairs. With vaccines, the basic science has to be right before we even think about the public health questions. This study will send the immunologists back to the drawing board. They need to figure out how we have a possibly succesful vaccine that makes no difference to viral loads in those who do get infected. They need to understand why people who are most exposed to HIV are least likely to be protected. They need to parse out the mechanism by which these two sets of shots, each of which has failed on its own, might be working together. If (and it is still only an if) they can do all of that, then develop something that really does work, the public health nerds can start worrying about how to deliver it, and to whom.