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Be PREPared

Could we use HIV drugs to prevent HIV? With hindsight it seems the most obvious thing in the world, and amazing that it has not been tried before.

I first came across the idea three years ago when talking to a gay medical worker who had access to antiretrovirals.
“ I take a pill before I go to the sauna,” he said. “Sure, I usually use condoms, but if I don’t, I’m still protected.”

The idea is born

At the Retrovirus Conference in Seattle in 2002, local squillionaire Bill Gates of Microsoft was asked by UK’s Dr Mike Youle: “If I’m having sex with my HIV positive boyfriend, wouldn’t it make sense for me to take a drug for HIV?”

Bill was, unusually, nonplussed. “Wouldn’t it be simpler to use condoms?” he replied.

But then the sharp Gates mind recovered and asked which drugs might be suitable. He clearly took away the idea and pondered it, because his Bill and Melinda Gates Foundation then went on to sponsor the world’s first large clinical trial of PREP - of which more below.

The need for new answers

An effective vaccine, everyone acknowledges, is decades away. There are only a handful of countries in the world where conventional prevention programmes have demonstrably reduced the spread of HIV. The UK’s Professor Brian Gazzard has said: “In parts of Africa, the only way to avoid HIV is not to have sex at all.”

Yes, we have Abstention. That may work for a few years only.

Yes, we have Be faithful. But maybe your boyfriend or husband isn’t.

Yes, we have Condoms... But in many parts of the world they are unobtainable, or stigmatised. Men dislike using them and the people who stand to benefit most from them, namely women in poor countries, are least able to insist on their use.

In the developed world, meanwhile, the pioneers of safer sex are turning away from condoms in droves. Forty-five per cent of UK gay men, according to the annual Gay Men’s Sex Survey, had unprotected anal sex last year, and nine per cent of the negative ones had it with someone they knew had HIV.

So we need something we can use to protect ourselves that permits full, squishy, spontaneous sex, and which can ideally be used without a partner knowing.

One such thing would be a microbicide. These barrier chemicals, incorporated into sexual lubricants, could eventually supplement or serve as a second-best to condoms. But putting on large microbicide trials has proved difficult (partly because the drug companies don’t see them as profitable), and they are unlikely to be widely available till at least 2010. Even then they may face social barriers to their use and are thought unlikely ever to prevent more than two-thirds of infections.

But what if the tool to prevent Aids can be held in your hand right now, in the shape of a little blue pill?

More than a mosquito net

illustrationThat would be what is called pre-exposure prophylaxis, chemoprophylaxis, or PREP for short.

“ I first got the idea,” says Mike Youle, “when I read a book called The Seeds of Change. It was about how technological innovations had changed history, and the author, Henry Hobhouse, wrote about how a preventative medicine, quinine, was the only thing that had enabled the white man to conquer Africa.

“ I thought: ‘Aids is disabling native Africans from exploiting their own continent. Why can’t we give them HIV drugs as a preventative too?’

“ Condoms are like a mosquito net: effective, but you can forget to pack them, and they tear. Microbicides are like insect repellent: convenient, but you might not cover every inch and sometimes the mosquitoes bite anyway. But tenofovir would be like quinine.”

What might work?

Tenofovir is the best candidate for PREP we have so far. It goes to work straight away in the body. Resistance to it arises relatively slowly and so far is not that common; only 2.7 per cent of people in its original phase III trial developed resistance within two years. It’s one pill, once a day.

It does have side effects, however. The most serious one is kidney damage. There is evidence of mild kidney problems in about seven per cent of people who take tenofovir as a treatment, but only one per cent stop tenofovir as a result, and serious problems are rare.

You can’t use the regular nucleosides like AZT, ddI and so on, because they require the body’s cellular machinery to ‘switch them on’ before they start working. You can’t use protease inhibitors, because they interfere with the HIV lifecycle too late to prevent HIV inserting itself into your cell’s genes. A fusion inhibitor would be ideal, as it completely blocks HIV getting into cells. But we’ll have to wait till we get one that costs less than £12,000 a year, as T-20 does.

The non-nucleoside (NNRTI) drugs might work but a trial using nevirapine for PREP in 2002 produced a high rate of side effects. Also, HIV easily becomes resistant to both the NNRTIs. PREP could sow the seeds of resistance in a population if it was given to people who unknowingly already had HIV.

How do we know PREP might work?

Logically, any drug that stops viruses reproducing can stop them infecting in the first place. We know this can be done with sexually-transmitted viruses because the drug valaciclovir was recently approved as PREP for people who had partners with herpes, and didn’t want to catch it.

There was a 48 per cent reduction in herpes transmission using valaciclovir. But herpes is a much more contagious virus than HIV, so HIV PREP might work much better. So much so, it could potentially stop infection dead in its tracks.

The only study that suggests tenofovir’s prevention potential was done on monkeys way back in 1995. Scientists working for Gilead, the company that makes tenofovir, then called PMPA, were far-sighted enough to test it as a preventative.

Gilead took 35 longtailed macaques, and during the experiment they injected them with a dose of SIV, the monkey HIV equivalent, sufficiently big to absolutely guarantee infection.
Ten monkeys were given a placebo. Ten were given tenofovir after the injection of SIV. That’s post-exposure prophylaxis.

Fifteen were given tenofovir 24-48 hours before infection. That’s pre-exposure prophylaxis.
No monkey treated with tenofovir caught SIV; there was no evidence of an even temporary infection, no immune response to a virus, no virus hiding in their lymph nodes. In contrast every one of the ten monkeys on placebo got SIV.

The trials about to start

Large-scale trials of PREP are now about to start. In West Africa Family Health International, backed by the Gates Foundation, is giving tenofovir to 1,600 people in Nigeria, Ghana and Cameroon, 1,200 women at three sites and 400 of their male partners at one.

In Cambodia, the University of California Center for Aids Prevention Studies will give tenofovir to 800-900 female sex workers. This may be extended to their clients. In Botswana, the US Centers for Disease Control (CDC) will recruit another 500 young women.

illustrationAnd in San Francisco and Atlanta, the CDC will give it to 400 very high-risk gay men. These are smaller studies, powered only to screen for safety rather than prove efficacy. Marta Ackers of the CDC explains:

"We realised that if  the developing-world studies came out with positive results, there would be a demand from the community and especially the gay community to make PREP available as an option. We are also already aware of the anecdotes of people using it before they go out to the baths.

"We figured that this was our one chance to establish long-term toxicity and safety data. For that reason, the SF and Atlanta trials will last 18 months, not a year like the other ones."

Ward Cates of Family Health International says this about their studies: “We have to know if PREP works. We don’t see it as the answer. Microbicides form part of it too, and indeed tenofovir is one of several HIV drugs also being tested for topical use in a microbicide.
“ We decided on once-daily dosing and if you miss a dose you should still be covered.

“ The sites are all in urban areas where there are documented high-risk activities.

“ PREP is an intervention that will always have to be carefully targeted. Condoms are targeted at single people because we know people in committed relationships tend not to use them. Microbicides could be targeted at serodiscordant couples.”

Kimberly Page-Shafer of the Center for Aids Prevention Studies, currently setting up the Cambodia study now, adds: “Young women, who may be especially vulnerable due to biological and social factors, are a specific group that this type of intervention should be targeted to, if it works.”

But will PREP encourage people to abandon condoms and create a wave of STDs? Tenofovir only works against HIV (and hepatitis B). Shafer’s expectation is that “the impact of regular counselling among our trial participants will result in minimal ‘behavioural disinhibition’.”

Objectors to PREP

Pre-exposure prophylaxis is a controversial subject and not everyone in the HIV prevention world likes the idea. Jim Pickett, former PN columnist and US HIV prevention expert, has reservations: “My concern is what the choice of PREP might mean. What about resistance? Many of our fellow non-Western human beings won’t have access to PREP in their dreams, or won’t have consistent access. In fact, let’s be clear, many of us here in the USA won’t have the dream of access either.

“ What will become of microbicide development and research? Will anyone want to continue putting money into a product that will be cheap and easy to obtain for most of us, when the real money will be pushing another costly pill?”

Cost is a real problem. One UK prevention expert says: “Our main concerns are about resistance, and using up some of the arsenal available for treatment. And cost. Tenofovir costs about £2,460 a year, or £6.78 a day.”

If the WHO’s effort to get three million people on antiretrovirals by 2005 is ambitious, what would it be like giving a daily pill to the world’s sexually active population?

Targeting HIV's targets

But this supposes that costs will not come down still further - and they might, especially if PREP proves really effective. Daily use may not be necessary. PREP could be used in all sorts of ways, from a daily dose to an occasional precaution.

Mike Youle doesn’t buy the reservations. He says: “It is the people who don’t or can’t use condoms and have lots of sex that pass on, and get, most of HIV. The ‘just say no’ message has failed for those people.

“ Yes, we must emphasise that abstention (by definition but not very interestingly) is the gold standard of HIV prevention, condoms the silver, and PREP (and microbicides) currently the bronze. And that PREP with anti HIV drugs won’t stop other STDs.

“ But I’m tired of arguments that PREP will ‘behaviourally disinhibit’ gay men, for instance, and that the way forward is to bolster their self esteem so they can maintain safer sex. People do take drugs, they do get drunk, they do get addictive about sex. Behaviour change can take a lifetime.

“ What I say is, if people use Viagra to have unsafe sex - well, then, let’s co-formulate it with tenofovir, so at least they won’t catch HIV at the same time!

“ My prediction is PREP will work and it will be revolutionary. There were the same arguments about the contraceptive pill in the 60s. They said there were other prevention technologies, and that women wouldn’t use it.

“ Despite documented, sometimes serious side effects, women took to it in their millions and still do.”

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