Treatment News

Compiled by Gus Cairns

A slippery hope

The search for a microbicide against HIV. Gus Cairns reports.

The last couple of years have seen a series of disappointing results in the search for a new method of preventing HIV infection. While a number of exciting new drugs, including some from totally new classes, were being made available, at the same time there was a series of failures in prevention trials.

The most devastating of these was the closure of the STEP trial of an HIV vaccine – see ‘Two STEPs Back’ in issue 136. This has sent HIV vaccine research back to the drawing board. Some scientists question whether a conventional vaccine against HIV will ever be possible.
There were some other disappointments too. A trial amongst African women called MIRA found that the diaphragm used in contraception did not protect against HIV. And a trial to see if treating people’s herpes infections would also protect them against catching HIV produced negative results.

The only positive results – and they were very positive – lay in three trials of male circumcision. They found men who got circumcised cut their risk of catching HIV by more than half. However circumcision will not protect women directly and it doesn’t protect gay men, so it’s only likely to change the course of the epidemic in the African countries that have large-scale heterosexually-spread epidemics.

There are two other ideas still being tested. One is pre-exposure prophylaxis or PrEP – giving people HIV drugs to stop them catching the virus, rather than to treat it. This is a controversial concept and it’s proved difficult to get trials off the ground. However we now have trials amongst gay men in South America and in heterosexuals in Africa taking place and researchers are hopeful that clear results will be achieved by 2010/11.

However PrEP is not going to be a prevention method everyone will want to use – would you take HIV drugs if you were HIV negative?
The other area of investigation is microbicides. These are HIV-preventative drugs that can be incorporated into gels, lubes, foams, pessaries and so on that can be applied before sex. The analogy often used is a ‘chemical condom’ though microbicide researchers stress that the first microbicides to be licensed probably will not be as effective as condoms and should ideally be used with them.

Microbicides could eventually be sold over the counter and incorporated into standard sex lubes. They’re the first HIV prevention method that would put the power to prevent HIV into the hand of women and passive gay men. And they could even make sex more fun!

Here too, however, we’ve had disappointing results. The first generation of microbicides consisted of cheap, non-HIV-specific chemicals that, it was hoped, would act as physical barriers against the virus. One called PRO2000 is still under trial but several other trials produced negative results. A couple of products actually seemed to make women more vulnerable to HIV – because they irritated the sensitive lining of the vagina in unexpected ways. The largest trial, of a substance called Carraguard, found that the gel was harmless but ineffective.

This is partly because the women in the trial found it hard to use consistently, and if you think about it you can understand why. Imagine you’re a poor woman in a developing country and you’ve agreed to squeeze a gel every day for a year (or every time you think hubby is going to want sex) into your tush, do it despite the disapproval of your conservative mum and your suspicious spouse, report regularly to a clinic for checkups, and answer impertinent questionnaires about your sex life to researchers. Trial volunteers need to be very dedicated, and the microbicide trials may be the most complex ever attempted in the history of medicine.

However – and despite this – microbicide researchers are confident that they will eventually find something that works. Unlike HIV vaccines, microbicides use technologies whose basics are already known. And the second generation will use anti-HIV drugs – some you already know such as tenofovir, some new – which are likely to be much more effective.

Microbicides don’t just need to be designed for vaginas. Gay men and heterosexuals alike have anal sex too, and are likely to use microbicides up the backside as soon as they become available. For all these reasons microbicides need to be tested for rectal safety and there is a parallel scientific programme trying to develop microbicides specifically for anal use.

Basic-science microbicide research is largely centred in the USA, and the large efficacy trials are in developing countries, but one outpost is the laboratory in St George’s Hospital in Tooting in south London, where Professor Robin Shattock leads a team pioneering research into both vaginal and rectal microbicides. Positive Nation interviewed him this spring, just before a major international conference on microbicides took place in Delhi.

Positive Nation: Do you think we’ll ever get a vaccine against HIV?
Robin Shattock: In terms of a conventional injectable vaccine, there’s no current approach that shows enough promise to be realised in a meaningful timescale. But you never know what’s round the corner.
However, that’s not the approach we’re looking at. People get infected with HIV through the mucous membranes of the vagina and rectum. So we’re 18 months into a five year programme looking at whether we can induce and maintain immunity against HIV with a mucosal vaccine - something that will essentially be a very long-lasting microbicide. This will be a gel incorporating proteins from the surface of HIV, which we hope will induce an immune response.

One of the lessons from the STEP trial was that what works in monkeys does not necessarily work in humans, and uniquely we’re taking forward human and animal trials at the same time. We’re hoping the HIV-protein microbicide will induce antibodies that will protect people at the sites of infection. However, we’ve no idea if we can elicit a broad enough immune response yet and we’re probably years away from positive results.

PN: Do you think the current microbicide trials will produce a positive result?
RS: There are still two massive efficacy trials happening in Africa amongst women. However these use large non-HIV-specific molecules – gels developed 10-15 years ago when we knew much less about what might work. We’re all hopeful the trials will show something positive but I don’t personally anticipate they’ll be the final product we want.

PN: Should we have undertaken such big trials if there was so little evidence of efficacy?
RS: They should definitely have tried the concept; there’s always an excuse not to try an idea because we will have something better tomorrow. Part of drug discovery is failure. The difference between these trials and the STEP vaccine trial is that if this particular approach fails, we already have another one ready – microbicides containing antiretroviral drugs. These are as different from the first generation as chalk from cheese. 4

PN: When are we going to start trials of antiretroviral-based microbicides?
RS: A South African trial called CAPRISA, using a gel containing the HIV drug tenofovir, started on 23 May this year and is due to produce results in 2010. However it’s probably not big enough to produce truly conclusive results, and some of us are worried that the dosing regimen – women are told to apply it any time within 12 hours before sex and again within 12 hours afterwards – leaves too long a time window for it to be effective. You really have to use these things pretty close to the time of sex. The really big trials, which use tenofovir and a drug called dapivirine that was never developed as an oral HIV drug, won’t produce results till 2013.

PN: There was a lot of disappointment earlier this year when the biggest trial so far, the Carraguard trial, showed no efficacy.
RS: Yes, but we learned a lot about why. Firstly, as I said, the non-specific gel used may not have been potent enough. Secondly, we learned a huge amount about how difficult it was for women to adhere to using it – and how much they lied about it. Reported microbicide use amongst the women was 94%, but when they actually found a way of directly measuring microbicide use they found that the gel was used on fewer than half the occasions the women had sex.

Thirdly, in nearly all the microbicide trials in poor countries, HIV infection rates have turned out to be much lower than expected in all trial participants, whether they use the active gel or the inactive placebo gel used for comparison. That means you end up not being able to establish a significant difference between the microbicide and the placebo. It happens because when you provide women with condoms and safer sex literature and get them together to talk about sex and men – all of which had to happen if the trial was to be ethical – it empowers them and they start taking fewer risks.

PN: Is that, then, an argument that we should do trials in the developed world amongst people who’ve already taken an active decision not to use condoms?
RS: I have some sympathy with that idea, but it would only work in gay men. Only in Africa do you get high enough infection rates in heterosexuals to test a vaginal microbicide.

PN: Talking about gay men, how are we doing in trying to find a microbicide for anal sex?
RS: We’ve come amazingly far considering how little funding there is in the field – funders don’t like paying for research into anal sex.
In animal studies we produced really promising results showing that a product that wasn’t ideal – it was designed as a vaginal microbicide – stopped more than half of potential infections in a situation where all the monkeys involved should have become infected. I thought it would have no chance of working; we know HIV loves to infect intestinal cells and the gut is a huge area to cover compared with the vagina. Now, I actually believe a rectal microbicide will work, and with enough investment I’m very optimistic we’ll be able to develop an effective one.

The key will be in the funding. We’re halfway through an initial safety trial in humans using a third antiretroviral, a drug never developed for oral use called UC-781. This has produced initial results that look very promising - but that’s using 36 volunteers. We’ll need an exponential increase in funding to do an
efficacy trial.

In the meantime, we may get a positive result from the PrEP trials, and clearly PrEP will have a place in high-risk individuals. But it involves taking doses of drugs that are just as high as those used in HIV treatment and if you’re giving them to HIV negative people you have to set a much higher standard for toxicity and the possibility of developing drug resistance.

PN: If we get a microbicide, will people use it?
RS: That’s the $64,000-dollar question, given that people don’t use condoms. All the evidence we have from focus groups and acceptability studies suggests that women are desperate to have a microbicide. However people are very poor judges of risk, and they may not use one at the right times. I struggle to think that women in Africa are going to walk around with four vaginal microbicide applicators in their handbag. The International Partnership for Microbicides is going to put on a trial of a cervical ring, a sort of diaphragm you could insert once a month that is infused with a microbicide. That might be a better answer, if we can make it work, because it’s not linked to sex.

One really promising thing to come out of such studies is that people like the idea of microbicides – they imagine they might be fun and sexy to use, and when they actually do use them, they enjoy it. In one African study that was stopped, the women wouldn’t give their gel back till the researchers gave them supplies of placebo. We’ll have to develop a lot of different brands and formulations. In one survey of college graduates, the girls wanted a microbicide that smelled of strawberries and the guys wanted one that glowed in the dark!

PN: Why are we doing all this? Why don’t people just use condoms?
RS: Because love is stronger than death, I think.

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