Pre-exposure prophylaxis (PrEP) was approved in the US in July 2012, following trials showing its efficacy in preventing sexual transmission of HIV. But, as Gus Cairns finds out, it remains a controversial addition to the HIV prevention options available to gay men in the US.

Last World AIDS Day, 1 December 2012, Online Buddies (OLB) Inc. (the company behind Manhunt.net, one of the most popular gay online dating sites in the US, and its affiliated health education site Manhunt Cares) sent out a bulk email to its members informing them of its World AIDS Day campaign to increase awareness of pre-exposure prophylaxis – PrEP.

The US Food and Drug Administration (FDA) approved tenofovir plus emtricitabine (Truvada), the two-drug pill used in the trials, for use as PrEP, in July last year.

The European Medicines Agency (EMA) is still considering approval. Throughout Europe, centrally funded health systems are likely to demand more rigorous guidelines on targeting and budgeting before authorising PrEP.

In practice, uptake rates in the US have been low and not many HIV-negative men are aware of this new HIV prevention option. In conjunction with Fenway Health, the LGBT sexual health centre in Boston, and the Harvard School of Medicine, Online Buddies researched Manhunt’s users and found that even after the iPrEX study results1 were announced, only one in five of its users were at all aware of PrEP and only 1% had ever used it, though when given a description of it, nearly 80% said they potentially might.2

For those depressed by ongoing high HIV incidence rates amongst gay men and impressed by the PrEP trial results, a campaign to alert the community to the possibility of this new HIV prevention method was needed.

“One of our guiding principles is to fill critical gaps in health promotion campaigns,” says David S Novak, Online Buddies’ senior health strategist. “Normally, we spotlight a variety of different issues, but this year PrEP was the obvious thing.”

A mailshot and its response

Manhunt Cares compiled a page containing articles and videos about PrEP and sent out a bulk email containing the page’s weblink to all its subscribers headlined “HIV Prevention Pill for Negative Men: a choice when condoms are in the way or not enough?”

They received a huge response to their mailshot. Initially, Novak says, the response was positive. But as the mailing was picked up on by gay blogs such as Towleroad and Joe.My.God, it attracted a variety of hostile comments.

A lot of the hostile commentary was directed at the idea of condoms being “in the way” of good sex, so Manhunt Cares revised their tagline to “HIV Prevention Pill for Negative Men: Another choice for staying HIV free?” and sent out a new message saying that “It is our hope that by changing the tagline, we can refocus the attention from this campaign where it belongs — on the information that Manhunt members need to make informed decisions about their own sexual health.”

PrEP has been controversial ever since activist protests led to the closure of the first trial in humans in Cambodia nine years ago.

Joe.My.God commented: “The use of Truvada as an HIV preventative has somewhat fractured the HIV/AIDS advocacy movement.” The treatment-provision and advocacy organisation, the AIDS Healthcare Foundation, campaigned vocally against PrEP around the time the FDA was considering approval.

“The most serious accusation was that we were promoting a drug,” says Novak; Manhunt was accused of running a campaign funded by Gilead, the manufacturers of Truvada. This was not the case; the only time Online Buddies has received funding from Gilead was in 2009, to assess PrEP awareness before and after the release of the iPrEx data.

Novak adds: “In my opinion it’s a pity that, because the politics of it get in the way, Gilead aren’t putting money into promoting PrEP. That’s why we felt we had to do it.”

One could dismiss the blog discussants as axe-grinders, but comments in blogs can also be the sound of an interested community making sense of an unfamiliar new idea. A review of the comments in the blogs isolates the principal concerns.

‘Safer sex means condoms; pro-PrEP means anti-condoms.’

This was a frequent concern, the most emotive issue, and the one seized upon first in most blogs. For some people, condoms were the core of safer sex. Not using them was always ‘barebacking’ and therefore dangerous, and PrEP would subvert them:

If you want to bareback you have a death wish.

Condoms are never in the way. That should be the philosophy, and the driving force behind all HIV prevention efforts.

Others liked one part of Manhunt’s message but not the other:

If they had stopped with “When condoms are not enough”, then that would have been OK. But “in the way” just encourages people to think, “Hey, if I find condoms inconvenient, I’ll just take this pill…” This leads down the wrong path.

Others had more nuanced responses:

PrEP is a great option for some guys who are in a risky phase of their lives (we’ve all been there) or who suspect their partner is cheating.

This is for the ‘high risk’ people. The ones who say: “I know I’ll make mistakes so this is my insurance”. I don’t agree with it but they should at least have that option.

Aren’t arguments against [PrEP] akin to opposing handing out condoms to teens on the premise that it will cause them to have sex?

Finally, a couple of contributors actively disliked condoms and were quite upfront about not using them:

Let’s be honest here, guys – condoms ruin sex. They destroy any illusion of spontaneity. You get aroused…but you have to stop and slip on a piece of latex, which is not always easy to do. [This contributor was comprehensively ‘flamed’ by others]

Condoms suck and most men agree, period.

The second contributor didn’t get ‘flamed’, probably because he quoted research3 (cited in HTU 212, see The gay globe), part of the US Men’s National Sex Survey4 showing that 55.0% of gay men didn’t use a condom last time they had anal sex.

The finding that ‘use a condom every time’ is minority behaviour in gay men is duplicated in other surveys.

Bob Grant, principal investigator of iPrEX, comments that just because people don’t use condoms, it doesn’t mean they’re being irresponsible. He cites evidence showing that many gay men are trying to reduce their HIV risk in other ways. These include withdrawing before ejaculation, seropositioning (being ‘top’ if you’re negative and ‘bottom’ if you’re positive because HIV is ten times less likely to be transmitted that way), and serosorting – restricting (unprotected) sex to same-status partners.

“People do want to be regarded as full members of society, and they do want to be responsible”, says Grant. “But serosorting is responsible too, and so is looking for PrEP. It’s proactively trying to manage your sexual health.”

‘Offering PrEP will mean people stop using condoms.’

In fact, the evidence from the randomised controlled trials of PrEP shows the opposite: condom use went up and sexual risks went down in both the iPrEx and the Partners PREP studies.

Anyone enrolled in these studies had free condom provision and a large amount of support about sexual health, so they may not be a good guide to how people taking PrEP will change their behaviour in the real world. Ken Mayer is the medical research director of Fenway Health. He says that “Condoms simply aren’t being used as much as they once were, and people are more able to say so. We still have men coming along to our clinic saying ‘I had a slip-up’” [a euphemism, implying it was accidental] but “We’re not talking about providing PrEP for people who have no difficulty using condoms. But if someone comes to us and says ‘You know, I really have a problem with them,’ then we’ll talk about alternatives, including PrEP. Even if people decide in the end it’s not for them, offering it as an option is valuable. We are telling them ‘HIV is not inevitable’.”

In the end, we simply don’t know whether the existence of PrEP will mean more or less condom use in the real world. One of the pieces of research directed at finding out is happening in the UK: the PROUD study, an open-label study of immediate versus delayed PrEP, which started recruiting in December (see www.proud.mrc.ac.uk for details).

‘Won’t people get more STIs?’

This is a concern for anyone contemplating the provision of PrEP. A blog comment put it this way:

What about STDs? The days when one shot of penicillin treated just about everything are gone. STDs are resisting medications. Herpes is not the only luggage you may be carrying around for life.

Certainly PrEP will not prevent other sexually transmitted infections (STIs) and recently we have seen reports of strains of gonorrhoea that are resistant to every antibiotic used against it.5 David Novak, however, sees an opportunity in PrEP to reduce the overall burden of STIs in gay men.

Because of the possibility of developing resistance, the FDA mandated that PrEP should never be provided for more than 90 days and that people receiving it be tested for HIV every time, before receiving a new prescription.

“This means they’ll be turning up at their doctor’s office every three months,” says Novak, “and this means they can be screened for gonorrhoea, syphilis and other STIs at the same time” – although STI screening isn’t mandatory to receive a prescription for PrEP.

‘People won’t take it, so it won’t work.’

People’s ability to adhere to PrEP has been the factor most crucial to is effectiveness. In the iPrEx study the overall effectiveness of Truvada PrEP was only 42% – but this was largely because only 50% of trial participants actually took the drug. In those with levels of drug in their body equivalent to taking it four or more days a week, it was 96% effective – and there were no infections at all in people who took it every single day.

David Novak makes a distinction some people have found confusing.

“It’s not true to sit down in front of a patient interested in PrEP and say ‘This will prevent four-in-ten HIV infections’ because with an individual patient, you have to use the per-protocol result: PrEP efficacy in people who took PrEP as prescribed. If you do that, its efficacy is 99%.”

On the other hand, he acknowledges, it’s important to use the ‘intent-to-treat’ result of 42% – the efficacy seen in every single person who was offered PrEP, regardless of whether they took it – when you are forecasting its likely effectiveness on a population, and therefore its cost.

One blog commenter put it this way:

It seems to me that the ones who are at high risk a lot are the ones least likely to keep up a daily regimen.

It depends if people are just risky people or have a specific problem with condoms. In addition, people with HIV have a huge incentive to take treatment, but will the incentive of avoiding HIV be strong enough to get people taking a dose every day?

One answer may be to take it only in advance of sex, but that can’t mean immediately in advance. Drug level studies show that drug concentration builds up slowly in tissues, suggesting one or two doses well in advance of sex, and probably a post-sex dose too. The one completed study of intermittent three-dose PrEP, in African gay men and female sex workers, showed that while most took the first pre-sex dose, only just over half took the second dose and only a quarter the post-sex dose.6

‘What about the side-effects?’

Some commentators were concerned about the side-effects of PrEP:

Even if toxicity is experienced by only 2% of those who take it, that’s still a lot of HIV-negative people needlessly harming their own bodies because they don’t want to use a condom.

Others thought they would be less of a problem than for those on treatment:

I don’t understand all the pearl-clutching about long-term side-effects. It’s not like PrEP is a lifelong med. Take it for a few months or a year or two, during periods of high risk.

While emtricitabine (3TC) seems to have little toxicity, in a minority of people tenofovir has been associated with significant losses in bone mineral density (BMD) and decreased kidney function. In the general HIV-positive population, however, the link between long-term kidney problems and tenofovir is not clear.7

BMD in participants in the iPrEx trial8 and in a smaller safety trial of tenofovir-only PrEP in America9 was slightly lower in people taking tenofovir than people taking placebo, but the long-term implications of this are unknown. Regular monitoring of kidney function and BMD are required by the FDA as part of their approval of PrEP.

The short-term side-effects of the first few weeks may be of more relevance. In iPrEx, twice as many people on Truvada experienced nausea, almost all of it in the first month, than people on placebo.10 Although this was only 2% of those taking the drug, it may understate the low-grade side-effects felt by many people who start ARVs – which, in HIV-negative people, may be sufficient to make them stop.

‘It’s too expensive.’

This is a big issue. If more than the current handful of people start taking PrEP in the US, it will become very costly. A year’s worth of Truvada, taken with even moderate adherence, would cost at least $4000 in the US, and about £2000 in the UK.

One recent study11 using the effectiveness level seen in iPrEx found that if you gave 20% of US gay men PrEP, it would cut HIV incidence by 13% over the next 20 years, but would cost $172,000 per life-year free of HIV. However, if you only gave PrEP to the men with over five partners a year it would cost $50,000 per life-year, which is within the US threshold for cost-effectiveness. The cost of doing this, however, would be $3.75 billion or 17.5% of the entire US domestic HIV budget per year.

The picture changes considerably if you reduce the price of Truvada. Another cost-effectiveness study used figures from Peru, the country with the biggest number of iPrEx participants. There tenofovir plus emtricitabine only cost $600 a year. The study found that if PrEP was highly targeted in Peru, the cost per life-year free of HIV would be no more than $500, at an annual cost of $24m to $152m depending on coverage.

The lesson is clear: if PrEP starts being used by more people, then it will put a strain on health systems. But this may increase the ability to negotiate price reductions, and here community pressure may be key.

‘No-one will come forward for it.’

In the end, PrEP will only work in the gay community if HIV-negative men who may prefer not to think at all about HIV are prepared to come forward and take a pill that they thought only ‘poz’ guys needed to take. One of the most hostile bloggers saw PrEP this way:

PrEP is an attempt to make the other person [i.e. the HIV-negative person] solely responsible for their health. Well, that other person may be young, may not know the facts, may have been to some deep-South school, so I think the HIV-positive person does have a responsibility to tell them and not lie.

In other words, ‘You have the virus; it’s your duty to protect me’ – an attitude fully endorsed by the criminal law in a lot of countries and US states.

Even if people are at high risk of HIV, they may not see themselves that way.

Among the successful scientific trials of PrEP was one failure – the FEM-PrEP trial. This took place in young women in South Africa, and the efficacy of Truvada PrEP was zero. The researchers found that although background HIV incidence in the group of women was 5% a year, 70% thought they were “not at high risk of HIV”. Stigma and lack of information or understanding may prevent people at high risk from coming forward for PrEP.

Conclusion – a hard sell

Meanwhile, in the US, the UK and other countries, HIV prevalence in gay men is still increasing. We need more than the same old safer sex messages. In PrEP, we have something that could virtually eliminate the chance of someone getting HIV if they took it faithfully.

But giving people medicines to prevent disease has always been a hot political issue in the media, even after science shows it works.

“PrEP is a hard sell. It will take time, and it may never be taken by a large number of HIV-negative people,” says Novak. “But it may get us thinking in a new way about how we as gay men reconcile our need for intimacy with our safety.”

This article was first published by NAM/Aidsmap.com and is republished with permission.

References

Grant RM et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. New Engl Jour Med 363(27):2587-2599, 2010.

Krakower DS et al. Limited awareness and low immediate uptake of pre-exposure prophylaxis among men who have sex with men using an internet social networking site. PLoS One 7(3), March 2012. See http://bit.ly/VbBE72 for online article.

Rosenberger JG et al. Condom use during most recent anal intercourse event among a U.S. sample of men who have sex with men. J Sex Med 9(4):1037-4, 2012.

See www.mensnationalsexstudy.com

Bolan GA et al. The Emerging Threat of Untreatable Gonococcal Infection. NEJM 366:485-487, 2012.

Mutua G et al. Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers. PLoS One doi:10.1371/journal.pone.0033103, April 2012. See http://bit.ly/VOKw0X for full-text article.

Scherzer R et al. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS, 26(7):867-75, 2012. (See http://1.usa.gov/13M7Qiz for the free abstract.)

Mulligan K et al. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the global iPrEx study. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 94LB, 2011.

Liu A et al. BMD loss in HIV– men participating in a TDF PrEP clinical trial in San Francisco. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 93, 2011.

Grant, op.cit.

Juusola JL et al. The cost-effectiveness of preexposure prophylaxis for HIV prevention in the United States in men who have sex with men. Ann Intern Med 156:541-550, 2012.