Today the leaders of the PROUD study of daily oral TDF/FTC (brand-name Truvada) for PrEP among gay men and other MSM in the UK announced that the trial protocol would change due to early evidence of effectiveness. The study’s official statement said, in part, “Interim analysis of the PROUD study data has shown that pre-exposure prophylaxis is highly protective against HIV for gay men and other men who have sex with men (MSM) at high risk of infection. On this basis, the PROUD Steering Committee has announced that participants currently on the deferred arm of the study, who have not yet started PrEP, will be offered the opportunity to begin PrEP ahead of schedule.”

The specific data on rates of HIV infections, PrEP adherence and risk behaviors that guided this decision were not made available. However, based on what has been released, it is clear that this is welcome news that confirms, once again, that this PrEP strategy works when it is taken correctly and consistently. It is also clear that rates of HIV infections among PROUD participants were higher than the study had originally anticipated. The number the team had anticipated at this stage in the trial would not have been sufficient to generate a conclusion about effectiveness. The study is thus also a grave reminder that comprehensive health care, including HIV prevention and treatment still isn’t reaching all gay men and transwomen who need it.

PROUD’s original design called for a two-phase investigation: A 500-person pilot study, scaling up to a 5000-person trial. In the pilot, which launched in 2012, half the participants were randomly assigned to receive daily oral PrEP immediately, along with a comprehensive prevention package including access to post-exposure prophylaxis (PEP). The other half were assigned to a deferred arm that would receive the comprehensive prevention package for 12 months and then be offered the opportunity to initiate the PrEP strategy. This two-arm design also would have been used in the expanded, second phase of the study.

This announcement came after a scheduled review of the data by the trial’s independent review body (the Independent Data Monitoring Committee, or IDMC). As a next step, the PROUD team has developed and submitted a protocol amendment that would allow all of the participants, including those in the deferred arm, to receive PrEP. They have also begun the process of calling participants back to inform them about the trial data. Right now, the UK National Health Service does not cover TDF/FTC for PrEP. Once the protocol amendment is approved, all PROUD participants will have access to PrEP. Additional steps, including analysis of all the data, will lead to NHS consideration of PrEP as public health tool.

One key question is: What does the development with PROUD mean for IPERGAY, a study of an intermittent PrEP strategy using TDF/FTC (that is also enrolling gay men and other MSM? IPERGAY is placebo-controlled, meaning that participants do not know whether they are receiving the active drug or an inactive pill. IPERGAY has been under some degree of scrutiny for its placebo-controlled design since it launched after the iPrEx trial which found efficacy among gay men, MSM and transgender women with once-daily dosing. The trial team has defended the design, in part by pointing out that IPERGAY was testing a different dosing strategy. With additional evidence of efficacy from PROUD, this placebo-controlled design needs to be re-examined once again. IPERGAY investigators have indicated that the PROUD and IPERGAY DSMBs will be communicating in the near future to share information and generate a recommendation for the IPERGAY protocol.

AVAC will be following developments and providing updates as more information becomes available, please watch the blog and also check out our resources on avac.org/prep and prepwatch.org. We congratulate the PROUD team and recognize with gratitude the commitment and contributions of all of the trial participants.

PxROAR member Nicholas Feustel spoke about PrEP to the German magazine Männer. What follows is a translation into English Nicholas did for us. The original article, in German, is available here.

PrEP (pre-exposure prophylaxis) is all the rage in the HIV prevention field, especially since the WHO reviewed the strategy positively. It‘s a heated debate: Do we still need to wear condoms to prevent HIV infection? Are HIV-negative people going to ‘prep‘, i.e. taking the HIV drug Truvada, the only one of which we know for sure that it can prevent HIV transmission? To help answer some of these questions, we spoke with Hamburg resident Nicholas Feustel, who advocates for PrEP.

Nicholas, you work with “AVAC – Global Advocacy for HIV Prevention”. What do they do and why are you with them?

AVAC is an organization headquartered in the USA, which advocates for biomedical HIV prevention. Much of their work is introducing new prevention options in addition to condoms. I personally would like to advocate for the destigmatization of PrEP and people who would like to take PrEP here in Germany, even before PrEP becomes available here.

Is AVAC associated with the pharmaceutical industry?

No, not at all.

Who should be taking PrEP in your opinion? Many read the World Health Organization recommendations and thought, “just because I’m gay, it doesn‘t mean that I have to take medication”.

Yes, the WHO statement was misinterpreted by very many people. The WHO is not saying that all gay men are to take PrEP, but that all gays should consider it. The WHO recommendations act also as political statements rather than individual instructions. In this case, the WHO wants to push PrEP as an option, now that we know that it works.

However, who should be taking PrEP?

The main target group are people who do not or do not always use condoms during sex. It is for those who find that condoms are not an appropriate way to protect against HIV for them. With PrEP, they could still make the decision to protect themselves from HIV. There just are many who do not get along with condoms. Be it because they lose their erection when putting on the condom or they want to be close to their partner without a latex barrier. And we know that many of the new infections occur in supposedly monogamous relationships. Or, for example for women, if it is not possible for them to get their partners to use condoms, PrEP could provide suitable protective ability. Ultimately, I do not care why people don‘t use condoms, I do not want to judge their behaviour morally. Some just don‘t, period.

But haven‘t we got used to condoms more or less? Why change our strategy now?

No one is to change their strategy. If condoms work for you, absolutely continue to use them! But consider this: When HIV and AIDS emerged, condoms were the only way to have safer sex. As a result, we got drummed for 30 years that only gays who have sex with condoms are good gays. And sex without a condom is evil, evil, evil. Imagine we already had a PrEP drug when HIV and AIDS emerged. Would people have chosen to use condoms or take a pill once a day? I think people who do not or do not always use condoms are not “hedonistic bareback sluts”. Condoms are simply not the appropriate means to protect themselves from HIV. PrEP could be an alternative for them.

Condoms also protect against other sexually transmitted infections (STIs).

Yes, but not fully. Many STIs are transmitted during oral sex. If someone who doesn‘t use condoms, but takes PrEP to protect themselves from HIV, that‘s already quite something! And also, for a new PrEP prescription you have to go to see your doctor every three months, where they will test not just for HIV but other STIs as well. With PrEP, people engaging in high-risk behavior would go to see a doctor regularly and other STIs would be detected and treated early. This might even reduce the spread of other STIs.

The drug used for PrEP, Truvada, does have side effects, right?

Commonly seen side effects of Truvada are short term gastrointestinal problems which usually disappear after a few weeks, and not everyone will experience these. Long-term side effects may include impairment of renal function and bone density. Again, not everyone will experience these. The good thing is, if you take Truvada as PrEP you can stop taking it any time.If, however, someone has been infected with HIV, they will be on treatment for the rest of their lives. When arguing against PrEP because of side effects, one must always consider PrEP and HIV therapy are two different things. PrEP with Truvada consists of two active ingredients, normal antiretroviral therapies have three active ingredients, so there is the possibility of more side effects. And in HIV therapy there is also HIV in the body—this is also a health aspect.

But we still don’t know the long-term effects of PrEP and what risk there might be.

Of course we do not know what long-term effects PrEP may have. But Truvada has been used for 10 years in HIV therapy and is considered one of the best tolerated HIV drugs. And as the activist Peter Wiesner once said: Do we know the side effect of long-term, 20 years condom use? What does it do to our psyche? Instead of being able to have truly uninhibited sex – and I think there is nothing wrong with this desire – there is this constant fear of HIV, always the bad conscience, if you didn’t use a condom.

I think these considerations are, however, irrelevant, because we do know not everyone uses condoms all the time. We have not reached these people despite 30 years of prevention messaging around “fucking with condoms”. We could tell them for another 30 years, they just won‘t. Wouldn’t it be better to offer an alternative?

Why do we only hear of Truvada? Are there no other drugs available as PrEP?

Truvada is the only one we know from studies that, when taken daily, has a really high level of protection against HIV, higher than condoms. Currently there are also so-called long-lasting injectables in development. Then PrEP could perhaps mean just a once per month injection, or every three months, and you would be protected against HIV. However, it will probably take another 10 years until that is available.

For Truvada manufacturer, Gilead, PrEP must be a gold mine.

-ish! The patent for Truvada expires in 2017, then there could be generics, that is, exactly the same active ingredients, but from another manufacturer and cheaper. This means the prices will go down then. The PrEP market is not really exciting for Gilead, because it‘s not like millions of people will take PrEP. It will be only a small group of people who find that PrEP is the better method of protection for them. Do you think PrEP will play a role in Europe? I hope so! We have to admit: we are moving towards a post-condom era.

For those who want to use them, that’s perfectly fine, but there are also many men who simply can not be bothered to continue to use them after more then 20 or 30 years of condom use. Or young people who just haven‘t experienced all the dying. They say: Sure, we know the films of yesteryear, but now those taking drugs do well. And that is also what we want to achieve with the whole anti-stigma work: Nowadays you can live a normal life with HIV. Nevertheless, I find it is worth still trying to protect yourself from HIV. Science has moved on, and we know that those drugs that let people with HIV live long and healthy lives, and under successful therapy renders them virtually uninfectious, can also protect HIV-negative people from acquiring HIV.

Data presented today at the International AIDS Conference in Melbourne and published simultaneously in the Lancet provides the first clear evidence for who wants PrEP—and how they use it outside of the United States.

While PrEP demand and demonstration projects have gathered steady momentum in the United States, the pace has been far slower in other parts of the world—including countries where some of the original trials happened. In the absence of evidence that people want and will use PrEP, there’s been plenty of debate about the viability of this strategy, particular in low- and middle-income settings.

The new data from the iPrEX Open Label Extension study (iPrEX OLE) are a welcome antidote to this skepticism. The study was open to iPrEx participants who remained HIV negative at the end of the blinded, randomized trial, as well as HIV-negative participants from two smaller safety studies. Participants were offered the chance to take daily oral tenofovir-based PrEP. Participants could also decline and remain enrolled, receiving the same counseling and care. The participants were gay men and other men who have sex with men and transgender women from Latin America, the US and South Africa. For much of the study, participants attended clinic visits every two months—less frequently than the monthly visits that were standard in the efficacy trials to date, including iPrEx.

There is much to learn from these data, and AVAC will be working with partners in the coming weeks to discuss the implications and findings in greater detail. For now, here are some key findings:

• Uptake of PrEP was higher among OLE participants than it has been in the general population of gay men, MSM and transgender women. This suggests that when people are informed—as these former trial participants were—of efficacy and safety of daily oral PrEP, they are more likely to use it. There’s a lot of work to be done to build awareness and demand in many countries—especially since the argument that “there’s low demand, so why roll it out?” is being used to justify a slow pace of oral PrEP roll out in many settings where it could reduce infections.

• PrEP works if you take it. This isn’t news but the study confirms it. In OLE, as with every other efficacy trial, people who had detectable drug in their blood—indicating that they had taken one or more PrEP doses—had less risk of HIV than those who did not. As with the original adherence/efficacy data, OLE calculated the risk at a given study visit, rather than in individuals over time. For example, the study is able to draw conclusions about the probability that someone with drug level “x” in their blood at a given study visit would test HIV positive at that visit. Higher drug levels means more protection. OLE also analyzed levels of protection based on levels corresponding to more-or-less daily dosing, compared with more infrequent dosing. Not surprisingly, more frequent dosing led to more protection. But even infrequent dosing reduced risk compared to people who weren’t taking PrEP at all. Overall, PrEP use was associated with a 50 percent reduction in risk of HIV compared to people in OLE who weren’t taking PrEP—and to HIV rates in participants in previous trials.

• People at higher risk of HIV were more likely to choose to take PrEP and more likely to take PrEP consistently over time. The study authors write, “Such preferential use of PrEP during times of greater risk is expected to increase the effect and cost effectiveness of PrEP services, and shows people’s capacity to recognize and respond appropriately to risks when given attractive options.” We couldn’t say it any better.

• Blood levels of tenofovir diphosphate (the active form of tenofovir-based PrEP) weren’t as high in transgender women, so protection also wasn’t as high. There is an urgent need to gather more data on how PrEP is used in transgender women, how tenofovir-based drugs interact with exogenous hormones, and how this strategy can be adapted for use by a population with soaring rates of HIV infection.

These are some basic top-line messages. Please subscribe to our Advocates’ Network and visit prepwatch.org for more in-depth information and analysis in the weeks to come.