A Pill to Prevent HIV? What the New iPrEx Results Mean for Women


“Pill May Prevent HIV” — it’s an attention-getting headline. On November 23, the announced results of a clinical trial conducted in Peru, Ecuador, Brazil, the United States, South Africa and Thailand showed that taking an antiretroviral drug (in the class of those used to treat HIV/AIDS) may help prevent an HIV-negative person from becoming infected if exposed to HIV. The study, called iPrEX (Iniciativa Prophylaxis in Spanish or the Pre-exposure Prophylaxis Initiative in English) showed that, overall, those taking the medication were 44 percent less likely to become infected than participants using the placebo pills. Researchers also reported that the study participants who took the drug strictly according to schedule and did not miss doses were 73 percent less likely to become infected. 

Pre-exposure Prophylaxis (PrEP) refers to the practice of using medicine to prevent yourself from getting a disease or condition before you are exposed (pre-exposure) to the thing that can cause it. You take malaria medication, for example, before traveling to areas where you may be bitten by mosquitoes that carry malaria. Having the medicine already in your system greatly reduces your chances of getting malaria if you are bitten. Some people who are severely allergic to cats may take an allergy medication before visiting a friend who has cats – another form of PrEP.  In this case, the iPrEx trial showed that HIV-negative people can reduce their risk of acquiring HIV by taking an antiretroviral pill every day.  Obviously, this strategy is nowhere nearly as effective as using condoms or having sex only with people who are HIV negative.  But it may be a good prevention tool for people who are at high risk of HIV because they do not or cannot use those risk reduction strategies.

Started in June 2007, the iPrEx study ended in 2009 after enrolling 2,499 HIV-negative gay men, male-to-female transgendered women, and other men who have sex with men (MSM).  It was conducted at 11 sites in six countries: two sites in Lima, Peru, one site in Iquitos, Peru, one site in Guayaquil, Ecuador, one site in Boston and one site in San Francisco in the United States, one site in Cape Town, South Africa, two sites in Rio de Janeiro and one site in Sao Paulo, Brazil and one site in Chiang Mai, Thailand. These locations were selected because the prevalence of HIV infection among the men and transgender women having sex with men there is extraordinarily high, between 10 and 28 percent. The iPrEx study was funded by the US National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation.  The medication tested in the study was donated by their manufacturer, Gilead Sciences. 

Proof that PrEP works – that there is, literally, a pill can help to prevent HIV — is an extraordinary breakthrough, as was the news received last summer that an effective vaginal microbicide had been identified.  But what does a study focused on people engaging in rectal-penile sex have to do with women and their reproductive health?  There are many ways to answer that question — some of them cause for celebration and some reasons for real concern. Consider the following:

1.  What do the iPrEx results mean for women? 

It’s great to know that PrEP may be an effective HIV prevention tool that women could use on their own, without a partner’s cooperation. Taken orally, the drug goes into the bloodstream and could help protect women who are having vaginal sex, anal sex or are exposed to HIV through other means. They may actually be of particular interest to women who have anal sex because many report that it is easier to insist on condom use during vaginal sex, where they can make the pregnancy prevention argument, than it is during anal sex.  This puts them at serious risk because, although estimates vary, unprotected receptive anal intercourse with an infected partner is probably five to twenty times more likely to transmit HIV than receptive vaginal sex.

Between 10 percent and 35 percent of heterosexual women in the US and UK acknowledge practicing receptive anal intercourse.  Among American men, 40 percent report having engaged in anal intercourse with a woman at some point in their lived. 

Clearly, we can’t assume that the PrEP medications tested in iPrEx will have the same effect in women’s bodies as they did in the bodies of the male and transgender study participants.  Additional PrEP trials are already underway, including a study enrolling heterosexual men and women in Botswana and the UK, one enrolling just heterosexual women in seven African countries, and one enrolling serodiscordant couples (couples with one HIV-positive and one HIV-negative member) in Kenya and Uganda.  Studies enrolling injection drug users and adolescents of all genders are also occurring. Expected to produce results in 2011-2013, these studies will tell us more about the gender-based differences (if any) in how the drugs tested in iPrEx work. But the iPrEx results are certainly cause for optimism that PrEP may provide women with another HIV prevention tool in the near future.

2.   Who will get these PrEP medications now?

Truvada® (a combination of Tenofovir Disoproxil Fumarate or TDF and Emtricitabine) is the medication tested in the iPrEx trial.   In the short term, this drug will only be legally available to iPrEx study participants, who will be offered the option to volunteer for the follow-up “open label” study. This standard procedure recognizes the ethical responsibility to allow those who took on the burden of study participation to be the first to benefit from the study results and it allows investigators to gather more information about use of the medication..    

The unusual aspect of this process, however, is that Truvada® is already on the market and regularly prescribed to treat people living with HIV.  Typically, it takes three to five years to get a new drug into consumers’ hands after it is proven to be effective. It has to be reviewed and approved by government regulators, manufacturing of it has to be scaled up, a supply chain has to be created to get it from factory to stores, etc. Truvada® is now only approved as a treatment for HIV and will have to go through a separate regulatory approval to be marketed for HIV prevention once  at least one other study confirms its efficacy at an acceptable rate.  Nevertheless, some consumers can already access it for prevention from private health care providers. Physicians in the U.S. and some other countries can, at their discretion, prescribe drugs for purposes other those for which they have been approved (a practice usually known as “off-label” use). Thus, these drugs are already available as prevention tools to those able to pay for them privately.

The third option — and one of which women’s health advocates need to be particularly mindful – is that the “pill may prevent HIV’ headlines could escalate the informal (or black market) sale of Truvada®.  Envision the following:  On one hand we have people who read the headlines and want to take a pill to protect themselves rather than having to use condoms. But they either don’t want to go to a doctor or can’t find one willing to prescribe these drugs for HIV prevention. 

On the other hand, we have people living with HIV who are being prescribed Truvada®. How do HIV-positive individuals who are poor choose between maintaining the treatment regimen they need to stay healthy and selling their pills at a high price on the street?  This may be particularly problematic for indigent women living with HIV who are trying to make ends meet for their families. What about the woman who brings the pills home only to have her partner or someone else take them away from her to use himself for prevention or to sell on the street?  This threat of mis-appropriation is one of the major differences between PrEP and microbicides. Men are foreseeably much less likely to grab up a woman’s microbicidal gel (once we have one) because they will not see it as something that other men want or that they can use, themselves.

Informal marketing and non-prescription use of PrEP drugs may also have serious public health implications. To get these pills prescribed for prevention, consumers will have to take an HIV test before each refill to ensure that they are still HIV negative. If you use PrEP when you are already HIV-positive, you may develop drug resistant virus.  You could pass this resistant strain on to other people and having it is likely to make it harder to treat your HIV infection on an on-going basis. Experts warn that epidemiological “train wrecks” could occur if access to these drugs used for both prevention and treatment is not well controlled.

Very little drug resistant virus was detected among participants in the iPrEx study because they received HIV tests monthly and stopped using the Truvada® immediately if they tested positive.  In real world use, people obtaining Truvada® without a prescription will likely not be tested regularly.  The longer they, unknowingly, continue to take the drug after acquiring HIV, the higher the chance that they may develop drug resistant virus.

Uncontrolled access could result in a rise in the prevalence and transmission of virus that is resistant to these drugs, resulting in reduced utility of first-line treatment regimens involving Viread® (an antiretroviral drug containing TDF) and Truvada® and a subsequent rise in the death rate. Someone using black market Truvada® occasionally (rather than daily) or those who sometimes buy counterfeit versions of Truvada® that contain no active drug may be particularly susceptible to developing resistant virus if they become HIV positive, are not tested, and continue to take non-prescription PrEP drugs. At the very least, we have to anticipate that increased levels of drug resistance would increase the cost of treating HIV because more second-line treatments (those able to overcome drug resistant virus) would be required.

3. How might PrEP work in the real world?

As women’s health advocates, there are things we can do to try to ensure that the iPrEx results lead to good outcomes for women that are not eclipsed by unintended consequences. Among other things, we must:

Insist that policy makers look at real world issues, not just clinical trial results:

The CDC is preparing a PrEP implementation plan that will include public education, guidance for physicians and health care providers regarding PrEP use, and implementation research.  Advocates need to insist that the implementation research agenda include examination of the impact of informal marketing and drug sharing on the well-being of people living with HIV and on public health generally.  If evaluators focus solely on the experience of people with legal access to PrEP drugs, they may miss effects such as treatment non-adherence due to drug misappropriation, increases in drug resistant virus levels due to sporadic use of illegally obtained and/or counterfeit PrEP drugs, and other consequences indicative of informal marketing and drug sharing practices.

Call for resistance monitoring systems:

Once approved for use in the U.S., PrEP is only likely to be prescribed to high-risk people who are demonstrably unable to use other HIV prevention methods consistently.  Nevertheless, we need to put systems in place now to do baseline assessments of population-level drug resistance and then monitor the level periodically so that any effect PrEP has on the prevalence of drug resistant virus can be tracked. Research has shown that, in places where anti-retroviral drugs are widely used, between 5 and 15 percent of new HIV infections transmit drug-resistant virus from one person to another. We will need an effective evidence base to determine whether or not use of PrEP—formal or informal/”off-label”—is increasing the prevalence of HIV that is resistant to PrEP drugs. 

Demand stakeholder involvement in setting the PrEP research agenda and roll-out:

As mentioned above, trials showing how PrEP works in women’s bodies are likely to produce results in the next few years. Additional data are needed to show whether gender-based differences occur in terms of overall effectiveness and the incidence and severity of side effects during long term use. Additional trials will also be needed to determine how use of PrEP drugs affects pregnancy or breastfeeding.  Advocacy will be required to get those trials on the research agenda sooner rather than later.

Implementation research is also needed to understand the barriers that keep people from accessing HIV testing and how they can be overcome.  Women who need PrEP because they have no other prevention alternative when their partners don’t use condoms will be unable to get it if they feel unable or unwilling to get HIV testing.

Most of all, community stakeholders need to play key roles in planning and delivering highly targeted community education about PrEP.  This is essential to ensuring that women and men in high risk communities understand about how PrEP works and why it is not a replacement for condoms. People will need to hear clearly, from those they perceive as credible, that they endanger their own health—and the community’s health—if they use PrEP without a prescription or buy it on the street.

No matter how well PrEP works to prevent HIV in tightly controlled clinical trials environments, significant stumbling blocks exist to its effective use in the real world. Unfortunately, these “real world” challenges are often set aside as issues that can be addressed once roll-out of an intervention to the target population has been achieved. Funders and policymakers often see work to address them prior to introduction as optional and aspirational, rather than as an investment that is essential to the intervention’s success.

We can’t let PrEP go the route of condoms and circumcision—becoming an HIV prevention tool primarily benefitting men. As we celebrate evidence of its potential effectiveness, we must also pay close attention to what next steps are needed to put this new HIV prevention tool into the hands of the women who need it most.

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  • mary-beth-hastings

    Thanks for this piece, Anna! This is a great and thorough summary that answers many questions and will help us to best advocate for women’s needs as this intervention moves forward.

  • kmn

    One of the most surprising parts of this study was the low adherence rate. Taking the pill regularly was one of the most important factors in preventing HIV and efficacy was higher among participants that took the study drug consistently. This begs the question: Why were so many individuals reluctant to take their pills, and what does that mean for efficacy, especially outside of the drug trial? The data from the iPrEx study are encouraging but the less than ideal adherence rate to oral PrEP clearly show that we need additional prevention approaches such as rectal microbicides that could be used by men and wome nat risk of HIV infection through unprotected receptive anal intercourse.  Check out http://irma-rectalmicrobicides.blogspot.com/2010/11/aids-drug-shown-to-prevent-hiv-in.html for a more comprehensive look at why the study above confirms a need for a multi-faceted approach to HIV prevention– one that includes a rectal microbicide.

  • the-abortioneers

    Thanks for this interesting and informative piece. I noticed you use the phrase “HIV-negative men, male-to-female transgendered women, and other men who have sex with men (MSM).” This is how it’s written on the study’s FAQ webpage, too, so I’m sure you were simply writing it as the study does. But I wonder WHY they identify transgender women as “men.” That seems like they are unilaterally overriding the subjects’ own self-identification, saying “It’s all well and good to identify as women, but for the purposes of HIV risk you really are men.” And that’s not right. If anything, it’s an example of how we struggle to continue categorizing risk based on identity even though it’s not all that useful to do so. Just thought I’d point this out as an often-overlooked issue in HIV prevention considerations. 

  • choice-joyce

    You are treating this like a definitive study, but it is far from it. In science, one can never take a single study as definitive, especially when only 6 out of 37 previous HIV prevention studies had some success, but none on men. However, this study is a failure too because a 44% reduction in risk is useless, and reliable conclusions cannot be drawn by analyzing only the sub-group that allegedly adhered to the drug dosages.

    Many people can’t/won’t adhere to HIV drugs like Truvada because they have unpleasant and often intolerable side effects, not to mention dangerous long-term effects such as kidney damage. To advocate giving such drugs to healthy people is unconscionable, especially when the risk of HIV infection is low to begin with, and the alleged risk reduction is not nearly high enough, even at 73%.

    The p<0.05 statistical criteria used (0.05 level test of at least 30% efficacy) may greatly overstate the significance of the results because a positive HIV test is essentially an anomalous event, even in a high-risk group: Of 1251 people who got the drug, 36 became infected, while of 1248 people who got the placebo pill, 64 became infected. That’s 3.5% versus 5.1% – so the placebo is hardly better than the drug!

    But the subjects in this study were not even representative of men who have sex with men – the study had a high proportion of men leading unhealthy lifestyles – including heavy drinkers, those with other STIs, sex workers, and highly promiscuous men (see Figure 3). Therefore, it would not be applicable to most gay men, and certainly not to women or any other randomized low-risk group, who would test HIV positive at far lower rates, thereby rendering the standard <0.05 statistical criteria for a significant result completely meaningless.

    For further info:

    http://blogs.poz.com/joseph/archives/2010/11/iprex_prep_trial_rep.html

  • crowepps

    a 44% reduction in risk is useless

    I’m sorry, I don’t understand this statement.  It sounds like you’re stating that there’s no value from a public health standpoint in reducing the number of people who catch a disease by 44% but that can’t possibly be right so could you explain what you really do mean?

  • choice-joyce

    There’s no value in having completely healthy people take a drug for years that has unpleasant side effects and serious long-term side effects, in order to prevent something they’re unlikely to get in the first place, given the low incidence of HIV infection in a population, particularly when the drug reduces that already-low risk by only 44%. The actual incidence of HIV infection in this study group was 3.5% with the drug and 5.1% without the drug, a difference of only 1.6%. So it’s not worth the risk – the “cure” is worse than the disease in this case.

  • squirrely-girl

    A lot of people have a difficult time understanding the impact of research results. They hear some percentages and don’t realize that depending on the sample and population sizes, the effect sizes (partial eta squared) for these studies could be huge. In layman terms, there is a difference between a 44% reduction in a sample size of 100 versus 1000.

  • crowepps

    I’m finding it difficult to imagine any competent physician prescribing this drug to completely healthy people unless he knew they were part of a population which was likely to be exposed.  It would be a lot more sensible to prescribe it for woman whose partner was known to have HIV, for women who use drugs, for sex workers and for nurses who work with patients who fit those categories.

     

    The statistical difference may seem tiny and yet be huge in a population.  Just for instance, the fastest increase in HIV in the United States right now is in Washington DC, where 3% of the population have been DIAGNOSED and it’s estimated that almost TWICE as many are probably positive.

     

    Since the population is apprx. 600,000 people we’re talking about maybe 570,000 people who do not yet have the disease.  Just for the sake of discussion let’s estimate that 10% have identifiable high risk factors like the ones I talked about so that a reasonable physician thought they should use the new drug, and 57,000 people got a prescription.  Without the drug, 2,907 would get HIV; with the drug, only 1,995 would be diagnosed. In addition to 912 people not getting a fatal disease, those 912 people would ALSO not be spreading the disease which would mean in subsequent years the increase would continue to be reduced.

     

    I’m not saying that this particular drug is suitable for such widespread use or that meeting the expense would be possible, and I certainly haven’t read up on any possible side effects, but don’t let yourself be fooled that it’s useless because it’s ‘only’ 1%. The percentage of our population killed in traffic accidents every year is .001%, one-tenth of 1%, and yet we all know someone who’s died in a car crash.

  • uksteve

    Crowepps – the number of *women* here in the West at anything remotely close to a moderate (let alone serious) risk of ‘HIV’ is miniscule. The rates of ‘infection’ by ‘HIV’ in the West are virtually no different now to 25 years ago: Gaymen (over 85%), and the remainder are mainly IV drug users.

    The rates of infection between discordant couples (gay or straight), where one is Neg and the other Poz, are also miniscule (Google for the ‘Padian Study’) and even then it is lower between straight discordant couples than gay discordant couples, and even lower rates of ‘transmission’ male to female, than female to male – and those studies were based on most of the sex taking place without condom use.

    The side effects of Truvada are well known and serious, especially in long term use. Everyone needs to know that the main causes of death of HIV+ gay men, who are asymptomatic with aids-defining conditions, but on long term use of ‘HAART’ (Highly Active AntiRetroviral Therapy) are Liver failure, Kidney Failure and Heart Failure – all caused by the anti-retroviral drugs. Truvada is probably one of, if not the most common drugs used in combination therapy.

    Everyone also needs to know – very clearly – that the long term prognosis of use of ARVs is completely unknown. Not enough people have been on them for long enough. Resistance after 10 years? Not known, Rates of ARV induced death after 10 years? Not Known, Failure of the ARVs to continue to maintain low viral load and higher CD4 cell counts after 10 years? Not Known.

    And the above is the danger for people who already ARE HIV+ but aysmptomatic.

    Why would a miniscule number of Women at even ‘serious’ risk of ‘HIV transmission’ (eg female partners, of promiscuous male bisexuals, who engage in frequent unprotected receptive vaginal and anal sex) put up with serious side effects and medium to long term organ failure & morbidity? Especially when this first study only suggests a small percentage of that miniscule number would even likely benefit?

    They would be better being given help, support and counselling to reduce their ‘risk’ in the first place which would most likely be as successful, if not much more successful than ARV prophylaxis, and with NO risk of life threatening side effects to any single participant.

     

  • uksteve

    Let’s put it another way.

    If all those vaccinations we subject children to, or the TB vaccine we take as early teenagers, or the Seasonal Flue vaccine we encourage millions of elderly and immuno-suppressed people to take once a year, had anything like the same side effects and long term organ failure and deaths rates as Truvada, *AND* had success rates of only 44% (even 73% is much lower than *any* of those vaccines) – do you REALLY think that ANYONE would take them???

    Because that is a reasonable comparison – protection *against* a possible threat.

     

  • arekushieru

    Neither of your comments adresses the points.  Nor do they attempt to understand the whole concept of choice that falls within this purview.  Because, unless you are going to force every person to reduce the risk, prior to engaging in sex, through help, counselling and support, then you are going to have at least some of the population that will still be at risk of infection.  And, I’m sure, they won’t care how significant or insignificant their chances of infection were, if they actually DO contract the disease.  So, talking about significance is completely irrelevant to this discussion.  And, like all other forms of medical treatment, informed, explicit and ongoing consent is necessitated, so each individual can determine for themselves whether they will receive this form of treatment or not, based on which risk they would prefer to take.