“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.
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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, 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:
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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 lives.
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.