The Problems With Pre-Exposure HIV Prevention
We are in the middle of what is perhaps the most productive period in research into the prevention of HIV/AIDS.
In the past few years, we have seen the promise of an HIV vaccine with the initial results from an HIV vaccine trial called RV144. We have also seen the promise of an HIV prevention gel (called a microbicide) with the release of the results from studies looking at the use of these products vaginally (a study called CAPRISA 004) and rectally (RMP-02/MTN-006).
On July 16th, we reached another landmark moment in the fight against HIV/AIDS with the U.S. Food and Drug Administration, or FDA approving Truvada© as the first drug for the prevention of HIV infection through what is referred to as pre-exposure prophylaxis, or PrEP—a preventative treatment administered before potential infection.
However, the approval of Truvada as an HIV prevention drug was initially expected to happen in June. The month-long postponement reflected pressing ethical concerns with the drug. First, questions linger about whether the availability of a pre-exposure preventative treatment could encourage more risky behavior and potentially lead to higher rates of infection. Second, since non-adherence to the strict dosing rules can lead to extra virulent strains of the virus, questions remain about whether the potential for non-adherence could cause more harm than the drug does good. The way that Truvada manufacturer Gilead addressed some of these concerns could have an impact on how future HIV prevention measures will be approved and implemented.
In order to understand these ethical issues, there are two important pieces of background information.
First, Truvada is a combination of two antiretroviral drugs (HIV is a retrovirus) that was initially approved by the FDA in August 2004 for the treatment of HIV. It has been on the market for nearly a decade, and has been known to be a safe and effective treatment for HIV for years.
Second, since the FDA approval of the first drug to fight HIV in the late eighties, we have known that individuals who take antiretroviral therapy shortly after being exposed to HIV have a high likelihood of avoiding HIV infection. This strategy, post-exposure prophylaxis, is now recognized as highly effective, especially if taken within 72 hours of exposure, although there is some evidence that it’s effective to some extent even after this initial window.
This effectiveness was the catalyst behind research into PrEP. If early intervention after exposure could prevent HIV acquisition, researchers thought that perhaps these drugs could also be effective in preventing infection before exposure to the virus. To explore this possibility, Gilead, Truvada’s manufacturer, collaborated with the U.S. National Institute of Allergy and Infectious Diseases, or NIAID, and the Bill and Melinda Gates Foundation on a study called iPrex that began in 2007. This study provided enough evidence to eventually convince the FDA that Truvada works as PrEP.
It might seem strange, then, for the FDA to be so cautious with the approval. However, a closer look reveals an approval fraught with significant ethical pitfalls. Many of these issues were already evident with post-exposure prophylaxis. There were practical issues related to consistently taking a harsh regimen of drugs daily for a month. Even if those drugs can save lives, it is difficult to get people to take all the required medicine when the regimen induces vomiting, nausea, hair loss, and could require weeks of being bed-ridden. So people sometimes skip doses. This not only prevents proper treatment of the virus, but also potentially creates drug-resistant viruses.
There were also potential psychological pitfalls. While post-exposure prophylaxis tends to be used for health workers exposed occupationally, in certain settings, it is also available for the general population. This has led to some concerns that its availability could actually encourage risky behavior.
These concerns are magnified with the introduction of Truvada as PrEP. The dosage in PrEP is lower than what’s used in post-exposure prophylaxis, so the physical risks are very low. The iPrex study also demonstrated that taking Truvada PrEP did not necessarily result in riskier behavior. However, Truvada PrEP will need to be taken daily in order to be effective. While this requirement is not, in itself, uniquely burdensome (birth control pills and many other pills are often taken daily after all), the risk of non-adherence could be catastrophic due to the potential for the creation of Truvada-resistant HIV strains in the event of infection. Resistance to Truvada could also result in resistance to other drugs that function in the same way as Truvada.
The risk of resistance is very real. In 1946, a drug called chloroquine was established as a safe and effective anti-malarial. Shortly after, physicians began using it for malaria prevention. By the 1950’s the first chloroquine resistant strains of Malaria were discovered, and today there are several regions in the world where there is widespread chloroquine resistance.
The example of chloroquine should be reason for pause. Anytime a drug commonly used as treatment is also available for the prevention of a disease in situations where adherence cannot be monitored or controlled, widespread resistance is a potential danger. Truvada PrEP has been shown to be effective, and there is no fear of resistance. But this is only true if it’s taken everyday as directed.
Of course, that’s precisely where the biggest concerns are. While resistance is naturally occurring, even in some individuals who take their medicines as directed, the main cause of drug-resistance is non-adherence. But our ability to combat non-adherence in the case of Truvada PrEP is in doubt, especially when consistent use would be required for an extended period.
The FDA approval of Truvada as PrEP was for adults at high risk of acquiring HIV-1. “Adults” were considered to be individuals 18 and over. However, it is estimated that in addition to certain high risk groups like men who have sex with men, injection drug users, and sex workers, one of the highest risk factors for acquiring HIV globally, is simply being between the ages of 16 to 24 years old.
According to the Center for Disease Control, almost half of U.S. high schoolers (46 percent) have had sexual intercourse, with approximately 6 percent having an age of sexual initiation as young as 13 years old. That means for the first few years a person is at the highest risk for acquiring HIV, they aren’t eligible for Truvada PrEP per the FDA approval. But more importantly, if we look at many of the groups both domestically and globally, that are at the greatest risk for acquiring HIV, we see that these are also the groups with the greatest risk factors for non-adherence. These risk factors include economic limitations as well as social circumstances that might impede their willingness and ability to freely and regularly take Truvada PrEP as directed up to and including intimate partner violence.
To address serious ethical issues surrounding the approval of Truvada PrEP, the FDA required Gilead to provide a Risk Evaluation and Mitigation Strategy, or REMS. While this strategy attempts to address some of the concerns surrounding non-adherence, there are two glaring shortcomings. First, the distribution of the information contained in the REMS to those taking the drug is voluntary. REMS are publicly available, and presumably, most providers will provide the information to patients, but there is a high likelihood that a significant number of people might not get important information about the risk of resistance. Second, the information on the REMS doesn’t seem to acknowledge, let alone suggest strategies for addressing the factors that could impede adherence.
The first issue is significant, but at least the REMS offers access to important information about adherence and the risk of developing drug resistance. However, it’s unclear whether the REMS does enough to address unrealistic risk analysis on the part of participants. It has been demonstrated repeatedly that people are very bad at assessing their own risks. Even though the iPrex study didn’t show an increase in risky behavior, results in the real world may be different. Simply telling participants that non-adherence potentially leads to resistance might not be enough to convince them that it would be an issue for them.
This second issue might be beyond the purview of the drug companies, but it is a significant problem that will need to be addressed as Truvada PrEP is rolled out. Unfortunately, the burden of addressing these issues will likely fall on ministries of health and communities in resource-limited settings as they begin wide-spread implementation of PrEP.
As we continue to make progress on the development of other HIV prevention methods, we also need to develop risk mitigation strategies that address the causes of non-adherence. There is on-going research into slow-release formulations of anti-retroviral drugs. Once developed, these formulations will allow us to bypass some of the problems related to non-adherence, but these will not be a final solution. Ultimately, addressing the background causes of non-adherence will have the greatest impact on the success of PrEP and other HIV prevention methods.
Takunda Matose is a human subjects protection specialist focusing on HIV/AIDS research at Technical Resources International and has a master of bioethics from the University of Pennsylvania.
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