New cases of HIV infection in the United States have been mounting at 56,300 per year for over a decade, and a nagging sense exists among many working in HIV that behavioral approaches to prevention alone may not be capable of reducing this number -- even with significant additional funding. The search for an effective HIV vaccine or microbicide has not proven easy, and success in these areas of biomedical prevention may still be years away. And so, the idea that HIV prevention might be strengthened using pre-exposure prophylaxis (PrEP) has caused cautious optimism among many HIV agencies, including Project Inform.
Simply put, PrEP would offer select HIV antiretrovirals, in combination with safer sex counseling, to sexually active HIV-negative individuals in order to increase the likelihood that they will remain uninfected. Such a strategy is not novel; medications are used to prevent other infectious diseases, including malaria and tuberculosis. PrEP, however, would involve longer courses of therapy and its administration is much more complicated than other forms of therapeutic prevention. And because PrEP involves sexual harm reduction, it is initially thought of by many people as dubious in the same way that the birth control pill was first thought of -- not as a legitimate choice for prevention purposes, but as an inducement to flagrant sexual behavior.
PrEP trials funded by the U.S. Centers for Disease Control & Prevention (CDC), National Institutes of Health and Bill & Melinda Gates Foundation are currently underway around the globe in various populations at risk for HIV infection. Early results could be in hand as early as November of 2009. In the meantime, data from studies on Macaques has demonstrated that the oral administration of two antiretroviral drugs before and after exposure to immunodeficiency virus (SHIV) prevented rectal infection.
PrEP may or may not be proven to be safe and effective for humans, whose biology and behavior are obviously different from that of simians, and real world results may differ from those in very carefully controlled clinical trials. But many PrEP researchers find reason to believe that this novel prevention strategy will be shown to be effective. It is therefore not too early to begin conversations about the many complicated issues that would be involved in actually implementing it.
Project Inform is a member of the National PrEP Committee, whose other founding members include the Community HIV/AIDS Mobilization Project (CHAMP), the AIDS Vaccine Advocacy Coalition (AVAC) and the National Associated of State & Territorial AIDS Directors (NASTAD). The Committee is monitoring current clinical trials on PrEP, educating AIDS Service Organizations and community members about it, and discussing the many issues that would surround implementation if evidence supports it as a safe and effective intervention. The Committee is doing so in close collaboration with the CDC, which will publish guidelines for its use as a function of the success of clinical trials.
This paper describes many of the key issues that would need to be addressed in order to implement PrEP in the United States, and attempts to partially answer some. Because it is focused primarily on issues of delivery and financing, this document touches on only a few of the scientific or clinical questions surrounding PrEP. Broad, thoughtful and open-minded participation is needed to answer these and potentially other questions in the interest of developing a potentially revolutionary new way to significantly reduce new cases of HIV infection. Additional research may be needed to answer many of the questions posed here, particularly with regard to impacts of PrEP on risk behavior, community acceptability and cost-effectiveness.
What Will the PrEP Intervention Consist Of?
Delivering PrEP will require a comprehensive package of services. Among other potential requirements, candidates will need to determine if they are eligible for PrEP by taking an appropriate HIV test or tests to establish that they are HIV-negative. (Because of the need for testing in order to initiate it, PrEP could benefit current efforts to increase the number of high-risk HIV-negatives and others who know their HIV status.) PrEP will have to be thoroughly explained and candidates will need to consent to it. They will be prescribed medication and will be counseled about the importance of adherence. They will need to be counseled initially and in regular follow- up visits about the fact that taking medications alone may not protect them from HIV. Safe sex or injection practices must be continued. Periodically, their blood will have to be tested for evidence of any side effects of the medications, and they will need to be re-tested periodically to determine their HIV status.
Who Would Receive It?
In part because of what is likely to be its high cost, PrEP may not be available to all HIV-negative individuals. Nor is it needed by all HIV-negatives. Instead, decisions will have to be made about who is at greatest risk for HIV infection, who is most likely to benefit from PrEP, and to whom it can be made available. The focus of PrEP might be on groups that epidemiology would suggest are at highest risk for HIV infection -- gay and other men who have sex with men, particularly young men of color; women of color; injection drug users; male-to-female transgenders and others. Partners in relationships where one of the partners is HIV-positive may also be good candidates for PrEP.
Additionally, eligible candidates might be selected both as a function of the extent of their reported risk behaviors, such as unprotected intercourse or injecting with shared needles, as well as histories of sexually transmitted diseases, substance use and mental health issues. The worried well, HIV-negatives who fear infection but whose behaviors do not place them at substantial risk, may be attracted to PrEP and should perhaps have the choice of taking it, but might not be ideal candidates if limited funds are available for its delivery.
The issue of social justice surrounding PrEP and whether it will be available only to those who have medical insurance, can afford to pay for it on their own, or are easiest to recruit to its use, is a significant one. While all HIV-negative individuals deserve support to remain uninfected, the current epidemiology of HIV, which clearly shows that MSM and women of color, as well as injections drug users and MTF transgenders are especially at risk for HIV, should undoubtedly be a guide in making resource allocation decisions regarding PrEP.
Will PrEP Be a Lifelong Intervention for Individuals?
When contemplating the high cost of PrEP and its cost-effectiveness, people often assume that individuals will need to take PrEP for all of the years during which they are sexually active. While this may be true for a subset of PrEP eligible people, it is not likely to be true for most. A number of psychosocial factors cause some HIV-negative people to be at risk for exposure to HIV during certain times during their lives, but not at others. Helping HIV-negative individuals to understand when they are truly at risk and encourage them to consider using PrEP during those periods will be an important feature of its implementation.
The fact that most people will not have to use PrEP for years on end may help to address two other challenges with its implementation -- concern about the toxicities that may result from extended use of HIV antiretrovirals, and the possible development of drug resistance.
Will People Want to Use PrEP?
In addition to the question of who PrEP can or should be made available to, there is the question of who will want to use it -- a consideration that will, of course, have much to do with its total cost. PrEP will necessitate knowing one's HIV status -- something not all at-risk individuals want as much as we want it for them. It requires perfect or near-perfect adherence to medicines that have minimal but some toxicities over time and that have potential side-effects. (The two drugs currently used in trials are Tenofovir and Truvada, chosen in part because they are long-lasting in the body and have minimal side-effect profiles.) PrEP will require willingness to keep regular visits to a medical provider and behavioral counselors. Its use could be a signal to loved ones, acquaintances or insurers that an individual is engaging in behaviors that place them at risk for HIV. For those with regular sex partners, its use could be taken to mean that they are unfaithful or fearful about the faithfulness of their partner(s). Some may worry about the impact that taking preventive medications might have on their efforts to practice safe behaviors consistently and fear that the strategy could backfire for them. And many other considerations could cause individuals to decide that PrEP is not for them.
Still, many sexually active individuals who strive but do not always succeed in practicing safe behaviors may welcome PrEP as a strong potential backup strategy in their efforts to remain uninfected.
All of this points to the thoughtful, extensive, and perhaps costly counseling that will be needed by HIV-negative people in order to decide whether to engage in and maintain PrEP.
How Will PrEP Be Delivered?
The kinds of services that are likely to be needed as part of the PrEP package are discussed above, including testing, counseling and follow-up clinical monitoring. The settings in which these comprehensive services can be delivered will probably differ among jurisdictions, and identifying appropriate providers may pose a significant challenge for some communities.
Private physicians may not be great sources for PrEP because the time that will be required to obtain consent, provide regular behavioral counseling and other psychosocial services needed to support adherence could easily outstrip available time and capacity. (We know that many providers are not offering HIV testing because of the time and paperwork required to do so.) Many existing HIV clinics have indicated a fear that adding PrEP to their services could present a major challenge both in terms of mission and capacity.
Community-based health clinics could be ideal sources for offering PrEP because they frequently combine the ability to deliver clinical, behavioral counseling and psychosocial services. Additionally, their services are generally targeted to and enjoy the trust and respect of the very demographic groups for whom there is particular hope that PrEP will have impact. Similarly, many community based HIV prevention agencies capable of delivering or housing appropriate clinical services could be organized to deliver PrEP. And if sufficient public dollars are made available to implement it, this new intervention holds the possibility of creating interesting partnerships of community-based medical providers, HIV prevention organizations and perhaps mental health and substance abuse providers to provide an unprecedented level of support to high-risk uninfected individuals in their efforts to remain HIV-negative.
Before PrEP is fully implemented on a national level, and if data from clinical trials support doing so, the CDC has indicated that it might support demonstration projects in a small number of cities to assess the merits of PrEP delivery in different settings. These demonstration projects could provide an ideal opportunity to understand and resolve a host of issues in order to maximize the effectiveness of this new intervention.
What Will PrEP Cost?
Many of the potential contributors to the cost of PrEP have been discussed above. The PrEP package will include many elements, making its total cost potentially quite high. Not the least of these costs is that of the HIV medications themselves. Daily doses of Tenofovir and Truvada for the treatment of HIV cost approximately $7,100 and $10,500 a year respectively, depending on what source is paying for them. Current clinical trials on PrEP are assessing the safety and effectiveness of daily dosing. Future studies will assess whether less frequent dosing, perhaps twice or three times weekly, may convey the same protective effect. Additionally, future studies may assess whether taking PrEP at some point shortly before expected sexual activity and for some period after, may provide protection. Obviously, the amount of drug that is needed to make PrEP effective will heavily influence its total cost.
Pricing of the specific medications used in PrEP will also be important. Advocates may seek to press the manufacturers of any effective drugs for PrEP to price them more favorably than for treatment of HIV, but it is not clear that such a request would be approved. Tenofovir and Truvada are both manufactured by Gilead Sciences, but drugs made by other manufacturers are being considered as potential candidates for PrEP. Ultimately having more than one source for PrEP drugs could support lower pricing.
Will Current HIV Medications Be Approved by the FDA for PrEP?
A major issue facing PrEP is whether HIV antiretrovirals used for treatment of HIV-positive people will be approved for use in HIV-negative individuals. Gilead has not yet made a decision about whether or not it will request approval from the FDA for labeling of Truvada or Tenofovir for preventive purposes. It is assumed that the company is concerned about the potential liability associated with the use of its drugs for an intervention that may be less than 100 percent effective in preventing HIV infection, even if a patient consents to its use knowing that the drug may not confer complete protection. Entities that will be looked to pay for PrEP may refuse to pay for off-label medications, meaning medications that are being prescribed for other than their FDA approved uses, even if they are prescribed by a physician.
Advocates and even government agencies might pressure Gilead or other PrEP manufacturers to seek labeling of their drugs for prevention purposes. In the absence of FDA approval requested by the maker, there are complex legal avenues available to provide for the approved manufacturing of drugs for public benefit. And it might be possible that if appropriate federal agencies, including the Public Health Service, issue guidelines for the use of specific drugs for PrEP, they would be paid for by public payers including Medicare and Medicaid.
In any case, the issue of whether companies will seek and the FDA will approve the use of HIV antiretrovirals for PrEP is a thorny one that could significantly impact both the availability and cost of this intervention.
Will PrEP Be Cost-Effective?
If it is effective in preventing HIV infection, advocates should press for its implementation solely on the basis that it will save lives. However, the willingness of private of public entities to pay for PrEP will not depend entirely on whether it prevents HIV infection, but on whether it is cost-effective. To date, analyses of PrEP cost-effectiveness come to differing conclusions.
The cost of delivering PrEP to an individual for one to several years during which they are at risk for HIV infection is certainly much lower than the lifetime cost of care if they become HIV-positive. But deciding whether the delivery of PrEP to an individual HIV-negative person is cost-effective depends upon the answers to at least two questions. Was it PrEP that prevented HIV infection or the much less expensive condom by itself? And would the individual have become infected even if they had not used condoms or engaged in PrEP? From a humane perspective, the investment in PrEP for any given individual is entirely justified. From a financial standpoint, however, it may only be cost-effective to offer PrEP to those who are clearly engaging in behaviors that place them at risk for infection.
On a population-wide basis, cost-effectiveness may become even more difficult to prove. After all, how many people would need to take PrEP in order to avert the 56,300 infections that are occurring each year? One hundred thousand? One million? How many people will ask to use it even though they are at little or no risk for infection? It is possible to see how the cost of providing PrEP to hundreds of thousands of individuals could outstrip the money saved from providing care and treatment to the smaller number of individuals who would otherwise become infected with HIV.
Complex analysis will be needed to establish whether PrEP is cost-effective, and for whom. This analysis might benefit from additional research that determines how acceptable PrEP will be among HIV-negative people, particularly those in high-risk groups.
Who Will Pay for PrEP?
Depending on how well it does its job, the demand for it and its cost-effectiveness, advocates will face varying levels of difficulty in assuring that HIV-negative people have PrEP paid for.
Most private insurers say that they do not pay for prevention interventions like PrEP, even though we know that they pay dearly for the prevention of chronic medical conditions like heart disease and hypertension that require many of the same things as PrEP -- costly pharmaceuticals, behavioral counseling, and regular clinical monitoring. Advocates will undoubtedly have to press hard to have private insurers pay for PrEP -- assuming that many candidates for PrEP will even want to have their private insurers pay for it. Many insured individuals may not want to have their physician or insurance company deduce that they are engaging in behaviors that place them at risk for HIV infection.
Although they may be the most likely of sources to agree to pay for it, Medicare and Medicaid are not likely to be large providers of PrEP. In order to be eligible for both programs, an individual either needs to be of retirement age or disabled, and the vast majority of people at risk for HIV infection will meet neither of these requirements.
The Ryan White Program is also a possible, but highly unlikely, source of funding for PrEP. This program was clearly intended to serve HIV-positive people, and it is currently unable to provide even for the care and treatment of all who need or are eligible for it. HIV-positive people and their advocates are likely to vigorously oppose any attempt to add PrEP to the services provided by Ryan White or the AIDS Drug Assistance Program, which is part of it.
This seems to lead to one of three possibilities. The first is the creation of a completely new program, with its own dedicated source of funds that pays for the delivery of PrEP, presumably in public settings. Or, advocates might argue that some percentage of existing CDC prevention dollars should be directed to PrEP if it is highly effective. Or perhaps it will take both approaches to secure adequate resources for large-scale PrEP delivery. For many reasons, it is likely that advocates will need to make a request to Congress and the President to fund PrEP as a completely new, stand-alone program to which states and even localities might add funding, if they choose.
Finally, it is important that advocates insist that national health care reform provide for coverage of the cost of interventions that effectively prevent chronic diseases, including HIV.
Is PrEP Ethical and How Effective Will it Need to Be in Order to Be Implemented?
Many question whether PrEP will be an ethical intervention if it is shown to be any less than 100 percent effective in preventing HIV transmission. Is it ethical, even if they consent to it, to provide PrEP to individuals who report that, despite behavioral counseling, they occasionally engage in behaviors that place them at risk for HIV infection -- especially if they are not 100 percent adherent to their PrEP medications? On one hand, this is precisely the person for whom PrEP is likely to have the greatest benefit -- someone who, despite their best intentions or owing to psychosocial issues including mental health and substance use, finds it impossible to consistently practice safe sex. Tenofovir and Truvada were considered strong candidates for PrEP because they have long half-lives and present less risk if adherence is not perfect. Still, it is possible to see how poor adherence both to PrEP medications and safe behaviors could actually increase an individual's risk of infection.
To date, available data suggest that PrEP actually increases condom use among participants in carefully structured trials. But real world results could show that PrEP is counter-productive for many participants because pill-taking reduces safe sex and needle-sharing behaviors. If antiretrovirals are 100 percent effective at blocking infection whether condoms are used or not, that may not matter. But if antiretrovirals are 70 or 80 or 90 percent effective, it could matter considerably.
The question of whether PrEP is ethical can also be turned on its head by asking whether it is ethical not to offer this intervention to individuals who report that they periodically engage in unsafe behaviors. If taking antiretrovirals might protect the individual where a condom did not, how could we ethically deny PrEP to them? For a community that has advocated for harm-reduction approaches to HIV prevention, PrEP would seem to be a great addition to the arsenal of interventions that could be available to HIV-negative people to protect themselves from infection. Who would dare to deny it to them if it is shown to be largely effective in preventing disease?
In the final analysis, the most ethical approach to delivering PrEP may well be to make its uptake a matter of informed choice for HIV-negative people themselves.
Precisely how effective PrEP is shown to be in clinical trials will have obvious impact on how many HIV-negative people are willing to use it, whether public or private health insurance companies are willing to pay for it, and to whom it should be delivered. Is there any sense in implementing such a costly and complicated intervention if it is only 50 percent effective? If it is between 50 and 75 percent effective, should PrEP be available only to the highest risk individuals but not to those at lower risk of HIV infection? Will PrEP only be cost-effective for administration on a widespread basis if it is 75 to 100 percent effective? These are difficult decisions to make, but they are ones that advocates are likely to face once the results of clinical trials are in hand.
What Political Issues Will Surround PrEP Implementation?
The politics of PrEP are likely to be intense, both within the HIV/AIDS community and on the national political scene. Within the community, there will be the obvious concern, touched on above, about paying for a costly prevention program at a time when people with HIV are not universally able to access comprehensive health care, pharmaceutical and social services benefits. The problem of scarcity is exacerbated in the face of the much-needed but unfunded goals of significantly increasing the percentages of Americans who know their HIV status and who enter care and treatment if they are positive.
As already discussed, others in the HIV community have expressed concerns that PrEP may backfire by reducing safe sex and eroding a community-wide norm of condom use. This phenomenon, which began well before PrEP was a glimmer in anyone's eye, is of course precisely what this new intervention is meant to address. Interestingly, it is the potential impact of PrEP on safe behaviors that is also likely to be the objection of conservative politicians and decision-makers to it, although their denunciation is likely to be described differently. Just as the advent of the pill was viewed as nothing more than a boon to promiscuity and immoral behavior, so too, PrEP will be seen as a social evil by most conservatives. Needless to say, cost and cost-effectiveness could also be taken up by many policy makers as reasons to reject PrEP implementation.
Could PrEP Have Unintended or Harmful Consequences?
There are ways in which PrEP could create or exacerbate problems. The principal one has already been discussed -- that it could further reduce the use of condoms among those at risk for HIV infection while failing to confer sufficient protection population-wide benefit to compensate for unsafe behavior. Concern has been expressed that multiple factors could result in PrEP contributing to drug resistance within the community -- an issue that has not been completely resolved. Some have expressed concern that HIV-positive people will engage in pill-sharing; providing their medications to HIV-negative sex or needle-sharing partners at the expense of their own clinical outcomes. These and other problems could accompany an otherwise desirable prevention intervention. Anticipating and planning to address unintended consequences of PrEP is worth doing thoroughly and early.
PrEP appears to have potential to add a significant new intervention to the list of options available to individuals and communities to prevent HIV infection. At the same time, and true to the history of an epidemic that has involved unprecedented complexities, it seems to present one of the most challenging issues of all time in disease prevention. Efforts by multi-disciplinary groups to fully describe those complexities and begin to resolve them quickly and thoughtfully are vital. The PrEP Committee is the major community-based entity doing this work, and interested AIDS service organizations are welcomed and encouraged to join its deliberations. To join, email firstname.lastname@example.org.