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AHEC Capstone 2014 Remigio A. Roque Are we PrEPared? An overview and discussion surrounding the practical and ethical implementation of preexposure prophylaxis (PrEP) for HIV. Great strides have been made in HIV care since the first cases were identified in 1981. In the early years, testing was not available, treatments did not exist, and diagnosis carried a grim prognosis. Three decades later, testing can be done at home, more than 100 drug therapies exist, and with early diagnosis living with HIV does not imply a drastic reduction in lifespan. Despite these advances, rates of new infection in the United States have been relatively stable since the mid-1990s. Approximately 50,000 people are diagnosed each year, with certain populations being disproportionately affected. One new approach to preventing transmission, especially in vulnerable subgroups, is pre-exposure prophylaxis (PrEP). In 2012, supported by data from several clinical trials, the FDA approved the prophylactic use of Truvada (emtricitabine/tenofavir) in individuals at high-risk for infection. Guidelines have since been suggested for PrEP use in men who have sex with men (MSM), heterosexual high-risk individuals, and intravenous drug users. However, along with the promise PrEP presents, there also arise several questions regarding the practicality of its implementation and the ethicality of treating healthy patients with extremely potent therapies. These issues will be explored further in this essay. Introduction Currently, there are over 100 pharmaceutical agents available to treat HIV in an infected person. The mainstays of treatment include the use of several anti-retroviral classes of medications (ARVs), including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, entry inhibitors, integrates strand transfer inhibitors, and multi-class combination products. While this armamentarium of drugs allows healthcare providers to adequately treat those patients who are infected, they do not solve the problems of preventing new infections or identifying infected persons who are not aware of their status. In the U.S. alone, it is estimated that there are 1.1 million people living with HIV and nearly one in six are not aware that they are infected. The rate of new infections is approximately 50,000 annually, and hard-hitting campaigns towards prevention have helped to keep this rate stable since over the last decade.1 However, it has not declined. Since the beginning, prevention efforts have relied on education and consistent condom use. Other strategies include treatment as prevention (TasP) – early treatment of infected persons who may not need treatment yet themselves, but by being treated will reduce overall viral load – and post-exposure prophylaxis (PEP). However, it is obvious that new tools need to be implemented if we are to ever slow (or stop) new infections. One such promising new strategy is the use of pre-exposure prophylaxis (PrEP). What is PrEP? PrEP is a strategy that encompasses the use of ARVs in uninfected persons at high risk for infection to protect against HIV acquisition. It reduces but does not eliminate the risk of infection. Part of the rationale behind utilizing prophylaxis in persons who have ongoing exposure to the virus is based on its efficacy in infants of infected mothers. Another part of its appeal is that it is the first preventive measure to place sole control to the at-risk individual, which could have revolutionary impacts to protect individuals who are unable to negotiate condom use. Importantly, PrEP does not just encompass the isolated use of ARVs. It is encouraged to be AHEC Capstone 2014 Remigio A. Roque designed as a “PrEP Package”2 – to include comprehensive HIV prevention services such services as counseling, HIV testing, STD screening/treatment, and free condoms. What data currently exist to support the use of PrEP? The FDA approved the prophylactic use of Truvada (emtricitabine/tenofavir; TDF-FTC), a combination of two NRTIs, in July 2012 after several randomized clinical trials demonstrated its effectiveness and safety at preventing HIV acquisition in high risk populations.3 The results of studies to date have been varied but promising. The first of these studies, the multi-national Preexposure Prophylaxis Initiative (iPrEx) trial, demonstrated a 44% relative reduction in the incidence of new infection among men who have sex with men (MSM) and transgender women who have sex with men with the use of daily oral TDF-FTC. Additionally, the prophylactic effect correlated with the detectable level of drug in the blood. For those patients with detectable levels, a 92% relative reduction of risk was observed compared to those without detectable levels.4 Similar results were observed in heterosexual subjects. The Partners PrEP study examined the effect of daily oral prophylaxis (tenofavir alone, or combined with emtricitabine) on the prevention of infection in serodiscordant heterosexual couples. The relative reduction in new acquisition of HIV was 67% for TDF alone and 75% for TDF-FTC, again with better protection (86% and 90%, respectively) seen in those with detectable drug levels.5 The TDF2 study in Botswana also demonstrated effectiveness of prophylaxis in heterosexuals, with daily TDF-FTC use resulting in 62% reduction in infections.6 Research has expanded to looking at intravenous drug users as well. The Bangkok Tenofavir Study showed a 49% reduction in infection compared to placebo in IV drug users taking daily tenofavir.7 Common to all of these studies were issues of suboptimal adherence. In fact, two other studies, FEM-PrEP (Preexposure Prophylaxis Trial for HIV Prevention among African Women) and VOICE (Vaginal and Oral Interventions to Control the Epidemic) failed to show any effectiveness of antivirals for prophylaxis in African women, with the hypotheses being that adherence played a significant role.8,9 One other issue universally discussed was resistance. In many of the studies, those persons who were found to have resistant strains of HIV were discovered to have been infected prior to starting the study drug.4,5 Resistance was rare in persons who seroconverted after initiation of the drug. Low adherence may not offer protection but may also result in a lower probability of developing resistance, whereas high adherence may actually increase the risk of drug resistance, especially if treatment is initiated in someone already infected.5 What are the current guidelines for using PrEP? Several agencies worldwide have released guidelines to help providers to implement PrEP into their practice.10 In the United States, efforts to establish comprehensive public health service guidelines are being led by the Centers for Disease Control (CDC). Until more comprehensive guidelines are developed, the agency has released interim guidelines for the use of PrEP among MSM, 11 heterosexually active men and women, 12 and intravenous drug users. 13 Even more recently, the New York State Department of Health AIDS Institute released its own set of treatment priorities.14 AHEC Capstone 2014 Remigio A. Roque These documents collectively provide input on how to navigate determining a patient’s eligibility for treatment, how to prescribe and begin treatment, the recommended follow-up, and how to properly discontinue the use of PrEP. Highlights are summarized below. Key Principles:14,15 PrEP should not be a sole intervention for HIV prevention but should be used only as part of a comprehensive prevention plan to include counseling services, HIV testing, STD screening/treatment, and condoms. PrEP is indicated for individuals who have documented negative HIV test results (preferably on the same day as initiation of PrEP) and are at ongoing high risk of HIV infection. If the patient has symptoms consistent with acute infection or has knowingly had sex with an HIV-positive person in the last month, HIV serologic screening and a plasma HIV RNA assay should be obtained before proceeding. Efficacy is dependent on adherence and should therefore only be prescribed to those who are able and express willingness to adhere. PrEP is contraindicated in individuals with documented HIV infection, creatinine clearance <60mL/min, and those not ready to adhere to the regimen. Lack of use of barrier protection methods, however, should not be a contraindication. Breastfeeding individuals should not be started on PrEP. Initial prescription should be for only 30 days to allow for proper follow-up and assessment of adherence, tolerance, and commitment. At any one time, no more than three months’ worth of medication should be prescribed and only after confirmation that the patient has remained HIVnegative. Follow-up visits should occur every two to three months to determine HIV and pregnancy status, monitor adherence, assess risk behaviors, screen for STDs, and provide condoms. STD testing should occur every six months regardless of symptoms, and creatinine should be checked every three to six months. PrEP should be immediately discontinued if the individual receives a positive HIV test, experiences adverse effects, or requests to stop treatment. All patients who are stopping PrEP should be tested for HIV infection. If positive, genotypic testing should be performed and the patient linked to HIV care. If negative, patient should be referred to appropriate risk reduction support services. What potential barriers – both practical and ethical – exist regarding the successful implementation of PrEP? As already discussed, the data suggest that PrEP may be a promising addition to the provider’s toolbox in efforts to prevent new HIV infection. Like any other new treatment, the initiation of widespread use of PrEP faces many challenges, especially until more data is available. The barriers that exist are complex and encompass issues of ethicality, practicality, and acceptability. And as many ideas surrounding HIV care are multifaceted, so are these concerns. The following discussion will attempt not to strictly stratify these ideas but to examine the potential obstacles in the context of all three. Provider Willingness, Adherence, and Safety AHEC Capstone 2014 Remigio A. Roque With any new therapy, it is crucial for providers to accept and be willing to utilize the treatment for it to be successful. Several studies have shown that while many providers are aware of PrEP, most have not prescribed it.16,17 Many would be willing to do so, however, in certain contexts or with more information. A study by Karris et al. examined the opinions of a subgroup of providers in the U.S. and Canada regarding PrEP. It found that the majority (74%) of providers supported the idea of PrEP; yet, only 9% had actually provided it to patients, and an additional 43% stated they would be willing to do so. Of those 48% who stated they would not provide PrEP treatment, several concerns and perceived barriers to implementation were identified.16 The major concern among these physicians was adherence and whether or not this would have implications on future resistance. Worries about adherence are certainly valid, as efficacy has been shown to be strongly linked to adherence in the major studies to date.4-9 Because PrEP is not a complete regimen aimed to treat active HIV infection, there are concerns that if a person becomes infected while using PrEP and continues to use the medications that resistance may develop, impacting both the future treatment of the individual but also of the broader community if resistance is transmitted. Whether or not these concerns are valid remains to be seen. In the iPrex, TDF2, Partners-PrEP, and Bangkok Tenofavir trials, cases of resistance were not observed in participants who seroconverted after PrEP initiation.4-7 Only in cases of unidentified HIV infection at enrollment was resistance observed, highlighting the importance of ensuring uninfected status at enrollment and of regular testing during PrEP use. Related to adherence are the issues of safety and another concern identified by Karris et al. – reluctance to use potentially toxic drugs in healthy persons. Some have argued that safety may play a role in low adherence, with side effects causing erratic or inconsistent use. This brings about the fear of transmitting resistant strains of the virus as already mentioned.18 The adverse effects of antiretroviral medications are known, with renal toxicity being a known complication of tenofavir (and therefore the rationale behind regular testing of creatinine). It should be noted, though, that in the iPrex and Partners-PrEP trials, while more individuals taking PrEP experienced elevations in creatinine over those taking placebo, the results were not statistically significant, and all elevations returned to baseline after discontinuation of the study drug.4,5 Taking the study drug resulted in more nausea and weight loss than placebo4 and modestly increased amounts of GI symptoms and fatigue.5 While it seems that the safety profile of PrEP is favorable, it is yet to be seen how many adverse effects will be encountered if treatment is expanded outside of research participants who are likely to have been selected because they had fewer comorbidities.18 Even so, in the Karris cohort, more than 50% of providers were concerned about giving healthy patients treatment with drugs.16 Whereas current treatment-as-prevention methods also involve the use of ARVs in patients that may not actively need them, those treated individuals are actively infected. There is a known potential risk of transmitting the virus which differs from using the medications “in case” a person is exposed. Proponents of PrEP might justify its use by comparing it to malarial prophylaxis. Venter et al. argue that malarial prophylaxis involves prescribing healthy people with a drug that is expensive, may cause various side effects, must be taken consistently over a set period of time, and which will allow them to engage in risky behavior that may expose them to an infection that the prophylaxis may not even prevent.19 Whereas providing a chloroquine for a person to go on holiday generally does not raise any ethical issues for most providers, the same is not true for all when it comes to PrEP. In addition to safety concerns, some providers may feel that engaging in risky sexual behavior requires a more active role than that of the vacationer who travels to areas where malaria is AHEC Capstone 2014 Remigio A. Roque endemic and therefore is not as valid a reason for prophylactic treatment. However, both activities may also be seen as voluntary and for pleasure and thus could be considered equally valid. Furthermore, some providers fear that by providing PrEP to patients that they will be encouraging risky behavior rather than decreasing it. Risk compensation Risk compensation is the idea that individuals adjust their behavior in response to changes in their perceived level of risk. In terms of PrEP, if behavior disinhibition were to occur, it might be manifested in unprotected sex, an increased number of sexual partners, or engaging in other high-risk behaviors. Potential consequences of such behavior include both increased rates of other STIs which are not covered by PrEP and/or HIV infection resulting from the protective ability of the PrEP regimen being overwhelmed.18 It is unclear whether or not such behavior would be likely to occur. In the original iPrex trial, self-reported high-risk behavior decreased after enrollment and remained lower than baseline afterwards. It was hypothesized that these behavioral changes might have been due to the intensive “package” of prevention services, the “daily reminder” of taking a pill serving as a warning of imminent risk, and the fact that participants did not know whether or not they were taking placebo or active drug.4 Would this hold up if the study was open-label? Unfortunately, no open-label studies have been completed, but Marcus et al. re-examined the data from iPrex to analyze participants’ behavior in the context of their assumed treatment group and their beliefs about PrEP’s efficacy. That study found no evidence of risk compensation in the group of participants who believed that they were receiving PrEP, a surrogate for an open-label group. In both the group believing that they were receiving placebo and the one believing they were receiving treatment, trends towards less risky behavior and higher condom use was observed.20 Studies should be expanded to observe whether or not this will prove to be applicable to a greater population. Access, Allocation, Stigma and Cost Up to this point, many of the concerns discussed could fall under the ethical domain of well-being – the idea that the well-being of the individual and community must be balanced against the strong moral claim to prevent HIV infection. Another relevant ethical domain is that of justice – the concept that interventions must be fair both in terms of processes and distribution of benefits.18 In this regard, special attention should be given to the subject of access to and allocation of PrEP. These are not only points of concern with PrEP but also with TasP methods. Simply, when it comes to ARVs, there are competing priorities. On one hand, the use of these medications for PrEP and TasP is designed to prevent the incidence of new infection and therefore decrease overall HIV burden. On the other hand, is it fair to use these medications for healthy individuals, both HIV-positive and HIV-negative, when there are many HIV-positive individuals who are symptomatic or at risk of disease progression who may not have the resources available to obtain the same medications? Furthermore, will users of PrEP divert their medications, for altruistic or selfish means (sharing of pills was observed in the Bangkok trial7 and such action may have larger implications in terms of adherence and resistance)? More studies will need to be conducted to examine whether the rollout of PrEP would impact the availability of ARVs for those who need them for immediate treatment. Conversely, as PrEP places the burden of responsibility on the uninfected person to obtain treatment, an individual must be willing to seek it out. Until AHEC Capstone 2014 Remigio A. Roque more readily accepted, PrEP users may face many of the stigmatizing factors that those living with HIV encounter despite actually taking a responsible preventive measure.18 Stigma may prevent those who would benefit most from PrEP from accessing it. This is especially true in communities where homosexuality or sex work are rejected practices, unless avenues become available for access that do not require identifying in either subgroup.21. Providers are also concerned about access and rationing, especially when there are other known-to-work, nonmedication prevention methods16 that may actually be more cost effective. As PrEP has not yet been utilized on a large scale, there is still uncertainty on what its cost-benefit ratio will be. Cost-effectiveness analysis is beyond the scope of this document and depends very much on the price of the available drugs, the type of modeling utilized, and what parameters are chosen to guide them. Studies have varied widely thus far, but targeting PrEP to only the highest risk individuals seems to be the most promising strategy when it comes to cost.22-24 Even still, Horberg et al. suggest an estimate of about $17,900 annually to cover the entire “PrEP package, with the majority being made up of the price of name-brand Truvada, for which there is currently no generic.”25 With such a hefty price tag, consumers will likely need the aid of insurance to help deflect out-ofpocket spending, and at this time it is not sure whether or not insurance companies, both private and public, will cover. More work will need to be done as PrEP gains in popularity and more outcomes data is collected in order to work towards feasible payer solutions. Conclusion/Opinion Statement While much advancement in HIV care has occurred in the last three decades, the rate of new infections has not significantly declined since the 1990s. Prevention efforts focused on education and consistent condom use are cheap, easily accessible, and have made large impacts, but it is clear that more needs to be done. Antiretrovirals have been used as part of treatment-as-prevention strategies (TasP), and the stage is set for them to be potentially groundbreaking as part of a new strategy, pre-exposure prophylaxis (PrEP). In the U.S., which is relatively resource-rich, PrEP should be made available to individuals at very-high risk for infection but should be seen as a temporary measure to be discontinued when the risk is lower. Efforts should still be focused on changing risky behavior if possible. In areas that are more resource-poor, ARVs should be prioritized to treat HIV-positive individuals who require treatment before TasP or PrEP programs are initiated. A push should be made to increase resources and equalize costs because PrEP is uniquely situated to give the most at-risk individuals control over their own prevention in ways that condom programs cannot always do. Data have revealed that PrEP is effective and safe, and while more studies need to be conducted to determine long-term feasibility and cost-effectiveness, physicians should feel comfortable in the meantime prescribing the regimen with assistance from the CDC and NY State guidelines. As adherence is strongly tied to efficacy and may have impacts on future resistance, providers must confirm that patients are suitable candidates prior to prescribing and that the appropriate follow-up and counseling services will be readily accessible. Providers must also do their part to ensure that users understand that PrEP is just like any other prevention method in that it is not 100% effective, and patients should be counseled on potential side effects and the importance of timely discontinuation in the event of seroconversion. Simply stated, providers should embrace PrEP as another addition to their clinical toolbox. AHEC Capstone 2014 Remigio A. Roque References 1. Centers for Disease Control and Prevention (CDC). Today's HIV/AIDS epidemic. http://www.cdc.gov/nchhstp/newsroom/docs/HIVFactSheets/TodaysEpidemic-508.pdf. Accessed February 14, 2014. 2. The Fenway Institute. Introducing the "PrEP package" for enhanced HIV prevention: A practical guide for clinicians. http://www.lgbthealtheducation.org/wp-content/uploads/121.125_PrEPdocuments_clinicians_v3.pdf. Updated 2012. Accessed February 14, 2014. 3. U.S. Food and Drug Administration. FDA approves first drug for reducing the risk of sexually acquired HIV infection. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312210.htm. Updated 07/17/2012. Accessed February 14, 2014. 4. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. doi: 10.1056/NEJMoa1011205; 10.1056/NEJMoa1011205. 5. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. doi: 10.1056/NEJMoa1108524; 10.1056/NEJMoa1108524. 6. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in botswana. N Engl J Med. 2012;367(5):423-434. doi: 10.1056/NEJMoa1110711; 10.1056/NEJMoa1110711. 7. Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in bangkok, thailand (the bangkok tenofovir study): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381(9883):2083-2090. doi: 10.1016/S0140-6736(13)61127-7; 10.1016/S01406736(13)61127-7. 8. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among african women. N Engl J Med. 2012;367(5):411-422. doi: 10.1056/NEJMoa1202614; 10.1056/NEJMoa1202614. 9. Microbicide Trials Network. Daily HIV prevention approaches didn't work for african women in the VOICE Study<br />. http://www.mtnstopshiv.org/node/4877. Accessed February 14, 2014. 10. PrEPWatch. Clinical guidance. http://www.prepwatch.org/prep-access/guidance/. Accessed February 14, 2014. 11. Centers for Disease Control and Prevention (CDC). Interim guidance: Preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep. 2011;60(3):65-68. 12. Centers for Disease Control and Prevention (CDC). Interim guidance for clinicians considering the use of preexposure prophylaxis for the prevention of HIV infection in heterosexually active adults. MMWR Morb Mortal Wkly Rep. 2012;61(31):586-589. AHEC Capstone 2014 Remigio A. Roque 13. Centers for Disease Control and Prevention (CDC). Update to interim guidance for preexposure prophylaxis (PrEP) for the prevention of HIV infection: PrEP for injecting drug users. MMWR Morb Mortal Wkly Rep. 2013;62(23):463-465. 14. New York State Department of Health AIDS Institute. Guidance for the use of pre-exposure prophylaxis (PrEP) to prevent HIV transmission. http://www.hivguidelines.org/clinical-guidelines/pre-exposureprophylaxis/guidance-for-the-use-of-pre-exposure-prophylaxis-prep-to-prevent-hiv-transmission/. Updated 2014. Accessed February 15, 2014. 15. Centers for Disease Control and Prevention (CDC). PrEP: A new tool for HIV prevention. http://www.cdc.gov/hiv/prep/pdf/PrEPfactsheet.pdf. Updated 2012. Accessed February 14, 2014. 16. Karris MY, Beekmann SE, Mehta SR, Anderson CM, Polgreen PM. Are we prepped for preexposure prophylaxis (PrEP)? provider opinions on the real-world use of PrEP in the united states and canada. Clin Infect Dis. 2013. doi: 10.1093/cid/cit796. 17. Krakower D, Mayer KH. Engaging healthcare providers to implement HIV pre-exposure prophylaxis. Curr Opin HIV AIDS. 2012;7(6):593-599. doi: 10.1097/COH.0b013e3283590446; 10.1097/COH.0b013e3283590446. 18. Sugarman J, Mayer KH. Ethics and pre-exposure prophylaxis for HIV infection. J Acquir Immune Defic Syndr. 2013;63 Suppl 2:S135-9. doi: 10.1097/QAI.0b013e3182987787; 10.1097/QAI.0b013e3182987787. 19. Venter F, Allais L, Richter M. Exposure ethics: Does hiv pre-exposure prophylaxis raise ethical problems for the health care provider and policy maker? Bioethics. 2013. doi: 10.1111/bioe.12021; 10.1111/bioe.12021. 20. Marcus JL, Glidden DV, Mayer KH, et al. No evidence of sexual risk compensation in the iPrEx trial of daily oral HIV preexposure prophylaxis. PLoS One. 2013;8(12):e81997. doi: 10.1371/journal.pone.0081997; 10.1371/journal.pone.0081997. 21. Haire B, Kaldor JM. Ethics of ARV based prevention: Treatment-as-prevention and PrEP. Dev World Bioeth. 2013;13(2):63-69. doi: 10.1111/dewb.12026; 10.1111/dewb.12026. 22. Juusola JL, Brandeau ML, Owens DK, Bendavid E. The cost-effectiveness of preexposure prophylaxis for HIV prevention in the united states in men who have sex with men. Ann Intern Med. 2012;156(8):541-550. doi: 10.7326/0003-4819-156-8-201204170-00001; 10.7326/0003-4819-156-8-201204170-00001. 23. Hellinger FJ. Assessing the cost effectiveness of pre-exposure prophylaxis for HIV prevention in the US. Pharmacoeconomics. 2013;31(12):1091-1104. doi: 10.1007/s40273-013-0111-0; 10.1007/s40273-013-0111-0. 24. Schackman BR, Eggman AA. Cost-effectiveness of pre-exposure prophylaxis for HIV: A review. Curr Opin HIV AIDS. 2012;7(6):587-592. doi: 10.1097/COH.0b013e3283582c8b; 10.1097/COH.0b013e3283582c8b. 25. Horberg M, Raymond B. Financial policy issues for HIV pre-exposure prophylaxis: Cost and access to insurance. Am J Prev Med. 2013;44(1 Suppl 2):S125-8. doi: 10.1016/j.amepre.2012.09.039; 10.1016/j.amepre.2012.09.039.