Download AHEC Capstone 2014 Remigio A. Roque Are we PrEPared? An

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
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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
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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
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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
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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
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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.
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References
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