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Are We Prepped for PrEP? Provider Opinions on the Real-World Use of PrEP in the U.S. and Canada
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Status of Truvada (TVD) for HIV Pre-Exposure Prophylaxis (PrEP) in the United States: An Early Drug Utilization Analysis.....ICAAC 2013
Almost Half of Early US PrEP Are Women, Often in Southern States.....ICAAC, September 10-13, 2013
Clinical Infectious Diseases Advance Access published December 6, 2013
Karris, Maile Y1, Beekmann, Susan E2, Mehta, Sanjay R1, Anderson, Christy M1, Polgreen, Philip M2,3 1Department of Internal Medicine, University of California San Diego, La Jolla, California, USA 2Departments of Internal Medicine and 3Epidemiology, University of Iowa Carver College of Medicine
Article Summary: We present the results of a nationwide survey regarding HIV pre exposure prophylaxis (PrEP) opinions and practices of infectious diseases physicians. Providers supported PrEP, but very few had provided it. Despite CDC guidance documents real-world PrEP practices were highly variable.
Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (Truvada) has demonstrated efficacy in placebo controlled clinical trials involving men who have sex with men[1], high risk heterosexuals[2], serodiscordant couples[3] and intravenous drug users[4]. To assist in the real-world provision of PrEP, the Centers for Disease Control has released guidance documents for PrEP use
Methods: Adult infectious diseases physicians were surveyed about their opinions and current practices of PrEP through the Emerging Infections Network (EIN). Geographic Information Systems analysis was used to map out provider responses across the United States (U.S.).
Results: 573 out of 1175 (48.8%) EIN members across the country responded to the survey. A majority of clinicians supported PrEP but only 9% had actually provided it. Despite CDC guidance, PrEP practices were variable and clinicians reported many barriers to its real-world provision.
Conclusions: The majority of adult infectious disease physicians across the U.S. and Canada support PrEP but have vast differences of opinion and practice, despite the existence of CDC guidance. The success of real-world PrEP will likely require multifaceted programs addressing barriers to its provision and will be assisted with the development of comprehensive guidelines for real-world PrEP.
Implementation of HIV prevention measures such as perinatal antiretroviral prophylaxis [5], needle-syringe programs in intravenous drug users [6], and antiretroviral treatment as prevention [7] are having a dramatic impact on the HIV epidemic [8-10]. The observation that HIV pre-exposure prophylaxis (PrEP) decreases the risk of HIV infection in clinical trials of high-risk men who have sex with men (MSM), HIV serodiscordant couples, heterosexual persons in areas of high HIV incidence [1-3, 11] and intravenous drug users (IVDU) [4] has generated enthusiasm [12]. However, two studies of PrEP use in women were not promising, with the FEM-PrEP [13] study requiring an early discontinuation for futility and the VOICE study reporting no effect in the intention-to-treat analyses [14]. The divergent results of PrEP studies are largely attributed to differences in PrEP adherence between studies, but other potential factors (biologic differences or complex sociodemographic issues) have not been evaluated [15]. The divergent results also raise concerns about the feasibility and efficacy of real-world PrEP. To assist clinicians in the implementation of PrEP the Centers for Disease Control (CDC) has published guidance documents detailing how to determine eligibility, begin, follow-up and discontinue PrEP [16, 17] until comprehensive U.S. Public Health Service (PHS) guidelines are available. The main purpose of this survey was to assess provider opinions, readiness and current practices of PrEP in the U.S. and Canada.
Study Population

The Infectious Disease Society of America's (IDSA) Emerging Infections Network (EIN) is a provider based network of infectious diseases physicians actively involved in clinical practice who belong to the IDSA. In June 2013, this electronic survey was sent by staff at the EIN coordinating center to members with an adult infectious diseases practice. We sent two reminders to non-responders at 1-week intervals.
PrEP Survey
A 10 question survey was developed to evaluate the current practices and attitudes of PrEP among infectious disease experts who are members of the EIN. This survey included a screening question to elicit provider opinions about PrEP in general. For participants who had or would provide PrEP our survey inquired about: the participant's HIV practice, to whom they had provided or would provide PrEP, how they assess eligibility, how they measure adherence, when PrEP would be discontinued, and what perceived barriers exist.
Geographic Information System:
ArcGIS (ESRI, Redlands, CA) was utilized to provide geographic visualization of provider responses from the survey. All surveys were geo-tagged according to the location of the provider's practice. To ensure provider anonymity only the first three digits of the participating provider's practice zip code was used. Responses to questions 1, 2, 3 and 10 were mapped. We did not include the number of respondents per area. Given that Canadian respondents were only coded by country, we elected not to include them in our GIS analysis.
Statistical Analyses:
For comparisons between respondents and non-respondents only active query members who have previously participated in at least one EIN survey were included. For this survey n=115 persons (the EIN has a percentage of members who register but never participate in the query process and they were not included). We analyzed the data in SAS, version 9.3 (SAS Institute). We calculated differences in responses between participants who prescribed PrEP and those who would prescribe PrEP but had not yet prescribed it. For questions in which participants could only select one response, we used Fisher's exact test. For questions in which participants could select more than one response, we used chi-square tests with a second-order Rao-Scott adjustment. For multi-response questions, individual responses were analyzed separately using Fisher's exact test.
Survey Population:

A total of 573 out of 1175 (48.8%) active physician members responded to this survey from June 5, 2013 to July 7, 2013. Respondents included broad representation from the U.S. and Canada with 51% of members responding from New England, 53% from the Mid Atlantic, 49% from East North Central, 46% from West North Central, 46% from South Atlantic, 45% of East South Central, 63% of West South Central, 42% of Mountain, 50% from Pacific and 35% from Canada (no responses were received from members in Puerto Rico). A similar breadth existed when respondents were evaluated by type of employment with responses from 48% of the members employed by hospital/clinic, 48% private practice, 49% University/medical school and 49% VA and military. Respondents were significantly more likely than non-respondents to have had at least 15 years of infectious diseases experience (p <0.0001). This response rate and difference in demographics is typical of EIN surveys [18, 19].
Providers are Willing to Provide PrEP, but Few Have:
A majority of respondents support the provision of PrEP (74%), but a fair proportion remained unsure (14%) and 12% did not support PrEP. Despite this strong support for PrEP only 9% had actually provided PrEP, 43% had not provided PrEP but would, 34% believed PrEP was not relevant to their practice and 14% would not provide PrEP. When asked why physicians would not provide PrEP, 77% were worried about adherence and the risk for future resistance, 57% were concerned about cost and reimbursement issues, 53% did not want to use potentially toxic drugs in healthy persons, and 53% felt there was insufficient evidence for the efficacy of real-world PrEP (Table 1). Other reasons for not prescribing PrEP included risk compensation ("Efficacy is limited and creates a false sense of security.", "Concern about irresponsible sexual activity.", "If they won't use condoms they won't use pills."), a lack of resources and information ("Don't have the capacity to see the potential large number.", "Don't know enough about it to feel comfortable.", "Lack of effectiveness data in local context."), limited resource allocation ("There are better prophylactics.", "Transmission can be prevented without medications.", "Concern about the selling of [PrEP] from HIV positives to HIV negative.") and personal ideology ("Moral issues.", "Medicine should not attempt to reverse bad behaviors artificially.", "The balance is not right in terms of risks/benefits.")
Providers Would Use PrEP for Patients with a Range of Risk Factors:
Respondents who had provided PrEP or who would provide PrEP were then asked questions regarding the "real-world" use of PrEP. A majority of respondents stated they would provide PrEP if their patients had risk factors. Similarly a majority of respondents would provide PrEP if their patient requested it. The main risk factor that would prompt PrEP was an HIV-infected partner who was not on HAART, followed by reported unprotected sex, multiple sex partners, and patients with an HIV-infected partner on HAART. A minority of respondents would provide PrEP for intravenous drug users (Table 2). Other reasons physicians would prescribe PrEP included for "discordant couple who are attempting to get pregnant", in a "abusive or coercive sexual relationship", for "heterosexual commercial sex workers", and "transgender females with risk factors"
Providers Report Variations in PrEP Practices
When specifically asked about the use of HIV nucleic acid testing (NAT) in determining eligibility and in follow-up, physicians report they would use NAT before starting PrEP and every 3 months while on PrEP. 15% reported they would not use HIV NAT for PrEP and 19% stated they would use it only when patients had symptoms of acute HIV. In terms of measuring adherence, 81% of clinicians would rely on patient self-report, 45% would rely on pharmacy refills, 14% would use pill counts, and 3% mentioned drug levels in the blood. 11% of providers would not measure adherence. Most physicians would measure PrEP adherence every 3 months with 16% evaluating more frequently and 13% less frequently (Table 2). Other respondents commented that they would measure PrEP "More frequently early on, then less frequently if adherent.", "Depends on the patient's risk." and "Depends on the stability of patient relationships." PrEP discontinuation would occur most commonly with the development of any toxicity, than with severe toxicity, when adherence is < 80%, when risk behavior decreases, and least commonly if the sexual partner of the at-risk person is virologically suppressed on HAART (Table 2).
Perceived Barriers to PrEP are Many:
Physicians who have or would give PrEP were then asked to score barriers to PrEP from 1 (least) to 6 (greatest) but no one barrier could be differentiated as carrying more weight than another (based on mean and median value). Summing the ranks of the barriers demonstrated that the cost of PrEP was the highest concern for providers, followed by: future drug resistance, starting a toxic drug in healthy persons, efficacy of real-world PrEP, provision is time consuming, and patients were not at risk. Based on other comments provided, physicians polled did not seem to believe they were going to be seeing patients seeking PrEP ("Ours is HIV clinic and not HIV negative care.", "PrEP needs to be in the primary care setting."), had concerns about the cost-effectiveness of PrEP ( "It's an expensive condom." "Limited money to go around is this the best use of such monies.", "Bigger bang for the buck is getting all the HIV positive patients on ART and keeping them adherent."), did not believe the potential benefits outweigh the costs ("Is virtually a model for development and spread of resistant viruses.", "Not a good idea."), reiterated doubt for the uptake and difficulty of implementation of real-world PrEP ("I have offered PrEP to partners of HIV positive patients and they have all declined.", "The patients most at risk (appropriate for PrEP) don't come into care.", "The details need to be fleshed out in guidance a lot better.")
Differences in Practices of Persons Who Have Provided PrEP Compared to Those Who Would--
To evaluate if experience impacted PrEP opinions and practices we evaluated the differences between participants who had provided PrEP and participants who had not but would. Not surprisingly clinicians who had provided PrEP in the last 12 months saw more persons with HIV (p=0.04) (Table 2). Participants who had provided PrEP seemed more likely to provide PrEP to MSM regardless of risk factors, and more likely to provide PrEP to MSM or heterosexuals with a partner on HAART (Table 3). Participants who had provided PrEP also appeared more likely to use NAT testing only in settings of acute HIV infection and trends existed suggesting they were more likely to continue to use PrEP with patients with adherence < 80% and in persons with a virologically suppressed HIV positive partner (Table 3). There were no differences in provider demographics between those that had provided PrEP and those that would.
Interestingly physicians who had provided PrEP had mixed feelings about the practice with comments such as "This will never impact the overall incidence of HIV in the US.", "Not all are convinced by the data that is presented." And "If a person has an HIV positive partner who is not on HAART, would first counsel HAART."
A Geographic Dimension To Survey Responses:
To illustrate the responses of physicians across the U.S. ArcGIS software was utilized (Supplemental Figure 1). Respondents who support the idea of PrEP and those who do not did not appear to be clustered geographically. In fact, both populations were spread across the country and even within the same zip codes (Figure 1.) Persons who had provided PrEP or would provide PrEP were also widespread and not exclusively located in areas of high HIV prevalence (Figure 2.) Top ranked barriers were also widespread across the country with most areas containing providers that prioritized different barriers (Supplementary Figure 2 A-F). Statistical analyses of regional differences revealed that the only barrier that appeared to differ based on region was that provision of PrEP was time consuming with providers in the Pacific and Mountain regions ranking this highly compared to providers in New England and the Mid-Atlantic (p=0.0005) Supplemental Table 1.
We provide the results of the largest-to-date survey of infectious disease physicians' opinions and practices of PrEP across the U.S. and Canada [20-22]. Following the release of CDC guidance documents and FDA approval of Truvada for PrEP strong support exists for PrEP but very few clinicians (9%) had actually provided it. Additionally a wide range of PrEP practices existed among those who have or would give PrEP including differences in deciding who is eligible for PrEP, how persons on PrEP are followed-up and how PrEP is discontinued. Barriers to the provision of PrEP were many with concerns about PrEP efficacy in the real-world being the greatest concern. A previous study of in-depth interviews of healthcare providers (n=22) performed in 2011 in San-Francisco, Oakland, and Los Angeles revealed similar concerns with providers reporting little demand for PrEP, disagreement about appropriate PrEP patients, and insufficient capacity for PrEP despite beliefs in the potential for PrEP to impact the HIV epidemic [20].
Of interest was the finding that despite CDC guidance documents, great variability exists in the real-world practice of PrEP suggesting either unawareness of, disagreement with, or ambiguity of CDC guidance (we did not ask specific questions about this). The providers surveyed reported PrEP would be initiated for a wide variety of risk factors, although persons who had provided PrEP did appear to be less discriminating. While guidance documents do provide the appropriate populations for PrEP (MSM, high risk heterosexuals, serodiscordant couples, and high risk IVDU) it is vague about what constitutes "ongoing very high risk for acquiring HIV infection."[4, 16, 17]. Physicians stated they would use HIV NAT more frequently than what is currently recommended in the guidance documents. This opinion may have been bolstered by the findings that in published PrEP studies (iPrEX and TDF2) ART resistance only occurred in acutely infected participants who were seronegative at time of PrEP initiation [1, 2]. Providers were more consistent on how they would assess PrEP adherence with a majority stating patient self-report would be used. However, unlike with HIV positive persons who demonstrate increases in HIV viral load with poor medication adherence, no objective point-of-care measure exists for determining adherence to PrEP. The experience of VOICE (participants reported 90-91% adherence, but only ~30% had any evidence of tenofovir levels in the blood) and FEM-PrEP (95% of women reported taking pills as recommend, but only 25-33% had detectable tenofovir in blood) suggests that self-report may not be a sufficient marker of adherence for PrEP [23, 24]. Lastly, providers varied on when PrEP would be discontinued with half stopping for decreased adherence or decreases in risk behaviors and only a third stopping PrEP when an HIV positive partner is completely suppressed. This likely represents a gap in current knowledge of the exact level of adherence that reaps the benefits of PrEP and whether PrEP provides additional protective benefit when used in serodiscordant couples when the HIV positive partner is suppressed (the HIV positive partners in Partners PrEP were not on suppressive ART [3].
These results reveal that while PrEP acceptability is high, the uptake and practice is still low and perception persists that multiple barriers exist to adequately provide PrEP. A modest level of skepticism about the efficacy of real-world PrEP also still exists. Many physicians expressed concern that PrEP may lead to risk compensation (i.e. practice higher-risk behaviors) negating the PrEP benefit, and that PrEP would be resource heavy and not cost-effective. These concerns may not be abated with increased provider education as has been recommend by previous studies[21, 22], but most likely requires the completion of ongoing open-label PrEP studies (iPrEX OLE etc.), future studies of real-world PrEP implementation and an increase in the collective experiences of healthcare providers. GIS mapping of top ranked barriers also demonstrated individual providers in the same area had differently ranked barriers to PrEP provision. This suggests that successful real-world PrEP will require strategies that address multiple barriers.
Limitations of this study include the use of convenience sampling which may introduce selection bias. The EIN is not a random sample of providers, and clinicians that participate in the EIN may not necessarily represent the opinions of clinicians that do not participate. Additionally our response rate was 48.8% and respondents were more likely to have had more years of infectious diseases experience, but these providers may have a greater level of infectious diseases knowledge. We attempted to minimize response fatigue by restricting the survey to 10 questions but this does not completely eliminate bias. Lastly we did not perform an audit of actual practices which may have been more accurate than reported practices.
Our results show that that the majority of adult infectious disease providers across the U.S. and Canada are supportive of PrEP but have vast differences of opinions and practices despite the CDC guidance documents. CDC guidance is based on available clinical trial data and may be deliberately ambiguous because of the lack of information regarding real-world PrEP. The results of this survey and the additional comments provided by participants have highlighted the importance of future studies that specifically address the efficacy and risk compensation that occurs in open-label PrEP, the development of point-of-care objective adherence measures, description of long-term consequences of PrEP in HIV negative persons, the design of successful and "resource-light" approaches to risk reduction and adherence counseling, and novel approaches to improving PrEP cost-effectiveness.

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