Abstract
Until recently there have been few primary care office-based strategies to reduce the transmission of HIV. In May 2014 the Centers for Disease Control and Prevention published updated practice guidelines recommending the use of preexposure prophylaxis (PrEP) with daily oral dosing of tenofovir/emtricitabine to help prevent HIV infection in high-risk individuals (strength of recommendation, A). Knowledge of PrEP among primary care providers is low, however, and this intervention is likely reaching only a small fraction of eligible patients. PrEP is recommended for certain injection drug users, nonmonogamous men who have sex with men, heterosexual women who have sex with men who have sex with men or injection drug users, and those in HIV serodiscordant relationships. Providers should obtain baseline laboratory values and provide initial counseling before prescribing PrEP. Regular office visits are necessary to ensure adherence, provide ongoing counseling, and monitor for side effects, including nausea, abdominal pain, headache, and, less commonly, increased creatinine. Guidelines and toolkits have been developed to assist in incorporating PrEP into primary care practice. PrEP is gaining widespread acceptance and has become a crucial tool in the fight to stop the spread of HIV.
More than 1.2 million Americans were living with HIV in 2013. Of those, 15% (n = 168,300) were not aware of their infection. There also were 47,000 new infections (15.0 per 100,000). This overall incidence masks a wide range of rates, from 1.8 per 100,000 among white women to 105.7 per 100,000 among African American men. Over 60% of new infections occurred among men who have sex with men (MSM).1
Most HIV prevention strategies, such as condom distribution and HIV testing and counseling campaigns, have been implemented on a population level.2 By contrast, 4 office-based approaches to HIV prevention are currently available to primary care clinicians. The US Preventive Services Task Force recommends high-intensity behavioral counseling on sexual risk reduction for sexually transmitted infections (STIs) (grade B), but the time and resources required for such intensive counseling may be prohibitive for many providers and patients.3 Treatment-as-prevention with combination antiretroviral therapy prevents HIV transmission by lowering community viral loads; this method has only an indirect effect on seronegative individuals.4 Male circumcision significantly reduces the risk of contracting HIV, but it has not been evaluated in low-prevalence settings and may not be acceptable to some uncircumcised men.5
The fourth and potentially most feasible strategy for clinicians and high-risk, HIV-negative patients is preexposure prophylaxis (PrEP)—the use of daily antiretroviral medication to reduce the risk of acquiring HIV infection. In May 2014 the Centers for Disease Control and Prevention (CDC) published updated practice guidelines recommending the use of PrEP with daily oral dosing of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (Truvada; Gilead Sciences, Foster City, CA) for this indication.6 This recommendation is based on several randomized controlled trials (RCTs)7⇓⇓⇓–11 and a Cochrane review12 supporting the safety and efficacy of PrEP for high-risk individuals, including MSM, injection drug users (IDUs), and heterosexual women who have sex with MSM or IDUs. The Vancouver Consensus, which emerged from the 2015 International AIDS Society Conference, states that PrEP “must be made available to protect those at high risk of acquiring HIV.”13
Despite the evidence, it is likely that this intervention is reaching only a small fraction of eligible individuals. One 2014 study of physicians in Massachusetts showed that although 99% of infectious disease specialists and 83% of generalists had heard of PrEP, only 40% of each group thought that PrEP should be readily available to all at-risk persons.14 Another 2014 study of American infectious disease specialists showed that only 9% had prescribed PrEP.15
Patients who might benefit from PrEP are likely not presenting to infectious disease physicians. Despite low awareness, primary care providers are already writing more prescriptions for PrEP than are specialists.16 If more family physicians and other primary care providers feel comfortable prescribing PrEP, this strategy for reducing HIV prevalence may reach more individuals who are vulnerable to infection.17 This article reviews the use of PrEP as an HIV prevention strategy that complements other established strategies to reduce HIV risk, and helps primary care clinicians understand how to most effectively prescribe TDF/FTC.
Evidence Base
A number of RCTs have established the efficacy of PrEP with TDF/FTC or TDF alone to prevent HIV transmission among high-risk populations. PrEP has significantly reduced HIV transmission rates among sexually active men and women in Botswana, a country with a high HIV burden9; among serodiscordant heterosexual couples in eastern Africa8; among IDUs in Thailand10; and among a global sample of MSM that included participants in San Francisco and Boston.7 A Cochrane meta-analysis of these studies found a relative risk of acquiring HIV infection of 0.49 (95% confidence interval, 0.28–0.85) for those taking TDF/FTC daily and 0.33 (95% confidence interval, 0.20–0.55) for those taking TDF alone. There was no statistically significant difference in HIV incidence between groups using TDF/FTC compared with TDF alone, and neither group had a significantly increased risk of adverse events.12 Early results from subsequent open-label studies suggest that PrEP is effective18 and adherence is high19 in real-world as well as investigational settings.
The benefits of PrEP for female patients who do not use intravenous drugs are less clear. Three randomized controlled trials conducted in Africa failed to show any statistically significant reduction in HIV incidence among heterosexual women using daily oral PrEP.20⇓–22 Two studies also investigated the use of pre- and postcoital tenofovir vaginal gel, but only one of these found a statistically significant effect on HIV incidence.22,23 While nonadherence likely contributed to the lack of effect, the authors of one study noted that some HIV infections occurred in female study participants with detectable serum concentrations of tenofovir.21
Trials published to date have investigated only the daily use of TDF or TDF/FTC among adults. Early results show that PrEP may also be effective as a “bridge” to antiretroviral therapy in serodiscordant African couples.24 RCTs are currently underway to investigate the use of PrEP with TDF/FTC in adolescents,25⇓⇓–28 intermittent “on-demand” dosing with TDF/FTC in adults,29,30 and an injectable depot formulation in adults that would only require treatment once every 3 months.31,32 Early results from one trial of “on-demand” PrEP for MSM are encouraging.33
Indications for Use
The CDC recommends the use of daily TDF/FTC in selected patients who are at high risk of acquiring HIV through sexual contact and/or intravenous injection of drugs not prescribed for them.6 Candidates should be adults known to be HIV negative immediately before starting PrEP. TDF/FTC for PrEP is approved by the US Food and Drug Administration only for adults who are not breastfeeding and have a creatinine clearance >60 mL/min.6,34 TDF/FTC is probably safe during pregnancy (US Food and Drug Administration pregnancy category B), but because of a small number of observed fetal exposures, fetal outcomes among pregnant women should be monitored using the Antiretroviral Pregnancy Registry (www.apregistry.com/). Specific selection criteria are listed in Table 1.
Because the risks of long-term use of TDF/FTC for PrEP are not fully known (see “Individual-Level Risks,” below), some clinicians use a time-limited prevention strategy to refine the use of PrEP for appropriate candidates. These clinicians consider prescribing PrEP for use in high-risk time periods, such as when previously safe relationships are disrupted, at one's sexual debut and during struggles with sexual orientation, or when a seronegative male is attempting to conceive with a seropositive female partner.35,36 Resources exist for helping clinicians choose appropriate candidates, including the PrEPline, a PrEP support hotline (1-855-448-7737, or 1-855-HIV-PREP) for clinicians that is operated by the Clinical Consultation Center at the University of California, San Francisco.
Initial Evaluation and Ongoing Monitoring
After behavioral screening identifies a patient as a potential candidate for PrEP, laboratory testing is necessary before the medication can be prescribed (Table 2). It is of critical importance that patients using PrEP be HIV negative. TDF/FTC alone is not adequate for HIV treatment; the use of PrEP in patients who are already infected with HIV may select for resistant HIV strains. Since it is difficult to clinically distinguish acute HIV from other acute viral syndromes, treatment should be deferred and testing for HIV RNA should be considered if fever, myalgias, arthralgias, or new lymphadenopathy is present.6
If all indicated testing is negative, PrEP should ideally be started 7 to 21 days before intercourse or other high-risk behaviors.35 Once a patient is taking PrEP, CDC guidelines recommend reevaluation in the clinic every 90 days to test for HIV (to prevent inadvertent use in HIV infection); to reinforce risk reduction behaviors; and to assess for medication side effects, STIs (including hepatitis B), pregnancy, and pregnancy intent (Tables 2 and 3). New York State guidelines are more conservative and recommend follow-up 30 days after initiating PrEP to assess for adherence, tolerance, and commitment to continuing PrEP.40 PrEP should be prescribed for ≤90 days to ensure adherence to screening and counseling recommendations.6 No study has investigated the question of when to stop PrEP, but a conservative approach that emphasizes the adoption of alternative means of protection before discontinuing PrEP is reasonable.35
Supporting Adherence to PrEP
Since adherence to a daily regimen of TDF/FTC is clearly associated with a reduced risk of HIV seroconversion, clinicians should consider using motivational interviewing and other techniques shown to improve adherence to PrEP.7,23,38 An evaluation of interventions to promote adherence to PrEP recommended participant-centered approaches, including addressing the specific context in which an individual incorporates and negotiates PrEP use.41 While complex, resource-intensive interventions are most effective for improving adherence to medical interventions in general, a systematic review also found evidence to support low-cost, low-intensity interventions that provided education or telephone calls.38 CDC guidelines recommend that clinicians incorporate motivational interviewing into their visits for prescribing PrEP with 4 simple items: (1) When you have taken medications previously? (2) How did you remember to take them? (3) Please tell me about any problems you had taking your pills. (4) What was most helpful in remembering to take them?6
Individual-Level Risks
In studies of PrEP, TDF/FTC caused side effects in a minority of patients. In some patients these symptoms were most acute in the first 1 to 2 months of use (called “start up syndrome”) and abated after longer use.8,9,39 When TDF/FTC was studied as part of a multidrug HIV treatment regimen, side effects were more severe (Table 4). The patient populations receiving PrEP and HIV treatment may vary in their baseline health and risk for complications.
Some have expressed concern that use of PrEP may increase high-risk sexual behaviors,46 but studies in investigational and real-world settings have not found this correlation; in two RCTs the opposite was found.7,19 This finding may reflect the services (eg, counseling, testing, and dispensing of condoms) that are provided along with the PrEP prescription and/or the possibility that taking a daily pill is a regular reminder of imminent risk and promotes safer sex practices.7
The cost of Truvada is estimated at $800 to $1000 per month, with additional costs related to clinic visits and HIV, STI, and pregnancy testing.39,47 Insurance coverage varies, though websites dedicated to tracking the issue note that there has not yet been a reported case of an insurer denying coverage, including Medicare and Medicaid.48 Patient assistance programs have been developed to assist those without insurance coverage (Table 5).
Preparing the Primary Care Office
Armed with the information above, a busy clinician can begin prescribing PrEP to eligible patients. But improving patient access to PrEP also includes increasing patients' and nonclinical staff's awareness of this service. Advertising and educational materials in the waiting room or examination rooms may increase patient awareness. New York City's Department of Health and Mental Hygiene uses an “academic detailing” program to increase awareness among clinicians and patients about the availability of PrEP, and to help clinics prepare themselves to offer PrEP services.49 This includes a checklist for clinic readiness that recommends identifying a clinic PrEP champion; preparing clinical and reception staff; understanding billing codes and PrEP patient assistance programs; and updating clinic procedures to include appropriate patient education materials, condoms, and protocols for routine follow-up tests.50 Once the clinic and staff are prepared, many additional resources are available to help prescribers safely provide PrEP (Table 6).
Systems-Level Risks and Benefits
The decision to use PrEP has ethical implications.51 The use of PrEP to prevent HIV seroconversion benefits not only the individual but also potentially his or her close contacts and wider community, including others participating in high-risk behaviors, insurers, and health care systems. Several cost-benefit analyses have been done to explore these issues.47,52 One study of a high-risk population of MSM found that use of PrEP compared favorably with other interventions that are considered to be cost-effective, but could result in PrEP expenditures exceeding $4 billion annually.47 That study found that the cost per quality-adjusted life year is more than US$100,000 when PrEP is offered to all MSM. The cost per quality-adjusted life year falls below US$50,000 when PrEP is limited to high-risk MSM, but it increases if PrEP uptake becomes more widespread within this population. These cost-benefit analyses are likely to change when generic formulations of TDF/FTC become available.
The inappropriate use of PrEP (eg, in a patient who is already HIV positive or is nonadherent, resulting in new HIV seroconversion) is problematic for the patient and his or her loved ones, as well as for the greater community if antiviral-resistant strains of HIV occur.6 PrEP may divert resources away from the treatment of HIV-infected patients, especially in settings that already have few resources.35,37,39,51,53,54 PrEP may exacerbate health inequities if uptake occurs disproportionately among those with greater health literacy and access to care, or siphons resources away from underinsured persons who are already infected with HIV and on wait-lists for treatment.39 These health inequities could be more severe in low-resource countries.
PrEP has both proponents and detractors among lay members of the populations for whom it has the greatest potential benefit. Larry Kramer, an HIV-positive activist, playwright, and cofounder of Gay Men's Health Crisis, is a notable critic who has accused Truvada users of having “rocks in their heads” and being “cowardly.”55 In a recent article in New York Magazine, some New York City MSM expressed concern based on anecdotes from their social networks that PrEP would encourage men to engage in high-risk sexual activity. Others worried that widespread use of PrEP would harm the popular image of gay men, similar to women in the 1960s who worried that their generation would be branded as promiscuous for adopting oral contraception. Finally, to some gay men PrEP seems like a betrayal of the lessons learned by previous generations ravaged by AIDS: the importance of condoms and sexual prudence.56
To other gay men, PrEP promises to finally free sex from stigma and paranoia.56 Some writers have heralded the dawn of an “HIV sexual revolution” thanks to PrEP, which they argue promises to succeed where the traditional ABCs of HIV prevention—abstinence, being faithful, and condoms—have failed.57 These men are grateful for the peace of mind they derive from the additional protection against HIV that PrEP provides. As Andrew Sullivan, a well-known HIV-positive gay blogger, writes: “It seems to me simply prudent to have as many weapons in our arsenal against HIV as possible. That means condoms and Truvada… . Fight Back. Fight AIDS. Back Truvada.”58
Conclusion
PrEP with daily oral TDF /FTC reduces the risk of HIV infection among high-risk MSM and transgender women who have sex with men, IDUs, and high-risk heterosexual men and possibly women. As the reduction in HIV incidence plateaus, and with a lack of better office-based strategies for preventing HIV transmission, it is important that all primary care clinicians be aware of PrEP and consider ways to safely implement this effective strategy for reducing HIV risk.
Discussion regarding the cost-effectiveness and opportunity costs will continue, and researchers will explore different delivery methods and dosing. In the meantime, there is widespread consensus that many more people could benefit from PrEP than are currently taking it. Primary care providers are at the front line of PrEP implementation and should embrace this opportunity to increase awareness of PrEP and to prevent HIV infection among those at risk.
Acknowledgments
The authors thank Mindy Smith, MD, MS, for her assistance with manuscript preparation.
Notes
This article was externally peer reviewed.
Funding: The work was funded by a Health Resources and Services Administration Ruth T. Kirschstein training grant (grant no. T32 HP10010-23-00 to JC).
Conflict of interest: none declared.
- Received for publication July 18, 2015.
- Revision received September 15, 2015.
- Accepted for publication September 25, 2015.
