Douglas Krakower, MD; Kenneth H. Mayer, MD
Grant Support: This work was supported in part by the Harvard T32 postdoctoral HIV Clinical Research Fellowship grant NIAID AI 007433 to Dr. Krakower and the National Institutes of Health Center for AIDS Research grant P30AI42853 and National Institutes of Health Clinical Trial Unit for HIV Prevention and Microbicide Research grant U01AI069480 to Dr. Mayer. The funding sources had no role in the design, conduct, or analysis of this work or the decision to submit this manuscript for publication.
Potential Conflicts of Interest: Dr. Krakower: Grant (money to institution): Harvard T32 postdoctoral HIV Clinical Research Fellowship (grant NIAID AI 007433); Grants/grants pending (money to institution): Gilead Sciences, Bristol-Myers Squibb. Dr. Mayer: Grant (money to institution): National Institute of Health Center for AIDS Research (grant P30AI42853), National Institute of Health Clinical Trial Unit for HIV Prevention and Microbicide Research (grant U01AI069480); Grants/grants pending (money to institution): Gilead Sciences, Bristol-Myers Squibb, Merck. Disclosures can be also viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1390.
Requests for Single Reprints: Kenneth H. Mayer, MD, Fenway Health, 1340 Boylston Street, Boston, MA 02215; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Krakower: Division of Infectious Diseases, Beth Israel Deaconess Medical Center, 110 Francis Street, Lowry Medical Office Building, Suite GB, Boston, MA 02215.
Dr. Mayer: Fenway Health, 1340 Boylston Street, Boston, MA 02215.
Author Contributions: Conception and design: D. Krakower, K.H. Mayer.
Analysis and interpretation of the data: D. Krakower, K.H. Mayer.
Drafting of the article: D. Krakower, K.H. Mayer.
Critical revision of the article for important intellectual content: D. Krakower, K.H. Mayer.
Final approval of the article: D. Krakower, K.H. Mayer.
Obtaining of funding: D. Krakower, K.H. Mayer.
Collection and assembly of data: D. Krakower, K.H. Mayer.
Krakower D., Mayer K.; What Primary Care Providers Need to Know About Preexposure Prophylaxis for HIV Prevention: A Narrative Review. Ann Intern Med. 2012;157:490-497. doi: 10.7326/0003-4819-157-7-201210020-00510
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Published: Ann Intern Med. 2012;157(7):490-497.
As HIV prevalence climbs globally, including more than 50 000 new infections per year in the United States, we need more effective HIV prevention strategies. The use of antiretrovirals for preexposure prophylaxis (PrEP) among high-risk persons without HIV is emerging as one such strategy. Randomized, controlled trials have demonstrated that once-daily oral PrEP decreased HIV incidence among at-risk men who have sex with men and African heterosexuals, including serodiscordant couples. An additional randomized, controlled trial of a topical pericoital antiretroviral microbicide gel decreased HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population.
The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee reviewed these studies and additional data in May 2012 and voted to advise the approval of oral tenofovir–emtricitabine for PrEP in high-risk populations. On 16 July 2012, the FDA recommended that this combination medication be approved for use as PrEP in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic.
Human immunodeficiency virus continues to spread, with more than 2 million new infections globally (1) and 50 000 new infections in the United States per year (2). Thus, more effective HIV prevention strategies are urgently needed. Administration of antiretroviral medications to uninfected persons at high risk to protect against HIV acquisition, known as preexposure prophylaxis (PrEP), has recently emerged as a promising prevention strategy.
Over the past 2 years, randomized, controlled trials have demonstrated that PrEP can decrease HIV incidence in high-risk populations (3–6). With the FDA's approval of oral tenofovir–emtricitabine for PrEP in high-risk populations (7), clinicians can now prescribe PrEP to prevent HIV acquisition in their at-risk patients. Thus, it is important that practicing physicians understand this new evidence and its implications.
In 2010, the CAPRISA (Center for the AIDS Programme of Research in South Africa) 004 trial demonstrated that pericoital use of 1% tenofovir vaginal gel was associated with a 39% decrease in the risk for HIV acquisition among at-risk South African women after 2.5 years compared with placebo (3). This study was the first to demonstrate that PrEP can protect against HIV acquisition in humans. Several months later, the multinational iPrEx (Preexposure Prophylaxis Initiative) trial showed that a once-daily oral tablet containing a fixed-dose combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) decreased HIV incidence among men who have sex with men (MSM) by 44% after a median follow-up of 1.2 years (4).
More recently, the Partners PrEP Study showed that daily oral PrEP reduced the risk for HIV acquisition by the HIV-uninfected partner in serodiscordant, heterosexual African couples by 67% with tenofovir and 75% with TDF-FTC after a median follow-up of nearly 2 years (5). In the TDF2 study, daily oral TDF-FTC for at-risk heterosexual men and women in Botswana decreased HIV incidence by 62% after 2 years (6). Although whether the efficacy of PrEP protection will persist after long-term use is unknown, these studies demonstrated no waning of protection over follow-up.
Of note, 2 other trials failed to demonstrate the efficacy of oral or topical PrEP for African women. FEM-PrEP (Preexposure Prophylaxis Trial for HIV Prevention among African Women) randomly assigned at-risk women in several African countries to oral TDF-FTC or placebo. An independent data safety monitoring board terminated the study early because of ineffectiveness of the intervention (8, 9). The VOICE (Vaginal and Oral Interventions to Control the Epidemic) study randomly assigned 5000 at-risk African women to receive either a gel (tenofovir vs. placebo) or a pill (tenofovir or TDF-FTC vs. placebo) to use once daily. The oral tenofovir and topical gel groups of the study were terminated because of a lack of efficacy (10), but evaluation of oral tenofovir-emtricitabine versus placebo is still ongoing.
Suboptimal adherence to study medications is 1 possible explanation for the conflicting results among PrEP trials. The proportion of participants with detectable levels of the study drug was far lower in the FEM-PrEP study than in the Partners PrEP study, suggesting substantially poorer adherence in the study that failed to show efficacy (8, 11). It is also possible that the women enrolled in studies that did not show efficacy engaged in riskier behavior than the women in the other studies or had increased levels of genital tract inflammation, which could increase susceptibility to HIV acquisition (12).
It is conceivable that, in a setting where increased numbers of activated leukocytes are expressed in the genital tract mucosa because of local infections, the protective benefit of antiretroviral drugs could be attenuated. Another factor that might explain some of the discrepant results is the relatively lower genital tissue drug concentrations of tenofovir achieved in the female genital mucosa than in colorectal mucosa (13).
The differences in the findings that pericoital tenofovir gel was protective whereas daily gel use was not could be due to deleterious alterations in mucosal immunity with daily use compared with pericoital application of vaginal gel. This hypothesis is supported by findings of downregulation of the expression of many genes in mucosal tissue exposed to tenofovir gel (14). Thus, although multiple studies have demonstrated the proof of concept for the efficacy of oral tenofovir-emtricitabine for chemoprophylaxis, resolving the questions that some of the discrepant studies raised will be important in addressing how best to provide this new preventive method.
Several other PrEP studies, including the oral TDF-FTC group of the VOICE study, are ongoing, and another trial of pericoitally administered tenofovir gel among South African women is under way (15). Results from a study of oral tenofovir PrEP to prevent HIV transmission among Thai injection drug users are expected to be announced soon (16). While awaiting results of ongoing studies (Table 1), the urgency of the HIV epidemic and positive findings from several PrEP studies justify consideration of implementing PrEP before these results are available.
Completed and Ongoing Efficacy Trials of HIV Antiretroviral PrEP
Translating the efficacy of PrEP observed in trials to public health effectiveness will require successful implementation in real-world clinical settings. Realization of the benefits of PrEP will require identifying persons who are most likely to benefit from it, monitoring for adverse effects, addressing costs, and training providers to responsibly prescribe it. Specialists in HIV who routinely prescribe antiretroviral medications and may identify at-risk persons who are sexual partners of their HIV-infected patients are likely to be among the first clinicians involved in PrEP delivery. However, such settings as sexually transmitted infection clinics and primary care practices may be other venues for PrEP prescription. Because primary care physicians may care for many at-risk persons, the successful implementation of PrEP will also require their engagement.
The only PrEP regimen that has demonstrated efficacy and is currently recommended and available for prescribing is TDF-FTC (4–6). Tenofovir, a nucleotide reverse transcriptase inhibitor, is rapidly absorbed and provides sustained drug concentrations in blood and genital tissue and secretions for many days (17). Its long intracellular half-life could allow for intermittent dosing strategies to decrease cost and adverse effects. The nucleoside analogues emtricitabine and lamivudine are also well-tolerated and concentrate well in genital tissue (17, 18) but have a propensity to quickly select for resistant mutants.
Other agents examined for PrEP include oral agents from drug classes not commonly used for HIV treatment (for example, the chemokine receptor 5 antagonist maraviroc) and topical agents that can be delivered by gel or intravaginal rings (for example, the nonnucleoside reverse transcriptase inhibitor dapivirine) (19). Agents that should be avoided as PrEP include nevirapine and abacavir because of risks for severe hypersensitivity reactions (20, 21).
Oral and topical PrEP each have theoretical merits and drawbacks, but only oral TDF-FTC is currently available. Tenofovir gel is still being evaluated in the FACTS (Follow-on African Consortium for Tenofovir Studies) 001 trial, and these data will be an important part of submission for FDA approval of tenofovir gel for PrEP.
Daily ingestion of oral PrEP results in sustained systemic and genital antiretroviral concentrations, which provide a continuous antiretroviral barrier to establishment of HIV infection by inhibiting HIV integration into host cell genomes. Continuous protection is desirable when potential exposure is frequent, as with serodiscordant couples, MSM who have multiple partners, or sex workers, particularly when exposure is largely through unplanned sexual encounters. In addition, HIV-uninfected persons who cannot negotiate the use of condoms during sexual contact because of power inequality between partners (22) or cultural and legal barriers (23) could use oral PrEP without notifying their partners.
Potential challenges for implementing daily oral PrEP include cost (more than $10 000 per person annually in the United States for the drugs alone); the need for ongoing clinical monitoring for drug toxicities; and suboptimal adherence to a daily regimen, especially if risky behavior is intermittent.
The benefits of pericoital topical PrEP include high local drug exposure with lower systemic drug levels (24), presumably leading to a decreased likelihood of drug toxicity and potentially improved adherence. Less-frequent dosing may make PrEP more affordable, especially in resource-constrained environments. Yet, topical PrEP will be more difficult to use without partner knowledge. Unless the gel is used daily, even in the absence of sex, it may not provide sufficient protective drug exposure if intercourse is unplanned.
Available data suggest that PrEP with TDF-FTC has no serious short-term safety or tolerability concerns. Yet, tenofovir use has been associated with renal toxicity and decreased bone mineral density when used as part of treatment regimens in HIV-infected persons (25, 26), so clinicians will need to be alert for similar toxicities in patients who use tenofovir-based PrEP.
The iPrEx study reported infrequent and similar rates of serious adverse events between daily oral TDF-FTC and placebo, although the TDF-FTC group had more nausea and minimal but significant weight loss in the first few weeks of the study than did the placebo group (4). Counseling patients about these potential symptoms might decrease self-discontinuation of drugs.
In the iPrEx study, those assigned to TDF-FTC more often developed elevated serum creatinine levels (2% of participants) than did those in the placebo group (1% of participants); however, this difference was not significant, and elevated creatinine levels normalized after discontinuation of therapy (4). Among 5 iPrEx participants whose creatinine levels increased, 4 did not experience a new elevation when TDF-FTC therapy was restarted. Other PrEP trials have also been reassuring, with no differences in adverse renal events between men receiving daily oral tenofovir or placebo in a U.S. safety study (27) or among heterosexuals in 3 African PrEP studies (5, 6, 8).
Long-term effects of tenofovir on bone demineralization also need to be assessed because of minor changes in bone density seen in the U.S. PrEP safety study and the iPrEx and TDF2 trials (6, 28, 29). However, the level of demineralization was not clinically significant in these studies and increased fractures or other adverse clinical sequelae were not evident (6, 28, 29). Although the safety findings in these first PrEP studies are reassuring, long-term safety data are lacking and patients who initiate PrEP therapy will need ongoing monitoring for adverse effects.
Serious adverse events from topical PrEP were rare and similar among the women in the tenofovir gel and placebo gel groups of the CAPRISA 004 trial. However, women who used tenofovir gel reported a higher rate of diarrhea than placebo gel users. Investigators speculated that this could be due to local drug effect, but the mechanism remains unknown (3).
A safety study of the vaginal gel applied rectally documented increased local discomfort compared with placebo gel, probably because the vaginal gel contains glycerin (30). A glycerin-free rectal formulation of tenofovir gel was well-tolerated by men and women in a phase 1 safety study (14), and phase 2 studies are being planned for MSM. Yet, because the iPrEx and CAPRISA 004 trials had high levels of nonadherence and the longest follow-up was 72 weeks in the iPrEx study (31), the “true” adverse event profile among persons who routinely use PrEP remains uncertain.
The Centers for Disease Control and Prevention (CDC) has published guidance for the prescription of daily oral TDF-FTC as PrEP to at-risk MSM (32) (Table 2). Now that the FDA has accepted the advice of its advisory panel, the CDC will probably revise this guidance to extend to serodiscordant heterosexual couples and other high-risk persons.
Baseline and Follow-up Assessment, Testing, and Counseling that Clinicians Should Provide When Prescribing HIV Antiretroviral PrEP
The CDC recommends that providers document negative HIV antibody test results immediately before starting PrEP and test for acute HIV infection if symptoms consistent with this syndrome are present. The CDC also recommends regular, serial HIV testing during PrEP use. Persons who acquire HIV during PrEP use should immediately discontinue therapy to reduce the risk for drug resistance and enable initiation of a therapeutic antiretroviral regimen.
Optimal frequency of HIV testing requires further study. Rapid HIV antibody testing was performed monthly in the iPrEx trial, and no emergent drug resistance was detected in participants assigned to TDF-FTC who seroconverted (4), but monthly testing may be impractical in some clinical settings. Home HIV testing, which is currently being studied, may enable patients to monitor themselves and be a useful adjunct to clinical testing. The CDC currently suggests HIV antibody testing every 2 to 3 months for MSM who receive TDF-FTC daily as PrEP (32).
The CDC also advises screening for sexually transmitted infections before initiating PrEP and then at least every 6 months in the absence of symptoms suggesting these infections (32). Of course, patients should be tested if symptoms suggesting infection are present and be treated if infection is diagnosed.
The CDC recommends baseline screening for hepatitis B virus (HBV) infection (32). Both tenofovir and emtricitabine have activity against HBV, and clinically significant hepatitis flares have occurred in HIV-infected persons with active HBV infection during antiviral therapy initiation or interruption (33, 34). Completed PrEP trials have shown no evidence of increased rates of hepatic inflammation in persons using tenofovir versus those using placebo, including trials conducted in regions with high prevalence of HBV (3, 35).
The CDC suggests that providers offer HBV vaccination to seronegative MSM, which is sound clinical practice for sexually active persons. For MSM with active HBV infection, providers are advised to consider using TDF-FTC for both treatment of active HBV infection and as PrEP, monitor liver function carefully, and avoid sudden discontinuation of therapy (32). The CDC also recommends documenting that the estimated creatinine clearance is greater than 60 mL/min per 1.73 m2 before initiating TDF-FTC therapy and repeating renal function testing at 3 months after initiation and then yearly thereafter (32).
Patients receiving PrEP may believe that the protection of this therapy will compensate for high-risk behavior, and such beliefs could mitigate the benefits of PrEP. Thus, in addition to monitoring for medication-related adverse effects and HIV acquisition, providers should monitor PrEP users for high-risk behaviors. Such behavior has not been observed in studies of PrEP to date (3–5, 8, 35). Levels of risk-taking actually decreased during the iPrEx trial, with the total number of receptive anal sexual partners decreasing over time and the percentage of sexual partners using condoms increasing to a plateau over the first 6 months of trial participation (4). However, this could be attributable to the intensive behavioral counseling that accompanied PrEP administration as part of the informed consent process, as well as participants' realization that they might be assigned to placebo.
The CDC suggests behavioral counseling and providing condoms at least every 2 to 3 months during PrEP use (32). Patients and providers must understand that PrEP does not provide complete protection against HIV. Further studies of how providers can deliver effective counseling against risk compensation during PrEP use in the context of routine clinical care will be essential.
Preexposure prophylaxis recipients who acquire HIV require immediate testing for antiretroviral resistance. The use of 1 to 2 antiretrovirals during acute infection facilitates the development of resistance by selecting for transmitted or newly evolved resistant strains. Early detection of resistance allows for therapeutic choices that minimize additional mutations that could compromise therapeutic options.
Persons who acquired HIV after being randomly assigned to receive PrEP in the iPrEx study and several other PrEP trials did not exhibit drug resistance; however, many acute infections may have occurred in nonadherent persons, limiting the opportunities for resistance to evolve (3–6). Four of 33 women who acquired HIV after being randomly assigned to receive daily TDF-FTC therapy in the FEM-PrEP study exhibited resistance to emtricitabine, but whether these women were infected with drug-resistant viruses or whether resistance emerged after infection is not known. None of the women had detectable resistance to tenofovir (8).
A modeling study concluded that PrEP use is likely to have a detectable but relatively minor effect on the development of drug resistance (36). However, assessment of drug resistance among those who become infected while using PrEP beyond the clinical trial environment will be important.
Clinicians will need to counsel persons who use PrEP about the importance of adherence. A case–control analysis in the iPrEx study showed that 9% of men who acquired HIV after being randomly assigned to TDF-FTC had detectable levels of the study drug compared with 51% of men who remained uninfected (4), underscoring that PrEP's effectiveness depends on adherence. Although self-reported rates of pill use in the iPrEx study were high (more than 89% average pill use), only 54% of persons randomly assigned to the TDF-FTC group had detectable serum levels of the study drug during random screenings, suggesting that actual adherence was lower (37).
It will be important to determine the least amount of medication that provides optimal protection and which patterns of nondaily use result in the best adherence, particularly for persons whose risky behavior is intermittent. Intermittent dosing could mitigate nonadherence, and feasibility trials are currently under way (38, 39). However, event-driven dosing regimens may confront similar challenges to optimal adherence as regimens with more frequent schedules, because only approximately 40% of women in the CAPRISA 004 study reported using the gel at least 50% of the time (3).
Awareness and use of PrEP are currently limited among at-risk persons, but interest in using PrEP exists. A national survey of U.S. MSM using a social-networking Web site conducted 1 month after release of the iPrEx study results demonstrated that 19% of participants were aware of PrEP, fewer than 1% had used PrEP, and 79% expressed interest in PrEP once they knew about it (40). More than 97% of women who participated in the CAPRISA 004 study found 1% tenofovir gel to be acceptable and expressed intent to use it if it was approved (3).
A survey of Massachusetts-based HIV specialists and generalist physicians suggested that many clinicians (73%) would be willing to prescribe PrEP to at-risk MSM on the basis of the iPrEx trial results (41). Recommendations from public health authorities and the safety and efficacy data that emerge from clinical trials of PrEP will influence actual prescribing behavior (42).
Costs will be a substantial barrier to PrEP. A modeling study of PrEP use among MSM in the United States estimated that the cost to administer TDF-FTC once daily with associated monitoring and care would be $11 740 annually per person, with 91% due to drug costs (43). Models suggest that, in the absence of an increase in high-risk behavior among people receiving PrEP, oral PrEP could be cost-effective among high-risk MSM in the United States (43, 44) and serodiscordant heterosexual couples (45) in South Africa. Topical PrEP is likely to be cost-effective among South African women (46). Availability of generic drugs could reduce costs for oral PrEP, but the patent for TDF-FTC under the brand name Truvada (Gilead Sciences, Foster City, California) does not expire until 2021 (47).
Whether insurers will cover PrEP is unknown. Without insurance, out-of-pocket expenses are likely to be prohibitive for many high-risk persons. Moreover, because nearly 3000 Americans are on waiting lists to receive funds for treatment (48) and fewer than 50% of persons who need treatment globally are receiving it (1), issues of how best to use limited resources must be considered. Increased funding for both treatment and prevention will be crucial to reduce discord (47). Because of limited resources, clinicians and policymakers will need to think carefully about who is most likely to benefit from PrEP.
Identifying persons who are most likely to benefit from PrEP requires an understanding of local transmission dynamics. Generalized epidemics in heterosexual populations predominate in some nations (for example, South Africa), whereas concentrated epidemics, including those among injection drug users, sex workers, and MSM, exist in others (for example, Thailand ). In the United States, MSM are associated with the largest number of new infections (61%) (2), and the epidemic disproportionately affects African Americans in urban areas and in smaller cities in the South (50).
The incorporation of HIV risk assessment into primary care has remained challenging since the beginning of the HIV epidemic but will be essential to implement PrEP on a wide scale (51–53). Individual risk behaviors change over time, so serial risk assessment is necessary (54). The stigma of homosexuality in many cultures and criminalization of sexual practices in some nations (55) may limit the willingness of providers to ask, and that of patients to disclose, risky practices. Computer-assisted self-interviews may enable disclosure of risky behaviors (56). Strategies to develop provider comfort and skills around risk assessment will be important to optimize PrEP use.
A recent study of 1763 serodiscordant heterosexual couples showed that during a median follow-up of 1.7 years early administration of antiretroviral therapy (ART) to the HIV-infected partner (who had to have a CD4 count between 0.350 and 0.550 × 109 cells/L) decreased the risk for HIV transmission to the uninfected partner by 96% compared with those whose initiation of ART was delayed (57). These results suggest that early administration of ART to HIV-infected persons offers an additional strategy for using antiretrovirals to decrease HIV transmission.
Clinical events (primarily extrapulmonary tuberculosis) were less frequent among persons who initiated ART sooner, suggesting that earlier treatment benefited the index participants, as well as their partners. However, genotypic testing demonstrated that 11 of 39 participants who were initially uninfected acquired HIV from persons other than their primary partner during the study, highlighting that treating infected partners does not completely protect uninfected partners who have other sexual contacts.
The efficacy of administering PrEP to the uninfected partner of a monogamous, serodiscordant couple whose HIV-infected partner receives antiretroviral medications is unknown. Preexposure prophylaxis could potentially offer protection in this context when the HIV-infected partner is viremic, such as soon after initiating ART (that is, before virologic suppression), when adherence is suboptimal, or after virologic failure. Clinicians caring for serodiscordant couples will need to discuss the relative merits of early ART for the infected partner with or without PrEP for the uninfected partner to determine the optimal strategies. For high-risk persons without a single defined partner, PrEP may be the best option.
Primary care providers can play an important role in identifying persons who are at high risk for HIV acquisition and helping them to make informed decisions about PrEP in combination with other prevention strategies. The efficacy of PrEP for MSM (44%), serodiscordant couples (67% to 75%), and heterosexual men and women in Africa (62%) is favorable compared with other prophylactic measures, including voluntary medical male circumcision for African men (38% to 66%) (58) and early ART in HIV-infected members of serodiscordant couples (96%) (57, 59). Antiretrovirals can also decrease rates of mother–child transmission to 1% to 2% (60) and offer protection when administered as postexposure prophylaxis (61).
Similar to other prevention strategies, PrEP does not provide complete protection against HIV acquisition. Available evidence suggests that PrEP would be most effective as part of a multifaceted “prevention package.” Clinicians and policymakers must tailor prevention interventions to address local epidemic dynamics (62) and individual patient preferences.
This article was published on www.annals.org on 22 July 2012.
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