“No more excuses. We have the tools to end the [HIV/AIDS] pandemic.”
—Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, in the January 8, 2016, Washington Post
HIV incidence in the United States is stable at about 40,000 new diagnoses each year.1 From 2012 to 2016, HIV transmission has fallen 8% among heterosexuals and 17% among people who inject drugs, although men who have sex with men (MSM), black patients, and Hispanic patients remain disproportionally affected, with stable incidence.1 Rates are increasing among MSM ages 25 to 34 years, Hispanic MSM, and American Indian/Alaska Native, and Asian populations.1,2 Southern states, which represent 37% of the US population, account for 50% of incident HIV infections.3 An estimated 1.1 million people over age 13 years are living with HIV infection, and up to 15% of these people may be undiagnosed.1
HIV preexposure prophylaxis (PrEP) can reduce the risk of HIV acquisition among at-risk populations by up to 99%.4 PrEP prescribing is part of primary care and does not need to be restricted to infectious disease specialists. Pharmacotherapeutic HIV prevention is the responsibility of clinicians who should be ready to prescribe for appropriate patients. Clinicians should be aware of indications for emtricitabine/tenofovir disoproxil fumarate (F/TDF) and the recently approved emtricitabine/tenofovir alafenamide (F/TAF). Increasing the number of clinicians prescribing these drugs across the country increases access to and use of PrEP, and is essential to reducing HIV transmission.
Once-daily F/TDF was the first PrEP regimen recommended by the CDC for adults and adolescents weighing at least 35 kg (77 lb).5 Although F/TDF became synonymous with PrEP after it was approved by the FDA in 2012, additional options have been explored and many options are under development. In late 2019, the FDA approved a second PrEP option, once-daily F/TAF for adults and adolescents, excluding patients who are at risk through receptive vaginal sex.
In 2015, the CDC determined that more than 1.2 million patients in the United States met eligibility for PrEP, and in 2019, the US Preventive Services Task Force (USPSTF) provided a grade A recommendation that clinicians offer PrEP to patients at high risk of acquiring HIV (Table 1).2,6
TRANSMISSION AMONG DIVERSE POPULATIONS
HIV epidemiologic data and clinical research on PrEP often fail to address sexual and gender diversity. The literature particularly lacks robust data on gender-diverse patients who were assigned female at birth and identify as male (including transgender men) and patients who do not identify exclusively with either a male or female gender (including gender nonbinary, gender-fluid, and two-spirit identities). Regardless of a patient's sexual or gender identity, the following risk factors for sexual transmission of HIV should be considered in all patients who:
- Live in areas of high HIV incidence
- Are not using barrier protection consistently (unwilling, unable, or have barriers to negotiating use with partners)1,2,6
- Live with a recent diagnosis of a bacterial sexually transmitted infection (STI)1,2,6,7
- Engage in anal intercourse1,2,6,8
- Engage in transactional sex (that is, sex for money, drugs, or housing)1,2,6
- Have sexual partners who are at high risk for unsuppressed HIV (for example, partners with social and institutional barriers to HIV testing and treatment)1,2,6
- Have more than one sexual partner1,2,6
- Have partners with more than one sexual partner.1,2,6
F/TDF was approved after a series of clinical trials showing 44% to 73% efficacy; however, among the most adherent patients, F/TDF PrEP has demonstrated a 92% to 100% risk reduction for acquiring HIV.4,9,10 Very few seroconversions have occurred among patients using PrEP in the real world, and studies have shown no seroconversions among cohorts of hundreds of PrEP users at risk of sexual acquisition of HIV.11-13 In the United States from 2012-2016, the quintile of states with the lowest PrEP use had an increased rate of HIV diagnoses; the quintile with highest PrEP use had a 23% reduction.14 A 2016 meta-analysis demonstrated that F/TDF was effective in preventing HIV transmission across populations, including those at risk from rectal or vaginal/penile exposure regardless of sex, age, and dosing strategy.15
The DISCOVER trial showed that F/TAF was noninferior to F/TDF in reducing the risk of HIV acquisition among men and transgender women who have sex with men. Compared with F/TDF, F/TAF has higher intracellular drug levels and lower plasma drug levels, which account for less potential for systemic adverse reactions.16
Because of the lack of clinical data supporting efficacy, the FDA approval of F/TAF excludes patients exposed to HIV through receptive vaginal intercourse. F/TAF is safe for patients with vaginas (including those of childbearing potential) but the drug has not undergone testing for efficacy for vaginal exposure to HIV. The intracellular concentration of drug in vaginal genital tissue is consistent with levels that could confer protection, but it is unclear whether this translates clinically. Pharmacodynamic and pharmacokinetic data may be used to validate for vaginal exposure.16
MONITORING AND ADVERSE REACTIONS
Patients on PrEP require quarterly monitoring of laboratory tests including HIV antibody/antigen (Ab/Ag) (Table 2). Current PrEP regimens are inadequate to suppress HIV infection after seroconversion, so in patients on antivirals, the expeditious detection of HIV is crucial to reducing their risk of developing resistance. Educate patients about the quarterly monitoring requirements before starting therapy, because the cost and inconvenience of these requirements may be a barrier for patients. STI screening is indicated for patients at risk of STI exposure but not required for monitoring PrEP. Using outpatient laboratory facilities may reduce inconvenience for patients, but these facilities often cannot perform extragenital STI screening. Assess patients' medication adherence at each quarterly follow-up visit and address barriers to PrEP use with compassionate and patient-centered strategies.17
Common adverse reactions to F/TAF and F/TDF include nausea, gastrointestinal upset, and headache. In most patients, these symptoms resolve after a few weeks. If necessary, antiemetics and other supportive measures can be used to reduce symptoms until they are resolved.17 Changes in renal function and bone mineral density are associated with F/TDF, but not with F/TAF.16 Adverse reactions including changes in serum creatine did not lead to drug discontinuation among a significant portion of trial participants; they are rare in clinical practice.9,10,16,17 Although adverse reactions could discourage PrEP use, a systematic review demonstrated generally high adherence among at-risk populations globally.18
Patients can be started on F/TAF if their glomerular filtration rate (GFR) is 30 mL/min or greater, or on F/TDF if their GFR is 60 mL/min or greater. F/TDF can reduce GFR and elevate serum creatinine, and monitoring creatinine is recommended before therapy, at 6 to 12 weeks after drug initiation, and during therapy.17 Incidents of proximal renal tubulopathy have been reported among patients with HIV who take F/TDF, although fewer than 10 cases have been reported among those taking it for PrEP. Renal tubulopathy necessitates immediate discontinuation of the drug. For most patients, the GFR recovers within 4 weeks of drug discontinuation.19
F/TDF can reduce bone mineral density, but increased fracture risk has not been clinically appreciated to date. Monitoring bone mineral density is not recommended unless otherwise indicated (for example, for osteoporosis screening and monitoring). In most patients, bone mineral density is expected to recover within 6 months after drug discontinuation.20
PrEP AND VIRAL HEPATITIS
F/TDF and F/TAF have anti-hepatitis B virus (HBV) activity. Test patients for HBV infection and immunity at the time of PrEP initiation and vaccinate or revaccinate as appropriate. If PrEP is discontinued in a patient with active HBV, consider appropriate HBV therapy to prevent viral rebound, which can progress to fulminant hepatic failure.21
Sexual transmission of hepatitis C virus (HCV) is increasingly recognized among PrEP users. A study showed that 2 out of 485 PrEP users acquired HCV via sexual transmission.22 The authors recommend routinely testing patients for HCV; F/TDF and F/TAF do not have activity against HCV.
BACTERIAL STIs AND RISK COMPENSATION
Rates of bacterial STIs (including Neisseria gonorrhoeae, Chlamydia trachomatis, and syphilis) are increased among patients using PrEP.23,24 However, PrEP users have a baseline increased risk of STIs and may be tested more frequently because they are in quarterly care, compared with other patients who may only be tested when symptomatic. Recent studies showed that PrEP users were twice as likely to be tested for STIs in the past year, and three times as likely to report an STI in the past year. However, study participants had similar or only slightly increased rates of bacterial STIs when they were tested for bacterial STIs at a single time point.25,26 These studies suggest that STI rates are likely similar among PrEP users and peers with similar risk profiles, but PrEP users are being screened, diagnosed, and treated more frequently because they visit healthcare providers on a quarterly basis. Even if patients have slight increases in risk-taking behavior, PrEP must be put in the context of overall sexual health, which is not just a lack of STIs.27
The CDC recommends screening for STIs every 6 months for patients on PrEP; however, this may not be adequate.17 In a PrEP demonstration project, the SPARK study screened participants for STIs every 3 months.28 About 75% of patients with bacterial STIs were asymptomatic, and the study determined that if patients were screened only every 6 months, STIs would have been missed among 24% of patients.28 Additionally, patients using PrEP in the context of a monogamous, serodiscordant relationship (in which one patient is HIV-positive and the other HIV-negative) may not require frequent bacterial STI screening. Of note, viral suppression among HIV-positive patients is a more effective means of reducing risk of HIV transmission in serodiscordant relationships, and PrEP should be used judiciously in accordance with the patient's risk.29,30 The decision about frequency and site-specific STI screening should be made via discussion of risk and benefit between the patient and clinician.
The only FDA-approved dosing regimens are once-daily. The following regimens and dosing strategies are not FDA-approved or recommended by the CDC, but represent studies that are underway or have been concluded. Patients may want to discuss these strategies with their clinicians.
On-demand or 2-1-1 dosing
These strategies use F/TDF before and after sexual episodes rather than daily. Although this is not FDA-approved or CDC-recommended, it could be considered in some patients; those prescribed daily F/TDF may implement this strategy without provider guidance. The Ipergay study showed efficacy similar to that seen in trials of daily F/TDF when patients took 2 tablets 2 to 24 hours before a sexual encounter, and 1 tablet 24 and 48 hours each after a sexual encounter.31 For subsequent sexual episodes, daily dosing should be continued until the patient has had two doses after the last sexual encounter. Study limitations were a small patient population (N = 400), and the 4-pill median pill use per week, which correlated with high serum drug concentrations that may have conferred longer-term protection rather than incident prevention. Most participants enrolled in an open-label extension that showed a 97% efficacy at reducing risk of HIV acquisition.32 This strategy relies on patients anticipating intercourse, which might not be possible or realistic. Compared with daily dosing, less-than-daily dosing could reduce cost and the potential for adverse reactions.
Ts and Ss
Due to the long half-life of F/TDF, drug levels adequate for protection might be maintained with less-than-daily dosing. Participants in the iPrex trial who adhered to 4 doses per week had protection similar to those employing daily dosing.33 The dosing strategy of Ts and Ss employs dosing regularly 4 times per week (Tuesday, Thursday, Saturday, and Sunday). This dosing strategy relies on strict adherence. It has not been evaluated in a prospective controlled clinical trial and is not recommended by the CDC or the authors. Patients prescribed daily PrEP may use this strategy to reduce cost and potential for adverse reactions compared with daily dosing, with or without discussing this with their healthcare provider. Of note, patients who may occasionally miss doses of daily F/TDF are likely to maintain adequate drug levels if they adhere to at least 4 doses per week.
Several medications and alternative regimens for HIV prevention are in the drug development pipeline. A vaginal ring containing dapivirine was 27% effective among women in sub-Saharan Africa due to low adherence.34 Injected cabotegravir is in Phase 3 testing and may provide effective prophylaxis with dosing every 8 weeks.35 Implantable PrEP is under evaluation and could provide long-term prophylaxis without requiring daily adherence. Topical PrEP (called microbicides) could provide prophylaxis by including antiretrovirals in a product similar to a commercial sexual lubricant. Researchers have hypothesized that some PrEP interventions could be combined with contraception.36
As a CDC-recommended drug, daily F/TDF PrEP is widely covered by insurance, including Medicare. Generic F/TDF is expected to become available later this year, and generic F/TAF is not expected to be available for many years. Despite widespread insurance coverage and the availability of copay assistance plans, cost (or perception of cost) can be a limiting factor for patients indicated to use PrEP.18 The current cash price for F/TAF or F/TDF is $1,845 per month.37,38 Additional costs are associated with quarterly bloodwork and visits, especially among uninsured and underinsured patients. Transgender women are at an increased risk of being uninsured because of poverty compared with the general population; transgender adults of color especially experienced much higher rates of being uninsured.39 The cost of PrEP may contribute to widening inequality in new HIV diagnoses, especially among already disproportionately burdened populations, including transgender patients and patients of color.
HIV RISK REDUCTION
HIV risk reduction is limited by the patient's knowledge of and choice to employ different techniques. Condoms are effective but only if used consistently and correctly, nonoccupational postexposure prophylaxis can be implemented when the patient seeks and is provided care expeditiously, and reduction in exposure to body fluids can reduce the risk of HIV acquisition.40-42 The use of antiretroviral therapy among HIV-positive patients to suppress the viral load to levels below the threshold of detection eliminates the risk of transmission (often called undetectable = untransmittable, or U=U), but is outside of the control of the HIV-negative patient who is at risk.29,30 Safer-sex counseling is unlikely to affect individual behaviors in a manner that can significantly reduce patient risk of HIV.43
Expanding PrEP prescribing will provide patients with effective options that can be applied to diverse lifestyles. With increased use of antiretroviral prophylaxis, clinicians with prescriptive authority are in a unique and responsible position to help reduce HIV transmission. PAs in settings including primary care, internal medicine, and infectious diseases are positioned to serve as optimal prescribers of PrEP. The quarterly follow-up schedule recommended for PrEP prescribing creates an opportunity for counseling, prevention, and addressing patients' comprehensive healthcare needs. Increasing PrEP use among appropriate populations is fundamental to reducing HIV transmission and helping to end the HIV epidemic.
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