Pre-Exposure Prophylaxis for HIV: Is a Pill the New Condom?

Despite 35 years of prevention and health education efforts, increased access to health care, and improvements in HIV medication efficacy and tolerability, the disease continues to spread across both developed and developing countries. In 2017, almost 40,000 cases of HIV were diagnosed in the United States. The main route of transmission is sexual contact, predominantly in men who have sex with men (MSM).¹ It is well documented that if a person living with HIV/AIDS (PLWH) is undetectable (HIV viral load <200 copies/mL), the risk of viral transmission to others is virtually zero.

However, in the United States, just 61% of PLWH are consistently undetectable,²and 91.5% of new HIV infections are transmitted by people who have either not received a diagnosis or not engaged in care.³This continued transmission of HIV illustrates the need for additional tools for prevention.

In July 2012, the FDA approved tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 200 mg/300 mg taken once daily as pre-exposure prophylaxis (PrEP) for individuals at a higher risk of HIV infection. The approval was based on the results of various studies showing PrEP to be highly effective at preventing HIV transmission when used daily.^4,5The CDC recommends PrEP for heterosexual men and women who report inconsistent condom use and in a high-prevalence area or network, injection drug users who share equipment, individuals with a sexual partner who is HIV positive, MSM with a recent sexually transmitted infection (STI) diagnosis or who report inconsistent condom use, and those who participate in transactional sex.⁶TDF/FTC is the first and only FDA-approved nonbarrier method of HIV prevention. Because of the novelty of using a medication to prevent HIV, lack of long-term data and the potential for increased resistance or increase in STI transmission have led to providers using caution with PrEP. However, more recent data continue to support the safety and efficacy of daily TDF/FTC. An analysis of real-world demonstration projects in 16 countries combining more than 8000 individuals showed a <1% HIV acquisition rate and few adverse events.⁷Populations included in the analysis included heterosexual women, injection drug users, MSM, serodiscordant couples, and transgender women. In the first 5 years of PrEP, about 100,000 individuals have started and about 60,000 individuals are currently taking it.^8,9This number is less than the 10% of the individuals who the CDC estimates fit the criteria for being at a higher risk of HIV infection. Although the data show that PrEP implementation is expanding, few of the individuals are people of color or younger than 25—2 populations that are at higher risk of HIV acquisition.⁸

Results from retrospective studies on real-world use have shown that early patients on daily PrEP have high adherence and motivation for continuing PrEP.¹⁰However, a concern of practitioners is that inconsistent PrEP adherence will decrease efficacy and lead to HIV resistance and increased transmission. Pharmacologic modeling analyses predict 96% to 99% protection in rectal tissue after just 4 tablets of TDF/FTC and continued protection with adherence of 4 to 6 tablets per week.¹¹In addition, the inferred risk reduction remained ≥90% for 7 days after discontinuation of a 30-day regimen of daily TDF/FTC.¹¹However, PrEP is not 100% effective, even with perfect adherence. Results of published case reports show HIV acquisition, despite evidence of high adherence. No method of HIV prevention is 100% effective. Therefore, individuals need to be aware of the risks and benefits of each method to make an informed decision.

An important aspect of PrEP use and prescribing is the management of STIs. PrEP effectively reduces HIV transmission but is inactive against other STIs. It is recommended that individuals continue to receive education in safer sex practices, be given access to condoms, and get screened at least every 6 months for STIs, with some data suggesting every 3 months in the MSM population.⁶Will daily PrEP lead to a decrease in condom use and an increase in STI transmission? Data on real-world PrEP have shown similar STI rates pre- and post-PrEP initiation and suggest that PrEP may not replace other types of safer sex practices.^7,10,12-16More long-term data are needed to better understand how certain populations view PrEP and safer sex options and how its use affects sexual behaviors.

Clinicians and prescribers are concerned about the short- and long-term safety risks of PrEP. TDF can reduce renal function and bone mineral density (BMD) in those living with HIV. Is PrEP potentially harmful? A recent meta-analysis of randomized, placebo-controlled PrEP studies demonstrated that the risk of any adverse event or grade 3/4 adverse events was not statistically significantly different in tenofovir-based PrEP compared with placebo.⁷However, results from a BMD substudy in the iPrEx cohort comprising 498 patients showed a small decrease in hip and spine BMD in the TDF/FTC group at 24 weeks.^17,18Fortunately, this did not lead to a difference in bone fracture rates, and BMD recovered within 6 months of the patients discontinuing PrEP.^17,18Additionally, PrEP is meant to prevent transmission during a period of high risk. Risk continues to change throughout an individual’s life, and PrEP is not anticipated to be lifelong therapy for many individuals.

Although results from studies have shown that PrEP is safe and effective in many different patient populations, the majority of data are in MSM. Different populations have different routes of transmission for HIV: female genital tissue for heterosexual women, intravenously in injection drug users, and penile and rectal tissues for MSM. Pharmacologic analyses have shown that FTC and TFV have different tissue distribution patterns, with FTC favoring female genital tissue and TFV favoring colorectal tissue.¹⁹Additionally, competing nucleotides are lower in colorectal than female genital tissue, suggesting that higher adherence is required to achieve sufficient drug concentrations in vaginal than in rectal tissue. More data are needed to fully understand this issue.

Daily TDF/FTC is the only FDA-approved regimen for PrEP. However, innovative formulations and routes of administration of PrEP that do not rely on daily adherencewould offer further options for HIV protection.On-demand, or event-driven, PrEP is the practice of dosing medication(s) around a risk for transmission such as a sexual encounter. Results from the IPERGAY study and open-label extension showed an 86% to 97% risk reduction when MSM used TDF/FTC around a sexual encounter.^13,14Although more data are needed before this can be recommended in practice, this is a potential option for individuals with infrequent episodes of risk.Various delivery methods such as intravaginal rings and long-acting injectable antiretroviral agents are under investigation and showing promise.^20,21Subdermal implants have been designed but not tested in clinical trials yet.^22,23Additionally, there is a lot of interest in rectal and vaginal microbicides, though trials have been disappointing. Ideally, individuals would have a variety of HIV and STI prevention products—both barrier and nonbarrier forms&mdash;that are safe, effective, and available when needed.

Jacob A. Langness, PharmD, BCPS, is a clinical pharmacist specializing in infectious disease and internal medicine at Abbott Northwestern Hospital in Minneapolis, Minnesota. He completed his doctorate of pharmacy at the University of Minnesota and his PGY1 residency at University of Colorado Hospital.

References

• CDC. HIV surveillance report. cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2016-vol-28.pdf. Published November 2017. Accessed March 27, 2018.
• Singh S, Mitsch A, Wu B. HIV care outcomes among men who have sex with men with diagnosed HIV infection - United States, 2015. MMWR Morb Mortal Wkly Rep. 2017;66(37):969-974. doi: 10.15585/mmwr.mm6637a2.
• Skarbinski J, Rosenberg E, Paz-Bailey G, et al. Human immunodeficiency virus transmission at each step of the care continuum in the United States. JAMA Intern Med.2015;175(4):588-596.doi: 10.1001/jamainternmed.2014.8180.
• Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med.2010;363(27):2587-2599. doi: 10.1056/NEJMoa1011205.
• Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med.2012;367(5):399-410. doi: 10.1056/NEJMoa1108524.
• CDC. PrEP clinical practice guidelines. cdc.gov/hiv/pdf/guidelines/PrEPGL2017_CommentNotice.pdf. Accessed March 27, 2018.
• McCallister S, Magnuson D, Guzman R, Shvachko V, Rawlings K, Mera R. HIV-1 seroconversion across 17 international demonstration projects with pre-exposure prophylaxis (PrEP) with oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy 2016; June 16-20, 2016; Boston, MA. natap.org/2016/HIV/062216_01.htm. Accessed April 3, 2018.
• Mera Giler R, Magnuson D, Trevor H, et al. Changes in Truvada (TVD) for HIV pre-exposure prophylaxis (PrEP) utilization in the United States: (2112-2016). Presented at: 9th International AIDS Society Conference on HIV Science (IAS 2017); ) July 23-26, 2017; Paris, France. Abstract 1614.
• Siegler AJ, Mouhanna F, RobertinoGiler-Mera, et al. Distributions of PrEP prescriptions and the PrEP-to-need ratio, US Q2 2017. Conference on Retroviruses and Opportunistic Infections; March 4-7, 2018; Boston, MA.
• Mugo NR, Ngure K, Kiragu M, Irungu E, Kilonzo N. The preexposure prophylaxis revolution; from clinical trials to programmatic implementation. Curr Opin HIV AIDS. 2016;11(1):80-86. doi: 10.1097/COH.0000000000000224.
• Seifert SM, Glidden DV, Meditz AL, et al. Dose response for starting and stopping HIV pre-exposure prophylaxis for men who have sex with men. Clin Infect Dis. 2015;60(5):804-810. doi: 10.1093/cid/ciu916.
• Fonner VA, Dalglish SL, Kennedy CE, et al. Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS.2016;30(12):1973-1983.doi: 10.1097/QAD.0000000000001145.
• Molina JM, Capitant C, Spire B, et al. On-demand pre-exposure prophylaxis in men at high risk for HIV-1 infection. N Engl J Med.2015;373(23):2237-2246. doi: 10.1056/NEJMoa1506273.
• Molina JM, Charreau I, Spire B, et al. Efficacy, safety, and effect on sexual behaviour of on-demand pre-exposure prophylaxis for HIV in men who have sex with men: an observational cohort study. Lancet HIV.2017;4(9):e402-e410. doi: 10.1016/S2352-3018(17)30089-9.
• Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis. 2014;14(9):820-829. doi: 10.1016/S1473-3099(14)70847-3.
• Gafos M, Nutland W, Wayal S, et al. Experiences and perceptions of PrEP among gay and other men who have sex with men (MSM) using PrEP in the PROUD study in England. Presented at: 9th International AIDS Society Conference on HIV Science (IAS 2017); July 23-26, 2017; Paris, France. Abstract TUAC0105.
• Mulligan K, Glidden DV, Anderson PL, et al. Effects of emtricitabine/tenofovir on bone mineral density in HIV-negative persons in a randomized, double-blind, placebo-controlled trial. Clin Infect Dis.2015;61(4):572-580.doi: 10.1093/cid/civ324.
• Grant R, Mulligan K, McMahan V, et al. Recovery of bone mineral density after stopping oral HIV preexposure prophylaxis. Conference on Retroviruses and Opportunistic Infections; February 22-25, 2016; Boston, MA.Abstract 48LB.
• Cottrell ML, Yang KH, Prince HM, et al. A translational pharmacology approach to predicting outcomes of preexposure prophylaxis against HIV in men and women using tenofovir disoproxil fumarate with or without emtricitabine. J Infect Dis. 2016;214(1):55-64. doi: 10.1093/infdis/jiw077.
• Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133-2143. doi: 10.1056/NEJMoa1602046.
• Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med.2016;375(22):2121-2132. doi: 10.1056/NEJMoa1506110.
• Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015;59(7):3913-3919. doi: 10.1128/AAC.00656-15.
• Schlesinger E, Johengen D, Luecke E, et al. A tunable, biodegradable, thin-film polymer device as a long-acting implant delivering tenofovir alafenamide fumarate for HIV pre-exposure prophylaxis. Pharm Res. 2016;33(7):1649-1656. doi: 10.1007/s11095-016-1904-6.