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Pre-exposure Prophylaxis (PrEP)

What Is It, How Does It Work, and More

Author:Kelsey LaFayette, DNP, ARNP, FNP-C

Editors:Ali Syed, PharmD,Emily Miao, PharmD

Illustrator:Jessica Reynolds, MS


What is pre-exposure prophylaxis?

Pre-exposure prophylaxis (PrEP) is a pharmacologic regimen containing antiretrovirals, which may be taken prior to exposure to the human immunodeficiency virus (HIV), the virus responsible for acquired immunodeficiency syndrome (AIDS). PrEP is commonly prescribed to high-risk individuals who are HIV negative, to prevent the acquisition and spread of the virus. 

What is HIV?

HIV is an enveloped RNA virus in the Lentivirus genus and Retroviridae family. There are two types: HIV-1 and HIV-2. Both types are relatively similar, though HIV-2 typically has a lower rate of transmission and is more rare. 

Transmission of HIV occurs through bodily fluids including blood, semen, vaginal fluids, and breast milk. When HIV enters the bloodstream, it targets a type of immune cell called a CD4+ cell. CD4+ cells’ main purpose is to help other immune cells communicate with each other, with the goal of mounting an immune response against a foreign antigen, like HIV. If HIV targets a CD4+ cell, it attaches to the cell membrane and fuses with it, which allows HIV to inject its enzymes (e.g., reverse transcriptase, integrase, protease) and RNA into the cell. Once inside the cell, reverse transcriptase converts viral RNA into DNA, which can then move into the cell’s nucleus. Once inside the nucleus, the viral DNA uses integrase (i.e., HIV enzyme), to integrate itself into the cell’s DNA; once this happens, the CD4+ cell will inadvertently replicate more HIV. As more HIV is replicated, it buds off the CD4+ cell and uses protease (i.e., HIV enzyme) to mature fully, allowing it to infect more CD4+ cells. If an HIV infection goes undetected or untreated, the number of CD4+ cells slowly decreases over time; once the total number of CD4+ cells is below 200 cells per cubic millimeter (cells/mm3), the HIV infection is considered to have progressed to AIDS, which is a chronic immune system disorder that can lead to life-threatening infections and death.

Individuals at high-risk of HIV infection include those who engage in unprotected sexual intercourse; those with multiple sexual partners; those with a sexual partner with known or suspected HIV; those who use intravenous drugs, specifically if sharing needles; fetuses of a mother with HIV; and breastfeeding infants of a mother with HIV.

Of note, certain types of sexual intercourse, like receptive anal intercourse, carry a higher risk of HIV transmission. This is due to the thin mucous membrane found in the anal canal, which allows HIV to enter the bloodstream more easily compared to other routes. Receptive anal intercourse carries the highest risk of HIV transmission through sexual activity and insertive vaginal intercourse carries the lowest risk.

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How does PrEP work?

While there are a variety of medications to treat active HIV infections and prevent progression to AIDS, PrEP has been shown to be effective in preventing infection with HIV, thereby reducing the burden of active infection. Currently, in the United States, there are two oral medications and one injectable medication approved for PrEP. Oral medications include a combination of emtricitabine-tenofovir disoproxil fumarate (i.e., Truvada®) and emtricitabine-tenofovir alafenamide (i.e., Descovy®); as well as the injectable medication cabotegravir (i.e., Apretude®). 

Emtricitabine-tenofovir is classified as a nucleoside and nucleotide reverse transcriptase inhibitor (NRTI) combination, whereas cabotegravir is an integrase strand transfer inhibitor (ISTI). NRTIs work by blocking reverse transcriptase, which leads to incomplete, non-functional viral DNA that is unable to infect other CD4+ cells. On the other hand, ISTIs irreversibly bind to the active site of integrase, which inhibits the viral DNA’s ability to integrate into the CD4+ cells’ DNA, thereby decreasing the replication of HIV. 

How effective is PrEP?

The effectiveness of PrEP depends strongly on mode of transmission and adherence. In preventing transmission sexually, efficacy can range from 44%, when not taken as prescribed, to approximately 92% or higher when taken as prescribed. Efficacy also depends on individual sexual history. For example, emtricitabine-tenofovir alafenamide is not indicated for individuals at risk from receptive vaginal intercourse as it may not be as effective in such cases.

In preventing viral transmission through intravenous drug use, the efficacy of PrEP may be lower, around 74% when taken as prescribed. In pregnant individuals taking PrEP to prevent HIV transmission to the fetus, efficacy ranges from 41-80%. The effectiveness of PrEP in breastfeeding individuals varies considerably, due to adherence.

To increase the efficacy of any PrEP regimen, strict adherence is vital. Adherence involves taking the correct dosage of the prescribed medication(s) at the suggested frequency, and starting and/or stopping the regimen following the recommended guidelines. To help facilitate and support adherence, healthcare providers may offer counseling; routine and frequent follow-up appointments; and suggestions on how to simplify adherence, like setting a phone alarm for when to take the medication(s). 

How should PrEP be taken?

As the name suggests, PrEP medications are taken before known exposure to or infection with HIV. Individuals identified as high-risk for HIV infection can discuss PrEP with a healthcare provider, which could include a primary care provider or a provider at a clinic specializing in preventative medicine or HIV. 

Currently, in the United States, and depending on your PrEP regimen, a continuous (i.e., daily) administration schedule is recommended; and although not approved by the Federal Drug Administration (FDA) or Centers for Disease Control and Prevention (CDC), some individuals may take PrEP on-demand (i.e., intermittently) after discussing with their healthcare provider. On-demand PrEP involves taking medications only when planning to engage in high-risk sexual activity. This administration schedule depends on which medication regimen is prescribed and may not be appropriate for all individuals. 

What are the risks of taking PrEP?

PrEP has been deemed relatively safe with no significant health effects being noted in individuals who have taken the medications for at most five years. The adverse effects of each PrEP regimen may differ, but most common effects across all three medications include nausea, diarrhea, headache and fatigue, which typically resolve over time, with continued use of the medication. More rare side effects can include kidney damage and osteoporosis (i.e., decreased bone mineral density and bone mass) with emtricitabine-tenofovir disoproxil fumarate; and injection site reactions with cabotegravir. 

It’s important to note PrEP does not prevent infection of other sexually transmitted infections (STIs) like chlamydia or gonorrhea, so it’s important to use PrEP alongside condoms to prevent other STIs. 

How does PrEP differ from post-exposure prophylaxis (PEP)?

The main difference between PrEP and post-exposure prophylaxis (PEP) is that PrEP is taken before an individual is exposed to HIV, with the goal of preventing an infection and spread of the virus. On the other hand, PEP is taken after an individual has had a known exposure to HIV, but has not yet acquired an active infection, with the same goal of preventing infection and viral spread. PEP includes a combination of emtricitabine and tenofovir with either raltegravir or dolutegravir

What are the most important facts to know about pre-exposure prophylaxis (PrEP)?

Pre-exposure prophylaxis (PrEP) is a pharmacologic regimen containing antiretrovirals which may be taken prior to exposure to human immunodeficiency virus (HIV), the virus responsible for acquired immunodeficiency syndrome (AIDS). PrEP is commonly prescribed to high-risk individuals who are HIV negative, to prevent the acquisition and spread of the virus. Individuals at high-risk of infection with HIV include those who engage in unprotected sexual intercourse; those who have multiple sexual partners; those with a sexual partner with known or suspected HIV; those who use intravenous drugs, specifically those who share needles; fetuses of pregnant individuals with HIV; and breastfeeding infants of mothers with HIV. Currently, in the United States, there are two oral medications and one injectable medication approved for PrEP: emtricitabine-tenofovir disoproxil fumarate (i.e., Truvada®) and emtricitabine-tenofovir alafenamide (i.e., Descovy®); as well as the cabotegravir (i.e., Apretude®), respectively. These medications interrupt the normal processes of certain HIV enzymes (e.g., reverse transcriptase, integrase) to decrease host cell infection or minimize viral replication. PrEP is recommended to be taken continuously (i.e., daily or at set intervals). Efficacy of PrEP is dependent upon mode of transmission (e.g., sexual intercourse, intravenous drug use) and adherence to the prescribed administration regimen; and can be as high as 99% in those at risk of infection through sexual intercourse who are taking the medication as prescribed. Common side effects of PrEP can include nausea, diarrhea, headache, and fatigue, which typically resolve over time with continued use of the medication. Individuals can discuss PrEP with their primary care provider or a healthcare provider at a clinic specializing in preventative medicine or HIV.

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Related links

HIV and AIDS: Nursing
Integrase and entry inhibitors
Nucleoside reverse transcriptase inhibitors

Resources for research and reference

Centers for Disease Control and Prevention. HIV Risk Behaviors. Published 2019. https://www.cdc.gov/hiv/risk/estimates/riskbehaviors.html

Chou R, Evans C, Hoverman A, et al. Preexposure prophylaxis for the prevention of HIV infection: evidence report and systematic review for the US preventive services task force. JAMA. 2019;321(22):2214–2230. doi:10.1001/jama.2019.2591

Hillis A, Germain J, Hope V, McVeigh J, Van Hout MC. Pre-exposure prophylaxis (PrEP) for HIV prevention among men who have sex with men (MSM): a scoping review on PrEP service delivery and programming. AIDS Behav. 2020;24(11):3056-3070. doi:10.1007/s10461-020-02855-9

HIV.gov. Pre-Exposure Prophylaxis: PrEP Medication. HIV.gov. Published April 12, 2023. https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-medication-to-reduce-risk/pre-exposure-prophylaxis/

Mitchell KM, Dimitrov D, Hughes JP, et al. In what circumstances could nondaily preexposure prophylaxis for HIV substantially reduce program costs?. AIDS. 2018;32(6):809-818. doi:10.1097/QAD.0000000000001766

Nucleoside Reverse Transcriptase Inhibitor (NRTI) | ClinicalInfo. clinicalinfo.hiv.gov. https://clinicalinfo.hiv.gov/en/glossary/nucleoside-reverse-transcriptase-inhibitor-nrti

O Murchu E, Marshall L, Teljeur C, et alOral pre-exposure prophylaxis (PrEP) to prevent HIV: a systematic review and meta-analysis of clinical effectiveness, safety, adherence and risk compensation in all populations. BMJ Open. 2022;12:e048478. doi:10.1136/bmjopen-2020-048478

Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the international antiviral society-USA panel. JAMA. 2018;320(4):379-396. doi:10.1001/jama.2018.8431