PrEP for HIV Prevention: Who Should Take It, Which Option Is Right for You, and Does It Really Work

Research-informed explainer — last updated April 12, 2026

Pre-exposure prophylaxis (PrEP) reduces the risk of acquiring HIV through sex by more than 99% when taken as prescribed — and a long-acting injectable form now extends protection through every-two-month injections rather than daily pills. The clinical science behind PrEP is among the most robust in infectious disease, and the main barrier to access is no longer evidence — it is awareness and connection to care.

This article draws on research from Myron Cohen, MD, at UNC Hospitals, who led the landmark HPTN 052 trial and co-authored the cabotegravir prevention trial; Connie Celum, MD, Professor at the University of Washington, who led the PARTNERS PrEP trial defining oral PrEP efficacy in serodiscordant couples; Rajesh Gandhi, MD, Professor of Medicine at Harvard Medical School and Director of HIV Clinical Services at Massachusetts General Hospital; Pablo Tebas, MD, Professor of Medicine at the University of Pennsylvania; and Rochelle Walensky, MD, at Massachusetts General Hospital, who published the cost-effectiveness analysis that shaped U.S. expanded HIV screening policy.

The Evidence That ART Prevents Transmission

The scientific foundation for PrEP is the same biology that makes treatment-as-prevention work. Dr. Cohen's HPTN 052 trial (cited 6,931 times) enrolled 1,763 serodiscordant couples across 13 countries and found that early antiretroviral therapy reduced HIV transmission to sexual partners by 96% compared to deferred therapy. This landmark finding established that undetectable viral load equals untransmittable virus — and that the same drugs used to treat HIV can protect uninfected partners when taken prophylactically.

Dr. Cohen's 2016 PARTNERS2 study (cited 1,706 times) followed 888 serodiscordant couples for 1,553 couple-years with the HIV-positive partner on suppressive ART, and recorded zero linked transmissions. The U=U (Undetectable = Untransmittable) message is grounded in this data.

The PARTNERS PrEP Trial: Oral PrEP in Serodiscordant Couples

Dr. Celum led the PARTNERS PrEP trial (cited 3,272 times), a randomized double-blind placebo-controlled trial in 4,758 serodiscordant heterosexual couples across Kenya and Uganda. Daily oral tenofovir alone reduced HIV acquisition by 67%; daily tenofovir-emtricitabine (the combination marketed as Truvada) reduced acquisition by 75% compared to placebo. Both effects were statistically significant and clinically meaningful.

Importantly, the trial also showed that adherence was the dominant determinant of efficacy. Drug concentrations in plasma and peripheral blood mononuclear cells were used to verify compliance. Among participants with high adherence — defined as detectable study drug in blood — protection approached 90%.

Who Should Be Offered PrEP

Current U.S. guidelines (DHHS and CDC) recommend PrEP for any adult at substantial risk of HIV, including:

• Adults with an HIV-positive sexual partner
• Adults who have had a bacterial STI (gonorrhea, syphilis, chlamydia) in the past 6 months
• Men who have sex with men reporting inconsistent condom use with partners of unknown HIV status
• People who inject drugs and share equipment
• Individuals requesting PrEP regardless of stated risk factors

Dr. Gandhi's JAMA review (cited 651 times) synthesizes the clinical evidence for antiretroviral drugs in both treatment and prevention contexts, providing the prescribing framework clinicians use. A key point: PrEP is indicated before exposure, not after. It is not post-exposure prophylaxis (PEP), which requires a different drug regimen initiated within 72 hours of exposure.

Dr. Walensky's New England Journal of Medicine cost-effectiveness analysis (cited 552 times) demonstrated that expanded HIV screening is cost-effective at the population level even with low prevalence — providing the public health rationale for broad PrEP eligibility criteria rather than restricting access to objectively high-risk individuals only.

Choosing Between Oral TDF/FTC, TAF/FTC, and Injectable Cabotegravir

TDF/FTC (Truvada or generic) is the original oral PrEP formulation. It is highly effective (>99% in trials when taken daily), generic, inexpensive, and covered by most insurance plans. Tenofovir disoproxil fumarate has a small but real effect on bone mineral density and renal tubular function — relevant for patients with pre-existing kidney disease or osteoporosis risk.

TAF/FTC (Descovy) uses tenofovir alafenamide, which delivers equivalent antiviral activity at lower systemic drug concentrations, reducing bone and kidney side effects. Dr. Tebas's Lancet trial comparing bictegravir/emtricitabine/TAF versus dolutegravir/abacavir/lamivudine (cited 370 times) confirmed the favorable safety profile of TAF-based regimens, data that informed the extension to PrEP use. TAF/FTC is currently approved only for cisgender men and transgender women — not for receptive vaginal sex, where PK data is insufficient.

Cabotegravir long-acting injectable (Apretude) — co-authored by Dr. Cohen — is given as two initial injections one month apart, followed by every-two-month injections. The HPTN 083 trial in men who have sex with men and transgender women (cited 800 times) found cabotegravir superior to daily oral TDF/FTC by 66%. Long-acting injectable PrEP eliminates adherence as a variable for patients who struggle with daily pills or who prefer not to have medication visible at home.

One caution: injectable cabotegravir has a long pharmacological tail (detectability up to 12 months after last injection). If HIV is acquired during a gap in dosing — when drug levels are low but detectable — it can select for integrase resistance mutations. This is an uncommon but serious concern that should be reviewed with a prescribing clinician.

What Happens Before Starting and During PrEP

Before starting PrEP, a clinician will:

• Confirm HIV-negative status (HIV antibody/antigen test)
• Check renal function (BMP or comprehensive metabolic panel)
• Test for active hepatitis B (discontinuation of TDF/FTC can trigger hepatitis B flares in coinfected patients)
• Screen for active STIs

Follow-up every 3 months is standard, including HIV testing, renal monitoring, and STI screening. The frequent contact with the healthcare system is itself a benefit — it creates regular touchpoints for sexual health counseling, STI treatment, and vaccination updates.

Questions to ask your doctor

• Which PrEP formulation is right for me — daily oral pills or every-two-month injections?
• Does my kidney function or bone density history affect which oral PrEP is safer?
• How does PrEP interact with my current medications?
• If I miss doses or delay an injection, how does that affect my protection?
• What STI screening should I be getting every 3 months on PrEP?
• Is there any reason cabotegravir injections might not be appropriate for my situation?

The bottom line

Daily oral PrEP with tenofovir-emtricitabine reduces HIV acquisition by 99% in adherent users, and injectable cabotegravir every two months outperforms daily pills by removing adherence variability. PrEP is safe, effective, and covered by insurance (and federal programs for uninsured patients) — the main barrier is connecting with a prescribing clinician for a baseline evaluation. Anyone who thinks they may benefit should ask their primary care physician or infectious disease specialist directly.