Preexposure Prophylaxis (PrEP) for HIV

Preexposure prophylaxis (PrEP) involves use of antiviral medication for HIV prevention in HIV-negative adults or adolescents at risk for HIV through sex or injection drug use. The United Nations Programme on HIV/AIDS (UNAIDS) recently set a goal for 95% of people at risk of HIV (approximately 10 million people worldwide) to have access to and use PrEP in 2025, although only 3.5 million individuals at risk of HIV were receiving PrEP as of 2023. The UNAIDS 2024 global AIDS update reported no decrease in HIV incidence since 2021, with an estimated 1.3 million new infections reported globally in 2023.

The US Preventive Services Task Force strongly recommends that clinicians prescribe PrEP to prevent HIV for those at risk. Several therapies to prevent HIV have been approved in the past 12 years, beginning with daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 2012. Other currently available PrEP agents include (1) daily tenofovir alafenamide (TAF)/FTC (approved by the US Food and Drug Administration [FDA] in 2019), (2) monthly vaginal dapivirine ring (approved by the European Medicines Agency in 2020), and (3) intramuscular long-acting injectable cabotegravir administered bimonthly (approved by the FDA in 2021). Long-acting lenacapavir was shown to be highly effective in preventing HIV in studies performed in 2024,¹ although FDA approval is pending. None of the PrEP agents investigated to date interfere with contraception.

PrEP Indications

Individuals at risk of HIV include those with a sexually transmitted infection in the past 6 months, those who have condomless sexual intercourse with 1 or more partners who have an unknown HIV status, and/or those who have a sexual partner living with HIV with an unsuppressed viral load (not consistently <200 copies/mL). Additionally, because some patients may not be willing to provide their sexual history, all patients should receive PrEP counseling and PrEP prescription if requested. For people who inject drugs, PrEP is indicated for those who share injection equipment.

PrEP Medications

In a randomized clinical trial of 2499 men who have sex with men (MSM) and transgender women assigned to receive the daily oral TDF/FTC pill or placebo, 36 of 1251 in the TDF/FTC group and 64 of 1248 in the placebo group became infected, indicating a 44% reduction in the incidence of HIV (95% CI, 15%−63%; P = .005).² Using a modified intention-to-treat analysis, this study reported an HIV seroconversion rate of 2.9% in the TDF/FTC group vs 5.1% in the placebo group overa median follow-up of 1.2 years (P = .005).² HIV prevention efficacy increased to 92% (95% CI, 40%−99%) among those with detectable plasma tenofovir levels (eTable in the Supplement).² In a pooled analysis from 11 studies (2995 cisgender women with adherence data), TDF/FTC was efficacious for preventing HIV infection among those who took 4 to 6 doses a week (incidence rate, 0.13 [95% CI, 0.02–0.92] infections per 100 person-years).³ In a randomized trial of 2413 people who inject drugs in Thailand, those assigned to receive TDF had 0.35 infections per 100 person-years compared with 0.68 infections per 100 person-years for those assigned to receive placebo (P = .01).⁴

A randomized trial among 5857 MSM and transgender women reported that TAF/FTC was noninferior to TDF/FTC in preventing HIV, with an incidence of 0.16 HIV infections per 100 person-years vs 0.34 per 100 person-years (rate ratio, 0.47 [95% CI, 0.19–1.15]).⁵ Ina 2024 randomized clinical trial including 5338 adolescent girls and young women in South Africa and Uganda, there was no difference in HIV incidence between those receiving TAF/FTC vs TDF/FTC (incidence rate ratio, 1.20 [95% CI, 0.67–2.14]); however, there was generally low adherence to both TAF/FTC and TDF/FTC, as confirmed by drug levels.¹ Given the lower risk of kidney and bone toxicity compared with TDF/FTC, TAF/FTC may be preferred for individuals at higher risk of kidney injury or osteoporosis.

The monthly dapivirine vaginal ring is the first effective microbicide for HIV prevention. In a randomized trial of 2629 women aged 18 to 45 years in sub-Saharan Africa, those assigned to receive dapivirine had 3.3 HIV infections per 100 person-years vs 4.5 infections per 100 person-years among those assigned to receive placebo (P = .046).⁶ The dapivirine ring was added to the World Health Organization’s HIV prevention guidelines in 2021 and has been approved by the European Medicines Agency, but has not yet received FDA approval.

Cabotegravir, a long-acting antiretroviral administered intramuscularly every 8 weeks, demonstrated superiority for prevention of HIV infection compared with TDF/FTC among 4566 MSM and transgender women (0.41% vs 1.2% infected; hazard ratio, 0.34 [95% CI, 0.18–0.62])⁷; among 3224 cisgender women, there were 0.20 HIV infections per 100 person-years in those assigned to receive cabotegravir vs 1.85 per 100 person-years for those assigned to receive TDF/FTC (P < .001).⁸ The most common adverse effect of cabotegravir was injection site reaction (81%), although medication discontinuation was rare (2%).⁷ Barriers to utilization include the need for bimonthly in-person visits to receive cabotegravir injections, prior authorizations, and dedicated staff to perform injections and coordinate follow-up. Cabotegravir’s high up-front cost ($22 000 per patient per year) is another barrier, because insurance plans require purchase of the drug in advance before receiving reimbursement. The drug currently has scarce availability throughout low- and middle-income countries. If available, injectable cabotegravir is an option for those who are not willing or able to take a daily pill but can attend a clinic visit every 8 weeks for injections.

A second long-acting agent, biannual subcutaneous lenacapavir, was efficacious in preventing HIV infection among cisgender women in the PURPOSE 1 trial, leading the study to close early in June 2024. The incidence of HIV was 0 per 100 person-years (95% CI, 0.00–0.19) among 2134 females (age 16–25 years) in the lenacapavir group compared with an incidence of 1.69 per 100 person-years (95% CI, 0.96–2.74) in the 1068 participants in the TDF/FTC group and 2.02 per 100 person-years (95% CI, 1.44–2.76) in the 2136 participants in the TAF/FTC group.¹ The PURPOSE 2 trial is evaluating lenacapavir for HIV prevention in men, transgender women, and non-binary individuals, and FDA approval for lenacapavir is expected after these study results are available in late 2024.

On-Demand PrEP

On-demand PrEP is an alternate dosing strategy in which a double dose of PrEP is taken at least 2 hours prior to sex, followed by a single dose taken 24 and 48 hours later (“2–1-1 PrEP”). This regimen was effective at preventing HIV infection in a randomized clinical trial of 400 MSM; the incidence of HIV infection was 0.91 per 100 person-years in the TDF/FTC group and 6.60 per 100 person-years in the placebo group, a relative reduction in the TDF/FTC group of 86% (95% CI, 40%−98%; P = .002).⁹ On-demand PrEP has not been studied among cisgender women and data on 2–1-1 PrEP dosing have not been submitted to the FDA.

PrEP Adherence

The efficacy of PrEP is dependent on adequate patient adherence, defined as taking at least 4 doses a week.³ Clinicians should discuss the importance of adherence to PrEP at each visit. Strategies such as text message and telephone reminders, point-of-care urine tenofovir drug-level feedback counseling,¹⁰ and peer counseling can improve adherence among people who use PrEP.

Conclusions

PrEP is effective for HIV prevention and PrEP options are expanding, although newer agents, such as cabotegravir, have had limited utilization. Clinicians should offer PrEP to all HIV-negative adolescents and adults at risk of HIV infection through sexual activity or injection drug use, discuss the importance of adherence, and offer PrEP adherence support interventions if needed.¹⁰