HIV Post-Exposure Prophylaxis After Sex or Drug Use: CDC’s 2025 Guidelines

Post-exposure prophylaxis (PEP) uses antiretroviral (ARV) medicines to lower the chance of HIV infection after a high-risk exposure. Nonoccupational PEP (nPEP) covers exposures through sex, shared needles or similar contact, as opposed to occupational exposures such as a needlestick at work. The medicines are the same, but the people differ, so CDC issues separate guidance. In 2025 CDC updated its 2016 nPEP guidelines; this is a summary of the main points, prepared by a CDC team led by Mary R. Tanner and Jesse G. O'Shea (and later corrected by an erratum, whose figures are used here).

New HIV infections in the United States have fallen from a peak of about 130,000 a year in the mid-1980s to 32,800 in 2022, and nPEP is one of the tools for bringing that down further.

This summarizes guidance for health care professionals. Anyone who thinks they may have been exposed to HIV should seek care immediately. Clinicians can get free expert advice from the National Clinician Consultation Center's PEPline, 888-448-4911.

What changed in 2025

• newer ARV drugs, including new preferred regimens;
• updated guidance on when nPEP is indicated, including for people already taking PrEP;
• testing and regimens for people who have received long-acting injectable ARVs;
• new delivery strategies, such as nurse- and pharmacist-led care and "PEP-in-pocket";
• sexual assault testing aligned with CDC's current sexually transmitted infection guidelines.

Because clinical trials are few, the guidance rests on observational data, animal studies, evidence from HIV treatment and PrEP, and expert opinion. No drug is FDA-approved specifically for nPEP, so all recommended medicines are used off-label.

When nPEP is recommended

Assessing risk means weighing whether the source has HIV and how much virus they carry, the body fluid involved, where the exposure happened, any barriers, and whether the exposed person takes PrEP. nPEP should never be delayed to investigate the source. A source with HIV who has sustained viral suppression is not expected to transmit it.

People on PrEP who haven't been taking it consistently enough to be protected may need nPEP. For oral PrEP among gay, bisexual and other men who have sex with men, estimated protection was 99% at four or more doses a week and 84% at two to three; protecting vaginal tissue required six to seven doses a week. Where data are limited, as with injectable or intermittent PrEP, any use outside guidelines may be treated as nonadherence.

Timing: an emergency

HIV exposure is a medical emergency. Start nPEP as soon as possible — ideally within 24 hours, and no later than 72 hours — and never delay the first dose for lab results. The 72-hour window comes from animal studies in which protection fell the longer treatment was delayed. Evidence doesn't support starting later; people seeking care after 72 hours should be tested, counseled about PrEP and given a follow-up testing plan.

The regimen

• A clinical assessment first: other conditions, current medicines, allergies.
• A 28-day course. A 30-day supply is fine for practical dispensing, but the course is complete at 28 days.
• Preferred regimens for adults and adolescents without contraindications:
• • bictegravir/emtricitabine/tenofovir alafenamide, or
  • dolutegravir plus tenofovir alafenamide or tenofovir disoproxil fumarate plus emtricitabine or lamivudine.
• Tailor the choice to kidney or liver disease, pregnancy, drug interactions, earlier ARV use including long-acting injectables, any known resistance in the source's virus, and practical factors — pill burden, side effects, cost and access.

Three-drug regimens are recommended because they suppress the virus most strongly and better guard against drug-resistant strains; the short course keeps toxicity risk low. The two-drug dolutegravir/lamivudine treatment combination is not recommended for nPEP. If a preferred regimen isn't available, any three-drug regimen suitable for starting HIV treatment may be used, as long as it needs no pretesting and isn't contraindicated.

Testing and follow-up

The first-visit test cannot detect an infection from the exposure that just happened; it shows whether the person already had HIV. Patients should know the signs of acute HIV — fever, rash, flu- or mono-like illness — and return if they appear. Oral-fluid rapid tests are not recommended in this setting. If HIV is diagnosed while someone is on PEP, they should continue it until seen by an HIV specialist. People who decline nPEP should still be tested at baseline and again at 6 weeks.

During the course, people should take steps to avoid passing on HIV if they acquired it: avoiding condomless sex and shared injection equipment, and not donating blood or tissue until eligible.

From PEP to PrEP

Some people who need nPEP face ongoing exposure. Observational studies found that 0.37% to 9% of people acquired HIV after completing nPEP. PrEP cuts the risk of HIV from sex by about 99% and from injection drug use by at least 74% when taken as prescribed. For people expecting repeated or continuing exposure, CDC recommends moving straight from nPEP to PrEP, with an HIV test at the end of the course and no gap, and counseling that tests before the 12-week mark could be falsely negative.

Special situations

Guidance also covers sexual assault survivors (including presumptive treatment for other STIs, and hepatitis B, HPV or mpox vaccination where indicated), pregnancy and breastfeeding, children and adolescents, people who inject drugs, and people on hormone therapies. Severe drug reactions can be reported to FDA's MedWatch, and pregnancies to the Antiretroviral Pregnancy Registry.

Getting nPEP to people

Stigma, cost, trouble getting medicines quickly and a shortage of knowledgeable clinicians all block access. CDC urges health systems and health departments to set up nPEP protocols, and suggests:

• informing all adolescents and adults that nPEP exists;
• clinician education, checklists and order sets;
• nurse- and pharmacist-led care and partnerships with pharmacies and syringe services programs;
• social workers or navigators to help with medication access;
• "PEP-in-pocket": giving a 28-day supply in advance to people with infrequent high-risk exposures who decline PrEP, to start immediately after an exposure and follow up promptly. Centers using it report correct use, good follow-up and no HIV infections so far.

Open questions

No randomized trial has ever tested nPEP regimens, timing or length, and ethical limits make one difficult. Open questions include whether the 72-hour window could be shorter or longer, whether a shorter course would work (especially if started within 24 hours), whether two-drug regimens could widen access, and whether long-acting injectables could serve as nPEP.

Sources

Based on Tanner MR, O'Shea JG, Byrd KM, et al., "Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV — CDC Recommendations, United States, 2025," MMWR Recommendations and Reports, Centers for Disease Control and Prevention (with its erratum); a work of the United States government in the public domain.