What is the recommended post-exposure prophylaxis (PEP) for an individual with an unknown sexual history after exposure?

Post-Exposure Prophylaxis for Unknown HIV Status Sexual Partner

For a patient with sexual exposure to a partner of unknown HIV status, post-exposure prophylaxis (PEP) should be evaluated on a case-by-case basis and initiated within 72 hours if the exposure represents substantial risk, considering local HIV prevalence and specific exposure characteristics. 1, 2

Immediate Assessment and Decision Framework

Timing is Critical

• PEP must be initiated within 72 hours of exposure to be effective, with optimal efficacy when started within 24 hours. 1, 3
• Do not delay PEP initiation while awaiting HIV test results or attempting to determine the source partner's status 1
• PEP is not routinely recommended if presentation occurs beyond 72 hours, as effectiveness decreases markedly 1, 4

Risk Stratification for Unknown Source Partners

Substantial risk exposures that warrant PEP consideration include: 1

• Receptive anal intercourse (highest transmission risk) 2
• Insertive anal intercourse 2
• Receptive vaginal intercourse 2
• Any exposure involving blood, semen, vaginal secretions, or rectal secretions 1

Additional risk factors favoring PEP initiation: 2

• Source partner belongs to high-prevalence group (men who have sex with men, injection drug users, commercial sex workers) 2
• High local HIV prevalence in the community 1
• Condom breakage during high-risk sexual activity 2

Negligible risk exposures that do NOT warrant PEP: 1

• Exposure to non-bloody saliva, urine, feces, or sweat 1
• Intact skin contact only 1

Baseline Testing Protocol

For the Exposed Person

• Perform rapid HIV antibody or antigen-antibody test immediately to rule out pre-existing infection 1
• Do not wait for test results before initiating PEP if clinically indicated 1
• If the exposed person tests HIV-positive, discontinue PEP and refer for HIV treatment 1

For the Source Partner (if accessible)

• Attempt to obtain fourth-generation HIV antigen-antibody test, which can detect recent infection earlier than standard antibody tests 1
• If source tests negative and has no signs of acute HIV infection, PEP can be discontinued 1
• In most cases with unknown partners, source testing will not be possible 1

PEP Regimen When Indicated

Preferred Medication Regimens

The CDC 2025 guidelines recommend three-drug regimens: 1, 3

• Bictegravir/emtricitabine/tenofovir alafenamide (preferred) 3
• Dolutegravir plus (tenofovir alafenamide or tenofovir disoproxil fumarate) plus (emtricitabine or lamivudine) 3

Treatment Duration and Initiation

• Complete 28-day course of antiretroviral therapy 1, 3, 5
• Start medications as soon as possible, ideally within 24 hours 1, 3
• Provide first dose immediately at the initial visit 1

Comprehensive STI Management

Test and treat for other sexually transmitted infections concurrently: 1

• Screen for chlamydia, gonorrhea, and trichomonas 1
• Assess hepatitis B vaccination status and provide post-exposure hepatitis B prophylaxis if indicated 1, 2
• Consider presumptive STI treatment, particularly in sexual assault cases 1
• For gay, bisexual, and other men who have sex with men, consider doxycycline post-exposure prophylaxis (doxy-PEP) for bacterial STI prevention 1

Follow-Up Testing Schedule

HIV testing timeline: 1, 3

• Follow-up within 24-72 hours to assess medication tolerability and adherence 1
• HIV testing at 4-6 weeks after PEP initiation 1, 3
• Final HIV testing at 12 weeks after PEP initiation using both laboratory-based antigen/antibody test and diagnostic nucleic acid test 1

Transition to Pre-Exposure Prophylaxis (PrEP)

For patients with ongoing HIV risk: 1, 4, 3

• Assess PrEP eligibility at 4-6 week follow-up visit 1
• Consider direct transition from PEP to PrEP after completing the 28-day course and confirming HIV-negative status 1, 3
• PrEP guidelines do not recommend a gap between nPEP completion and PrEP initiation 1

Critical Pitfalls to Avoid

• Never delay PEP initiation beyond 72 hours while gathering additional information 1
• Do not use PEP as a substitute for ongoing prevention in patients with recurrent high-risk behaviors; transition these patients to PrEP 1, 4
• Do not prescribe two-drug regimens; always use three-drug combinations 1
• Avoid initiating PEP in patients who are already HIV-positive, as inadequate regimens may lead to drug resistance 1
• Do not skip baseline HIV testing of the exposed person, even when initiating PEP emergently 1

Risk Reduction Counseling

• Provide comprehensive sexual health counseling and risk reduction strategies at initial and follow-up visits 1, 4
• Discuss safer sex practices and consistent condom use 1
• Address substance use and injection drug practices if relevant 1
• Offer behavioral interventions and prevention services 1