What is post-exposure prophylaxis (PEP) for Human Immunodeficiency Virus (HIV)?

Post-Exposure Prophylaxis (PEP) for HIV

What PEP Is

Post-exposure prophylaxis (PEP) is a 28-day course of antiretroviral medications that must be initiated within 72 hours (ideally within 24 hours) after potential HIV exposure to prevent infection. 1, 2

PEP is an emergency intervention designed for situations where primary prevention has failed, such as:

• Unprotected sexual contact with a person known or suspected to be HIV-positive 1, 2
• Needle-sharing during injection drug use 1
• Sexual assault 1, 2
• Occupational exposures (healthcare workers) 3
• Accidental exposures (e.g., needlestick injuries) 1, 2

When to Initiate PEP

Start PEP immediately for any substantial-risk exposure that occurred within the past 72 hours, without waiting for HIV test results or source person assessment. 1, 4

Substantial-Risk Exposures Include:

• Contact with blood, blood-stained fluids, genital secretions, or breast milk from an HIV-positive source 2
• Receptive or insertive vaginal or anal intercourse without a condom 1
• Sharing needles or injection equipment 1

Do NOT Use PEP When:

• The exposed person is already HIV-positive 2
• The source person is confirmed HIV-negative with no clinical signs of acute infection 4
• Exposure involves bodily fluids that don't pose significant risk (saliva, tears, urine) 2
• More than 72 hours have elapsed since exposure (though some experts may consider it for serious exposures on a case-by-case basis) 1

Timing Is Critical

The effectiveness of PEP decreases significantly with each passing hour after exposure—initiate within 24 hours for maximum benefit, but PEP can still be started up to 72 hours post-exposure. 1, 2, 4

Do not delay PEP initiation for:

• HIV test results 1, 4
• Source person identification or testing 4
• Risk assessment completion 2

Recommended PEP Regimens

The CDC's 2025 preferred regimens for adults and adolescents are: 1, 2, 4

First-Line Options:

• Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) - single tablet once daily 2, 4
• Dolutegravir (DTG) plus tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) 2, 4

These integrase inhibitor-based regimens are prioritized over older zidovudine-based regimens due to superior tolerability and adherence rates. 4, 5 Three-drug therapy is now favored for all potential HIV exposures. 5

Baseline Testing Before Starting PEP

Perform rapid HIV testing immediately using a point-of-care antibody/antigen test, but do not delay PEP initiation while awaiting results. 1, 4

Required Baseline Tests:

• Rapid (point-of-care) HIV Ag/Ab test PLUS laboratory-based Ag/Ab test for increased sensitivity 1, 4
• HIV nucleic acid testing (NAT) if the person recently took oral antiretrovirals or received cabotegravir injection within the past year 1, 4
• Sexually transmitted infection testing 1, 4
• Hepatitis B surface antigen and hepatitis C antibody 4
• Pregnancy test for persons of childbearing potential 4
• Serum creatinine for renal function assessment 4

Critical pitfall: Never use oral fluid-based rapid HIV tests in the PEP context—they are less sensitive for detecting acute or recent infection than blood tests. 1, 4

Follow-Up Testing Schedule

PEP requires a specific follow-up testing protocol because antiretroviral medications can suppress viral load and delay seroconversion, potentially causing false-negative results. 1, 4

Testing Timeline:

• Within 72 hours of starting PEP: Evaluate for drug toxicity and monitor adherence 4
• 4-6 weeks after PEP initiation: Perform both laboratory-based Ag/Ab test AND diagnostic HIV NAT 1, 4
  • This identifies HIV in persons who didn't adhere to or complete the regimen 1
  • Can be deferred for persons who started PEP within 24 hours, were fully adherent, and aren't considering PrEP 1
• 12 weeks after PEP initiation (8 weeks after completion): Perform both laboratory-based Ag/Ab test AND diagnostic HIV NAT—this is the conclusive test 1, 4

The dual testing approach (Ag/Ab plus NAT) is essential because diagnostic NAT can detect acute HIV infection approximately 1 week before laboratory-based Ag/Ab tests. 1

Duration and Adherence

Complete the full 28-day course of PEP for maximum effectiveness. 1, 2, 6

• Evaluate patients within 72 hours of starting PEP and monitor for drug toxicity for at least 2 weeks 4
• Counsel patients to seek immediate medical evaluation for any acute illness during follow-up, as this may indicate acute retroviral syndrome 4
• Provide precautions to prevent secondary transmission during the follow-up period 4

Transitioning to PrEP

For individuals with ongoing HIV risk or anticipated repeat exposures, transition directly from PEP to pre-exposure prophylaxis (PrEP) after completing the 28-day course and confirming HIV-negative status. 2, 4

• Assess PrEP indications at the 4-6 week follow-up visit 1
• PrEP guidelines do not recommend a gap between PEP conclusion and PrEP initiation 1
• Persons initiating PrEP before the final 12-week HIV test should be counseled about the possibility of false-negative results and the importance of ongoing HIV testing 1

Additional Considerations

STI Management:

Any sexual exposure that presents HIV risk also poses risk for other sexually transmitted infections. 1 CDC guidelines recommend presumptive STI treatment after sexual assault, which may include empiric antimicrobials effective against chlamydia and other common STIs. 1

Source Person Testing:

When possible, test the source person with a fourth-generation HIV antigen/antibody test, which detects infection several weeks earlier than standard antibody tests. 4 However, never delay PEP initiation to obtain source testing. 4

Do not test discarded needles or syringes for virus contamination—this is not a reliable method for risk assessment. 4

Risk-Reduction Counseling:

PEP should be viewed as an educable moment and potential bridge to comprehensive HIV prevention strategies. 5 Risk-reduction counseling should be an integral component of PEP provision to reduce the likelihood of recurrent exposures. 1, 5