What post‑exposure prophylaxis (PEP) regimen should be administered to someone exposed to HIV to prevent infection before symptoms appear?

HIV Post-Exposure Prophylaxis (PEP) Regimen

For someone exposed to HIV who seeks prophylactic treatment before symptoms appear, start bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) 50/200/25 mg once daily for 28 days, initiated as soon as possible and ideally within 72 hours of exposure. 1, 2

Preferred First-Line Regimens

The CDC recommends two equally preferred three-drug regimens for adults and adolescents without contraindications: 1

• Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) – single-tablet regimen, one pill daily 1, 2
• Dolutegravir (DTG) plus (tenofovir alafenamide [TAF] OR tenofovir disoproxil fumarate [TDF]) plus (emtricitabine [FTC] OR lamivudine [3TC]) 1, 2

BIC/FTC/TAF is generally preferred because it offers superior renal and bone safety compared to TDF-based regimens, particularly important for individuals with any degree of renal impairment or osteopenia. 3

Critical Timing Requirements

Initiate PEP as soon as possible—ideally within 24 hours but no later than 72 hours after exposure—because efficacy decreases significantly with each hour of delay. 2, 3

• Do not wait for laboratory results, detailed risk assessment, or source patient testing before starting the first dose 2, 3
• Evidence is insufficient to support PEP initiation beyond 72 hours, though some experts argue risk-benefit considerations could favor a longer window in select cases 1
• Stop PEP only if the source is definitively determined to be HIV-negative 1

Duration and Dispensing

• Complete the full 28-day course regardless of subsequent source information; incomplete adherence markedly reduces efficacy 2, 3
• Provide the full 28-day prescription at the initial visit to maximize adherence 2
• Consider providing anti-emetics proactively to mitigate nausea and support adherence 3

Baseline Assessment Before Starting PEP

Perform these tests but do not delay the first dose while awaiting results: 1, 2

• Fourth-generation HIV antigen/antibody (Ag/Ab) combination immunoassay
• Add HIV nucleic acid test (NAT) if the exposed person received injectable cabotegravir within the past 12 months 3
• Serum creatinine to calculate creatinine clearance (guides TAF vs. TDF selection)
• Hepatitis B surface antigen
• Hepatitis C antibody
• Gonorrhea and chlamydia nucleic acid amplification testing from all exposed sites (genital, rectal, pharyngeal)
• Pregnancy test for persons capable of pregnancy 2

Follow-Up Testing Schedule

The CDC now recommends a shortened follow-up period using fourth-generation testing: 1, 2

• 24-72 hours: Clinical evaluation for early safety monitoring and adherence assessment 2
• 4-6 weeks: Fourth-generation HIV Ag/Ab test plus diagnostic HIV NAT 1, 2
• 12 weeks (3 months): Final fourth-generation HIV Ag/Ab test plus diagnostic HIV NAT to definitively confirm negative status 1, 2

This represents a significant change from older guidelines that required 6-month follow-up; the 12-week endpoint is now standard when using fourth-generation testing. 1, 4

Special Populations and Regimen Selection

Individualize regimen selection based on: 1

• Renal impairment: Use TAF-based regimens for creatinine clearance 30-60 mL/min; TAF has minimal renal toxicity compared to TDF 2, 3
• Pregnancy: TDF/FTC-based regimens are safe during pregnancy; pregnancy does not contraindicate optimal PEP regimens 2, 3
• Drug interactions: Assess concurrent medications, particularly those affecting integrase inhibitor levels 1
• Source patient history: Consider if the source has known resistance or previous antiretroviral exposure 1

When PEP Is Indicated

PEP is recommended for: 1

• Anal or vaginal intercourse without a condom with a source known to have HIV or unknown HIV status
• Percutaneous injuries (needlesticks, sharps) with blood or potentially infectious fluids 3
• Non-intact skin or mucous membrane contact with blood, semen, vaginal/rectal secretions, or breast milk 3

PEP is NOT routinely recommended for: 1

• Oral-genital sexual contact without a condom (case-by-case determination)
• Intact condom use during intercourse
• Exposure when the exposed person is taking PrEP as recommended
• Source patient with sustained viral suppression (case-by-case determination)
• Exposure to non-infectious fluids (tears, non-bloody saliva, urine, feces) 3

Transition to Pre-Exposure Prophylaxis (PrEP)

For persons with anticipated repeat or ongoing HIV exposures, transition immediately from PEP to PrEP after completing the 28-day course. 1, 2, 3

• Perform HIV testing at PEP completion to confirm seronegative status before starting PrEP 1, 3
• This seamless transition is critical for individuals with ongoing risk and represents an important prevention opportunity 3

Common Pitfalls to Avoid

• Never delay PEP initiation beyond 72 hours while awaiting source testing or detailed risk assessment 2, 3
• Never prescribe two-drug PEP regimens when three-drug options are available; triple therapy is the standard of care 2, 3
• Never discontinue PEP early based on later source information; always complete the full 28-day course 3
• Never test discarded needles or syringes for HIV; this is unreliable and delays care 3
• Do not routinely order laboratory tests for antiretroviral drug toxicity during the 28-day PEP course unless clinically indicated 5

Expert Consultation Resources

For complex cases or questions about PEP management: 1

• National Clinicians' Postexposure Prophylaxis Hotline: 888-448-4911
• Online consultation: https://nccc.ucsf.edu/clinician-consultation/pep-post-exposure-prophylaxis
• Perinatal HIV Line: 888-448-8765