What is the efficacy of HIV post‑exposure prophylaxis (PEP) and the recommended regimen and duration?

HIV Post-Exposure Prophylaxis Effectiveness

HIV post-exposure prophylaxis (PEP) is highly effective at preventing HIV infection when initiated within 72 hours of exposure, with the strongest evidence supporting a 28-day course of three-drug antiretroviral therapy started ideally within 24 hours. 1

Evidence for PEP Efficacy

While no randomized controlled trials have been conducted in humans (due to ethical constraints), the effectiveness of PEP is supported by multiple lines of evidence 1:

• Animal model data demonstrate clear prevention of HIV transmission when antiretroviral therapy is initiated promptly after exposure 1
• Observational human studies show extremely low rates of HIV seroconversion when PEP is used as recommended 1, 2
• Occupational exposure data in healthcare workers provides compelling indirect evidence of efficacy 3, 4
• Prevention of mother-to-child transmission studies demonstrate that antiretrovirals can prevent HIV transmission when given prophylactically 1

The San Francisco PEP Study, which enrolled 401 participants receiving PEP after sexual or injection drug exposures, reported zero HIV seroconversions at 6 months follow-up, despite 78% completing the full 4-week course 2. This provides real-world evidence of PEP's protective effect.

Critical Timing Requirements

The efficacy of PEP is time-dependent and decreases dramatically with each passing hour after exposure 5, 6:

• Optimal initiation: within 24 hours of exposure for maximum effectiveness 1
• Maximum window: 72 hours after exposure, beyond which PEP is generally not recommended 1
• Never delay the first dose for laboratory results, risk assessment, or source testing 5, 6

The 72-hour window is based on animal models with known limitations, and human data consistently support earlier initiation as more effective 1.

Recommended Regimen and Duration

Preferred Regimens (2025 CDC Guidelines)

The first-line regimen is bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as a single-tablet daily dose 1, 5, 6:

• This regimen offers superior renal and bone safety compared to older formulations 5
• Single-tablet formulation improves adherence and completion rates 5

Alternative regimen: dolutegravir (DTG) plus (tenofovir alafenamide [TAF] OR tenofovir disoproxil fumarate [TDF]) plus (emtricitabine [FTC] OR lamivudine [3TC]) 1, 6

The WHO guidelines from 2015 recommended TDF + 3TC (or FTC) as the backbone with LPV/r or ATV/r as the third drug, but these have been superseded by newer, better-tolerated integrase inhibitor-based regimens 1.

Duration

PEP must be continued for exactly 28 days from initiation with no option for early discontinuation 1, 5:

• This duration is based on animal data and represents the current standard of care 1
• Complete the full course regardless of any subsequent information about the source patient 5
• Incomplete adherence significantly reduces effectiveness 6
• Newer animal data suggest shorter courses might be effective if initiated within 24 hours, but this is not yet standard practice 1

Follow-Up Testing Schedule

Baseline testing 1, 5, 6:

• Rapid or laboratory-based HIV antigen/antibody combination test immediately
• Add HIV nucleic acid test (NAT) if the patient received long-acting injectable PrEP in the past 12 months 1, 5

Interim testing at 4-6 weeks 1, 5, 6:

• Laboratory-based HIV Ag/Ab test PLUS diagnostic HIV NAT
• May be deferred if PEP started within 24 hours and no doses were missed 1

Final testing at 12 weeks 1, 5, 6:

• Laboratory-based HIV Ag/Ab combination immunoassay AND diagnostic HIV NAT

Common Pitfalls to Avoid

Do not delay PEP initiation for source testing, baseline laboratory results, or detailed risk assessment 5, 6. Every hour of delay reduces efficacy.

Do not use two-drug regimens unless three-drug options are absolutely unavailable 5. While two-drug regimens have some supporting evidence from animal studies and other prevention contexts, three-drug regimens are now standard 1.

Do not stop PEP early even if the source is later found to be HIV-negative or if the patient experiences mild side effects 1, 5. Provide anti-emetics and supportive medications proactively to manage side effects like nausea 5.

Do not prescribe PEP when the exposed person is already HIV-positive or when the source is confirmed HIV-negative 1, 6. In these scenarios, prophylaxis provides no benefit.

Special Considerations

Pregnancy is not a contraindication to PEP and should not be a reason to deny treatment 5. Expert consultation is advised for pregnant patients.

For patients with renal impairment, use tenofovir alafenamide (TAF) instead of tenofovir disoproxil fumarate (TDF) due to improved renal and bone safety 5.

Assess for drug interactions with the patient's current medications, as this may influence regimen selection 1, 5, 6.

Transition to PrEP

Consider immediate transition from PEP to PrEP for persons with anticipated repeat or ongoing HIV exposures 1, 5, 6. Perform HIV testing at completion of the 28-day PEP course before transitioning to pre-exposure prophylaxis 5, 6.