What is the recommended protocol for post-exposure prophylaxis of HIV?

Post-Exposure Prophylaxis for HIV

Start bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as a single-tablet regimen immediately after a substantial-risk HIV exposure, ideally within 24 hours but no later than 72 hours, and continue for 28 days. 1

When to Initiate PEP

Initiate PEP when:

• The exposure occurred within the past 72 hours 1
• The exposure presents substantial risk for HIV transmission (receptive anal intercourse carries highest risk, followed by insertive anal intercourse, receptive vaginal intercourse, insertive vaginal intercourse) 2
• The source person has HIV without sustained viral suppression OR their viral suppression status is unknown 1, 3

Case-by-case determination required when:

• The exposure occurred within 72 hours with substantial transmission risk, but the source's HIV status is completely unknown 1, 2
• Consider source risk factors: injection drug use, commercial sex work, or membership in high-prevalence groups 2

Do NOT initiate PEP when:

• The exposure presents no substantial risk for HIV transmission 1
• More than 72 hours have elapsed since exposure (efficacy significantly diminished) 1, 3
• The source is confirmed HIV-negative 1

Preferred Medication Regimens

First-line options for adults and adolescents without contraindications:

1. Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) - single daily tablet 1, 3

2. Dolutegravir (DTG) plus (tenofovir alafenamide [TAF] OR tenofovir disoproxil fumarate [TDF]) plus (emtricitabine [FTC] OR lamivudine [3TC]) 1, 3

These represent updates from older 2005 guidelines that recommended generic "highly active antiretroviral therapy (HAART)" without specific agents 1. The 2025 CDC guidelines now provide explicit preferred regimens based on newer integrase inhibitors with improved tolerability profiles 1.

Regimen selection factors:

• Renal or hepatic dysfunction 1
• Pregnancy status 1
• Drug interactions with current medications 1, 3
• Previous exposure to antiretrovirals, including long-acting injectable PrEP 1
• Source person's antiretroviral history and potential resistance 1
• Pill burden, dosing frequency, side effects, cost, and access 1

Timing and Duration

Critical timing considerations:

• Provide the first dose as soon as possible, ideally within 24 hours of exposure 1, 3
• Do NOT delay the initial dose for pending laboratory results 1, 3
• PEP can still be initiated up to 72 hours post-exposure, though efficacy decreases with each passing hour 1, 3
• Complete the full 28-day course without interruption 1, 3

The 72-hour window is a hard cutoff in current guidelines, though some older guidance suggested clinicians might consider PEP beyond 72 hours for "serious risk" exposures on a case-by-case basis 1. However, the 2025 CDC guidelines do not support this practice 1.

Laboratory Testing Protocol

At initial assessment (before starting PEP):

• Rapid (point-of-care) HIV test AND/OR laboratory-based antigen/antibody combination (Ag/Ab) test 1, 3
• Special consideration: If the exposed person received long-acting injectable PrEP in the past 12 months, ADD a diagnostic HIV nucleic acid test (NAT) to detect acute infection that may be masked by residual drug levels 1, 3
• Assess for medical comorbidities, current medications, and allergies 1, 3

At 4-6 weeks post-exposure:

• Laboratory-based HIV Ag/Ab test PLUS diagnostic HIV NAT 1, 3
• This interim testing may be deferred ONLY if PEP was started within 24 hours of exposure AND no doses were missed 1

At 12 weeks post-exposure (final testing):

• Laboratory-based HIV Ag/Ab combination immunoassay PLUS diagnostic HIV NAT 1, 3

The dual testing approach (Ag/Ab plus NAT) at follow-up visits represents an important update from older guidelines and provides earlier detection of potential breakthrough infections 1.

Follow-Up Care

Structured follow-up schedule:

• 24-hour visit (remote or in-person) with medical provider for adherence support 1
• 4-6 week visit for interim HIV testing and toxicity monitoring 1, 3
• 12-week visit for final HIV testing 1, 3

Stop PEP immediately if:

• The source person is definitively found to not have HIV at any point during the 28-day course 1

Transition to PrEP

For persons with ongoing HIV exposure risk:

• Perform HIV testing at completion of the 28-day PEP course 3, 2
• If HIV-negative, immediately transition to a recommended PrEP regimen without a gap 1, 3
• This seamless transition is beneficial for persons with anticipated repeat or ongoing potential HIV exposures 1, 3

Critical Pitfalls to Avoid

Common errors that compromise PEP effectiveness:

• Delaying initiation beyond 24 hours significantly reduces effectiveness; every hour counts 1, 3
• Waiting for laboratory results before dispensing the first dose 1, 3
• Incomplete adherence to the full 28-day course dramatically reduces protection 3
• Failing to screen for drug interactions with current medications, particularly with integrase inhibitors 1, 3
• Not considering long-acting injectable PrEP exposure history, which requires additional NAT testing to detect acute infection 1, 3
• Using PEP as a substitute for ongoing prevention in persons with recurrent high-risk exposures (these individuals need PrEP instead) 2
• Inadequate follow-up for adherence support and toxicity monitoring 3

Special Considerations

Resistance concerns:

• Initiating PEP in undiagnosed acute HIV infection can lead to M184 resistance mutations within 7-12 days, particularly with 2-drug regimens 4
• However, even with M184 mutations, persons achieve viral suppression when rapidly linked to care 4
• This underscores the importance of baseline HIV testing, including NAT for those with recent long-acting injectable PrEP exposure 1, 3

Consultation resources:

• For complex cases, consult the National Clinician Consultation Center (NCCC) at 888-448-4911 or https://nccc.ucsf.edu/clinician-consultation/pep-post-exposure-prophylaxis 1