What is the recommended first-line drug regimen for HIV post-exposure prophylaxis (PEP) in an adult or adolescent with potential exposure to HIV?

HIV Post-Exposure Prophylaxis: Recommended Drug Regimens

For adults and adolescents requiring HIV post-exposure prophylaxis, the first-line regimen is bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) or dolutegravir plus (tenofovir alafenamide or tenofovir disoproxil fumarate) plus (emtricitabine or lamivudine), initiated within 72 hours of exposure and continued for 28 days. 1

Timing and Initiation

• Start PEP as soon as possible—ideally within 24 hours, but no later than 72 hours after exposure 1
• Do not delay the first dose while waiting for laboratory test results 1
• Perform a rapid HIV antibody test or laboratory-based antigen/antibody combination test before initiating PEP, but begin treatment immediately regardless of pending results 1

Preferred Regimens for Adults and Adolescents

First-Line Options (2025 CDC Guidelines)

Option 1: Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as a single-tablet regimen, one pill daily 1

Option 2: Dolutegravir (DTG) plus either:

• Tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF), plus
• Emtricitabine (FTC) or lamivudine (3TC) 1

These newer integrase inhibitor-based regimens have superseded older recommendations because they offer superior tolerability, once-daily dosing, high barrier to resistance, and minimal drug-drug interactions 1, 2.

Alternative Regimens (When Preferred Options Unavailable)

The 2025 International Antiviral Society-USA Panel also supports:

• TDF/FTC plus raltegravir (twice daily) 1
• TDF/FTC plus ritonavir-boosted darunavir 1
• TDF/FTC/elvitegravir/cobicistat 1

The WHO 2015 guidelines (now superseded but still relevant in resource-limited settings) recommended:

• TDF + 3TC (or FTC) as the backbone, plus
• Lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r) as the third drug 1

Regimens for Children ≤10 Years

• Backbone: Zidovudine (ZDV) + lamivudine (3TC) 1
• Alternative backbones: Abacavir (ABC) + 3TC or TDF + 3TC (or FTC) 1
• Third drug: Lopinavir/ritonavir (LPV/r) preferred 1
• Alternatives: Age-appropriate regimens from ATV/r, raltegravir, darunavir, efavirenz, or nevirapine 1

Duration and Dispensing

• Provide a full 28-day prescription at the initial visit 1
• Avoid "starter packs" or partial prescriptions, which were previously used but are no longer recommended as they reduce completion rates 1
• The complete 28-day course is essential to maximize protective benefit 1

Why These Specific Regimens?

BIC/FTC/TAF advantages:

• Single-tablet, once-daily dosing improves adherence 2, 3
• Completion rates exceed 96% compared to 90% with older regimens 2, 3
• Minimal side effects: nausea (15%), fatigue (10%), diarrhea (8%) in clinical studies 2
• High barrier to resistance with no documented treatment-emergent resistance 2, 3
• Well-tolerated across diverse populations including cisgender men, women, and transgender individuals 2, 3

Dolutegravir-based regimens:

• Once-daily dosing with excellent tolerability 1
• High genetic barrier to resistance 1
• Extensive safety data from treatment studies 1

Follow-Up Testing Schedule

• 24 hours: Remote or in-person visit to assess adherence and tolerability 1
• 4-6 weeks: HIV testing, clinical assessment 1
• 12 weeks: HIV testing (final confirmation) 1
• Monitor for drug toxicity during the first 2 weeks 1

Critical Adherence Support

• Enhanced adherence counseling is mandatory for all individuals starting PEP 1
• Completion of the full 28-day course is required to maximize protective efficacy 1
• Address barriers to adherence at the initial visit and 24-hour follow-up 1

Special Considerations

Pregnancy: TDF/FTC-based regimens are safe during pregnancy with no documented adverse fetal effects 4

Renal impairment: TAF-based regimens are preferred for creatinine clearance 30-60 mL/min 1

Suspected acute HIV infection: If acute HIV is suspected clinically or by testing, add a boosted protease inhibitor (ritonavir-boosted darunavir) or continue dolutegravir pending HIV RNA and resistance testing 1

Transition to PrEP: Offer pre-exposure prophylaxis to individuals with ongoing HIV exposure risk after completing the 28-day PEP course, with HIV testing confirmed negative before transition 1, 4

Common Pitfalls to Avoid

• Do not wait beyond 72 hours to initiate PEP—efficacy decreases significantly with delayed initiation 1
• Do not prescribe only 2-drug regimens when 3-drug options are available—triple therapy is the standard of care 1
• Do not use older regimens (zidovudine-based) as first-line—they have higher toxicity and lower completion rates 1
• Do not forget to assess for drug-drug interactions, particularly with hormonal contraceptives, tuberculosis medications, or other antiretrovirals 1