What is the recommended post-exposure prophylaxis (PEP) regimen after unprotected sexual intercourse to prevent Human Immunodeficiency Virus (HIV) infection?

Post-Exposure Prophylaxis After Unprotected Sexual Intercourse

For persons presenting within 72 hours after unprotected sexual intercourse with a known HIV-positive partner or high-risk exposure, initiate a 28-day course of antiretroviral therapy immediately—the preferred regimens are bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) or dolutegravir plus tenofovir (TAF or TDF) plus emtricitabine or lamivudine. 1, 2

Timing and Initiation

• Start the first dose as soon as possible, ideally within 24 hours but no later than 72 hours after exposure. 1, 2 The sooner treatment begins, the higher the likelihood of preventing HIV transmission. 1

• Do not delay PEP initiation while waiting for HIV test results or source person assessment. 2 Begin treatment immediately after the initial rapid HIV test is performed. 2

• Evidence suggests PEP may reduce HIV transmission risk by approximately 81% when used appropriately, though this is based primarily on occupational exposure data. 3, 4

Risk Assessment Algorithm

High-risk exposures warranting PEP (within 72 hours): 1

• Receptive or insertive anal intercourse without a condom with an HIV-positive partner
• Receptive or insertive vaginal intercourse without a condom with an HIV-positive partner
• Receptive anal intercourse without a condom with a partner of unknown HIV status (particularly men who have sex with men)
• Any sexual assault involving potential HIV exposure 1, 5

Lower-risk exposures requiring case-by-case evaluation: 1

• Oral-genital contact without a condom
• Exposures with partners of unknown HIV status (except high-risk scenarios above)

PEP not routinely recommended: 1

• Intact condom use during intercourse
• Exposure >72 hours prior
• Oral-genital contact with known HIV-negative partner
• Exposed person already taking PrEP as recommended with a virally suppressed partner 1

Preferred Antiretroviral Regimens

First-line options for adults and adolescents: 1, 2

• Bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg (single tablet once daily)
• Dolutegravir 50mg once daily PLUS (tenofovir alafenamide 25mg OR tenofovir disoproxil fumarate 300mg) PLUS (emtricitabine 200mg OR lamivudine 300mg) once daily

These integrase inhibitor-based regimens are prioritized over older zidovudine-based combinations due to superior tolerability and adherence rates. 1, 2 The 2025 CDC guidelines represent a significant shift from 2005 recommendations that included efavirenz and lopinavir/ritonavir-based regimens. 1

Baseline Testing Protocol

Before initiating PEP (but do not delay first dose): 2

• Perform rapid HIV antibody or fourth-generation antigen/antibody test at point of care 2
• Add laboratory-based fourth-generation HIV Ag/Ab test to increase detection sensitivity 2
• For persons with long-acting injectable PrEP exposure in past 12 months, add diagnostic HIV nucleic acid testing (NAT) at baseline 2
• Test for other sexually transmitted infections 2
• For women of reproductive age, discuss and offer emergency contraception 1, 5

Source person testing (when possible): 2

• Test with fourth-generation HIV antigen/antibody test, which detects infection weeks earlier than standard antibody tests 2
• If source tests negative with no clinical signs of acute HIV infection, PEP can be discontinued 2
• Never test discarded needles or syringes for virus contamination 2

Follow-Up Testing Schedule

At 4-6 weeks post-exposure: 2

• Perform both laboratory-based HIV Ag/Ab test AND diagnostic HIV NAT 2
• Exception: Skip this testing for persons who started PEP within 24 hours of exposure and did not miss any doses 2

At 12 weeks post-exposure (conclusive): 1, 2

• Perform both laboratory-based HIV Ag/Ab combination immunoassay AND diagnostic HIV NAT 2
• This represents the final conclusive testing timepoint per CDC guidelines 2

Clinical Monitoring and Support

• Evaluate patients within 72 hours after starting PEP and monitor for drug toxicity for at least 2 weeks 2
• Counsel patients on the critical importance of completing the full 28-day course—studies show 20% of patients prematurely discontinue treatment 6
• Advise immediate medical evaluation for any acute illness during follow-up, as this may indicate acute retroviral syndrome 2
• Provide risk-reduction counseling to prevent future exposures, as behavioral interventions are more cost-effective than repeated PEP use 1

Critical Pitfalls to Avoid

Never use oral fluid rapid tests in the PEP context—they are significantly less sensitive for acute/recent infection than blood-based tests. 2

Do not switch between different formulations (film-coated tablets, chewable tablets, or oral suspension) without consulting the prescribing physician. 7

Recognize that antiretroviral medications can suppress viral load and delay antibody formation, potentially reducing HIV detection ability during follow-up testing. 2

Be aware that completion rates are particularly low in certain populations: younger patients, heterosexuals (compared to MSM), and those without knowledge of their partner's HIV status have lower completion rates. 6 Sexual assault survivors also face significant barriers to completing PEP. 5

Special Considerations for Sexual Assault

• Sexual assault typically presents multiple features that increase HIV transmission risk if the perpetrator is infected, including genital trauma and presence of semen. 5
• Consult a sexual assault forensic examiner or nurse when available for optimal care coordination. 5
• Provide comprehensive support services and psychological counseling through sexual assault crisis centers to improve adherence. 5

Transition to Pre-Exposure Prophylaxis (PrEP)

For persons with anticipated repeat or ongoing HIV exposures: 1, 2, 5

• Offer immediate transition from PEP to PrEP after completing the 28-day course and final HIV testing 1, 2
• Create a specific transition plan during the PEP follow-up period 5
• This approach provides continuous protection for individuals at ongoing risk 1

Cost-Effectiveness Context

PEP is most cost-effective for unprotected receptive anal intercourse with a known HIV-positive partner or with a man who has sex with men of unknown status. 1 It is less cost-effective for penile-vaginal sex or insertive anal intercourse, though clinical judgment should guide decisions when substantial risk exists. 1 The improved tolerability of modern regimens has substantially reduced potential harms compared to earlier antiretroviral combinations. 1