What is the recommended Pre-Exposure Prophylaxis (PrEP) treatment regimen for individuals at high risk of Human Immunodeficiency Virus (HIV) infection?

PrEP Treatment Recommendations

For individuals at high risk of HIV infection, daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada) is the first-line recommended PrEP regimen, with proven efficacy exceeding 90% when adherence is maintained. 1

Primary PrEP Regimen Selection

Standard First-Line Option

• Daily oral TDF/FTC (300mg/200mg) once daily is recommended for all populations at risk of HIV infection, including men who have sex with men (MSM), heterosexual men and women, transgender individuals, and people who inject drugs 1, 2
• For MSM specifically, initiate with a double dose (2 pills) on the first day, followed by daily single-pill dosing thereafter 1
• Efficacy is highly adherence-dependent, reaching >90% with consistent daily use 3

Alternative Regimen for Specific Populations

• Daily oral tenofovir alafenamide/emtricitabine (TAF/FTC, Descovy) is recommended specifically for MSM and transgender women who have sex with men with or at risk for kidney dysfunction (creatinine clearance 30-60 mL/min), osteopenia, or osteoporosis 1, 4
• TAF/FTC dosing: one tablet (200mg/25mg) once daily—no loading dose required 4
• Critical limitation: TAF/FTC is NOT approved for cisgender women or prevention from receptive vaginal sex 4, 5

On-Demand (Event-Driven) PrEP

• The "2-1-1" dosing regimen with TDF/FTC is recommended only for MSM with infrequent sexual exposures 1
• Dosing schedule: 2 pills taken 2-24 hours before sex (preferably closer to 24 hours), 1 pill 24 hours after the first dose, and 1 pill 24 hours after that 1
• For consecutive sexual contacts, continue 1 pill daily until 2 days after the last sexual encounter 1
• This regimen demonstrated 86% risk reduction in the IPERGAY trial 1
• Not recommended for women, people who inject drugs, or those with active hepatitis B infection 1

Injectable PrEP

• Long-acting injectable cabotegravir every 8 weeks is recommended for cisgender men and transgender women who have sex with men (pending regulatory approval and availability) 1
• Dosing: 600mg intramuscularly after an initial 4-week interval separating the first 2 injections 1
• An oral lead-in period to establish tolerability is optional 1
• This option demonstrated superiority over daily oral TDF/FTC in a randomized trial of 4,570 MSM and transgender women 1

Pre-Initiation Requirements

Mandatory Testing Before Starting PrEP

Before prescribing PrEP, the following tests must be completed 1, 2:

• Combined HIV antibody and antigen testing (fourth-generation assay)—if acute HIV infection is suspected based on symptoms (fever, rash, lymphadenopathy), add HIV RNA testing 1
• Serum creatinine level and estimated creatinine clearance—do not initiate TDF-based PrEP if creatinine clearance <60 mL/min 1, 5
• Hepatitis B surface antigen (HBsAg) 1, 2
• Hepatitis C IgG antibody (if positive, confirm HCV RNA) 1, 2
• Hepatitis A IgG antibody for MSM and people who inject drugs 1
• Genital and nongenital gonorrhea and chlamydia testing by NAAT (three-site testing for MSM: rectal, pharyngeal, urogenital) 1, 5
• Pregnancy testing for individuals of childbearing potential 2

Critical Pre-Initiation Considerations

• PrEP should be initiated as soon as feasible once the individual has chosen to use it—same-day initiation is reasonable if rapid HIV testing is negative 1
• If clinical suspicion of acute HIV infection exists, withhold PrEP until HIV RNA results confirm negative status 1
• Initial prescription should not exceed 30 days; subsequent prescriptions can be for 90 days 1

Ongoing Monitoring Schedule

At 1 Month After Initiation

• Combined HIV antibody and antigen test 1
• Assess adherence and tolerability 1

Every 3 Months (Quarterly)

• Combined HIV antibody and antigen test 1, 5
• Three-site STI screening (gonorrhea and chlamydia by NAAT at all potentially exposed sites) 1, 5
• Estimated creatinine clearance at first quarterly visit, then annually thereafter 1
• More frequent renal monitoring (every 3-6 months) for patients >50 years old, those with baseline creatinine clearance <90 mL/min, or those with comorbidities predisposing to kidney dysfunction (diabetes, hypertension) 1, 5

Annually

• Hepatitis C antibody testing (more frequently—every 3-6 months—for MSM engaging in sex while using methamphetamine or people who inject drugs) 1

Key Monitoring Principle

• PrEP prescriptions should never exceed 90 days without interval HIV testing 1, 2

Discontinuation Considerations

Timing After Last Exposure

• For rectal and penile exposures: continue TDF/FTC for 1 week after the last sexual exposure 1
• For vaginal exposures: continue for at least 7 days after the last sexual exposure 2
• A 1-week lead-in period is recommended before adequate tissue levels are achieved for protection 1, 5

Hepatitis B Considerations

• For individuals with active hepatitis B infection (detectable HBsAg), discontinuation of TDF/FTC can lead to acute hepatitis flares or hepatic decompensation, particularly in those with cirrhosis 1, 5
• Careful monitoring of HBV infection and liver function is mandatory after discontinuation 1

Special Clinical Scenarios

Recent High-Risk Exposure

• If a PrEP candidate reports high-risk exposure within the past 72 hours, initiate 3-drug post-exposure prophylaxis (PEP) for 28 days, followed by seamless transition to 2-drug PrEP 1
• If exposure occurred >72 hours before the visit, initiate PrEP according to standard guidelines 1

HIV Seroconversion During PrEP

• Any positive HIV screening test requires immediate confirmatory testing with HIV RNA and genotype testing 1
• If HIV infection is confirmed, immediately start a fully suppressive ART regimen (not just PrEP) 1, 5
• Resistance (typically M184V/I mutation) is rare (<0.1%) but can occur if PrEP is initiated during undiagnosed acute HIV infection 1, 3

Common Pitfalls and Caveats

Contraindications to Avoid

• Never prescribe TDF-based PrEP if creatinine clearance <60 mL/min 1, 5
• Never prescribe TDF-based PrEP for MSM with osteopenia or osteoporosis—use TAF/FTC instead 4, 5
• Never use TAF/FTC for cisgender women or on-demand dosing 4, 5
• Never use TDF/lamivudine, TAF/FTC (for women), or TDF alone for PrEP—these are not recommended regimens 1

Adherence and Efficacy

• Efficacy is highly correlated with adherence—daily dosing is required for optimal protection, especially for women, as tenofovir concentrates 10-fold lower in vaginal tissue than rectal tissue 1, 3
• Only 2% of people discontinue PrEP due to adverse effects, which are typically mild gastrointestinal symptoms 3, 6

STI Prevention

• PrEP does not prevent other sexually transmitted infections—condom use should be encouraged for all genital contact 1
• Bacterial STI rates may increase modestly with PrEP use due to decreased condom use, reinforcing the need for quarterly STI screening 6