What pre‑exposure prophylaxis (PrEP) medication should be given to an HIV‑negative adult starting a new sexual relationship?

Pre-Exposure Prophylaxis (PrEP) for HIV Prevention in New Relationships

Start daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) 300 mg/200 mg once daily immediately after confirming HIV-negative status. This is the gold-standard first-line regimen with >90% efficacy when adherence is maintained, supported by the strongest evidence across all populations and exposure routes. 1, 2

Immediate Action Steps

Confirm HIV-Negative Status Before Prescribing

• Perform a combined fourth-generation HIV antibody/antigen test within 7 days before starting PrEP to exclude both chronic and acute HIV infection. 1, 2
• If clinical suspicion exists for acute HIV (fever, rash, lymphadenopathy, recent high-risk exposure), add an HIV RNA test and withhold PrEP until results confirm negative status. 1
• Critical pitfall: Never prescribe PrEP without confirmed HIV-negative status—inadvertent use in undiagnosed HIV-positive individuals selects for drug-resistant virus (M184V/I mutation). 2, 3

Same-Day PrEP Initiation

• If a fourth-generation HIV test performed within the prior 7 days is negative and the patient has no symptoms of acute HIV, start PrEP immediately without waiting for other baseline laboratory results. 2
• When no recent test exists, perform rapid point-of-care HIV testing and begin PrEP as soon as the result is negative, then confirm with laboratory-based fourth-generation testing. 1, 2

First-Line Regimen: TDF/FTC

Standard Dosing for Most Populations

• One tablet (300 mg/200 mg) once daily for cisgender women, transgender women, people who inject drugs, and heterosexual men. 1, 2
• Full protective effect requires approximately 7 days of continuous daily dosing for vaginal exposures because tenofovir concentrations in vaginal tissue are ten-fold lower than in rectal tissue and drug clearance is faster. 1, 4
• When stopping PrEP, continue daily dosing for 7 days after the last at-risk exposure to maintain protection during washout. 1, 4

Accelerated Dosing for Men Who Have Sex with Men (MSM)

• Loading dose of 2 tablets (600 mg/400 mg) on day 1, then one tablet daily thereafter achieves maximal protection within 24 hours. 1, 2
• When stopping or interrupting PrEP, MSM should continue daily dosing for only 2 days after the last at-risk exposure. 1, 4

Alternative On-Demand "2-1-1" Dosing (MSM Only)

• Validated exclusively for cisgender MSM with planned receptive anal intercourse: 2 tablets taken 2–24 hours before sex, 1 tablet 24 hours after the first dose, and 1 final tablet 24 hours later. 1
• This regimen reduced HIV risk by 86% in the IPERGAY trial and is appropriate for MSM with infrequent sexual exposures. 1, 4
• Do not use on-demand dosing for women, transgender women, or people who inject drugs—it has not been validated for vaginal exposures or injection-related transmission. 1, 4

Pre-Initiation Laboratory Testing

Obtain the following baseline tests before or immediately after starting PrEP:

• Serum creatinine with calculated creatinine clearance: TDF-based PrEP is contraindicated when clearance is <60 mL/min/1.73 m². 1, 2, 4
• Hepatitis B surface antigen (HBsAg): Identify chronic HBV infection, as abrupt discontinuation of TDF/FTC can cause severe hepatitis flares or hepatic decompensation. 1, 2
• Hepatitis C antibody: Screen for HCV co-infection. 1, 2
• Nucleic acid amplification testing (NAAT) for gonorrhea and chlamydia at all exposure sites (genital, rectal, pharyngeal). 1, 2
• Syphilis serology. 1
• Pregnancy test for individuals of childbearing potential. 1

Ongoing Monitoring Schedule

Every 3 Months

• Combined HIV antibody/antigen test to detect seroconversion. 1, 2
• STI screening (gonorrhea, chlamydia, syphilis) by NAAT at all exposure sites. 1, 2
• Pregnancy testing for individuals of childbearing potential. 1, 2
• Adherence assessment and counseling. 2

Renal Function Monitoring

• At 3 months after initiation, then every 6 months if baseline creatinine clearance is ≥90 mL/min. 1, 2
• Every 3–6 months for patients with baseline creatinine clearance 60–90 mL/min, diabetes, hypertension, or age >50 years. 1, 2
• TDF causes a small, non-progressive, reversible decline in glomerular filtration rate that stabilizes after 3 months. 5

Annually

• Hepatitis C antibody (every 3–6 months for MSM who use recreational drugs during sex or people who inject drugs if liver function tests are abnormal). 1

Second-Line Regimen: TAF/FTC (Limited Indications)

Tenofovir alafenamide/emtricitabine (TAF/FTC) should be considered ONLY for MSM with creatinine clearance 30–60 mL/min or documented osteopenia/osteoporosis. 1, 2

• TAF/FTC demonstrates superior bone mineral density and renal biomarker safety compared to TDF/FTC but is not superior in efficacy. 1, 6
• TAF/FTC lacks efficacy data for receptive vaginal sex and should never be used as first-line for cisgender women or transgender women. 2, 4
• On-demand "2-1-1" dosing has not been validated with TAF/FTC—only daily dosing is recommended. 4

Long-Acting Injectable Cabotegravir

Injectable cabotegravir 600 mg intramuscularly every 8 weeks (after an initial 4-week interval between the first two injections) is recommended for cisgender men and transgender women who have sex with men where the product is available and approved. 1, 7

• An oral lead-in period with cabotegravir tablets to establish tolerability is optional. 1, 7
• Long-acting cabotegravir demonstrated superiority over daily TDF/FTC in the HPTN 083 trial, with comparable safety aside from injection site reactions. 1

Special Populations

Pregnancy and Breastfeeding

• Continue daily TDF/FTC (300 mg/200 mg once daily) throughout pregnancy and breastfeeding—the regimen is safe with no documented adverse fetal effects. 1, 2
• On-demand dosing is not recommended during pregnancy or breastfeeding. 1

Chronic Hepatitis B Co-Infection

• For HBsAg-positive individuals, consider indefinite continuation of TDF/FTC or transition to dedicated hepatitis B treatment if stopping PrEP, as abrupt discontinuation can cause hepatitis flares and hepatic decompensation. 2, 8
• On-demand PrEP is contraindicated in patients with active HBV infection. 4, 8

Condom Use and STI Prevention

Condoms are recommended for all penetrative sexual acts to prevent bacterial STIs (gonorrhea, chlamydia, syphilis), as PrEP does not protect against these infections. 2

Doxycycline Post-Exposure Prophylaxis (DoxyPEP)

• Doxycycline 200 mg taken within 72 hours after condomless sex is recommended for cisgender MSM and transgender women to reduce bacterial STI acquisition. 2
• Dosing must not exceed once daily; prescribe 30 doses (60 tablets) at a time. 2

Prescription and Follow-Up Strategy

• Prescribe no more than a 30-day supply initially, then 90-day supplies thereafter once adherence and tolerability are confirmed. 1
• PrEP prescriptions should not exceed 90 days without interval HIV testing. 4, 8
• After the initial 30-day visit, quarterly in-person or telemedicine visits are appropriate for stable patients who are adherent and doing well. 1

Key Safety Considerations

• Drug resistance is rare (<0.1%) when PrEP is used correctly and typically occurs only when initiated during undiagnosed acute HIV infection with a false-negative antibody/antigen test. 2, 3
• Only 2% of people discontinue PrEP due to adverse effects; both TDF/FTC and TAF/FTC are well tolerated. 6, 3
• The small, reversible declines in bone mineral density and glomerular filtration rate associated with TDF are outweighed by PrEP's substantial reduction in HIV acquisition risk. 5