Pre exposure prophylaxis of hiv
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"pre-exposure prophylaxis" AND HIV
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PMID: 41326046
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HIV PrEP lenacapavir 2025 FDA approval guidelines update
Excellent - I now have very comprehensive information from Harrison's, Goldman-Cecil, Roitt's, the 2025 Canadian guideline, and the latest web search confirming lenacapavir (Yeztugo) FDA approval in June 2025. I have enough to write a thorough, well-structured answer.
Pre-Exposure Prophylaxis (PrEP) of HIV
PrEP is the use of antiretroviral drugs in HIV-negative individuals at high risk of acquiring HIV, taken before potential exposure to prevent infection. It is one of the most effective biomedical prevention tools available today.
1. Rationale and Background
Despite ART scaling up to >27 million people worldwide with resultant dramatic reductions in transmission, ~1.5 million new HIV infections still occurred in 2020, with limited progress in the highest-risk groups. Biomedical prevention strategies like PrEP have demonstrated both efficacy in clinical trials and real-world effectiveness in reducing population-level HIV incidence. - Goldman-Cecil Medicine, p. 3701
2. Indications: Who Should Receive PrEP?
PrEP should be considered in HIV-negative individuals with:
| Risk Group | Details |
|---|---|
| MSM / MSMW | Men who have sex with men or men+women who do not consistently use condoms |
| Transgender individuals | Trans women and men at sexual risk |
| Multiple partners | Any gender with multiple concurrent partners |
| STI history | Recent or recurrent sexually transmitted infections |
| High-prevalence settings | From or partners from regions with HIV incidence ≥3% |
| Sex work | Individuals who have traded sex for money, goods, or services |
| Incarceration history | Individual or partner previously incarcerated |
| Injection drug users (IDUs) | Sharing of needles, syringes, or other equipment |
| Discordant couples | HIV-negative partner in a serodiscordant relationship |
The CDC estimates ~1.2 million people in the United States are at "substantial" risk and should be counseled about PrEP. - Harrison's Principles of Internal Medicine, 22nd Ed.
3. Available PrEP Regimens
3a. Daily Oral PrEP
Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC) - "Truvada"
- The original and most widely studied regimen
- 1 tablet daily (TDF 300 mg + FTC 200 mg)
- Up to 99% effective when taken with high adherence
- Approved for MSM, transgender women, heterosexual men and women, and IDUs
- Caution: nephrotoxic potential and slight decrease in bone mineral density
- Contraindicated if active hepatitis B infection is absent (stopping TDF can flare HBV - always screen for HBV first)
Tenofovir Alafenamide / Emtricitabine (TAF/FTC) - "Descovy"
- 1 tablet daily (TAF 25 mg + FTC 200 mg)
- Better renal and bone safety profile vs. TDF/FTC
- Approved for MSM and transgender women (not studied sufficiently in cisgender women or IDUs as of initial approval)
- Not recommended if eGFR <30 mL/min
3b. On-Demand (Event-Driven / "2-1-1") PrEP
- Only for cisgender men with planned sexual activity
- Not appropriate if: active HBV infection, high frequency of sex (>once/week), or women/IDUs
- Dosing: 2 tablets 2-24 hours before sex → 1 tablet 24 h after → 1 tablet 48 h after first dose
- Proven in the IPERGAY trial in MSM
- Individuals with ongoing exposures after the first dose should extend daily dosing until 48 hours after the last sexual activity
3c. Long-Acting Injectable Cabotegravir (CAB-LA) - "Apretude"
- Integrase strand-transfer inhibitor (INSTI)
- Dosing: 2 mL IM gluteal injection every 2 months (after 2 initiation injections 4 weeks apart)
- Phase 3 trials (HPTN 083, HPTN 084) showed superiority over daily oral TDF/FTC in MSM, transgender women, and cisgender women
- The adherence benefit of injection vs. daily oral dosing is strong
- HIV RNA testing (not just antibody testing) should be used for HIV status monitoring because long-acting agents can mask early seroconversion
- HPTN 083 trial demonstrated superiority of CAB-LA over TDF/FTC in MSM and trans women
3d. Twice-Yearly Injectable Lenacapavir (LEN) - "Yeztugo" (Newest, 2025)
- HIV-1 capsid inhibitor - a first-in-class mechanism (inhibits capsid protein function at multiple stages of the HIV lifecycle)
- FDA approved June 18, 2025 for PrEP to reduce the risk of sexually acquired HIV in adults and adolescents weighing ≥35 kg
- Dosing: subcutaneous injection every 6 months (twice-yearly)
- Phase 3 trials in South Africa/Uganda showed near-100% efficacy in cisgender women (PURPOSE 1 trial)
- CDC issued guidelines in September 2025 endorsing lenacapavir for PrEP; WHO issued guidelines in July 2025
- HIV testing required on the day of each injection
- Represents the longest-acting PrEP option currently available
3e. Dapivirine Vaginal Ring
- Releases the NNRTI dapivirine slowly over 28 days
- Reduces HIV infection by ~30% in women engaging in vaginal intercourse
- Approved by the European Medicines Agency and the South African government; endorsed by WHO as an additional prevention option for women at substantial risk
- Withdrawn from consideration before the U.S. FDA
4. Pre-PrEP Baseline Evaluation
Before starting PrEP, the following should be confirmed/tested:
| Test | Purpose |
|---|---|
| HIV test (rapid Ab/Ag, ideally 4th-gen or RNA) | Must confirm HIV-negative status |
| Serum creatinine / eGFR | Renal function (TDF/TAF contraindicated in severe CKD) |
| Hepatitis B sAg, sAb, cAb | Active HBV - stopping TDF/FTC can cause HBV flare |
| Hepatitis C antibody | Baseline; sexual transmission risk |
| STI screen (gonorrhea, chlamydia, syphilis) | Common co-infections |
| Pregnancy test (if applicable) | Safety data considerations |
| Blood pressure / weight | Baseline clinical parameters |
5. Follow-Up Monitoring on PrEP
| Interval | Assessment |
|---|---|
| Every 3 months | HIV test, STI screen, adherence counseling, renal function (eGFR) |
| Every 6 months | Hepatitis C antibody (in ongoing risk populations) |
| Annually | Bone density assessment consideration with long-term TDF/FTC |
- For CAB-LA: HIV RNA testing (not just antibody) at each injection visit
- For lenacapavir (Yeztugo): HIV testing on the day of each 6-monthly injection
6. Efficacy Summary
| Regimen | Efficacy | Population |
|---|---|---|
| Daily TDF/FTC | ~99% (with high adherence) | MSM, het. men & women, IDUs |
| On-demand TDF/FTC (2-1-1) | ~86-97% | Cisgender MSM only |
| CAB-LA (Q2 months) | Superior to TDF/FTC | MSM, trans women, cisgender women |
| Lenacapavir (Q6 months) | ~100% (PURPOSE 1 trial) | Cisgender women; trials ongoing in others |
| Dapivirine ring | ~30% | Women (vaginal intercourse) |
7. Contraindications and Cautions
- Active, untreated HIV infection - must not start PrEP in someone who is HIV-positive (risk of resistance)
- eGFR <30 mL/min - TDF/FTC and TAF/FTC not recommended
- Active HBV infection - require careful management (TDF/FTC actually treats HBV; stopping it can cause flare - HBV treatment should be maintained)
- Allergy to any component of the regimen
8. PrEP in Context: The Prevention Toolkit
PrEP is most effective when combined with other prevention strategies:
- Condoms - not 100% effective but reduce risk and prevent other STIs
- Treatment as Prevention (TasP) - U=U ("Undetectable = Untransmittable"): HPTN 052 and subsequent studies showed 0 linked transmissions when the HIV-positive partner is virally suppressed
- HIV testing - CDC recommends testing for all persons aged 13-64 at least once; high-risk individuals more frequently
- Needle exchange / syringe services programs (SSPs) - reduce HIV transmission in IDUs
- Male circumcision - 50-65% reduction in HIV acquisition in circumcised men
- PMTCT - prevention of mother-to-child transmission
- STI testing and treatment - reduces transmission efficiency
9. Key Recent Evidence
The Canadian 2025 guideline (CMAJ, 2025; PMID 41326046) recommends:
- Clinicians assess HIV risk during routine health visits and offer PrEP proactively
- Assess patient anatomy and sexual partners in a culturally sensitive manner
- Suitable options now include daily oral TDF/FTC, on-demand TDF/FTC, daily oral TAF/FTC, CAB-LA, and (per 2025 updates) lenacapavir
- Preferred PEP regimens: dolutegravir + TDF/FTC, or bictegravir/TAF/FTC
Sources: Harrison's Principles of Internal Medicine, 22nd Ed. (2025, McGraw Hill) - Goldman-Cecil Medicine, International Edition - Roitt's Essential Immunology - Canadian HIV PrEP/PEP Guideline 2025 (PMID 41326046) - CDC/FDA Lenacapavir (Yeztugo) PrEP Approval, June 2025
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