Dr. Ahmed For years, HIV prevention mostly meant taking a pill every day or getting an injection every two months.
Now there’s a new option that many people may find easier: lenacapavir (Yeztugo), a small set of injections given twice a year that showed near‑complete protection in large studies.
On June 18, 2025, the U.S. Food and Drug Administration (FDA) approved Yeztugo for pre‑exposure prophylaxis (PrEP) of HIV for adults and adolescents who weigh at least 35 kg.
That makes it the first and only HIV prevention option that protects for six months per dose in the United States.
Scientists and health agencies see this as a big step forward because many people who could benefit from PrEP do not start it or do not stay on it for long term.
That’s why, a twice‑yearly schedule could reduce barriers such as daily adherence, frequent clinic visits, and stigma around taking a visible pill.
The World Health Organization (WHO) has now recommended injectable lenacapavir as an additional PrEP choice worldwide. [Ref]
What exactly is Lenacapavir?
Lenacapavir is the first drug in a new class called capsid inhibitors. HIV has a protein shell (the capsid) that protects its genetic material and helps the virus carry out several steps of infection.
It binds to a pocket on this shell and throws off the capsid’s timing and stability, which blocks the virus at multiple stages, when the virus is trying to enter the cell nucleus, and later when it tries to assemble new virus particles.
Because this target is different from other HIV medicines, lenacapavir does not overlap with the usual resistance patterns seen with reverse‑transcriptase or integrase inhibitors.
Lenacapavir can be given as small subcutaneous (under‑the‑skin) injections in the abdomen. The medicine forms a “depot” that slowly releases the drug for months. This long half‑life is what allows twice‑yearly dosing.
FDA approval for PrEP: what changed on June 18, 2025?
The FDA cleared Yeztugo for PrEP after reviewing two large Phase 3 trials called PURPOSE 1 and PURPOSE 2. Together, they enrolled more than 4,300 participants across different populations.
- In PURPOSE 1 (cisgender adolescent girls and young women in South Africa and Uganda), there were zero HIV infections among 2,134 people who received lenacapavir.
- In PURPOSE 2 (cisgender, transgender women and men, and nonbinary people), ≥99.9% of people who received lenacapavir stayed HIV‑negative; only two infections occurred among 2,179 lenacapavir recipients during the primary analysis.
Both trials showed superiority compared with daily oral Truvada (tenofovir disoproxil fumarate/emtricitabine). [Ref]
Because of these results, and the potential to simplify prevention, WHO issued global guidance on July 14, 2025, recommending twice‑yearly lenacapavir as an additional PrEP option, regional regulators are moving too:
On July 25, 2025, the European regulator (EMA) recommended approval of lenacapavir for PrEP, with the brand name Yeytuo expected in the EU once the European Commission signs off.
How is lenacapavir used for PrEP?
The FDA‑approved schedule is straightforward:
- Day 1: one subcutaneous injection (927 mg) plus 600 mg oral tablets
- Day 2: 600 mg oral tablets
- Then: one injection every 6 months
A negative HIV test is needed before starting and before every repeat injection, because giving PrEP to someone who already has HIV could create resistance. If someone has flu‑like symptoms suggesting acute HIV, testing should be repeated carefully before any dose.
How is Lenacapavir different from other HIV medicines?
Most HIV drugs block enzymes the virus uses (reverse transcriptase, integrase, protease). Lenacapavir targets the capsid protein itself and acts at several steps of the life cycle, which is unusual and useful, especially when resistance to older classes is present.
Its dosing is easily manageable. After the 2‑day start, maintenance is every six months. That is less frequent than cabotegravir PrEP (Apretude), which is given every two months after an initial loading phase
Is Lenacapavir also a treatment for people living with HIV?
Yes, but for a different group and with a different brand name and plan. In December 2022, the FDA approved Sunlenca (lenacapavir) for adults with multi‑drug‑resistant HIV whose current regimen is failing.
Sunlenca is given with an optimized background regimen (OBR) designed from resistance tests. In the pivotal CAPELLA study, about 81–83% of participants reached viral loads <50 copies/mL at Week 26, and many maintained suppressions over longer follow‑up. [Ref]
However, Sunlenca is not a standard first‑line treatment for people starting therapy for the first time.
Is Lenacapavir safe to use?
Across studies, lenacapavir was generally well tolerated. The most common issues include
- Injection site reactions like, swelling, redness, pain, small nodules, or induration.
- Nausea is the most common non‑injection side effect.
Serious side effects are uncommon.
However, Yeztugo carries an FDA boxed warning about the risk of drug resistance if given to someone with an undiagnosed HIV infection. That is why HIV testing before each dose is required, and why any symptoms of recent infection should be evaluated carefully.
Could resistance develop?
Resistance is rare, but it is a real concern if someone has undiagnosed HIV and receives lenacapavir alone.
The safest strategy is strict HIV testing before each injection and prompt transition to full treatment if infection occurs
Other HIV prevention options
- Cabotegravir (Apretude): Two injections one month apart, then every 2 months; also, highly effective and guideline‑recommended. More frequent visits than lenacapavir.
- Daily oral pills: F/TDF (Truvada) and F/TAF (Descovy) remain excellent choices for many people, with strong evidence and wide availability. Choice depends on kidney/bone health, body site of exposure, and local guidance. Lenacapavir offers a longer‑acting alternative rather than a replacement.
Conclusion
Lenacapavir brings twice‑yearly protection with a new mechanism. In prevention studies, it achieved near‑perfect efficacy, and in treatment, it adds an important option for people with multi‑drug‑resistant HIV.
The key to using it safely is HIV testing before every injection, awareness of drug interactions, and robust follow‑up.
If health systems can expand access and affordability, lenacapavir could help many more people choose a prevention method that fits their lives and move us closer to ending new HIV transmissions.
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