Twice-yearly lenacapavir for PrEP: dose, tests, resistance

A 24-year-old woman returns to the health service asking again for HIV pre-exposure prophylaxis, PrEP. She already used the daily pills for a few months, but stopped: she forgot doses, was afraid her family would see the bottles and found it hard to keep up the routine. Her current partner has never had an HIV test, and she does not know his status. She read about an injection given twice a year and asks whether she can use it. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. It covers lenacapavir, an HIV-1 capsid inhibitor approved as PrEP with a subcutaneous injection every six months. The text explains the indication, the starting dose, the required test before each injection, the risk of resistance, the interactions and what the studies showed. It does not replace your country's PrEP protocol or the local package insert. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence.

Key points

• Lenacapavir for PrEP (brand name Yeztugo in the United States and Yeytuo in the European Union) is indicated for adults and adolescents weighing at least 35 kg who are at risk of sexual HIV-1 infection.
• Initiation has two subcutaneous injections totaling 927 mg plus 600 mg orally on day 1 and 600 mg orally on day 2; after that, 927 mg every 26 weeks.
• The US package insert carries a boxed warning: using the product in someone with undiagnosed HIV-1 can lead to resistance, so a negative test is required before starting and before each injection.
• In the PURPOSE studies, there were zero infections among 2134 young women in the lenacapavir group and an 89 percent reduction in risk compared with oral PrEP in the study with men and gender-diverse people.
• Nodules at the injection site are very common and can last for months; lenacapavir is also a moderate CYP3A inhibitor, with interactions that can last up to 9 months after the last dose.
• The regulatory dates in this text were checked against primary sources from the FDA, the EMA and the WHO on October 24, 2026.

Why this is a reasoning scenario

Oral PrEP works very well when it is taken, and that is the weak point. Many people at higher risk of HIV find it hard to keep up one pill a day, because of stigma, lack of privacy or an unstable routine. An option given twice a year changes the conversation: adherence now depends on attending two appointments, not on remembering every day. But the injection brings other requirements, and the main one is making sure the person does not have HIV before each dose.

The scenario is good for training because it brings together three decisions. The first is about indication: who benefits and who cannot receive it. The second is about diagnosis: ruling out a recent infection that the rapid test does not detect yet. The third is about follow-up: what to do when the person is late for an injection, becomes pregnant or starts a medicine that interacts. The post on signs, symptoms and history helps organize the collection of exposures and symptoms, and the post on clinical decision-making reminds us that choosing the right test is part of management.

What the scene teaches

The scene trains six habits. The first is asking why the previous PrEP failed, without judgment. The second is looking for signs of acute HIV infection before starting. The third is knowing the initiation schedule, with injection and pills. The fourth is setting the date of the next injection and the allowed window. The fifth is reviewing every medicine in use, including those the person buys without a prescription. The sixth is explaining the nodules at the injection site, so they do not become a reason to stop.

What is not at stake

The text does not discuss the use of lenacapavir in treating people who already live with HIV, which has a different package insert and a different schedule. It also does not compare costs between countries. The post on diagnostic uncertainty helps think about the test window period, which is the main source of doubt in this scene.

Why oral PrEP fails in so many people

A review of injectable PrEP recalls that high initial adherence to oral PrEP does not guarantee protection: the drug must be taken well and for long enough to cover exposures (Pike et al., 2023). In South Africa, the number of people who started oral PrEP by February 2023 passed 790,000, more than three times the national target, but persistence remained low (Pike et al., 2023). A review of adolescent girls and young women in Africa points to the burden of the daily pill as one of the main factors that hinder use in this group (Owuor et al., 2024).

The first generation of injectable PrEP

Before lenacapavir, long-acting cabotegravir, given every two months, proved superior to daily oral PrEP in reducing HIV incidence in two large studies (Landovitz et al., 2023). In the first year after the study opened with transgender men and women who have sex with men, the advantage of the injection held (Landovitz et al., 2023). These results paved the way for the idea that removing daily adherence from the equation reduces infections.

The access barriers

A public policy recommendations article in the United States lists barriers to injectable PrEP: prior authorizations from health plans, lack of staff and infrastructure in clinics, and the price of the products (Marcus et al., 2026). The authors ask manufacturers to consider equitable access when setting the price (Marcus et al., 2026). For the patient in the scene, the practical question is whether the service has the product and can guarantee the return visit every six months.

Applying it to the patient

The patient stopped oral PrEP out of forgetfulness and fear of exposure. These are exactly the reasons a twice-yearly option tries to solve. The partner with unknown status keeps the risk, and she has already made clear that she wants to protect herself. The indication seems good, but before any injection the most important question must be answered: does she have HIV today?

How lenacapavir works

The capsid is the protein shell that surrounds the genetic material of HIV inside the viral particle. A review of the discovery of lenacapavir explains that the capsid protein has several essential functions in the virus cycle: it helps with transport to the cell nucleus, with reverse transcription and with integration of viral DNA into the cell genome (Canales et al., 2025). By binding to the capsid, lenacapavir disrupts several steps at once (Canales et al., 2025).

Why one injection every six months is enough

After the subcutaneous injection, lenacapavir forms a depot and is released slowly. The US label states that the drug can remain in the blood for 12 months or more after the last injection (US Yeztugo label, 6/2025). By the oral route, the half-life is 10 to 12 days, which allows weekly tablets when the injection cannot be given (Ogbuagu et al., 2025).

A new class

A review published after the US approval describes lenacapavir as the first capsid inhibitor approved for PrEP (Sanaullah et al., 2025). Because it belongs to another class, it does not share cross-resistance with the reverse transcriptase inhibitors used in oral PrEP. On the other hand, if the person already has HIV and receives only lenacapavir, the virus is exposed to a single drug, a situation that favors resistance mutations (van Zyl et al., 2025).

What the label says about the heart, the kidneys and the liver

The US label does not describe a clinically relevant effect on the QT interval (US Yeztugo label, 6/2025). It does not require dose adjustment for creatinine clearance of 15 mL/min or more, nor for mild or moderate hepatic impairment, Child-Pugh A or B (US Yeztugo label, 6/2025). Outside these ranges, data are limited, and the label should be read before deciding.

Regulatory status: FDA, EMA and WHO

United States. The FDA approved Yeztugo on June 18, 2025, under NDA 220018, with priority review (Drugs@FDA, NDA 220018). On October 24, 2026, the Drugs@FDA page lists only the original approval, with no supplements, and the label consulted is from June 2025 (Drugs@FDA, NDA 220018) (US Yeztugo label, 6/2025). The indication is PrEP to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg (US Yeztugo label, 6/2025). Lenacapavir had already had US approval since 2022 under another brand name, for treatment, and that is the date of the first approval that appears in the label (US Yeztugo label, 6/2025).

European Union. The EMA committee adopted a positive opinion for Yeytuo on July 24, 2025, and the marketing authorization was issued on August 25, 2025 (EMA, Yeytuo). The EMA page was last updated on September 22, 2026 (EMA, Yeytuo). The European wording of the indication and the guidance may differ from the American one, so it is worth reading the summary of product characteristics before use.

WHO. On July 14, 2025, the WHO published a guideline recommending that long-acting injectable lenacapavir be offered as an additional prevention option, within combination prevention (WHO guideline, 7/14/2025). The same guideline recommends using rapid HIV tests for people starting or continuing injectable PrEP, with flexible testing approaches so that testing does not become a barrier (WHO guideline, 7/14/2025).

CDC. In 2025, the CDC PrEP work group strongly recommended lenacapavir injection every six months as a PrEP option for people weighing at least 35 kg who would benefit from prophylaxis, based on high-certainty evidence (Patel et al., 2025).

Other countries. This text does not describe registration in other countries. Availability depends on the local agency and prevention program.

What the PURPOSE studies showed

Two phase 3 studies supported the approval. The numbers below are from the US label, and the original articles were published in 2024.

PURPOSE 1: young women

PURPOSE 1 included cisgender women aged 16 to 25 in South Africa and Uganda (US Yeztugo label, 6/2025). There were 2134 participants in the lenacapavir group, 2136 in the emtricitabine with tenofovir alafenamide group and 1068 in the emtricitabine with tenofovir disoproxil group (US Yeztugo label, 6/2025). The median age was 21 years (US Yeztugo label, 6/2025). There were zero HIV-1 infections in the lenacapavir group over 1939 person-years, versus 16 infections over 949 person-years in the tenofovir disoproxil group, an incidence of 1.69 per 100 person-years (US Yeztugo label, 6/2025). The label describes this as a 100 percent reduction in risk compared with oral PrEP (US Yeztugo label, 6/2025).

PURPOSE 2: men and gender-diverse people

PURPOSE 2 included cisgender men, transgender people and non-binary people aged 16 or older, in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States (US Yeztugo label, 6/2025). There were 2179 participants in the lenacapavir group and 1086 in the tenofovir disoproxil group (US Yeztugo label, 6/2025). The median age was 29 years, and 22 percent identified as gender-diverse people (US Yeztugo label, 6/2025). There were 2 infections in the lenacapavir group, with an incidence of 0.1 per 100 person-years, versus 9 infections and an incidence of 0.93 in the oral group, an 89 percent reduction in risk (US Yeztugo label, 6/2025).

The table summarizes the two studies, according to the US label.

Study	Population	Infections with lenacapavir	Infections with oral PrEP (tenofovir disoproxil)	Source
PURPOSE 1	Cisgender women aged 16 to 25, South Africa and Uganda	0 over 1939 person-years	16 over 949 person-years (1.69 per 100)	(US Yeztugo label, 6/2025)
PURPOSE 2	Cisgender men and gender-diverse people aged 16 or older, seven countries	2 over 1938 person-years (0.1 per 100)	9 over 967 person-years (0.93 per 100)	(US Yeztugo label, 6/2025)

The infections that occurred

A resistance analysis of the two studies showed that, in PURPOSE 2, the two participants in the lenacapavir group who acquired HIV developed the N74D substitution in the capsid (Cox et al., 2026). In PURPOSE 1, seven participants already had unrecognized HIV at baseline (Cox et al., 2026). A commentary on resistance recalls that isolated N74D appeared in these two infections in PURPOSE 2 (van Zyl et al., 2025). This shows, with small numbers, why testing before each injection is the central rule.

Injection-site adverse events

In the US label, injection-site nodules appeared in 64 percent of participants, with a median duration of 350 days and a median maximum diameter of 3.0 cm (US Yeztugo label, 6/2025). Local pain was reported in 31 percent (US Yeztugo label, 6/2025). In PURPOSE 2, injection-site reactions occurred in 83 percent of the lenacapavir group and in 69 percent of the group that received placebo injections (US Yeztugo label, 6/2025). Common adverse reactions, besides local ones, were headache and nausea (US Yeztugo label, 6/2025). Accidental intradermal injection into the skin can cause necrosis or ulceration, and correct subcutaneous administration technique is part of staff training (US Yeztugo label, 6/2025).

From the first dose to the six-month return

For the patient, the sequence starts with the test. The US label contraindicates the product in people who are HIV-1 positive or of unknown status, and requires a negative test before the first dose and before each injection (US Yeztugo label, 6/2025). If there has been recent exposure or symptoms consistent with acute infection, such as fever, fatigue, muscle aches or skin rash, the label requires confirming status with a test approved for diagnosing acute or recent infection (US Yeztugo label, 6/2025). The CDC recommendation describes the use of antigen and antibody tests in the studies, with RNA testing for those who acquired infection (Patel et al., 2025).

The starting regimen

On day 1, the patient receives 927 mg subcutaneously, in two 1.5 mL injections, and takes 600 mg orally, as two 300 mg tablets (US Yeztugo label, 6/2025). On day 2, she takes another 600 mg orally (US Yeztugo label, 6/2025). After that, she receives 927 mg subcutaneously every 26 weeks, with a window of 2 weeks earlier or later from the date of the last injection (US Yeztugo label, 6/2025). In the studies, most injections were given in the abdomen, at two sites (US Yeztugo label, 6/2025).

If the injection is delayed

If the next injection cannot be given within the window, the label allows 300 mg tablets once every 7 days, for up to 6 months, until the injection is possible (US Yeztugo label, 6/2025). A study in people already living with HIV showed that this weekly oral bridge maintained drug levels and viral suppression when the injection could not be given (Ogbuagu et al., 2025). If more than 28 weeks pass since the last injection without the tablets, the starting regimen must be restarted, after a new negative test (US Yeztugo label, 6/2025).

Interactions

Before starting, the medication list must be reviewed. The label requires extra doses when the person starts a strong or moderate CYP3A inducer and does not recommend use with medicines that simultaneously inhibit P-glycoprotein, UGT1A1 and strongly inhibit CYP3A (US Yeztugo label, 6/2025). Lenacapavir itself is a moderate CYP3A inhibitor and can raise the level of other medicines for up to 9 months after the last injection (US Yeztugo label, 6/2025). The post on interprofessional clinical reasoning shows how the pharmacy helps with this review.

Pregnancy and breastfeeding

The patient is 24 years old and may become pregnant while using it. The US label states that, in PURPOSE 1, no risk associated with the drug was identified in exposed pregnancies (US Yeztugo label, 6/2025). In the pregnant participants in the study, the injections were given in the thigh, one on each side (US Yeztugo label, 6/2025). Lenacapavir passes into breast milk, with a ratio between the baby's plasma and the mother's of about 0.06 (US Yeztugo label, 6/2025). The WHO guideline includes an annex on outcomes of administration during pregnancy (WHO guideline, 14/7/2025).

The conversation about the tail

Because the drug stays in the body for many months, anyone who decides to stop needs to know that there will be a long period of low and declining levels (US Yeztugo label, 6/2025). If the person acquires HIV during this period, the risk of resistance increases (van Zyl and colleagues, 2025). For this reason, the label recommends considering another form of PrEP if the person stops and remains at risk (US Yeztugo label, 6/2025). The post about diagnostic pause reminds you to review the plan before ending follow-up.

• Negative HIV test before the first injection and before each injection.
• Symptoms of acute infection or recent exposure call for testing for acute or recent infection.
• Day 1: 927 mg subcutaneously plus 600 mg orally; day 2: 600 mg orally.
• Maintenance: 927 mg subcutaneously every 26 weeks, with a tolerance of 2 weeks.
• Delay: 300 mg orally every 7 days, for up to 6 months; more than 28 weeks without coverage calls for restarting.
• Review of interactions at the start and with each new drug, remembering the effect of up to 9 months.

Source of the list: (US Yeztugo label, 6/2025).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Twice-yearly PrEP is a good exercise because a recent fever, an injection date or a new drug changes the approach. The post about case-based learning explains why this format fixes knowledge, and the post about differential diagnosis helps you think about the febrile syndrome that may be acute HIV infection.

Three exercises with cases

Change the symptoms. Say what to do if the patient reported fever and sore throat for a week.

Change the date. Say what to do if she returned 30 weeks after the last injection, without having taken tablets.

Change the drugs. Say what to check if she needed to start tuberculosis treatment with rifampicin.

The post about simulation of a consultation helps train the explanation about nodules and return visits.

The limits on use of the game are described on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information on curation and on creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Do I need a test before each injection?

Yes. The US label requires a negative HIV-1 test before starting and before each injection (US Yeztugo label, 6/2025).

What is the interval between injections?

26 weeks, with a tolerance of 2 weeks more or less (US Yeztugo label, 6/2025).

What if I cannot come back on the date?

The label allows 300 mg orally once every 7 days, for up to 6 months (US Yeztugo label, 6/2025).

Is the nodule in the belly normal?

Nodules are very common and usually last for months; in the label, the median duration was 350 days (US Yeztugo label, 6/2025).

Can it be used during pregnancy?

In PURPOSE 1, no risk associated with the drug was identified in exposed pregnancies (US Yeztugo label, 6/2025). The decision should follow the local protocol.

Final checklist

• I asked why the previous PrEP failed, without judgment.
• I looked for symptoms of acute infection and recent exposures.
• I confirmed a negative HIV-1 test before the injection.
• I checked a weight of at least 35 kg.
• I reviewed the medications in use, including CYP3A inducers and inhibitors.
• I explained the nodules and the pain at the injection site.
• I scheduled the next injection in 26 weeks and explained the 2-week window.
• We agreed on what to do in case of delay, pregnancy or a wish to stop.

Want to practice your reasoning with progressive clues? Play the case of the day.

References

1. Canales E, Tse W, Schroeder SD, et al. Discovery of Lenacapavir: First-in-Class Twice-Yearly Capsid Inhibitor for HIV-1 Treatment and Pre-exposure Prophylaxis. J Med Chem. 2025. PMID 41032707.
2. Cox S, Andreatta K, Hendricks MR, et al. Resistance Analyses of Lenacapavir, Emtricitabine/Tenofovir Alafenamide and Emtricitabine/Tenofovir Disoproxil Fumarate in the PURPOSE 1 and 2 Studies. J Infect Dis. 2026. PMID 41130593.
3. European Medicines Agency. Yeytuo | European Medicines Agency (EMA). Opinion dated 07/24/2025; authorization issued on 08/25/2025. Accessed on 10/24/2026. Official source.
4. Gilead Sciences. YEZTUGO® (lenacapavir) injection, for subcutaneous use. Prescribing Information. Revised in 6/2025. Accessed on 10/24/2026. Official source.
5. Landovitz RJ, Hanscom BS, Clement ME, et al. Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial. Lancet HIV. 2023. PMID 37952550.
6. Marcus JL, Weddle A, Kelley CF, et al. Policy Recommendations to Support Equitable Access to Long-Acting Injectables for HIV Prevention and Treatment: A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association. Clin Infect Dis. 2026. PMID 39873495.
7. Ogbuagu OE, Avihingsanon A, Segal-Maurer S, et al. Efficacy, safety, and pharmacokinetics of lenacapavir oral bridging when subcutaneous lenacapavir cannot be administered. AIDS. 2025. PMID 39912752.
8. Owuor S, Kimani M, Kaplan R. The future of PrEP: novel long-acting HIV prevention agents for adolescent women. Pan Afr Med J. 2024. PMID 38766564.
9. Patel RR, Hoover KW, Lale A, et al. Clinical Recommendation for the Use of Injectable Lenacapavir as HIV Preexposure Prophylaxis - United States, 2025. MMWR Morb Mortal Wkly Rep. 2025. PMID 40966169.
10. Pike C, Rousseau E, Bekker LG. Promises and potential pitfalls of long-acting injectable pre-exposure prophylaxis. South Afr J HIV Med. 2023. PMID 38089889.
11. Sanaullah K, Hasan AH, Abid MA. FDA-Approved HIV-1 Capsid Inhibition With Lenacapavir: A Paradigm Shift in Pre-exposure Prophylaxis. Cureus. 2025. PMID 41084700.
12. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. NDA 220018, Yeztugo. Accessed on 10/24/2026. Official source.
13. van Zyl G, Prochazka M, Schmidt HA, et al. Lenacapavir-associated drug resistance: implications for scaling up long-acting HIV pre-exposure prophylaxis. Lancet HIV. 2025. PMID 40543515.
14. World Health Organization. Guidelines on lenacapavir for HIV prevention and testing strategies for long-acting injectable pre-exposure prophylaxis. Published on 07/14/2025. Accessed on 10/24/2026. Official source.