The U.S. Food and Drug Administration (FDA) has granted approval to lenacapavir, marketed as Yeztugo, as the first and only twice-yearly injectable option for HIV pre-exposure prophylaxis (PrEP). This landmark decision, announced on June 18, 2025, marks a significant advancement in the global fight against HIV.
Yeztugo, developed by Gilead Sciences, offers a discreet and highly effective alternative to daily oral pills, addressing critical barriers such as adherence challenges and stigma associated with traditional PrEP regimens. Its approval is based on groundbreaking clinical trials (PURPOSE 1 and PURPOSE 2) that demonstrated near-complete protection against HIV. The designation of Yeztugo as the "first and only" twice-yearly injectable HIV-1 capsid inhibitor is a strong market differentiator, providing a unique and highly convenient solution that could reshape the PrEP landscape. This distinct positioning is expected to drive rapid adoption among eligible populations.
While Yeztugo offers immense potential to accelerate global HIV prevention efforts, challenges related to cost, equitable access, and robust implementation strategies remain paramount to realizing its full impact. The high efficacy observed in controlled trials does not automatically translate to widespread public health benefit if systemic barriers prevent broad access and consistent use. Therefore, the transformative potential of this new option is contingent upon overcoming these real-world implementation hurdles, which necessitates coordinated efforts beyond the mere development of the drug.
1. A New Era in HIV Prevention: Introducing Yeztugo
1.1. The FDA's Historic Approval of Lenacapavir (Yeztugo)
On June 18, 2025, the U.S. Food and Drug Administration (FDA) officially approved lenacapavir for HIV prevention. This significant milestone was widely welcomed by global health organizations, including the World Health Organization (WHO), on June 19, 2025.
The drug, developed by Gilead Sciences, will be marketed under the brand name Yeztugo for prevention, distinguishing it from its existing use as Sunlenca for the treatment of multi-drug-resistant HIV. This strategic branding serves a crucial public health purpose. By assigning different names for prevention and treatment, Gilead aims to avoid confusion for both patients and healthcare providers, ensuring that the correct dosing and counseling are provided for each distinct indication. This differentiation also helps to mitigate any potential stigma associated with carrying a "treatment" drug for prevention purposes, thereby optimizing uptake and adherence in the broader community.
Yeztugo is administered as two subcutaneous injections in the abdomen, providing protection for six months, making it the world's first and only twice-yearly HIV prevention shot.
1.2. How Yeztugo Works: A Novel Mechanism of Action
Lenacapavir is a first-in-class HIV-1 capsid inhibitor. Unlike previous PrEP medications that target different stages of the viral lifecycle, lenacapavir works by disrupting the HIV capsid, a protein shell essential for the virus's replication cycle. This unique multi-stage mechanism prevents HIV from multiplying and spreading within the body.
The novel mechanism of action holds significant implications for the long-term management of the HIV epidemic, particularly concerning drug resistance. As a first-in-class inhibitor, lenacapavir exhibits no known cross-resistance to other existing drug classes in vitro. This is a critical advantage because it means that individuals who may have developed resistance to other PrEP or treatment drugs could still find lenacapavir effective. This property expands the pool of individuals who can benefit from PrEP, reducing the risk of prevention failure due to pre-existing resistance. Such a development provides a long-term strategic advantage in managing the evolving landscape of HIV, where drug resistance is a constant concern.
Its long-acting formulation allows the medication to remain active in the body for months after injection, providing sustained protection. This extended release is fundamental to its twice-yearly dosing schedule, offering unparalleled convenience.
2. Unprecedented Efficacy: Insights from Landmark Clinical Trials
2.1. The PURPOSE 1 and PURPOSE 2 Studies: Rigorous Design and Diverse Populations
The FDA approval of Yeztugo is underpinned by compelling data from two international Phase 3 clinical trials: PURPOSE 1 and PURPOSE 2. These trials rigorously evaluated the safety and efficacy of lenacapavir for PrEP across diverse populations and settings.
The PURPOSE 1 study enrolled over 5,300 sexually active young women and adolescent girls, aged 16-26, across 25 sites in South Africa and three in Uganda. The PURPOSE 2 trial included 3,267 participants, comprising cisgender men, transgender men, transgender women, and gender non-binary individuals who have sex with partners assigned male at birth. This trial was conducted at 88 sites across various countries, including Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States.
2.2. Key Results: Superior Protection and Near Elimination of Infections
The PURPOSE 1 trial demonstrated remarkable efficacy, reporting zero HIV infections among participants receiving twice-yearly lenacapavir. In contrast, the comparison groups receiving daily oral PrEP (TDF/FTC or TAF/FTC) experienced an infection rate of approximately 2%. This stark difference highlighted the superior protection offered by lenacapavir, particularly given the low adherence observed in the oral PrEP arms. The observation that poor adherence to daily oral PrEP directly correlated with HIV acquisition underscores a critical point: the effectiveness of a prevention method is not solely determined by its pharmacological action but significantly by a person's ability to consistently use it. Lenacapavir's long-acting nature inherently improves adherence by drastically reducing the dosing frequency, thereby directly contributing to its superior real-world effectiveness compared to daily oral regimens.
An interim analysis of the PURPOSE 2 trial revealed a 96% reduction in the risk of acquiring HIV among participants on lenacapavir, with 99.9% of individuals not acquiring HIV. Only two new HIV cases were recorded among 2,180 participants receiving twice-yearly lenacapavir, compared to nine new cases among 1,087 participants on daily oral TDF/FTC. Collectively, these studies showed that lenacapavir "nearly eliminated new infections" in high-risk populations, demonstrating "100% effectiveness" in one trial and "superior protection" compared to daily oral PrEP.
2.3. Safety Profile and Common Side Effects
Lenacapavir was generally well-tolerated in clinical trials. The most frequently reported adverse events were injection site reactions (ISRs), such as pain. While common, ISRs rarely led to discontinuation, with only 0.2% in PURPOSE 1 and 1.2% in PURPOSE 2 discontinuing due to these reactions. However, improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer, underscoring the importance of correct subcutaneous administration.
Individuals must test negative for HIV-1 before initiating Yeztugo and before each subsequent injection to prevent the development of drug-resistant HIV-1 variants, as Yeztugo alone is not a complete treatment regimen. The high efficacy of lenacapavir, along with existing PrEP options, presents a unique consideration for future HIV vaccine research. As noted by Dr. David Ho, the effectiveness of current prevention tools raises the ethical bar for vaccine development, making it difficult to justify placebo-controlled trials where participants would be deprived of highly effective prevention. This situation suggests a potential shift in the landscape of HIV research, possibly moving towards innovative trial designs that compare new vaccines against existing PrEP options, or a greater focus on other prevention modalities and combination strategies. This represents a significant long-term implication for the direction of scientific development in HIV prevention.
3. Transforming Prevention: Benefits and Advantages of Long-Acting PrEP
3.1. Addressing Adherence Challenges and Reducing Stigma
One of the most significant advantages of Yeztugo's twice-yearly dosing is its potential to dramatically improve adherence. Daily oral PrEP regimens often suffer from inconsistent adherence, which compromises their effectiveness. A twice-yearly shot removes the burden of daily pill-taking, making long-term protection much easier for many individuals.
The improved adherence facilitated by Yeztugo has a multiplier effect on public health goals. When more individuals consistently adhere to their PrEP regimen, the overall rate of new HIV infections at a population level decreases significantly. This directly accelerates progress towards global targets, such as the UNAIDS goals to reduce new HIV infections. The convenience of a twice-yearly injection acts as a force multiplier, making an already effective prevention tool even more impactful on a larger scale, thereby bringing the world closer to ending the HIV epidemic.
The discreet nature of an injectable, administered just twice a year, can also help overcome stigma associated with HIV prevention. Individuals can avoid the privacy concerns of carrying daily pills, which can be particularly important for those who need protection without a partner's knowledge or consent, or in communities where stigma remains high.
3.2. Expanding Access to Underserved and Vulnerable Populations
The convenience and discretion offered by Yeztugo are expected to expand PrEP access to populations that have historically been underserved or faced barriers with daily oral medication. This includes women, who account for about half of new HIV infections and often require discreet prevention options.
Healthcare providers anticipate that the twice-yearly injection will help reach more people who may struggle with daily oral regimens or prefer non-oral options, thereby expanding the promise of PrEP to underreached communities. This shift also impacts patient-provider dynamics and counseling. As noted by Dr. Jennifer Veltman, this new option "gives people more control over their HIV prevention". Historically, patient counseling for daily oral PrEP often involved frequent reminders and discussions about consistent use. With a twice-yearly injection, the adherence conversation simplifies to just two clinic visits a year. This change frees up time for more holistic health discussions, potentially reducing the "policing" aspect of daily adherence and fostering greater patient autonomy and engagement in their own prevention journey. This represents a transformative impact on healthcare delivery models and patient empowerment.
3.3. The "Breakthrough of the Year" Recognition
Lenacapavir was recognized as Science magazine's "Breakthrough of the Year" in 2024, a testament to its enormous potential to revolutionize HIV prevention. This prestigious recognition underscores the scientific community's excitement about this innovative drug.
4. Navigating the Path Forward: Challenges and Global Accessibility
4.1. Cost and Affordability Concerns
Despite its groundbreaking potential, the U.S. list price for Yeztugo is $28,218 per year, which Gilead states is comparable to some other PrEP options. This high price has drawn significant criticism from global health advocates, including UNAIDS, whose Executive Director Winnie Byanyima stated, "If this game-changing medicine remains unaffordable, it will change nothing". Research suggests generic lenacapavir could be produced for as low as $25-$46 per person per year.
Concerns about accessibility and affordability in the U.S. and globally remain a major hurdle, with some healthcare providers expressing initial difficulty in using the drug for PrEP due to financial barriers. This situation highlights a dual challenge: the immediate barrier of high cost, even with insurance, which can create access issues for individuals with high deductibles or limited coverage, and the systemic barrier of a potentially weakened public health infrastructure. Even if the drug becomes affordable, its impact will be limited if clinics, testing sites, and outreach programs are not robust enough to reach those who need it. These two challenges are interdependent; an affordable drug without a strong delivery system is ineffective, and a robust system without an affordable drug is constrained. Addressing the HIV epidemic therefore requires not just scientific breakthroughs but also significant policy and funding commitments to rebuild and strengthen public health infrastructure.
4.2. Gilead's Global Access Strategy
Gilead is implementing a multi-pronged access strategy to ensure broad, sustainable access, particularly in low- and middle-income countries. This includes signing non-exclusive, royalty-free voluntary licensing agreements with six generic drug manufacturers in October 2024 to supply low-cost versions of lenacapavir to 120 high-incidence, resource-limited countries.
Gilead plans to provide its branded product at no profit to these countries until generic versions are available, aiming to supply 2 million people. They are also pursuing accelerated global regulatory pathways and timely national regulatory submissions in countries like South Africa and Brazil. In the U.S., Gilead anticipates that 75% of individual insurance plans will cover Yeztugo within six months, and 90% within a year, with medication assistance programs available for the uninsured.
This differentiated pricing and access strategy, while commendable for the poorest countries, creates a potential for a two-tiered global prevention system. Many middle-income countries, not covered by the voluntary licenses, may struggle to afford the drug at higher prices and may lack the negotiating power of high-income nations. This could lead to a fragmented global response, where the benefits of this breakthrough are unevenly distributed, potentially exacerbating health inequalities between nations and undermining the universal goal of ending the HIV epidemic "for everyone, everywhere".
4.3. Ensuring Equitable Distribution, Follow-Up, and Comprehensive Risk Management
Despite the drug's potential, experts warn of "gaping holes in the system" in the U.S. and globally, which could hinder effective rollout and follow-up. This includes concerns about the dismantling of HIV prevention and testing programs.
Consistent follow-up is crucial for twice-yearly injections, and individuals must consistently test negative for HIV before each dose to prevent the emergence of drug resistance. Yeztugo only prevents HIV transmission and does not protect against other sexually transmitted infections (STIs), emphasizing the continued need for safer sex practices like condom use.
5. Comparing Prevention Options: Yeztugo in Context
The approval of Yeztugo adds a powerful new dimension to the existing landscape of HIV pre-exposure prophylaxis. To understand its full impact, it is helpful to compare it with previously available options.
5.1. Daily Oral PrEP (Truvada, Descovy): The Foundation
Before long-acting injectables, daily oral PrEP medications like Truvada (emtricitabine/tenofovir disoproxil fumarate) and Descovy (emtricitabine/tenofovir alafenamide) were the primary biomedical prevention tools. These pills are highly effective when taken consistently, reducing HIV risk from sex by about 99%. However, the daily pill burden and the need for consistent adherence have been significant challenges, often leading to suboptimal real-world effectiveness for many individuals.
5.2. Bi-Monthly Injectable PrEP (Cabotegravir/Apretude): A Predecessor
In December 2021, the FDA approved cabotegravir extended-release injectable suspension (Apretude) as the first long-acting injectable PrEP option, administered every two months. This was a major step forward in addressing adherence issues by reducing dosing frequency. Apretude also demonstrated superior efficacy to daily oral PrEP in clinical trials, offering an important alternative for those who preferred injections over daily pills.
5.3. Choosing the Right PrEP Option: Personalization and Patient Needs
Yeztugo's twice-yearly dosing makes it the longest-lasting PrEP option available, offering even greater convenience than bi-monthly cabotegravir. This progression from daily pills to bi-monthly, and now twice-yearly injections, reflects a broader trend in medicine: reducing the daily burden of chronic disease management. Less frequent dosing means less daily effort, fewer reminders, and less intrusion into one's life. This contributes to a "de-medicalization" of prevention, making it feel less like a daily medical chore and more like an integrated, discreet part of one's health routine. This psychological benefit can significantly impact uptake and long-term adherence beyond just the physical act of taking medication.
While a cost-effectiveness analysis suggested lenacapavir might not be as cost-effective as generic oral PrEP or cabotegravir from a U.S. payer perspective, its reduced administration frequency offers a viable alternative for individuals who prioritize convenience. This finding highlights a critical tension. Traditional cost-effectiveness models, which often focus on direct drug costs and immediate health outcomes, may not fully capture the broader public health and societal benefits of improved adherence, reduced stigma, and expanded reach to vulnerable populations. For example, preventing even a few more infections due to better adherence could offset higher drug costs in the long run by avoiding lifetime HIV treatment costs. This suggests a need for more comprehensive economic evaluations that account for social and behavioral factors in addition to direct medical costs.
The availability of multiple PrEP options—daily oral, bi-monthly injectable, and now twice-yearly injectable—allows for a more personalized approach to HIV prevention, enabling healthcare providers and individuals to choose the regimen best suited to their lifestyle, preferences, and needs.
Table 1: Key Features of FDA-Approved HIV PrEP Options
PrEP Option (Brand Name) | Active Ingredient(s) | Dosing Frequency | Administration Method | Mechanism of Action | FDA Approval Date (for PrEP) | Key Efficacy (Risk Reduction) | Key Advantages | Key Considerations/Side Effects |
Oral PrEP (Truvada) | FTC/TDF | Daily | Oral Pill | NRTI | 2012 | ~99% (when adhered) | Established, widely available | Daily adherence burden, stigma |
Oral PrEP (Descovy) | FTC/TAF | Daily | Oral Pill | NRTI | 2019 | ~99% (when adhered) | Established, bone/kidney profile | Not for receptive vaginal sex |
Injectable PrEP (Apretude) | Cabotegravir | Every 2 Months | Intramuscular Injection (Gluteal) | INSTI | Dec 2021 | 69-90% (vs Truvada) | Reduced dosing burden, discreet | Injection site reactions, bi-monthly visits |
Injectable PrEP (Yeztugo) | Lenacapavir | Twice-Yearly (Every 6 Months) | Subcutaneous Injection (Abdomen) | HIV-1 Capsid Inhibitor | June 2025 | 96-100% | Longest-acting, highly discreet | Injection site reactions, cost/access |
6. The Road to Ending the HIV Epidemic: Yeztugo's Role
6.1. Contribution to Global HIV Prevention Goals
The approval of Yeztugo is a significant step towards achieving global HIV prevention targets, such as the UNAIDS 2025 goals, which aim to reduce new HIV infections to fewer than 370,000 per year. The World Health Organization (WHO) has welcomed the approval and is developing new guidelines for injectable lenacapavir, expected to be released on July 14, 2025, during the International AIDS Conference in Kigali. This will facilitate its global adoption and integration into national health strategies. The CDC is also preparing for the global distribution of twice-yearly lenacapavir, working to identify and prioritize implementation where it can have the most significant impact on ending HIV as a public health threat.
This scientific triumph, however, is critically dependent on political decisions regarding funding and access. Experts have warned of "gaping holes in the system" and expressed concerns about funding cuts to HIV prevention programs. Without sustained political will and adequate investment, even the most revolutionary scientific tools, like Yeztugo, will fall short of their potential. This highlights a crucial dependency of public health progress on robust political and financial commitment, creating a tension between groundbreaking innovation and effective implementation.
6.2. Call to Action for Healthcare Providers, Policymakers, and Communities
To fully leverage Yeztugo's potential, concerted efforts are needed from all stakeholders. Healthcare providers must be equipped to offer consultations and administer the new injection, ensuring proper screening and follow-up.
Policymakers must address the critical issues of affordability and equitable access, ensuring that financial barriers do not prevent those most in need from receiving this life-changing prevention tool. This includes advocating for fair pricing and robust funding for prevention programs.
Communities and advocacy groups play a vital role in raising awareness, combating stigma, and ensuring that prevention messages and services reach vulnerable populations effectively. With highly effective PrEP options like Yeztugo, the definition of "ending the HIV epidemic" shifts. It becomes less about finding a cure (though still a desired goal) and more about achieving universal access and consistent uptake of these highly effective prevention tools. This transforms the challenge from a purely medical problem into a socio-political and logistical one, emphasizing that the "end" is within reach if systemic barriers to equitable distribution and sustained engagement are dismantled.
Conclusion: A Promising Step Towards a Future Free of HIV
The FDA's approval of the twice-yearly HIV prevention shot, Yeztugo (lenacapavir), represents a monumental leap forward in the fight against HIV. Its unprecedented efficacy, coupled with the convenience and discretion of its dosing, offers a powerful new tool to protect individuals and accelerate progress towards global prevention goals.
While challenges related to cost and equitable access demand urgent attention and collaborative solutions, Yeztugo embodies the ongoing innovation and unwavering commitment of the scientific and public health communities. By leveraging this breakthrough, and ensuring it reaches everyone who can benefit, the global community moves closer to a future where new HIV infections are a thing of the past.
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