Lenacapavir and global HIV prevention: a breakthrough at risk of leaving millions behind

Abstract

In June 2025, the FDA approved Lenacapavir, a twice-yearly injectable for HIV pre-exposure prophylaxis (PrEP), following striking trial results showing near-perfect efficacy. This long-acting injectable represents a game-changing innovation, promising to transform HIV prevention by reducing pill burden, stigma, and adherence challenges for individuals at high risk of infection. However, despite its potential, Lenacapavir is being launched into a system where access to life-saving treatments remains deeply unequal. Currently priced at over $28 000 annually in the United States, Lenacapavir may remain out of reach for millions in low- and middle-income countries (LMICs) unless global action is taken. Although, Gilead Sciences has entered voluntary licensing agreements, historical patterns suggest that production, registration, and distribution delays may once again exclude the most vulnerable. Without enforceable commitments, voluntary mechanisms risk perpetuating the same global health divides that once delayed antiretroviral access across sub-Saharan Africa. This perspective argues that Lenacapavir’s success must not be judged by regulatory approval alone, but by the speed and scale of equitable implementation. Unless governments, funders, and civil society act now, this biomedical triumph could widen the very disparities it seeks to overcome. The breakthrough and advancement is real but so is the risk of leaving millions behind.

Introduction

Lenacapavir (Yeztugo) is a first-in-class capsid inhibitor that provides biannual PrEP coverage. As a capsid inhibitor, Lenacapavir acts by binding to the HIV-1 capsid protein and disrupting several essential steps of the viral life cycle, including capsid assembly, nuclear import, and genome packaging. Because it interferes with the capsid at multiple points both early and late replication, Lenacapavir maintains potent antiviral pressure even at very low plasma concentrations. Lenacapavir multi-stage inhibition, combined with its exceptionally slow release kinetics from subcutaneous tissue, enables it to provide sustained protection for up to six months following a single injection.

Unlike oral PrEP regimens like tenofovir/emtricitabine (Truvada) or even monthly injectables like cabotegravir, Lenacapavir requires only two subcutaneous injections per year^[1]. In the PURPOSE 1 and 2 trials, it demonstrated 99.9% efficacy in men and gender-diverse individuals, and over 99% efficacy in cisgender women^[2,3]. Thus, outperforming oral PrEP regimens. This has enormous implications for young women in sub-Saharan Africa who account for more than 60% of new infections in the region as well as for men who have sex with men (MSM), transgender people, and people who inject drugs^[4,5]. For these populations, Lenacapavir could reduce the stigma of visible medication use, improve autonomy, unstable access to healthcare and eliminate barriers related to daily pill burden. In both high and low-resource settings, it offers the potential for discreet, long-term protection which is an essential step forward in HIV prevention strategy. In preparing this perspective, we adhered to the TITAN Guidelines 2025 for transparency in the use of artificial intelligence tools in scientific writing and data synthesis^[6].

Clinical trial evidence and its strengths

Lenacapavir’s efficacy data is primarily derived from the PURPOSE 1 and PURPOSE 2 trials, both large, randomized, double-blind studies comparing twice-yearly Lenacapavir to standard PrEP modalities^[2,3]. PURPOSE 1 enrolled more than 5000 cisgender women across high-incidence regions of sub-Saharan Africa, while PURPOSE 2 extended these to MSM, transgender women, and non-binary participants across the United States, Latin America, Europe, and Africa, with over 3000 participants^[2,3]. The trial designs employed their active comparators, event-driven endpoints, and diverse geographic representation. Hence, its scientific rigour and high-quality evidence. Lenacapavir demonstrated statistical superiority to oral PrEP in both trials, providing one of the strongest clinical prevention signals observed in the field to date^[2,3]. There are several features that strengthened the evidentiary quality.

First, both trials used active comparators: Lenacapavir was evaluated against daily oral PrEP (tenofovir/emtricitabine) rather than placebo. This design allows direct comparison with the current standard of care, thereby producing findings highly relevant for clinical decision-making. Second, the event-driven design ensured that the trials continued until a pre-specified number of HIV seroconversion events occurred^[1–3]. Thus, increasing statistical precision for estimating efficacy. This is a superior methodological approach because it anchors the outcome to real clinical endpoints rather than arbitrary timelines. Third, randomization and double blinding minimized selection, performance, and detection bias. Oral and injectable arms were matched using placebo injections or placebo pills, preserving blinding for participants and investigators^[1–3]. Fourth, the trials incorporated rigorous adherence monitoring, including drug level assessments, electronic pill monitoring, and cross-checks with clinic attendance. Accurately measuring adherence to oral PrEP in comparator arms ensured that the studies were better able to distinguish true biological superiority from adherence variability. Fifth, both trials were conducted across diverse epidemiologic contexts, covering rural and urban clinics, varying background incidence rates, and different healthcare infrastructures^[1–3]. This diversity enhances external validity and supports generalizability to real-world populations where HIV risk is driven by structural, social, and behavioral factors.

The results demonstrated statistical superiority. Lenacapavir showed HIV incidence reductions exceeding 99% compared to oral PrEP, reaching one of the lowest incidence rates observed in any HIV prevention trial. The few infections that did occur were largely associated with missed injections or occurred before participants had reached protective drug levels, highlighting the importance of maintaining the biannual dosing schedule^[1–3]. The combination of strong effect size, precise confidence intervals, and consistency across subgroups provides unusually compelling evidence that the drug’s long-acting mechanism overcomes adherence challenges that limit the effectiveness of daily oral regimens. Taken together, these methodological strengths establish PURPOSE 1 and PURPOSE 2 as high-quality, definitive trials whose findings provide credible, clinically actionable evidence for Lenacapavir’s use as a long-acting HIV prevention modality.

Limitations and unanswered clinical questions

Despite the remarkable efficacy demonstrated in the PURPOSE trials, several important uncertainties remain that must be addressed through longer-term follow-up and supplementary studies. First, long-term safety beyond the trial duration is not yet known. The current data span a limited timeframe that is insufficient to fully characterize any rare or delayed adverse events, cumulative tissue exposure, or potential long-term injection-site complications. For a drug designed to remain active for 6 months at a time, understanding multiyear safety and tolerability is essential.

Second, the potential for capsid inhibitor resistance remains an emerging concern. Resistance may occur when a person acquires HIV infection while Lenacapavir drug levels are declining between injections. This is referred to as a period of waning drug levels. During this window, drug concentrations may be too low to fully suppress viral replication but high enough to exert selective pressure, allowing the virus to mutate and develop resistance to capsid inhibitors. Although only a small number of breakthrough infections occurred in the PURPOSE trials, and were linked to missed or delayed injections, the true frequency and clinical consequences of resistance will require continued surveillance, especially as real-world adherence patterns may differ from those in clinical trials.

Third, while PURPOSE 1 and PURPOSE 2 enrolled diverse populations, they still do not cover all special groups for whom safety and efficacy must be clarified. Specifically, pregnant and breastfeeding individuals were excluded from both trials, meaning data on placental transfer, fetal exposure, or effects on breastfed infants are unavailable. Similarly, adolescents under age 16, i.e., a group with exceptionally high HIV vulnerability in many regions were not included. Trials also did not enroll sufficient numbers of individuals with significant comorbidities like those with uncontrolled epilepsy, tuberculosis requiring rifampicin-based therapy, or chronic conditions requiring multiple medications. These groups may experience altered drug metabolism or drug–drug interactions that were not fully evaluated in the original trials.

Potential pharmacologic interactions remain an important unanswered question. Lenacapavir is metabolized through pathways that may be influenced by commonly used medications, including certain antiepileptics, rifampicin-based tuberculosis treatment regimens, and gender-affirming hormone therapies. Each of these medications may affect Lenacapavir concentrations or vice versa, influencing effectiveness or safety. Dedicated interaction studies will be necessary to guide clinical decision-making for these populations.

These gaps demonstrates the need for continued research, long-term pharmacovigilance, and targeted studies in populations that fall outside the scope of the initial clinical trials. Addressing these uncertainties will be critical to ensuring that Lenacapavir’s introduction into global HIV prevention programs is safe, equitable, and scientifically informed.

Early implementation, integration and implications for clinicians

Early implementation should strategically prioritize populations most likely to benefit from Lenacapavir in the short term. Given supply constraints and the logistical hurdles of delivering twice-yearly injections, programs may need to initially focus on populations with the highest incidence and greatest structural vulnerability which includes adolescent girls and young women in sub-Saharan Africa, individuals experiencing homelessness or unstable access to healthcare, MSM and transgender women with adherence challenges, and people who inject drugs. Aligning rollout strategies with epidemiologic burden will maximize public health impact. At the same time, Lenacapavir must be integrated thoughtfully into the existing HIV prevention scheme rather than positioned as a replacement for oral PrEP or cabotegravir. Clinical decision-making will require shared discussions about patient mobility, comorbidities, adherence history, and personal preference, while its introduction also creates opportunities to co-deliver contraceptive services, STI screening, hepatitis B vaccination, and mental health care within streamlined, client-centered platforms. For clinicians, Lenacapavir presents both a powerful new tool and a set of emerging responsibilities: counseling patients on comparative options, monitoring for long-term safety, managing missed-dose windows, and interpreting evolving guidance on resistance and drug–drug interactions. Incorporating these clinical considerations will be essential to translating trial efficacy into real-world effectiveness, particularly in settings where resources and health system readiness vary widely.

Access, pricing, and the politics of power

Despite its clinical promise, Lenacapavir’s path to equitable access is far from guaranteed. In the United States, Gilead Sciences has priced Yeztugo at approximately $28 218 per person per year^[2,7]. Meanwhile, over 120 low- and lower-middle-income countries (LMICs) have been granted voluntary, royalty-free licenses through Gilead’s partnerships with six generic manufacturers^[8]. Modeling estimates suggest that once manufacturing scales, generic versions of Lenacapavir could cost $35–$46 per person-year, with $25/year possible at high volumes (5–10 million users annually)^[7–9].

However, this price reduction remains hypothetical. Gilead retains effective control over technology transfers, supply chains, and regulatory timelines. While the company has pledged to offer its branded formulation at no profit in the interim, generic production, WHO prequalification, and national registration may take several years^[7,8,10]. Regulatory approvals are still pending in many countries. Manufacturing scale-up will take time. And perhaps most critically, the infrastructure to deliver long-acting injectable PrEP including supply chains, cold storage, trained personnel, and monitoring systems remains underdeveloped in much of the Global South.

This delay is not new nor the gap between scientific availability and social accessibility. During the early ART era, lifesaving antiretroviral therapy remained inaccessible in sub-Saharan Africa for nearly a decade after its availability in the West^[11]. More recently, the COVID-19 pandemic revealed the cost of lack of access to scientific innovation. Lenacapavir may now risk becoming the latest example of scientific progress without equitable access.

Translating Lenacapavir’s potential into real-world impact will require political commitment and concrete operational mechanisms. First, the World Health Organization (WHO) could prioritize Lenacapavir for its accelerated prequalification or pre-certification pathway, allowing countries to rely on WHO’s assessment instead of initiating lengthy national reviews. This mechanism has historically shortened access timelines for essential medicines and vaccines. Second, global financing institutions including Gavi, the Global Fund, PEPFAR (President’s Emergency Plan for AIDS Relief), and Unitaid should evaluate and incorporate Lenacapavir into their procurement portfolios once generics or no-profit formulations are available, ensuring affordability and reducing the financial burden on LMIC governments. Third, LMIC regulatory authorities could adopt or expand regional co-registration platforms and joint review processes, such as the African Medicines Agency (AMA) and existing African Medicines Regulatory Harmonization (AMRH) pathways. These mechanisms enable simultaneous multi-country assessments, reducing duplication and accelerating approval. Coupled with transparent licensing terms, timely technology transfer, and accountability frameworks, these operational pathways offers avenues to ensure that Lenacapavir reaches high-incidence settings without avoidable delays.

Beyond licensing: will prevention be equitably shared?

Voluntary licensing, while helpful, is not a silver bullet. Though Gilead has granted rights to generic manufacturers, it has not made Lenacapavir available through the Medicines Patent Pool (MPP), a mechanism that could further streamline access^[8]. Voluntary models allow pharmaceutical companies to maintain control over terms and timelines, rather than being bound by accountable, enforceable global frameworks. Critics argue voluntary licensing serves more as public relations than enforceable access guarantees. Experts have called for a more aggressive approach: compulsory licensing, transparent regulatory pathways, technology transfer requirements, binding timelines, transparent licensing terms, transfer of comparator materials for bioequivalence studies, registration in LMIC and funding conditionalities tied to access guarantees^[10,12]. Without these measures, even the best-intentioned licensing agreements may fail to ensure timely, affordable access especially in the communities where HIV incidence remains highest.

This situation brings another moment to reflect on what a more just system of innovation might look like. We must begin by reimagining access as global and distributive. This requires legal and institutional reforms, such as expanding the use of compulsory licensing in public health emergencies, strengthening the capacity of LMIC regulatory agencies, and supporting local pharmaceutical manufacturing through technology transfer and infrastructure investment. It also calls for a shift in how countries engage with global health as partners committed to dismantling the structural barriers that drive global disparities.

Ultimately, Lenacapavir’s impact will not be determined in boardrooms or scientific publications. It will be measured in clinics, outreach centers, and informal settlements, in whether it becomes a universal prevention tool or a gated innovation.

At-risk populations cannot afford to wait

In sub-Saharan Africa, six out of seven new HIV infections among adolescents aged 15–19 are among girls^[4]. In the U.S., Black and Latino MSM account for a disproportionate number of new diagnoses, often facing structural racism, stigma, and underinsurance^[5]. In these groups, adherence to daily PrEP is hampered by social, economic, and cultural factors. Lenacapavir’s long-acting profile could address these barriers but only if it is made available rapidly, affordably, and with community engagement.

True equity demands more than donation pledges or pilot programs. It requires: (1) Investments in infrastructure to deliver injections in rural and underserved settings, (2) Regulatory support and capacity building in LMICs to approve and roll out the drug (3) Community-driven messaging and education, especially among youth and gender-diverse groups. Every delay risks preventable infections, further entrenching the very inequalities the global HIV response seeks to dismantle.

The HIV field of research has always been about more than medicine, it has been a fight for innovation and access. Lenacapavir represents a monumental step in biomedical innovation, but if its benefits are restricted to the wealthy or well-connected, it will become a symbol of exclusion rather than progress. We must resist the temptation to define success through regulatory milestones alone. Instead, we must ask: who gets protected, and who gets left behind? If Lenacapavir is to fulfill its promise, its rollout must be intentional, inclusive, and immediate. In the coming months and years, the success of Lenacapavir will be measured not only by its pharmacological impact but by the degree to which it is equitably implemented.

Also, Lenacapavir presents a strategic opportunity for integration with broader health services. Long-acting injectables could be paired with contraceptive delivery, STI screening, mental health care, and substance use services to create holistic, client-centered platforms. This would not only enhance efficiency but also address the multifaceted vulnerabilities that contribute to HIV risk. However, realizing this vision will require investment, coordination, and the political will to move beyond vertical, siloed approaches to health delivery.

As we continue the chart in HIV prevention, we must ask: will this breakthrough truly reach those at greatest risk, or will it become yet another innovation celebrated in headlines but inaccessible on the ground? Lenacapavir’s legacy must not be determined by scientific milestones alone, but by how wide and fair it is delivered. If we are to change the trajectory of the HIV epidemic, we must ensure that this innovation does not leave millions behind.

Future directions: building the evidence, infrastructure, and governance systems required for equitable rollout

Ensuring that Lenacapavir becomes a tool for equity rather than exclusion will require a coordinated agenda spanning clinical research, implementation science, health systems strengthening, regulatory innovation, and global financing mechanisms. The PURPOSE trials provide a compelling efficacy signal, but they represent the beginning not the endpoint of the scientific and operational work required to translate a biomedical breakthrough into population-level impact.

Implementation research must think comparative effectiveness and delivery science. Critical questions remain regarding how Lenacapavir performs in health systems with irregular clinic access, limited staffing, and fragmented supply chains. Future studies should evaluate differentiated service delivery models such as quarterly community injection days, pharmacy-based administration, mobile outreach teams, peer-delivered PrEP navigation, and integration with sexual and reproductive health services. Hybrid effectiveness-implementation designs (e.g., Type 2/3 hybrid trials) can simultaneously measure clinical outcomes, implementation fidelity, cost, acceptability, and scalability. Implementation research should also explicitly assess productivity losses, patient travel burdens, adherence to 6-month dosing schedules, and the feasibility of appointment reminders or digital adherence tools.

Long-term safety, pharmacovigilance systems, and resistance monitoring must be institutionalized. While breakthrough infections were rare in clinical trials, real-world conditions misaligned injection timing, migration, inconsistent follow-up, and health system disruptions may increase exposure to waning drug levels. A global capsid inhibitor resistance surveillance network, analogous to existing networks for Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) and integrase inhibitor resistance, will be required. Post-marketing cohort studies and pregnancy registries are needed to track outcomes among pregnant individuals, adolescents, breastfeeding individuals, and people with comorbidities. Pharmacokinetic substudies should measure drug concentrations during late dosing intervals under real-life conditions, identifying threshold levels below which risk accelerates. Countries will need laboratory capacity to detect capsid inhibitor mutations and incorporate them into national HIV treatment guidelines.

Comprehensive economic evaluations must determine where and how Lenacapavir provides the greatest value. Cost-effectiveness analyses should be stratified by baseline incidence, gender, age, mobility, and key population status. Budget impact analyses are essential for ministries of health facing constrained fiscal space. Multi-country modeling should compare Lenacapavir to oral PrEP and cabotegravir in various service delivery configurations, identifying which populations yield the greatest prevention benefit per dollar spent. These analyses should account for long-term savings from infections averted, productivity gains, and downstream reductions in HIV treatment costs. Without such data, large-scale procurement will remain difficult to justify for donors and governments.

Intersectional and equity-oriented research is needed to address the structural and social determinants of uptake. Biomedical efficacy alone does not guarantee population-level impact. Gender inequality, age-based consent barriers, stigma around injection use, criminalization of same-sex relationships or sex work, migration, and poverty all shape who will access Lenacapavir. Future qualitative and mixed-methods studies should map these structural drivers and co-develop tailored delivery strategies with affected communities. Adolescent girls and young women in sub-Saharan Africa require youth-centered, confidential services; transgender people need gender-affirming, non-stigmatizing environments; and people who inject drugs require harm-reduction integration including opioid agonist therapy.

Structural reforms will be essential for sustainable access. Regional manufacturing capacity in Africa, Asia, and Latin America would reduce reliance on a handful of suppliers and shorten supply chain delays. Regulatory harmonization through platforms such as the African Medicines Agency, PAHO’s regional review process, or ASEAN joint assessments could shorten approval timelines by years. Financing mechanisms must evolve: global institutions such as PEPFAR, the Global Fund, and Gavi will need to determine whether and how to support procurement, while bilateral donors may need to link funding to measurable access conditions, technology transfer, and timely generic entry. Importantly, ministries of health must develop long-term procurement plans and align them with national HIV strategic frameworks.

Operational governance for equitable rollout must anticipate the entire product lifecycle. This includes risk mitigation strategies for stock-outs, monitoring systems for injection adherence, integration with digital health tools, clear protocols for managing missed doses, and metrics for equity-focused monitoring and evaluation. Implementation frameworks should articulate who receives the drug first, how eligibility is determined, how follow-up is sustained, and how communities are engaged as active partners rather than passive recipients.

These follow-up priorities form a comprehensive roadmap for converting regulatory approval into meaningful public health benefit. They emphasize that the true legacy of Lenacapavir will not be defined by its clinical efficacy alone but by the global health community’s ability to build systems, policies, and accountability structures capable of ensuring equitable rollout at scale. Without deliberate and coordinated action across research, regulation, financing, and community engagement, the promise of long-acting PrEP could remain unequally distributed reproducing the very disparities it aims to eliminate.

Ethical approval

Ethical approval was not required for this study

Consent

This study did not involve patients, consent was not required for this study.

Sources of funding

No funding was received for this research.

Author contributions

G.D.M.: conceptualization and writing – manuscript.

Conflicts of interest disclosure

None declared.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Goshen David Miteu.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

Not applicable.