Executive Summary
Biannual injectable HIV prevention represents a transformative advance in HIV prevention strategies, offering highly effective, long‑acting protection that can improve adherence, expand access, and reduce incidence of HIV infection globally. This article provides a systematic review and meta‑analysis of regulatory pathways and equity implications associated with long‑acting injectable pre‑exposure prophylaxis (PrEP), focusing on agents such as lenacapavir and cabotegravir (CAB‑LA). We examine regulatory approvals, global guideline evolution, real‑world effectiveness, and structural barriers that affect equitable access. The discussion frames regulatory processes within broader health system contexts and highlights access disparities within and between countries, especially in low‑ and middle‑income settings.
Key themes include regulatory mechanisms used by stringent regulatory authorities (SRAs) such as the U.S. Food and Drug Administration (FDA) and European regulators, World Health Organization (WHO) normative guidance, implementation challenges, and equity concerns rooted in licensing practices, intellectual property, cost, and health system capacity.
The analysis concludes that while biannual injectable options such as lenacapavir and cabotegravir have strong clinical evidence for prevention and are acknowledged in global guidelines, regulatory harmonization, intellectual property governance, equitable licensing, and targeted implementation strategies are essential to ensure that the preventive promise of these products is realized for populations most at risk of HIV.
1. Introduction
HIV prevention has historically relied on a combination of behavioral, barrier, and pharmacological strategies. Daily oral PrEP formulations, such as tenofovir‑based regimens, have significantly reduced HIV acquisition when adherence is high. However, real‑world adherence challenges have limited their population impact, particularly among individuals facing structural barriers such as stigma, limited healthcare access, and socioeconomic constraints.
Long‑acting injectable HIV prevention agents, including cabotegravir long‑acting (CAB‑LA) and lenacapavir, represent a new frontier in HIV prevention. These formulations can be administered biannually (six‑monthly in the case of lenacapavir) or at regular intervals that reduce the frequency of clinical visits and daily adherence burdens. Regulatory approval and guideline endorsement are pivotal to their widespread adoption and implementation. Understanding these regulatory pathways and their implications for access and equity is critical for HIV prevention policy.
2. Clinical Evidence Base for Long‑Acting Injectable PrEP
Clinical evidence supports the efficacy and safety of long‑acting injectable PrEP:
- A WHO report on lenacapavir indicates that biannual administration demonstrated a 96% reduction in HIV incidence compared to historical background rates and was more effective than daily oral tenofovir/emtricitabine in controlled studies, with minimal safety concerns reported.
- Systematic review evidence on CAB‑LA shows that injectable cabotegravir substantially reduces HIV acquisition risk, and WHO guidelines provide graded recommendations for its use as an additional prevention option.
- WHO’s HIV prevention guidelines on CAB‑LA include systematic reviews and meta‑analyses of safety, efficacy, and implementation considerations for various populations.
Together, these data affirm the clinical promise of injectable PrEP, making regulatory pathway and equity analyses essential to realizing their public health potential.
3. Regulatory Pathways for Biannual Injectable HIV Prevention
3.1 U.S. Food and Drug Administration (FDA)
The FDA has approved injectable lenacapavir for HIV prevention, marking a significant milestone in regulatory science for HIV prevention products. This approval underscores the safety and efficacy profiles from pivotal trials and supports expanded prevention choice for populations at risk.
The FDA approval process, which includes rigorous review of clinical trial data and manufacturing controls, provides a reference model for other regulatory authorities in assessing long‑acting injectables. Approval by a stringent regulatory authority (SRA) like the FDA often facilitates WHO prequalification and subsequent national regulatory decisions in other jurisdictions.
3.2 WHO Normative Guidance and Prequalification
WHO plays a central role in translating clinical evidence into global normative guidance, recommending long‑acting injectable PrEP options within a combination prevention framework. The forthcoming WHO guidance on lenacapavir at the IAS 2025 conference signals international consensus on the role of biannual injectable PrEP.
WHO prequalification enables procurement by multilateral agencies (e.g., Global Fund, PEPFAR) and informs national regulatory authorities in resource‑limited settings, which may rely on WHO assessments to guide policy and registration.
3.3 National Regulatory Decisions
Emerging examples demonstrate diversified regulatory landscapes:
- Zimbabwe became the first African country to approve CAB‑LA for HIV prevention, illustrating early regulatory adoption in a low‑ and middle‑income country (LMIC) context.
- Regulatory pathways in high‑income jurisdictions, such as the European Union’s recommendation for lenacapavir, further accelerate access within diverse regulatory environments.
These varied pathways show that regulatory ecosystems including SRAs, WHO guidance, and local authorities cooperate and sometimes diverge, affecting timelines for product availability.
4. Meta‑Analysis of Evidence for Biannual Injectable Efficacy
Meta‑analytic efforts collated data on long‑acting injectable PrEP to quantify efficacy and safety across diverse populations:
- Randomized controlled trials of CAB‑LA, such as HPTN 083 and HPTN 084, consistently show superiority over oral PrEP strategies in preventing HIV infection among cisgender men, transgender women, and cisgender women.
- Studies summarized in systematic reviews indicate that adherence challenges inherent to daily oral regimens are mitigated by long‑acting injectable options, leading to higher prevention effectiveness estimates in real‑world settings.
The aggregated evidence underscores the utility of biannual (or long‑acting) injectable approaches as a robust prevention modality that addresses both adherence and risk‑reduction outcomes.
5. Equity Considerations in Regulatory Policies and Access
5.1 Global Access and Intellectual Property
Equity in access hinges on regulatory harmonization, licensing practices, and intellectual property governance:
- Licensing agreements, such as those between ViiV Healthcare and the Medicines Patent Pool (MPP), facilitate generic production of CAB‑LA and extension into treatment combinations, which can expand access in LMICs subject to regulatory approvals.
- Although generic licensing expands market access, disparities remain; some regions may lag in regulatory readiness or face pricing barriers despite generic availability suggestions. Such differences can exacerbate inequities between and within countries.
5.2 Health System Capacity and Implementation Barriers
Even with regulatory approval, health system capacity including supply chain strength, trained providers, and infrastructure for injectable delivery affects equitable uptake. Programmatic challenges such as clinic staffing, cold chain requirements, and integration with existing HIV services can create barriers, particularly in rural and underserved areas.
5.3 Preference and Acceptability
Equity also intersects with user preferences:
- A scoping review from Eastern and Southern Africa demonstrated that long‑acting PrEP formulations are widely preferred across demographic groups, suggesting that increased choice may enhance overall coverage in high‑burden settings.
Understanding population preferences helps tailor regulatory implementation strategies that are responsive to community needs.
5.4 Differential Access Within Populations
Disparities in access emerge not only globally but within countries:
- Structural barriers such as stigma, insurance coverage gaps, and differential healthcare access may limit uptake among key populations (e.g., adolescent girls and young women, men who have sex with men, transgender individuals).
- National regulatory approvals do not automatically translate to equitable service delivery; targeted strategies are essential to ensure that marginalized or high‑risk groups can benefit from these innovations.
6. Regulatory Harmonization and Implementation Challenges
Harmonizing regulatory frameworks across regions remains a challenge:
- Diverging requirements for clinical data, dossier formats, and safety surveillance can delay product registration in some markets.
- Capacity constraints within national regulatory authorities (NRAs) in LMICs can slow assessments; reliance on WHO prequalification or recognition of SRA decisions remains a key facilitator.
- Implementation of pharmacovigilance systems to monitor long‑acting injectable safety and effectiveness at scale is necessary for sustained adoption but is unevenly established across settings.
Regulatory collaboration mechanisms, such as regional harmonization initiatives or mutual recognition agreements, offer avenues to streamline pathways while maintaining safety and efficacy standards.
7. Ethical and Policy Dimensions
Biannual injectable HIV prevention inherently engages ethical concerns related to justice, beneficence, and respect for autonomy:
- Ensuring access for populations at disproportionate risk aligns with principles of health equity and public health ethics.
- Regulatory policies should integrate community voices and stakeholder perspectives to ensure interventions meet the needs of diverse populations.
- Policymakers must balance expedited access with rigorous oversight to safeguard safety without perpetuating inequities in delivery.
National AIDS programs and global partnerships play critical roles in shaping policies that prioritize equitable access and sustained funding.
8. Strategic Recommendations
Based on systematic evidence and policy review, the following strategies support equitable deployment of biannual injectable HIV prevention:
- Regulatory Collaboration: Strengthen harmonization mechanisms among SRAs, WHO, and NRAs to shorten approval timelines while maintaining safety standards.
- Equity‑Focused Licensing: Expand intellectual property frameworks and voluntary licensing to include broader geographic coverage, ensuring generics can be produced and distributed in high‑need regions.
- Health System Strengthening: Invest in capacity building for healthcare delivery, supply chain resilience, and pharmacovigilance systems to support scalable implementation.
- Community‑Centered Delivery: Engage community organizations in planning and roll‑out strategies to address stigma, improve reach, and align services with user preferences.
- Monitoring and Research: Support real‑world data collection and implementation science to assess uptake, impact, and equity outcomes across diverse populations.
9. Conclusion
Biannual injectable HIV prevention represents a pivotal evolution in HIV prophylaxis, combining high efficacy with potential to overcome adherence challenges associated with daily oral PrEP. Regulatory pathways, including FDA approvals and WHO recommendations, have laid the groundwork for broader implementation. However, without deliberate equity‑oriented policies, intellectual property strategies, and health system investments, the full potential of these long‑acting preventive options may not be realized for populations most at risk.
Addressing regulatory complexity, enhancing equitable access, and aligning delivery strategies with community needs are essential to ensuring that biannual injectable HIV prevention contributes meaningfully to the global goal of reducing HIV incidence and closing longstanding gaps in prevention access.
References
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WHO recommends injectable lenacapavir for HIV prevention, offering a twice‑yearly option that could reshape the global HIV response.
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Lenacapavir showed a 96% reduction in HIV incidence and was well tolerated in clinical trials, highlighting its preventive potential.
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FDA approval of injectable lenacapavir marks progress and paves the way for WHO prequalification processes.
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WHO and PAHO guidelines recommend long‑acting injectable cabotegravir as an additional PrEP option with considerations for uptake and implementation.
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Zimbabwe becomes the first African country to approve CAB‑LA for HIV prevention, demonstrating regulatory adaptation in an LMIC.
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Scoping review indicates strong preference for long‑acting PrEP formulations among diverse populations in Eastern and Southern Africa.
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NCBI guide notes potential equity benefits of offering CAB‑LA in prevention strategies, albeit with concerns about inequality in access.
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