HIV Therapeutics at a Crossroads as Long-Acting Drugs Meet Geopolitical Risk

The global HIV therapeutic landscape has entered a new chapter as regulators and global health bodies align around long-acting preventive and treatment modalities, even while political headwinds and funding retrenchment threaten hard-fought gains. After years of incremental improvements in daily antiretroviral therapy (ART), injectable regimens that can be administered twice a year are now clearing regulatory hurdles and entering policy frameworks, promising to reshape prevention efforts worldwide. But implementation is unfolding amid shifting donor strategies and diplomatic tensions that could slow access in high-burden regions.

Regulatory Milestones Signal a New Era

In mid-2025, the U.S. Food and Drug Administration (FDA) approved Gilead Sciences’ Yeztugo (lenacapavir) as the first twice-yearly injectable pre-exposure prophylaxis (PrEP) option, based on Phase III data showing near-complete prevention of HIV acquisition in study participants. 

The approval followed the FDA’s acceptance of Gilead’s priority review application earlier in the year, positioning lenacapavir to enter a prevention space long dominated by daily oral regimens and the earlier long-acting option, cabotegravir. Regulatory momentum has not stopped in the U.S. — Gilead has also filed for marketing authorization in the European Union, Australia, Brazil, Canada, South Africa and several other markets, with accelerated review pathways in progress. 

National regulators in Africa are beginning to follow suit: the Zambia Medicines Regulatory Authority formally registered lenacapavir for HIV prevention in late 2025, expanding access to long-acting prevention options alongside cabotegravir.

At the global policy level, the World Health Organization (WHO) issued new guidelines recommending twice-yearly injectable lenacapavir as an additional PrEP choice and incorporating long-acting cabotegravir + rilpivirine for ART switches in people with viral suppression. 

UNAIDS welcomed these updates as critical tools in a stagnant global prevention landscape that still sees more than a million new infections annually.

Updated voluntary licensing agreements, such as ViiV Healthcare’s expanded pact with the Medicines Patent Pool, seek to enable generic manufacture of long-acting injectables for broader global access in low- and middle-income countries — a critical step toward affordability should regulatory approvals follow.

Beyond Approvals — Implementation and Access Barriers

Innovation alone will not ensure impact. Even as regulators and policy bodies endorse new tools, the economics and logistics of delivering long-acting injectables present real challenges. Injection administration requires trained healthcare personnel, reliable cold-chain systems and community outreach to ensure adherence to six-monthly schedules — constraints in settings with overstretched health systems.

More troubling, analysts warn that the current global funding environment is deteriorating. Financial pressures from competing priorities and donor fatigue have led to significant retrenchment in international HIV funding, raising fears that the rollout of new technologies could be uneven and slow. Global health experts have expressed alarm that the loss of centralized funding and infrastructure — particularly after the dismantling of USAID — may reverse years of progress in HIV/AIDS programs. 

Political Headwinds and Geopolitical Strains

Politics are now deeply entwined with HIV policy. Under the Trump administration’s “America First Global Health Strategy,” the U.S. has pivoted foreign aid toward large bilateral compacts that emphasize recipient country responsibility, sometimes at the expense of broad HIV program support. Recent deals with Uganda and Kenya allocate significant funding for HIV and other diseases but tie resources to increased domestic spending and new delivery models. 

At the same time, South Africa — home to one of the world’s largest HIV burdens — finds itself in diplomatic conflict with Washington, complicating aid flows. Reports suggest that South Africa may be excluded from future U.S. HIV grants and shipments of long-acting preventive drugs amid political disagreement, despite its critical need for expanded prevention and treatment programs. 

Public health observers warn that these shifts could undermine established cooperative mechanisms like PEPFAR (the U.S. President’s Emergency Plan for AIDS Relief) and disrupt HIV testing, care, and prevention services at a time when new infections remain stubbornly high.

Long-Acting HIV Therapies, Vaccine Innovation, and Global Policy Will Shape the Next Phase of Treatment

Gilead has secured FDA Breakthrough Therapy Designation for a long-acting HIV regimen combining lenacapavir with broadly neutralizing antibodies (bnAbs), marking a shift beyond prevention toward simplified, twice-yearly treatment. At the same time, companies including Merck, Janssen (Johnson & Johnson), AbbVie, and multiple biotech firms are advancing entry inhibitors, bnAb platforms, and vaccine constructs, collectively driving a multi-modality strategy spanning prevention, durable treatment, cure research, and immune-based interventions. Several near- and mid-term developments will determine whether scientific momentum translates into global impact:

• Long-acting rollout and procurement pathways: Approval timelines, manufacturing scale-up, and procurement agreements for lenacapavir-based regimens—particularly through multilateral mechanisms such as UNITAID and the Global Fund—will shape access across Africa and Latin America.
• bnAb combination trial readouts: Early clinical signals demonstrating prolonged viral remission or reduced treatment burden could significantly shift R&D investment priorities and influence regulatory frameworks for functional cure strategies.
• mRNA and next-generation vaccine progress: Demonstrated success in reliably inducing broadly neutralizing antibody responses would redirect substantial capital toward prevention and bring an effective HIV vaccine closer to feasibility.
• Political and funding signals: Donor commitments, U.S. bilateral policy decisions, and manufacturing licensing agreements will materially affect timelines for scale, affordability, and regional deployment.

Access, Affordability, and Geopolitics Will Determine Whether Scientific Gains Reach Patients at Scale

As scientific breakthroughs in long-acting therapies and combination treatments accelerate, their real-world impact will hinge on regulatory decisions, funding priorities, and geopolitical dynamics.

• Regulatory approvals beyond the U.S. and Europe, particularly in high-burden countries, which will define real-world access and adoption timelines
• Licensing and pricing mechanisms, including the speed at which generics can enter long-acting treatment markets
• Global funding and diplomatic alignment, especially shifts in U.S. global health policy and partnerships with high-prevalence nations
• Clinical data from long-acting combination therapies, which will inform future treatment paradigms and guideline updates

Together, these factors will determine whether the next phase of HIV innovation delivers not only scientific breakthroughs, but durable, scalable solutions for global health systems. Ultimately the bottom line remains. HIV therapeutics stands at an inflection point: unprecedented scientific advances are converging with evolving global policy frameworks. But whether these gains translate into lives saved at scale will depend as much on regulatory agility and financing models as on the performance of new drugs themselves. In a world of tightening budgets and shifting geopolitics, the next chapter in the fight against HIV will be defined not only in laboratories and regulatory agencies but in the halls of finance ministries and diplomatic negotiations worldwide.

Author

Bernice Lottering