The next era of HIV care: How long-acting innovation is redefining treatment and prevention
For more than four decades, HIV treatment has been one of the greatest success stories in modern medicine. What was once an almost universally fatal diagnosis has evolved into a chronic, manageable condition for most people living with HIV (PLWH), with life expectancy now approaching that of the general population when treatment is initiated early and maintained consistently. Yet despite remarkable clinical progress, the focus of innovation has shifted. Today’s challenge is no longer simply suppressing HIV, it is delivering suppression in ways that better fit patients’ lives.
The pharmaceutical industry is therefore entering a new phase of HIV treatment development. The central question is no longer “can we control HIV?” but rather “how can we make lifelong treatment and prevention as convenient, acceptable and sustainable as possible?”
This shift has driven an explosion of interest in long-acting therapies, both injectable (LAIs) and oral (LAOs), alongside innovations in pre-exposure prophylaxis (PrEP). While the race to improve convenience is well underway, it remains uncertain whether a single modality will ultimately dominate. Instead, the future is increasingly likely to be characterized by personalized choice.
From survival to simplicity
Initial therapies in the earliest years of the HIV epidemic, focused on slowing immune deterioration by reducing viral replication, preventing CD4+ T-cell decline to delay progression to Acquired Immunodeficiency Syndrome (AIDS). Treatment regimens were complex, often requiring multiple antiretroviral (ARV) agents taken several times per day, with substantial pill burdens, dietary restrictions and toxicities.
The introduction of highly active antiretroviral therapy (HAART) in the mid-1990s transformed HIV outcomes, but treatment remained demanding. Throughout the following two decades, pharmaceutical innovation concentrated on improving potency, reducing resistance, and simplifying dosing schedules.
Gilead’s Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) exemplifies this evolution. It combined high efficacy, a strong resistance barrier and good tolerability in a once-daily single-tablet dosing. Merck has similarly focused on treatment simplification, initially through the once-daily DELSTRIGO (doravirine/lamivudine/tenofovir disoproxil fumarate) and, more recently, through the two-drug doravirine/islatravir regimen IDVYNSO. Together, these advances highlight the growing importance of convenience, treatment simplicity, and regimen differentiation alongside efficacy and safety in HIV care.
However, even the once-daily tablet required patients to remember medication every day for life to maintain viral suppression and keep immune suppression at bay. Missed doses, treatment fatigue and stigma associated with daily pill taking continue to present barriers for some individuals. As such, viral suppression below the threshold of molecular detection, patient preference, quality of life, and treatment flexibility have emerged as the next frontier of HIV innovation.
Long-acting therapies redefine the competitive landscape
Long-acting therapies aim to remove the burden of daily adherence by extending dosing intervals from weeks to months. This innovation extends beyond convenience alone. For some patients, less frequent dosing may reduce anxiety surrounding daily reminders of HIV, improve discretion and potentially enhance long-term adherence.
Today, two distinct strategies are emerging:
- Long-acting injectables (LAIs)
- Long-acting oral therapies (LAOs)
Both seek to reduce dosing frequency but approach the problem from fundamentally different perspectives.
Long-acting injectables: Establishing the first-mover advantage
ViiV Healthcare introduced Cabenuva (cabotegravir + rilpivirine), the first approved complete long-acting injectable regimen for maintenance treatment, marking an important milestone in the evolution of HIV care. Administered every one or two months, Cabenuva demonstrated that replacing daily oral therapy with infrequent injections was clinically feasible.
This momentum extended into HIV prevention with Apretude (long-acting cabotegravir), which established superior efficacy to daily oral PrEP in several populations and reinforced confidence in injectable prevention strategies.
More recently, Gilead’s Sunlenca (lenacapavir) introduced an entirely new mechanism of action through capsid inhibition. Approved as a six-monthly injectable for heavily treatment-experienced patients with multidrug-resistant HIV, Sunlenca highlighted the feasibility of extending dosing intervals to six months in these patients. Although currently limited to salvage therapy, lenacapavir’s pharmacokinetic profile has positioned it as the foundation for multiple next-generation long-acting regimens.
Long-acting treatment development continues to expand. Gilead is investigating lenacapavir in combination with broadly neutralizing antibodies and other long-acting agents, ViiV Healthcare is advancing next-generation injectable integrase inhibitor and antibody-based regimens, and Merck continues to develop islatravir-based long-acting approaches. Collectively, these programs reflect a broader industry focus on extending dosing intervals through novel mechanisms, antibody combinations, and formulation technologies.
The emergence of long-acting oral therapy
Although injectables have captured much of the attention, long-acting oral (LAO) therapies are emerging as an important parallel area of innovation, with the potential to broaden treatment choice and fit within established care pathways.
Rather than replacing pills entirely, LAOs seek to reduce dosing frequency while preserving the familiarity, convenience and autonomy associated with oral medication. Weekly dosing represents the leading approach, although even longer oral intervals remain an area of active research.
The most advanced and anticipated once-weekly oral treatment regimen in development is lenacapavir plus islatravir (LEN/ISL), being developed jointly by Gilead and Merck. The combination brings together two potent agents with pharmacokinetic profiles that support once-weekly dosing and highlights how capsid inhibition may become central to future long-acting treatment strategies across multiple modalities. Week 48 results from ISLEND-1 and ISLEND-2 Phase 3 trials of this regimen are being discussed at the International AIDS conference (July 26 – 31, 2026). Beyond LEN/ISL, both companies are advancing wholly owned once-weekly oral regimens: Merck is developing islatravir/ulonivirine (ISL/ULO), while Gilead is evaluating combinations of GS-3107, a lenacapavir prodrug, with an undisclosed integrase strand transfer inhibitor.
For many patients, weekly oral therapy may represent the optimal balance between convenience and familiarity. Weekly dosing also removes concerns surrounding prolonged pharmacologic “tails” that accompany injectable agents, whereby declining drug concentrations following discontinuation may theoretically increase resistance risk if alternative therapy is not promptly initiated.
From a healthcare system perspective, oral therapies also offer several potential additional advantages:
- Patients avoid injections entirely while still substantially reducing treatment burden.
- Treatment can be initiated or discontinued without requiring clinic-administered injections.
- Healthcare systems avoid additional administration capacity requirements.
- Supply chains remain more aligned with traditional pharmacy distribution models.
While oral and injectable long-acting therapies differ in how easily they fit within existing care pathways, the relative importance of these considerations will likely vary across healthcare settings. Much discussion within the industry focuses on whether injectable or oral long-acting therapies will ultimately dominate. Ultimately, it seems highly individualized physician and patient preferences will probably determine the decision.
Long-acting prevention enters a new era
The same trends are rapidly reshaping HIV prevention. Daily oral PrEP transformed HIV prevention globally, but adherence remains the primary determinant of effectiveness. Long-acting options therefore aim to reduce reliance on consistent daily behavior.
Long-acting cabotegravir developed by ViiV/GSK has already demonstrated superior efficacy compared with daily oral PrEP in clinical studies, although implementation challenges remain. Regular clinic attendance for injections, healthcare capacity and patient acceptance all influence uptake. More recently, Gilead’s twice-yearly injectable lenacapavir has introduced the potential to reduce PrEP dosing to two administrations annually, while a once-weekly oral lenacapavir regimen is under FDA review, with a PDUFA date of February 2, 2027 and another once-yearly regimen is in late-stage clinical trials. Together, these options could broaden patient choice and simplify adherence, although their impact will ultimately depend on access and real-world implementation.
Nevertheless, prevention introduces additional considerations beyond treatment. Individuals without HIV may have a lower tolerance for adverse events, invasive administration or clinic visits, making convenience and acceptability particularly important determinants of uptake.
The real differentiators extend beyond efficacy
Clinical efficacy alone is unlikely to determine market leadership. Most next-generation regimens are expected to achieve viral suppression rates that satisfy regulatory expectations, shifting competitive differentiation toward broader healthcare considerations and patient convenience
Several factors are likely to shape long-term adoption:
- Healthcare infrastructure. Injectable therapies require clinic capacity, trained personnel and scheduling systems. Resource-constrained health systems may find widespread implementation challenging
- Pricing and reimbursement. The economic value proposition will differ across healthcare systems. Administration costs associated with injectables may influence payer decisions alongside drug acquisition costs
- Patient lifestyle. Some individuals value freedom from daily medication, whereas others prioritize avoiding clinic appointments
- Needle acceptance. Needle anxiety remains common and should not be underestimated when considering population-level adoption
- Injection-site tolerability. While generally manageable, injection-site reactions remain an important consideration for long-term persistence
- Discretion and stigma. Daily pills may unintentionally disclose HIV status to family members or partners, whereas clinic-based injections introduce different visibility considerations
- Treatment flexibility. Oral regimens may offer greater ease when travelling, relocating or changing healthcare providers
- Physician familiarity. Established confidence in specific mechanisms or therapeutic classes may influence prescribing behavior during the early years following launch.
Ultimately, no single attribute will determine success. Rather, different patients will assign different values to each consideration.
The future is unlikely to be one-size-fits-all
The remarkable success of HIV drug development has created an enviable challenge for pharmaceutical companies. For the first time, innovation is no longer primarily about achieving viral suppression, it is about optimizing the patient experience.
Long-acting injectables have demonstrated that reducing treatment frequency is both clinically feasible and highly attractive for many individuals. At the same time, long-acting oral therapies promise many of the same adherence benefits while preserving the familiarity and autonomy of oral medication.
Rather than replacing one another, these modalities are likely to expand the range of therapeutic choices available to clinicians and patients. The next chapter of HIV innovation is unlikely to be defined by a single winning technology. Instead, success will depend on expanding the range of options available to patients and healthcare systems, allowing treatment and prevention strategies to better reflect diverse clinical needs, lifestyles and care pathways.
