Exploring groundbreaking strategies from twice-yearly injections to immune-based approaches that are transforming HIV treatment and prevention
August 21, 2025 10 min read
For over four decades, the human immunodeficiency virus (HIV) has represented one of the most formidable challenges in modern medicine, having claimed over 40 million lives worldwide since the beginning of the epidemic. While the development of antiretroviral therapy (ART) in the 1990s transformed HIV from a death sentence to a manageable chronic condition for those with access to treatment, the virus continues to infect 1.3 million people annually worldwide, with approximately 600,000 annual deaths persisting despite available treatments .
The limitations of current approaches—including the burden of daily adherence, emerging drug resistance, and significant access disparities—have underscored the urgent need for innovative strategies that could ultimately end the epidemic.
Today, we stand at a remarkable inflection point in HIV research, where scientific breakthroughs are converging to create what many experts believe could be the beginning of the end of HIV's reign.
From twice-yearly injections that eliminate daily pill-taking to novel immune-based approaches that could potentially lead to a functional cure, the landscape of HIV prevention and treatment is undergoing nothing short of a revolution. This article explores the cutting-edge science behind these developments, offering a glimpse into what many researchers are calling the most promising era in HIV research since the discovery of ART.
The first breakthrough came with the approval of zidovudine (AZT), a nucleoside reverse transcriptase inhibitor that offered modest benefits but extended lives by mere months.
The true transformation came with the introduction of highly active antiretroviral therapy (HAART), which combined multiple drugs to suppress viral replication dramatically . This approach reduced HIV-related mortality by 80% in countries where it was accessible.
Current ART regimens require lifelong daily adherence, which proves difficult for many people. Missing doses can lead to virological failure and the development of drug-resistant HIV strains, which can then be transmitted to others .
The latest revolution in HIV treatment and prevention centers around two complementary approaches: long-acting injectable therapies and novel immunotherapeutic strategies. These innovations aim to overcome the adherence challenges of daily pills while potentially offering more durable protection against the virus.
The most dramatic recent advancement comes in the form of lenacapavir (marketed as Yeztugo®), a first-in-class capsid inhibitor that requires just two injections per year to provide comprehensive protection against HIV infection. In June 2025, the U.S. Food and Drug Administration (FDA) approved lenacapavir for HIV prevention, hailing it as a potential "game changer" in the fight against HIV 6 .
Parallel to the development of long-acting antivirals, researchers are exploring how to harness the immune system itself to combat HIV more effectively. Recent research has identified novel peptides—short chains of amino acids—that are expressed in HIV-1 infection and appear to play a crucial role in controlling the virus 1 .
Scientists from the University of Sydney applied an immunoinformatics analysis pipeline (IMAP) to select 182 peptides from structurally important and mutation-intolerant regions of HIV-1 proteins. The results were remarkable: CD8 T-cells from individuals who naturally controlled HIV rebound after treatment interruption showed a 15- to 53-fold higher effector response to these IMAP peptides compared to non-controllers 1 .
To understand why lenacapavir represents such a significant advancement, it's essential to examine how it differs from previous antiretroviral drugs. HIV's genetic material and the enzymes necessary for its replication are housed in a central cone-shaped protein assembly called the capsid, which is composed of approximately 1,500 copies of the viral CA protein 5 .
HIV's capsid protects viral genome as it travels to the nucleus
Most existing drugs use "lock and key" mechanism on viral enzymes
Directly targets capsid itself, disrupting assembly and disassembly
Mutations that evade drug would likely impair capsid function
The development journey wasn't straightforward. Researchers at Gilead Sciences initially spent four years searching for compounds that would slow capsid assembly without success. When they switched tactics to look for compounds that would accelerate capsid assembly, they finally found their breakthrough—this approach led to the formation of misshapen capsids that couldn't properly deliver their contents to the nuclei of newly infected cells 5 .
The efficacy of lenacapavir for HIV prevention was established through the landmark PURPOSE program, the most comprehensive and diverse HIV prevention trial program ever conducted 2 . This program included five clinical trials across multiple continents, with intentional inclusion of populations historically underrepresented in HIV research.
PURPOSE 1 (NCT04994509) evaluated twice-yearly lenacapavir injections in cisgender women and adolescent girls in Sub-Saharan Africa, a population disproportionately affected by HIV. In a groundbreaking departure from historical exclusion, the trial deliberately included pregnant and lactating women, who face a heightened likelihood of acquiring HIV but have typically been excluded from prevention trials 2 .
| Population | Trial | Participants | Infections | Efficacy |
|---|---|---|---|---|
| Cisgender women | PURPOSE 1 | 5,000+ | 0 | 100% |
| Cisgender men, transgender individuals | PURPOSE 2 | 3,200+ | 2 | 96% |
PURPOSE 2 (NCT04925752) evaluated twice-yearly lenacapavir among a broad and geographically diverse range of cisgender men, transgender women and men, and gender non-binary individuals. The trial intentionally included young people aged 16-25 years, who face increased HIV risk globally but are often excluded from Phase 3 prevention trials 2 .
The results were equally impressive: just two HIV infections occurred among young people receiving lenacapavir, representing an efficacy rate of 96%. There were no clinically significant pharmacokinetic differences between the 16-25-year-old group and adults over 25, and lenacapavir was well tolerated across all age groups with no new safety concerns 2 .
| Population | PURPOSE 1 | PURPOSE 2 | Historical Representation |
|---|---|---|---|
| Adolescent/young (16-25) | Included | Included | Often excluded |
| Pregnant/lactating women | Included (487 participants) | N/A | Typically excluded |
| Transgender individuals | N/A | Included | Often excluded |
Perhaps as important as the dramatic efficacy results were the findings on patient preference. New qualitative and quantitative data from both PURPOSE trials showed a significant preference for twice-yearly injectable PrEP compared with daily oral PrEP 2 .
More than 75% of surveyed participants preferred the twice-yearly injection, with over half reporting a strong preference for this option. The reasons cited were telling: participants reported feeling more protected from HIV (69%) and more confident about not missing a dose (77%) with the twice-yearly injection compared to daily pills 2 .
Behind these dramatic clinical advances lies a sophisticated array of research tools and reagents that enable scientists to unravel HIV's complexities and develop novel interventions.
| Research Reagent | Function | Application in HIV Research |
|---|---|---|
| IMAP Peptides | 182 selected peptides from conserved HIV regions | Identifying immune targets for vaccine development 1 |
| Near full-length HIV-1 RNA sequencing | Comprehensive viral genetic analysis | Tracking rebound virus evolution in treatment interruption studies 1 |
| Capsid inhibitors | Small molecules disrupting HIV capsid function | Lenacapavir development and resistance mechanism studies 5 |
| CD8 T-cell effector response assays | Measuring immune cell activity | Evaluating vaccine-induced immune responses 1 |
| bNAbs (broadly neutralizing antibodies) | Antibodies neutralizing multiple HIV strains | Immunotherapy and prevention strategies |
These tools have enabled researchers to move beyond traditional approaches and develop increasingly sophisticated strategies to outmaneuver HIV. The immunoinformatics analysis pipeline (IMAP), for instance, allows scientists to identify the most promising peptide targets by analyzing which viral regions are both structurally important and mutation-intolerant—essentially identifying HIV's vulnerabilities 1 .
The remarkable progress in HIV research represented by lenacapavir and novel peptide vaccines now faces the critical challenge of translation from scientific breakthrough to real-world impact. The first step—regulatory approval—has already been achieved for lenacapavir in the United States 6 .
United States (FDA approval in June 2025)
European Medicines Agency, Australia, Brazil, Canada, South Africa, Switzerland
However, access and affordability remain significant concerns. With a U.S. list price of approximately $28,000 per year, the current cost of lenacapavir could limit its accessibility, particularly in low- and middle-income countries that bear the greatest HIV burden 6 .
The development of lenacapavir has been recognized with the 2025 Warren Alpert Foundation Prize, one of the most prestigious awards in medical science, honoring the scientists whose discoveries culminated in this novel HIV treatment 5 .
The landscape of HIV prevention and treatment is undergoing a transformation unlike any since the introduction of combination antiretroviral therapy nearly three decades ago. The development of twice-yearly injectable prevention options, the identification of novel peptide targets for vaccine development, and the exploration of immunotherapeutic approaches collectively represent the most promising advances in HIV research in a generation.
These breakthroughs offer more than just clinical efficacy—they offer the potential to overcome the adherence challenges, stigma, and access barriers that have hampered HIV efforts for decades. A twice-yearly injection that eliminates daily pill-taking could revolutionize prevention for populations who face the greatest barriers to consistent healthcare access.
While challenges remain—particularly regarding global access and affordability—the scientific progress showcased in these studies brings us closer than ever to ending HIV's reign as a global health threat. As these innovations continue to develop and reach those who need them most, we approach what many researchers believe could be the final chapter in the fight against HIV—a remarkable testament to four decades of scientific perseverance, collaboration, and innovation.