Long-Acting HIV Prevention: Advances and Challenges Explored at CROI 2025

The Conference on Retroviruses and Opportunistic Infections (CROI) 2025, a key event for HIV research, dedicated a session to pre-exposure prophylaxis (PrEP), with a specific focus on long-acting options for HIV prevention. Discussions centered on innovative treatments such as cabotégravir (CAB-La) and Lénacapavir, while also addressing critical issues of accessibility and cost, particularly in resource-limited settings. The session underscored a notable paradigm shift in HIV prevention, emphasizing the move towards long-lasting treatments to combat the ongoing epidemic.

Jonathan Li, from Brigham and Women’s Hospital in Boston, Massachusetts, highlighted the importance of treatment adherence for effective HIV prevention during the CROI 2025 session. Li presented promising alternatives to daily oral PrEP, specifically CAB-La and Lénacapavir, both of which offer extended protection against HIV. these long-acting options aim to address the challenges associated with consistent daily medication adherence, a known barrier to effective prevention.

The Challenge of Adherence to Oral PrEP

While oral PrEP has demonstrated its effectiveness in preventing HIV transmission, consistent adherence to the daily regimen remains a significant hurdle for many individuals. jonathan Li emphasized the critical importance of taking oral PrEP as prescribed,referencing earlier studies that have clearly demonstrated the direct impact of adherence on treatment efficacy. The effectiveness of oral PrEP hinges on consistent and correct usage.

“We will never say it too often: the oral prep is effective when we take it!” Li stated, underscoring the basic requirement for adherence to achieve the desired preventative outcome. He cited studies,including one by Corneli et al. in 2016, which revealed a lack of effect in initial PrEP trials among women in Africa due to “major observance difficulties.” This highlights the real-world challenges in maintaining consistent adherence, particularly in diverse populations and settings.

Data indicates that long-term adherence to oral PrEP can be inconsistent, impacting its overall effectiveness. According to Unigwe et al. in OFID 2024, approximately 40% of individuals on PrEP maintain good adherence, while adherence tends to decline over time in the remaining 60%.This underscores the urgent need for alternative solutions that bypass the challenges associated with daily pill-taking, offering more convenient and sustainable options for HIV prevention.

Emerging Long-Acting Alternatives

Recognizing the inherent limitations of oral PrEP, researchers have actively explored alternative methods of delivery to improve adherence and overall effectiveness. Currently, three short-term options exist: the dapivirine vaginal ring, bimonthly intramuscular injections of Cabotégravir (CAB-La), and biennial subcutaneous administrations of Lénacapavir. These alternatives offer varying degrees of convenience and duration of protection, catering to different needs and preferences.

The dapivirine vaginal ring provides an alternative for women, offering sustained drug release over a month.However, initial studies, including RING and ASPIRE, have indicated significant adherence challenges, particularly among younger women. These challenges highlight the need for further research and targeted interventions to improve the acceptability and usability of the vaginal ring.

Cabotégravir (CAB-La): promising but Not Without Challenges

Pharmacokinetic studies of CAB-La demonstrate that bimonthly injections typically result in drug concentrations four times higher than the levels considered protective against HIV. However, the HPTN 083 and 084 trials revealed that some infections occurred in patients who received injections every two months. In certain specific cases, concentrations appeared adequate, while others exhibited rapid metabolism, leading to pre-injection concentrations that were too low, raising concerns about potential breakthrough infections.

Furthermore, the emergence of resistance to integrase strand transfer inhibitors (INSTI) was observed in patients who became infected while on CAB-La. diagnosing these infections can also be challenging. As highlighted in the “Levi syndrome,” a participant in the HPTN test who became infected shortly before the first injection onyl had a detectable viral load four months after the infection, underscoring the complexities of monitoring and managing infections in individuals using long-acting PrEP.

Lénacapavir: A Major Advance

studies concerning Lénacapavir, including PURPOSE-1 and PURPOSE-2, have demonstrated excellent efficacy, with only two infections noted among several thousand participants. In both cases,resistant strains emerged,despite seemingly adequate measured concentrations. While tolerance to Lénacapavir was generally good, 1.2% of participants discontinued due to pain associated with the two simultaneous subcutaneous injections administered every six months.

researchers are also exploring new options, including implants, annual intramuscular injections of Lénacapavir (Len IM), and monthly oral treatments with MK-8527. The MK-8527 is administered monthly, and dosage test details were presented at CROI, showcasing the ongoing efforts to develop even more convenient and effective long-acting PrEP options.

Barriers to Scaling Up Long-Acting PrEP

Cissy Kityo, from the Clinical Research Center Joint in Kampala, Uganda, addressed the significant obstacles to scaling up these new long-acting PrEP options, particularly in resource-limited settings. She emphasized the critical importance of accessibility and affordability, advocating for innovative solutions and better regulation to ensure equitable access to PrEP for all who need it, nonetheless of their location or socioeconomic status.

It is estimated that approximately 8 million people have initiated PrEP,with 90% of these programs based on oral PrEP. While CAB-La was approved by the World Health Institution (WHO) in 2022, Lénacapavir has not yet received the same approval, highlighting the need for expedited regulatory processes to ensure timely access to these possibly life-saving interventions.

Despite the significant potential of CAB-La, its implementation has been slow, particularly in resource-limited settings. Along with organizational challenges, financial obstacles exist, as generic versions are not yet available. The annual cost of PrEP with Cabotégravir remains four times higher than that of oral PrEP, creating a significant barrier to access for many individuals and healthcare systems.

Even in industrialized countries,access to PrEP with CAB-La remains limited. In the United states, less than 1% of PrEP users utilize CAB-La, due to a complex administrative system. Kityo questioned whether the rollout of Lénacapavir could be more efficient, drawing a comparison to the rapid progress of molnupiravir against SARS-CoV-2, suggesting that lessons learned from other public health emergencies could be applied to accelerate the implementation of long-acting PrEP.

Kityo highlighted several obstacles to providing injectable long-acting PrEP, including limited product availability, a lack of dedicated funding, and complex care systems. She stressed the need for effective deregulation to facilitate rapid implementation, ensuring that these innovative prevention tools reach the people who need them most without unneeded delays or bureaucratic hurdles.

To ensure rapid access to cabotégravir or Lénacapavir in resource-limited countries, Kityo advocated for voluntary licenses to enable rapid manufacturing by credits. In the meantime, these products must be made available at reasonable prices. She also emphasized the importance of countries diversifying their methods of financing the fight against HIV to guarantee equitable access to prevention and treatment services for all.

Conclusion

The CROI 2025 session on long-acting PrEP highlighted both the immense promise and the significant challenges of this evolving field. While new treatments like cabotégravir and Lénacapavir offer potential advantages over daily oral PrEP, issues of adherence, accessibility, and cost must be addressed to ensure equitable access to effective HIV prevention strategies worldwide. The discussions underscored the need for continued innovation, strategic partnerships, and policy changes to overcome these barriers and accelerate progress towards ending the HIV epidemic.

Revolutionizing HIV Prevention: Long-Acting PrEP – A Giant Leap Forward or a Stumbling Block?

the quest to eradicate HIV hinges on our ability to overcome the persistent challenge of treatment adherence. long-acting PrEP offers a beacon of hope,but its transformative potential is threatened by significant hurdles.

The quest to eradicate HIV hinges on our ability to overcome the persistent challenge of treatment adherence. Long-acting PrEP offers a beacon of hope, but its transformative potential is threatened by significant hurdles.

Dr. Anya Sharma, Global HIV/AIDS Expert.

World-Today-News Senior Editor: Dr. Sharma, thank you for joining us. The Conference on Retroviruses and Opportun

Revolutionizing HIV Prevention: Long-Acting PrEP – A Giant Leap Forward or a Stumbling Block?

Is long-acting PrEP the game-changer we’ve been waiting for in the fight against HIV, or are important obstacles hindering its widespread adoption?

World-Today-News Senior Editor: Dr. Sharma, thank you for joining us. The Conference on Retroviruses and Opportunistic Infections (CROI) highlighted significant advancements in long-acting pre-exposure prophylaxis (PrEP), yet challenges remain. Can you summarize the current landscape of long-acting HIV prevention methods?

Dr. Sharma: Certainly. The HIV prevention landscape is evolving rapidly, with long-acting PrEP emerging as a promising strategy to overcome the significant adherence challenges associated with daily oral PrEP. Currently, we have several options: the dapivirine vaginal ring, Cabotégravir (CAB-La) delivered via bimonthly intramuscular injections, and Lénacapavir administered as biennial subcutaneous injections.Each of these offers a different approach to sustained HIV prevention,yet each faces unique hurdles.

World-Today-News Senior Editor: Let’s discuss adherence. Why is consistent adherence to daily oral PrEP such a major challenge, and how do long-acting options address this?

Dr. Sharma: You’re right to highlight adherence as a critical factor. Daily oral PrEP, while effective when taken consistently, requires unwavering commitment. Many factors contribute to inconsistent adherence, including forgetfulness, stigma, travel, and simply the disruption to daily routines. Long-acting PrEP aims to circumvent these issues by providing extended protection with fewer doses. However, while less frequent dosing improves adherence, challenges can still arise concerning administration, accessibility and the handling of potential side effects.We saw evidence of this in the initial trials of both CAB-La and Lénacapavir in several populations.

World-Today-News Senior Editor: The article mentions CAB-La and Lénacapavir specifically. Could you elaborate on their efficacy, limitations, and potential?

Dr. Sharma: Both CAB-La and Lénacapavir have shown significant promise in clinical trials. CAB-La,administered as bimonthly injections,provides sustained high concentrations of the drug,offering extraordinary protection. However, studies such as HPTN 083 and 084 reveal some breakthrough infections, highlighting the need for careful monitoring and a deeper understanding of individual pharmacokinetic variations. Similarly, Lénacapavir, given as a less frequent subcutaneous injection, has demonstrated excellent efficacy with few infections in large trials. The studies show a remarkable reduction in HIV infection risk. Though, the emergence of drug resistance in a small percentage of participants in clinical trials warrants vigilance and further scrutiny. Both medications have shown promise but are not failsafe, simply put, even with the high levels of the drugs, there have been breakthrough infections.

World-Today-News Senior Editor: What are the key barriers to scaling up long-acting PrEP, especially in resource-limited settings?

Dr.Sharma: Scaling up access to long-acting PrEP faces significant challenges, notably in resource-constrained environments. Cost is a major hurdle. These novel medications are considerably more expensive than oral PrEP, making them inaccessible to many.Supply chain limitations also pose a problem, as does the need for specialized healthcare infrastructure to administer injections safely and effectively. Moreover, effective public health strategies and efficient public awareness campaigns are needed to educate high risk populations on the benefits and proper utilization of these medications. Complex regulatory pathways and significant logistical hurdles must also be overcome.

World-Today-News Senior Editor: What steps are needed to overcome these obstacles and ensure equitable access to long-acting PrEP globally?

Dr. Sharma: Addressing these issues requires a multi-pronged approach. Firstly, innovative financing mechanisms and collaborative partnerships between governments, pharmaceutical companies, and non-profit organizations are essential to reduce the cost of these medications and make them more widely available. A reduction in the cost of long acting prep is paramount for providing wider access. Secondly, we need to streamline regulatory processes, especially in low- and middle-income countries. Simplified access mechanisms are crucial for timely distribution of these medications. Thirdly, bolstering healthcare infrastructure and training healthcare professionals to administer these injectables is fundamental and critical. and perhaps most importantly, we need ongoing research into the long-term safety and efficacy of these drugs, and to assess both cost effectiveness and the impact they have on the wider spread of HIV infection.

World-Today-News Senior Editor: What is the future of long-acting PrEP?

Dr. Sharma: The future of long-acting PrEP is shining, but it demands continued investment in research, development, and equitable access initiatives. New delivery methods, such as implants, are under investigation, promising even greater convenience and adherence. we also anticipate further refinements in drug formulations to improve efficacy and reduce side effects. The success of long-acting PrEP hinges on our ability to overcome financial barriers, navigate regulatory landscapes, and empower communities most affected by HIV.

world-Today-News Senior Editor: Dr. Sharma, thank you for your insightful outlook. This is a critical area in the ongoing fight against HIV,and your expertise sheds vital light on the opportunities and the challenges.

key Takeaways:

Long-acting PrEP offers a promising solution to the problem of inconsistent adherence.

While both CAB-La and Lénacapavir show great promise, they are not a “silver bullet”, with breakthrough infections and drug resistance observed.

Cost, access, and infrastructure limitations pose significant hurdles, especially in resource-limited settings.

addressing these challenges requires a multi-pronged approach including strategic partnerships, streamlined regulations, and innovative financing mechanisms.

We encourage you to share your thoughts and insights on long-acting PrEP in the comments section below. Let’s continue this significant conversation.