A New Era in HIV Prevention: Monthly Pills and Long-Acting Injections Transform PrEP
The global fight against Human Immunodeficiency Virus (HIV) has seen incredible progress, yet the need for innovative prevention methods remains urgent. In 2023 alone, 1.3 million people acquired HIV, underscoring the continuous demand for effective strategies. Among the most powerful tools in this fight is pre-exposure prophylaxis, or PrEP. PrEP involves taking medication before potential exposure to HIV to significantly reduce the risk of infection. (This explanation of PrEP is provided for clarity and is not directly from the provided sources.) Traditionally, PrEP has been available as a daily pill, but recent advancements are ushering in a new era of longer-acting options, promising greater convenience and wider reach. Key players like MSD and Gilead are at the forefront of this revolution, with MSD progressing a once-monthly oral PrEP into critical Phase III trials and Gilead already having a twice-yearly injectable therapy approved. These developments represent a monumental leap forward, holding the potential to transform HIV prevention efforts worldwide.
MSD's Once-Monthly Oral PrEP: A Game Changer on the Horizon
MSD, a leading pharmaceutical company, recently made a significant announcement at the International AIDS Society (IAS) 2025 conference, held from July 13-17 in Kigali, Rwanda. They unveiled the launch of Phase III trials for their investigational once-monthly oral PrEP candidate, MK-8527. This is a pivotal step, as Phase III trials are typically the final stage before a drug can be considered for regulatory approval. The decision to advance MK-8527 into this crucial stage was bolstered by promising results from a prior Phase II trial.
The Phase II trial (NCT06045507) was a double-blind, multi-center study that investigated three different doses of MK-8527 against a placebo. It included 350 participants, aged 18 to 65, who were considered to have a low likelihood of HIV-1 exposure. The results were encouraging: MSD reported that their once-monthly oral PrEP was safe and well-tolerated. Importantly, the rates of adverse events (side effects) were similar between those who received MK-8527 and those who received the placebo. Furthermore, laboratory tests, including important immune cell counts like total lymphocyte and CD4 T-cell counts, showed no clinically meaningful changes, indicating the drug's safety profile. These positive Phase II data were also presented at the IAS 2025 conference on July 14.
MK-8527 itself is an investigational drug that belongs to a class of medications known as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). In simple terms, this means it works by interfering with the process HIV uses to replicate within the body, thereby preventing infection.
To thoroughly evaluate its safety and effectiveness, MSD has launched two large-scale Phase III trials: EXPrESSIVE-10 (MK-8527-010) and EXPrESSIVE-11 (NCT07044297). These studies are designed to be comprehensive, ensuring the drug's performance is rigorously tested across diverse populations. Both trials will compare MK-8527 against the current gold standard for daily oral PrEP, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF). The primary goal for both studies is to measure the "incidence rate per year of adjudicated HIV-1 infections". In essence, this means they will carefully track how many new, confirmed HIV infections occur in each group over time to see how well MK-8527 prevents the virus compared to the established daily pill.
The EXPrESSIVE-10 trial has a crucial focus: it will specifically enroll women and adolescent girls in sub-Saharan Africa. This focus is particularly significant because, as Dr. Eliav Barr, global clinical development head at MSD Research Laboratories, pointed out, women in sub-Saharan Africa, along with men who have sex with men, "experience disproportionately high rates of HIV". This trial is a collaborative effort, run by the International Clinical Research Center (ICRC) within the University of Washington Department of Global Health, in partnership with the University of Alabama at Birmingham. It will receive substantial grant funding from the Gates Foundation to support ICRC’s work with 31 clinical research trial sites located in Kenya, South Africa, and Uganda.
The EXPrESSIVE-11 trial, on the other hand, is broader in scope, aiming to enroll 4,390 sexually active people who could benefit from PrEP. This study will also receive financing from the Gates Foundation, which will additionally support global community advisory groups. These advisory groups are vital, as they will "offer insight into community perspectives on a monthly PrEP pill," ensuring that the development considers the real-world needs and preferences of those who would use the medication.
This collaboration with the Gates Foundation is highly strategic, as Dr. Barr stated, it "will help us explore the potential of MK-8527 to contribute to global efforts to reduce the number of HIV infections and help support opportunities to accelerate access around the world". The goal is not just to develop an effective drug but also to ensure it can reach those who need it most, especially in regions with high HIV burdens.
Gilead's Leading Role in Long-Acting PrEP
While MSD is pushing forward with its monthly oral option, the broader landscape of long-acting HIV PrEP is rapidly accelerating, with Gilead Sciences already making significant strides. Just last month, Gilead achieved a major milestone by receiving approval from the US Food and Drug Administration (FDA) for its twice-yearly injectable therapy, Yeztugo (lenacapavir). This approval marks a substantial shift in how PrEP can be administered, moving away from daily pills to far less frequent injections.
The importance of Yeztugo was further underscored when the World Health Organization (WHO) officially recommended its use on July 14. The Director-General of the WHO even described the drug as the "next best thing" in the ongoing absence of an HIV vaccine. This strong endorsement from a global health authority highlights the potential impact of Yeztugo on worldwide HIV prevention efforts.
Gilead's approval and recommendation were based on robust data from its own extensive clinical trial program. The company conducted two Phase III trials for Yeztugo, demonstrating exceptional efficacy. One of these trials showed an incredible 100% prevention of HIV, while the second trial demonstrated a 96% prevention rate. Such high levels of effectiveness are critical for a preventive measure.
Not content to rest on its laurels, Gilead is already looking to the future and aiming to simplify PrEP even further. The company is actively trialling a once-yearly version of the therapy. Following successful results from an initial Phase I trial, this candidate is now being advanced to Phase III trials, indicating strong potential for an even more convenient long-acting option in the near future. The progression of both MSD's monthly pill and Gilead's injectable therapies signals a transformative shift in the HIV prevention toolkit.
Why These Advancements Matter for Global Health
The progression of MSD's once-monthly oral PrEP and Gilead's success with its long-acting injectable therapy are not just scientific achievements; they are crucial developments for global public health. The continued high rate of new HIV acquisitions, as reported by UNAIDS with 1.3 million people acquiring HIV in 2023, clearly illustrates the "continued need for new PrEP options".
The primary advantage of these long-acting forms of PrEP over daily pills is convenience and adherence. Remembering to take a daily pill can be challenging for many people due to busy schedules, stigma, or other life circumstances. A monthly pill or a twice-yearly (or even once-yearly) injection significantly reduces the burden of adherence, making it easier for individuals to consistently protect themselves from HIV. This improved adherence is critical for the real-world effectiveness of PrEP programs.
Furthermore, these new options address the disproportionately high rates of HIV observed in specific populations, such as women in sub-Saharan Africa and men who have sex with men. By offering diverse and discreet prevention methods, they can help overcome some of the barriers that have historically limited PrEP uptake and effectiveness in these vulnerable communities. The collaboration with organizations like the Gates Foundation, focusing on access and community perspectives, further reinforces the commitment to ensuring these life-saving innovations reach those who need them most, especially in regions with high disease burdens.
The accelerating landscape of long-acting PrEP options provides hope for a significant reduction in new HIV infections worldwide. The ability to choose between a monthly oral pill or an infrequent injection will empower individuals with more tailored and sustainable prevention strategies, moving the world closer to ending the HIV epidemic.
Consider these advancements like the evolution of a shield. For a long time, we had a very effective daily shield – you had to remember to pick it up and wear it every single day. If you forgot, even for a day, there was a small gap in your protection. Now, imagine if you could have a shield that, once activated, would stay protective for a whole month or even six months, just by taking a pill or getting a quick injection. These new long-acting PrEP options are like those advanced shields – they offer a much simpler, more consistent, and ultimately stronger line of defense against HIV, making it easier for people to stay protected in the long run.
HIV Researchers:
Ana María del Río-González, Ph.D. is an Assistant Research Professor of Psychology at the George Washington University who is researching peer-coaching programs to promote HIV prevention among Latina transgender women in Washington D.C.
S. Raquel Ramos, PhD, MBA, MSN, FNP-BC, an Assistant Professor at New York University's Rory Meyers College of Nursing, is involved in research on HIV prevention within the Latinx community.
Sandra Gracia Jones, PhD, RN, ACRN, FAAN, a Professor and Vanessa Von Wertheim Endowed Chair at Florida International University, focuses on chronic disease prevention and care, including HIV.
