As HIV pre-exposure prophylaxis (PrEP) has emerged as the standard of care for HIV prevention, clinical trials evaluating new prevention strategies, including vaccines, face unique challenges.  The goal of a vaccine to prevent HIV infection remains a top priority, but as difficult as it has been to technically produce, it is now becoming increasingly complex to research its effectiveness and safety in the real world. However, the need for an HIV vaccine remains. As recently quoted in Infectious Disease News, Larry Corey, MD, co-principal investigator of the HIV Vaccine Trials Network (HVTN) and former president of the Fred Hutchinson Cancer Center in Seattle, explained the “enormous need” to develop an HIV vaccine, noting that only half of new HIV infections in the United States — at most — occur among high-risk people who perceive themselves to be high risk. The rest, he said, are people who perceive themselves to be — and are, by all criteria — low risk and do not take the proper preventive measures. From there, all it takes is a “chance encounter” to become infected, Corey said.

The widespread adoption of PrEP as an effective HIV prevention strategy has been shown to significantly reduce the risk of HIV infection. The landmark iPrEx study, published in 2010, demonstrated the effectiveness of oral PrEP in men who have sex with men (MSM) showing that daily use of oral Truvada (a combination of tenofovir and emtricitabine) reduced the risk of HIV infection by 44% among MSM who had sex with HIV-positive partners or had a high-risk sexual behavior. It was then followed by several others including the Partners PrEP study (2012) and the PROUD study (2015) demonstrating an 86% to 90% reduction in HIV incidence respectively among individuals using daily oral PrEP compared to those who did not. This evidence has now made PrEP the standard of care for the prevention of HIV globally.

Researchers now face the challenge of conducting trials in this environment where PrEP is the established standard of care, necessitating careful consideration of trial design, participant recruitment, and ethical considerations.

a) Trial Design and Endpoint Selection: With PrEP being highly effective in reducing HIV transmission, clinical trials evaluating new prevention modalities need to establish appropriate endpoints that account for the impact of PrEP use. Traditional endpoints, such as HIV incidence or acquisition rates, may be challenging to assess due to the high levels of protection provided by PrEP. Alternative endpoints, such as immunogenicity, durability of protection, or prevention of drug-resistant strains, may need to be considered.  This will require a fundamental shift from regulatory bodies such as the FDA and EMA to accept these proxy endpoints as demonstration of effectiveness.

b) Participant Recruitment and Retention: Recruiting participants for clinical trials in the PrEP era can be challenging. Individuals at high risk of HIV infection may already be on PrEP, reducing their motivation to enroll in trials evaluating alternative prevention methods. Ensuring adequate recruitment and retention rates while considering the ethical implications of recruiting individuals who could potentially be exposed to HIV risk without access to PrEP is a complex issue.

c) Ethical Considerations: Conducting clinical trials in settings where PrEP is widely available raises ethical considerations. Balancing the potential benefits of participating in a trial, such as access to new prevention options or contributing to scientific knowledge, with the established standard of care provided by PrEP is essential. Ethical review boards and trial sponsors must carefully assess the risks and benefits to ensure participant safety and well-being.

In the context of PrEP as the standard of care, clinical trial implementation and adherence monitoring present additional challenges.

a) Differential Access to PrEP: Disparities in access to PrEP can arise, affecting participant recruitment and retention. Individuals with limited access to healthcare or financial resources may face barriers to obtaining PrEP, potentially influencing trial enrollment and compromising the generalizability of trial findings.

b) Adherence to Study Interventions: Ensuring adherence to study interventions becomes more complex when participants are already on PrEP. Differentiating between adherence to PrEP and adherence to the investigational intervention can be challenging, requiring careful monitoring and counseling to avoid potential confounding effects.

c) Participant Engagement and Retention: Participant engagement and retention become crucial in clinical trials conducted in the PrEP era. Clear communication regarding the benefits and limitations of the investigational intervention, regular follow-up visits, and support services are essential for maintaining participant motivation and retention throughout the trial duration.

While the emergence of PrEP as the standard of care for HIV prevention presents unique challenges for conducting clinical trials evaluating new prevention strategies, the need for a HIV vaccine remains paramount. Researchers must navigate the complexities of trial design, participant recruitment, adherence monitoring, and ethical considerations. Addressing these challenges requires collaboration between researchers, healthcare providers, and affected communities to ensure the successful implementation of clinical trials and the development of novel HIV prevention strategies that can complement and someday (maybe) replace PrEP.

References:
https://www.healio.com/news/infectious-disease/20230417/hiv-vaccine-research-at-a-crossroads-after-recent-failures