Gilead Sciences' Innovative Approach To An HIV Clinical Trial

By Moupali Das, MD, MPH, PrEP Clinical Program Lead, Gilead Sciences

Prevention is the cornerstone of ending the HIV epidemic. According to the U.S. Centers for Disease Control and Prevention, taking pre-exposure prophylaxis (PrEP) medicines as prescribed reduces the risk of getting HIV via sexual contact by about 99%.ⁱ Where PrEP uptake has been high, there are significant population-level declines in new HIV infections, though not all who may benefit from current PrEP options are accessing them. In the U.S. alone, only 20% of those who may benefit from PrEP (estimated 1.2 million) are on daily oral PrEP.ⁱⁱ Moreover, adherence to PrEP remains an ongoing challenge and there is a dire need to introduce innovative new PrEP options that will not only potentially improve adherence but also offer these necessary medicines to historically underserved populations. There remains a fundamental need to update traditional clinical approaches and trial designs to be more inclusive and informed by the communities ultimately served. HIV prevention remains at a crossroads due to clinical and socio-cultural factors limiting the adoption of PrEP treatments. Faced with the opportunity to drive meaningful change in this space, Gilead launched our Phase 3 study of investigational lenacapavir for PrEP, a potential long-acting, subcutaneous twice yearly PrEP option with a novel counterfactual design, and emtricitabine/tenofovir alafenamide (sold commercially as Descovy) in cisgender adolescent girls and young women (the PURPOSE 1 clinical trial, NCT04994509).

We recognized that any clinical pathways intent on introducing new PrEP options must commit to addressing and effectively bridging these existing gaps if we strive to drive real change in HIV prevention:

• Adherence to and availability of traditional PrEP. While PrEP medicines are a promising approach to preventing HIV acquisition across populations and geographies, there is broad consensus that additional PrEP options are needed to help meet different individual needs and lifestyles.ⁱⁱⁱ Long-acting formulations are currently being investigated, with fewer doses and longer intervals that may help encourage improved adherence for some individuals. Beyond those formulations in development, there are daily oral pills available in many countries around the world.
• Challenges with traditional study design. Given the availability of effective PrEP options, the gold standard of a randomized, placebo-controlled study is not ethical or feasible. Additionally, non-inferiority trials are not possible due to prohibitively large sample sizes and durations required if adherence to the comparator drug is high.
• Representation of cisgender adolescent girls and young women. Adolescent girls and young women (AGYW) are among the individuals who may benefit from PrEP medicines, with nearly 60% of new HIV infections among young people globally in 2016 occurring among AGYW.^iv Previously, we have not been able to include this population because of a lack of consensus among experts on the correct trial design because of the inability to do a non-inferiority trial due to inconsistent results among this specific population and the unethical design of a superiority to placebo trial with available PrEP options.
• Representation of pregnant or lactating people. Those who are pregnant or lactating have an increased risk of HIV acquisition during these periods yet are also a group of people lacking timely and focused HIV clinical research. We intend to examine the pharmacokinetic of the twice yearly subcutaneous investigational lenacapavir formulation in pregnant and postpartum people, as well as in breastmilk, and in mother-infant pairs.
• Focused research on areas of the world most impacted by the epidemic. While sub-Saharan Africa accounts for more than 65% of the global burden of new HIV infection, key populations who may benefit from PrEP medicines in this region are underrepresented in HIV research today. Historically, these groups are disproportionally impacted by the virus due to the inability to adapt strategic prevention strategies that fit their unique needs.^v

At the outset of our work on PURPOSE 1, we knew our mission to implement a more inclusive and effective trial could not be executed alone. Robust community and stakeholder engagement, from pre-trial planning to inception and development, and through execution, was the center of gravity for PURPOSE 1, and the axis upon which the following central and unique aspects of the study rested:

• Counterfactual HIV incidence design, with background HIV incidence serving as an additional control
• Leveraging community resources for trial recruitment, with the goal of intentionally including cisgender AGYW and pregnant and lactating people
• Flexible participant-focused design — utilizing digital tools and community-led touchpoints

Community Engagement And Inclusion

Repeated and dedicated community engagement was critical for Gilead. We began our stakeholder consultations in December 2019 in Kigali, Rwanda. Given the high prevalence of HIV among AGYW in sub-Saharan Africa, it was imperative for us to engage AGYW in the local communities, public health ministries, government organizations, potential trial site leaders, and people living with HIV (PLWH) in our early plans.^vi The people who serve these local communities are the most knowledgeable resources we could have to learn how we can best serve people who may benefit from PrEP and provide the thoughtful context we needed early on and throughout the whole process to date.

We first listened to what current gaps in biomedical HIV prevention efforts exist and what is needed to help bridge them in their local communities. It was through these deep and informative discussions that we began to map the diverse inclusion of AGYW, including those who are pregnant and lactating. Building upon this momentum of partnership and open communication, we held two additional workshop meetings that brought together all stakeholders involved in this study — a virtual two-day event in October 2020 with our Ugandan colleagues and a virtual all-day meeting with our South African colleagues the following month. In January of 2021, we established our PURPOSE 1 Global Community Accountability Group (G-CAG), with representatives from both Uganda and South Africa, and we maintain regulatory consultation meetings that review trial protocols, recruitment and screening materials, and best practices for trial execution. In summer 2021, we enrolled our first participant in PURPOSE 1, at one of our sites in South Africa.

South Africa and Uganda were selected as trial sites for PURPOSE 1 given their high background incidence of HIV among AGYW.^vi We collaborated with regulatory authorities, high-level health officials, and the leadership of HIV communities in those countries and sought guidance on a number of elements of the study.

Study Design

We designed PURPOSE 1 to be participant-centric. Given current efficacious medicine options for PrEP, designing clinical trials to evaluate the efficacy of novel PrEP methods has become progressively challenging: A superiority design comparing PrEP to placebo is unethical and would leave some participants at risk for HIV acquisition.

The counterfactual incidence design, used in studies for new contraceptive devices and products based on historical pregnancy rates without contraception, offered a unique model for investigational HIV prevention medications. This offers both a scientifically rigorous and ethically responsive framework. The counterfactual design avoids a placebo arm by calculating the estimated HIV incidence in a specific region and population in the absence of the prevention drug, and then compares that to the incidence of HIV in the study arms with the prevention drug. To calculate an accurate counterfactual background HIV incidence estimate, we use recency assays, plasma/dried blood spot (DBS) adherence-efficacy data, surveillance or clinical trial data, and STI-HIV incidence. The comparison of the counterfactual HIV incidence and the HIV incidence in the study arms allows researchers to understand the potential efficacy of a drug.

This innovative methodology shifts the landscape of future PrEP clinical research, as it eliminates the need for a placebo control group.

Further, our conversations with stakeholders were of immeasurable value in shaping the design of PURPOSE 1.

Site Selection

Our discussions with government officials, civil society leaders, advocates, and site investigators helped us identify the diverse, high incidence sites and their locations across South Africa and Uganda. Sites were also chosen based on their track record of collaborating with the community, including standing local community advisory boards, and those with staff that had deep roots in the local community Socio-cultural contexts were assessed and profiled for each site to understand the likely demographics of each trial location, in partnership with the G-CAG and investigators.

Recruitment

Our G-CAG again serves to advise the most appropriate modification of engagement and recruitment materials, depending on trial site location. We relied on the sites’ local community advisory boards and their deep knowledge of their local communities to lead recruitment efforts. We had specific targets across diverse groups, along with quantitative and qualitative assessment of the participants’ voices. The decision to include adolescents, pregnant, and lactating people was driven by our investigators and community leaders, including those in our G-CAG, along with feedback from potential trial participants who all reverberated the need for inclusion of some of the most at-risk and underrepresented populations in this space and addressing unmet need. We also refer trial participants for contraception and STI treatment.

Study Management

We created a trial website to reach potential participants, as well as offer updated trial information for confirmed investigators, confirmed participants, G-CAG members, and interested healthcare providers.

Person-First Communications

Another important value for us was terminology, specifically, the consistent use of human-centric language that reflects the world we live in today. We used a person-first communications approach throughout all study documentation, presentations, and any participant-facing materials to not only make the materials accessible but also reflect our recognition of the significance of the people involved in this trial— they truly did come first and will remain our guiding light for future endeavors in HIV research. Not only did we use language that is more easily understood by trial participants, but we also made sure to communicate via multiple channels throughout the trial.

With thought, with purpose, and with bold intention to reshape the future of HIV prevention and management, we continue to evolve our approach to study design and implementation in partnership with communities most impacted by the epidemic. Through our actions, we are committed to continuing to work closely with the global HIV community to help more people in need access the medicines that help them most. We will continue to focus our efforts with vigor and people-centricity, while challenging convention, to bring new innovations to the HIV space.

Lenacapavir is an investigational compound and is not approved by any regulatory authority for any use and its safety and efficacy are not established. The use of Descovy in cisgender adolescent girls and young women is investigational, and the safety and efficacy of Descovy for this use have not been established.