Equity in access to long-acting injectables in the USA

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor, recently received regulatory approval in the US, Canada, and the EU as a monthly intramuscular long-acting injectable (LAI) regimen in adults with HIV-1 who are virologically suppressed and have no history of treatment failure. Injectable cabotegravir administered every two months as pre-exposure prophylaxis (PrEP) also recently received US regulatory approval, and other treatment and prevention LAI formulations are in development. These new technologies eliminate the need for daily pill-taking and have the potential to dramatically change the HIV landscape. LAIs may lead to new strategies to engage with patients, especially with those who face challenges to daily oral medication adherence and retention in care. However, LAIs also have the potential to exacerbate existing health inequities if – given the stringent inclusion criteria of clinical trials – flexible models of delivery are not developed for key populations. In the US, African American and Latinx men who have sex with men, transgender women, youth, and young adults face a disproportionate HIV burden, but are more likely to experience gaps in HIV prevention and care. As LAI regimens are rolled out, several challenges to implementation require urgent attention to ensure equitable access to these key populations.

The inclusion criteria for the LAI cabotegravir-rilpivirine registration trials (ATLAS¹ and FLAIR²) required at least four months of virologic suppression on oral antiretroviral therapy and four weeks of oral cabotegravir and oral rilpivirine prior to starting the monthly LAI regimen (although a separate study showed that direct-to-inject without an oral lead-in was safe).³ The current cabotegravir-rilpivirine drug label requires monthly injections administered by a healthcare provider and uses the same criteria used in the registration trials (i.e., virologic suppression on oral treatment and an oral lead-in requiring high adherence due to rilpivirine’s low genetic barrier to resistance). These stringent criteria will drive the public health response and pose critical challenges to effective and equitable LAI delivery. Inflexible adherence to these requirements will especially impact patients struggling with individual, social, and structural barriers, as well as HIV and primary care clinics strained by limited staffing and resources. Patients report that frequent clinic visits for LAIs may worsen HIV stigma and stigmatization, increase the risk of unwanted disclosures, and lead to increased costs from co-pays and travel.⁴ Frequent clinic visits may also be prohibitive for patients who are unable to miss work or for those without transportation.⁵ Similarly, clinicians have expressed concerns that the number and frequency of injection clinic visits may overwhelm staffing and other clinic resources.^5,6 Data from a recent implementation study estimated that, on average, each cabotegravir-rilpivirine injection visit lasted approximately 32 minutes (excluding travel time to and from the clinic),⁷ which may not be feasible for many clinics on a larger scale.

Since cabotegravir-rilpivirine has now received US regulatory approval, clinicians can – with close monitoring – provide the agents to select patients who are not virologically suppressed and without an oral lead-in. Additionally, administration of LAIs (for treatment or prevention) by a trained layperson outside of healthcare settings, such as by a family member, may mitigate patient- and provider-identified barriers and optimize effectiveness in real-world settings. No study has yet examined home LAI administration, although this strategy has been used successfully for other medical purposes. For example, studies of self-administered intramuscular hormonal contraceptives have demonstrated that home administration was feasible, lowered healthcare costs, and resulted in greater patient satisfaction.^8,9 Administration by laypersons in community-based organizations (CBOs), such as housing and social service agencies, may also provide an alternative strategy that can help mitigate the social structural issues that impact the most vulnerable, including transportation, safety, stigma, and discrimination. The COVID-19 pandemic has underscored how effective community partnerships through CBOs can build trust and improve healthcare engagement, particularly in minoritized communities that may be hesitant or distrustful of medical institutions.

Until now, these models of care have not been possible for HIV treatment or prevention. However, the safety and efficacy profiles of newer generation antiretrovirals, including cabotegravir-rilpivirine and cabotegravir for PrEP, make them candidates for delivery in non-healthcare venues. There is precedent for and data to support the benefits of providing HIV care in community settings. In a meta-analysis of community-based HIV treatment models, provision of antiretroviral therapy by nurses and lay health workers outside of traditional healthcare settings was associated with improved uptake, retention, and viral suppression in persons living with HIV.¹⁰ The suitability of these models to LAI delivery should now be actively explored. Regulatory barriers that can impede innovation, including regulations around the inclusion of pregnant persons and youth in drug development trials and limitations on who can administer LAI medications (i.e., currently, only administered by a healthcare provider), also require reconsideration.

Research evaluating flexible LAI delivery strategies is needed to support equitable scale-up of these promising regimens for key populations. Important questions around implementation, the effectiveness of LAI cabotegravir-rilpivirine in non-suppressed individuals, pharmacy benefit coverage, and patient monitoring remain unanswered. It is apparent that a one-size-fits-all approach to LAI delivery is not an effective public health strategy and adaptive interventions that are responsive to the needs of different populations are critical. Adequate representation of racial, ethnic, and gender minorities, as well as other vulnerable groups such as youth, young adults, pregnant persons, those without stable housing, and those who use drugs or have mental health challenges in future trials is essential to identify population-specific barriers and ensure broad access to promising technologies. With increased approval of LAIs in countries around the world, it is also imperative that we focus on global equity and access to achieve the goal of ending HIV. Lastly, future explorations of how models of LAI delivery for HIV treatment may differ from prevention is warranted. As we prepare to broaden the availability of LAIs, there is an urgent need to engage with patients and stakeholders to evaluate a range of delivery strategies that can enhance equitable access, increase patient willingness to use these new technologies, and maximize public health impact.