Preparing for the Next Long-acting Antiretrovirals

The early days of the HIV/AIDS epidemic were full of both confusion and invention, with so much to learn about how to diagnose and treat an illness affecting vulnerable communities around the world. In the 40 years since, repeated medical and pharmaceutical breakthroughs have taken center stage as persons living with HIV (PLWH) progressed through multiple tablets with significant adverse effects taken multiple times daily, to single-tablet regimens, and most recently, to long-acting (LA) antiretrovirals (ARVs), including some available via non-oral routes.

The implementation of both currently available and upcoming LA-ARVs into HIV care delivery presents our next major challenge in the continued fight against HIV alongside PLWH who deserve medically appropriate options and choices in the treatments they receive. Adherence to an ARV regimen remains a major contributor to its continued efficacy. While patients may interrupt medication therapy because of lack of ease or adverse effects, quality-of-life factors such as pill fatigue, health care access, and privacy/stigma also contribute.

The concept of LA-ARV therapy aligns here, as increased adherence may be more likely if the ARV is administered on a non-daily basis vs the inconvenience of a lifelong daily (at a minimum) medication. LA-ARV may additionally have the potential to decrease pill burden/fatigue depending on the patient’s specific needs.¹ Currently available LA-ARVs include the full treatment regimen of cabotegravir- rilpivirine administered intramuscularly on a monthly or bimonthly basis among patients who are already virally suppressed or the intravenous infusion/ push of ibalizumab as adjunctive therapy among heavily treatment-experienced patients. As these specific medications are not necessarily restricted to be given through traditional health care delivery systems (eg, home infusion or alternative injection locations such as pharmacies), they may mitigate certain social determinants of health, such as ability to travel.¹ These innovations may contribute to increased privacy and reduced stigma amid concerns of an accidental disclosure. Depending on the structure of implementation (based on type of medication), LA-ARVs may provide for increased engagement with the health care team because of the regularity of medical and pharmaceutical touchpoints.

MEDICATIONS ON THE RISE
Two medications have received such considerable attention and research that practitioners should anticipate implementing them in the months or years ahead. The first, lenacapavir (LEN), is a first-in-class capsid inhibitor that has been studied as both an oral formulation (generally used during a lead-in phase) and as a subcutaneous injection that is administered every 6 months as adjunctive therapy among patients who are heavily treatment experienced. Of note, the European Commission approved lenacapavir for this indication based on the phase 3 registrational CAPELLA trial (NCT04150068) as of August 22, 2022. CAPELLA, which looked at the safety and efficacy of LEN among patients with HIV drug resistance, included 72 patients 12 years or older from 11 countries who had received at least 8 weeks of ARV treatment. Registrants were required to have resistance to at least 2 medications from at least 3 main drug classes of antiretrovirals with a viral load of greater than and equal to 400 copies/mL. Participants were then split into 2 cohorts. Cohort 1 (36 patients) received oral LEN vs placebo in a 2:1 ratio on days 1, 2, and 8, and cohort 2 (36 patients) received openlabel LEN on the same days. Patients in both the lenacapavir group and placebo group of cohort 1 received their original failing monotherapy in addition to oral LEN on days 1, 2, and 8, while the placebo group continued to take oral LEN on days 15, 16, and 22. Both arms of cohort 1 switched to subcutaneous LEN given on day 15 and at 6 months, plus an optimized background regimen. In contrast, cohort 2 initially received an optimized background regimen from day 1, oral LEN on days 15, 16, and 22, and subcutaneous LEN once every 6 months starting on day 15.²

Primary results of CAPELLA demonstrated successful viral suppression and increases in CD4 counts among patients who were previously on failing drug regimens. At 26 weeks, 81% of participants from cohort 1 and 83% of participants in cohort 2 had viral loads of less than 50 copies/mL. A highly valuable feature of LEN is the absence of cross-resistance among heavily treatment-experienced patients who have received ARV for numerous years. Although injection site pain/erythema were notable, reported adverse effects, others, including headache and gastrointestinal upset, were minimal. None of the trial patients experienced serious adverse events directly related to LEN.³

The US Food and Drug Administration (FDA) approved the therapy on December 22, 2022. Beyond the use of LEN in treatment-experienced PLWH with multidrug resistance, the CALIBRATE study (NCT04143594) is evaluating LEN in treatment-naïve PLWH, and the PURPOSE 1 and 2 studies (NCT04994509 and NCT04925752) will evaluate its use in preexposure prophylaxis (PrEP). The FDA-sanctioned partial resumption of the islatravir (ISL) development program provides the second medication of note for the HIV community. Islatravir, a nucleoside reverse transcriptase translocation inhibitor, had been studied for both treatment-naive and PrEP indications using multiple delivery systems, including an implanted option for prophylaxis.

In late 2021, all trials containing ISL were stopped or held after the development of CD4 declines. After further research and review, the pharmaceutical company released a statement indicating that while all PrEP development will be permanently discontinued, treatment trials for daily dosing (combined with the non-nucleoside reverse transcriptase inhibitor rilpivirine) will resume, albeit with a standardized 0.75-mg daily dose. Concurrently, the phase 2 trial combining oral ISL and oral LEN will resume under an amended protocol and lower dose ISL to be dosed weekly, with further results to be seen.³

INCORPORATING LONGACTING ANTIRETROVIRALS INTO CLINICAL CARE
If pharmaceutical research continues to demonstrate potential for LA-ARVs, we may make advancements in health equity by bridging patients to care that is convenient for them; however, successful implementation remains a challenge as we grow into this paradigm shift of care delivery. For example, the health care worker shortages caused by the pandemic, may spur innovation in health care delivery. Continued reliance on traditional mechanisms in the face of worker shortages may lead to lagging schedules or increased wait times for appointments, which in turn creates space for patients to disengage from their health care needs.

Although LA oral medications can be delivered to patients through pharmacy mechanisms, LA injections may provide unique challenges/opportunities for innovation to ensure accessibility. One such issue has developed with the capitation of benefits to medical rather than pharmacy benefits, or the potential restriction of pharmacies via limited distribution models. Regardless of injection location, whether a medical clinic or pharmacy, appropriate documentation would be required after administration with appropriate communication to the prescriber if happening off-site.

The ability to delegate tasks to nontraditional members of the care team who can perform medication injections, such as pharmacists as permitted by state regulation or statute, may provide 1 such avenue and free time among practitioners to attend to acute clinical encounters and follow-up patient visits. As observed with COVID-19 vaccine clinics, increasing medication access beyond traditional health care (eg, work hours of 8 am to 5 pm) may prove beneficial to patients with multiple responsibilities. Leveraging technology to remind patients of appointments (eg, emails or text messages) may additionally increase engagement. As LA-ARVs are shifting the landscape for HIV care, we, as a health care community, should evolve as well by implementing innovative practices that best meet the needs of our patients instead of asking them to meet our traditional needs. Creating accessible care while ensuring safety and efficacy allows the greater HIV-treating community to continuously inform PLWH that they can and will live a long, relatively unchanged life. As PLWH continue to live longer, healthier lives, we can all do our part to ameliorate the negative stigma surrounding this diagnosis and make space for innovation to drive an increased quality of life.

References

1. ART adherence. Centers for Disease Control and Prevention. Reviewed October 21, 2019. Accessed November 1, 2022. https://www.cdc.gov/hiv/clinicians/treatment/art-adherence.html#ART-barriers

2. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 Infection. N Eng J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542

3. Merck to initiate new phase 3 clinical program with lower dose of daily oral islatravir in combination with doravirine for treatment of people with HIV-1 infection. News release. Merck; September 20, 2022. Accessed October 22, 2022. https://www.merck.com/news/merck-to-initiate-new-phase-3-clinical-program-with-lower-dose-of-daily-oral-islatravir-in-combination-with-doravirine-for-treatment-of-people-with-hiv-1-infection/