This novel therapeutic option represents the first long-acting injectable approved for maintenance of HIV-1 suppression.
In January, the FDA approved the first long-acting injectable (LAI) anti-
retroviral regimen, cabotegravir/rilpivirine (Cabenuva), for maintenance of HIV-1 suppression. The approval was based on results from the phase 3 ATLAS (NCT02951052) and FLAIR (NCT02938520) studies demonstrating that cabotegravir/rilpivirine, administered as 2 intramuscular gluteal injections once monthly, was noninferior to standard oral therapy in maintaining virologic suppression.1-4
Approval of this novel antiretroviral therapy (ART) for treatment simplification represents a revolutionary milestone in the HIV treatment paradigm. For eligible patients, this therapy may offer a solution for improved medication adherence and improved clinical outcomes. Furthermore, it offers convenience and potential for improved quality of life for people with HIV by reducing pill fatigue and stigma associated with HIV. In an exploratory end point assessing patient preference, data from clinical trials demonstrated that most patients (88%) preferred LAI cabotegravir/rilpivirine to their previous oral regimen at week 48 despite the high incidence of mild to moderate injection-site reactions (84%).3,4
With the long-awaited official stamp of approval, ambulatory clinics and health care systems across the US are now focused on successful and sustainable implementation. Because this represents a major shift in HIV treatment as we know it, attention to potential clinical and logistical challenges is essential prior to widespread implementation. Certain aspects of therapy, including strict clinical criteria for use, administration by a health care provider, and initiation of an oral lead-in prior to injection to ensure tolerability, are unfamiliar concepts and necessitate thorough patient, provider, and staff education.
The following article will review key clinical and logistical factors to take into consideration prior to rollout of LAI cabotegravir/rilpivirine and offer solutions to barriers that may arise.
Use of LAI cabotegravir/rilpivirine requires careful consideration for potential clinical risks. Similar to other long-acting medications, management of adverse effects can be challenging because drug levels may persist in the body for several months. However, unlike other long-acting agents for other chronic conditions, there is a risk for treatment failure and development of HIV resistance if patient eligibility is not assessed prior to use or if injection appointments are missed.
Prior to prescribing, it’s essential to confirm patients meet the following clinical criteria: on stable ART with an undetectable viral load (< 50 copies/mL), no known or suspected resistance to cabotegravir or rilpivirine, no prior treatment failure, not pregnant or planning to become pregnant, and not coinfected with hepatitis B virus (HBV) unless receiving additional oral medication for treatment of HBV. A comprehensive chart review should be performed to assess patient eligibility and ensure no contraindications exist. Ideal candidates are those who have consistently attended provider visits because it will now be necessary to attend monthly visits for medication administration, which should be incorporated into patient education materials and counseling sessions. An updated medication list should be obtained, and assessment for potential drug-drug interactions should also be performed. Certain interactions require attention with oral rilpivirine and cabotegravir but are not clinically relevant with injectable therapy because gastrointestinal (GI) absorption is bypassed. For example, oral rilpivirine requires an acidic GI environment for absorption and concomitant use with omeprazole is contraindicated, but absorption is not impacted when rilpivirine is administered intramuscularly. The same is true for cabotegravir and polyvalent cations, as chelation can occur with oral cabotegravir.
Another major clinical consideration for use is the risk of virologic rebound and development of HIV resistance if injection appointments are missed. Maintenance injections can be administered up to 7 days before or after the scheduled monthly injection. For planned missed doses beyond this 7-day window, patients should be bridged with oral cabotegravir and rilpivirine until their next injection can be administered. If it has been 2 months or less since the last injection, maintenance dose injectable therapy can be continued; however, if more than 2 months have passed, the loading dose must be repeated. If unplanned missed doses occur, patients can have detectable but subtherapeutic levels of cabotegravir and rilpivirine for many months after an injection, generating risk for drug resistance. Data from the ATLAS and FLAIR trials demonstrated that resistance rates were similar across both arms with only 3 patients in the LAI cabotegravir/rilpivirine group developing resistance mutations in each trial. The most common mutations were E138K (rilpivirine resistance), which developed in 4 patients across both trials, and Q148R (cabotegravir resistance), which developed in 2 patients in the ATLAS trial.3,4 A combination of at least 2 of the following baseline factors may be associated with an increased risk of virologic failure: archived rilpivirine-resistance mutations, HIV-1 subtype A6/A1, or body mass index (BMI) equal to or greater than 30 kg/m2.
In addition to clinical considerations, successful implementation of LAI cabotegravir/rilpivirine requires attention to potential logistical barriers. There are several logistical barriers related to medication access. Unlike traditional ART, which is covered through pharmacy benefits, LAI cabotegravir/rilpivirine may be covered under pharmacy and/or medical benefits. Clinics may need to establish new workflows to investigate medical benefits for medication coverage.
Medication procurement is also not straightforward; the oral lead-in is only available from a mail-order specialty pharmacy (TheraCom Pharmacy). This may complicate initiating therapy and bridging patients for missed visits, as medication delivery will require additional coordination. For example, if a patient has an unplanned missed visit, they cannot go to their local pharmacy to obtain additional oral cabotegravir and rilpivirine. The clinic and the patient must reach out to TheraCom and await mail delivery of medication, which could delay access.
New processes will need to be developed for obtaining LAI cabotegravir/rilpivirine. If it is covered under pharmacy benefits, clinics will need to determine if they will utilize white, brown, or clear bagging. Obtaining the medication from an internal pharmacy (clear bagging) may be the most feasible, if possible. However, clinics may also require patients to obtain medication from an outside pharmacy and bring it into the clinic for administration (brown bagging) or may request office delivery through an external pharmacy (white bagging). If the injection is white bagged, then clinics will need to develop a procedure for medication disposal upon missed visits because the external pharmacy may not accept the medication for return. If it is covered under medical benefits, practices will need to set up a process for buy and bill—buying the medication from a pharmacy and then subsequently billing a patient’s medical insurance after administration. Lastly, LAI cabotegravir/rilpivirine must be stored under refrigeration until the time of administration. Brown bagging is generally not recommended because it would require the patient to transport the medication under refrigerated conditions, which may not be possible for all patients. Additional refrigeration space within the clinic may be needed depending on the volume of patients.
LAI cabotegravir/rilpivirine may also increase the consumption of human resources and office space. It may be necessary to provide training sessions on injection preparation and administration prior to implementation. Each monthly administration visit will likely require 30 to 45 minutes for checking in patients, rooming, bringing the medication to room temperature, monitoring post injection, and checking out. This will increase demand for exam rooms and demand on support-staff time (secretaries, medical assistants, and nurses). Support staff may also be responsible for patient tracking, coordination of patient transportation, appointment reminders, and periodic patient follow-up. Furthermore, it may be necessary to purchase additional supplies. For example, a longer needle (which is not included in the dosing kit) may be required for intramuscular administration to individuals with a BMI equal to or greater than 30 kg/m.2
To tackle these clinical and logistical challenges, a multidisciplinary approach to implementation is key. Results from the CUSTOMIZE study (NCT04001803) emphasize the importance of teamwork and staff communication and outline key strategies for patient adherence and successful clinic implementation of LAI cabotegravir/rilpivirine.5 In addition to the strategies highlighted in this study, clinics may also consider developing a protocol outlining patient eligibility criteria for LAI cabotegravir/rilpivirine to assist with identification of appropriate candidates. Incorporating a process for prescreening to confirm eligibility by assessing adherence, resolving drug-drug interactions, constructing treatment history, and reviewing the results of resistance testing may be beneficial. Clinical pharmacists are well positioned to conduct this type of review. Clinics with collaborative practice agreements in place could also incorporate this process into their agreements to decrease burden on providers and improve sustainability.
Patient counseling and appropriate tracking/follow-up are also essential, as demonstrated in the CUSTOMIZE study. A counseling session should review the 7-day dosing window, assess potential barriers to adherence to monthly clinic visits, and provide solutions to overcome these obstacles. There should be designated staff members to track patient appointments and a system in place to remind patients of upcoming appointments and follow-up appointments if scheduled visits are cancelled. Clinics can rely on web-based treatment planners or leverage information technology (IT) and electronic health record resources to reduce the burden of patient tracking. For example, IT may be able to develop reports or construct a dashboard for all patients on LAI cabotegravir/rilpivirine and highlight patients who are overdue for an administration. Even with these processes in place, patients may need rapid initiation of the oral components (bridging) or alternative oral ART, which should be made readily available in these situations. If resistance is suspected, it may be prudent to empirically initiate oral therapy with a high genetic barrier to resistance (twice-daily dolutegravir or a boosted protease inhibitor–based regimen) while awaiting resistance testing results, but this decision should be based on patient-specific factors and resistance history.
Additional staffing support may be required to overcome logistical barriers. Scheduling administration visits can be optimized to off-peak clinic days and times. Depending on the clinic model, pharmacists, pharmacy technicians, medical assistants, and/or nurses can assess insurance coverage and address medication procurement. The manufacturer of LAI cabotegravir/rilpivirine, ViiV Healthcare, also provides benefit investigation services. Social workers can potentially assist patients with barriers to transportation. Despite these potential barriers, the CUSTOMIZE study demonstrated that most providers (78%) were able to successfully implement LAI cabotegravir/rilpivirine at their practice or clinic within 1 to 3 months.5
LAI cabotegravir/rilpivirine offers a convenient and liberating treatment option to patients with HIV for maintenance of virologic suppression. Replacing daily oral therapy with 12 monthly injections may facilitate adherence and improve overall well-being. To ensure clinical success and minimize risks, clinics may need to incorporate the following into their practices: a tool for identifying eligible patients, an outline for key patient counseling points prior to therapy initiation, and a mechanism for patient tracking and follow-up upon missed injection appointments. Establishing processes for medication acquisition, billing, and on-site medication storage and anticipating the need for additional staffing are essential logistical considerations. In addition, developing a multidisciplinary team and assigning roles for each step in the process will promote successful implementation.
Ongoing studies are evaluating the elimination of oral lead-in and extending administration of LAI cabotegravir/rilpivirine to every 8 weeks, which may decrease medication access barriers in the future and reduce the number of injection visits by 50%.6,7
Ann-Marie Idusuyi, PharmD, is a clinical specialist in infectious diseases at The Miriam Hospital Infectious Diseases and Immunology Center in Providence, Rhode Island. She is a member of Making a Difference in Infectious Diseases and the Society of Infectious Diseases Pharmacists. Her clinical interests include HIV, outpatient parenteral antimicrobial therapy, and treatment of infections in immunocompromised hosts.
Rajeev Shah, PharmD, AAHIVP, BCIDP, is a clinical pharmacy specialist in infectious diseases at The Miriam Hospital Infectious Diseases and Immunology Center and an assistant professor of medicine for the Warren Alpert Medical School of Brown University, both in Providence, Rhode Island. He is also a committee member for the American College of Clinical Pharmacy HIV Practice Research Network Newsletter Committee and the Society of Infectious Diseases Pharmacists Publications and Podcast Committee.
Amy L. Brotherton, PharmD, AAHIVP, BCIDP, is a clinical pharmacist specialist in infectious diseases at The Miriam Hospital Infectious Diseases and Immunology Center and an assistant professor of medicine for the Warren Alpert Medical School of Brown University, both in Providence, Rhode Island. She is also a committee member for American College of Clinical Pharmacy HIV Practice Research Network Advocacy Committee. She is also an active member of the Society of Infectious Diseases Pharmacists and of Making a Difference in Infectious Diseases.