Viral suppression is one of the major goals of the Centers for Disease Control and Prevention (CDC) Ending the HIV Epidemic in the US (EHE) initiative.1 Viral suppression is defined in this context as fewer than 200 copies of HIV per mL of blood by 2025 in at least 95% of the individuals infected with HIV in the US, with the further goal of remaining at or above 95% suppression in 2030 (Figure 1).2 This is important because viral suppression not only minimizes an individual’s HIV disease activity but also reduces transmission of HIV from infected individuals to their uninfected sexual partners. Large studies have demonstrated that if viral load is further suppressed to the point that HIV becomes undetectable, risk of transmission via sexual activity is largely eliminated.
In turn, adherence to antiretroviral (ART) medication is generally considered to be the strongest predictor of HIV treatment success. However, even assuming that the patient is promptly linked to suitable care and interventions upon diagnosis (Figure 2),2 poor long-term adherence remains a notable challenge and is associated with virologic failure, disease progression, and adverse effects including increased mortality.2,3 Patients who take a daily oral ART regimen may have problems with adherence due to “pill fatigue,” dosing complexity and its demands on attention, and subsequent lost motivation. Other barriers to patient adherence include the stigma related to HIV status and concern about inadvertent disclosure, disruptive life events or long-term instability in living conditions, and mental or emotional comorbid conditions.
Long-acting (LA) ART regimens may offer advantages in ensuring medication adherence. A drug combination administered at longer intervals, as opposed to one self-administered daily, may reduce stigma and patients’ cognitive and emotional loads. Physician-patient contact may increase, providing further potential to ensure full adherence. An injectable form of LA ART therapy may also improve absorption, reduce gastrointestinal side effects, and circumvent difficulty in swallowing pills.4
A Long-Acting Injectable Regimen
To date, combination therapy with cabotegravir plus rilpivirine,5 administered by intramuscular injection, is the only US Food and Drug Administration (FDA)-approved complete LA regimen for HIV-1 viral suppression. Cabotegravir is an HIV-1 integrase strand transfer inhibitor (INSTI); rilpivirine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). Cabotegravir and rilpivirine are most commonly used in combination, although cabotegravir is also approved as a single agent as oral preexposure prophylaxis.
Phase 3 trials demonstrated cabotegravir plus rilpivirine to be noninferior to standard-of-care oral ART. In the phase 3 FLAIR study (ClinicalTrials.gov Identifier: NCT02938520), ART-naive patients received oral induction therapy comprising dolutegravir, abacavir, and lamivudine for 20 weeks.6 Participants who had a plasma HIV-1 level of fewer than 50 copies per mL were randomly assigned 1:1 to continue the current oral therapy or switch to LA therapy, which required a 4-week period of oral lead-in therapy with cabotegravir and rilpivirine, for a 48-week study period. At the initial 48-week endpoint, LA cabotegravir plus rilpivirine was found to be noninferior to the standard-of-care regimen.
In a subsequent extension phase of FLAIR, patients initially assigned to remain on oral therapy were given the option to extend their participation by switching to LA cabotegravir plus rilpivirine, either on a direct-to-injection basis or following oral lead-in therapy. Efficacy, safety, and tolerability were comparable across the 2 extension switch groups. In reporting 124-week results for the LA therapy group from the initial phase of FLAIR, the investigators concluded that LA cabotegravir plus rilpivirine offered durability as maintenance therapy.
The randomized phase 3 ATLAS study (ClinicalTrials.gov Identifier: NCT02951052) tested LA cabotegravir plus rilpivirine in treatment-experienced patients who were assigned to continue their current therapy or switch to the LA cabotegravir plus rilpivirine after the oral lead-in period of 4 weeks.7 This investigation, which stratified patients into subgroups based on the drug classes represented in their baseline ART regimen, showed LA therapy to be noninferior to the baseline regimens at 48 weeks in terms of efficacy, safety, and tolerability.
Subsequent phase 2 and phase 3 studies, including ATLAS-2M (ClinicalTrials.gov Identifier: NCT03299049), have demonstrated highly comparable clinical results whether participants received LA cabotegravir plus rilpivirine every 8 weeks or every 4 weeks.8 Through week 96, participants more strongly preferred administration every 8 weeks compared with 4-week (injection) or daily (oral) dosing intervals. More recent reporting at 152 weeks9 has demonstrated durable viral suppression with administration at both 4-week and 8-week intervals. The most common drug-related adverse event in these studies has been injection-site reaction, followed by pyrexia and fatigue.
In 2021 the FDA approved the LA cabotegravir plus rilpivirine regimen for administration every 4 weeks; in early 2022, the FDA expanded its approval to administration every 8 weeks.10 The European Medicines Agency (EMA) has also approved this regimen at both the 4-week and 8-week intervals.11
Who Is Eligible for Long-Acting Therapy?
Currently, LA cabotegravir plus rilpivirine is recommended for patients with HIV-1 twelve years of age or older weighing at least 35 kg and without a history of treatment failures/viral resistance to either cabotegravir or rilpivirine.10 Notably, a pooled analysis of data from the ATLAS and FLAIR trials12 showed that mutations conferring drug resistance were widespread among the small proportion of patients receiving LA cabotegravir plus rilpivirine with confirmed virologic failure. Candidates for this treatment regimen also should be willing and able to commit to injection visits every 4 or 8 weeks.
The LA cabotegravir plus rilpivirine regimen is contraindicated in patients with a history of hypersensitivity reaction to either agent, and in patients who concurrently receive carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone, or St John’s wort. There is a risk of torsade de pointes when given in combination with some antibiotics.10
Patients with hepatitis B virus (HBV) were excluded from both the FLAIR and ATLAS trials. Cabotegravir and rilpivirine have not demonstrated efficacy against HBV13; this limits the clinical utility of these drugs in patients who are coinfected with HIV-1 and HBV. Given the exclusion criteria of the ATLAS and FLAIR trials, there is also limited information regarding whether the LA cabotegravir plus rilpivirine regimen is suitable for patients who are pregnant, those with serious hepatic or renal pathology, patients with poorly-controlled HIV infection, and young children. These trials excluded patients with viral mutations associated with resistance to INSTIs or NNRTIs, except for the HIV-1 RT K103N mutation in isolation; clinicians have been advised to test patient who are candidates for this regimen for resistance-associated mutations, given that these mutations appear to be associated with virologic failure of this regimen.14
Finally, it is important for patients to understand that treatment adherence remains essential to maintaining HIV-1 suppression, even though they will not self-administer their medications daily. Patients who find it challenging to attend 4-week (or 8-week) visits for maintenance injections, and clinics facing challenges (eg, with staffing, other resources) offering routine visits, must bear in mind the risk of viral rebound and evolution of drug resistance if patient adherence is incomplete. Clinics offering LA cabotegravir plus rilpivirine must maintain cold-chain storage for these medications and should designate staff resources, time, and clinic space for injection visits and dose preparation.
Although improved adherence is commonly considered a key motivator behind implementing a long-acting regimen such as cabotegravir plus rilpivirine, there is a lack of real-world data regarding whether this LA regimen indeed lowers barriers to adherence. These data will likely emerge from future long-term, prospective studies.
LA Cabotegravir Plus Rilpivirine Combination Injection: Administration and Dosage
During the optional oral lead-in period, which allows the clinician to assess drug tolerability, the recommended daily dosage is 30 mg cabotegravir plus 25 mg rilpivirine, administered for at least 28 days5 or until the first injection dose is given (Table). The loading dose for the complete LA injection regimen, if administered every 4 weeks, consists of 3 mL injections each of cabotegravir (600 mg) and rilpivirine (900 mg), generally in opposite gluteal muscles. Maintenance administration begins 1 month after these initiation injections; the monthly dose is 2 mL injections each of cabotegravir (400 mg) and rilpivirine (600 mg).
If this therapy is administered every 8 weeks, the loading dose includes 3-mL injections each of cabotegravir (600 mg) and rilpivirine (900 mg) after the oral lead-in period and 1 month after. Maintenance administration begins 2 months after the second loading dose at the same dose (Table).5
Results of the aforementioned phase 3 trials indicated that receipt of injection approximately 7 days from the monthly (or bimonthly) scheduled date was acceptable. If the patient misses, or plans to miss, a scheduled LA injection, bridging with oral medication is recommended to maintain virological drug activity. This relies on the availability of the cabotegravir and rilpivirine oral formulations, such as those used during the lead-in to the LA injection study regimens. Ideally clinics and patients should plan to secure those equivalents in advance,15 because their availability through community pharmacies cannot be assured. Cabotegravir, in particular, is not available at pharmacies.16
Additional Existing and Emerging Options for Use of LA HIV Treatment Regimens
Ibalizumab is a humanized immunoglobulin G4 (IgG4) antibody approved for treatment of multidrug-resistant HIV infections. It is not a complete regimen, but is used in combination with the patient’s existing or optimized background ART regimen.17 The loading dose is 2000 mg administered intravenously followed by maintenance intravenous infusions of 800 mg, saline-diluted, every 2 weeks. It has the disadvantage of more frequent administration than other LA drugs and requires patients to adhere to their previous ART regimens. Nevertheless, the advent of this drug may represent a step toward less-than-daily dosing for patients with multidrug-resistant HIV-1.
Numerous other ART drugs and novel formulations of existing ART are in development. Advances in LA ART will likely address and overcome the disadvantages and limitations of currently available LA regimens.15 For example, subcutaneous implant formulations, currently in preclinical and early phase studies, may permit longer release time with improved cellular uptake. Other future LA ART may be self-administered at home by subcutaneous injection. Reduced volume of injectable doses may limit the frequent injection site reactions secondary to relatively large (2 mL and 3 mL) intramuscular injections. Such advances should help to address challenging medication adherence problems and possibly reduce the need for oral lead-in therapy.
1. Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844-845. doi:10.1001/jama.2019.1343
2. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention and care objectives by using HIV surveillance data—United States and 6 dependent areas, 2019. HIV Surveillance Supplemental Report 2021;26(No. 2). Published May 2021. Accessed September 24, 2022. https://www.cdc.gov/hiv/library/reports/hiv-surveillance/vol-26-no-2/index.html
3. Nachega JB, Marconi VC, van Zyl GU, et al. HIV treatment adherence, drug resistance, virologic failure: evolving concepts. Infect Disord Drug Targets. 2011;11(2):167-174. doi:10.2174/187152611795589663
4. Akinwunmi B, Buchenberger D, Scherzer J, et al. Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries. Sex Transm Infect. 2021;97(8):566. doi:10.1136/sextrans-2020-054648
5. Cabenuva. Prescribing information. ViiV Healthcare; 2022. Accessed September 24, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Cabenuva/pdf/CABENUVA-PI-PIL-IFU2-IFU3.PDF
6. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEJMoa1909512
7. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. doi:10.1056/NEJMoa1904398
8. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV. 2021;8(11):E679-E689. doi:10.1016/S2352-3018(21)00185-5
9. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir + rilpivirine every 2 months: ATLAS-2M week 152 results. Poster presented at: Conference on Retroviruses and Opportunistic Infections 2022; February 12-16, 2022; Seattle, Washington; Poster 479.
10. ViiV Healthcare announces US FDA approval of Cabenuva (cabotegravir, rilpivirine) for use every two months, expanding the label of the first and only complete long-acting HIV treatment. ViiV Healthcare. Published February 1, 2022. Accessed September 24, 2022. https://viivhealthcare.com/hiv-news-and-media/news/press-releases/2022/january/viiv-healthcare-announces-fda-approval-of-cabenuva-for-use-every-two-months/
11. First long-acting injectable antiretroviral therapy for HIV recommended approval. European Medicines Agency. Published October 16, 2020. Accessed September 24, 2022. https://www.ema.europa.eu/en/news/first-long-acting-injectable-antiretroviral-therapy-hiv-recommended-approval
12. Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498-506. doi:10.1097/QAI.0000000000002466
13. Bollinger RC, Thio CL, Sulkowski MS, McKenzie-White J, Thomas DL, Flexner C. Addressing the global burden of hepatitis B virus while developing long-acting injectables for the prevention and treatment of HIV. Lancet HIV. 2020;7(6):E443-E448. doi:10.1016/S2352-3018(19)30342-X
14. McGowan JP, Fine SM, Vail RM, et al; on behalf of Medical Care Criteria Committee of the New York State Department of Health AIDS Institute (NYSDOH AI). Use of injectable CAB/RPV LA as replacement ART in virally suppressed adults. Johns Hopkins University; 2022. Accessed September 24, 2022.
15. Scarsi KK, Swindells S. The promise of improved adherence with long-acting antiretroviral therapy: what are the data? J Int Assoc Provid AIDS Care. Published online April 27, 2021. doi:10.1177/23259582211009011
16. Preparing for long-acting antiretroviral treatment. American Academy of HIV Medicine. February 25, 2021. Accessed September 24, 2022. https://aahivm.org/wp-content/uploads/2021/03/Long-Acting-ARVs-_Final-2-25-21_PDF.pdf
17. Emu B, Fessel WJ, Schrader S, et al. Forty-eight-week safety and efficacy on-treatment analysis of ibalizumab in patients with multi-drug resistant HIV-1. Open Forum Infect Dis. 2017;4(suppl 1):S38-S39. doi:10.1093/ofid/ofx162.093
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Reviewed October 2022