Thompson1, K. Collins2, S. Lambert-Johnson3
1Department of Community Health & Psychiatry, The University of the West Indies, Mona, Kingston 7, Jamaica, W.I.
2Department of Medicine, The University Hospital of the West Indies, Kingston 7, Jamaica, W.I.
3Independent Researcher, Tucson, Arizona, USA 85747
Dr. Chadane Thompson
Department of Community Health & Psychiatry
The University of the West Indies, Mona
Email: [email protected]
Copyright: This is an open-access article under the terms of the Creative Commons Attribution License which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.
©2022 The Authors. Caribbean Medical Journal published by Trinidad & Tobago Medical Association.
Since its discovery in the 1980’s, the human immunodeficiency virus (HIV) has evolved into a global epidemic.1 Worldwide, an estimated 37.7 million people were infected with HIV as of the end of 2020.2 Notably, of the people living with HIV (PLWHIV) in 2020, only 73% were on antiretroviral therapy (ART), and only 66% of those accessing treatment had viral suppression.2 The rates were recorded at 82% and 89% in the Caribbean region, respectively.2 Though this marks steady progress for the global community, we were still below the 90% target of the Joint United Nations Programme on HIV/AIDS (UNAIDS) for HIV treatment and viral suppression in 2020. Importantly, the advent of ART has made this once universally fatal condition now treatable. Therefore, ART is recommended for all PLWHIV. Strict ART adherence limits viral transmission, prevents resistance, reduces morbidity, improves quality of life, and prevents progression to acquired immunodeficiency syndrome (AIDS).3 However, to maintain therapeutic plasma level concentrations of antiretrovirals and achieve these ideal targets, 95% medication adherence is needed—this is difficult for most individuals to sustain.3-4
Drug adherence describes the degree to which a patient follows the prescriber’s exact recommendations for a particular medication. Successful adherence to ART is multifactorial and depends on considerations such as the patients’ sociodemographics, psychological state, stage and duration of illness, and complexity of treatment regimens. In PLWHIV, drug adherence greatly influences the rate of progression to AIDS and subsequent demise. Conveniently, ART is mainly given today as a daily oral prescription. However, compliance to this treatment regimen is still hindered by lifetime pill burden, daily dosing frequency, and the timing of medication administration. Cabenuva has been a recent innovation formulated as a long-acting (LA) injectable antiretroviral combination drug. This 2-drug regimen, comprising cabotegravir (CAB) and rilpivirine (RPV), was approved for use by the US Food and Drug Administration (FDA) in 2021 for virally suppressed PLWHIV-1 who (i) are on a stable regimen, (ii) have no past treatment failure with CAB or RPV and (iii) have no resistance to CAB or RPV.5 Cabenuva can revolutionize the lives of PLWHIV-1 by improving ART adherence and optimizing personal and public health outcomes.
HIV is a retrovirus with two known infecting strains, HIV-1 and HIV-2. After transfer, commonly through unprotected sexual contact, vertical transmission, or sharing contaminated drug paraphernalia, HIV replicates and destroys CD4+ T cells and leads to a cellular immune deficiency. Consequently, there is an increased susceptibility to opportunistic infections and predisposition to malignancies. Nevertheless, significant strides have been made in HIV treatment since the first antiretroviral drug, Zidovudine, was approved by the US FDA in 1987. Today, there are seven classes of antiretroviral drugs that target HIV using varying mechanisms of action. These drugs are mainly in oral preparation. Antiretroviral therapy (ART) has the endpoint of either preventing fusion of HIV with CD4+ T cells or blocking enzymes needed for HIV replication which ultimately yields viral suppression, ideally to undetectable levels.
The most crucial goal for PLWHIV is to achieve sustained viral suppression, which requires a commitment to daily oral multi-drug treatment for life. However, there are many concerns surrounding these oral ART treatment regimens. Some drawbacks of daily oral ART include high lifetime pill burden, daily dosing frequency, recalling correct timing of doses, the health impact of drug resistance with poor compliance, drug-drug interaction, and fears or social stigma attached to being seen with antiretroviral drugs.5 In approaching the inadequacies surrounding adherence to oral therapies, alternate but efficacious antiretrovirals can minimize or eliminate these major treatment hurdles for PLWHIV. In an effort to resolve this issue of adherence to oral ART, LA injectables such as Cabenuva were developed.
Cabenuva consists of two (2) drugs, cabotegravir (CAB) plus rilpivirine (RPV). CAB is an HIV integrase strand transfer inhibitor that disrupts a critical step in the viral replication cycle by binding to the integrase active site.6 This subsequently interferes with the strand transfer step of retroviral integration into deoxyribonucleic acid.6 On the other hand, RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 that blocks its replication via non-competitive inhibition of HIV-1 reverse transcriptase.6 In 2020, two randomized, international, multicenter, parallel-group, open-label clinical trials were published: FLAIR (First Long-Acting Injectable Regimen) and ATLAS (Antiretroviral Therapy as Long-Acting Suppression). In these phase III clinical trials, the first once monthly LA injectable CAB plus RPV were evaluated as alternatives to oral antiretroviral medications in PLWHIV-1.
The FLAIR trial consisted of randomized participants who were HIV-1 positive and ART-naive and it comprised four phases. After the initial screening phase, the participants underwent a 20-week induction phase with a course of oral dolutegravir and two oral nucleoside reverse transcriptase inhibitors. Thereafter, participants with HIV RNA < 50 copies/ml proceeded to the maintenance phase, which first consisted of 4 weeks of oral lead-in CAB and oral RPV to establish drug safety. Finally, participants were maintained on once-monthly intramuscular injections with CAB plus RPV alone. At trial week 48, the percentage of participants who were not virally suppressed was assessed as the primary endpoint. On the other hand, the ATLAS trial included ART-experienced participants with at least six months of viral suppression. After the initial screening phase, randomized participants directly entered the maintenance phase with LA injectable CAB plus RPV after completing the same 4-week oral lead-in as in FLAIR. At trial week 48, ATLAS assessed the same primary end point as FLAIR did. The main adverse reactions included mild-to-moderate injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.5 Of note, drug interactions that may decrease CAB and/or RPV plasma concentration include anticonvulsants, antimycobacterials, systemic glucocorticoids, and herbal products like St. John’s wort.5
These trials demonstrated that the combination of LA injectable CAB plus RPV was non-inferior to daily oral ART in maintaining HIV-1 viral suppression in individuals on a stable regimen and no past treatment failure with or resistance to these drugs.7-9 Additionally, LA CAB plus RPV were found to be acceptable for eight weekly dosing regimens as outlined by an extension of ATLAS, termed the ATLAS-2M (Antiretroviral Therapy as Long-Acting Suppression every 2 Months) trial. In the ATLAS-2M trial, the eight weekly LA CAB plus RPV were a safe and preferred therapeutic option over the previous oral therapy by participants, demonstrating high treatment satisfaction and acceptance.10 In addition, high rates of viral suppression and low failure rates were also reported. Compared with daily lifetime oral ART, LA injectables can therefore make treatment more acceptable, tolerable, and convenient for PLWHIV-1.10
Following a single 4-week oral lead in, the monthly or two-monthly administration of LA injectable CAB plus RPV eliminates pills and complex daily dosing schedules that can hinder adherence. This long-acting regimen affords PLWHIV-1 more freedom from a “daily reminder” of their HIV status, and a greater degree of privacy by not having to take antiretroviral medications at home or work.10 An additional benefit to this includes the potential for more frequent physician-patient contact on a monthly or two-monthly basis, which is often not the case when prescribing oral therapies. Moreover, in this way, additional concerns that may affect antiretroviral adherence can be readily addressed at each visit. Finally, LA injectable CAB plus RPV form a dominant and cost-effective option for PLWHIV-1.11
The implementation of long-acting formulations has proven effective in other conditions such as contraception and mental health.12-13 Similarly, long-acting antiretroviral therapy could provide positive effects and additional treatment choices to PLWHIV. This treatment option can fill the gaps for other HIV therapy options and address behavioral barriers to medication adherence. This high level of medication adherence is crucial to achieving virologic suppression to increase the scope of patients who can achieve ‘undetectable equals untransmittable’ (U=U) status.13 Despite the considerable potential of long-acting antiretroviral drugs, some potential challenges exist, including accessibility, affordability, and long-lasting drug concentrations that could lead to the development of drug resistance.13 Further research into the advances of long-acting injectable HIV therapy can aid in overcoming these challenges and implementing strategies that can have a positive impact on HIV treatment and health care burden.
In conclusion, HIV is a significant global public health concern. Use of LA injectable drugs CAB plus RPV (Cabenuva) is an economical, viable and sustainable therapeutic addition to the treatment armamentarium that can significantly improve adherence to ART for PLWHIV-1. This further contributes to an overall improvement in quality of life. As the UNAIDS has proposed 95% treatment goals for 2030, providing access to LA injectable ART in HIV treatment programmes will be instrumental. This breakthrough regarding LA injectable CAB plus RPV is only a preview of the revolutionary innovations that are still to come for HIV treatment.
Ethical Approval statement: Not applicable
Conflict of Interest statement: None to declare
Informed Consent statement: Not applicable
Funding statement: None
Author Contributions: All authors, Dr. Chadane Thompson, Dr. Kristina Collins and Dr. Shana-Kay Lambert-Johnson equally participated in all stages that led to the successful completion of this article. All authors wholly contributed to the conceptualization of the study, formulation and completion of the methodology, writing, revision, and approval of the final version of the manuscript submitted.
- National Institutes of Health: Office of NIH History and Stetten Museum. Discovery of HIV. https://history.nih.gov/display/history/Discovery+of+HIV (Accessed 12/11/21)
- Joint United Nations Programme on HIV/AIDS. Global AIDS Updates 2021, 2021. https://reliefweb.int/sites/reliefweb.int/files/resources/2021-global-aids-update_en.pdf (Accessed 31/8/21)
- Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral Treatment of Adult HIV Infection: 2012 Recommendations of the International Antiviral Society-USA panel. JAMA 2012 Jul 25; 308(4):387-402. doi: 10.1001/jama.2012.7961
- Iacod SA, Iacob DG, Jugulete G. Improving the Adherence to Antiretroviral Therapy, a Difficult but Essential Task for a Successful HIV Treatment—Clinical Points of View and Practical Considerations. Frontiers in Pharmacology 2017 November 23; 8:831. doi: 10.3389/fphar.2017.00831
- US Food and Drug Administration. FDA Approves Cabenuva and Vocabria for the Treatment of HIV-1 Infection, 2021. https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/fda-approves-cabenuva-and-vocabria-treatment-hiv-1-infection (Accessed 31/8/21)
- HIV.gov. Cabotegravir/Rilpivirine, 2021. https://clinicalinfo.hiv.gov/en/drugs/cabotegravir-rilpivirine/kit (Accessed 31/8/21).
- Swindells S, Andrade-Villanueva J, Richmond G et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. New England Journal of Medicine 2020; 382:1112-1123 doi: 10.1056/NEJMoa1904398
- Orkin C, Arasteh K, Hernández-Mora MG et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. New England Journal of Medicine 2020; 382:1124-1135. doi: 10.1056/NEJMoa1909512
- Rizzardini G, Overton E, Orkin C et al. Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials. Journal of Acquired Immune Deficiency Syndromes 2020; 85(4):498-506. doi 10.1097/QAI.0000000000002466
- Chounta V, Overton E, Mills A et al. Patient‐Reported Outcomes Through 1 Year of an HIV‐1 Clinical Trial Evaluating Long‐Acting Cabotegravir and Rilpivirine Administered Every 4 or 8 Weeks (ATLAS‐2M). Patient 2021; doi: 10.1007/s40271-021-00524-0
- Parker B, Ward T, Hayward O, et al. Cost-effectiveness of the Long-acting Regimen Cabotegravir plus Rilpivirine for the Treatment of HIV-1 and its Potential Impact on Adherence and Viral Transmission: A Modelling Study. PLoS ONE 2021 February 2; 16(2): e0245955. doi: 10.1371/journal.pone.0245955
- Cobb DA, Smith NA, Edagwa BJ, et al. Long-acting Approaches for Delivery of Antiretroviral Drugs for Prevention and Treatment of HIV: A Review of Recent Research. Expert Opinion on Drug Delivery 2020 July 6; 17(9):1227-1238. doi: 10.1080/17425247.2020.1783233
- Scarsi KK & Swindells S. The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data? Journal of the International Association of Providers of AIDS Care 2021 April 27; 20:23259582211009011. doi: 10.1177/23259582211009011