{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T12:39:49Z","timestamp":1791722389285,"version":"4.3.4"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T00:00:00Z","timestamp":1754956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The use of long-acting cabotegravir and rilpivirine (LA CAB\/RPV) is a novel approach to manage human immunodeficiency virus (HIV). This injectable regimen offers benefits such as an improved quality of life, reduced stigma and enhanced treatment satisfaction by minimising the need for daily medication adherence. This review summarises the findings of clinical trials and real-world studies on the safety, tolerability and metabolic effects of LA CAB\/RPV, which are areas that have received less extensive coverage in previous reviews. Clinical trial data suggest that LA CAB\/RPV is generally safe and well tolerated. The most common side effects were injection site reactions, affecting 70\u201397% of participants. However, these were typically mild and short lived, rarely leading to treatment discontinuation in fewer than 2\u20133% of cases. Systemic side effects were minimal and comparable to those observed with traditional oral antiretroviral therapy. Real-world studies corroborated these findings, reporting low discontinuation rates due to adverse events. Regarding metabolic impact, clinical trials showed minimal weight gain (an average increase of 1\u20132 kg over 48\u201396 weeks) with no significant differences or impact on lipid and glucose levels. Although real-world data are still emerging, they suggest similar trends, including a possible improvement in lipid profiles. Overall, LA CAB\/RPV appears to be a safe, well-tolerated and effective treatment option, although longer-term follow-up is needed.<\/jats:p>","DOI":"10.3390\/v17081108","type":"journal-article","created":{"date-parts":[[2025,8,12]],"date-time":"2025-08-12T15:51:02Z","timestamp":1755013862000},"page":"1108","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Safety, Tolerability, and Metabolic Effects of Long-Acting Cabotegravir and Rilpivirine in HIV Care: A Comprehensive Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1162-3513","authenticated-orcid":false,"given":"Martina","family":"Bottanelli","sequence":"first","affiliation":[{"name":"Infectious Diseases Unit, \u201cAlessandro Manzoni\u201d Hospital, ASST-Lecco, 23900 Lecco, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Castagna","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy"},{"name":"Infectious Diseases Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0900-5639","authenticated-orcid":false,"given":"Camilla","family":"Muccini","sequence":"additional","affiliation":[{"name":"Infectious Diseases Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ofae326","DOI":"10.1093\/ofid\/ofae326","article-title":"One Year of Long-Acting Cabotegravir and Rilpivirine in People With Human Immunodeficiency Virus and Long Exposure to Antiretroviral Therapy: Data From the SCohoLART Study","volume":"11","author":"Muccini","year":"2024","journal-title":"Open Forum Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1007\/s40121-024-01062-6","article-title":"Expanding Treatment Opportunities: Reviewing the Current State of Injectable Antiretrovirals for Treatment of HIV","volume":"13","author":"Binkley","year":"2024","journal-title":"Infect. Dis. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1097\/QAD.0000000000002883","article-title":"Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: A multivariable analysis","volume":"35","author":"Cutrell","year":"2021","journal-title":"AIDS"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/cid\/ciae579","article-title":"Real world virologic outcomes in patients with elevated body mass index receiving long acting cabotegravir\/rilpivirine","volume":"81","author":"Maguire","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1056\/NEJMoa1904398","article-title":"Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression","volume":"382","author":"Swindells","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1097\/QAI.0000000000002466","article-title":"Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials","volume":"85","author":"Rizzardini","year":"2020","journal-title":"J. Acquir. Immune. Defic. Syndr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1016\/S0140-6736(20)32666-0","article-title":"Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2 M), 48-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority study","volume":"396","author":"Overton","year":"2021","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/QAD.0000000000003025","article-title":"Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment","volume":"36","author":"Swindells","year":"2022","journal-title":"AIDS"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e679","DOI":"10.1016\/S2352-3018(21)00185-5","article-title":"Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2 M), 96-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority study","volume":"8","author":"Jaeger","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1056\/NEJMoa1909512","article-title":"Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection","volume":"382","author":"Orkin","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e185","DOI":"10.1016\/S2352-3018(20)30340-4","article-title":"Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study","volume":"8","author":"Orkin","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e668","DOI":"10.1016\/S2352-3018(21)00184-3","article-title":"Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: Week 124 results of the open-label phase 3 FLAIR study","volume":"8","author":"Orkin","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e566","DOI":"10.1016\/S2352-3018(23)00136-4","article-title":"Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): A randomised, open-label, phase 3b, non-inferiority trial","volume":"10","author":"Ramgopal","year":"2023","journal-title":"Lancet HIV"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1016\/S0140-6736(17)31917-7","article-title":"Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial","volume":"390","author":"Margolis","year":"2017","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"ofab439","DOI":"10.1093\/ofid\/ofab439","article-title":"Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study","volume":"8","author":"Smith","year":"2021","journal-title":"Open Forum Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1097\/QAD.0000000000003085","article-title":"Long-acting cabotegravir and rilpivirine for HIV-1 suppression: Switch to 2-monthly dosing after 5 years of daily oral therapy","volume":"36","author":"Mills","year":"2022","journal-title":"AIDS"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1093\/cid\/ciae557","article-title":"Long-Acting Cabotegravir Plus Rilpivirine in People with HIV with Adherence Challenges and Viremia: Current Data and Future Directions","volume":"80","author":"Davis","year":"2025","journal-title":"Clin. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1097\/QAI.0000000000003448","article-title":"Safety and Effectiveness From the Cabotegravir and Rilpivirine Implementation Study in European Locations Study: Phase 3b Hybrid Type III Implementation Study Integrating Cabotegravir + Rilpivirine Long-Acting Into European Clinical Settings","volume":"96","author":"Ghosn","year":"2024","journal-title":"J. Acquir. Immune. Defic. Syndr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2807","DOI":"10.1007\/s40121-023-00890-2","article-title":"cabotegravir + rilpivirine long-acting injections for HIV treatment in the US: Real world data from the OPERA cohort","volume":"12","author":"Sension","year":"2023","journal-title":"Infect. Dis. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"ofad500.1443","DOI":"10.1093\/ofid\/ofad500.1443","article-title":"Real-world effectiveness of long-acting cabotegravir + rilpivirine in virologically suppressed treatment-experienced individuals: Two years of data from the OPERA\u00ae cohort","volume":"10","author":"Sension","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"ofad500.1442","DOI":"10.1093\/ofid\/ofad500.1442","article-title":"Clinical Outcomes at Month 6 after Initiation of Cabotegravir and Rilpivirine Long-Acting (CAB + RPV LA) in an Observational Real-World Study (BEYOND)","volume":"10","author":"Sinclair","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"ofaf220","DOI":"10.1093\/ofid\/ofaf220","article-title":"Clinical outcomes and perspectives of people with HIV type 1 twelve months after initiation of long-acting cabotegravir and rilpivirine in an observational real-world US study (BEYOND)","volume":"12","author":"Dandachi","year":"2025","journal-title":"Open Forum Infect. Dis."},{"key":"ref_23","first-page":"100793","article-title":"Swiss HIV Cohort Study: Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: A multicenter prospective observational study in Switzerland","volume":"36","author":"Thoueille","year":"2023","journal-title":"Lancet Reg. Health\u2014Eur."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1111\/hiv.13647","article-title":"Real-world use of long-acting cabotegravir and rilpivirine: 12-month results of the inJectable Antiretroviral therapy feasiBility Study (JABS)","volume":"25","author":"John","year":"2024","journal-title":"HIV Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1007\/s40121-025-01178-3","article-title":"Long-Term Real-World Use of Cabotegravir\/Rilpivirine: Adherence and Virological Efficacy over a 44-Month Observation Period","volume":"14","author":"Dannenberg","year":"2025","journal-title":"Infect Dis. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Konishi, K., Onozuka, D., Okubo, M., Kasamatsu, Y., Kutsuna, S., and Shirano, M. (2024). Long-acting antiretroviral therapy effectiveness and patient satisfaction using patient questionnaires: Data from a real-world setting. BMC Infect. Dis., 24.","DOI":"10.1186\/s12879-024-09904-x"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"ofad500.1427","DOI":"10.1093\/ofid\/ofad500.1427","article-title":"1592. Real-World Utilization and Effectiveness of Long-Acting Cabotegravir + Rilpivirine Among People with HIV with De-tectable Viral Loads at Initiation: Trio Cohort Study","volume":"10","author":"Elion","year":"2023","journal-title":"Open Forum Infect. Dis."},{"key":"ref_28","unstructured":"Borch, J., Scherzer, J., Jonsson-Oldenb\u00fcttel, C., Weinberg, G., Wyen, C., Rodriguez, E., Scholten, S., Dakhia, S., Dymek, K., and Westermayer, B. (2022, January 23\u201326). 6-month outcomes of every 2 months long-acting cabotegravir and rilpivirine in a real-world setting\u2014Effectiveness, adherence to injections, and patient-reported outcomes of people living with HIV in the German CARLOS Cohort. Proceedings of the HIV Drug Therapy Glasgow 2022, Glasgow, UK\/Virtual. Presentation 043."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.1093\/jac\/dkae308","article-title":"Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results","volume":"79","author":"Serris","year":"2024","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1093\/jac\/dkae480","article-title":"Safety and efficacy of long-acting cabotegravir\/rilpivirine versus standard oral antiretroviral therapy: A systematic review and meta-analysis","volume":"80","author":"Manalu","year":"2025","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e46767","DOI":"10.2196\/46767","article-title":"Safety and Efficacy of Long-Acting Injectable Agents for HIV-1: Systematic Review and Meta-Analysis","volume":"9","author":"Wang","year":"2023","journal-title":"JMIR Public Health Surveill."},{"key":"ref_32","unstructured":"European Medicines Agency (2024, February 14). Vocabria (cabotegravir). An Overview of Vocabria and Why It Is Authorised in the EU. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/overview\/vocabria-epar-medicine-overview_en.pdf."},{"key":"ref_33","unstructured":"(2024, February 14). Cabenuva\u2014US Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/212888s000lbl.pdf."},{"key":"ref_34","unstructured":"(2024, February 14). Vocabria EU Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/vocabria-epar-product-information_en.pdf."},{"key":"ref_35","unstructured":"(2024, February 14). Rekambys EU Summary of Product Characteristics. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/rekambys-epar-product-information_en.pdf."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107312","DOI":"10.1016\/j.ijantimicag.2024.107312","article-title":"Improvement in high-density lipoprotein cholesterol in people with HIV who switched from a tenofovir alafenamide-containing regimen to cabotegravir plus rilpivirine","volume":"64","author":"Muccini","year":"2024","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_37","first-page":"990","article-title":"Swiss HIV Cohort Study (SHCS). Weight, Anthropometric and Metabolic Changes After Discontinuing Antiretroviral Therapy Containing Tenofovir Alafenamide in People with HIV","volume":"79","author":"Damas","year":"2024","journal-title":"Clin. Infect Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12981-023-00590-4","article-title":"Brief communications: Changes in inflammatory biomarkers and lipid profiles after switching to long-acting cabotegravir plus rilpivirine","volume":"21","author":"Adachi","year":"2024","journal-title":"AIDS Res. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1097\/QAI.0000000000003584","article-title":"Weight and Metabolic Changes With Long-Acting Cabotegravir and Rilpivirine or Bictegravir\/Emtricitabine\/Tenofovir Alafenamide","volume":"98","author":"Tan","year":"2025","journal-title":"J. Acquir. Immune. Defic. Syndr."},{"key":"ref_40","first-page":"e78384","article-title":"The Real-World Impact of Long-Acting Injectable Cabotegravir-Rilpivirine on Weight and Renal Function","volume":"17","author":"McNaboe","year":"2025","journal-title":"Cureus"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e191","DOI":"10.1016\/S2352-3018(24)00344-8","article-title":"Safety of combined long-acting injectable cabotegravir and long-acting injectable rilpivirine in virologically suppressed adolescents with HIV (IMPAACT 2017\/MOCHA): A phase 1\/2, multicentre, open-label, non-comparative, dose-finding study","volume":"12","author":"Moore","year":"2025","journal-title":"Lancet HIV"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/8\/1108\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:25:29Z","timestamp":1760034329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/8\/1108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,12]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["v17081108"],"URL":"https:\/\/doi.org\/10.3390\/v17081108","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,12]]}}}