OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Cabotegravir – Cabenuva®, Apretude®, Vocabria®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Cabotegravir	1051375-10-0	C19-H17-F2-N3-O5
Rilpivirine	500287-72-9	C22-H18-N6

ANNOTATED BIBLIOGRAPHY

References updated: 17 June 2023

Abbreviations: HIV, human immunodeficiency virus; im, intramuscular.

• Núñez M. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 505-18.

  (Review of hepatotoxicity of antiviral agents including raltegravir but not cabotegravir).
• Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Hillal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1137-57.

  (Textbook of pharmacology and therapeutics).
• https://hivinfo​.nih.gov​/hiv-source/medical-practice-guidelines​/hiv-treatment-guidelines .

  (Clinical guidelines on the use of antiretroviral agents in HIV-1 infected adults, adolescents and children).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2021/212887Orig1s000,212888Orig1s000IntegratedR​.pdf.

  (FDA website with product labels and the integrated review of the data submitted in support of its approval, mentions that liver injury suspected to be drug induced arose in early phase 2 trials of cabotegravir but there were no cases in the large-scale, phase 3 registration trials; however, there were multiple cases of acute hepatitis A, B and C that were not identified in control groups, some of which may have related to withdrawal of antiretroviral agents with activity against HBV since cabotegravir and rilpivirine have no activity against hepatitis B, furthermore patients with HIV infection should be given both hepatitis A and B vaccines as these are preventable diseases).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 12 were due to antiretroviral agents, but none were attributed to cabotegravir or other HIV integrase inhibitors).
• Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, Eron JJ, Yazdanpanah Y, Podzamczer D, Lutz T, et al. 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. Lancet. 2017;390(10101):1499–1510. [PubMed: 28750935]

  (Among 309 treatment naïve adults with HIV infection who were treated with oral cabotegravir [30 mg once daily], lamivudine and abacavir for 20 weeks, 286 had a virologic response [HIV RNA <50 copies/mL] and were randomized to continue oral therapy or switch to long acting intramuscular [im] cabotegravir and rilpivirine every 4 weeks [400 mg and 600 mg] or every 8 weeks [600 mg or 900 mg] and followed for up to 96 weeks, during which the 3 treatment arms had similar rates of virologic response maintenance and similar rates of adverse events except for injection site reactions with the im regimens; ALT elevations above 5 times ULN arose in 3% on im regimens and 5% on oral regimens mostly due to hepatitis C infection, but two patients on the oral regimen were judged to have probable drug induced liver injury which resolved with stopping therapy [no details provided]).
• Kolakowska A, Maresca AF, Collins IJ, Cailhol J. Update on adverse effects of HIV integrase inhibitors. Curr Treat Options Infect Dis. 2019;11:372–387. [PMC free article: PMC7758219] [PubMed: 33380904]

  (Review of the adverse events with HIV integrase inhibitors including dolute-, ralte-, bicte- and elvite-gravir mentions that there is little evidence that this class of antiretrovirals causes elevations in serum aminotransferase or alkaline phosphatase levels, but that data on the safety and efficacy of cabotegravir are promising but still incomplete).
• Swindells S, Andrade-Villanueva JF, Richmond GJ, Rizzardini G, Baumgarten A, Masiá M, Latiff G, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382:1112–1123. [PubMed: 32130809]

  (Among 616 adults with HIV infection and maintained suppression of HIV RNA [less than 50 copies/mL] on oral antiretroviral therapy, who were either continued on oral therapy or switched to monthly injections of long acting cabotegravir and rilpivirine, effective suppression was maintained in 95.5% on oral therapy vs 92.5% or long acting parenteral therapy, while adverse event rates were similar except for injection site reactions [none vs 81%], while acute viral hepatitis [A, B and C] was identified as an adverse event in 1 case on oral and 4 on parenteral therapy [0.3% vs 1.3%]).
• Orkin C, Arasteh K, Górgolas Hernández-Mora M, Pokrovsky V, Overton ET, Girard PM, Oka S, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382:1124–1135. [PubMed: 32130806]

  (Among 566 adults with previously untreated HIV infection with a virologic response [HIV RNA less than 50 copies/mL] to a 20-week induction regimen of dolutegravir, abacavir, and lamivudine who were then continued on oral therapy or switched to once-monthly injections with long acting cabotegravir and rilpivirine, maintenance of a virologic response was similar in the two groups [93.3% vs 93.6%] while adverse event rates were similar except for injection site reactions [none vs 80%] and acute hepatitis A, B, or C [1 vs 7 cases: 0.3% vs 2.5%]).
• Currier JS. Monthly injectable antiretroviral therapy – version 1.0 of a new treatment approach. N Engl J Med. 2020;382:1164–1165. [PubMed: 32130808]

  (Editorial accompanying publications of Swindells and Orkin [2020] discussing the promise of a once monthly or bimonthly therapy for HIV infection).
• Cabotegravir/rilpivirine (Cabenuva) for HIV-1 infection. Med Lett Drugs Ther. 2021;63(1625):81–83. [PubMed: 34180282]

  (Concise review of the mechanism of action, clinical efficacy, safety, and costs of the fixed combination of cabotegravir and rilpivirine given orally for one month and then as monthly injections for long term management of HIV infection).
• Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, Cabello R, et al. HPTN 083 Study Team. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385:595–608. [PMC free article: PMC8448593] [PubMed: 34379922]

  (Among 4566 adults at high risk of acquiring HIV infection given prophylaxis with oral tenofovir and emtricitabine daily or intramuscular cabotegravir [600 mg a baseline, week 4 and 9 and then every 8 weeks], incident HIV arose in 39 on oral prophylaxis [1.22 per 100-person years] vs 13 on cabotegravir infections [0.41 per 100-person years], while both total and serious adverse event rates were similar in the two groups with ALT elevations in 8.4% vs 7.0% which were above 3 times ULN in 1.0% vs 1.2%).
• Delany-Moretlwe S, Hughes JP, Bock P, Ouma SG, Hunidzarira P, Kalonji D, Kayange N, et al. HPTN 084 study group. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. Lancet. 2022;399(10337):1779–1789. [PMC free article: PMC9077443] [PubMed: 35378077]

  (Among 3224 sexually active, Subsaharan African women, ages 18 to 45, treated with oral tenofovir and emtricitabine daily or intramuscular cabotegravir [600 mg at baseline, week 4 and every 8 weeks thereafter], incident HIV arose in 36 on oral prophylaxis vs 4 on injected cabotegravir [1.85 vs 0.2 per 100 person-years], while adverse events, except for injection site reactions, were similar in the two groups; 2 subjects on oral prophylaxis but none on cabotegravir developed serious hepatic adverse events).
• Cabotegravir (Apretude) for HIV-1 pre-exposure prophylaxis. Med Lett Drugs Ther. 2022;64(1644):29–31. [PubMed: 35171897]

  (Concise review of the mechanism of action, efficacy, side effects, and costs of long acting, parenterally administered cabotegravir shortly after its approval an preventive therapy of HIV infection, mentions that hypersensitivity reactions, hepatotoxicity, and depressive disorders have been reported with cabotegravir therapy).
• Sutton KC, De Vente J, Leblanc R, Dejesus E, Smith G, Mills A, Baril JG, et al. Long-term efficacy, safety, and durability of cabotegravir and rilpivirine as 2-drug oral maintenance therapy after 6 years of study. Open Forum Infect Dis. 2022;9:ofac067. [PMC free article: PMC8946678] [PubMed: 35350172]

  (Among 160 patients enrolled in a long-term extension study of long acting cabotegravir and rilpivirine injections, adverse events included injection site reactions, headaches, nausea, depression, and vivid dreams and serious adverse events were uncommon, one patient developing “increased liver function test”).
• Nachega JB, Scarsi KK, Gandhi M, Scott RK, Mofenson LM, Archary M, Nachman S, et al. Long-acting antiretrovirals and HIV treatment adherence. Lancet HIV. 2023;10:e332–e342. [PubMed: 37062293]

  (Review of the availability, efficacy, safety, advantages and disadvantages of long-acting antivirals used for therapy and prevention of HIV including cabotegravir and rilpivirine; no mention of ALT elevations or hepatotoxicity).
• Overton ET, Richmond G, Rizzardini G, Thalme A, Girard PM, Wong A, Porteiro N, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with human immunodeficiency virus 1 type 1 infection: 152-week results from ATLAS-2M, a randomized, open-label, phase 3b, noninferiority study. Clin Infect Dis. 2023;76:1646–1654. [PMC free article: PMC10156123] [PubMed: 36660819]

  (Among 1054 adults with HIV infection treated with injections of long acting cabotegravir and rilpivirine for up to three years, maintenance of HIV RNA suppression to less than 50 copies/mL was similar with every 4- vs 8-weekly administration [86% vs 87% at 3 years] with similar adverse event rates, ALT elevations above 3 times ULN arose in 6 subjects, 4 transiently and 2 requiring discontinuation of therapy - one being due to pancreatic cancer and one to chronic hepatitis C and alcohol abuse).