OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Doravirine	1338225-97-0	C17-H11-Cl-F3-N5-O3

ANNOTATED BIBLIOGRAPHY

References updated: 12 April 2019

• 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, but does not include a discussion of doravirine).
• Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1137-48.

  (Textbook of pharmacology and therapeutics).
• http://aidsinfo​.nih.gov/guidelines/

  (Regularly updated clinical guidelines on the use of antiretroviral agents in HIV-1 infected adults, adolescents and children).
• https://www​.accessdata​.fda.gov/scripts/cder/daf/

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy).
• Torti C, Lapadula G, Casari S, Puoti M, Nelson M, Quiros-Roldan E, Bella D, et al.; EPOKA-MASTER Study Group. Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort. BMC Infect Dis 2005; 5: 58. [PMC free article: PMC1188059] [PubMed: 16018804]

  (Among 1038 HIV-HCV coinfected patients starting antiretroviral therapy, the risk of ALT elevations above 5 times ULN was 17.1% yearly in treatment-naïve and 8.2% in treatment-experienced patients, risk factors being baseline ALT levels and use of nonnucleoside reverse transcriptase inhibitors).
• Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, Casado R, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis 2007; 196: 670-6. [PubMed: 17674307]

  (Among 133 patients with HIV-HCV coinfection who were treated with interferon or peginterferon, 33% had a sustained response and subsequent yearly rate of hepatic events was higher among nonresponders [12.9%] than responders [3.1%]; also more common with dideoxynucleosides).
• Rivero A, Mira JA, Pineda JA. Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors. J Antimicrob Chemother 2007; 59: 342-6. [PubMed: 17255142]

  (Review of liver toxicity of nevirapine and efavirenz, ALT elevations >5 times ULN reported in 1-8% of efavirenz compared to 4-16% of nevirapine recipients; no mention of delavirdine or rilpivirine).
• Soriano V, Puoti M, Garcia-Gascó Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. Antiretroviral drugs and liver injury. AIDS 2008; 22: 1-13. [PubMed: 18090386]

  (Review of hepatotoxicity of antiretroviral drugs with recommendations on management, stopping therapy if symptoms arise, with overt jaundice [direct bilirubin], evidence of mitochondrial toxicity, ALT >10 times ULN, ALT at lower levels if newly marketed agent; important to rule out other causes; problematic agents include didanosine, stavudine and zidovudine, nevirapine and efavirenz, full dose ritonavir and tipranavir).
• 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 attributed to antiretroviral agent, but none to rilpivirine or doravirine).
• Colombier MA, Molina JM. Doravirine: a review. Curr Opin HIV AIDS 2018; 13: 308-14. [PubMed: 29794817]

  (Review of the structure, mechanism of action, pharmacology, drug-drug interactions, antiviral resistance patterns, clinical efficacy and safety of doravirine; no specific discussion of ALT elevations or hepatotoxicity).
• Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, et al.; DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV 2018; 5: e211-e220. [PubMed: 29592840]

  (Among 769 HIV infected patients treated with doravirine vs darunavir/R combined with 2 antiretroviral nucleoside analogues, rates of HIV RNA suppression were similar [84% vs 80%], and common side effects included diarrhea, nausea and headache, ALT elevations above 5 times ULN occurring in 1% vs 2% and not requiring discontinuation in any doravirine-treated subject).
• Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, Kaplan R, et al.; DRIVE-AHEAD Study Group. Doravirine/lamivudine/tenofovir disoproxil fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results of the DRIVE-AHEAD trial. Clin Infect Dis 2019; 68: 535-44. [PMC free article: PMC6355823] [PubMed: 30184165]

  (Among 728 HIV infected patients treated with doravirine vs efavirenz [both combined with 2 antiretroviral nucleoside analogues], rates of viral suppression were similar [84% vs 81%] while adverse events were less with doravirine including drug-related adverse events [31% vs 63%], serious adverse events [4% vs 6%], rash [5% vs 12%] and ALT elevations above 5 times ULN [0.6% vs 1.4%]).
• Deeks ED. Doravirine: first global approval. Drugs 2018; 78: 1643-50. [PubMed: 30341683]

  (Review of the structure, pharmacology, clinical efficacy, resistance patterns, and safety of doravirine shortly after its approval for use in the US; does not mention ALT elevations or hepatotoxicity).