OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Etravirine	269055-15-4	C20-H15-Br-N6-O

ANNOTATED BIBLIOGRAPHY

References updated: 20 February 2018

• Núñez M. Hepatotoxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 505-518.

  (Review of hepatotoxicity of antiviral agents; etravirine is listed as having been linked to cases of hepatic failure and associated with ALT elevations in ~3% of patients).
• Flexner C. Antiretroviral agents and treatment of HIV infection. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1623-1664.

  (Textbook of pharmacology and therapeutics).
• http://aidsinfo.nih.gov/drugs/398/etravirine/0/patient.

  (Summary of clinical information on etravirine for the public).
• 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 above 5 times ULN were reported in 1-8% of efavirenz compared to 4-16% of nevirapine recipients; no mention of etravirine).
• Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, Towner W, et al.; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 39-48. [PubMed: 17617271]

  (Trial of etravirine vs placebo combined with an optimized antiretroviral regimen for 24 weeks in 591 treatment experienced patients with HIV infection; little difference found in frequency of adverse reactions except for rash [14% vs 9%]; ALT elevations above 5 times ULN occurred in 2% on etravirine and 1% on placebo; no mention of clinically apparent liver injury, hepatitis or death from liver disease).
• Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, Pialoux G, et al.; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007; 370: 29-38. [PubMed: 17617270]

  (Trial of etravirine vs placebo combined with a stable antiretroviral regimen for 24 weeks in 612 patients with HIV infection; adverse events were comparable except for rash in 20% on etravirine vs 10% in controls; ALT increase above 5 times ULN in 3% of etravirine vs 2% of controls; no mention of clinically apparent liver injury, hepatitis or death from liver disease in list of adverse events).
• Soriano V, Puoti M, Garcia-Gascó P, 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 above 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).
• No hepatotoxicity found for etravirine. AIDS Patient Care STDS 2008; 22 (12): 1022. [PubMed: 19097262]

  (New report of results of controlled trials of etravirine vs placebo for 48 weeks in 1203 patients with HIV infection; there were no differences in rates of serum enzyme elevations between etravirine vs placebo therapy and most were attributable to underlying chronic HBV or HCV coinfection).
• Hughes CA, Robinson L, Tseng A, MacArthur RD. New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir. Expert Opin Pharmacother 2009; 10: 2445-66. [PubMed: 19678794]

  (Review of the efficacy and safety of tipranavir, darunavir, etravirine, rilpivirine, maraviroc and raltegravir; the incidence and severity of adverse events were similar between etravirine and placebo groups except for rash [19% vs 11%], generally arising in the first few weeks and resolving even with continuing therapy, requiring discontinuation in 2%; no mention of hepatotoxicity).
• Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, Cahn P, et al.; International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008; 300: 555-70. [PubMed: 18677028]

  (Updated recommendations on use of antiviral therapy in adults with HIV infection, including use of recently approved agents raltegravir, maraviroc and etravirine).
• Etravirine (Intelence) for HIV infection. Med Lett Drugs Ther 2008; 50 (1288): 47-8. [PubMed: 18551091]

  (Concise review of the clinical efficacy and safety of etravirine published shortly after its approval in the US; mentions that rash is common and can be severe and serum aminotransferase elevations can occur).
• Portilla J. [Safety and tolerability of etravirine]. Enferm Infecc Microbiol Clin 2009; 27 Suppl 2: 21-6. Spanish. [PubMed: 20116624]

  (Review of tolerability of etravirine; skin rash occurs in 19% of patients, but severe skin rash in <1%; in clinical trials, ALT elevations were reported in 5% of etravirine treated patients, but similar rates were found with comparator regimens and acute liver failure was not reported).
• Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, Schechter M, et al.; DUET-1, DUET-2 study groups. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS 2009; 23: 2289-300. [PubMed: 19710593]

  (Abstract only: Combined results of registration trials of etravirine for HIV treatment-experienced patients; rash occurred in 19% of etravirine treated vs 11% of controls).
• Drugs for HIV infection. Treat Guidel Med Lett 2011; 9 (106): 29-40. [PubMed: 21617596]

  (Concise summary of status of therapies for HIV infection states that etravirine is effective in combination with other agents in achieving virologic control in treatment-experienced patients with documented resistance to other agents; mentions that it can cause rash and increases in serum aminotransferase levels).
• Vispo E, Fernández-Montero JV, Labarga P, Barreiro P, Soriano V. Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients. AIDS 2013; 27: 1187-8. [PubMed: 23739226]

  (Among 1982 patients starting antiretroviral therapy between 2010-2011, liver enzyme elevations occurred in 9% overall [17% vs 6% in those with or without HCV coinfection], but were above 5 times ULN in only 0.4%; no patient developed jaundice and only 6 required change in agents; the lowest rates were with etravirine).
• Casado JL. Liver toxicity in HIV-infected patients receiving novel second-generation nonnucleoside reverse transcriptase inhibitors etravirine and rilpivirine. AIDS Rev 2013; 15: 139-45. [PubMed: 24002197]

  (Review of hepatotoxicity of etravirine and rilpivirine from controlled trials and expanded access studies during which 1.7% of 2578 patients on etravirine had ALT elevations above 5 times ULN [3.7% in those with HBV or HCV coinfection]; no mention of clinically apparent liver injury with jaundice).
• Surgers L, Lacombe K. Hepatoxicity of new antiretrovirals: a systematic review. Clin Res Hepatol Gastroenterol 2013; 37: 126-33. [PubMed: 23522569]

  (Review of literature on the hepatotoxicity of newer antiretroviral agents used to treat HIV infection mentions that etravirine therapy is accompanied by a low rate of transient serum enzyme elevations and has not been linked to cases of severe hepatotoxicity).
• Casado JL, Bañón S, Rodriguez MA, Moreno A, Moreno S. Efficacy and pharmacokinetics of the combination of etravirine plus raltegravir as novel dual antiretroviral maintenance regimen in HIV-infected patients. Antiviral Res 2015; 113: 103-6. [PubMed: 25460844]

  (Among 25 patients with HIV infection and previous exposure to multiple antiretroviral agents who were treated with raltegravir and etravirine for an average of 2 years, there were no virologic breakthroughs and no ALT elevations requiring dose modification or interruption).
• 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. [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 [1.3%] cases were attributed to antiretroviral agents, but none to etravirine).
• Casado JL, Mena A, Bañón S, Castro A, Quereda C, Moreno A, Pedreira J, Moreno S. Liver toxicity and risk of discontinuation in HIV/hepatitis C virus-coinfected patients receiving an etravirine-containing antiretroviral regimen: influence of liver fibrosis. HIV Med 2016; 17: 62-7. [PubMed: 26122981]

  (Among 211 patients with HIV infection treated with an etravirine containing antiretroviral regimen and followed for a median of 1.8 years, only one had an ALT elevation above 5 times ULN [who had HCV coinfection] and there was no association between preexisting hepatic fibrosis [assessed by elastography] and any degree of ALT elevation during therapy).
• Fabbri G, Mastrorosa I, Vergori A, Mazzotta V, Pinnetti C, Grisetti S, Zaccarelli M, et al. Reactivation of occult HBV infection in an HIV/HCV Co-infected patient successfully treated with sofosbuvir/ledipasvir: a case report and review of the literature. BMC Infect Dis 2017; 17: 182. [PMC free article: PMC5333431] [PubMed: 28249574]

  (54 year old woman with HIV and HCV coinfection as well as anti-HBc and anti-HBs [without HBsAg] was treated for HIV with darunavir/r and etravirine [without nucleoside analogues] and with sofosbuvir and ledipasvir for HCV, and shortly thereafter developed acute HBV reactivation [bilirubin 7.1 mg/dL, ALT 435 U/L, HBV DNA 1 million IU/L, HBsAg and HBeAg positive], resolving with addition of entecavir but remaining HBsAg positive).
• http://www​.aidsinfo.nih.gov/guidelines .

  (Current and regularly updated guidelines on therapy of HIV infection in adults, adolescents and children).