OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 10 February 2018

• Núñez M. Hepatic toxicity of antiviral agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 567-91.

  (Review of hepatotoxicity of antiviral medications; based upon product labeling, enfuvirtide is shown as having a ~6% incidence of "severe" drug induced liver injury).
• 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/guidelines.

  (Regularly updated guidelines on use of antiretroviral agents in adults, adolescents and children with HIV infection).
• Kilby JM, Lalezari JP, Eron JJ, Carlson M, Cohen C, Arduino RC, Goodgame JC, et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide(T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res Hum Retroviruses 2002; 18: 685-93. [PubMed: 12167274]

  (Analysis of safety and efficacy of enfuvirtide in 78 patients with HIV treated for 28 days; "no significant or clinically meaningful changes or differences between dosage groups in clinical chemistry results").
• Lalezari JP, Henry K, O'Hearn M, Montaner JS, Piliero PJ, Trottier B, Walmsley S, et al.; TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348: 2175-85. [PubMed: 12637625]

  (Large, registration trial of adding enfuvirtide to an "optimized" regimen in 501 patients with HIV infection and resistance to conventional antiretrovirals; updated combined safety analysis in 663 patients on enfuvirtide found 2 instances of hypersensitivity, but no mention of hepatotoxicity and rates of laboratory abnormalities were not different in enfuvirtide as control [optimal regimen] patients).
• Lazzarin A, Clotet B, Cooper D, Reynes J, Arastéh K, Nelson M, Katlama C, et al.; TORO 2 Study Group. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: 2186-95. [PubMed: 12773645]

  (Controlled trial of adding enfuvirtide to an "optimized" regimen in 512 patients with HIV infection and resistance to conventional antiretrovirals; updated combined safety analysis for 813 patient-years of exposure reported: "No consistent pattern was evident to suggest a definitive association of enfurvitide with any particular laboratory abnormality").
• Hardy H, Skolnik PR. Enfuvirtide, a new fusion inhibitor for therapy of human immunodeficiency virus infection. Pharmacotherapy 2004; 24: 198-211. [PubMed: 14998221]

  (Review of structure, pharmacology, mechanism of action, clinical efficacy and safety of enfuvirtide: 36-amino acid synthetic peptide derived from sequence motif of HIV protein gp41, a transmembrane protein necessary for HIV fusion to CD4 cells; found to suppress HIV in culture and in humans, but must be given by injection; metabolized to amino acids which are probably reused; large registration trials [TORO-1 and 2] demonstrated efficacy and that side effects were similar to controls except for injection site reactions [97% vs nil] and eosinophilia [10% vs 2.4%], but not associated with systemic features and no mention of hepatotoxicity).
• Church JA, Hughes M, Chen J, Palumbo P, Mofenson LM, Delora P, Smith E, et al.; Pediatric AIDS Clinical Trials Group P1005 Study Team. Long term tolerability and safety of enfuvirtide for human immunodeficiency virus 1-infected children. Pediatr Infect Dis J 2004; 23: 713-8. [PubMed: 15295220]

  (Analysis of efficacy and safety of up to 96 weeks of enfuvirtide therapy in 14 children with HIV infection; no mention of hepatotoxicity and no instances of liver test abnormalities above 5 times ULN).
• Trottier B, Walmsley S, Reynes J, Piliero P, O'Hearn M, Nelson M, Montaner J, et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. J Acquir Immune Defic Syndr 2005; 40: 413-21. [PubMed: 16280695]

  (Follow up to 48 weeks of patients in registration trials of enfuvirtide [Lazzarin 2003 and Lalezari 2003]; no mention of hepatotoxicity or rates of ALT elevations; eosinophilia in ~12.5% per year; 6 cases of hypersensitivity, 5 recurring with rechallenge and some patients developed "elevated serum liver transaminases").
• Jülg B, Bogner JR, Goebel FD. Severe hepatotoxicity associated with the combination of enfuvirtide and tipranavir/ritonavir: case report. AIDS 2006; 20: 1563. [PubMed: 16847416]

  (52 year old man with HIV-HBV co-infection developed marked increase in ALT [538 U/L] without jaundice, 2 weeks after adding tipranavir and ritonavir to a regimen of zidovudine, lamivudine and enfuvirtide, resolving in 4 weeks of stopping; possibly related to effects of enfuvirtide on drug levels, no analysis of HBV reactivation and lamivudine resistance: Case 1).
• Shibuyama S, Gevorkyan A, Yoo U, Tim S, Dzhangiryan K, Scott JD. Understanding and avoiding antiretroviral adverse events. Curr Pharm Des 2006; 12: 1075-90. [PubMed: 16515487]

  (Class wide adverse effects of antiretroviral agents include lactic acidosis for di-deoxynucleosides, rash and hepatitis for nonnucleoside reverse transcriptase inhibitors and lipodystrophy for protease inhibitors; fusion inhibitors such as enfuvirtide are well tolerated, but associated with frequent sometimes troubling injection site reactions and eosinophilia ).
• Raffi F, Battegay M, Rusconi S, Opravil M, Blick G, Steigbigel RT, Kraft M, et al. Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST. AIDS 2007; 21: 1977-80. [PubMed: 17721109]

  (Analysis of clinical trial of tipranavir/ritonavir [r] vs comparator protease inhibitors/r who received enfuvirtide; tipranavir [+31%], lopinavir [+19%] and saquinavir levels [+39%] were higher in enfuvirtide treated, but rates of ALT elevations above 5 times ULN were lower in the enfuvirtide treated [6.5% vs 13%; 1% vs 2.5%; 0.9% vs 1.6%]).
• Reynes J, Arastéh K, Clotet B, Cohen C, Cooper DA, Delfraissy JF, Eron JJ, et al. TORO: ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals. AIDS Patient Care STDS 2007; 21: 533-43. [PubMed: 17711378]

  (In follow up analysis of the registration trials of enfuvirtide extended to 96 weeks, no new safety issues emerged; no mention of hepatotoxicity or ALT elevations).
• DeJesus E, Gottlieb MS, Gathe JC Jr, Greenberg ML, Guittari CJ, Zolopa AR. Safety and efficacy of enfuvirtide in combination with darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study. Antimicrob Agents Chemother 2008; 52: 4315-9. [PMC free article: PMC2592875] [PubMed: 18809940]

  (Among 137 patients with HIV infection receiving enfuvirtide with darunavir/ritonavir for for 24 weeks, there were 4 discontinuations and 18 serious adverse events, none were liver related; no mention of ALT elevations).
• 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).
• Wright D, Rodriguez A, Godofsky E, Walmsley S, Labriola-Tompkins E, Donatacci L, Shikhman A, et al. Efficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patients. HIV Clin Trials 2008; 9: 73-82. [PubMed: 18474492]

  (Comparison of once vs twice daily enfuvirtide added to an optimized regimen for 48 weeks in 61 patients with HIV infection; the two regimens had similar efficacy and safety; no mention of hepatotoxicity or ALT elevations).
• Drugs for HIV infection. Treat Guidel Med Lett 2014; 12 (138): 7-16; [PubMed: 24457549]

  (Concise review of drugs for HIV infection discusses enfuvirtide as the only fusion inhibitor approved for use in the US and mentions adverse side effects of local pain and irritation, eosinophilia, hypersensitivity reactions and increased rate of bacterial pneumonia, but does not mention ALT elevations or hepatotoxicity).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 5 of which were attributed to antiretroviral agents, including lamivudine, zidovudine and nevirapine, but not enfuvirtide).
• 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 [1.3%] were attributed to antiretroviral medications, but none specifically to enfuvirtide).
• Xu F, Acosta EP, Liang L, He Y, Yang J, Kerstner-Wood C, Zheng Q, et al. Current status of the pharmacokinetics and pharmacodynamics of HIV-1 entry inhibitors and HIV therapy. Curr Drug Metab 2017; 18: 769-81. [PubMed: 28738768]

  (Summary of the mechanism of action, pharmacokinetics and safety of enfuvirtide; no mention of ALT elevations or hepatotoxicity).
• de Castro N, Braun J, Charreau I, Lafeuillade A, Viard JP, Allavena C, Aboulker JP, et al.; EASIER ANRS 138 study group. Incidence and risk factors for liver enzymes elevations in highly treatment-experienced patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS-138 EASIER trial. AIDS Res Ther 2016; 13: 17. [PMC free article: PMC4818923] [PubMed: 27042193]

  (Among 169 HIV infected patients on long term antiretroviral therapy who were either maintained on enfuvirtide or switched to raltegravir, serum ALT levels were more frequently elevated [above 3 times ULN] in those switched to raltegravir [7% vs 2%], but no patient developed clinically apparent liver injury and multivariate analysis suggested that tipranavir was more likely the cause of the abnormalities).