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Chemical Compound Review

Eravirenz     (10R)-3-chloro-10-(2- cyclopropylethynyl)...

Synonyms: Stocrin, Sustiva, efavirenz, PubChem5812, zoxazin-2-one, ...
 
 
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Disease relevance of efavirenz

  • Efavirenz in HIV infection [1].
  • Pulmonary hypersensitivity reaction induced by efavirenz [2].
  • Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge [3].
  • Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections [4].
  • Using 800 mg/day of efavirenz, high levels and toxicity were detected in seven out of nine patients, necessitating reduction or discontinuation [5].
 

Psychiatry related information on efavirenz

  • Efavirenz-induced catatonia [6].
  • A previously published, nine-step, decision-making algorithm has been used to evaluate the utility of therapeutic drug monitoring of efavirenz and nevirapine [7].
  • OBJECTIVES: Pharmacokinetic interactions between rifampicin and antiretroviral therapy (ART), including efavirenz, are problematic and need to be better defined to determine proper dose and to be correlated with short-term and long-term clinical outcomes [8].
  • Updates on the risk of neuropsychiatric manifestations with efavirenz use in patients with a history of psychiatric disorders or substance abuse are reviewed [9].
  • Depressive symptoms predict increased incidence of neuropsychiatric side effects in patients treated with efavirenz [10].
 

High impact information on efavirenz

  • Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection [11].
  • The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures [3].
  • Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1 [12].
  • Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz [13].
  • Patients and methods: A prospective, multicentre, open, comparative study in which HIV-1-infected patients on HAART and with plasma HIV-1 RNA <50 copies/ml for longer than 6 months were switched to tenofovir, didanosine and efavirenz (QD arm) or remained on the same treatment regimen (control arm) [14].
 

Chemical compound and disease context of efavirenz

  • OBJECTIVE: To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen [15].
  • Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial [16].
  • A series of targeted molecular dynamics simulations have been carried out in an attempt to assess the effect that the common Lys103Asn mutation in HIV-1 reverse transcriptase (RT) has on the binding of three representative non-nucleoside RT inhibitors (NNRTI), nevirapine, efavirenz, and etravirine [17].
  • OBJECTIVE: We have shown that HIV-1 clade C variants contain a valine codon 106 polymorphism (GTG) that facilitates a V106M transition (GTG<--ATG) after selection with efavirenz (EFV) [18].
  • Thus, in patients treated with efavirenz plus indinavir, levels of residual viremia were established by 9 months, were predicted by baseline proviral DNA, and remained constant for 5 years [19].
 

Biological context of efavirenz

  • The virological response of multiple protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor-naive, HIV-1-infected subjects was examined with respect to baseline viral phenotype and genotype through 72 weeks of therapy with lopinavir/ritonavir plus efavirenz and nucleoside reverse transcriptase inhibitors (Study M98-957) [20].
  • Measurement of [(3)H]deoxyglucose uptake, basal and agonist-stimulated lipolysis, and cell viability indicated that these pathways are not involved in efavirenz effects on triacylglycerol accumulation [21].
  • Better adherence was found in NNRTI-treated patients, especially when efavirenz was included in the regimen, compared with single PI-treated patients and in those with CD4 cell counts less than 200 x 10(6)/l. By contrast, younger age, self-report of active drug use, fatigue or vomiting negatively affected adherence [22].
  • Failure of treatment of tuberculous adenitis due to an unexpected drug interaction with rifabutin and efavirenz [23].
  • No patient with a viral isolate with an increased IC50 to efavirenz by virtual phenotype had a virological response[24]
 

Anatomical context of efavirenz

  • A constellation of factors could be correlated with early failure events in patients receiving this combination such as resistance mutations or polymorphisms present at baseline, low CD4+ T-cell count or advanced disease and unexpectedly low efavirenz plasma levels [25].
  • The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism [21].
  • When considered together, these results demonstrate for the first time that the NNRTI efavirenz induces a strong inhibition of the SREBP-1c-dependent lipogenic pathway that might contribute to adipose tissue atrophy [21].
  • Inter-individual differences in metabolism may, in part, explain susceptibility to efavirenz central nervous system side effects [26].
  • Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men [27].
 

Associations of efavirenz with other chemical compounds

 

Gene context of efavirenz

  • OBJECTIVE: The capacity of the non-nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P-glycoprotein, was evaluated in healthy volunteers during and after a 10-day treatment course with two different daily doses [32].
  • Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure [33].
  • In contrast, carbamazepine (CMZ), efavirenz (EFV), and nevirapine (NVP) were classified as negligible or weak hPXR activators at concentrations associated with efficacious CYP2B6 reporter or endogenous gene induction in primary human hepatocytes, suggesting potential activation of hCAR [34].
  • Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A [35].
  • Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001) [36].
  • Relatively frequent CYP2B6 polymorphisms may predict decreased plasma efavirenz exposure in patients of African descent [37].
 

Analytical, diagnostic and therapeutic context of efavirenz

References

  1. Efavirenz in HIV infection. Casado, J.L., Moreno, S. N. Engl. J. Med. (2000) [Pubmed]
  2. Pulmonary hypersensitivity reaction induced by efavirenz. Behrens, G.M., Stoll, M., Schmidt, R.E. Lancet (2001) [Pubmed]
  3. HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription. Goffinet, C., Allespach, I., Keppler, O.T. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  4. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Sulkowski, M.S., Thomas, D.L., Mehta, S.H., Chaisson, R.E., Moore, R.D. Hepatology (2002) [Pubmed]
  5. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all. Brennan-Benson, P., Lyus, R., Harrison, T., Pakianathan, M., Macallan, D. AIDS (2005) [Pubmed]
  6. Efavirenz-induced catatonia. Sabato, S., Wesselingh, S., Fuller, A., Ray, J., Mijch, A. AIDS (2002) [Pubmed]
  7. Efavirenz and Nevirapine in HIV-1 Infection : Is There a Role for Clinical Pharmacokinetic Monitoring? Dahri, K., Ensom, M.H. Clinical pharmacokinetics (2007) [Pubmed]
  8. Administration of efavirenz (600 mg/day) with rifampicin results in highly variable levels but excellent clinical outcomes in patients treated for tuberculosis and HIV. Friedland, G., Khoo, S., Jack, C., Lalloo, U. J. Antimicrob. Chemother. (2006) [Pubmed]
  9. Neuropsychiatric complications of antiretroviral therapy. Cespedes, M.S., Aberg, J.A. Drug safety : an international journal of medical toxicology and drug experience. (2006) [Pubmed]
  10. Depressive symptoms predict increased incidence of neuropsychiatric side effects in patients treated with efavirenz. Boly, L., Cafaro, V., Dyner, T. J. Acquir. Immune Defic. Syndr. (2006) [Pubmed]
  11. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. Albrecht, M.A., Bosch, R.J., Hammer, S.M., Liou, S.H., Kessler, H., Para, M.F., Eron, J., Valdez, H., Dehlinger, M., Katzenstein, D.A. N. Engl. J. Med. (2001) [Pubmed]
  12. Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Rodríguez de la Concepción, M.L., Yubero, P., Domingo, J.C., Iglesias, R., Domingo, P., Villarroya, F., Giralt, M. Antivir. Ther. (Lond.) (2005) [Pubmed]
  13. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Kappelhoff, B.S., van Leth, F., MacGregor, T.R., Lange, J., Beijnen, J.H., Huitema, A.D. Antivir. Ther. (Lond.) (2005) [Pubmed]
  14. Simplification therapy with once-daily didanosine, tenofovir and efavirenz in HIV-1-infected adults with viral suppression receiving a more complex antiretroviral regimen: final results of the EFADITE trial. Barrios, A., Negredo, E., Domingo, P., Estrada, V., Labarga, P., Asensi, V., Morales, D., Santos, J., Clotet, B., Soriano, V. Antivir. Ther. (Lond.) (2005) [Pubmed]
  15. HIV-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study. Ait-Khaled, M., Rakik, A., Griffin, P., Stone, C., Richards, N., Thomas, D., Falloon, J., Tisdale, M. Antivir. Ther. (Lond.) (2003) [Pubmed]
  16. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. Maitland, D., Moyle, G., Hand, J., Mandalia, S., Boffito, M., Nelson, M., Gazzard, B. AIDS (2005) [Pubmed]
  17. The molecular basis of resilience to the effect of the Lys103Asn mutation in non-nucleoside HIV-1 reverse transcriptase inhibitors studied by targeted molecular dynamics simulations. Rodríguez-Barrios, F., Balzarini, J., Gago, F. J. Am. Chem. Soc. (2005) [Pubmed]
  18. A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. Brenner, B., Turner, D., Oliveira, M., Moisi, D., Detorio, M., Carobene, M., Marlink, R.G., Schapiro, J., Roger, M., Wainberg, M.A. AIDS (2003) [Pubmed]
  19. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. Havlir, D.V., Strain, M.C., Clerici, M., Ignacio, C., Trabattoni, D., Ferrante, P., Wong, J.K. J. Virol. (2003) [Pubmed]
  20. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Kempf, D.J., Isaacson, J.D., King, M.S., Brun, S.C., Sylte, J., Richards, B., Bernstein, B., Rode, R., Sun, E. Antivir. Ther. (Lond.) (2002) [Pubmed]
  21. In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. Hadri, K.E., Glorian, M., Monsempes, C., Dieudonné, M.N., Pecquery, R., Giudicelli, Y., Andreani, M., Dugail, I., Fève, B. J. Biol. Chem. (2004) [Pubmed]
  22. Adherence to highly active antiretroviral therapy is better in patients receiving non-nucleoside reverse transcriptase inhibitor-containing regimens than in those receiving protease inhibitor-containing regimens. Trotta, M.P., Ammassari, A., Cozzi-Lepri, A., Zaccarelli, M., Castelli, F., Narciso, P., Melzi, S., De Luca, A., Monforte, A.D., Antinori, A. AIDS (2003) [Pubmed]
  23. Failure of treatment of tuberculous adenitis due to an unexpected drug interaction with rifabutin and efavirenz. Edelstein, H.E., Cuadros, Y. AIDS (2004) [Pubmed]
  24. Non-nucleoside reverse transcriptase inhibitor failure impairs HIV-RNA responses to efavirenz-containing salvage antiretroviral therapy. Walmsley, S.L., Kelly, D.V., Tseng, A.L., Humar, A., Harrigan, P.R. AIDS (2001) [Pubmed]
  25. Early virological failure after tenofovir + didanosine + efavirenz combination in HIV-positive patients upon starting antiretroviral therapy. Torti, C., Quiros-Roldon, E., Regazzi, M., Antinori, A., Patroni, A., Villani, P., Tirelli, V., Cologni, G., Zinzi, D., Lo Caputo, S., Perini, P., Carosi, G. Antivir. Ther. (Lond.) (2005) [Pubmed]
  26. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. Haas, D.W., Ribaudo, H.J., Kim, R.B., Tierney, C., Wilkinson, G.R., Gulick, R.M., Clifford, D.B., Hulgan, T., Marzolini, C., Acosta, E.P. AIDS (2004) [Pubmed]
  27. Penetration of efavirenz into the male genital tract: drug concentrations and antiviral activity in semen and blood of HIV-1-infected men. Taylor, S., Reynolds, H., Sabin, C.A., Drake, S.M., White, D.J., Back, D.J., Pillay, D. AIDS (2001) [Pubmed]
  28. Virological and immunological responses to a once-a-day antiretroviral regimen with didanosine, lamivudine and efavirenz. Maggiolo, F., Migliorino, M., Maserati, R., Pan, A., Rizzi, M., Provettoni, G., Rizzi, L., Suter, F. Antivir. Ther. (Lond.) (2001) [Pubmed]
  29. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. Mira, J.A., Lozano, F., Santos, J., Ramayo, E., Terrón, A., Palacios, R., León, E.M., Márquez, M., Macías, J., Fernández-Palacin, A., Gómez-Mateos, J., Pineda, J.A. Antivir. Ther. (Lond.) (2004) [Pubmed]
  30. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. Dubé, M.P., Parker, R.A., Tebas, P., Grinspoon, S.K., Zackin, R.A., Robbins, G.K., Roubenoff, R., Shafer, R.W., Wininger, D.A., Meyer, W.A., Snyder, S.W., Mulligan, K. AIDS (2005) [Pubmed]
  31. Risk of AIDS and death at given HIV-RNA and CD4 cell count, in relation to specific antiretroviral drugs in the regimen. Olsen, C.H., Gatell, J., Ledergerber, B., Katlama, C., Friis-Møller, N., Weber, J., Horban, A., Staszewski, S., Lundgren, J.D., Phillips, A.N. AIDS (2005) [Pubmed]
  32. Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Mouly, S., Lown, K.S., Kornhauser, D., Joseph, J.L., Fiske, W.D., Benedek, I.H., Watkins, P.B. Clin. Pharmacol. Ther. (2002) [Pubmed]
  33. Pharmacogenetics of long-term responses to antiretroviral regimens containing Efavirenz and/or Nelfinavir: an Adult Aids Clinical Trials Group Study. Haas, D.W., Smeaton, L.M., Shafer, R.W., Robbins, G.K., Morse, G.D., Labbe, L., Wilkinson, G.R., Clifford, D.B., D'Aquila, R.T., De Gruttola, V., Pollard, R.B., Merigan, T.C., Hirsch, M.S., George, A.L., Donahue, J.P., Kim, R.B. J. Infect. Dis. (2005) [Pubmed]
  34. Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers. Faucette, S.R., Zhang, T.C., Moore, R., Sueyoshi, T., Omiecinski, C.J., Lecluyse, E.L., Negishi, M., Wang, H. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  35. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. von Moltke, L.L., Greenblatt, D.J., Granda, B.W., Giancarlo, G.M., Duan, S.X., Daily, J.P., Harmatz, J.S., Shader, R.I. Journal of clinical pharmacology. (2001) [Pubmed]
  36. Multilocus genetic interactions and response to efavirenz-containing regimens: an adult AIDS clinical trials group study. Motsinger, A.A., Ritchie, M.D., Shafer, R.W., Robbins, G.K., Morse, G.D., Labbe, L., Wilkinson, G.R., Clifford, D.B., D'Aquila, R.T., Johnson, V.A., Pollard, R.B., Merigan, T.C., Hirsch, M.S., Donahue, J.P., Kim, R.B., Haas, D.W. Pharmacogenet. Genomics (2006) [Pubmed]
  37. CYP2B6 variants and plasma efavirenz concentrations during antiretroviral therapy in Port-au-Prince, Haiti. Leger, P., Dillingham, R., Beauharnais, C.A., Kashuba, A.D., Rezk, N.L., Fitzgerald, D.W., Pape, J.W., Haas, D.W. J. Infect. Dis. (2009) [Pubmed]
  38. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. Matthews, G.V., Sabin, C.A., Mandalia, S., Lampe, F., Phillips, A.N., Nelson, M.R., Bower, M., Johnson, M.A., Gazzard, B.G. AIDS (2002) [Pubmed]
  39. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. Marzolini, C., Telenti, A., Decosterd, L.A., Greub, G., Biollaz, J., Buclin, T. AIDS (2001) [Pubmed]
  40. Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case-control study from the Swiss HIV Cohort. Hirschel, B., Flepp, M., Bucher, H.C., Zellweger, C., Telenti, A., Wagels, T., Bernasconi, E., Ledergerber, B. AIDS (2002) [Pubmed]
 
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