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• Overview

  Efavirenz[brand names Sustiva® and Stocrin®] is a kind of non-nucleoside reverse transcriptase inhibitor(NNRTI) and can be used as part of highly active antiretroviral therapy(HAART) for the treatment of a human immunodeficiency virus(HIV) type 1^[1,2]. For HIV infection that has not previously been treated, efavirenz and lamivudine in combination with zidovudine or tenofovir is the preferred NNRTI-based regimen^{[1, 2]}. Efavirenz can also be used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission^[1].
  Efavirenz is one of the most commonly prescribed antiretroviral medications in the world. Several large randomized, controlled trials[RCTs] have demonstrated the superior ability of efavirenz to suppress the HIV virus when used as part of a 3-drug cocktail^[2]. The introduction of Atripla in 2006 combined efavirenz and two other agents into a single pill, once-daily formulation. This formulation was more convenient and better tolerated than alternatives, and thus resulted in improved adherence to antiretroviral medications^[3]. However, neuropsychiatric side effects associated with efavirenz have been reported to occur in 40–50% of patients and represent one of the limiting factors of this regimen^[4].
  Chemically it is described as[S]-6-chloro-4-[cyclopropylethynyl]-1,4-dihydro-4-(trifluoromethyl]-2H-3,1-benzoxazin-2-one. It has the empirical formula C14H9ClF3NO2, and its structural formula is presented in Figure 1^[5].
  
  Figure 1 The chemical structure of Efavirenz;

• Pharmacological aspects

  Efavirenz D5 can be taken with or without food, but if taken with fatty food, its bioavailability and toxicity may increase. The oral solution has lower bioavailability than tablets or capsules. Efavirenz D5 is highly bound to human plasma proteins(approximately 99.7%), predominantly albumin^[7]. It is principally metabolized by the cytochrome P450(CYP) system to hydroxylated metabolites with subsequent glucuronidation. These metabolites are essentially inactive against HIV-1. Efavirenz D5 drug has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200–400 mg per day for 10 days resulted in a lower-than predicted extent of accumulation(22%–42% lower) and a shorter terminal half-life of 40–55 hr(single-dose half life of 52–76 hr)^6,7.
  Drug interaction studies, through in vivo and in vitro tests, demonstrated that EFV is able to induce or inhibit the CYP isoenzymes. Efavirenz D5 has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A(human gene of CYP, family 3, subfamily A), including auto-induction of its own metabolism. The inducing effect on CYP3A is expected to be similar for Efavirenz D5 doses of 200–600 mg. In vitro, the 2C9, 2C19, and 3A4 isoenzymes were inhibited by Efavirenz D5. Co-administration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A4 iso-zymes may result in altered plasma concentrations of the co-administered drug. Drugs that induce CYP3A activity would be expected to increase the clearance of Efavirenz D5, resulting in lowered plasma concentrations^{[5, 7,9,10]}. ;

• Indications and action

  Efavirenz is used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1(HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz takes effect through inhibiting the activity of viral RNA-directed DNA polymerase(i.e., reverse transcriptase)^{[1, 11]}. Antiviral activity of efavirenz is largely dependent on intracellular conversion to the active triphosphorylated form^[1]. The rate of efavirenz phosphorylation varies, depending on the specific targeted cell type. It is generally proposed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, thus inhibiting the synthesis of new virions^[1]. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body^[1]. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. Efavirenz is an NNRTI of HIV-1, and its activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase is not inhibited by Efavirenz^[12,13]. ;

• Drug resistance

  Despite the good antiretroviral activity of efavirenz in vitro, repeated passage of HIV-1 in the presence of drug leads to a rapid selection of drug-resistant HIV-1 strains. A single mutation in the HIV-1 genome can increase the 50% inhibitory concentration(IC50) by up to 100-fold^[14]. Clinical studies confirmed that resistant viruses also rapidly emerge in vivo, when efavirenz is used in the context of persistent viral replication^[15]. The K103N mutation is most frequently the first resistance mutation to be selected^[16,17]. However, the majority of patients go on to develop additional mutations, most commonly L100I, V106M, V108I, Y181C/I, Y188L, G190A/S and P225H^[16,17] Although the Y181C mutation only reduces efavirenz susceptibility approximately twofold, efavirenz is often ineffective because of the fact that most patients failing a NNRTI-containing regimen harbour multiple different NNRTI-resistance mutations that are not detectable by standard genotyping. Double mutants are associated with higher levels of resistance to efavirenz. Joly et al^[17]. Observed that, after switching to a non-NNRTI-containing regimen because of virological failure, NNRTI resistance mutations persist in two-thirds of the patients after 1 year. Thus, NNRTI mutations do not decrease replicative capacity, and, therefore, there is apparently no benefit in continuing NNRTI therapy once resistance has emerged. ;

• Adverse reactions

  Efavirenz administration has been frequently associated with the manifestation of neuropsychiatric disorders including dizziness, confusion, lethargy, impaired concentration, amnesia, hallucinations, abnormal dreams, and insomnia^{[18, 19]}. Anxiety, depression, and suicide have also been reported^{[20, 21]}. Animal studies also confirm that Efavirenz affects anxiety-related behavior and cognitive performance^[22,23].
  Symptoms commonly appear in the first week of treatment^[24-26], and most reports indicate that they usually disappear or reduce in severity after several weeks^[21,24]. However, in a cross-sectional study of patients treated with Efavirenz, the psychiatric effects remained for up to 200 days, with a reduction in symptoms after this period^[27]. A prospective study showed that neuropsychiatric symptoms occurred in the first 2 weeks of treatment but that those patients who continued to take Efavirenz showed an improvement in symptoms and were able to tolerate continued treatment^[28]. Another study demonstrated that neuropsychiatric disorders might persist in patients chronically treated with Efavirenz^[29]. Adverse effects and interactions of Efavirenz can affect the CNS. ;

• Precaution

  The following tips should be concerned^[30]:
  You should not use efavirenz if you are allergic to it. The patients should consult his/her doctor if he/she has ever had liver disease(including hepatitis B or C), a seizure, mental illness or psychosis, heart disease or if he/she has alcoholism or injection drug administration history.
  Since efavirenz can harm the unborn baby or cause birth defects, pregnant should be disabled. Use 2 forms of birth control, including a barrier form(condom, cervical cap, contraceptive sponge, or diaphragm with spermicide gel) to prevent pregnancy while you are using efavirenz and for at least 12 weeks after your last dose. Tell your doctor if you become pregnant during treatment. It should not be noted that hormonal contraception(birth control pills, injections, implants, skin patches, and vaginal rings) might fail in preventing pregnancy while you are taking efavirenz.
  Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk. ;

• References

  1. https://www.drugbank.ca/drugs/DB00625
  2. Gallant JE, DeJesus E, Arribas JR, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3]:251–60.
  3. Ena J, Pasquau F. Once-a-day highly active antiretroviral therapy: a systematic review. Clin Infect Dis. 2003;36(9]:1186–90.
  4. Vrouenraets SM, Wit FW, van Tongeren J, et al. Efavirenz: a review. Expert Opin Pharmacother. 2007;8(6]:851–71.
  5. Efavirenz.[2009]. Sustiva. Rhodes, Greece: Cerner Multum.
  6. Date, H. L., & Fisher, M.[2009]. HIV infection. In R. Walker and C. Whittlesea[eds.], Clinical Pharmacy and Therapeutics, 4th ed. London: Churchill Livingstone Elsevier, 568–598
  7. Wande, A. N.[1994]. Handbook of Pharmaceutical excipients, 2th ed. Washington, DC: American Pharmaceutical Association.
  8. Skidmore-Roth, L.[2009]. Mosby’s Drug Guide of Nurses, 8th ed. St. Louis, MO: Mosby Elsevier, 346 pp.
  9. Almond, L. M., Hoggard, P. G., Edirisinghe, D. E., Khoo, S. H., & Back, D. J.[2005]. Intracellular and plasma pharmacokinetics of efavirenz in HIV-infected individuals. Journal of Antimicrobial Chemotherapy, 56, 738–744.
  10. Liu, P., Foster, G., LaBadie, R. R., Gutierrez, M. J., & Sharma, A.[2005]. Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy subjects. Clinical Pharmacology & Therapeutics, 77, 40.
  11. https://www.rxlist.com/sustiva-drug.htm#indications
  12. Clercq, E.[2001]. Antiviral drugs: Current state of the art. Journal of Clinical Virology, 22, 73–89.
  13. Langmann, P., Schirmer,D., Vath, T., Zilly,M., &Klinker, H.[2001]. High-performance liquid chromatographic method for the determination of HIV-1 non-nucleoside reverse transcriptase inhibitor efavirenz in plasma of patients during highly active antiretroviral therapy. Journal of Chromatography. B, Biomedical Sciences and Applications, 755, 151–156.
  14. YOUNG SD, BRITCHER SF, TRAN LO et al.: L-743, 726(DMP-266]: a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. (1995] 39(12]:2602-2605.
  15. DEEKS SG: International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. J. Acquir. Immune Defic. Syndr.[2001] 26[Suppl. 1]: S25-S33.
  16. BACHELER LT, ANTON ED, KUDISH P et al.: Human immunodeficiency virus type 1 mutations selected in patients failing efavirenz combination therapy. Antimicrob. Agents Chemother.[2000] 44(9]:2475-2484. 
  17. JOLY V, DESCAMPS D, PEYTAVIN G et al.: Evolution of human immunodeficiency virus type 1(HIV-1] resistance mutations in nonnucleoside reverse transcriptase inhibitors[NNRTIs] in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob. Agents Chemother.[2004] 48(1]:172-175.
  18. Jena, A., Sachdeva, R. K., Sharma, A., &Wanchu, A.[2009]. Adverse drug reactions to nonnucleoside reverse transcriptase inhibitorbased antiretroviral regimen: A 24-week prospective study. Journal of the International Association of Physicians in AIDS Care, 8, 318–322.
  19. Paterson, D. L., Swindells, S., Brester, M., & Vergis, E. N.[2000]. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Annals of Internal Medicine, 133, 21–30.
  20. Arendt, G., Nocker,D., VonGiesen, H. J., & Nolting, T.[2007].Neuropsychiatric side effects of efavirenz therapy. Expert Opinion on Drug Safety, 6, 147–154.
  21. Lochet, P., Peyriere, H., Lotth´e, A., Mauboussin, J. M., Delmas, B., & Reynes, J.[2003]. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Medicine, 4, 62–66.
  22. O’Mahony, S. M., Myint, A., Steinbusch, H., & Leonard, B. E.[2005]. Efavirenz induces depressive like behaviour, increased stress response and changes in the immune response in rats. Neuroimmunomodulation, 12, 293–298.
  23. Rom˜ao, P. R. T., Lemos, J. C., Moreira, J., de Chaves, G., Moretti, M., Castro, A. A., et al.[2009]. Anti-HIV drugs nevirapine and efavirenz affect anxiety-related behavior and cognitive performance in mice. Neurotoxicity Research.
  24. Bickel, M., Stephan, C., Rottmann, C., Carlebach, A., Haberl, A., Kurowski, M., et al.[2005]. Severe CNS side effect and persistent high efavirenz plasma levels in a patient with HIV/HCV coinfection and liver cirrhosis. Scandinavian Journal of Infectious Diseases, 37, 520–252.
  25. Guti´errez, F., Navarro, A., Padilla, S., Ant´on, R., Masi´a, M., Borr´as, J., et al.[2005]. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clinical Infectious Diseases, 41, 1648–1653.
  26. Treisman, G. J., & Kaplan, A. I.[2002]. Neurologic and psychiatric complications of antiretroviral agents. AIDS, 16, 1201–1215.
  27. Hawkins, T., Geist, C., Young, B., Giblin, A., Mercier, R. C., Thornton,K., et al.[2005]. Comparison of neuropsychiatric side effects in an observational cohort of efavirenzand protease inhibitor-treated patients. HIV Clinical Trials, 6, 187–196.
  28. 28. Blanch, J., Corbella, B., Garcia, F., Parellada, E., & Gatell, J. M.[2001]. Manic syndrome associated with efavirenz overdose. Clinical Infectious Diseases, 15, 270–271.
  29. Fumaz, C. R., Mun˜oz-Moreno, J. A., Molt ´ o, J., Negredo, E., Ferrer, M. J. M. A., Sirera, J., et al.[2005]. Long-term neuropsychiatric disorders on efavirenz-based approaches: Quality of life, psychologic issues, and adherence. Journal of Acquired Immune Deficiency Syndromes, 38, 560–565.
  30. https://www.drugs.com/mtm/efavirenz.html
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