Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study

The Pharmacogenomics Journal volume 12, pages 499–506 (2012)Cite this article

Subjects

Abstract

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n=285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography–mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P=0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P=0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Walker UA . Antiretroviral therapy-induced liver alterations. Curr Opin HIV AIDS 2007; 2: 293–298.

    Article  PubMed  Google Scholar 

  2. Reisler RB, Han C, Burman WJ, Tedaldi EM, Neaton JD . Grade 4 events are as important as AIDS events in the era of HAART. J Acquir Immune Defic Syndr 2003; 34: 379–386.

    Article  PubMed  Google Scholar 

  3. Hernandez LV, Gilson I, Jacobson J, Affi A, Puetz TR, Dindzans VJ . Antiretroviral hepatotoxicity in human immunodeficiency virus-infected patients. Aliment Pharmacol Ther 2001; 15: 1627–1632.

    Article  CAS  PubMed  Google Scholar 

  4. Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21: 1301–1308.

    Article  PubMed  Google Scholar 

  5. Kontorinis N, Dieterich DT . Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis 2003; 23: 173–182.

    Article  CAS  PubMed  Google Scholar 

  6. Nunez M, Soriano V . Hepatotoxicity of antiretrovirals: incidence, mechanisms and management. Drug Saf 2005; 28: 53–66.

    Article  CAS  PubMed  Google Scholar 

  7. Sulkowski MS, Mehta SH, Chaisson RE, Thomas DL, Moore RD . Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004; 18: 2277–2284.

    Article  CAS  PubMed  Google Scholar 

  8. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD . Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182–189.

    Article  CAS  PubMed  Google Scholar 

  9. Martin-Carbonero L, Nunez M, Gonzalez-Lahoz J, Soriano V . Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 2003; 4: 115–120.

    Article  PubMed  Google Scholar 

  10. Desta Z, Saussele T, Ward B, Blievernicht J, Li L, Klein K et al. Impact of CYP2B6 polymorphism on hepatic efavirenz metabolism in vitro. Pharmacogenomics 2007; 8: 547–558.

    Article  CAS  PubMed  Google Scholar 

  11. Kwara A, Lartey M, Sagoe KW, Kenu E, Court MH . CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid-dose concentration in HIV-infected patients. AIDS 2009; 23: 2101–2106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mukonzo JK, Roshammar D, Waako P, Andersson M, Fukasawa T, Milani L et al. A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans. Br J Clin Pharmacol 2009; 68: 690–699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Elens L, Vandercam B, Yombi JC, Lison D, Wallemacq P, Haufroid V . Influence of host genetic factors on efavirenz plasma and intracellular pharmacokinetics in HIV-1-infected patients. Pharmacogenomics 2010; 11: 1223–1234.

    Article  CAS  PubMed  Google Scholar 

  14. Burger D, van der Heiden I, la Porte C, van der Ende M, Groeneveld P, Richter C et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006; 61: 148–154.

    Article  CAS  PubMed  Google Scholar 

  15. Lindfelt T, O′Brien J, Song JC, Patel R, Winslow DL . Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms. Ann Pharmacother 2010; 44: 1572–1578.

    Article  CAS  PubMed  Google Scholar 

  16. Ribaudo HJ, Liu H, Schwab M, Schaeffeler E, Eichelbaum M, Motsinger-Reif AA et al. Effect of CYP2B6, ABCB1, and CYP3A5 polymorphisms on efavirenz pharmacokinetics and treatment response: an AIDS Clinical Trials Group study. J Infect Dis 2010; 202: 717–722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carr DF, la Porte CJ, Pirmohamed M, Owen A, Cortes CP . Haplotype structure of CYP2B6 and association with plasma efavirenz concentrations in a Chilean HIV cohort. J Antimicrob Chemother 2010; 65: 1889–1893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Verdon R, Six M, Rousselot P, Bazin C . Efavirenz-induced acute eosinophilic hepatitis. J Hepatol 2001; 34: 783–785.

    Article  CAS  PubMed  Google Scholar 

  19. Hoffmann CJ, Fielding KL, Charalambous S, Sulkowski MS, Innes C, Thio CL et al. Antiretroviral therapy using zidovudine, lamivudine, and efavirenz in South Africa: tolerability and clinical events. AIDS 2008; 22: 67–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bruck S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine. Eur J Med Res 2008; 13: 343–348.

    PubMed  Google Scholar 

  21. Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 2005; 191: 825–829.

    Article  CAS  PubMed  Google Scholar 

  22. Ocama P, Castelnuovo B, Kamya MR, Kirk GD, Reynolds SJ, Kiragga A et al. Low frequency of liver enzyme elevation in HIV-infected patients attending a large urban treatment centre in Uganda. Int J STD AIDS 2010; 21: 553–557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. UNAIDS. 2008 Report on the Global AIDS Epidemic. UNAIDS: Geneva, Switzerland, 2008.

  24. The Ministry of Health (MOH), HIV/AIDS Prevention Control Office (HAPCO). Aids in Ethiopia 6th report (http://www.etharc.org/aidsineth/publications/Factsheetfor6threport.pdf), accessed August 2011.

  25. Ngaimisi E, Mugusi S, Minzi OM, Sasi P, Riedel KD, Suda A et al. Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients. Clin Pharmacol Ther 2010; 88: 676–684.

    Article  CAS  PubMed  Google Scholar 

  26. Benichou C . Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990; 11: 272–276.

    Article  CAS  PubMed  Google Scholar 

  27. Torti C, Lapadula G, Casari S, Puoti M, Nelson M, Quiros-Roldan E et al. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shipton LK, Wester CW, Stock S, Ndwapi N, Gaolathe T, Thior I et al. Safety and efficacy of nevirapine- and efavirenz-based antiretroviral treatment in adults treated for TB-HIV co-infection in Botswana. Int J Tuberc Lung Dis 2009; 13: 360–366.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Servoss JC, Kitch DW, Andersen JW, Reisler RB, Chung RT, Robbins GK . Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group (1989–1999). J Acquir Immune Defic Syndr 2006; 43: 320–323.

    Article  CAS  PubMed  Google Scholar 

  30. Montessori V, Harris M, Montaner JS . Hepatotoxicity of nucleoside reverse transcriptase inhibitors. Semin Liver Dis 2003; 23: 167–172.

    Article  CAS  PubMed  Google Scholar 

  31. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T . Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. Aids 2001; 15: 71–75.

    Article  CAS  PubMed  Google Scholar 

  32. Gazzard B, Balkin A, Hill A . Analysis of neuropsychiatric adverse events during clinical trials of efavirenz in antiretroviral-naive patients: a systematic review. AIDS Rev 2010; 12: 67–75.

    PubMed  Google Scholar 

  33. Gounden V, van Niekerk C, Snyman T, George JA . Presence of the CYP2B6 516G> T polymorphism, increased plasma Efavirenz concentrations and early neuropsychiatric side effects in South African HIV-infected patients. AIDS Res Ther 2010; 7: 32.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther 2005; 10: 489–498.

    CAS  PubMed  Google Scholar 

  35. Saitoh A, Fletcher CV, Brundage R, Alvero C, Fenton T, Hsia K et al. Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic Syndr 2007; 45: 280–285.

    CAS  PubMed  Google Scholar 

  36. Apostolova N, Gomez-Sucerquia LJ, Moran A, Alvarez A, Blas-Garcia A, Esplugues JV . Enhanced oxidative stress and increased mitochondrial mass during efavirenz-induced apoptosis in human hepatic cells. Br J Pharmacol 2010; 160: 2069–2084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Abrescia N, D′Abbraccio M, Figoni M, Busto A, Butrico E, De Marco M et al. Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection. J Antimicrob Chemother 2002; 50: 763–765.

    Article  CAS  PubMed  Google Scholar 

  38. Turkova A, Ball C, Gilmour-White S, Rela M, Mieli-Vergani G . A paediatric case of acute liver failure associated with efavirenz-based highly active antiretroviral therapy and effective use of raltegravir in combination antiretroviral treatment after liver transplantation. J Antimicrob Chemother 2009; 63: 623–625.

    Article  CAS  PubMed  Google Scholar 

  39. Figueroa SC, de Gatta MF, Garcia LH, Hurle AD, Bernal CB, Correa RS et al. The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy. Ther Drug Monit 2010; 32: 579–585.

    Article  CAS  Google Scholar 

  40. Nunez MJ, Martin-Carbonero L, Moreno V, Valencia E, Garcia-Samaniego J, Castillo JG et al. Impact of antiretroviral treatment-related toxicities on hospital admissions in HIV-infected patients. AIDS Res Hum Retroviruses 2006; 22: 825–829.

    Article  CAS  PubMed  Google Scholar 

  41. Aklillu E, Dandara C, Bertilsson L, Masimirembwa C . Pharmacogenetics of cytochrome P450s in African populations: clinical and molecular evolutionary implications. In: Suarez-Kurtz G (ed). Pharmacogenomics in Admixed Populations. Austin, TX: Landes Bioscience, 2007, pp 99–119.

    Google Scholar 

  42. Gebeyehu E, Engidawork E, Bijnsdorp A, Aminy A, Diczfalusy U, Aklillu E . Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians. Pharmacogenomics J 2011; 11: 130–137.

    Article  CAS  PubMed  Google Scholar 

  43. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M . Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441–446.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the European and Developing Countries Clinical Trials Partnership, CG_TA.05.40204_005, CT.2005.32030.001 and SIDA/SAREC grants number HIV-2006-031, SWE 2007–270.

Author information

Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    G Yimer, A Habtewold, N Ueda, A Suda & E Aklillu

  2. Department of Pharmacology, Medical Faculty, Addis Ababa University, Addis Ababa, Ethiopia

    G Yimer, A Habtewold & E Makonnen

  3. Department of Internal Medicine, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia

    W Amogne & G Aderaye

  4. Division of Infectious Diseases, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden

    W Amogne & L Lindquist

  5. Department of Community Health, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia

    A Worku

  6. Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

    W E Haefeli & J Burhenne

Authors
  1. G Yimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Amogne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Habtewold
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Makonnen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Suda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Worku
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W E Haefeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Burhenne
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G Aderaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Lindquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. E Aklillu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Aklillu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yimer, G., Amogne, W., Habtewold, A. et al. High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study. Pharmacogenomics J 12, 499–506 (2012). https://doi.org/10.1038/tpj.2011.34

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2011.34

Keywords

This article is cited by

Search

Advanced search

Quick links