Skip to main content

Thank you for visiting 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.

Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana


Inter-individual variability in efavirenz (EFV) pharmacokinetics and dynamics is dominantly driven by the polymorphism in cytochrome P450 (CYP) isoenzyme 2B6 516G>T. We hypothesized that additional CYP polymorphisms mediate the relationship between CYP2B6 516G>T, EFV metabolism, and clinical events. We investigated 21 SNPs in 814 HIV-infected adults initiating EFV-based therapy in Botswana for population pharmacokinetics, CNS toxicities, and treatment outcomes. Two SNPs (rs28399499 and rs28399433) showed reduced apparent oral EFV clearance. Four SNPs (rs2279345, rs4803417, rs4802101, and rs61663607) showed extensive clearance. Composite CYP2B-mediated EFV metabolism was significantly associated with CNS toxicity (p = 0.04), with extensive metabolizers reporting more and slow and very slow metabolizers reporting less toxicity after 1 month compared to intermediate metabolizers. Composite CYP2B6 metabolism was not associated with composite early treatment failure. In conclusion, our data suggest that CNS-related toxicities might not be solely the result of super-therapeutic parent EFV concentrations in HIV-infected individuals in patients of African ancestry.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2


  1. 1.

    UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2014. Geneva: UNAIDS; 2014.

    Google Scholar 

  2. 2.

    Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet. 2001;40:893–905.

    CAS  Article  Google Scholar 

  3. 3.

    Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18:388–99.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    World Health Organization. Global update on the health sector response to HIV 2014. WHO: Geneva, Switzerland; 2014.

  5. 5.

    Leutscher PD, Stecher C, Storgaard M, Larsen CS. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse effects. Scand J Infect Dis. 2013;45:645–51.

    CAS  Article  Google Scholar 

  6. 6.

    Group ES. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383:1474–82.

    CAS  Article  Google Scholar 

  7. 7.

    OARAC. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Internet]. 2016. Accessed 6 July 2016.

  8. 8.

    Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306:287–300.

    CAS  Article  Google Scholar 

  9. 9.

    Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS, et al. Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa. Br J Clin Pharmacol. 2015;80:146–56.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Haas DW, Kwara A, Richardson DM, Baker P, Papageorgiou I, Acosta EP, et al. Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. J Antimicrob Chemother. 2014;69:2175–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Holzinger ER, Grady B, Ritchie MD, Ribaudo HJ, Acosta EP, Morse GD, et al. Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS clinical trials group protocols implicates several CYP2B6 variants. Pharm Genomics. 2012;22:858–67.

    CAS  Article  Google Scholar 

  12. 12.

    Gross R, Aplenc R, Tenhave T, Foulkes AS, Thakur R, Mosepele M, et al. Slow efavirenz metabolism genotype is common in Botswana. J Acquir Immune Defic Syndr. 2008;49:336–7.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Gross R, Bellamy SL, Ratshaa B, Han X, Vujkovic M, Aplenc R, et al. CYP2B6 genotypes and early efavirenz-based HIV treatment outcomes in Botswana. AIDS. 2017;31:2107–13.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Vujkovic M, Bellamy SL, Zuppa AF, Gastonguay M, Moorthy GS, Ratshaa BR, et al. Brief report: CYP2B6 516G T minor allele protective of late virologic failure in efavirenz-treated HIV-infected patients in Botswana. J Acquir Immune Defic Syndr. 2017;75:488–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mukonzo JK, Owen JS, Ogwal-Okeng J, Kuteesa RB, Nanzigu S, Sewankambo N, et al. Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes. PLoS One. 2014;9:e86919

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharm Genomics. 2005;15:1–5.

    CAS  Article  Google Scholar 

  18. 18.

    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;202:717–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Rotger M, Tegude H, Colombo S, Cavassini M, Furrer H, Decosterd L, et al. Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals. Clin Pharmacol Ther. 2007;81:557–66.

    CAS  Article  Google Scholar 

  20. 20.

    Mukonzo JK, Okwera A, Nakasujja N, Luzze H, Sebuwufu D, Ogwal-Okeng J, et al. Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study. BMC Infect Dis. 2013;13:261

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Sarfo FS, Zhang Y, Egan D, Tetteh LA, Phillips R, Bedu-Addo G, et al. Pharmacogenetic associations with plasma efavirenz concentrations and clinical correlates in a retrospective cohort of Ghanaian HIV-infected patients. J Antimicrob Chemother. 2014;69:491–9.

    CAS  Article  Google Scholar 

  22. 22.

    Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005;143:714–21.

    CAS  Article  Google Scholar 

  23. 23.

    Takahashi M, Ibe S, Kudaka Y, Okumura N, Hirano A, Suzuki T, et al. No observable correlation between central nervous system side effects and EFV plasma concentrations in Japanese HIV type 1-infected patients treated with EFV containing HAART. AIDS Res Hum Retrovir. 2007;23:983–7. 10.1089/aid.2006.0193.

    CAS  Article  Google Scholar 

  24. 24.

    Fumaz CR, Munoz-Moreno JA, Molto J, Negredo E, Ferrer MJ, Sirera G, et al. Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr. 2005;38:560–5.

    Article  Google Scholar 

  25. 25.

    Stahle L, Moberg L, Svensson JO, Sonnerborg A. Efavirenz plasma concentrations in HIV-infected patients: inter- and intraindividual variability and clinical effects. Ther Drug Monit. 2004;26:267–70.

    CAS  Article  Google Scholar 

  26. 26.

    van Luin M, Bannister WP, Mocroft A, Reiss P, Di Perri G, Peytavin G, et al. Absence of a relation between efavirenz plasma concentrations and toxicity-driven efavirenz discontinuations in the EuroSIDA study. Antivir Ther. 2009;14:75–83.

    Google Scholar 

  27. 27.

    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;10:489–98.

    CAS  Google Scholar 

  28. 28.

    Csajka C, Marzolini C, Fattinger K, Decosterd LA, Fellay J, Telenti A, et al. Population pharmacokinetics and effects of efavirenz in patients with human immunodeficiency virus infection. Clin Pharmacol Ther. 2003;73:20–30.

    CAS  Article  Google Scholar 

  29. 29.

    Srivastava P, Moorthy GS, Gross R, Barrett JS. A sensitive and selective liquid chromatography/tandem mass spectrometry method for quantitative analysis of efavirenz in human plasma. PLoS One. 2013;8:e63305

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    International HapMap C. The International HapMap Project. Nature. 2003;426:789–96.

    CAS  Article  Google Scholar 

  31. 31.

    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005.

  32. 32.

    Grossberg R, Zhang Y, Gross R. A time-to-prescription-refill measure of antiretroviral adherence predicted changes in viral load in HIV. J Clin Epidemiol. 2004;57:1107–10.

    Article  Google Scholar 

  33. 33.

    Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM, et al. Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials. 2009;10:343–55.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Brinkhof MW, Boulle A, Weigel R, Messou E, Mathers C, Orrell C, et al. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. PLoS Med. 2009;6:e1000066

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Swart M, Evans J, Skelton M, Castel S, Wiesner L, Smith PJ, et al. An expanded analysis of pharmacogenetics determinants of efavirenz response that includes 3’-UTR single nucleotide polymorphisms among Black South African HIV/AIDS patients. Front Genet. 2015;6:356

    CAS  Article  Google Scholar 

  36. 36.

    Winzer R, Langmann P, Zilly M, Tollmann F, Schubert J, Klinker H, et al. No influence of the P-glycoprotein genotype (MDR1 C3435T) on plasma levels of lopinavir and efavirenz during antiretroviral treatment. Eur J Med Res. 2003;8:531–4.

    CAS  Google Scholar 

  37. 37.

    Dirson G, Fernandez C, Hindlet P, Roux F, German-Fattal M, Gimenez F, et al. Efavirenz does not interact with the ABCB1 transporter at the blood-brain barrier. Pharm Res. 2006;23:1525–32.

    CAS  Article  Google Scholar 

  38. 38.

    Stormer E, von Moltke LL, Perloff MD, Greenblatt DJ. Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture. Pharm Res. 2002;19:1038–45.

    Article  Google Scholar 

  39. 39.

    Janneh O, Chandler B, Hartkoorn R, Kwan WS, Jenkinson C, Evans S, et al. Intracellular accumulation of efavirenz and nevirapine is independent of P-glycoprotein activity in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother. 2009;64:1002–7.

    CAS  Article  Google Scholar 

  40. 40.

    Burhenne J, Matthee AK, Pasakova I, Roder C, Heinrich T, Haefeli WE, et al. No evidence for induction of ABC transporters in peripheral blood mononuclear cells in humans after 14 days of efavirenz treatment. Antimicrob Agents Chemother. 2010;54:4185–91.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Winston A, Amin J, Clarke A, Else L, Amara A, Owen A, et al. Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. Clin Infect Dis. 2015;60:1026–32.

    CAS  Article  Google Scholar 

  42. 42.

    Ashraf T, Robillard K, Chan GN, Bendayan R. Role of CNS transporters in the pharmacotherapy of HIV-1 associated neurological disorders. Curr Pharm Des. 2014;20:1543–63.

    CAS  Article  Google Scholar 

  43. 43.

    Aouri M, Barcelo C, Ternon B, Cavassini M, Anagnostopoulos A, Yerly S, et al. In vivo profiling and distribution of known and novel phase I and phase II metabolites of efavirenz in plasma, urine, and cerebrospinal fluid. Drug Metab Dispos. 2016;44:151–61.

    CAS  Article  Google Scholar 

  44. 44.

    Abdelhady AM, Desta Z, Jiang F, Yeo CW, Shin JG, Overholser BR. Population pharmacogenetic-based pharmacokinetic modeling of efavirenz, 7-hydroxy- and 8-hydroxyefavirenz. J Clin Pharmacol. 2014;54:87–96.

    CAS  Article  Google Scholar 

  45. 45.

    Ngaimisi E, Mugusi S, Minzi O, Sasi P, Riedel KD, Suda A, et al. Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis. Clin Pharmacol Ther. 2011;90:406–13.

    CAS  Article  Google Scholar 

  46. 46.

    Bienvenu E, Swart M, Dandara C, Ashton M. The role of genetic polymorphisms in cytochrome P450 and effects of tuberculosis co-treatment on the predictive value of CYP2B6 SNPs and on efavirenz plasma levels in adult HIV patients. Antivir Res. 2014;102:44–53.

    CAS  Article  Google Scholar 

  47. 47.

    Swart M, Skelton M, Ren Y, Smith P, Takuva S, Dandara C. High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients. Pharm Genom. 2013;23:415–27.

    CAS  Article  Google Scholar 

  48. 48.

    Gandhi M, Greenblatt RM, Bacchetti P, Jin C, Huang Y, Anastos K, et al. A single-nucleotide polymorphism in CYP2B6 leads to 3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women. J Infect Dis. 2012;206:1453–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Leger P, Dillingham R, Beauharnais CA, Kashuba AD, Rezk NL, Fitzgerald DW, et al. CYP2B6 variants and plasma efavirenz concentrations during antiretroviral therapy in Port-au-Prince, Haiti. J Infect Dis. 2009;200:955–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    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;65:1889–93.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Sukasem C, Cressey TR, Prapaithong P, Tawon Y, Pasomsub E, Srichunrusami C, et al. Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV-1 infected Thai adults. Br J Clin Pharmacol. 2012;74:1005–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Sukasem C, Manosuthi W, Koomdee N, Santon S, Jantararoungtong T, Prommas S, et al. Low level of efavirenz in HIV-1-infected Thai adults is associated with the CYP2B6 polymorphism. Infection. 2014;42:469–74.

    CAS  Article  Google Scholar 

  53. 53.

    Sukasem C, Chamnanphon M, Koomdee N, Santon S, Jantararoungtong T, Prommas S, et al. Pharmacogenetics and clinical biomarkers for subtherapeutic plasma efavirenz concentration in HIV-1 infected Thai adults. Drug Metab Pharmacokinet. 2014;29:289–95.

    CAS  Article  Google Scholar 

  54. 54.

    Manosuthi W, Sukasem C, Thongyen S, Nilkamhang S, Manosuthi S, Sungkanuparph S. CYP2B6 18492T- C polymorphism compromises efavirenz concentration in coinfected HIV and tuberculosis patients carrying CYP2B6 haplotype *1/*1. Antimicrob Agents Chemother. 2014;58:2268–73.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Penell J, Lind L, Fall T, Syvanen AC, Axelsson T, Lundmark P, et al. Genetic variation in the CYP2B6 gene is related to circulating 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47) concentrations: an observational population-based study. Environ Health. 2014;13:34

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Pozo K, Harner T, Wania F, Muir DCG, Jones KC, Barrie LA. Toward a global network for persistent organic pollutants in air: results from the GAPS study. Environ Sci Technol. 2006;40:4867–73.

    CAS  Article  Google Scholar 

  57. 57.

    Shunthirasingham C, Gouin T, Lei YD, Wania CO, Mmereki BT, Masamba W, et al. Year-round measurements of PBDEs in the atmosphere of tropical Costa Rica and subtropical Botswana. 5th International Symposium on Brominated Flame Retardants; April 7–9, 2010; Kyoto, Japan; 2010.

  58. 58.

    Sueyoshi T, Li L, Wang H, Moore R, Kodavanti PR, Lehmler HJ, et al. Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes. Toxicol Sci. 2014;137:292–302.

    CAS  Article  Google Scholar 

  59. 59.

    von Richter O, Pitarque M, Rodriguez-Antona C, Testa A, Mantovani R, Oscarson M, et al. Polymorphic NF-Y dependent regulation of human nicotine C-oxidase (CYP2A6). Pharmacogenetics. 2004;14:369–79.

    Article  Google Scholar 

  60. 60.

    Kheradpour P, Kellis M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 2014;42:2976–87.

    CAS  Article  Google Scholar 

  61. 61.

    Al Koudsi N, Ahluwalia JS, Lin SK, Sellers EM, Tyndale RF. A novel CYP2A6 allele (CYP2A6*35) resulting in an amino-acid substitution (Asn438Tyr) is associated with lower CYP2A6 activity in vivo. Pharm J. 2009;9:274–82.

    CAS  Article  Google Scholar 

  62. 62.

    Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518:317–30.

    CAS  Article  Google Scholar 

  63. 63.

    Dhoro M, Zvada S, Ngara B, Nhachi C, Kadzirange G, Chonzi P, et al. CYP2B6*6, CYP2B6*18, body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe. BMC Pharmacol Toxicol. 2015;16:4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Gross R, Bilker WB, Friedman HM, Strom BL. Effect of adherence to newly initiated antiretroviral therapy on plasma viral load. AIDS. 2001;15:2109–17.

    CAS  Article  Google Scholar 

  65. 65.

    Quinn TC, Brookmeyer R, Kline R, Shepherd M, Paranjape R, Mehendale S, et al. Feasibility of pooling sera for HIV-1 viral RNA to diagnose acute primary HIV-1 infection and estimate HIV incidence. AIDS. 2000;14:2751–7.

    CAS  Article  Google Scholar 

Download references


We thank the medical staff at the Bontleng, BH3, Broadhurst Traditional Area, Morwa, Nkoyaphiri, Phase II, and Village Infectious Diseases Care Clinics for their assistance with carrying out this study. We also thank the Ministry of Health of Botswana for supporting the project and the patients who participated.

Author contributions

MV wrote the article; RG, GPB, MV, BLS, and MM designed the research; MV, SLB, AFZ, MRG, BR, XH, APS, MM, BLS, GPB, RA, and RG performed the research; MV analyzed the data. The final manuscript reviewed and approved by all authors.

Author information



Corresponding author

Correspondence to Robert Gross.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Vujkovic, M., Bellamy, S.L., Zuppa, A.F. et al. Polymorphisms in cytochrome P450 are associated with extensive efavirenz pharmacokinetics and CNS toxicities in an HIV cohort in Botswana. Pharmacogenomics J 18, 678–688 (2018).

Download citation

Further reading


Quick links