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.
Subscribe to Journal
Get full journal access for 1 year
only $104.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
UNAIDS. Global report: UNAIDS report on the global AIDS epidemic 2014. Geneva: UNAIDS; 2014.
Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet. 2001;40:893–905. https://doi.org/10.2165/00003088-200140120-00002.
Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18:388–99. https://doi.org/10.1007/s13365-012-0120-3.
World Health Organization. Global update on the health sector response to HIV 2014. WHO: Geneva, Switzerland; 2014.
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. https://doi.org/10.3109/00365548.2013.773067.
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. https://doi.org/10.1016/S0140-6736(13)62187-X.
OARAC. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Internet]. 2016. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 6 July 2016.
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. https://doi.org/10.1124/jpet.103.049601.
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. https://doi.org/10.1111/bcp.12590.
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. https://doi.org/10.1093/jac/dku110.
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. https://doi.org/10.1097/FPC.0b013e32835a450b.
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. https://doi.org/10.1097/QAI.0b013e31817c1ed0.
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. https://doi.org/10.1097/QAD.0000000000001593.
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. https://doi.org/10.1097/QAI.0000000000001442.
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 https://doi.org/10.1186/1742-6405-7-32.
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 https://doi.org/10.1371/journal.pone.0086919.
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.
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. https://doi.org/10.1086/655470.
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. https://doi.org/10.1038/sj.clpt.6100072.
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 https://doi.org/10.1186/1471-2334-13-261.
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. https://doi.org/10.1093/jac/dkt372.
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.
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.
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.
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.
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.
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.
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. https://doi.org/10.1067/mcp.2003.22.
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 https://doi.org/10.1371/journal.pone.0063305.
International HapMap C. The International HapMap Project. Nature. 2003;426:789–96. https://doi.org/10.1038/nature02168.
Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005.
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. https://doi.org/10.1016/j.jclinepi.2004.04.002.
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. https://doi.org/10.1310/hct1006-343.
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 https://doi.org/10.1371/journal.pmed.1000066.
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 https://doi.org/10.3389/fgene.2015.00356.
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.
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. https://doi.org/10.1007/s11095-006-0279-5.
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.
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. https://doi.org/10.1093/jac/dkp335.
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. https://doi.org/10.1128/AAC.00283-10.
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. https://doi.org/10.1093/cid/ciu976.
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.
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. https://doi.org/10.1124/dmd.115.065839.
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. https://doi.org/10.1002/jcph.208.
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. https://doi.org/10.1038/clpt.2011.129.
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. https://doi.org/10.1016/j.antiviral.2013.11.011.
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. https://doi.org/10.1097/FPC.0b013e328363176f.
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. https://doi.org/10.1093/infdis/jis508.
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. https://doi.org/10.1086/605126.
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. https://doi.org/10.1093/jac/dkq260.
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. https://doi.org/10.1111/j.1365-2125.2012.04288.x.
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. https://doi.org/10.1007/s15010-013-0560-6.
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.
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. https://doi.org/10.1128/AAC.02384-13.
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 https://doi.org/10.1186/1476-069X-13-34.
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. https://doi.org/10.1021/es060447t.
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.
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. https://doi.org/10.1093/toxsci/kft243.
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.
Kheradpour P, Kellis M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 2014;42:2976–87. https://doi.org/10.1093/nar/gkt1249.
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. https://doi.org/10.1038/tpj.2009.11.
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. https://doi.org/10.1038/nature14248.
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 https://doi.org/10.1186/s40360-015-0004-2.
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.
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.
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.
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.
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
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) doi:10.1038/s41397-018-0028-2
Two-way mobile phone intervention compared with standard-of-care adherence support after second-line antiretroviral therapy failure: a multinational, randomised controlled trial
The Lancet Digital Health (2019)
Meta-analysis of the associations of CYP2B6-516G>T polymorphisms with efavirenz-induced central nervous system side effects and virological outcome in HIV-infected adults
The Pharmacogenomics Journal (2019)