Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-Group Prospective Cohort Study in Two Sub-Saharan Africa Populations

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Abstract

Objectives

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations.

Methods

ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done.

Result

Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART.

Conclusion

We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations.

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Most cited references 31

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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.

Julia Gorski, Philip Ward, D Flockhart … (2003)

We used human liver microsomes (HLMs) and recombinant cytochromes P450 (P450s) to identify the routes of efavirenz metabolism and the P450s involved. In HLMs, efavirenz undergoes primary oxidative hydroxylation to 8-hydroxyefavirenz (major) and 7-hydroxyefavirenz (minor) and secondary metabolism to 8,14-dihydroxyefavirenz. The formation of 8-hydroxyefavirenz in two HLMs showed sigmoidal kinetics (average apparent Km, 20.2 micro M; Vmax, 140 pmol/min/mg protein; and Hill coefficient, 1.5), whereas that of 7-hydroxyefavirenz formation was characterized by hyperbolic kinetics (Km, 40.1 micro M and Vmax, 20.5 pmol/min/mg protein). In a panel of 10 P450s, CYP2B6 formed 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz from efavirenz (10 micro M) at the highest rate. The Km value for the formation of 8-hydroxyefavirenz in CYP2B6 derived from hyperbolic Eq. 12.4 micro M) was close to that obtained in HLMs (Km, 20.2 micro M). None of the P450s tested showed activity toward 7-hydroxylation of efavirenz. When 8-hydroxyefavirenz (2.5 micro M) was used as a substrate, 8,14-dihydroxyefavirenz was formed by CYP2B6 at the highest rate, and its kinetics showed substrate inhibition (Ksi, approximately 94 micro M in HLMs and approximately 234 micro M in CYP2B6). In a panel of 11 HLMs, 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz formation rates from efavirenz (10 micro M) correlated significantly with the activity of CYP2B6 and CYP3A. N,N',N"-Triethylenethiophosphoramide (thioTEPA; 50 micro M) inhibited the formation rates of 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz from efavirenz (10 micro M) by > or = 60% in HLMs) and CYP2B6, with Ki values < 4 micro M. In conclusion, CYP2B6 is the principal catalyst of efavirenz sequential hydroxylation. Efavirenz systemic exposure is likely to be subject to interindividual variability in CYP2B6 activity and to drug interactions involving this isoform. Efavirenz may be a valuable phenotyping tool to study the role of CYP2B6 in human drug metabolism.

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Population-based hematologic and immunologic reference values for a healthy Ugandan population.

Elling Ulvestad, E Lugada, Robert G. Downing … (2003)

To assess the validity of the reference values for hematologic and immunologic indices currently used in Africa, we evaluated blood samples from 3,311 human immunodeficiency virus (HIV)-negative Ugandans aged 1 week to 92 years. Erythrocyte, hemoglobin, and hematocrit levels and mean corpuscular volume all significantly increased with age (P < 0.001) and were independent of gender until the age of 13 years, after which the levels were higher in males than in females (P < 0.001). White blood cell, neutrophil, lymphocyte, basophil, and monocyte counts significantly declined with age until the age of 13 years (P < 0.001), with no differences by gender, while platelet counts declined with age (P < 0.001) and showed differences by gender only among adults older than age 24 years. CD4+- and CD8+-cell counts declined with age until the age of 18 years; thereafter, females had higher counts than males. The absolute values for many of these parameters differed from those reported for populations outside Africa, suggesting that it may be necessary to develop tables of reference values for hematologic and immunologic indices specific for the African population. This may be particularly important with regard to CD4+-cell counts among children because significant differences in absolute and percent CD4+-cell counts exist between the values for Western populations and the values for the population evaluated in our study. These differences could influence the decision to initiate antiretroviral therapy among children infected with HIV.

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Immunohematological reference ranges for adult Ethiopians.

R Doorly, T Sahlu, E Hailu … (1999)

A cross-sectional survey was carried out with 485 healthy working adult Ethiopians who are participating in a cohort study on the progression of human immunodeficiency virus type 1 (HIV-1) infection to establish hematological reference ranges for adult HIV-negative Ethiopians. In addition, enumeration of absolute numbers and percentages of leukocyte subsets was performed for 142 randomly selected HIV-negative individuals. Immunological results were compared to those of 1,356 healthy HIV-negative Dutch blood donor controls. Immunohematological mean values, medians, and 95th percentile reference ranges were established. Mean values were as follows: leukocyte (WBC) counts, 6.1 x 10(9)/liter (both genders); erythrocyte counts, 5.1 x 10(12)/liter (males) and 4.5 x 10(12)/liter (females); hemoglobin, 16.1 (male) and 14.3 (female) g/dl; hematocrit, 48.3% (male) and 42.0% (female); platelets, 205 x 10(9)/liter (both genders); monocytes, 343/microl; granulocytes, 3, 057/microl; lymphocytes, 1,857/microl; CD4 T cells, 775/microl; CD8 T cells, 747/microl; CD4/CD8 T-cell ratio, 1.2; T cells, 1, 555/microl; B cells, 191/microl; and NK cells, 250/microl. The major conclusions follow. (i) The WBC and platelet values of healthy HIV-negative Ethiopians are lower than the adopted reference values of Ethiopia. (ii) The absolute CD4 T-cell counts of healthy HIV-negative Ethiopians are considerably lower than those of the Dutch controls, while the opposite is true for the absolute CD8 T-cell counts. This results in a significantly reduced CD4/CD8 T-cell ratio for healthy Ethiopians, compared to the ratio for Dutch controls.

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Author and article information

Contributors

Sean Emery: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 5 July 2013

Volume: 8

Issue: 7

Electronic Location Identifier: e67946

Affiliations

[1 ]Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

[2 ]Unit of Pharmacology, School of Pharmacy, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

[3 ]Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia

[4 ]Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

[5 ]Venhälsan, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden

[6 ]Department of Internal Medicine, Muhimbili National Hospital, Dar es Salaam Tanzania

[7 ]Department of Medicine, Unit of Infectious Diseases, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden

[8 ]Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia

[9 ]Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

University of New South Wales, Australia

Author notes

* E-mail: Eleni.Aklillu@ 123456ki.se

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: EA JB EM OM AH EN SM WA LB FM GY MJ LB. Performed the experiments: EA JB AH EN SM WA GA KDR. Analyzed the data: EA EN AH. Contributed reagents/materials/analysis tools: EA JB. Wrote the paper: EA EN AH.

¶ These authors also contributed equally to this work.

Article

Publisher ID: PONE-D-13-10117

DOI: 10.1371/journal.pone.0067946

PMC ID: 3702506

PubMed ID: 23861838

SO-VID: 5197b53a-5770-4b24-a915-ee38370a3fc3

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 7 March 2013

Date accepted : 23 May 2013

Page count

Pages: 13

Funding

This study is supported by grant from EDCTP (grant No. CT.2005.32030.001), Swedish research council (grant No. VR 3902, 521-2011-3437, 348-2011-7383), the Swedish International Development Cooperation Agency SIDA (grant No. SWE 2004–098, HIV-2006-031, SWE 2007–270) and Karolinska Institutet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-Group Prospective Cohort Study in Two Sub-Saharan Africa Populations

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Abstract

Objectives

Methods

Result

Conclusion

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PLOS Climate

Most cited references 31

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.

Population-based hematologic and immunologic reference values for a healthy Ugandan population.

Immunohematological reference ranges for adult Ethiopians.

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