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The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV.

Methods

Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks.

Results

The patients had a median age of 32 (range 19–55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment.

Conclusion

Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

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Acknowledgments

The authors acknowledge the contribution of START study staff and the staff of the Prince Cyril Zulu Communicable Disease Centre, particularly Ms. Chandraprabha Singh, Dr. Surie Chinnapa, and Sister Jeanne Liebertrau. CAPRISA is supported by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH) (grant no. AI51794). The START study was supported by grant no. U19 AI051794-0453. The antiretroviral drugs provided were funded by the Global Fund to fight AIDS, Tuberculosis and Malaria. Efavirenz assays were funded by a Hasso Platner Foundation scholarship, awarded to TG. TG was also supported by the Columbia University–Southern African Fogarty AIDS International Training and Research Programme (grant no. D43TW00231). Efavirenz assays were performed at the Division of Clinical Pharmacology, University of Cape Town, South Africa. The assistance and advice of Prof. Peter Smith, Dr. Helen McIlleron, and Mr. Emmanuel Chigutsa are acknowledged.

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Authors and Affiliations

  1. Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

    Tanuja N. Gengiah, Andrew L. Gray, Kogieleum Naidoo & Salim S. Abdool Karim

  2. Department of Pharmacology & Clinical Pharmacology, University of Auckland, Auckland, New Zealand

    Nicholas H. G. Holford

  3. Department of Therapeutics and Medicines Management, University of KwaZulu-Natal, Durban, South Africa

    Julia H. Botha & Andrew L. Gray

  4. Department of Epidemiology, Mailman School of Public Health, Columbia University, Columbia, NY, USA

    Salim S. Abdool Karim

  5. CAPRISA, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Private Bag X7, Congella, 4013, South Africa

    Tanuja N. Gengiah

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  1. Tanuja N. Gengiah
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Correspondence to Tanuja N. Gengiah.

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Gengiah, T.N., Holford, N.H.G., Botha, J.H. et al. The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis. Eur J Clin Pharmacol 68, 689–695 (2012). https://doi.org/10.1007/s00228-011-1166-5

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