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A quantitative basis for antiretroviral therapy for HIV-1 infection

Nature Medicine volume 18, pages 446–451 (2012)Cite this article

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Abstract

Highly active antiretroviral therapy (HAART)1,2,3 has dramatically decreased mortality from HIV-1 infection4 and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication3,5,6,7,8,9, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines10,11 are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.

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Figure 1: Determining inhibitory potential from complex dose-response curves of antiretroviral drugs.
Figure 2: Combined effects.
Figure 3: Estimating the inhibitory potential of triple combinations.
Figure 4: Inhibitory potential of three drug combinations.

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Acknowledgements

We thank J. Blankson, A. Spivak, C. Durand, J. Gallant, J. Cofrancesco and W. Greco for helpful discussions. This work was supported by US National Institutes of Health grant AI081600 and by the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Benjamin L Jilek, Maame E Sampah, S Alireza Rabi, Cynthia K Bullen, Jun Lai, Lin Shen & Robert F Siliciano

  2. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Melissa Zarr, Lin Shen & Robert F Siliciano

  3. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Robert F Siliciano

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  1. Benjamin L Jilek
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Contributions

B.L.J., M.Z., M.E.S., C.K.B. and J.L. conducted the experiments. B.L.J., M.Z., S.A.R., L.S. and R.F.S. carried out the computational analysis. R.F.S. supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Robert F Siliciano.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7, Supplementary Tables 1–8, Supplementary Methods and Supplementary Notes 1–3 (PDF 5880 kb)

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Jilek, B., Zarr, M., Sampah, M. et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med 18, 446–451 (2012). https://doi.org/10.1038/nm.2649

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