Application of fractional factorial designs to study drug combinations

Herpes simplex virus type 1 (HSV-1) is known to cause diseases of various severities. There is increasing interest to find drug combinations to treat HSV-1 by reducing drug resistance and cytotoxicity. Drug combinations offer potentially higher efficacy and lower individual drug dosage. In this paper, we report a new application of fractional factorial designs to investigate a biological system with HSV-1 and six antiviral drugs, namely, interferon alpha, interferon beta, interferon gamma, ribavirin, acyclovir, and tumor necrosis factor alpha. We show how the sequential use of two-level and three-level fractional factorial designs can screen for important drugs and drug interactions, as well as determine potential optimal drug dosages through the use of contour plots. Our initial experiment using a two-level fractional factorial design suggests that there is model inadequacy and that drug dosages should be reduced. A follow-up experiment using a blocked three-level fractional factorial design indicates that tumor necrosis factor alpha has little effect and that HSV-1 infection can be suppressed effectively by using the right combination of the other five antiviral drugs. These observations have practical implications in the understanding of antiviral drug mechanism that can result in better design of antiviral drug therapy.

[1]  James P. Hughes,et al.  Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. , 2010, The New England journal of medicine.

[2]  Don X. Sun,et al.  Optimal Blocking Schemes for 2n and 2n—p Designs , 1997 .

[3]  Jiahua Chen,et al.  Fractional resolution and minimum aberration in blocked 2 n−k designs , 1997 .

[4]  Chih-Ming Ho,et al.  An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells. , 2011, Nature communications.

[5]  Robert W. Mee,et al.  Minimum Aberration Blocking Schemes for 128-Run Designs , 2010 .

[6]  Hongquan Xu,et al.  Minimum aberration blocking schemes for two- and three-level fractional factorial designs , 2006 .

[7]  R. Sun,et al.  Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm , 2008, Proceedings of the National Academy of Sciences.

[8]  Chih-Ming Ho,et al.  Cascade search for HSV-1 combinatorial drugs with high antiviral efficacy and low toxicity , 2012, International journal of nanomedicine.

[9]  T. Chou.  Drug combination studies and their synergy quantification using the Chou-Talalay method. , 2010, Cancer research.

[10]  C. F. Jeff Wu,et al.  Experiments: Planning, Analysis, and Parameter Design Optimization , 2000 .

[11]  Robert W. Mee.  A Comprehensive Guide to Factorial Two-Level Experimentation , 2009 .

[12]  Erik De Clercq,et al.  Antiviral drugs in current clinical use. , 2004 .

[13]  J. Mullins,et al.  Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. , 2010, The New England journal of medicine.

[14]  Hongquan Xu,et al.  Algorithmic Construction of Efficient Fractional Factorial Designs With Large Run Sizes , 2007, Technometrics.

[15]  Fujie Xu,et al.  Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. , 2006, JAMA.

[16]  Håvard Jenssen,et al.  Lactoferrin and lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit synergy when combined with acyclovir. , 2003, Antiviral research.

[17]  R. Whitley,et al.  Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. , 1995, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  Don X. Sun,et al.  Optimal blocking schemes for 2 n and 2 n−p designs , 1997 .

[19]  K. Rosenthal,et al.  Multiple mechanisms for HSV-1 induction of interferon α production by peripheral blood mononuclear cells , 2003, Archives of Virology.

[20]  Ching-Shui Cheng,et al.  Theory of optimal blocking of $2^{n-m}$ designs , 1999 .

[21]  Hongquan Xu,et al.  Two-Level Nonregular Designs From Quaternary Linear Codes , 2011 .

[22]  Hongquan Xu,et al.  Blocked Regular Fractional Factorial Designs With Minimum Aberration , 2005, math/0702702.

[23]  M. Croxson,et al.  Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome , 1997, Journal of neurology, neurosurgery, and psychiatry.

[24]  C. F. Jeff Wu,et al.  Choice of Optimal Blocking Schemes in Two-Level and Three-Level Designs , 2002, Technometrics.

[25]  Lin Wang,et al.  Integrating multiple types of data to predict novel cell cycle-related genes , 2011, BMC Systems Biology.

[26]  Margaret J. Robertson,et al.  Design and Analysis of Experiments , 2006, Handbook of statistics.

[27]  E. De Clercq.  Antiviral drugs in current clinical use. , 2004, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[28]  Hongquan Xu,et al.  A catalogue of three-level regular fractional factorial designs , 2005 .

[29]  Kenneth Joseph Ryan,et al.  Minimum Aberration Fractional Factorial Designs With Large N , 2010, Technometrics.

[30]  Subhajit Biswas,et al.  Drug resistance mutations in HSV-1 UL5 selected using a helicase–primase inhibitor: frequency and effects on virus growth and pathogenicity , 2009 .

[31]  John Norrie,et al.  Longitudinal study of genital infection by herpes simplex virus type 1 in western Scotland over 15 years , 2002, BMJ : British Medical Journal.

[32]  David M J S Bowman,et al.  Flammable biomes dominated by eucalypts originated at the Cretaceous-Palaeogene boundary. , 2011, Nature communications.

[33]  Luc Bijnens,et al.  Design and Analysis of Drug Combination Experiments , 2005, Biometrical journal. Biometrische Zeitschrift.

[34]  Jeff S. Shamma,et al.  Systematic quantitative characterization of cellular responses induced by multiple signals , 2011, BMC Systems Biology.

[35]  S Hercberg,et al.  Seroprevalence of HSV-1 and HSV-2 infection in the general French population , 2002, Sexually transmitted infections.

[36]  Connie Celum,et al.  Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. , 2007, The Journal of infectious diseases.

[37]  Douglas C. Montgomery,et al.  Response Surface Methodology: Process and Product Optimization Using Designed Experiments , 1995 .

[38]  G. Box,et al.  Response Surfaces, Mixtures and Ridge Analyses , 2007 .