Combine operations research with molecular biology to stretch pharmacogenomics and personalized medicine - A case study on HIV/AIDS

Abstract The dramatic reduction in morbidity and mortality associated with the use of highly active antiretroviral therapy has created new challenges for clinicians: AIDS has become a chronic, potentially life-threatening, condition in many clinical instances. In this paper, a novel system engineering approach based on mixed-integer linear programming (MILP) is presented to support HIV/AIDS clinicians when formulating real-world therapeutic plans for heavily treatment-experienced patients under variable settings. Our results suggest that, while current practices (standard protocols and/or subjective recommendations based on the clinician's experience) can generally provide satisfactory management of drug resistance in the short-term , optimization-based therapy planning has a far greater potential to achieve this goal over expanded time horizons thereby changing paradigms and rethinking best practices in the HIV/AIDS clinical arena. Moreover, the ability of this methodology to address other viral pathologies (e.g., hepatitis B and C virus) can make this work appeal to a broader audience.

[1]  Robert S. Parker,et al.  Clinically relevant cancer chemotherapy dose scheduling via mixed-integer optimization , 2009, Comput. Chem. Eng..

[2]  Antonios Armaou,et al.  Sensitivity analysis of HIV infection response to treatment via stochastic modeling , 2008 .

[3]  D. Odloak,et al.  Modeling interleukin-2-based immunotherapy in AIDS pathogenesis. , 2013, Journal of theoretical biology.

[4]  I. Grossmann,et al.  Global optimization of bilinear process networks with multicomponent flows , 1995 .

[5]  David S. Johnson,et al.  Computers and Intractability: A Guide to the Theory of NP-Completeness , 1978 .

[6]  P. Rondó,et al.  Dyslipidaemia and insulin resistance in vertically HIV-infected children and adolescents , 2011 .

[7]  N Oreskes,et al.  Verification, Validation, and Confirmation of Numerical Models in the Earth Sciences , 1994, Science.

[8]  A. Vandamme,et al.  A Genotypic Drug Resistance Interpretation Algorithm that Significantly Predicts Therapy Response in HIV-1-Infected Patients , 2001, Antiviral therapy.

[9]  C. Mackay,et al.  The HIV coreceptors CXCR 4 and CCR 5 are differentially expressed and regulated on human T lymphocytes , 1997 .

[10]  D. Odloak,et al.  Rescue therapy planning based on HIV genotyping testing , 2013 .

[11]  A S Perelson,et al.  Drug concentration heterogeneity facilitates the evolution of drug resistance. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Ian Wilson,et al.  Planning of patient-specific drug-specific optimal HIV treatment strategies , 2009 .

[13]  Theresa Frangiosa,et al.  Challenges, Opportunities, and Evolving Landscapes in Pharmacogenomics and Personalized Medicine An Industry Perspective , 2008 .

[14]  Marc S Jacobson,et al.  Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing. , 2007, Circulation.

[15]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[16]  Peter Gluckman,et al.  Developmental origins of noncommunicable disease: population and public health implications. , 2011, The American journal of clinical nutrition.

[17]  J. Lopreato,et al.  General system theory : foundations, development, applications , 1970 .

[18]  D. Edwards,et al.  HIV-1 Drug Resistance Evolution Among Patients on Potent Combination Antiretroviral Therapy With Detectable Viremia , 2005, Journal of acquired immune deficiency syndromes.

[19]  Marcel Joly,et al.  CXCR4 and CCR5 regulation and expression patterns on T- and monocyte-macrophage cell lineages: implications for susceptibility to infection by HIV-1. , 2005, Mathematical biosciences.

[20]  A. Perelson Modelling viral and immune system dynamics , 2002, Nature Reviews Immunology.

[21]  Olaf Wolkenhauer,et al.  Systems Biology: the Reincarnation of Systems Theory Applied in Biology? , 2001, Briefings Bioinform..

[22]  Soo-Yon Rhee,et al.  HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance , 2007, AIDS.

[23]  D. Noble Claude Bernard, the first systems biologist, and the future of physiology , 2008, Experimental physiology.

[24]  Mike Mannion,et al.  Complex systems , 1997, Proceedings International Conference and Workshop on Engineering of Computer-Based Systems.

[25]  Lawrence F. Shampine,et al.  The MATLAB ODE Suite , 1997, SIAM J. Sci. Comput..

[26]  K. Anastos,et al.  Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy. , 2001, The Journal of clinical investigation.

[27]  A. Curran,et al.  Raltegravir, Etravirine, and Ritonavir-Boosted Darunavir: A Safe and Successful Rescue Regimen for Multidrug-Resistant HIV-1 Infection , 2009, Journal of acquired immune deficiency syndromes.

[28]  S. Hughes,et al.  Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication , 2010, Journal of Virology.

[29]  Jose M. Pinto,et al.  PLANNING AND SCHEDULING MODELS FOR REFINERY OPERATIONS , 2000 .

[30]  George M. Hall,et al.  Sustainability of the chemical manufacturing industry—Towards a new paradigm? , 2010 .

[31]  Lidia Ruiz,et al.  Clinical utility of HIV-1 genotyping and expert advice: the Havana trial , 2002, AIDS.

[32]  Alan S. Perelson,et al.  Mathematical Analysis of HIV-1 Dynamics in Vivo , 1999, SIAM Rev..

[33]  C. Benson,et al.  Viral Dynamics in Human Immunodeficiency Virus Type 1 Infection , 1995 .

[34]  Takayuki Itoh,et al.  Microglia Express CCR5, CXCR4, and CCR3, but of These, CCR5 Is the Principal Coreceptor for Human Immunodeficiency Virus Type 1 Dementia Isolates , 1999, Journal of Virology.

[35]  Lígia Cardoso dos Reis,et al.  Dyslipidaemia and insulin resistance in vertically HIV-infected children and adolescents. , 2011, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[36]  L. Hawkley,et al.  Perceived social isolation and cognition , 2009, Trends in Cognitive Sciences.

[37]  P. Rondó,et al.  Lipid profile of HIV-infected patients in relation to antiretroviral therapy: a review. , 2013, Revista da Associacao Medica Brasileira.

[38]  Eoin Coakley,et al.  Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[39]  B. Korber,et al.  HIV sequence compendium 2002 , 2002 .

[40]  Christian Laurent,et al.  Scale-up of antiretroviral treatment in sub-Saharan Africa is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients , 2011, AIDS.

[41]  Anne-Mieke Vandamme,et al.  Predictive value of HIV-1 genotypic resistance test interpretation algorithms. , 2009, The Journal of infectious diseases.

[42]  H. Inadera,et al.  Developmental origins of obesity and type 2 diabetes: molecular aspects and role of chemicals , 2013, Environmental Health and Preventive Medicine.

[43]  Robert W Shafer,et al.  HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. , 2008, AIDS reviews.

[44]  Jose M. Pinto,et al.  Role of mathematical modeling on the optimal control of HIV-1 pathogenesis , 2006 .

[45]  Richard E. Rosenthal,et al.  GAMS -- A User's Guide , 2004 .

[46]  J. E. Cuthrell,et al.  On the optimization of differential-algebraic process systems , 1987 .

[47]  C. Mackay,et al.  The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[48]  José M. Pinto,et al.  An in-depth analysis of the HIV-1/AIDS dynamics by comprehensive mathematical modeling , 2012, Math. Comput. Model..

[49]  Luis Menéndez-Arias,et al.  DR_SEQAN: a PC/Windows-based software to evaluate drug resistance using human immunodeficiency virus type 1 genotypes , 2006, BMC infectious diseases.

[50]  S. Cole Social regulation of human gene expression: mechanisms and implications for public health. , 2013, American journal of public health.

[51]  P. Rondó,et al.  Omega-3 Fatty Acids and Hypertriglyceridemia in HIV-Infected Subjects on Antiretroviral Therapy: Systematic Review and Meta-analysis , 2011, HIV clinical trials.

[52]  V. Pathak,et al.  Retroviral mutation rates and reverse transcriptase fidelity. , 2003, Frontiers in bioscience : a journal and virtual library.

[53]  I. Grossmann,et al.  A combined penalty function and outer-approximation method for MINLP optimization : applications to distillation column design , 1989 .

[54]  Christoph Königs,et al.  Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents , 2012, AIDS.