Balancing immunological benefits and cardiovascular risks of antiretroviral therapy: when is immediate treatment optimal?

We developed a mathematical model to identify the timing of antiretroviral therapy (ART) initiation that optimizes patient outcomes as a function of patient CD4 count, age, cardiac mortality risk, sex, and personal preferences. Our goal was to find the conditions that maximize patient quality-adjusted life expectancy (QALE) in the context of our model. Under the assumption that ART confers disease progression and mortality benefits at any CD4 count, immediate treatment initiation yields the greatest remaining QALE for young patients under most circumstances. The timing of ART initiation depends on the magnitude of benefit from ART at high CD4 counts, the magnitude of increases in cardiac risk, and patients' preferences. If ART reduces HIV progression at high CD4 counts, immediate ART is preferable for most newly infected individuals <35 years even if ART doubles age- and sex-specific cardiac risk.

[1]  J. Meigs,et al.  Association of Immunologic and Virologic Factors With Myocardial Infarction Rates in a US Healthcare System , 2010, Journal of acquired immune deficiency syndromes.

[2]  O. Kirk,et al.  Class of antiretroviral drugs and the risk of myocardial infarction. , 2007, The New England journal of medicine.

[3]  Andrew J. Schaefer,et al.  The Optimal Time to Initiate HIV Therapy Under Ordered Health States , 2008, Oper. Res..

[4]  Ruiguang Song,et al.  Estimated HIV Incidence in the United States, 2006–2009 , 2011, PloS one.

[5]  Joseph A Hill.  United States Life Tables , 2013 .

[6]  A. Phillips,et al.  Considerations in the rationale, design and methods of the Strategic Timing of AntiRetroviral Treatment (START) study , 2013, Clinical trials.

[7]  Y. Yazdanpanah,et al.  A decision tree to help determine the best timing and antiretroviral strategy in HIV-infected patients , 2011, Epidemiology and Infection.

[8]  D. Ho,et al.  Time to hit HIV, early and hard. , 1995, The New England journal of medicine.

[9]  J Darbyshire,et al.  CD4+ count-guided interruption of antiretroviral treatment. , 2006, The New England journal of medicine.

[10]  Maria Deloria-Knoll,et al.  Survival Benefit of Initiating Antiretroviral Therapy in HIV-Infected Persons in Different CD4+ Cell Strata , 2003, Annals of Internal Medicine.

[11]  Jiaquan Xu,et al.  Deaths: final data for 2006. , 2009, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[12]  James M Robins,et al.  When to Initiate Combined Antiretroviral Therapy to Reduce Mortality and AIDS-Defining Illness in HIV-Infected Persons in Developed Countries , 2011, Annals of Internal Medicine.

[13]  A. Telenti,et al.  CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. , 2003, Archives of internal medicine.

[14]  O. Kirk,et al.  The use of the Framingham equation to predict myocardial infarctions in HIV‐infected patients: comparison with observed events in the D:A:D Study , 2006, HIV medicine.

[15]  Mark Harrington,et al.  Hit HIV-1 hard, but only when necessary , 2000, The Lancet.

[16]  Melissa R Pfeiffer,et al.  Causes of Death among Persons with AIDS in the Era of Highly Active Antiretroviral Therapy: New York City , 2006, Annals of Internal Medicine.

[17]  J. J. Henning,et al.  Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, January 28, 2000 , 1998, HIV clinical trials.

[18]  J. Chmiel,et al.  Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[19]  A. Mocroft,et al.  Serious Fatal and Nonfatal Non-AIDS-Defining Illnesses in Europe , 2010, Journal of acquired immune deficiency syndromes.

[20]  Roger Detels,et al.  Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection , 1997, Annals of Internal Medicine.

[21]  Jonathan AC Sterne,et al.  Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies , 2002, The Lancet.

[22]  Stephen R Cole,et al.  Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies , 2009, The Lancet.

[23]  D. Cooper,et al.  Immunodeficiency and the risk of serious clinical endpoints in a well studied cohort of treated HIV-infected patients , 2010, AIDS.

[24]  E. Vittinghoff,et al.  Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons , 2011, AIDS.

[25]  E. Arias,et al.  United States life tables, 2006. , 2010, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[26]  B. Gazzard,et al.  Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count , 2007, AIDS.

[27]  Rodolphe Thiébaut,et al.  Combination antiretroviral therapy and the risk of myocardial infarction , 2003 .

[28]  Dimitri P. Bertsekas,et al.  Dynamic Programming and Optimal Control, Two Volume Set , 1995 .

[29]  D. Vlahov,et al.  Mortality in HIV-seropositive versus -seronegative persons in the era of highly active antiretroviral therapy: implications for when to initiate therapy. , 2004, The Journal of infectious diseases.

[30]  O. Kirk,et al.  Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration , 2008, The Lancet.

[31]  Michael J Silverberg,et al.  Effect of early versus deferred antiretroviral therapy for HIV on survival. , 2009, The New England journal of medicine.

[32]  Andrew N. Phillips,et al.  When to start highly active antiretroviral therapy in chronically HIV-infected patients: evidence from the ICONA study , 2001, AIDS.

[33]  A. Zolopa,et al.  Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial , 2009, PloS one.

[34]  Milton C Weinstein,et al.  Cost-effectiveness implications of the timing of antiretroviral therapy in HIV-infected adults. , 2002, Archives of internal medicine.

[35]  S. Cole,et al.  Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. , 2011, Archives of internal medicine.

[36]  O. Kirk,et al.  Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. , 2010, The Journal of infectious diseases.

[37]  Sally S Bebawy,et al.  Estimating the Optimal CD4 Count for HIV-infected Persons to Start Antiretroviral Therapy , 2010, Epidemiology.

[38]  Andrew Schaefer,et al.  Influence of Alternative Thresholds for Initiating HIV Treatment on Quality-Adjusted Life Expectancy: A Decision Model , 2008, Annals of Internal Medicine.