An internationally generalizable risk index for mortality after one year of antiretroviral therapy

Objective:Despite the success of antiretroviral therapy (ART), excess mortality continues for those with HIV infection. A comprehensive approach to risk assessment, addressing multiorgan system injury on ART, is needed. We sought to develop and validate a practical and generalizable mortality risk index for HIV-infected individuals on ART. Design and methods:The Veterans Aging Cohort Study (VACS) was used to develop the VACS Index, based on age, CD4 cell count, HIV-1 RNA, hemoglobin, aspartate and alanine transaminase, platelets, creatinine and hepatitis C status, and a Restricted Index based on age, CD4 cell count and HIV-1 RNA with an outcome of death up to 6 years after ART initiation. Validation was in six independent cohorts participating in the ART Cohort Collaboration (ART-CC). Results:In both the development (4932 patients, 656 deaths) and validation cohorts (3146 patients, 86 deaths) the VACS Index had better discrimination than the Restricted Index (c-statistics 0.78 and 0.72 in VACS, 0.82 and 0.78 in ART-CC). The VACS Index also demonstrated better discrimination than the Restricted Index for HIV deaths and non-HIV deaths, in men and women, those younger and older than 50 years, with and without detectable HIV-1 RNA, and with or without HCV coinfection. Conclusions:Among HIV-infected patients treated with ART, the VACS Index more accurately discriminates mortality risk than traditional HIV markers and age alone. By accounting for multiorgan system injury, the VACS Index may prove a useful tool in clinical care and research.

[1]  Ralph B D'Agostino,et al.  Presentation of multivariate data for clinical use: The Framingham Study risk score functions. , 2005, Statistics in medicine.

[2]  S. Fisher,et al.  Mortality ascertainment in the veteran population: alternatives to the National Death Index. , 1995, American journal of epidemiology.

[3]  E. Beutler,et al.  The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? , 2006, Blood.

[4]  K. Leveno,et al.  The continuing value of the Apgar score for the assessment of newborn infants. , 2001, The New England journal of medicine.

[5]  J. Sterne,et al.  The Coding Causes of Death in HIV (CoDe) Project: Initial Results and Evaluation of Methodology , 2011, Epidemiology.

[6]  T. Stijnen,et al.  Review: a gentle introduction to imputation of missing values. , 2006, Journal of clinical epidemiology.

[7]  Ross J. Harris,et al.  Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[8]  S. Leone,et al.  Causes of death and risk factors among HIV-infected persons in the HAART era: analysis of a large urban cohort , 2011, Infection.

[9]  R. Vasan,et al.  Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations , 2006, Circulation.

[10]  B. Thiers,et al.  CD4+ Count–Guided Interruption of Antiretroviral Treatment , 2007 .

[11]  John W. Mellors,et al.  Panel on Clinical Practices for Treatment of HIV Infection , 2000 .

[12]  R. Newson Confidence Intervals for Rank Statistics: Somers’ D and Extensions , 2006 .

[13]  Mara A Schonberg,et al.  Prognostic indices for older adults: a systematic review. , 2012, JAMA.

[14]  L. Kuller,et al.  Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  A. Phillips,et al.  The role of HIV in serious diseases other than AIDS , 2008, AIDS.

[16]  Handan Wand,et al.  Plasma levels of soluble CD14 independently predict mortality in HIV infection. , 2011, The Journal of infectious diseases.

[17]  A. Mocroft,et al.  Use of risk equations for predicting disease progression in HIV infection. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  Tom Greene,et al.  Assessing kidney function--measured and estimated glomerular filtration rate. , 2006, The New England journal of medicine.

[19]  J. Sterne,et al.  The changing incidence of AIDS events in patients receiving highly active antiretroviral therapy. , 2005, Archives of internal medicine.

[20]  Melissa Skanderson,et al.  Development and Verification of a “Virtual” Cohort Using the National VA Health Information System , 2006, Medical care.

[21]  Ross J. Harris,et al.  Prognostic importance of anaemia in HIV type-1-infected patients starting antiretroviral therapy: collaborative analysis of prospective cohort studies. , 2008, Antiviral therapy.

[22]  K. Covinsky,et al.  Towards a combined prognostic index for survival in HIV infection: the role of ‘non‐HIV’ biomarkers , 2010, HIV medicine.

[23]  A. Justice HIV and Aging: Time for a New Paradigm , 2010, Current HIV/AIDS reports.

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

[25]  J. Sterne,et al.  Development and validation of a prognostic model for survival time data: application to prognosis of HIV positive patients treated with antiretroviral therapy , 2004, Statistics in medicine.

[26]  A. Phillips,et al.  HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity , 2009, BMJ : British Medical Journal.

[27]  P. Decouflé,et al.  National sources of vital status information: extent of coverage and possible selectivity in reporting. , 1990, American journal of epidemiology.

[28]  D. Levy,et al.  Prediction of coronary heart disease using risk factor categories. , 1998, Circulation.

[29]  J. Neaton,et al.  Risk of cancers during interrupted antiretroviral therapy in the SMART study , 2007, AIDS.

[30]  Lewis H Kuller,et al.  Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection , 2008, PLoS medicine.

[31]  V. Stone,et al.  Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV medicine Association of the Infectious Diseases Society of America. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  K. Covinsky,et al.  Assessing the Generalizability of Prognostic Information , 1999, Annals of Internal Medicine.

[33]  N. Cook Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction , 2007, Circulation.

[34]  P. Phanuphak,et al.  Short-term clinical disease progression in HIV-infected patients receiving combination antiretroviral therapy: results from the TREAT Asia HIV observational database. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[35]  J. Montaner,et al.  Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection , 2006, Hepatology.

[36]  J. Halter,et al.  Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[37]  S. Deeks Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy. , 2009, Topics in HIV medicine : a publication of the International AIDS Society, USA.

[38]  D. Jacobs,et al.  Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. , 2010, The Journal of infectious diseases.

[39]  Ross J. Harris,et al.  Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[40]  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.

[41]  A. Mocroft,et al.  A clinically prognostic scoring system for patients receiving highly active antiretroviral therapy: results from the EuroSIDA study. , 2002, The Journal of infectious diseases.