The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals

Objective:To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication. Design:A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62 760 HIV-infected, therapy-naive individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Results:Two thousand and thirty-nine individuals died during the follow-up. The mortality hazard ratio was 0.48 (95% confidence interval 0.41–0.57) for cART initiation versus no initiation. In analyses stratified by CD4 cell count at baseline, the corresponding hazard ratios were 0.29 (0.22–0.37) for less than 100 cells/μl, 0.33 (0.25–0.44) for 100 to less than 200 cells/μl, 0.38 (0.28–0.52) for 200 to less than 350 cells/μl, 0.55 (0.41–0.74) for 350 to less than 500 cells/μl, and 0.77 (0.58–1.01) for 500 cells/μl or more. The estimated hazard ratio varied with years since initiation of cART from 0.57 (0.49–0.67) for less than 1 year since initiation to 0.21 (0.14–0.31) for 5 years or more (P value for trend <0.001). Conclusion:We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up.

[1]  Anton Pozniak,et al.  Surrogacy in HIV-1 clinical trials , 1998, The Lancet.

[2]  Evan Wood,et al.  Continued improvement in survival among HIV-infected individuals with newer forms of highly active antiretroviral therapy , 2007, AIDS.

[3]  Kholoud Porter,et al.  Survival following HIV infection of a cohort followed up from seroconversion in the UK , 2008, AIDS.

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

[5]  Laurence Meyer,et al.  Does transient HAART during primary HIV-1 infection lower the virological set-point? , 2004, AIDS.

[6]  C Maurath,et al.  Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. , 1998, Lancet.

[7]  Gemma Navarro,et al.  Determinants of HIV Progression and Assessment of the Optimal Time to Initiate Highly Active Antiretroviral Therapy: PISCIS Cohort (Spain) , 2008, Journal of acquired immune deficiency syndromes.

[8]  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.

[9]  Andrew N. Phillips,et al.  The UK Register of HIV Seroconverters: methods and analytical issues , 1996, Epidemiology and Infection.

[10]  Jonathan AC Sterne,et al.  Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study , 2005, The Lancet.

[11]  Abdel Babiker,et al.  An evaluation of HIV RNA and CD4 cell count as surrogates for clinical outcome. Delta Coordinating Committee and Virology Group. , 1999, AIDS.

[12]  R B D'Agostino,et al.  Relation of pooled logistic regression to time dependent Cox regression analysis: the Framingham Heart Study. , 1990, Statistics in medicine.

[13]  Mark A van de Wiel,et al.  Mortality and progression to AIDS after starting highly active antiretroviral therapy , 2003, AIDS.

[14]  J. Robins,et al.  Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. , 2000, Epidemiology.

[15]  A. Mocroft,et al.  HIV survival benefit associated with earlier antiviral therapy. , 2004, Annals of internal medicine.

[16]  David D Celentano.  Mortality among urban drug users and the impact of highly active antiretroviral therapy. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[17]  J. Robins,et al.  A Structural Approach to Selection Bias , 2004, Epidemiology.

[18]  Geneviève Chêne,et al.  Mortalité des adultes infectés par le VIH comparée à la population générale - Données à long terme et selon les lymphocytes CD4 , 2008 .

[19]  M J Daniels,et al.  CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta‐analysis of studies of the AIDS Clinical Trials Group , 1998, AIDS.

[20]  M A Fischl,et al.  A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[21]  A. Telenti,et al.  Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study , 1999, The Lancet.

[22]  M. Leal,et al.  Incidence and risk factors for tuberculosis in HIV-positive subjects by HAART status. , 2008, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[23]  J. Robins,et al.  Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. , 2003, American journal of epidemiology.

[24]  Santiago Pérez-Hoyos,et al.  Effectiveness of highly active antiretroviral therapy in Spanish cohorts of HIV seroconverters: differences by transmission category , 2003, AIDS.

[25]  Kholoud Porter,et al.  The creation of a large UK‐based multicentre cohort of HIV‐infected individuals: The UK Collaborative HIV Cohort (UK CHIC) Study , 2004, HIV medicine.

[26]  Michael Rosenblum,et al.  Marginal Structural Models , 2011 .

[27]  Jonathan A C Sterne,et al.  HIV treatment response and prognosis in Europe and North America in the first decade of highly active antiretroviral therapy: a collaborative analysis , 2006, The Lancet.

[28]  Gitte Pedersen,et al.  Survival of Persons with and without HIV Infection in Denmark, 19952005 , 2007, Annals of Internal Medicine.

[29]  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.

[30]  Cyril Dalmasso,et al.  Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study , 2008, PloS one.

[31]  Santiago Pérez-Hoyos,et al.  Survival and progression to AIDS in a seroconverter cohort in the post-highly active antiretroviral therapy era: effectiveness goes on , 2006, AIDS.

[32]  N. Nagelkerke,et al.  Evaluating the role of CD4-lymphocyte counts as surrogate endpoints in human immunodeficiency virus clinical trials. , 1994, Statistics in medicine.

[33]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[34]  Sheldon Brown,et al.  Veterans Aging Cohort Study (VACS): Overview and Description , 2006, Medical care.

[35]  Kholoud Porter,et al.  Determinants of survival following HIV-1 seroconversion after the introduction of HAART , 2003, The Lancet.

[36]  D. Costagliola,et al.  Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy , 2008, AIDS.

[37]  Robert Schooley,et al.  CD4+ Lymphocytes Are an Incomplete Surrogate Marker for Clinical Progression in Persons with Asymptomatic HIV Infection Taking Zidovudine , 1993, Annals of Internal Medicine.

[38]  Santiago Pérez-Hoyos,et al.  [Spanish cohort of naïve HIV-infected patients (CoRIS): rationale, organization and initial results]. , 2007, Enfermedades infecciosas y microbiologia clinica.