Mortality and progression to AIDS after starting highly active antiretroviral therapy

Objectives: To examine survival and progression to AIDS among HIV-infected patients after starting highly active antiretroviral therapy (HAART). Methods: The study population consisted of 3724 patients from the ATHENA observational cohort who initiated HAART. We considered progression to either an AIDS-defining disease or death, distinguishing HIV-related and non-related (including therapy-related) deaths. A time-dependent multivariate hazards model was fitted to the patient data and 5-year survival probabilities under various therapy scenarios estimated. Results: A total of 459 patients developed AIDS and 346 died during 12 503 person-years of follow-up. HIV-related mortality decreased from 3.8 to 0.7 per 100 person-years between 1996 and 2000 whereas non-HIV-related mortality did not change (0.4 and 0.9, respectively, P = 0.25). For asymptomatic and symptomatic therapy naive patients younger than 50 years with CD4 counts above 10 × 106 and 150 × 106 cells/l, respectively, predicted 5-year survival probabilities were above 90% when HAART was used continuously. This limit was 450 × 106 cells/l when HAART was used during 20 weeks in each 24 week-period of follow-up, and 110 × 106 cells/l when patients delayed initiation of HAART for 1 year after becoming eligible for treatment. Conclusions: Survival probabilities were high among HIV-infected patients initiating HAART at an early stage of infection. The best therapy strategy is therefore to start HAART at this stage of infection. However, deferring HAART in patients with high CD4 cell counts may be clinically more appropriate given toxicity and adherence problems. The lack of any change in non-HIV-related mortality suggests that toxicity has not yet become a major risk factor for death.

[1]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[2]  P. Eilers,et al.  Non-proportional hazards models in survival analysis , 2000 .

[3]  Mortality in a cohort of HIV-infected adults started on a protease inhibitor-containing therapy: standardization to the general population. , 2001, Journal of acquired immune deficiency syndromes.

[4]  D. Revicki,et al.  A randomized trial of the effect of ritonavir in maintaining quality of life in advanced HIV disease , 1998, AIDS.

[5]  M Egger,et al.  AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. , 1999, JAMA.

[6]  Richard D Moore,et al.  HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy , 2001, AIDS.

[7]  P. Couzigou,et al.  Is hepatitis C virus co-infection associated with survival in HIV-infected patients treated by combination antiretroviral therapy? , 2002, AIDS.

[8]  M. Lederman,et al.  Changing spectrum of mortality due to human immunodeficiency virus: analysis of 260 deaths during 1995--1999. , 2001, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  C. Sabin,et al.  Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre , 2001, AIDS.

[10]  K. Hertogs,et al.  Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: Effects on virologic, immunologic, and toxicity parameters , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Cooper,et al.  Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: acohort study , 1999, The Lancet.

[12]  M. Moroni,et al.  Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients , 2000, AIDS.

[13]  D. Cooper,et al.  Adverse effects of antiretroviral therapy , 2000, The Lancet.

[14]  D. Richman,et al.  Predictors of Self‐Reported Adherence and Plasma HIV Concentrations in Patients on Multidrug Antiretroviral Regimens , 2000, Journal of acquired immune deficiency syndromes.

[15]  G. M. Ortiz,et al.  The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection , 2001, AIDS.

[16]  T F Blaschke,et al.  Patient compliance and drug failure in protease inhibitor monotherapy. , 1996, JAMA.

[17]  A. Mocroft,et al.  Relations among CD4 Lymphocyte Count Nadir, Antiretroviral Therapy, and HIV-1 Disease Progression: Results from the EuroSIDA Study , 1999, Annals of Internal Medicine.

[18]  Manuel Battegay,et al.  Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study , 1997, BMJ.

[19]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[20]  D Johnson,et al.  The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group. , 1999, AIDS.

[21]  JD Lundgren,et al.  Changing patterns of mortality across Europe in patients infected with HIV-1 , 1998, The Lancet.

[22]  D. Revicki,et al.  Quality of life outcomes of combination zalcitabine-zidovudine, saquinavir-zidovudine, and saquinavir-zalcitabine-zidovudine therapy for HIV-infected adults with CD4 cell counts between 50 and 350 per cubic millimeter , 1999 .

[23]  R. Paredes,et al.  HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection , 2001, AIDS.

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

[25]  R. Weber,et al.  Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 cell count > 350 × 106/l , 2002, AIDS.

[26]  Michael S Saag,et al.  Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. , 2002, JAMA.

[27]  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.

[28]  S. Paulous,et al.  Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. , 1999, AIDS.

[29]  H. Furrer,et al.  Impact of occasional short interruptions of HAART on the progression of HIV infection: results from a cohort study , 2002, AIDS.

[30]  John W. Ward,et al.  1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. , 1993, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[31]  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.

[32]  I Spijkerman,et al.  AIDS prognosis based on HIV‐1 RNA, CD4+ T‐cell count and function: markers with reciprocal predictive value over time after seroconversion , 1997, AIDS.

[33]  M. Sprangers,et al.  Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study. , 2001, Archives of internal medicine.