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      All-cause mortality in treated HIV-infected adults with CD4 >=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration 

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          Abstract

          Using data from a large European collaborative study, we aimed to identify the circumstances in which treated HIV-infected individuals will experience similar mortality rates to those of the general population. Adults were eligible if they initiated combination anti-retroviral treatment (cART) between 1998 and 2008 and had one prior CD4 measurement within 6 months. Standardized mortality ratios (SMRs) and excess mortality rates compared with the general population were estimated using Poisson regression. Periods of follow-up were classified according to the current CD4 count. Of the 80 642 individuals, 70% were men, 16% were injecting drug users (IDUs), the median age was 37 years, median CD4 count 225/mm(3) at cART initiation and median follow-up was 3.5 years. The overall mortality rate was 1.2/100 person-years (PY) (men: 1.3, women: 0.9), 4.2 times as high as that in the general population (SMR for men: 3.8, for women: 7.4). Among 35 316 individuals with a CD4 count ≥500/mm(3), the mortality rate was 0.37/100 PY (SMR 1.5); mortality rates were similar to those of the general population in non-IDU men [SMR 0.9, 95% confidence interval (95% CI) 0.7-1.3] and, after 3 years, in women (SMR 1.1, 95% CI 0.7-1.7). Mortality rates in IDUs remained elevated, though a trend to decrease with longer durations with high CD4 count was seen. A prior AIDS diagnosis was associated with higher mortality. Mortality patterns in most non-IDU HIV-infected individuals with high CD4 counts on cART are similar to those in the general population. The persistent role of a prior AIDS diagnosis underlines the importance of early diagnosis of HIV infection.

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          CD4+ count-guided interruption of antiretroviral treatment.

          Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV). We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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            Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

            Mortality among human immunodeficiency virus (HIV)-infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. Excess mortality among HIV-infected individuals compared with that of the general uninfected population. Of 16,534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31,302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14,703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.
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              Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.

              AIDS-related death and disease rates have declined in the highly active antiretroviral therapy (HAART) era and remain low; however, current causes of death in HAART-treated patients remain ill defined. To describe mortality trends and causes of death among HIV-infected patients in the HAART era. Prospective, multicenter, observational cohort study of participants in the HIV Outpatient Study who were treated from January 1996 through December 2004. Rates of death, opportunistic disease, and other non-AIDS-defining illnesses (NADIs) determined to be primary or secondary causes of death. Among 6945 HIV-infected patients followed for a median of 39.2 months, death rates fell from 7.0 deaths/100 person-years of observation in 1996 to 1.3 deaths/100 person-years in 2004 (P=0.008 for trend). Deaths that included AIDS-related causes decreased from 3.79/100 person-years in 1996 to 0.32/100 person-years in 2004 (P=0.008). Proportional increases in deaths involving liver disease, bacteremia/sepsis, gastrointestinal disease, non-AIDS malignancies, and renal disease also occurred (P=or<0.001, 0.017, 0.006, <0.001, and 0.037, respectively.) Hepatic disease was the only reported cause of death for which absolute rates increased over time, albeit not significantly, from 0.09/100 person-years in 1996 to 0.16/100 person-years in 2004 (P=0.10). The percentage of deaths due exclusively to NADI rose from 13.1% in 1996 to 42.5% in 2004 (P<0.001 for trend), the most frequent of which were cardiovascular, hepatic, and pulmonary disease, and non-AIDS malignancies in 2004. Mean CD4 cell counts closest to death (n=486 deaths) increased from 59 cells/microL in 1996 to 287 cells/microL in 2004 (P<0.001 for trend). Patients dying of NADI causes were more HAART experienced and initiated HAART at higher CD4 cell counts than those who died with AIDS (34.5% vs 16.8%, respectively, received HAART for 4 of more years, P<0.0001; 22.4% vs 7.8%, respectively, initiated HAART with CD4 cell counts of more than 350 cells/microL, P<0.001). Although overall death rates remained low through 2004, the proportion of deaths attributable to non-AIDS diseases increased and prominently included hepatic, cardiovascular, and pulmonary diseases, as well as non-AIDS malignancies. Longer time spent receiving HAART and higher CD4 cell counts at HAART initiation were associated with death from non-AIDS causes. CD4 cell count at time of death increased over time.
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                Author and article information

                Journal
                International Journal of Epidemiology
                International Journal of Epidemiology
                Oxford University Press (OUP)
                0300-5771
                1464-3685
                April 04 2012
                April 01 2012
                November 28 2011
                April 01 2012
                : 41
                : 2
                : 433-445
                Article
                10.1093/ije/dyr164
                22493325
                5cf5a6d3-2383-4a31-980c-90f2fc801c36
                © 2012
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