Trends in Causes of Death
Figure 2 demonstrates the causes of death for HIV-infected decedents from 1995 through 2004 (the 4 deaths without known date are not included). During the early part of the study, as expected, AIDS deaths predominated. In the later years, AIDS still accounted for approximately half of the deaths, but non-AIDS deaths increased as a proportion of deaths. The total number of non-AIDS deaths per year increased slightly in the HAART era but the increase was not significant. The major causes of non-AIDS deaths were liver-related (42), cardiovascular mortality (33), non-AIDS malignancies (31), and accidental, self-induced or violent deaths (55). Miscellaneous causes of non-AIDS deaths included renal (12), neurologic (11), gastrointestinal (10), infections (5), pulmonary (4), complications of surgery or childbirth (4), and other causes (10) with no discernable trends over time.
Although AIDS deaths decreased over time, they still accounted for 53% of deaths from 1998 to 2004, an era during which potent ART was widely available. Of 183 WIHS participants who died of AIDS during 1998-2004, 165 had a visit in the 14 months before death. Of those 165, 61 (37%) were on HAART during at least 1 visit before death. Of the 61 women on HAART, only 4 had undetectable plasma HIV RNA during a WIHS visit in the 14 months before death. In fact, these 61 women had nonsuppression for 217 of 239 WIHS visits (90%) where they reported HAART. Nonadherence to antiretroviral regimens may account for some but not all of the lack of viral response; of 80 visits during the year before death with adherence data, adherence of least 95% was reported for 57 (71%) of the visits where HAART was reported. The majority of these women started ART with a regimen that was not considered HAART.
No death certificate information was available for 20 of 710 deaths (2.8%). Death certificates were indeterminate, that is lacked adequate information to determine cause, in 54 of 710 deaths (7.6%). The majority of indeterminate deaths (29) had death certificates with “HIV infection” as the only cause of death in women who had a recent WIHS CD4 count ≥200 cells per cubic millimeter, 21 had conflicting or uninterpretable causes of death, and 4 certificates listed “cardiopulmonary arrest” as the only cause of death.
Predictors of Mortality
We analyzed predictors of all-cause mortality, AIDS-related and non-AIDS death among HIV-infected women (Table 1). As expected, HIV-associated characteristics including CD4 count and plasma HIV RNA level were potent predictors of mortality, with HIV RNA predicting non-AIDS and AIDS deaths. Low BMI and HBsAg positivity were also predictive across analyses. Hepatitis C status predicted all-cause and non-AIDS mortality. A predictor of particular note was depressive symptoms, as defined by CES-D score ≥16, which was predictive of all categories of mortality. High BMI was negatively associated with AIDS death compared with women of normal weight.
To understand why the death rate among HIV-infected women has not continued to decline after introduction of potent antiretroviral regimens, we examined the predictors of mortality assessed in Table 1 for 2001-2004, during which HAART was widely used among WIHS participants, and compared these with predictors in the pre- and early-HAART era (1995-1997). We chose 2001-2004 because the age-adjusted death rate and SMR had clearly plateaued among HIV-infected WIHS women through that period. Predictors of all-cause mortality were much the same in both eras (data not shown). CD4 cell depletion to <200 cells per cubic millimeter [HR 6.02 (3.86 to 9.40), 1995-1997 and 4.38 (2.74 to 6.99), 2001-2004] and HIV RNA level [HR 1.69 (1.44 to 1.99), 1995-1997 and 1.29 (1.10 to 1.53) 2001-2004] remained important predictors of mortality in both periods although with reduced HRs in the recent era. Depressive symptoms, older age, and BMI <18.5 were significant predictors for overall mortality in both eras with nonsignificant increases in HRs in the recent era. Hepatitis C viremia was not a significant predictor in the early HAART era but became predictive for 2001-2004 [HR 1.78 (1.15 to 3.12) 2001-2004].
We analyzed the potential predictors listed in Table 1 for the major causes of non-AIDS mortality, including liver, cardiovascular, non-AIDS malignancies, and self-induced/traumatic death. Table 2 summarizes the significant predictors with CD4 count included as a predictor of interest. CES-D ≥16 was again an important predictor, especially for cardiovascular deaths and non-AIDS malignancies. Liver deaths, as expected, were associated with HCV viremia and the presence of HBsAg in serum.
In this 10-year study of mortality trends among HIV-infected US women, we found that the death rate has plateaued after a substantial decrease during the early HAART era, despite the addition of younger healthier women to the cohort in 2001-2002. Mortality from non-AIDS causes has become increasingly common; with the major causes of non-HIV related death being violence or self-harm, non-HIV associated cancers, cardiac, and liver disease. Although these findings are largely consistent with those of other recent cause of death studies among HIV-infected persons, we identified several trends and predictors that suggest interventions that may reduce morbidity and mortality among HIV-infected US women.
Despite the increasing role of non-AIDS deaths, women with HIV in the WIHS continue to die of AIDS; 53% of deaths with known cause from 1998 to 2004 were due to AIDS. Several other large cohorts have reported a smaller proportion of deaths due to AIDS in the HAART era than that observed in the WIHS11-13 though differences in the definition of AIDS death must be taken into account. For example, in the multicenter Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) collaboration, AIDS death accounted for only 37% of deaths with known cause from 1998 to 2003 among 7680 HIV-infected individuals.12 In the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, among 23,441 HIV-infected persons from December 1999 through February 2004, 31% of deaths were due to AIDS although the definition of AIDS death was restrictive.13 In contrast, the US HIV Outpatient Study found that 61% of deaths with known cause from 1998-2004 were due to AIDS, although, again, the definition of AIDS death differed slightly from ours.14 In our study, HIV-related characteristics continue to be predictive of all-cause mortality, even in the present era. Several large epidemiologic studies have shown that female sex is associated with increased morbidity and mortality among HIV-infected persons,15-17 and CDC mortality data reveal that since the widespread availability of potent treatments, women with HIV have not enjoyed the same magnitude of decline in mortality as men.3 It is also clear that women have not used HAART at rates equivalent to those of men since the beginning of the HAART era.18,19 In our study, of 165 women who died of AIDS during 1998-2004, only 61 were on HAART at any visit in the 14 months before death. The majority of these women reported adherence but had detectable HIV RNA for 90% of the visits before death. In a cross-sectional study in the WIHS in 2000-2001, we demonstrated that among 889 women with medical indications for HAART, 29% were not using it; recreational drug use, history of physical or sexual abuse, and non-white race were associated with nonuse of HAART.20
The most common cause of non-AIDS death in our cohort was trauma and intentional or unintentional self-harm, most commonly overdose. This rate exceeds that reported in many cohorts,11,21 though it is similar to cohorts of HIV-infected injection drug users and HIV-infected persons in Southern Alberta where the prevalence of drug abuse among HIV-infected persons is high.15,22 Factors in the WIHS that may contribute to this high rate of violent death and suicides are the prevalence of depressive symptoms, the high rates of physical abuse suffered by WIHS women,23 and the ongoing vulnerability associated with poverty and substance abuse. There may be physiologic reasons for this high rate as well; HIV-infected drug users in the AIDS Link to Intravenous Experience study were more than twice as likely to die of overdose than HIV-uninfected drug users. The authors of this report postulated that a portion of this discrepancy was due to medical conditions and abnormal liver function in the HIV-infected drug users.24 We found an unexpected relationship between HIV RNA level and overdose/traumatic death. Of interest, the Strategies for the Management of Antiretroviral Therapy study reported a relationship between overdose and deferred ART.25 Rates of accidental- or injury-related mortality in the WIHS were specifically compared with rates for men in the Multicenter AIDS Cohort Study by Hessol et al.21 Women participating in the WIHS had significantly higher death rates from injury and accident than men in the Multicenter AIDS Cohort Study and, in multivariate comparisons traumatic deaths, were associated with female sex, injection drug use, depressive symptoms, unemployment, and smoking.
One striking finding of our analysis was the consistency of the predictive role of depressive symptoms on mortality among HIV-infected women. CES-D ≥16 was an independent predictor of AIDS and non-AIDS-related mortality throughout the decade of study observation. Depression is generally more common among women than men and highly prevalent in the WIHS, with 31% of women chronically reporting depressive symptoms and an additional 37% with intermittent depressive symptoms.26,27 The association of depression with AIDS-related death was described previously by the WIHS and other studies,27,28 although has not been consistently found by all investigators.29 We originally postulated that this association was mediated through nonuse of potent ART among depressed persons; however, we found the association was independent of HAART use. Furthermore, depressive symptoms were associated with the 4 most common causes of non-AIDS mortality affecting these women; these associations were statistically significant for cardiovascular disease and non-AIDS malignancies (Table 2).
A notable finding was the negative association between high BMI and AIDS death. Overweight and obesity are very common in the WIHS, with 54.2% of women overweight (BMI ≥ 25) including 25.7% obese (BMI ≥ 30) at WIHS baseline. Compared with women with normal BMI, women who were overweight had a significantly lower HR of AIDS deaths and the hazard was smaller as BMI increased, 0.63 (95% CI 0.45 to 0.89) for overweight nonobese women and 0.48 (95% CI 0.31 to 0.73) for obese women. This association has been found in mixed-gender cohorts and smaller cohorts of HIV-infected women.30,31 Others have found that obesity affects T-cell subset frequency and may be associated with higher CD4+ T-lymphocyte counts in HIV-infected and HIV-uninfected persons.32-34
There has been much interest in the role of viral hepatitis in HIV disease progression and mortality, and several studies have reported that liver disease is the most common cause of non-AIDS death among HIV-infected persons.11,13 Liver-related deaths were the second most common cause of non-AIDS death in our cohort. Liver-related deaths were associated with viral hepatitis, as expected. Although there was a trend toward a predictive role for low CD4 count, we did not find the significant association of markers of immune dysfunction and liver deaths that has been found in other studies. In the large D:A:D and CASCADE studies, low CD4 counts strongly predicted liver-related mortality.13,35 In contrast to some investigators, we did not find that viral hepatitis was predictive of AIDS death.36
Causes of death, in our study, were ascertained by death certificate. Although this is the method used in the vast majority of published mortality analyses, the limitations of death certificate data are well known and may be a particular problem in HIV/AIDS.37-39 We have attempted to increase the accuracy of cause of death classification using other data available in the WIHS. Because we used consistent and thorough methodology for ascertaining cause of death and a well-defined algorithm to classify deaths consistently over time, we believe that the trends we identified are robust. The use of CD4 count as part of the definition of AIDS death, we believe, increases the accuracy of certain categories of death, but it precludes the use of CD4 as a predictor of AIDS death and complicates the evaluation of the relationship between CD4 and non-AIDS deaths.
Although the CES-D has been found to be sensitive tool in a variety of populations and is widely used and validated in HIV-infected persons,40-42 it contains several questions that could reflect physical debility rather than depression. Thus there is the potential that the CES-D may overestimate depression in some women.
In this cohort of HIV-infected US women, mortality declined dramatically with the introduction of HAART. However, mortality has not continued to decline but has plateaued over the last several years at a rate 10 times greater than age-matched US women. We found that HIV-related factors were the most potent predictors of mortality, but a number of treatable conditions, most notably depression and viral hepatitis, were also associated with mortality across time and analyses. Further gains in reducing mortality among HIV-infected women may require broader access to available therapies for depression, viral hepatitis, and HIV itself.
Data in this article were collected by the WIHS Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, NY (Howard Minkoff); Washington, DC Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); and Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
HIV; mortality; non-AIDS mortality, women; viral hepatitis