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Trends in perimortal conditions and mortality rates among HIV-infected patients: HIV deaths decline 75%; Hepatitis deaths Up 4-Fold
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AIDS:Volume 21(15)1 October 2007p 2093-2100
Hooshyar, Dinaa,b; Hanson, Debra Lb; Wolfe, Mitchellc; Selik, Richard Mb; Buskin, Susan Ed; McNaghten, ADb
From the aEpidemic Intelligence Service, Office of Workforce and Career Development, USA
bDivision of HIV/AIDS Prevention, USA
cGlobal AIDS Program, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
dPublic Health, Seattle and King County, Seattle, Washington, USA.
Of 9225 deaths, 58.6% occurred during 1992-1995, 29.5% during 1996-1999, and 11.9% during 2000-2003.......Liver disease, viral hepatitis, ischemic heart disease, hypertension, and diabetes showing significant increases in proportionate causes of death 1992-2003.
Abstract
Objectives: To describe trends in perimortal conditions (pathological conditions causing death or present at death but not necessarily the reported cause of death) during three periods related to the availability of HAART, pre-HAART (1992-1995), early HAART (1996-1999), and contemporary HAART (2000-2003); annual mortality rates; and antiretroviral therapy (ART) prevalence during 1992-2003.
Design: Multicenter observational clinical cohort in the United States (Adult/Adolescent Spectrum of HIV Disease [ASD] project).
Methods: Proportionate mortality for selected perimortal conditions, annual mortality rates, and ART prevalence were standardized by sex, race/ethnicity, age at death, HIV transmission category, and lowest CD4 cell count of ASD decedents. Multivariable generalized linear regression was used to estimate trends in proportionate mortality, as linear trends through all three HAART periods, mortality rates, and ART prevalence.
Results:
Of 9225 deaths, 58.6% occurred during 1992-1995, 29.5% during 1996-1999, and 11.9% during 2000-2003.
Linear trends in proportionate mortality for noninfectious diseases (e.g., liver disease, hypertension, and alcohol abuse) increased significantly; proportionate mortality for AIDS-defining infectious diseases (e.g., pneumocystosis, nontuberculous mycobacterial disease, and cytomegalovirus disease) decreased significantly. Mortality rates decreased from 487.5/1000 person-years in 1995 to 100.6 in 2002. Of 36 256 patients from ASD, 75.7% (standardized average) were prescribed ART annually.
Conclusions: Among HIV-infected patients, the majority of whom were prescribed ART, the increasing trend in common noninfectious perimortal conditions support screening and treatment for these conditions in order to sustain the trend in declining mortality rates.
Results
From 1992 through 2003, a total of 13 895 deaths occurred; for 9225 (66.4%), specific perimortal conditions were documented. Of these, 5407 (58.6%) deaths occurred during the pre-HAART period, 2722 (29.5%) in the early HAART period, and 1096 (11.9%) during the contemporary HAART period. Of the total 9225 decedents, 16% were female, 47% were men who had sex with men but did not inject drugs, 39% were black, 93% were 25-54 years of age at death, and the lowest CD4 cell count for 73% was < 100 cells/ƒÊl (Table 1). The distributions of the decedents by sex, race/ethnicity, age at death, HIV transmission category, and lowest CD4 cell count differed significantly for the three periods (P < 0.001). Compared with decedents included in the analysis, decedents excluded on the basis of nonspecific perimortal diagnoses (17.9%) differed significantly by sex, HIV transmission category, race/ethnicity, and lowest CD4 cell count. Compared with decedents included in the analysis, decedents excluded owing to missing perimortal diagnoses (15.8%) differed significantly by HIV transmission category, race/ethnicity, and lowest CD4 cell count (Table 1).
Liver disease, viral hepatitis, ischemic heart disease, hypertension, and diabetes showing significant increases in proportionate causes of death 1992-2003.
The trend in proportionate mortality during 1992-2003 reflected a significant increase for perimortal conditions such as liver disease (excluding viral hepatitis), viral hepatitis, hypertension, and alcohol abuse and a significant decrease for perimortal conditions such as pneumocystosis, nontuberculous mycobacterial disease, and cytomegalovirus disease (Table 2). When the multiyear periods were compared, significant changes in proportionate mortality were observed for several perimortal conditions. For example, from the early to contemporary HAART period, the proportionate mortality for viral hepatitis, tuberculosis, and diabetes mellitus increased significantly; proportionate mortality for nontuberculous mycobacterial disease, Kaposi sarcoma, cytomegalovirus disease, anemia, and chorioretinitis decreased significantly. These same trends occurred when the early HAART period was compared with the pre-HAART period, except for the proportionate mortalities associated with anemia and diabetes mellitus, which did not change significantly, and tuberculosis, which decreased significantly.
Discussion
This analysis of data from a large cohort of HIV-infected patients in care during 1992-2003 demonstrated significant changes in the proportionate mortality for several perimortal conditions and a decline in annual mortality rates. Specifically, overall trends in proportionate mortality for many infectious AIDS-defining opportunistic illnesses decreased significantly. Although the proportionate mortality for infectious diseases decreased, infectious diseases continued to contribute most perimortal conditions, even during the most recent period. This finding may be attributable to the relative youth of the cohort members, since their deaths are less likely to be associated with chronic noninfectious diseases, which increase in prevalence among older populations [22]. The greatest decrease in annual mortality rates occurred during the early HAART period. During the contemporary HAART period, the trends in overall ART and NNRTI prevalence leveled off and the trends in PI prevalence declined among this cohort, in which ART was prescribed for three quarters annually. Concurrently, the dramatic decline in mortality slowed. Identifying the reasons for this is beyond the scope of this study but could include the consequences of delaying HIV care [23] and barriers to HAART effectiveness, such as ART-associated toxicity, nonadherence, and resistance [7,24].
In addition to the improved immune status of patients receiving care during the HAART era, the changes in the proportionate mortalities for perimortal conditions likely reflected multiple factors, including changes in screening practices and evolving endeavors (e.g., antimicrobial prophylaxis guidelines, effective opportunistic illness-specific therapy, and public health control efforts [4,8,19]). For example, the increasing trend in proportionate mortality for viral hepatitis should be interpreted with caution because recommendations to screen for hepatitis C in HIV-infected patients were not issued until late 1998 [25]; hence, this increase could reflect increases in the number of diagnoses rather than an increase in prevalence or incidence. Other analyses have also shown statistically significant increases in the number of viral hepatitis diagnoses reported at death during the HAART era [4,8,19]. As for evolving endeavors, recommendations were amended on when to discontinue prophylaxis for primary and secondary opportunistic illnesses, new anti-cytomegalovirus therapies were approved, and concerted public health programs to control tuberculosis were established [26-28]. However, the increasing number of cases of multidrug-resistant tuberculosis nationally reported [27] and the increase in proportionate mortality for tuberculosis in ASD during the contemporary HAART period, compared with the early HAART period, could be early indicators that the trend is reversing.
Given the improved immune status associated with HAART, the significant increase in proportionate mortality for septicemia and the nonsignificant findings for pneumonia and meningitis were unexpected. Studies of death [4,8,17,19] have demonstrated both increasing and decreasing trends in septicemia and no change in the proportion of deaths caused by unspecified pneumonia during 1992-1999 [4].
Changes in HAART could also have been associated with decreases in proportionate mortality for specific noninfectious conditions. For example, the availability of tenofovir as an alternative to zidovudine [7], where zidovudine is associated with the side-effect of anemia, could have contributed to the decline in anemia among our cohort, whose use of prescribed zidovudine declined during the study period (data not shown). Also, the decrease in chorioretinitis may be attributed to decreases in other perimortal conditions that cause chorioretinitis and respond favorably to HAART and opportunistic illness prophylaxis (e.g., cytomegalovirus and toxoplasmosis).
In tandem with interventions involving HAART, chemotherapy advancements for the treatment of Kaposi sarcoma have continued [29]. Our observed decline in perimortal Kaposi sarcoma has also been seen in other studies of deaths of HIV-infected persons [4,8,19]. However, we found no changes in proportionate mortality of cancers other than Kaposi sarcoma. The trends in these cancers among HIV-infected patients are inconsistent [30], and that inconsistency is reflected in other death analyses [4,8,17,19,20].
For less common perimortal conditions, our analysis did not detect any significant trends. For example, some studies have reported declining trends in primary multifocal leukoencephalopathy and cryptococcosis among decedents; others have found no trend [4,8,19]. Limited data on the occurrence of candidiasis before versus during the HAART era make a similar comparison difficult. Although we found a significantly decreasing trend in proportionate mortality for dementia, our definition of dementia was not limited to dementia secondary to HIV infection. Other death analyses have found conflicting results for HIV-related dementia [4,8,17,19].
Although this study could not measure the side effects of HAART [6], they may have contributed to our observed increasing trend in proportionate mortality for diabetes mellitus, ischemic heart disease, and hypertension, and they could explain the increases in proportionate mortality for kidney disease and liver disease in other analyses of causes of death [4,17,19,20]. Another consideration is that even though the prevalence of a condition (e.g., gastrointestinal hemorrhage [31]) is low, its association with mortality may be high. We also found an increasing trend in proportionate mortality for alcohol abuse. The speculated alcohol-induced adverse immunomodulation [32] and the decreased HAART adherence associated with active alcohol abuse and illicit drug use [33] may contribute to the presence of these perimortal conditions.
Although we controlled for potential confounding factors, residual confounding and differences in the design of our analysis compared with that of others (especially in terms of patients' access to care, type of care facility, study calendar period, and limitation to causes of death rather than perimortal conditions) could explain differences in the magnitude of our trends in proportionate mortality compared with the trends identified by other researchers. Furthermore, we could not compare our trends for non-AIDS related illnesses in ASD with those in a comparable HIV-seronegative cohort. Therefore, we were unable to determine whether the use of HAART and opportunistic illness prophylaxes has modified these trends among HIV-infected patients to be more similar to the trends among comparable HIV-seronegative persons.
Our findings must be interpreted in the context of several limitations. First, the generalizability of our results may be limited because the decedents with known perimortal conditions in the seven ASD metropolitan areas may not have been representative of all deaths among the HIV-infected population in the United States. However, the ASD catchment areas included large geographic areas that were the source of care for a substantial proportion of HIV-infected patients. Second, the data may have been affected by incomplete ascertainment of vital status; ASD patients who were lost to follow-up during 1992-2003 (27.7%) were more likely to be younger, white, and have higher lowest CD4 cell count. Third, data on perimortal conditions were missing or were not specific for 34% of decedents, precluding our ability to estimate disease-specific perimortal rates. Fourth, although changes in ICD coding could have led to discontinuity in trends, these changes had the potential to affect approximately only 1 of 12 study years. Finally, although ASD used a standardized data collection tool, the medical information available for abstraction was dependent on the individual clinician's clinical management style.
Since HAART became available to HIV-infected patients obtaining care in the United States, the proportions and numbers of many infectious perimortal diseases and annual mortality rates have declined. Further investigation is needed to determine the causes of the increase in proportionate mortality for several noninfectious perimortal diseases in a population with many prevalent comorbidities (e.g., psychiatric disorders, substance use, and alcohol abuse [34,35]), which could interfere with the effectiveness of HAART.
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