Due to highly active antiretroviral therapy (HAART), individuals with human immunodeficiency virus (HIV) infection are living longer1, are less likely to develop acquired immunodeficiency syndrome (AIDS) [1,2], and are more likely to die from a non-AIDS related cause [1-8]. Consequently, major causes of death (e.g., heart disease, kidney disease, and liver disease) that are not clearly attributable to HIV infection have acquired greater importance in the clinical management of HIV-infected persons. Previous analyses of multiple-cause data from death certificates found that liver, kidney, and heart diseases had become the third, fourth, and fifth most common causes of death, respectively, among HIV-infected individuals by 1999, after pneumonia and septicemia [9]. The percentage of deaths due to these three diseases increased during 1996- 2006 [10]. The risk of some types of heart disease and kidney disease may also be greater among HIV-infected persons than in the general population [11, 12]. Because of this relationship, the Health Resources and Services Administration’s Guide for HIV/AIDS Clinical Care recommends physicians to work closely with HIV-infected patients to reduce the risks of heart [13] and renal diseases [14]. Previous research investigating rates of death due to chronic disease in individuals diagnosed with HIV were conducted in Spain [2, 15], and France [16], but did not compare rates between individuals diagnosed with HIV and the general population [9, 10]. To our knowledge, this is the first study to compare rates of death due to kidney disease, specific types of heart disease (ischemic heart disease, heart failure, and cardiomyopathy) and liver disease (hepatitis B, hepatitis C, and other liver diseases) among individuals diagnosed with HIV infection with the corresponding rates in the general US population using data from all 50 states and the District of Columbia. This study controlled for age, sex, race/ethnicity, and region of residence. The study period was 2009-2011, which provided almost 2 million person-years of follow-up. This analysis was not limited to underlying causes of death because such a limitation might conceal a cause of interest among deaths for which the underlying cause was HIV infection.

Our comparison of death rates could be biased by under-reporting of heart, liver, or kidney disease on death certificates that report HIV infection. To look for evidence suggesting this, we also measured the percentage of death certificates in which HIV infection was the only cause reported (except for cardiac arrest or respiratory arrest) among death certificates with any mention of HIV infection. These would represent instances of under-reporting of other causes if it is assumed that HIV infection can cause death only through other diseases due to the HIV infection.

Linkage of multiple-cause death-certificate data to persons reported to the national HIV surveillance system is incomplete at the individual level. To calculate cause-specific national death rates for individuals diagnosed with HIV infection, therefore, we used an “ecologic” method, defining numerators and denominators at only aggregate, demographic-group levels. We chose 2009 as the beginning of the study period because it followed the first year (2008) in which all 50 states and the District of Columbia had implemented confidential name-based reporting of HIV infection. Earlier then, health departments in some jurisdictions did not collect data on non-AIDS cases of HIV infection or accepted codes in places of names (which made removal of duplicate reports more difficult).

Most individuals diagnosed with HIV infection who died during the study period were male, black/African American (hereafter referred to as black), and lived in the South. The same was true for the individuals not diagnosed with HIV infection who died in the study period (Table 1).

This analysis is unique because it was based on reporting of HIV infection diagnoses and causes of death for the population of the entire nation (all 50 states and the District of Columbia). The large number of observations and all the person years of follow-up argue in favor of the validity of our findings.

We found that HIV-infected persons have significantly higher rates of death due hepatitis B, hepatitis C, and liver disease excluding hepatitis B or C, when compared to the general population. These findings are consistent with the results of previous research [12]. The higher rates may not necessarily be due to HIV infection itself, but could be due to common risk factors for both HIV infection and the liver diseases, such as shared modes of transmission of HIV and viral hepatitis [17-19], or high-risk life styles that expose persons to multiple diseases. Thus, the higher rates of death with both types of hepatitis among persons diagnosed with HIV infection than in the general population could have been due to higher prevalence of hepatitis among HIV-infected persons. If we had been able to control for the prevalence of hepatitis among the two populations by limiting the death rate denominators to persons with hepatitis, we might have found no differences between their rates of death with hepatitis.

Our finding that rates of death with hepatitis C were higher than rates of death with hepatitis B among both persons diagnosed with HIV infection and the general population is consistent with hepatitis C being more prevalent than hepatitis B in both populations. The fact that the rate ratio comparing the death rate among persons diagnosed with HIV infection with that in the general population was higher for hepatitis B than for hepatitis C is due to the rates of death in the two populations being more similar for hepatitis C than for hepatitis B. This, in turn, may be explained by the prevalence of hepatitis C in the general population being more similar to that among persons diagnosed with HIV infection.

Individuals diagnosed with HIV infection had significantly higher rates of death due to kidney disease than their counterparts in the general population for every sexual and racial/ethnic group, and region of residence. These findings are consistent with previous studies that found that kidney disease is more common in HIV-infected individuals [31]. One possible explanation for the increased risk of death due to kidney disease among individuals diagnosed with HIV infection may be HIV-associated nephropathy, some of which may be due to nephrotoxicity of antiretroviral drugs rather than to HIV alone [32, 33].

We also found that females, males, persons in most racial/ethnic groups, and individuals residing in most regions of the country who were diagnosed with HIV infection had significantly lower rates of death due to ischemic heart disease than the general population. This seems to contradict the association of HIV infection with ischemic heart disease found by other studies, such as the finding that highly active antiretroviral therapy was associated with an increase in intima media thickness of the carotid artery [23]. However, previous studies have produced conflicting results regarding whether individuals with HIV infection are more susceptible to ischemic heart disease [34-39].

Males, blacks, and individuals residing in the Northeast or South who were diagnosed with HIV infection had significantly lower rates of heart failure when compared to their counterparts in the general population. The lower rates were found despite age adjustment, and thus are not explained by HIV-infected persons dying younger than the general population. These findings contradict previous studies that found that individuals with HIV infection had an increased risk of death due to heart failure [24, 25]. Other investigators have attributed the increased risk that they found to factors such as increased atherosclerosis due to inflammation [40] or endothelial dysfunction to HIV replication [41, 42].

Females, blacks, whites, and individuals who resided in the South or Midwest who were diagnosed with HIV infection had significantly higher rates of cardiomyopathy than the general population. These results are consistent with previous research which determined that individuals diagnosed with HIV infection had had an increased risk of dying with cardiomyopathy [26]. Previous research has attributed the increased risk of cardiomyopathy to HIV infection of the myocardium, HIV treatment toxicity, opportunistic infections, or nutritional deficiencies [43, 44].

In this analysis, we made full use of the multiple-cause mortality data by counting a disease as a cause of death if there was any mention of it on the death certificate, regardless of whether it was classified as the underlying cause, the immediate cause, an intermediate cause, or only a contributing cause. The alternative of limiting the analysis to underlying causes would have concealed most of the diseases of interest (liver, kidney or heart disease) whenever they and HIV infection were reported together, as HIV was selected as the underlying cause in most such deaths. As an infectious disease, viral hepatitis would have been even more likely to be concealed than the non-infectious diseases, because the ICD-10 rules for selecting the underlying cause state that “any infectious disease …should be considered… a direct consequence of reported HIV disease.” Consequently, even if viral hepatitis initially appeared to be the underlying cause, HIV infection would ultimately have been selected as the underlying cause if HIV infection were reported anywhere on the death certificate, “whether in Part I or Part II. [45]. Alternative approaches, such as review of medical records, laboratory reports, and autopsy results by an independent panel of physicians, have been suggested as ways to recognize the contribution of non-underlying causes to the deaths of persons dying of HIV infection, and possibly to correct errors made by certifiers [46], but these would have been impractical to apply to the large numbers of deaths in our analysis.

This study has some limitations. First, our data on deaths due to liver, kidney, or heart diseases were based on information from death certificates, which is subject to error, especially for deaths without autopsies [47]. Possibly reflective of this, 16% of the deaths in which HIV was mentioned as a cause had no other cause mentioned, which suggests that other causes, such as liver, kidney, or heart disease, may have been under-reported among deaths reported with HIV infection. Second, because all 50 states did not implement name-based HIV reporting until 2008, we did not think it would be worthwhile to investigate national trends in causes of death, as these would have been limited to the short period 2009--2011. However, limiting the study to 2009-2011 enabled us to include all 50 states and the District of Columbia, which made the data nationally representative of individuals diagnosed with HIV infection. This study did not control for some factors that could contribute to heart, liver, or kidney diseases (e.g., smoking, obesity, diabetes, hypertension, hypercholesterolemia). Finally, we did not link the death data with reported cases of HIV infection at the individual level, but instead estimated the number of deaths among persons diagnosed with HIV infection by depending on HIV infection being reported on death certificates. According to the instructions on death certificates, diseases or injuries should not be reported unless they caused or contributed to the death. Thus, if a person diagnosed with HIV infection died of a condition that the certifier thought was not attributable to or aggravated by HIV infection, and HIV infection did not contribute to the death in any other way, then the HIV infection should not have been reported on the death certificate. Consequently, we must have under-counted deaths among persons diagnosed with HIV infection, which reduced our chances of finding higher rates of death with other diseases (e.g., heart diseases) in this population, but we found some higher rates (e.g., with liver and kidney diseases) despite this limitation. Because death certificates were not linked to HIV case reports, we could not determine persons with unreported HIV infection. Therefore, we were unable to perform a sensitivity analysis.

Understanding the relationship between HIV infection and liver, kidney, and heart diseases will enable public health practitioners and physicians to intervene more effectively to address these illnesses and improve health outcomes for individuals diagnosed with HIV infection [11, 12, 19, 23, 48]. This becomes even more important as the percentage of older individuals increases among persons diagnosed with HIV infection. Our findings reemphasize the need for healthcare providers to consider these common diseases that seem unrelated to HIV infection when caring for patients with HIV infection. These findings also highlight the need to further explore the effect that chronic HIV infection and concurrent infection with liver, kidney, or heart disease has in the long term health of women.