Background
The widespread uptake of combination antiretroviral therapy (cART) has led to substantial reductions in morbidity and mortality associated with HIV/AIDS [
1‐
3]. Over the last 20 years, cART regimens have become, not only more effective and less toxic, but also simpler in terms of pill burden and frequency, thus enhancing adherence [
4,
5]. This has translated into improvement in survival among cART-treated persons living with HIV [
6]. Today in many regions, HIV/AIDS is widely viewed as a manageable chronic condition [
7], with the life expectancy of HIV-infected individuals receiving cART approaching that of the general population in some settings [
8‐
10].
Improved survival rates now observed among HIV-infected individuals treated with cART have been accompanied by a gradual shift in their morbidity and mortality patterns in some studies [
11,
12]. Non-HIV-specific diseases, including non-AIDS-defining cancers, cardiovascular diseases (CVD), renal and liver diseases, are becoming more prevalent with many HIV-infected individuals now experiencing one or more of these comorbid conditions [
11‐
16]. As a result, causes of death among people living with HIV have shifted in several important ways. In particular, deaths from these chronic diseases and other complications typically associated with natural aging have gained prominence as individuals are living longer on cART. It is thus important to monitor changes in the causes of death as this information will be useful in projecting future morbidity and mortality trends. Ultimately, such knowledge will provide guidance that may inform how risk factors for such increasingly common adverse health outcomes are addressed in this population.
Although decreases in all-cause mortality rates have been well documented among HIV-infected individuals in British Columbia (BC), Canada [
1,
6,
17‐
21], changes in cause-specific deaths in this population following cART introduction in this setting is less well characterized. Furthermore, it is unclear how the trends and causes of death among HIV-infected individuals in this setting compare to that of the general uninfected population. Given the changing pattern of causes of death reported among HIV-infected individuals in other settings after cART introduction [
11‐
14], we hypothesized that similar patterns may be observed among HIV-infected BC residents. Our objective was, therefore, to characterize the changes in mortality rates and causes of death over time following cART introduction among a population-based cohort of HIV-infected individuals in BC. Secondly, we compared these patterns of death to that observed in a population-based sample of uninfected individuals drawn from the BC general population over the same time period.
Discussion
Since cART introduction in 1996, this is the first population-based study in Canada to characterize changes in mortality and causes of death among persons living with HIV infection as compared to uninfected individuals from the same geographical and health care setting. Compared to uninfected individuals, our result demonstrates that the causes of death among HIV-infected individuals in BC have changed dramatically over time. We observed significant mortality rate reductions in all-cause, HIV/AIDS-related, drug abuse and overdose, and liver disease mortality among people living with HIV in the period from 1996 to 2012. Despite the remarkable decline in mortality from HIV-related causes, HIV/AIDS is still the leading cause of death among HIV-infected individuals and the relative risk of death remains in excess of that for uninfected individuals. Relative to other causes of death, the proportion of total mortality attributable to non-AIDS-defining cancer and CVD has increased among HIV-infected individuals since cART introduction, however, this did not necessarily translate into a trend of increasing mortality rates from these causes; a finding that may be likely due to the overall increased survival in the population. In both HIV-infected and uninfected individuals, we observed significant increases over time in mortality rates from neurologic disorders.
The overall proportion of deaths due to HIV/AIDS-related causes in our study (50.2%) was comparable to those reported from Spain (40.4%) [
36], Italy (41.4%) [
16], Denmark (44.4%) [
37], England and Wales (46.0%) [
38], France (47.3%) [
39], USA (51.4%) [
15] and from multinational cohort collaborations such as Antiretroviral Therapy Cohort Collaboration (49.6%) [
14], but higher than that reported in the Data collection on Adverse events of Anti-HIV Drugs [D:A:D] study (28.7%) [
40]. While our overall findings are broadly consistent with the mortality declines and cause of death trends presented in previous studies of HIV-infected individuals from other settings [
13‐
16,
38,
40,
41]; variations in the range of such estimates may exist across studies and are likely due to heterogeneity in the population (e.g., by age, sex, CD4 levels, cART history, underlying clinical characteristics, ethnicity), differences in the observation period, or the coding scheme for causes of death categories. In sensitivity analysis stratified by ART uptake (ever vs. never), we observed a better mortality prognosis among those who had ever been treated with ART, thus demonstrating the benefit associated with ART. This is supported by a recent BC study among HIV-infected individuals receiving cART since 2001 which demonstrated that cART initiation was independently associated with reduced mortality [
21].
The current study reflects major changes since the introduction of cART in terms of non-HIV/AIDS-related causes; in 1996, only 21% of the deaths among HIV-infected individuals were attributable, as compared to 73% by 2012. Our results confirm two recent reports suggesting that non-AIDS-defining cancers are currently the leading non-HIV/AIDS-related cause of death among HIV-infected individuals [
40,
42]. Similarly, we observed that cancers have also recently overtaken CVD to become the principal cause of death among the uninfected population. Like the D:A:D study [
40] but unlike a report from the HIV Outpatient Study [
15], we observed a statistically significant mortality rate decrease from hepatic and liver disease deaths. Contrary to a finding among HIV-infected hemophiliacs in Canada [
43], liver disease is an important cause of death especially among individuals co-infected with HIV and hepatitis C virus [
44], although not the main non-HIV/AIDS-related cause of death in the current study. The observed increase in mortality rates attributable to neurologic disorders is likely a reflection of the increased longevity in both populations.
Our results indicating that HIV-infected individuals continue to have a mortality risk ratio that is decreasing as time passes but remains approximately three times more than in uninfected individuals as of 2011-2012 is supported by comparable findings from other studies that have compared mortality rates among persons with and without HIV infection [
37,
45]. We suspect the continuing high relative risk of death among HIV-infected, compared to uninfected individuals may in part be explained by the higher prevalence of behavioral risk factors such as smoking, alcohol abuse and other lifestyle factors that are more common among HIV-infected individuals and predisposes them to higher mortality risk compared to uninfected individuals.
Readers should interpret our findings in light of the potential strengths and limitations of the study. The HIV-infected cohort includes the vast majority of all known HIV-infected adults in BC, irrespective of whether they had ever received cART. Despite universal access to HIV treatment in BC, approximately 25% of HIV-infected individuals had no record of HIV treatment initiation during this study (1996 to 2012). Reassuringly, the rates have declined substantially with the implementation of the Treatment as Prevention strategy in BC [
46‐
48], as in a 2008 study we found that 40% of those who died from HIV did not access treatment [
49]. Our uninfected cohort includes randomly sampled BC residents who accessed the same universal health care system as the HIV-infected participants, thus minimizing potential selection bias that may arise from using an external comparison group. Unlike most clinic-based cohorts [
11,
13,
16,
36,
39,
40,
50], the relatively large, linked and population-based nature of the COAST study is unique to BC and has allowed us to ascertain mortality and cause of death information for all study participants through the same source – the BC Vital Statistics Agency -[
31], which is the provincial office that collects vital statistic records in BC. However, since this dataset does not capture deaths to BC residents that occur out-of-province, such deaths were unaccounted for in our analyses. While we suspect this number is likely small, it also will have affected the HIV-infected and uninfected cohorts equally. Finally, our cause of death assessment is limited by the accuracy of the ICD-9/10 coding used for attribution of the underlying cause of death; and the study as a whole, by unmeasured confounding due to its observational nature.
Acknowledgements
The authors would like to thank the BCCfE, BC Ministry of Health, BC Vital Statistics Agency, and the institutional data stewards for granting access to the data, and Population Data BC, for facilitating the data linkage process. The COAST steering committee includes: Julio Montaner, Robert Hogg, Oghenowede Eyawo, Mark Hull, Jeannie Shoveller, David Moore, Paul Sereda and Viviane Lima.