Elsevier

The Lancet

Volume 384, Issue 9939, 19–25 July 2014, Pages 241-248
The Lancet

Articles
Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration

https://doi.org/10.1016/S0140-6736(14)60604-8Get rights and content

Summary

Background

With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011.

Methods

Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression.

Findings

3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11).

Interpretation

Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement.

Funding

Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Introduction

In settings with access to antiretroviral therapy (ART), AIDS-related mortality in HIV-positive individuals in care has decreased substantially, with life expectancy now approaching that seen in the general population.1, 2, 3 As a result, the relative importance of other traditionally non-AIDS-related morbidities has increased, and a wider range of complications has been seen than in previous years.1

The occurrence of some non-AIDS-related morbidities might be higher in people with HIV than in the general population for three main reasons. First, the HIV-positive population in high-income settings has a high level of traditional risk factors for non-AIDS morbidities, such as smoking and hepatitis co-infection.4, 5, 6 Second, available evidence suggests that the persistent immunodeficiency, immune dysregulation, immune activation, and inflammation associated with HIV infection, including in patients on ART, might increase the risk of some of these morbidities.7, 8 Third, antiretroviral-related adverse events such as dyslipidaemia and diabetes might also play a part. Although ART has clear benefits, lifelong exposure to these drugs is likely to be needed. Thus, long-term surveillance for emerging or not-yet-identified serious adverse events caused by extended exposure to these novel agents is important. The reporting of such events using a passive, clinician-initiated approach will probably not be sensitive enough to detect emerging issues should they occur. A major aim of the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study is to identify whether emerging serious toxicities are linked with use of ART by looking for increases in the rates of mortality either from a particular organ system, from cancers, or from other as-yet unanticipated causes.

We aimed to investigate trends over time in all-cause mortality and for specific causes of death from 1999 to 2011 within the D:A:D study. We examined whether any recorded changes over time in death rates (overall and cause-specific) could be explained by changes in the characteristics of the HIV-positive population, including HIV immunological and virological status. Finally, we assessed whether any unexpected increases in rates of death from any specific cause emerged.

Section snippets

Study design

Participants included were from the D:A:D study,9 a collaboration of 11 (nine ongoing) cohort studies of 49 731 individuals with HIV-1 receiving care at 212 clinics in Europe, USA, and Australia. All participants were under active follow-up in their cohorts at the time of enrolment. Prospective follow-up, with visits of at least every 8 months, began in January, 1999, irrespective of ART status. Participants were recruited during three recruitment waves: December, 1999–April, 2001; December,

Results

Most of the 49 731 D:A:D study participants were men, the most common mode of HIV acquisition was sex between men, and the median age at study entry was 38 years (table 1). Compared with participants who were being followed up on Jan 1, 2001 (when the first wave of recruitment was nearing completion), those who were being followed up in 2011 were less likely to have acquired HIV through intravenous drug use, less likely to be hepatitis B virus-positive or hepatitis C virus-positive, less likely

Discussion

Our findings suggest that death rates in HIV-positive individuals with access to care and antiretroviral therapy have decreased since 1999–2000. We can detect no indication of an increase in risk of death from any specific cause as a potential result of long-term adverse effects of ART, and the risk of death from other causes—ie, those other than AIDS-related disease, cardiovascular disease, liver disease, and non-AIDS cancers—is low. These findings provide further evidence of the substantial

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