Date Published: November 7, 2017
Publisher: Public Library of Science
Author(s): Mark A. Boyd, Amanda Mocroft, Lene Ryom, Antonella d’Arminio Monforte, Caroline Sabin, Wafaa M. El-Sadr, Camilla Ingrid Hatleberg, Stephane De Wit, Rainer Weber, Eric Fontas, Andrew Phillips, Fabrice Bonnet, Peter Reiss, Jens Lundgren, Matthew Law, Steven G Deeks
Abstract: BackgroundThe Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events.Methods and findingsWe included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%–5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants’ CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints.ConclusionsWe found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV-positive people.
Partial Text: Combination antiretroviral therapy has transformed the lives of HIV-positive people. Over the past 20 years in high-income countries, rates of opportunistic diseases have declined and life expectancy has reached levels similar to that of the HIV-negative population [1–4]. However, there is evidence suggesting that people living with HIV experience greater and earlier onset of comorbidities compared with their HIV-negative peers [5–7]. The relative extent to which this observation relates to a higher prevalence of behaviours and risks associated with such comorbidities, increased levels of immune activation and coagulopathy despite sustained virological suppression, antiretroviral treatment, and/or other mechanisms remains unclear [8,9].
The D:A:D study is a prospective observational study that combines 11 cohorts of HIV-positive people. Its objective is to establish whether the use of combination antiretroviral therapy is associated with an elevated risk of CVD, end-stage renal disease (ESRD), liver disease, cancer, and death. The 11 cohorts contribute data on 49,717 participants enrolled at 212 clinics in Europe, the US, Argentina, and Australia. The standardised dataset includes information on socio-demographics, AIDS events and death, known CVD risk factors, height and weight, laboratory markers, antiretroviral treatment history, estimated glomerular filtration rate (eGFR) (Cockcroft—Gault equation), and treatments including those prescribed for CVD risk.
In this analysis we found that HIV-positive people with high predicted CVD or CKD risk were at significant risk for a future CVD or CKD event, and that this risk was multiplicative for those with greater degrees of risk. For instance, we observed a far higher CKD event rate for those at high risk (>5%) for both CVD and CKD (44.0 per 1,000 pyrs) compared to those at low risk for both (0.5 per 1,000 pyrs) and those at intermediate risk for both (5.1 per 1,000 pyrs). We found that the CKD event rate in those with a high CKD risk was highly sensitive to the degree of CVD risk, with a CKD event rate of 7.1, 21.9, and 44.0 events per 1,000 pyrs for a CVD risk of ≤1%, >1%–5%, and >5%, respectively. For CVD events we found that event rates were multiplicative in that there was a gradient from those at low risk for both events (0.45 per 1,000 pyrs) to those at high risk for both events (16.50 per 1,000 pyrs), with those at intermediate risk in between.