Judith Schoutenon behalf of the AGEhIV study group

XIX International AIDS Conference July 26th 2012, Washington DC

Comorbidity and ageing with HIVA prospective comparative cohort study

Background & Rationale

• Combination antiretroviral therapy (cART): decline in AIDS-associated morbidity and mortality

• Life-expectancy: still shorter than expected, particularly when cART started late1

• Large proportion of HIV-patients: broad range of comorbidities2

1 Bhaskaran K, Hamouda O, Sannes M, et al. JAMA 2008 Jul 2;300(1):51-9. 2 Hasse B, Ledergerber B, Furrer H, et al. Clin Infect Dis 2011 Dec;53(11):1130-9.

Are age-related comorbidities more prevalent and/or occurring at a younger age in HIV-infected individuals

as compared to in HIV-uninfected individuals?

Design & Study population

Prospective comparative cohort study (started October 2010)

Prevalence (and incidence) of age-associated non-communicable comorbidities (AANCC) and their risk factors in persons ≥45 yrs

Participants:

• HIV-1-infected: from the HIV outpatient clinic at the Academic Medical Center (Amsterdam)

• HIV-1-uninfected: from the Amsterdam Municipal Health Service sexual health clinic, and the ongoing Amsterdam Cohort Studies on HIV/AIDS

Statistical analysis

Preliminary comparison of prevalence of AANCC using currently available baseline data

Multivariable ordinal logistic regression (proportional odds model) to assess the contribution of HIV and traditional risk factors towards AANCC

Outcome measure: Number of AANCC per participant

Covariates explored: age, gender, ethnicity, packyears of smoking, alcohol abuse, substance abuse (XTC, cocaine, cannabis), BMI, sexual orientation (MSM), HIV-status

Comorbidities analyzed

In addition, objective assessment of:• Hypertension:

3 measurements with a 1-minute interval;RR ≥140 and/or ≥90 in all 3 measurements

• Chronic Obstructive Pulmonary Disease: 3 forced expiratory measurements; FEV1/FVC < 0.7 in all 3 measurements

• Diabetes mellitus:HbA1c (IFCC) ≥ 48 mmol/mol and/or Glucose (non-fasting) ≥ 11.1 mmol/L and/orGlucose (fasting) ≥ 7.0 mmol/L

• Reduced renal function:eGFR (CKD-EPI) < 60 mL/min

• Osteoporosis:DXA T-score < -2.5 SD

Hypertension

Angina pectoris

Myocardial infarction

Peripheral arterial insufficiency

Cerebrovascular disease

Diabetes mellitus type 2

Chronic Obstruct Pulm Disease

Chronic liver disease

Reduced renal function

Cancer

Atraumatic fracture/osteoporosis

• Data on the following AANCC were available for analysis• Most of the AANCC were identified as self-reported by participants using a

standardized questionnaire (validation in progress)

Demographic and HIV characteristics

HIV neg(n=452)

HIV pos(n=489) p-value

Age (years) 51.5 (47.5-57.6) 52.9 (48.1-59.8) 0.009 Male gender 83.8% 89.4% 0.013Dutch 82.1% 75.1% 0.037MSM 63.5% 68.5% 0.105Years of known HIV-1 seropositivity (years) 12.2 (6.5-17.3)Mean CD4 count in year prior to enrollment (cells/mm3) 573 (436-748)

Nadir CD4 count (cells/mm3) 210 (130-310)Undetectable during year prior to enrollment 85.0%Prior AIDS 30.1%

On cART

91.2%• 74% started Rx-naive • 26% started ART-exp.

Years since start of first ART (years) 11.2 (5.5-14.9)

Data presented as median (IQR) or percentage as appropriate

Comorbidity risk factors

HIV neg(n=452)

HIV pos(n=489) p-value

Smoking (packyears) 3.0 (0.0-18.5) 7.6 (0.0-31.0) <0.001

Currently smoking 23.9% 31.9% 0.006

Heavy daily drinking 6.9% 3.5% 0.019

Daily to monthly use of cannabis and/or XTC and/or cocaine 17.5% 17.6% 0.965

BMI (kg/m2) 24.5 (22.9-27.0) 24.1 (22.3-26.7) 0.021

Blood pressure systolic (mmHg) 133 (125-143) 135 (126-147) 0.028

Blood pressure diastolic (mmHg) 79 (72-85) 82 (75-89) <0.001

Data presented as median (IQR) or percentage as appropriate

Comorbidity prevalence

HIV neg(n=452)

HIV pos(n=489) p-value

≥1 AANCC (%) 60.4% 74.4% <0.001

Number of AANCC (mean (SD)) 0.9 (0.95) 1.4 (1.27) <0.001

Comorbidity in relation to age

Comorbidity in relation to age

Comorbidity in relation to age

Comorbidity distribution

*

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• BMI, use of XTC/cocaine/cannabis/alcohol, ethnicity and sexual orientation (MSM) were not found to be independent risk factors

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• BMI, use of XTC/cocaine/cannabis/alcohol, ethnicity and sexual orientation (MSM) were not found to be independent risk factors

OR 2.1

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• Adding estimated duration of HIV infection to the model

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• Adding estimated duration of HIV infection to the model

OR 1.16

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• Adding duration of ART exposure to the model

Risk factors for comorbidity• Multivariable ordinal logistic regression model

• Adding duration of ART exposure to the model

OR 1.35

The role of AGE accumulation

• AGEs = Advanced Glycation Endproducts• Non-enzymatic glycation of proteins/lipids/DNA• AGE accumulation is influenced by age, smoking, inflammation, renal

function, diabetes• Level of AGEs increases with age (ageing biomarker?)• AGEs in the skin measured with skin autofluorescence (AGE-reader)• Measured AGE-values were compared to existing reference values,

according to age, gender and smoking1

1 Koetsier M, Lutgers HL, de Jonge C, et al. Diabetes Technol Ther 2010 May; 12(5); 399-403.

The role of AGE accumulation

The role of AGE accumulation

The role of AGE accumulation

The role of AGE accumulation• Adding excess AGE accumulation to the model (per 10% above the reference AGE value)

The role of AGE accumulation• Adding excess AGE accumulation to the model (per 10% above the reference AGE value)

OR 1.08

Conclusions

• AANCC were significantly more prevalent amongst HIV-positives compared to uninfected controls of similar age

• (Longer duration of) being HIV infected / exposure to cART were associated with a higher prevalence of AANCC(in a cohort almost exclusively on cART)

• HIV-positive participants consistently had excess accumulation of AGEs

• Excess accumulation of AGEs was independently associated with a higher prevalence of AANCC (causality cannot be established in a cross-sectional analysis)

AgehIV Study Team

Academic Medical CenterP. Reiss (PI) F.W. WitM. van der Valk J. Schouten K. KooijB.C. Elsenga A. Henderiks

Public Health Service AmsterdamM. Prins (co-PI)I.G. StolteM. Martens J. BerkelS. MollA. van RoosmalenG.R. Visser

HIV Monitoring Foundation F. de Wolf S. Zaheri Y.M. Ruijs L. GrasA. KesselringAmsterdam Institute of Global Health and DevelopmentM. HeidenrijkR. Meester F. Janssen Financial support:The Netherlands Organisation for Health Research and Development (ZonMW) grant nr. 300020007 & Stichting AIDS Fonds grant nr. 2009063Additional unconditional grants from: Gilead Sciences Boehringer Ingelheim ViiV Healthcare Abbott

Janssen PharmaceuticalsMerck & CoBristol Myers Squibb

AgehIV Study Team: additional collaborators

AMC Dept. of Infectious Diseases S.E. Geerlings, J.M. Prins, J.T. van der Meer, F.J. Nellen, M.H. Godfried, T. van der Poll, M. van Vugt, W.J. Wiersinga, H.E. Nobel, J. van Eden, M. Mutschelknauss-Rikken, A. van Hes, A. Westerman, F. Pijnappel

Experimental Immunology & Lab Viral ImmunopathogenesisN. Kootstra, J. Hamann, E. van Leeuwen, M. Joerink, A.B. van ‘t Wout, H. Schuitemaker, P. Baars, R. Lutter

CardiologyJ. de Jong

Vascular medicineB.J. van den Born, E. Stroes, B. van den Bogaard, E. de Groot

EndocrinologyM. Serlie, P. Bisschop, P. Lips (VUMC)

OncologyD. Richel

Geriatric medicineS. de Rooij

Nuclear medicine B. van Eck-Smit, M. de Jong

Pulmonary medicine R. van Steenwijk, E. Dijkers

Nefrology J. Willemsen, R. Krediet

Gastro-enterology E. Dekker

Psychology P. Nieuwkerk

Sexuology R. van Lunsen, M. Nievaard

Neurology P. Portegies

Neuropsychology B. Schmand

Neuroradiology C. Majoie, M. Caan, T. Su, F. Vos

Ophthalmology F. Verbraak, N. Demirkaya

Psychiatry E. Ruhé, I. Visser

HIV Vereniging Nederland M. Mulder

And of course many thanks to all study participants!