HIV, Co-morbidity and Ageing

Transcription

1 HIV, Co-morbidity and Ageing A good head and a good heart are always a formidable combination V Encuentro de Salud Pública 8 October 2015, Madrid, Spain Peter Reiss Director HIV Monitoring Foundation Professor of Medicine Division of Infectious Diseases & Department of Global Health Amsterdam Institute for Global Health and Development Academic Medical Center, University of Amsterdam

2 Disclosures Dr. Reiss reports having received: Unrestricted investigator-initiated grant support through his institution from Gilead Sciences, Janssen Pharmaceutica NV., Merck&Co, Bristol- Myers Squibb, ViiV Healthcare and Boehringer- Ingelheim Honoraria through his institution from Gilead Sciences and Janssen Pharmaceutica NV. for scientific advisory board and data safety monitoring committee participation

3 Changing Age Structure of Population with HIV in Care in The Netherlands 42% older than 50 yrs; 14% older than 60 yrs

4 As expected co-morbidity burden & use of co-medication in HIV increases with ageing % of participants % of participants Comedications No comedication One comedication Two comedications Three comedications Four or more comedications Comorbidities No comorbidity One comorbidity Two comorbidities Three comorbidities Four or more comorbidities 20 0 <50 years years 65+ years n=5761 n=2233 n=450 Agegroups Swiss H I V Cohort Study Hasse B. et al. Clin Infect Dis ;

5 Modelling the Changing Age-structure of PLWHIV in the Netherlands Median age will increase from 43.9 years in 2010 to 56.6 years in 2030 Proportion of HIV-patients aged 60 will increase from 8% to 39% and aged 70 years from 8% to 12% Smit M, et al, on behalf of the ATHENA observational cohort; Lancet Infect Dis 2015

6 Many chronic diseases of ageing have been shown to be more common in those with HIV, even after adjustment for ART use and traditional (lifestyle-related) risk factors Do HIV-positive persons age faster than HIV-uninfected persons? Cardiovascular disease Non-Aids cancers Osteoporosis & Fragility fractures Diabetes mellitus Frailty Neurocognitive decline Chronic liver disease COPD Chronic kidney disease Deeks SG, et al. BMJ 2009; 338:a3172

7 Deeks SG, et al. BMJ 2009; 338:a3172 Chronic disease drivers (known and suspected) acting in concert in HIV ART Host Lifestyle (smoking etc) Genetic Toxicity HIV Persistent Immune Dysregulation & Inflammation in treated HIV disease Clinical Chronic Co-morbidity AGEING

8 Are these age-related chronic conditions just Accentuated or also Accelerated? Accentuated risk Condition occurs at the same age but more often in those with HIV than among HIV-uninfected comparators Accentuated & Accelerated risk Condition occurs more often and at younger age among those with HIV than among HIV-uninfected comparators Shiels MS. Age at Cancer Diagnosis among persons with AIDS in the US. Ann Intern Med 2010

9 Comorbidity and Ageing with HIV A prospective comparative cohort study Prevalence and incidence of age-associated non-communicable comorbidities (AANCC) and their risk factors in persons 45 yrs Started October 2010 Participants: HIV-1-infected: from the HIV outpatient clinic at the Academic Medical Center (Amsterdam) HIV-1-uninfected: from the Amsterdam Public Health Service sexual health clinic, and the ongoing Amsterdam Cohort Studies on HIV/AIDS

10 Populations Age Structure

11 Demographic and HIV characteristics HIV neg (n=524) HIV pos (n=540) p-value Age (years) 52.1 ( ) 52.9 ( ) 0.20 Male gender 85.1% 88.1% 0.15 Dutch 81.3% 72.2% <0.001 MSM 69.7% 73.9% Time since HIV-1 diagnosis (yrs) 12.1 ( ) Mean CD4 count at enrollment (cells/mm 3 ) 565 ( ) Nadir CD4 count (cells/mm 3 ) 180 (78-260) Viral load > 200 at or within 4 mos prior to enrolment among cart-treated participants 1.5% Prior clinical AIDS 31.3% On cart 95.7% 79.1% started R x -naive 20.9% started ART-exp. Years since ART was first initiated (yrs) 10.4 ( ) Duration of viral load < 200 (since last > 200 ) (yrs) 5.8 ( ) Known cumulative duration CD4 < 200(mos) 0.8 ( ) Data presented as median (IQR) or percentage as appropriate. P-value represents Wilcoxon Rank Sum or Chi2 as appropriate Schouten J et al. Clin Infect Dis. 2014

12 Comorbidity risk factors HIV neg (n=524) HIV pos (n=540) Smoking status currently / ever (%) 24.6 / 38.9% 32.0 / 35.0% p-value / 0.23 Smoking (packyears, smokers only) 15.0 ( ) 22.2 ( ) <0.001 Severe alcohol use 7.3% 4.8% Daily to monthly use of: cannabis cocaine ecstasy 11.6% 2.9% 8.6% 13.5% 3.7% 4.3% BMI (kg/m 2 ) 24.5 ( ) 24.2 ( ) Blood pressure systolic (mmhg) 133 ( ) 135 ( ) Blood pressure diastolic (mmhg) 79 (72-85) 81 (75-89) <0.001 Data presented as median (IQR) or percentage as appropriate. P-value represents Wilcoxon Rank Sum or Chi2 as appropriate Schouten J et al. Clin Infect Dis. 2014

13 Age-associated Noncommunicable Comorbidity Prevalence HIV neg (n=524) HIV pos (n=540) p-value 1 AANCC* (%) 61.8% 69.4% Number of AANCC (mean (SD)) 1.0 (0.95) 1.3 (1.14) <0.001 Schouten J et al. Clin Infect Dis. 2014

14 Comorbidity in relation to age Schouten J et al. Clin Infect Dis. 2014

15 Osteopenia/osteoporosis in 3 bone locations K. Kooij et al, J Infect Dis, 2014

16 Hypertension Prevalence of hypertension % 69% Normotension % 17% Hypertension, measured 0 23% 14% Hypertension, treated HIV-infected HIV-uninfected R. Van Zoest et al 16 th Int Wkshp on Comorb and ADR in HIV, Philadelphia, October 2014

17 More frailty and pre-frailty at any age in HIV+ participants HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ HIV- HIV+ K.Kooij et al 8th Netherlands Conference on HIV Pathogenesis, Epidemiology, Prevention and Treatment, Amsterdam, November 2014

18 All frailty factors more prevalent in HIV+ participants K.Kooij et al 8th Netherlands Conference on HIV Pathogenesis, Epidemiology, Prevention and Treatment, Amsterdam, November 2014

19 Neurocognitive impairment AIDS Mar 13;29(5):547-57

20 Comorbidity in relation to age Schouten J et al. Clin Infect Dis. 2014

21 Comorbidity Burden After 2 Year Follow-up baseline 2-years 436 HIV-pos en 437 HIV-neg % % mean # comorbidities 1,23 (baseline) 1,26 (follow-up) mean # comorbidities 0,84 (baseline) 0,84 (follow-up)

22 Risk Factors Associated with Comorbidity Recognized risk factors Nr of AANCC Hypertension CVD Low BMD Frailty HIV + (- once time spent with low low CD4 accounted for) ART duration + ( WHR; both waist& hip circumf. ) + + ( body weight) ( (history of)low BMI) Specific ART exposure +/- (RTV) Prior d4t +(RTV) +(RTV) +/- (PI) AANCC: Age Associated NonCommunicable Comorbidity

23 Chronic disease drivers, known and suspected ART Host Lifestyle (smoking etc) Genetic Toxicity HIV Persistent Immune Dysregulation & Inflammation in treated HIV disease Clinical Chronic Co-morbidity AGING Deeks SG, et al. BMJ 2009; 338:a3172

24 Early ART is associated with less inflammation during ART Will this result in benefit? Strategic Timing of AntiRetroviral Treatment (START) Study HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm 3 Immediate ART Group Initiate ART immediately following randomization N=2,326 Deferred ART Group Defer ART until the CD4+ count declines to < 350 cells/mm 3 or AIDS develops N=2,359 Primary composite endpoint, target = 213 Serious AIDS or death from AIDS Serious Non-AIDS Events and death not attributable to AIDS o CVD, ESRD, decompensated liver disease, & non-aids defining cancers Slide courtesy of Steve Deeks

25 Strategic Timing of AntiRetroviral Treatment (START) Study No. of Participants Type of event Imm. ART Def. ART Serious AIDS Serious non-aids Total* * One participant in each group had both a Serious AIDS and a Serious Non-AIDS Event Lundgren et al, IAS 2015, Vancouver July 2015

26 Chronic disease drivers, known and suspected ART Host Lifestyle (smoking etc) Genetic Toxicity HIV Persistent Immune Dysregulation & Inflammation in treated HIV disease Clinical Chronic Co-morbidity AGING Deeks SG, et al. BMJ 2009; 338:a3172

27 The Host and Lifestyle:the importance of smoking Well treated HIV-infected individuals may lose more life years through smoking than through HIV. Excess mortality associated with smoking increases markedly with age. Therefore, increases in smoking-related mortality can be expected as the treated HIV-infected population ages. Interventions for smoking cessation should be prioritized. ART Cohort Collaboration Helleberg et al. AIDS 2015 Helleberg M et al. Clin Infect Dis. 2013;56:

28 Chronic disease drivers, known and suspected ART Host Lifestyle (smoking etc) Genetic Toxicity HIV Persistent Immune Dysregulation & Inflammation in treated HIV disease Clinical Chronic Co-morbidity AGING Deeks SG, et al. BMJ 2009; 338:a3172

29 ART has clearly become less toxic, but it remains amongst the most common reasons for modifying treatment Reasons for modifying treatment within 3 years of starting cart

30 ARV toxicities may accentuate the clinical expression of certain co-morbidities Some examples: TDF ATV/r,LPV/r,(DRV/r?) Some PI s ABC (?)

31 GS-US Switch to E/C/F/TAF in Virologically Suppressed Adults Primary Endpoint HIV-1 RNA <50 c/ml Randomized (2:1), active-controlled, open-label study Week E/C/F/TDF (n=459) n=959 Switch to E/C/F/TAF Virologically Suppressed Adults EFV/FTC/TDF (n=376) Boosted* ATV + FTC/TDF (n=601) n=477 Continue TDF-Based Regimen All patients HIV-1 RNA <50 copies/ml for 96 weeks on stable TDF-based regimen Estimated GFR >50 ml/min E/C/F/TAF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TAF 10 mg E/C/F/TDF = EVG 150 mg, COBI 150 mg, FTC 200 mg, TDF 300 mg *Boosted by RTV or COBI 35

32 Median % Change in BMD (Q1, Q3) GS-US DXA Scan Results: Spine BMD Change From Baseline to Week 48 All Participants (N=1,369) E/C/F/TAF TDF-Based Regimen 1,79-0,28 p < Baseline Week 24 Week 48 Regardless of prior treatment regimen, differences between arms were statistically significant More than 2% difference between the arms at Week 48 36

33 Median % Change in BMD (Q1, Q3) GS-US DXA Scan Results: Hip BMD Mills, et al, IAS 2015, Vancouver July 2015 Change From Baseline to Week 48 All Participants (N=1,354) 3 2 E/C/F/TAF TDF-Based Regimen ,37-0,26 p < Baseline Week 24 Week 48 Regardless of prior treatment regimen, differences between arms were statistically significant More than 1.6% difference between arms at Week 48 37

34 Median % Change GS-US Renal Safety Results Mills, et al, IAS 2015, Vancouver July Tubular Proteinuria UPCR UACR RBP: RBP:Cr Ratio B2MG: β-2-m:cr Ratio E/C/F/TAF TDF-Based Regimen Each difference between treatment arms was statistically significant (p <0.001). -52 Statistically significant improvements for participants who switched from either E/C/F/TDF or from boosted ATV + FTC/TDF Serum creatinine (p <0.001); egfr (p <0.001) Fractional excretion of phosphate, FEPO4 (p=0.05); fractional excretion of uric acid, FEUA (p <0.001) Changes began by Week 2 and persisted to Week 48 UPCR: urine protein: creatinine ratio; UACR: urine albumin: creatinine ratio; RBP, retinol-binding protein; β-2-m:cr, beta-2 microglobulin. 38

35 Do HIV-positive persons age faster than HIV-uninfected persons? vs.

36 May HIV and ART in Addition Interact with Biological Aging? Chronic disease drivers (known and suspected) act in concert ART Host Lifestyle (smoking etc) Genetic Toxicity HIV Persistent Immune Dysregulation & Inflammation in treated HIV disease Clinical Chronic Co-morbidity AGING

37 Lopez-Otin et al Cell , Torres RA & Lewis W, Lab.Investigation 2014;94: Hallmarks of Biological Aging Several of these may be affected by HIV and/or ART ART HIV HIV (nrti/pi) & ART (PI) HIV & ART (nrti) ART (PI) HIV? &ART? HIV & ART (nrti/pi) ART(nRTI/PI) ART (PI)

38 The COHORTS AMSTERDAM LONDON POPPY: Pharmacokinetic and Clinical Observations in People over Fifty Status: Fully recruited and in follow up phase 598 +ve over controls over 45 AGEhIV: Several outputs from this cohort including 3 publications Status: Recruited over 900 subjects 500 +ve over ve under controls over 50 Recruitment continue until end 2015 Expect recruit 2000 subjects First output last month at BHIVA meeting COBRA: the clinical studies are run as sub-studies of POPPY and Collecting the extra information required Whilst utilising the existing infrastructure

39 Summary of the COBRA project FP7 project of 4 year duration with 12 partners from 6 countries Primary research question: are HIV-infected patients on successful cart prone to develop AANCC at an earlier age (accelerated ageing)? Establish link between HIV and AANCC: o longitudinal HIV cohort studies in Amsterdam and London o biomarkers and neuro-imaging studies Elucidate causative link between HIV and AANCC o Humanised Immune System (HIS) mouse model Clarify pathogenic mechanisms underlying link between HIV and AANCC o Promising biomarkers, including those coming out of the FP7 MARK-AGE project

40 C 3 NL Neuroimaging modalities FLAIR Proton density T2-weighted T1-weighted Voxel-based morphometry Cortical thickness Diffusion Tensor Imaging (DTI)

41 C 3 NL Brain age - Methods

42 C 3 NL Brain age Preliminary results Group comparisons of PAD score

43 MARK-AGE Project Project full title: European Study to Establish Biomarkers of Human Ageing (HEALTH-F ) 1 April September 2013 Scientific Co-ordinator: Alexander Bürkle University of Konstanz, Konstanz, Germany

44 Projections of burden of disease - Proportion with at least one NCD increase from 29% in 2010 to 84% in Proportion with 3 or more NCDs increase from 0.3% in 2010 to 28% in In 2030 only 16% will have none of the NCDs investigated in this study Smit M, et al, on behalf of the ATHENA observational cohort; Lancet Infect Dis 2015 The increase in NCDs will be driven by CVD mainly - In % of patients are diagnosed with some CVD compared to 78% in 2030.

45 Aging with HIV will Increasingly Occur in Resource-limited Settings as well The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-saharan Africa. Hontelez JAC. et al. AIDS 2012, 26 (Suppl 1): & NCHIV 2012, poster 44.

46 Regional Ranking of leading causes of years of life lost (YLL), 2010 Global Burden of Disease Study 2010, modified from Lancet 2012; 380: Kuala Lumpur, Malaysia, 30 June - 3 July 2013

47 Summary and Conclusions Burden of various co-morbidities consistently increased in HIV Traditional risk factors play an important role. Needs to be reflected in our clinical management and care Independent associations with HIV are observed for some but not all co-morbidities Longer time spent at low CD4 counts, rather than longer overall exposure to ART, generally contributes to greater co-morbidity risk. Early HIV diagnosis and treatment now definitively shown to beneficially modify this risk. Persistent inflammation and innate immune activation generally seem to additionally contribute towards risk Pathogenic pathways involving effects on the biology of aging need further exploration

48 Do not regret growing older. It is All a privilege our study denied participants to many Author Unknown Grant nrs & EU 7th FP for research, technological development and demonstration under grant agreement no