Improving HIV chronic care and health outcomes Antonella d’Arminio Monforte Institute of Infectious and Tropical Diseases, Department of Health Sciences University of Milano
% suppressed among those on ART:
Prevalence of different non-AIDS related co-morbidities at different age strata in naive patients 14.8% 16% 14% 12% 10% 8% 6% 3.7% 2.9% 2.9% 4% 2.1% 1.6% 1.6% 1.4% 1.2% 0.8% 0.8% 0.8% 0.8% 0.7% 0.5% 0.5% 0.5% 0.4% 0.3% 2% 0.2% 0.2% 0.1% 0% <=50 51-60 >60 n=12569 n=486 n=1780 naive Cerebrovascular Diabetes Hypertension Myocardial infarction Lipodystrophy eGFR <60 Non-AIDS defining malignancies ESLD Jan 2017 Report
Prevalence of different non-AIDS related co-morbidities at different age strata in ART - treated patients 26.7% 30% 25% 20% 15% 9.8% 10% 6.1% 5.7% 5.2% 4.3% 3.9% 3.4% 3.1% 3.1% 2.4% 2.4% 1.9% 1.7% 1.6% 1.4% 5% 1.2% 1.1% 1.0% 1.1% 0.9% 0.7% 0.7% 0.5% 0% <=50 51-60 >60 n=10787 n=997 n=2997 experienced Cerebrovascular Diabetes Hypertension Myocardial infarction Lipodystrophy eGFR <60 Non-AIDS defining malignancies ESLD Jan 2017 Report
D:A:D - CAUSES OF DEATH IN HIV-POSITIVE INDIVIDUALS Prospective cohort of 49,731 HIV-positive individuals from the D:A:D study at 212 clinics in Europe, the USA and Australia, 1999–2011 Most common causes of death in HIV-positive individuals 100% 90% Unknown 80% Other 70% All deaths Non-AIDS cancer 60% CVD-related 50% Liver-related 40% AIDS-related 30% 20% 10% 0% Total 1999–2000 2001–2002 2003–2004 2005–2006 2007–2008 2009–2011 (n=3909) (n=256) (n=788) (n=862) (n=718) (n=658) (n=627) Year Non-AIDS cancer is the leading non-AIDS cause of mortality and there is no evidence of improvement Smith CJ et al. Lancet 2014;384:241–248
Increase in non-AIDS-defining malignancies (NADM) AIDS-defining malignancy NADM 8000 7000 2500 800 Number of AIDS-defining malignancies Incidence rate per 100,000 person-years Incidence rate per 100,000 person-years 2250 7000 700 6000 2000 6000 Number of NADM 600 5000 1750 5000 500 1500 4000 4000 1250 400 3000 1000 3000 300 750 2000 2000 200 500 1000 1000 100 250 0 0 0 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 0–12 years 13–19 years 20–29 years 30–39 years 40–49 years 50–59 years 60 years and older Adapted from Shiels MS et al. J Natl Cancer Inst. 2011;103:753-62
VACS PREVALENCE OF END-STAGE RENAL DISEASE (ESRD) In a clinical prospective study, 98,687 HIV-positive and demographically matched HIV-negative veterans in the USA contributed 583,178 PYFU, 2003–2010 Overall and age-specific IRs (and 95% CIs) for ESRD HIV-negative HIV-positive 9.00 8.00 7.00 Incidence rate per 1,000 PY 6.00 5.00 4.00 3.00 2.00 1.00 0.00 <40 40–49 50–59 60–69 ≥ 70 Age group (years) HIV-positive adults have a higher risk of ESRD age-associated events, but they occur at similar ages than those without HIV Althoff KN et al. Clin Infect Dis 2015;60:627–638
PATHOPHYSIOLOGY OF CVD IN HIV-POSITIVE INDIVIDUALS Dyslipidemia, lipodystrophy, insulin resistance Adipose tissue and liver dysfunction Adipocytes Chronic inflammation Immune activation Viral replication HIV Lymphocytes ART T cell activation Coagulation (CD38 + ) disorders Vascular and endothelial dysfunction Hypertension, atherosclerosis, myocardial infarction Hemkens LG and Bucher HC. Eur Heart J 2014;35:1373–1381
NA-ACCORD SMOKING, HTN, AND ALCOHOL CONTRIBUTE TO MI RISK IN HIV Retrospective meta-analysis of pts with • validated MI events from 7 clinical Adjusted Population Attributable Fractions for BMI MI MI,* [1] % cohorts within NA-ACCORD from Subgroup 1/2000 to 12/2013 (N = 29,515) [1] § Smoking 38 † 36 Traditional – Population attributable fraction: § Elevated TC 43 † 39 † MI risk proportion of MIs avoidable by § HTN 41 † 39 † factors prevention of modifiable HIV-related § All 3 (smoking, TC, HTN) 86 and traditional MI risk factors § DM 2 4 347 pts (1.2%) had type 1 MI due to – plaque rupture § CKD 3 3 Sensitivity analysis added for 16,687 pts HIV-related – § CD4+ cell count 10 † 14 † MI risk (57%) with BMI data, 227 had type 1 MI § VL 6 8 factors ~ 40% MI reduction achievable through • § AIDS 2 -1 prevention of smoking, elevated TC, or § HCV coinfection 8 † 14 † HTN, regardless of BMI *Adjusted for age, sex, race, and all listed risk factors. † P < .05 In separate study (D:A:D), smoking cessation reduced overall cancer • rate after 1 yr, except lung cancer (rate high even after > 5 yrs) [2] 1. Althoff KN, et al. CROI 2017. Abstract 130. 2. Shepherd L, et al. CROI 2017. Abstract 131.
Higher risk of MI with PI exposure (but not with NNRTI exposure) D:A:D study Adjusted relative rate/year of PI : 1.15 (1.06, 1.25) Adjusted relative rate/year of NNRTI : 0.94 (0.74, 1.19) 10 Number of MIs per 1000 8 PYFU (IC 95%) 6 4 2 0 0 <1 1–2 2–3 3–4 4–5 5–6 >6 Years of exposure to PI or NNRTI Friis-Møller N et al. N Engl J Med 2007;356:1723-35
RISK FACTORS IN DEVELOPING HIV NEUROCOGNITIVE DISORDERS HIV CSF escape 3 CD4 nadir 1 Mental health 1,4 Duration of HIV infection 2 Race 1 Education 1 CNS toxicity of Alcohol & ART 4 recreational drugs 2,4 CNS penetration of ART 3 NCD 4 Other CNS OI 3 HCV 1,4 dementias 4 1. Cross S et al. J Neuroimmune Pharmacol 2013;8:1114–1122; 2. Attonito JM et al. Front Public Health 2014;11:105; 3. Ellis R and Letendre SL. Neurotherapeutics. 2016;13(3):471–476; 4. Anand P et al. AIDS Behav 2010;14(6):1213–1226
ALLRT IMPACT OF ADVANCING AGE ON COGNITION IN HIV+ The AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) study was a prospective cohort of HIV+ ART-naive individuals (n=3313) enrolled in 7 randomized ART parent trials. In the context of long-term ART (2 or more years after starting initial treatment), older age was a significant • risk factor for neurocognitive impairment. Age-related neurocognitive impairment was seen despite continued virologic suppression in most and despite • neurocognitive improvement (lower impairment rate at later follow-up visits) in the cohort as a whole. • Potential causes of age-related neurocognitive impairment: a) ART-related adverse effects of common age- related comorbidities (diabetes, hypertension, hyperlipidemia); b) greater CNS toxicities of ART in older versus younger participants. Coban H, et al. CROI 2017, Seattle (WA). Abst.#343
Odds of osteoporosis in HIV-infected patients compared with HIV-uninfected controls Brown and Qaqish. AIDS 2006;20:2165-74
FACTORS ASSOCIATED WITH RISK OF ABNORMAL BMD OF SPINE AND HIP IN HIV+ INDIVIDUALS Tobacco, Low Older age alcohol and (>40 years) vitamin D opiate abuse Female Race ART gender Elevated Low CD4 cell parathyroid count BMI hormone levels 1. Das S et al. Recent Pat Antiinfect Drug Discov 2014;9:6–13; 2. McComsey GA et al. Clin Infect Dis 2010;51(8):937–946
Novel CVD Risk Factors in HIV: Inflammation and Immune Activation • SMART study showed increased CVD event rates in drug conservation (episodic treatment) vs. viral suppression (continuous treatment) group • HR=1.57, P=0.05 • Primary endpoint recurrent OI/death Inflammatory markers IL-6 and • d-dimer increased 1 month after treatment interruption in SMART Baseline hsCRP, IL-6, and d- • dimer strongly correlated to overall mortality El-Sadr NEJM 2006; Phillips AIDS 2008; Kuller PLoS 2008.
Improving HIV chronic care and health outcomes: conclusions ü Despite good viral control on ART there are still unmet needs in HIV positive patients on care ü Chronic degenerative illnesses occur earlier and more frequently than HIV negative population ü Cancer, CV, renal, bone, liver and cognitive diseases ü Screening and monitoring are mandatory to garantee prolonged life span in healthy conditions
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