New Insights in Pathogenesis Inflammation and Immune Activation

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1 Activity Code TM809

2 New Insights in Pathogenesis Inflammation and Immune Activation Turner Overton, M.D. Associate Professor of Medicine University of Alabama at Birmingham

3 Learning Objectives Upon completion of this presentation, learners should be better able to: Highlight potential mechanism for persistent inflammation with chronic HIV infection. Demonstrate how chronic inflammation contributes to metabolic comorbidities.

4 Case 1 A 40 yo male presents for care. His CD4 count is 325 c/mm3 (16%) with a plasma HIV RNA of 42,000 cp/ml. He smokes and had a BMI of 24.5 kg/m 2. Total cholesterol is 196 mg/dl, LDL 125 mg/dl, HDL 25 mg/dl, TG 175mg/dL. His parents are alive and healthy. BP is 145/80. He does not exercise. What is the most important intervention to reduce cardiovascular disease risk?

5 What is the most important intervention to reduce cardiovascular disease risk? A. Smoking cessation B. Initiate Mediterranean Diet C. Initiate statin D. Initiate daily aspirin E. Initiate ART 20% 20% 20% 20% 20% A. B. C. D. E. 10

6 Cumulative probability of event Are we treating patients SMART-ly? 0.20 Hazard ratio, 2.6; 95% CI, ; P< Treatment Interruption No. at Risk Drug conservation (DC) Viral suppression (VS) Months Continuous Treatment The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med. 2006;355:

7 Epidemiology of HIV Infection as a Chronic Disease ART Use Over Time, HOPS, % Patients on ART Deaths per 100 Person-years 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% % Year Palella et al.nejm 1998, 338: Palella et al. JAIDS. 2006; 43:27-34

8 Proportion (%) Deaths (%) Overall Mortality and Causes of Death Overall Mortality* Causes of Death 80 Pre-HAART % Pre-HAART (n=1424) HAART (n=514) % HAART OIs 10.0% 2.5% Not Specified 6.5% 6.4% Malignancy 3.2% 9.9% Hepatitis/ Liver 2.5% 4.9% Malignancy 1.3% 4.3% CVD/ DM Years Since Seroconversion* AIDS-Related Non-AIDS-Related *N=7680 seroconverters from 22 cohorts, of whom 1938 died (26%; 1424 pre-haart and 514 during HAART). No change in the following causes of death: AIDS-related malignancy, other infections, organ failure, and unknown causes. Smit C, et al. AIDS. 2006;20:

9 Improving Survival But Still Below General Population Population controls HIV: Current ART HIV: Early ART HIV: Pre-ART Lohse N et al. Ann Intern Med. 2007

10 Cumulative Mortality Cumulative Mortality Estimates NA-ACCORD CD4+ >500 cells/mm 3 & Defer HAART (n=6539) Kitahata M, et al. NEJM Years after 1996 CD4+ >500 cells/mm 3 & Initiate HAART (n=2616) Calculated Using Extended Kaplan-Meier Survival Estimates 10

11 Schouten et al. 19 th International AIDS Conf Washington, DC. Abstract THAB0205

12 Diseases more Common Among HIV-infected Persons Diabetes Mellitus Cardiovascular Disease Cancer Kidney Problems Cognitive Problems Osteoporosis/Fragility Fractures Hypogonadism Frailty Inflammation Aging HIV

13 Non-AIDS Comorbidities Significant contribution of traditional risk factors Genetics Diet Lifestyle/environment Increasing substance and tobacco use increase risk Issues for the future Role of HIV Role of ART Are effects reversible Is early treatment key? Is management different in HIV infection? HIV infection and ART likely increase the risk Chronic viral infection Persistent inflammation Immune activation

14 HIV Pro-coagulation Pro-atherogenic lipid profile Immune activation and inflammation CD4+ T cell depletion Immune senescence Host Family history Smoking Alcohol/Illicit drug use Obesity Latent virus co-infection Natural aging process Non AIDS-defining comorbidities Antiretroviral Direct toxicity Insulin resistance Pro-atherogenic lipid profile Mitochondrial toxicity Body fat changes Önen and Overton. Current Aging Science :

15 Relative Risk of Myocardial Infarction Increases with Age Among HIV-Infected Persons Triant et al. J Clin Endo Metab. 2007; 92:

16 Incident rate ratio for acute MI by age Models adjusted for recognized risk factors Impact of HIV on risk comparable to traditional risk factors including HTN, DM and hyperlipidemia. Freiberg et al. JAMA Intern Med Apr 22;173(8):

17 Uncontrolled HIV Replication is Bad Baker JV and Duprez D. Curr Opin HIV AIDS. 2010; 5:

18 Residual CV Disease Risk Even With Suppressed HIV Viremia Atherosclerosis is an inflammatory process Endothelial smooth muscle disruption Macrophage activation and infiltration Oxidized lipid accumulation Plaque formation Vascular inflammation is greater with HIV infection Increased metabolically active macrophages Greater non-calcified, metabolically active, ruptureprone plaque Yarasheski et al. J Inflammation Zanni et al. AIDS

19 Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals Biomarker Odds ratios*: 1 st vs 4 th Quartile Effect of HAART Other HIV disease Associations D-dimer 12.4 (SMART), 2.4 (FIRST) 2.6 (Phidisa) Decreases CVD hs-crp 2.0 (SMART), 2.1 (FIRST), 3.6 (Phidisa) No decrease CVD, OD IL (SMART), 1.8 (FIRST), 3.8 (Phidisa), 1.5** (ACTG 384 and 5015 ) May decrease CVD, OD scd (SMART) Unknown Microbial translocation -While HAART partially reduces some biomarker levels, they may still remain elevated compared with healthy non-hiv infected individuals. -Furthermore, inflammatory markers are more strongly associated with end organ disease and mortality than in HIV negative populations. Adapted from Nixon and Landay, Curr Opin HIV/AIDS 2010

20 Desai S, Landay A. Curr HIV AIDS Rep.2010; 7(1) HIV Immune Aging Model

21 HIV production HIV replication HIV-associated fat Metabolic syndrome CMV Excess pathogens Loss of regulatory cells Inflammation Monocyte activation T cell activation Dyslipidemia Hypercoagulation Microbial translocation Adapted from Steve Deeks. Co-morbidities Aging

22 Obesity Among HIV Populations SUN Study 494 persons 78% male 61% White 27% Black 10% Hispanic Median BMI: 26 kg/m 2 Obesity was associated with Insulin resistance Elevated cholesterol Elevated inflammation markers Increased atherosclerosis Overweight 38% Normal Weight 38% Obese 23% Underweight 2% Conley et al. IAS Washington, DC. Paper# WEPE096.

23 Comorbidity with Obesity Metabolic HTN DM CKD Behavioral Dyslipidemia OA Cardiac Mood disorders Substance use HCV Alcohol Tobacco Substance use Kim et al. JAIDS. 2012;61:600-5.

24 Obesity Trends* Among U.S. Adults BRFSS, 1990, 1998, 2007 (*BMI 30, or about 30 lbs. overweight for 5 4 person) No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% Source: CDC Behavioral Risk Factor Surveillance System.

25 Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS, 1990,1995 and No Data <4% 4%-6% 6%-8% 8%-10% >10% Source: Mokdad et al., Diabetes Care 2000;23: ; J Am Med Assoc 2001;286:10.

26 Inflammation predicts disease in treated HIV infection Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011) Cardiovascular Disease (Baker, AIDS 2014) Lymphoma (Breen, Cancer Epi Bio Prev, 2010) Venous Thromboembolism (Musselwhite, AIDS, 2011) Type II Diabetes (Brown, Diabetes Care, 2010) Cognitive Dysfunction (Burdo AIDS 2012) Frailty (Erlandson, JID 2013)

27 The ABCDs of Cardiovascular Disease Management A: Aspirin B: Blood pressure C: Cholesterol D: Diabetes S: Smoking

28 Hurley L, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 710.

29 Hurley L, et al. 16th CROI; Montreal, Canada; February 8-11, Abst. 710.

30 Effect of Cutting 500 cal/day over 8 weeks in Obese Persons Effect on Weight Effect on Inflammation Hermana, Endocrine, 2009

31 Healthy aging requires aggressive risk factor management, exercise and diet

32 Brisk Walking Improves Inflammatory Markers in Treated HIV 29 Walk group 20 Strength-Walk 29 Walk group 20 Strength-Walk All on cart Median age 48 years 12 week program 3X weekly exercise 60 mins brisk walking +/- 30 mins strength training Longo et al. CROI 2014.

33 Brisk Walking Improves Inflammatory Markers in Treated HIV At week 12 Improved functional status Reduced some inflammation markers IL-6, d-dimer, hscrp T cell activation Longo et al. CROI 2014.

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35 Aging Chronologic Age= Age on driver s license Biologic Age= wear and tear on organs/age we look and feel Chronological Age Biological Age

36 Passage of Time Why do we age? Other diseases (Diabetes, Heart Disease, etc) Behaviors (smoking, drugs, heavy alcohol use, physical inactivity, etc) Genes Life Stressors

37 Case 2 32 yo AAM newly diagnosed with candidal esophagitis, wasting syndrome, and AIDS CD4 163 c/mm3 (8%) HIV VL 86,000 cp/ml Weight 120 lbs (BMI 17.2 kg/m 2 ) Glucose 94 mg/dl Initiated on ART with excellent response 1 year later CD4 305 c/mm3 (18%) HIV VL <20 cp/ml Weight 195 lbs (BMI 28.0 kg/m 2 ) Glucose 110 mg/dl

38 His 75 pound weight gain represents: A. Restoration of health B. Evidence that weight training is working C. He will star in a remake of Raging Bull D. Concern for metabolic complications 25% 25% 25% 25% A. B. C. D. 10

39 Therapeutic Options in Development Chemokine receptor inhibitors: maraviroc, TB-652 Anti-infective therapy: CMV, EBV, HSV, HCV/HBV Microbial translocation: sevelamer, colostrum, rifaximin, pre-biotics, probiotics, isotrentinoin Enhance T cell renewal: growth hormone, IL-7 Anti-fibrotic drugs: perfenidone, ACE inhibitors, ARBs Anti-aging: caloric restriction, sirtuin activators, vitamin D, omega-3 fatty acids, sirolimus, diet, exercise Anti-inflammatory drugs Chloroquine, hydroxychloroquine Minocycline NSAIDs (COX-2 inhibitors), aspirin Statins Methotrexate (low-dose; CIRT) Talidomide, lenalidomide, pentoxyfylin Biologics (e.g., TNF inibitors, IL-6 inhibitors, anti-inf-alpha) Anti-coagulants: low dose warfarin, dabigatran, aspirin, clopidogrel Adapted from Daniel Douek.

40 How to Beat Inflammation Continue ART. Maintain undetectable viremia Stop smoking Maintain normal weight If overweight, lose at least 5-10% of body weight Exercise Have a healthy diet Cut down on alcohol, avoid drugs

41 Activity Code TM809