Slide 1 of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor of Medicine University of California San Diego San Diego, California From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Learning Objectives Recognize that HIV-infected people can suffer from ‘unsuccessful aging’. Identify possible drivers of persistent inflammation during treated HIV-infection. Describe possible interventions to reduce inflammation during HIV-infection.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Background The development of antiretroviral therapy (ART) for the treatment of HIV is one of the greatest achievements of modern medicine.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. HIV+ Aging Population in the United States (people over 50 years of age)

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Projected Age Distribution of HIV+ Population. Smit, Lancet ID, 2015

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Farahani, International Journal of STD & AIDS, 2016 Non-AIDS infection 16.3% CVD 15.7% Violence, Substance abuse 15.4% Non-AIDS Causes of Death (2005-2015)

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Trends of Mortality due to CVD in HIV (US- 1999-2013) Feinstein, Am J Cardiol, 2016

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Accelerated Aging During HIV Infection Pathai et al, J of Gerontology 2013

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Legarth/Obel, JAIDS, 2016 Survival of Older HIV+ Adults in the ART Era HIV- Controls 1996-2014 HIV+ 2006-2014 2000-2005 1996-2000 ~9y shorter life expectancy even among those with no comorbidity

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Why do HIV infected people suffer from “unsuccessful aging”? Burning Question 1

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Why do HIV infected people suffer from “unsuccessful aging”? 1.Unhealthy Lifestyle. 2.Genetic Predisposition. 3.ART toxicity. 4.Persistent Inflammation. 5.All of the above.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Possible Reasons for “Unsuccessful Aging” among HIV+ Adapted from Deeks and Phillips, BMJ, 2009 Genetics and Lifestyle Genetics and Lifestyle ART Toxicity ART Toxicity Persistent Inflammation Persistent Inflammation Unsuccessful Aging Unsuccessful Aging

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. SMART Study: Interrupting ART Increases the Risk of Heart Disease % with a Major CVD Event DCVS Death from CVD74 Non-fatal clinical MI12 Non-fatal silent MI115 Non-fatal stroke83 CAD requiring surgery for invasive procedure 2214 All major CVD events4831 El-Sadr, NEJM, 2006 2752130671337910 2720 129269637710 No. at Risk 0.51.52.53.501234 0 Years from Randomization 5 10 2.5 7.5 Intermittent CD4-guided ART (DC) Continuous ART (VS) Intermittent ART Continuous ART

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Time Magazine, February 23, 2004

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Sooty Mangabey Infect with SIV High Levels of Viral Replication No AIDS, normal lifespan Rhesus Macaque Infect with SIV High Levels of Viral Replication AIDS and death Silvestri, Immunity, 2003 An Important Clue from Nature Minimal Immune Activation Massive Immune Activation

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. T Cell Activation Declines with ART Hunt et al, JID, 2003; PLoS One, 2011

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What are the consequences of persistent inflammation during ART?

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Inflammation Can Cause Lymphoid Tissue Fibrosis Estes, JID, 2008; Schacker, JCI, 2002; Zeng, JCI, 2011 Associated with low %naïve T cells and poor CD4+ T cell recovery May impair functional immune responses

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006) High T Cell Activation Associated with Blunted CD4 Recovery

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. SMART: Inflammatory Markers Strongly Associated with Mortality and CVD Events Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) ORP-valueORP-value hs-CRP3.10.021.60.20 IL-612.4<0.00012.80.003 Amyloid A3.10.051.60.12 Amyloid P1.10.782.80.002 D-dimer41.2<0.00012.00.06 F1.21.30.640.80.56 Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Baseline IL-6 Predicts CVD Events for >4 Years Adapted from: Duprez DA et al. PLOS ONE, 2012

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Monocyte Activation Associated with Cognitive Impairment during ART Burdo, AIDS 2013 (see also Letendre, CROI 2012, #82; Lyons, JAIDS, 2011; Ancuta PLoS One, 2012)

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Inflammation Predicts Disease in Treated HIV Mortality (Kuller, PLoS Med, 2008; Tien, JAIDS, 2010; Justice, CID 2012) Cardiovascular Disease (Duprez, Atherosclerosis, 2009) Cancer (Breen, Cancer Epi Bio Prev, 2010; Borges, AIDS, 2013) Venous Thromboembolism (Musselwhite, AIDS, 2011) Type II Diabetes (Brown, Diabetes Care, 2010) COPD (Attia, Chest, 2014) Bacterial Pneumonia (Bjerk, PLoS One, 2014) Cognitive Dysfunction (Burdo, AIDS, 2013; Letendre CROI 2012) Depression (Martinez, JAIDS, 2014) Frailty (Erlandson, JID, 2013) Slide courtesy from Peter Hunt 2016

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What is causing inflammation during suppressive ART? Burning Question 2

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What is NOT causing inflammation during suppressive ART? 1.Translocation of bacterial products from the GUT. 2.Co-infections (including CMV). 3.Cannabis use. 4.Residual HIV replication. 5.High-fat diet.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Model of Inflammation Deeks, Lancet 2013

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008, Lorenzo-Redondo Nature, 2016. Low-level Viremia <75 copies/ml is Common During Apparent Viral Suppression on HAART 80% Patients had detectable viremia Median 3.1 copies/ml

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Microbial Translocation J. Brenchley and D. Douek Healthy GI tract Damaged GI tract during HIV infection

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Microbial Translocation Decreases with ART but Persists for Years Jiang et al, JID, 2009 (also Marchetti, AIDS, 2008)

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Viral Co-infection Gianella, JVI, 2011

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What proportion of HIV-infected men present evidence of subclinical CMV replication despite high CD4 T cell counts? Burning Question 3

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What proportion of HIV-infected men present evidence of subclinical CMV replication despite high CD4 T cell counts? 1.When CD4 T cells counts are >500cells/μl there is no CMV replication going on. Everything is under control! 2.Less than 20% 3.20-39% 4.40-59% 5.More than 60%

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What can we do to reduce Inflammation?

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Immune Activation Remains Abnormal Even in Patients Treated during Acute HIV (RV254) Thai study of HIV+ individuals dx very early during acute HIV infection Compared to high-risk HIV- controls and ART-suppressed HIV+ who initiated during chronic HIV infection Chronic HIV on ART HIV-uninfected Utay, CROI 2015, #47 : 12 days : 16 days : 18 days Estimated Duration of HIV Infection

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Any Benefit to ART Intensification? Most studies fail to show benefit on low-level viremia by single-copy assay. 1-3 Recent studies of Raltegravir intensification showed: –↓infection of new cells (transient ↑2-LTR circles). 4-5 –↓T cell activation 4-5 or D-dimer levels. 6 –Mostly PI-based regimens. Recent study of Maraviroc intensification showed: –↓CD16+ monocytes and improvement in Neurocognitive functioning. 7 1 Dinoso JB, et al. Proc Natl Acad Sci USA. 2009. 2 Gandhi R, et al. J Infect Dis. 2010. 3 Gandhi R, et al. PLoS Med. 2010. 4 Buzon M, et al. Nature Medicine. 2010. 5 Llibre J. Antiviral Therapy, 2011; 6 Hatano H, et al. J Infect Dis, 2013. 7 Ndhlovy L.C., J Neurovirol, 2014.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Funderburg, 2014 CID Statins Decrease Monocyte Activation in Treated HIV Infection (SATURN-HIV Trial)

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. High fat or carbohydrate meal ↑ inflammation (Deopurkar, Diabetes Care, 2010). Diet-induced weight loss ↓ inflammation in elderly ( Nicklas, Am J Clin Nutr, 2004) RCTs of exercise in elderly have been shown to: –Decrease inflammation (Nicklas, J Am Ger Soc, 2008) –Increase functional status (McMurdo, Geriatrics, 1992) –Decreases insulin resistance (Diabetes Care, 2002) –Improve cognitive function (Muscari, Int J Ger Psych, 2010) Studies in HIV ongoing Diet and Exercise

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Despite optimal ART, HIV is associated with shorter life expectancy and an increase in several age-associated morbidities. Immune activation / inflammation persist despite ART and may predict these morbidities. Earlier initiation of ART decreases persistent immune activation. Statins, steroids, probiotics, diet, and exercise may hold promise and need to be studied. Targeted interventions directed at the underlying causes of inflammation may hold promise –HIV reservoirs, co-infections/CMV, microbial translocation. Summary

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What are you going to recommend to slow aging in your patients? Burning Question 4

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. What are you going to recommend to slow aging in your patients? 1.Eat more black licorice. 2.Drink more red wine. 3.Exercise more. 4.Take daily Rapamycin.

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Recommendations for Patients Follow-up with your medical provider regularly. – Follow guidelines for checking and controlling vascular risk factors (cholesterol, blood pressure). Start early ART. Stop smoking. Exercise regularly, eat healthful diet, maintain healthy weight. Get regular cancer screening. Consider daily aspirin (if indicated for primary prevention). Avoid or treat co-infections. – Viral hepatitis, syphilis, tuberculosis – Vaccinations – No current recommendations for CMV

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Physical Health vs. Satisfaction with Life from Age 21 to 100 Jeste DV, et al., Am J Psychiatry, 2013

of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Acknowledgments Peter Hunt for sharing his slides. Dilip Jeste, David Moore, Scott Letendre, Davey Smith, Sanjay Metha, Nadir Weibel, Susan Little for helpful discussion.

Slide 1 of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor.

Similar presentations

Presentation on theme: "Slide 1 of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Slide 1 of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor.

Similar presentations

Presentation on theme: "Slide 1 of 44 From SG Weibel, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Getting Hotter As We Get Older Sara Gianella Weibel, MD Assistant Professor."— Presentation transcript:

Similar presentations

About project

Feedback