From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Inflammation and Its Role in HIV Pathogenesis and Aging

Sara Gianella-Weibel, MDAssistant Professor of Medicine

University of California San Diego

San Diego, California

Slide 2 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Financial Relationships With Commercial Entities

Dr Gianella Weibel has no relevant financial affiliations to

disclose. (Updated 11/18/19)

Slide 3 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Learning Objectives

Upon completion of this webinar, learners will be able to:

• Describe the changing face of the HIV epidemic

• Describe the complexity of older adults with HIV

• List factors that contribute to unsuccessful aging

• List the main factors associated with inflammation

• Describe how to best care for aging PWH

Slide 4 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Describe the Changing Face of the

HIV Epidemic

Slide 5 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

“We just felt it was time that people saw the truth about AIDS” Kay Kirby

Photography by Therese Frare, 1990, no copyright infringement is intended

Slide 6 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Background

The development of antiretroviral therapy (ART) for the treatment of HIV is one of the greatest

achievements of modern medicine.

Slide 7 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

http://www.cdc.gov/vitalsigns/hiv-aids-medical-care/infographic.html#infographic

Slide 8 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Slide 9 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

https://www.cdc.gov/hiv/group/age/olderamericans/index.html

45% of PLWH in USA >50 years of age

Slide 10 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Projected Age Distribution of PWH

Smit, Lancet ID, 2015

Slide 11 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Describe the Complexity of Older Adults with HIV

Slide 12 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Multi-Morbidity is Increasing

Smit, Lancet ID, 2015

70-80% people aging with HIV (50 years and older) have at least one co-morbidity other than HIV

Slide 13 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Farahani, International Journal of STD & AIDS, 2016

Non-AIDS

infection

16.3%

Non-AIDS Causes of Death (2005-2015)

Slide 14 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Accelerated Aging in PWH

Pathai et al, J of Gerontology 2013

Slide 15 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Greene JAIDS 2015

Includes Geriatric Syndromes

Slide 16 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Contributes to Disability

Johs CID 2017

• HAILO (observational study of ACTG A5322) evaluated 1015 participants with median age 51 years

• At least 1 IADL impairment was reported in 18%

Slide 17 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

… And Medical Cost

Zingmond Plos One 2017

• Study examining Medicare expenditures for 9767 PWH aged 40+ in California in 2010• 89.3% male, 56.9% white, 52.4% were >50 years• Average cost $47,036 for Californian with HIV and medications account of 2/3 of that cost

Slide 18 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

List Factors that Contribute to Unsuccessful Aging

Slide 19 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Possible Reasons for “Unsuccessful

Aging” among PWH

Adapted from Deeks and Phillips, BMJ, 2009

Genetics andLifestyle

ARTToxicity

PersistentInflammation

UnsuccessfulAging

Slide 20 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

SMART Study: Interrupting ART

Increases the Risk of Heart Disease

% w

ith

a M

ajo

r C

VD

Even

t

DC VS

Death from CVD 7 4

Non-fatal clinical MI 12 12

Non-fatal silent MI 11 5

Non-fatal stroke 8 3

CAD requiring surgery

for invasive procedure22 14

All major CVD events 48 31

El-Sadr, NEJM, 2006

2752 1306 713 379 10

2720 1292 696 377 10

No. at

Risk

0.5 1.5 2.5 3.50 1 2 3 40

Years from Randomization

5

10

2.5

7.5

Intermittent ART

Continuous ART

Slide 21 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

T Cell Activation Declines with ART

Hunt et al, JID, 2003; PLoS One, 2011

Slide 22 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

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

An Important Clue from Nature

• Minimal Immune Activation • Massive Immune Activation

Slide 23 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

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

Slide 24 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)

High T Cell Activation Associated

with Blunted CD4 Recovery

Slide 25 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

SMART: Inflammatory Markers Strongly

Associated with Mortality and CVD Events

Biomarker

All-Cause Mortality

(N=85)

Fatal or Non-fatal CVD

(N=136)

OR P-value OR P-value

hs-CRP 3.1 0.02 1.6 0.20

IL-6 12.4 <0.0001 2.8 0.003

Amyloid A 3.1 0.05 1.6 0.12

Amyloid P 1.1 0.78 2.8 0.002

D-dimer 41.2 <0.0001 2.0 0.06

F1.2 1.3 0.64 0.8 0.56

Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009

Slide 26 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

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

Slide 27 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

List the Main Factors Associated

with Inflammation

Slide 28 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Model of Inflammation

Deeks, Lancet 2013

Slide 29 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008, Lorenzo-Redondo Nature, 2016.

Low-level Viremia <20 cp/ml is Common During ART

80% Patients had detectable

viremia

Median 3.1 copies/ml

Slide 30 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Yukl et al. JID 2010

HIV RNA Is Detectable in GUT During ART

Figure 2.

HIV DNA copy numbers (2A) were measured in peripheral blood mononuclear cells

(PBMC) and total gut cells using real time PCR, normalized to total cell numbers by DNA

mass (NanoDrop), and normalized to CD4 cells by flow cytometry. Total unspliced HIV

RNA levels (2B) were measured using qRT-PCR, normalized to cell numbers by GAPDH,

and normalized to CD4 cells by flow cytometry. Whiskers represent the maximum and

minimum; upper and lower box borders represent the 75th and 25th percentile; the horizontal

line indicates the median.

Yukl et al. Page 12

J Infect Dis. Author manuscript; available in PMC 2011 November 15.

NIH

-PA

Author M

anuscriptN

IH-P

A A

uthor Manuscript

NIH

-PA

Author M

anuscript

Slide 31 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Microbial Translocation

J. Brenchley and D. Douek

Healthy GI tract Damaged GI tract during HIV infection

Slide 32 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Microbial Translocation Decreases with ART but

Persists for Years

Jiang et al, JID, 2009 (also Marchetti, AIDS, 2008)

Slide 33 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Microbial Translocation is Associated

with Inflammation

Perez Santiago 2013, AIDS

Slide 34 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

CMV Associated with CD8 Expansion and Inflammation in HIV Infection

Freeman, JID, 2014 (see also: Sacre, AIDS, 2011; Mudd, JID, 2016; Musselwhite, AIDS 2011 and many Gianella papers)

CD8+ T Cell Counts sTNF-RII

Slide 35 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Valganciclovir Reduces Inflammation

Slide 36 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

What can we do to reduce Inflammation?

Slide 37 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Early ART can Greatly Reduce T Cell Activation

Jain et al, JID, 2013See also: Burdo, JID, 2011; Vinikoor, CROI 2012, Abstract #554

Slide 38 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Funderburg, 2014 CID

Statins Decrease Monocyte Activation in

Treated HIV Infection(SATURN-HIV Trial)

Slide 39 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

• 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?

Diet and Exercise

Slide 40 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

• 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, 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

Slide 41 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Recommendations for Patients

• Follow-up with your medical provider regularly.

– Follow guidelines for checking and controlling vascular risk factors (cholesterol, blood pressure, diabetes).

• Stop smoking.

• Exercise regularly, eat healthful diet, maintain healthy weight.

• Get regular cancer screening.

• Assess Polypharmacy, Safety at home, Quality of life

• Avoid or treat co-infections.

– Viral hepatitis, syphilis, tuberculosis

– Vaccinations

– No current recommendations for CMV

Slide 42 of 43 From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Acknowledgments

• Peter Hunt, Maile Karris for sharing their slides.

• Dilip Jeste, David Moore, Scott Letendre, Davey Smith, Sanjay Metha for helpful discussion.

From S Gianella Weibel, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.

Question-and-Answer Period