The role of innate immunity in the pathogenesis of Serious Non-AIDS Events
Inflammation and Its Role in HIV Pathogenesis and Aging€¦ · Farahani, International Journal of...
Transcript of Inflammation and Its Role in HIV Pathogenesis and Aging€¦ · Farahani, International Journal of...
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