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AIDS CLINICAL ROUNDS

Inflammation Persists Even During HIV Therapy

Sara Gianella Weibel, MD Assistant Professor of Medicine

UCSD/CFAR

Slide adapted from P. Hunt

Background

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

achievements of modern medicine.

Improved Survival in ART Era

Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95

Prob

abilit

y of S

urviv

al

Pre-ART (1995–1996)

Early ART (1997–1999)

Survival from Age 25 Years N= 3,990

1

0.75

0.5

0.25

0

25 30 35 40 45 50 55 60 65 70

Age (years)

Late ART (2000–2005)

Population controls

Non-AIDS Diseases Now Account for Majority of Deaths in HIV

(1996-2006) • 1,876 deaths among 39,727 patients • Non-AIDS related deaths accounted for 50.5%

Antiretroviral Therapy Cohort Collaboration (ART-CC). Clin Infect Dis. 2010;50:1387-1396.

Non-AIDS infection

16.3%

CVD 15.7%

Non-AIDS Malignancy

23.5%

Violence, Substance

abuse 15.4%

Liver-related 14.1%

Other 9.0% Respiratory

3.1%

Renal 3.0%

Respiratory 3.1%

Renal 3.0%

Antiretroviral Therapy Cohort Collaboration (ART-CC). Clin Infect Dis. 2010;50:1387-1396.

HIV and Aging

• HIV is associated with increased risk of: • Cardiovascular disease • Malignancy (non-AIDS) • Bone fractures/Osteoporosis • Liver Disease • Kidney Disease • Neurocognitive Impairment

The age of the HIV epidemic in the US is increasing

Effros et al; CID 2008

Why do HIV infected people suffer from “unsuccessful aging”?

Burning Question

Possible Reasons for “Unsuccessful Aging” in HIV+

• Lifestyle factors (e.g. smoking) • ART toxicity

SMART Study: Interrupting ART Increases the Risk of Heart Disease

% w

ith a

Maj

or C

VD E

vent

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 procedure

22 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 3.5 0 1 2 3 4 0

Years from Randomization

5

10

2.5

7.5

Intermittent CD4-guided ART (DC) Continuous ART (VS)

Intermittent ART

Continuous ART

Many chronic diseases of aging are more common in HIV+’s, even after adjustment

for ART use and lifestyle factors

• Lifestyle factors (e.g. smoking) • ART toxicity • Persistent Inflammation

Time Magazine, February 23, 2004

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

Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency

MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon

Dec 10, 1981

T10=CD38

Leu3=CD4

T Cell Activation Declines with ART

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

What are the consequences of persistent inflammation during ART?

Burning Question

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

High T Cell Activation Associated with Blunted CD4 Recovery

Immune activation and HIV latent reservoir

Monocyte Activation Associated with Cognitive Impairment during ART

Burdo, AIDS 2013 (see also Letendre, CROI 2012, #82; Lyons, JAIDS, 2011; Ancuta PLoS One, 2012)

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

What is causing inflammation during suppressive ART??

Burning Question 2

Maldarelli F. et al., PLOS Path, 2007; Palmer S. et al, PNAS, 2008.

Low-level Viremia <75 copies/ml is Common During Apparent Viral Suppression on HAART

N=130 80% Patients had detectable viremia

Median 3.1 copies/ml

Yukl et al. JID 2010

HIV RNA Is Also Readily Detectable in GUT Tissue During “Suppressive” HAART

Microbial Translocation

J. Brenchley and D. Douek

Healthy GI tract Damaged GI tract during HIV infection

Microbial Translocation

Perez Santiago 2013, AIDS

Microbial Translocation Decreases with HAART but Persists for Years

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

Viral Co-infection

Model for Inflammation

Deeks, Lancet 2013

What can we do to reduce Inflammation?

Burning Question 3

Early ART Appears to Cause Greater Reduction in Residual T Cell Activation

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

Any Benefit to ART Intensification?

• Most studies fail to show benefit on low-level viremia by single-copy assay.1-4

• Recent studies of RGV intensification showed:

– ↓infection of new cells (transient ↑2-LTR circles).5-7

– ↓T cell activation5-6 or D-dimer levels.7

– Mostly PI-based regimens

1Dinoso JB, et al. Proc Natl Acad Sci USA. 2009;106:9403-9408. 2Gandhi R, et al. J Infect Dis. 2010; 201(2): 293-296. 3Jones J, et at. CROI 2009. Abstract 423b. 4Gandhi R, et al. PLoS Med. 2010; 7(8). 5Buzon M, et al. Nature Medicine. 2010; 16(4): 460-465; 6Llibre J. Antiviral Therapy, 2011; 7Hatano H, et al. J Infect Dis, 2013; 208(9):1437-1442.

RGV May Transiently ↑2-LTR Circles

Funderburg, 2014 CID

Statins Decrease Monocyte Activation in Treated HIV Infection

SATURN-HIV Trial

• 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

Effects of Prednisolone On CD4 Counts and HIV Disease Progression: A two-year Clinical Trial

• Randomized, double-blinded placebo-controlled trial to assess the effect of Prednisolone 5mg on HIV disease (n=326)

• Primary study endpoints were: progression to AIDS-defining conditions or drop of CD4 <200 cells/μl

Kasang, CROI 2014

• 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 may decrease the degree of 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 (i.e., HIV reservoirs, co-infections/CMV, microbial translocation).

Summary

Acknowledgments

• Peter Hunt and Michael Lederman for sharing their slides

• Davey Smith, Doug Richman, Susan Little, Sanjay Mehta, Josue Perez Santiago, Marta Massanella and everybody in my lab.