The presentation discussed how inflammation persists even during HIV therapy and may contribute to non-AIDS related health issues in HIV patients. It reviewed evidence that low-level viremia, microbial translocation, and viral co-infections can drive inflammation. Early ART, ART intensification, statins, diet, exercise, and steroids may help reduce inflammation, but more research is needed on interventions targeting the underlying causes of persistent inflammation during HIV therapy.

1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS

2. Inflammation Persists Even During HIV Therapy
Sara Gianella Weibel, MD
Assistant Professor of Medicine
UCSD/CFAR
Slide adapted from P. Hunt

3. Background
The development of antiretroviral therapy (ART)
for the treatment of HIV is one of the greatest
achievements of modern medicine.

4. Improved Survival in ART Era
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95
ProbabilityofSurvival
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

5. 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.

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

7. The age of the HIV epidemic in the US is increasing
Effros et al; CID 2008

8. Why do HIV infected people suffer
from “unsuccessful aging”?
Burning Question

9. Possible Reasons for “Unsuccessful
Aging” in HIV+
• Lifestyle factors (e.g. smoking)
• ART toxicity

10. SMART Study: Interrupting ART Increases the Risk
of Heart Disease
%withaMajorCVDEvent
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 3.50 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

11. 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

12. Time Magazine, February 23, 2004

13. 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

14. 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

15. T Cell Activation Declines with ART
Hunt et al, JID, 2003; PLoS One, 2011

16. What are the consequences of
persistent inflammation during ART?
Burning Question

17. Hunt et al, JID, 2003 (see also Goicoechea, JID, 2006; Gandhi, JAIDS, 2006)
High T Cell Activation Associated with
Blunted CD4 Recovery

18. Immune activation and HIV latent reservoir

19. Monocyte Activation Associated with
Cognitive Impairment during ART
Burdo, AIDS 2013 (see also Letendre, CROI 2012, #82; Lyons, JAIDS, 2011; Ancuta PLoS One, 2012)

20. 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

22. What is causing inflammation during
suppressive ART??
Burning Question 2

23. 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

24. Yukl et al. JID 2010
HIV RNA Is Also Readily Detectable in GUT
Tissue During “Suppressive” HAART

25. Microbial Translocation
J. Brenchley and D. Douek
Healthy GI tract Damaged GI tract during HIV infection

26. Microbial Translocation
Perez Santiago 2013, AIDS

27. Microbial Translocation Decreases with
HAART but Persists for Years
Jiang et al, JID, 2009 (also Marchetti, AIDS, 2008)

28. Viral Co-infection

29. Model for Inflammation
Deeks, Lancet 2013

30. What can we do to reduce
Inflammation?
Burning Question 3

31. Early ART Appears to Cause Greater Reduction in
Residual T Cell Activation
Jain et al, JID, 2013See also: Burdo, JID, 2011; Vinikoor, CROI 2012, Abstract #554

32. 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

33. Funderburg, 2014 CID
Statins Decrease Monocyte Activation in
Treated HIV Infection
SATURN-HIV Trial

34. • 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

35. 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

37. • 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

38. 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.