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Inflammation Persists Even During HIV Therapy

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Sara Gianella Weibel, M.D., of UC San Diego Department of Medicine, presents "Inflammation Persists Even During HIV Therapy" for AIDS Clinical Rounds at UC San Diego

Sara Gianella Weibel, M.D., of UC San Diego Department of Medicine, presents "Inflammation Persists Even During HIV Therapy" for AIDS Clinical Rounds at UC San Diego

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  • 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
  • 21. What is causing inflammation during suppressive ART?? Burning Question 2
  • 22. 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
  • 23. Yukl et al. JID 2010 HIV RNA Is Also Readily Detectable in GUT Tissue During “Suppressive” HAART
  • 24. Microbial Translocation J. Brenchley and D. Douek Healthy GI tract Damaged GI tract during HIV infection
  • 25. Microbial Translocation Perez Santiago 2013, AIDS
  • 26. Microbial Translocation Decreases with HAART but Persists for Years Jiang et al, JID, 2009 (also Marchetti, AIDS, 2008)
  • 27. Viral Co-infection
  • 28. Model for Inflammation Deeks, Lancet 2013
  • 29. What can we do to reduce Inflammation? Burning Question 3
  • 30. 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
  • 31. 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
  • 32. Funderburg, 2014 CID Statins Decrease Monocyte Activation in Treated HIV Infection SATURN-HIV Trial
  • 33. • 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
  • 34. 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
  • 35. • 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
  • 36. 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.