1. HIV and Inflammation
Jihad Slim, MD
June 2016

2. HIV + Patients are living longer
Estimated Percentage of Persons Living With HIV Who Are Aged ≥50 Years
Effect of ART on Mortality Over Time
In the US, a 20-year-old HIV+ patient can now expect to live into his/her early 70s

3. Life expectancy in cART-treated patients
At age 20
ART-Cohort Collaboration
22,937 individuals (82,022 person-year)
Samji et al. ART-Cohort Collaboration. PlosOne 2013

4. COMORBIDITIES ARE MORE PREVALENT IN HIV+ PATIENTS
Subjects ≥45 Years With Age-Associated Noncommunicable
Comorbidities, by HIV Serostatus
(AGEhIV Study, )2
P <.0001
HTN
Non-AIDS Cancer
Angina Pectoris MI
PAD
CLD
Cerebrovascular
Disease
Participants, % 20 30 40 50 10
P <.05
HIV-Uninfected Individuals (n=349)
HIV+ Patients (n=381)
Age-Associated Noncommunicable Comorbidity
Similarities between aging and the courses of HIV and AIDS suggest that HIV infection may compress certain aging processes, thereby accelerating comorbidities and frailty1
Duration of ART use (OR 1.24 per 5 additional years of ART use) and lower nadir CD4 cell count (OR 1.12 per 100 fewer cells) were associated with an increased risk of a higher number of comorbidities
CLD, chronic liver disease; HTN, hypertension; MI, myocardial infarction; OR, odds ratio; PAD, peripheral artery disease.
1 Effros RB, et al. Clin Infect Dis. 2008;47: ; 2 Schouten J, et al. IAC Washington, DC. THAB0205.

5. Some HIV-positive patients have higher-risk Behaviors that may lead to increased risk of early death
HIV-Uninfected Individuals
HIV-Positive Patients
Persons Using Tobacco, Alcohol and/or Illicit Drugs, %
Prevalence of Tobacco, Alcohol, and/or Illicit Drug Use Among
HIV-Positive Patients and HIV-Uninfected Individuals1-3
Use of tobacco, alcohol, and/or illicit drugs is higher in HIV-positive patients
1 CDC. Behavioral and Clinical Characteristics of Persons Receiving Medical Care for HIV Infection—Medical Monitoring Project, United States, HIV Surveillance Special Report 10; 2 CDC. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2012; 3 United Nations Office on Drugs and Crime, World Drug Report ,2014.

6. All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136)
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
hs-CRP
3.1
0.02
1.6
0.20
IL-6
12.4
<0.0001
2.8
0.003
Amyloid A
0.05
0.12
Amyloid P
1.1
0.78
0.002
D-dimer
41.2
2.0
0.06
F1.2
1.3
0.64
0.8
0.56
Even after adjusting for CD4 count!
Kuller L et al. PLoS Med, 2008; Duprez, Atherosclerosis, 2009

7. What Is Driving Disease Activity During ART? Traditional Risk Factors
CD4
Lymphopenia
Non-AIDS
Morbidity /
Mortality
Inflammation
Coagulation
T and B Cell
Activation/
Dysfunction
Traditional Risk Factors
(co-infections)
ART

8. What drives persistent immune activation/inflammation in cART-treated patients?
Gut epithelial barrier dysfunction, microbiome and microbial translocation
Co-infections (CMV et al….)
Residual HIV replication
Lack of immunoregulatory responses- Lymphoid fibrosis

9. T Cell Activation Declines with ART
But Remains Abnormally High During ART-mediated Viral Suppresion
Hunt et al, JID, 2003; PLoS One, 2011

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

11. Inflammation and Innate Immune Activation are Increased in Patients with Poor CD4+ T cell Recovery on ART
IL-6
sCD14
CD4<350
CD4>500
HIV-
CD4<350
CD4>500
HIV-
Lederman et al., JID, 2011

12. Persistent microbial translocation during cART
Brenchley J et al. Nat Med 2006; also Jiang et al. J Infect Dis 2009 12

13. HCV co-infection is associated with higher T-lymphocyte activation on cART
Hunt et al. JID 2003; also Greub G Lancet 2000

14. Gut Epithelial Barrier Dysfunction Inflammation / Coagulation
Innate Markers Predict Mortality Independent of Nadir AND Current CD4 count
Gut Epithelial Barrier Dysfunction
IDO-1 Induction
Monocyte Activation
Inflammation / Coagulation
Hunt, CROI 2012, Abstr #278 (see also : Tenorio, CROI 2013, Abstr# 790)

15. Inflammation and Immune Activation
HIV
Destroy GALT
Persistent Viral
Replication
Immunodeficiency
Microbial Translocation
Reactivation of Co-infectiing Viruses
Chronic Activation of the Immune System and Endothelium
Immune
Senescence
Hypercoagulation
Macrophage/ T Cell
Infiltration of Arteries
Co-Morbidity
Hsue, P et al. JID.
2012; 13: S375-82

16. CVD

17. HIV-related CVD – Significant Mortality
1,876 deaths among 39,727 patients
Non-AIDS related deaths accounted for 50.5%
~16% were due to CVD
Renal 3%
Other 9.0%
Respiratory 3.1%
13 HIV Cohorts
Non-AIDS
Malignancy
23.5% )
Liver-related
14.1%
Non-AIDS
infection
16.3%
Violence,
Substance abuse
15.4%
CVD
15.7%
Antiretroviral Therapy Cohort Collaboration. Clin Infect Dis. 2010;50:

18. Factors Affecting Risk for CVD in Patients with HIV
Family history of CVD
Older age
Male gender
HIV infection
Hypertension
Smoking DM
Obesity
Metabolic abnormalities
ART

19. Cancer

20. Cancer is the One of the Most Frequent Causes of Death in HIV-Infected Patients
Cause of Death
2000
2005
Cancer (all)
29%
34%
Cancer - AIDS defining
16%
13%
Cancer - Non-AIDS defining
21%
Hepatitis (non cancer)
14%
12%
Other infections 7% 4%
Mortalité 2000 and 2005 studies:
Bonnet et al., Cancer 101; 317:2004 and
CID 48;633: 2009. 20

21. Categorizing Cancers in PWHA
AIDS Defining Cancer
(decreasing) KS
NHL (CNS)
Cervical Cancer
Non AIDS defining Cancers (increasing)
Anal Cancer
Lung Cancer
Hodgkin Lymphoma
Liver Cancer
Elevated risk but rare
Merkel Carcinoma
Leiomyosarcoma
Conjunctival cancer
Salivary gland LEC
Unchanged risk
Breast
Colorectal
Prostate
Follicular lymphoma 21

22. Oncogenic Viruses in HIV Disease
AIDS-Defining Virus
Kaposi’s Sarcoma HHV-8
Non-Hodgkin’s Lymphoma EBV, HHV-8
(systemic and CNS)
Invasive Cervical Carcinoma HPV
Non-AIDS Defining
Anal Cancer HPV
Hodgkin’s Disease EBV
Leiomyosarcoma (pediatric) EBV
Squamous Carcinoma (oral) HPV
Merkel cell Carcinoma MCV
Hepatoma HBV, HCV

23. Kidney Disease

24. HIV+ PATIENTS ARE MORE LIKELY TO DEVELOP ESRD
Despite declining rates of ESRD, HIV-positive patients continue to have a higher incidence of kidney disease1
Incidence of ESRD Among 38,354 HIV+ Patients vs the General Population
(NA-ACCORD and US Renal Database System, )2
400
300
200
100
2001
2002
2003
2004
2005
2006
2007
2008
Calendar Year
Incidence Rate per 100,000 PY
HIV-Positive Patients
US General Population
CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; NA-ACCORD, The North American AIDS Cohort Collaboration on Research and Design.
1 Lucas GM, et al. Clin Infect Dis. 2014;59:e96-e138; 2 Abraham AG, et al. Clin Infect Dis. 2015;60:

25. Risk Factors for Kidney Disease
Race (African American)
Family history of kidney disease
CD4 cell count (<200 cells/mm3)
HIV RNA level (>4000 copies/mL)
Use of nephrotoxic agents (medications…)
Diabetes mellitus
HTN
Hepatitis C infection
ART

26. Liver Disease

27. Significant Liver-related Mortality
1,876 deaths among 39,727 patients
Non-AIDS related deaths accounted for 50.5%
~16% were due to CVD
Renal 3%
Other 9.0%
Respiratory 3.1%
13 HIV Cohorts
Non-AIDS
Malignancy
23.5%
Liver-related
14.1%
Non-AIDS
infection
16.3%
Violence,
Substance abuse
15.4%
CVD
15.7%
Antiretroviral Therapy Cohort Collaboration. Clin Infect Dis. 2010;50:

28. TRADITIONAL and hiv-related RISK FACTORS are Associated with hepatic failure
Traditional risk factors for liver disease, such as chronic hepatitis infection and alcohol abuse, are more prevalent in HIV-positive patients1-4
Adjusted Rate Ratiosa for Hepatic Failure for Selected Risk Factors
Among 20,775 HIV-Positive Patients,
Adjusted Rate Ratiosa for Hepatic Failure for Selected Risk Factors
Among 20,775 HIV-Positive Patients,
Greater Risk
Adjusted HR
a Rate ratios adjusted for all other variables presented.
1 Price JC, et al. Clin Gastroenterol Hepatol. 2010;8: ; 2 Fernandez-Montero JV, et al. Best Pract Res Clin Gastroenterol. 2012;26: ; 3 Sullivan LE, et al. Addiction. 2008;103: ; 4 Towner WJ, et al. J Acquir Immune Defic Syndr. 2012;60:

29. BONE Disease

30. HIV+ PATIENTS ARE AT INCREASED RISK OF BONE LOSS AND FRACTURES
Compared with HIV-uninfected individuals, HIV-positive patients have a 6.4-fold increased risk of low BMD and a 3.7-fold increased risk of osteoporosis1
Many HIV-positive patients (58%) believe that they are at low risk of fracture3
Incidence of Bone Fractures Among 8525 HIV-Positive Patients and
2,208,792 HIV-Uninfected Individuals, by Gender,
HIV-Positive Patients
HIV-Uninfected Individuals
Women
Men
Women
Men
P =.002
(overall comparison)
P =.002
(overall comparison)
Frequency per 100 Persons
Frequency per 100 Persons
P <.0001
(overall comparison)
P <.0001
(overall comparison)
BMD, bone mineral density.
1 Brown TT, et al. AIDS. 2006;20: ; 2 Triant VA, et al. J Clin Endocrinol Metab. 2008;93: ;
3 Taras J, et al. Patient Prefer Adherence. 2014;8:

31. Many Potential Contributors to Decreased BMD in Patients With HIV
Decreased physical activity
Liver disease
Premature menopause
Hypogonadism
Smoking
Malnutrition
Vitamin D deficiency
Medications
ART
Family history
Female sex
Increasing age
HIV infection

32. Assess: risk for Bone Disease in HIV+ Patients
Assess risk factors for all HIV+ patients Age, sex, history of fractures, BMI, ART, secondary causes
Provide lifestyle advice Smoking cessation, vitamin D and calcium intake, weight-bearing exercise, sun exposure
<50 Years (Male)/Premenopausal (Female) No History of Fracture
≥50 Years (Male)/Postmenopausal (Female) and/or History of Fracture
Wait
Measure BMD
McComsey GA, et al. Clin Infect Dis. 2010;51: 32

33. HAND (HIV Associated Neurocognitive DisorderS)

34. Decreasing Neurological Severity
Incidence of severe neurological Disorders is declining while less severe forms are increasing
HAND is the result of neural damage caused by HIV replication and immune activation1
HAND is fairly prevalent, even in patients with low viral loads and high CD4 cell counts2
Rapid initiation of ART can arrest and sometimes reverse severe HAND, but milder forms of cognitive impairment persist because they are more difficult to identify and treat2,3
Pre-ART Era (Before 1996)
ART Era (Post-1996)
Frequency, %
Decreasing Neurological Severity
HAND, HIV-associated neurocognitive disorders.
1 Letendre S. Top Antivir Med. 2011;19: ; 2 McArthur JC, et al. Ann Neurol. 2010;67: New York State Department of Health AIDS Institute. Cognitive disorders and HIV/AIDS: HIV-associated dementia and delirium

35. HIV Infection of the CNS
HIV-Associated Neuro-cognitive Disorder
Other medical conditions
HIV-Associated Neurocognitive Disorders may share symptoms with:
Mood disorders
Drug and alcohol abuse
Mania and psychosis
Other infections and neurologic problems
Oversedation with medications commonly given for sleep, mood problems and other disorders
Eric Miller - Epi April 2013 35

36. Multifactorial Etiology of HAND
Medical Conditions: Nutritional, Metabolic, Vascular, HCV infection, Depression/other psychiatric conditions, Sleep disorders
HIV
ART
Concomittent medications and comorbidities: Substance use, Aging and Alzheimer

37. ‘Immunosenescence’ - Summary -
HIV-associated immunosenescence contributes to persistent immunodeficiency and early onset of age-related diseases
Further investigation into these pathways may lead to novel therapeutic interventions in HIV-infected persons

38. AGING Immune Immune activation dysregulation Microbial Translocation
Reactivation of co-existing Pathogens
Inflammation
- Low Thymic output
LN Fibrosis
GALT damage
Immune
activation
AGING
Immune
dysregulation
Inflammation
Immune dysfunction
Tissue Damage