HIV and Aging: A Paradigm Shift in the Management of HIV Disease Increased use of anti-retroviral therapy has resulted in significant declines in mortality and increased survival. As a result, older persons are the fastest growing population of people living with AIDS.   The aging nature of the HIV/AIDS epidemic is significant and will continue given trends in older age at diagnosis and declining deaths. Faced with both HIV/AIDS-related and age-related co-morbidities, the growing population of older persons with HIV presents new challenges for research, medical care, and support services. Anthony Mills MD / Director of Clinical Research / Anthony Mills MD Inc. / Assistant Professor of Clinical Medicine, UCLA

This educational activity is brought to you by Janssen Therapeutics, Division of Janssen Products, LP, and is not certified for continuing medical education The speakers are paid consultants for Janssen Therapeutics, Division of Janssen Products, LP, and must present information in compliance with FDA requirements applicable to Janssen Therapeutics, Division of Janssen Products, LP The information that will be presented is in compliance with FDA requirements applicable to Janssen Therapeutics, Division of Janssen Products, LP This educational activity is brought to you by Janssen Therapeutics, Division of Janssen Products, LP, and is not certified for continuing medical education The speakers are paid consultants for Janssen Therapeutics, Division of Janssen Products, LP, and must present information in compliance with FDA requirements applicable to Janssen Therapeutics, Division of Janssen Products, LP The information that will be presented is in compliance with FDA requirements applicable to Janssen Therapeutics, Division of Janssen Products, LP 7. 23. 2012 2

Dramatically Improved Life Expectancy in Early HAART Era 25 30 35 40 45 50 55 60 65 70 Probability of survival Pre-HAART (1995–1996) Survival From Age 25 Years N=3,990 1 0.75 0.5 0.25 Early HAART (1997–1999) Age, years 18 years 7-year life expectancy In this study plotting the risk of death from untreated HIV in the pre-HAART era, you can see that the life expectancy of your average 25 year old with HIV was only about 7 years. With the introduction of HAART in the mid-to-late 90s, we saw a dramatic improvement in life expectancy – about 18 years. Adapted from Lohse N, et al. Ann Intern Med. 2007;146:87–95. HAART: Highly Active Anti-retroviral Treatment 7. 23. 2012 3 3

Does HAART restore normal health? A key question is whether ART restores normal health. 7. 23. 2012 4

Study on Incomplete Peripheral CD4+ Cell Count Restoration in HIV-Infected Patients Receiving Long-Term ARV Treatment Found That ~60% of Patients with a Nadir CD4+ <200 Remain <500, Even After 10 Years of Viral Suppression (N=300) This study found that about 60% of patients with low CD4+ cell nadirs (less than 200) failed to achieve a normal CD4+ cell count even after 10 years of suppression, which is important because guidelines have moved toward recommending earlier and earlier therapy in the course of HIV infection. Kelley CF, et al. Clin Infect Dis. 2009;48:787-794. (see also: Byakwaga, ARHR. 2009; Lok, AIDS. 2010.) 7. 23. 2012 5

Improved Survival in Early HAART Era: Age- and Gender-Matched Controls Probability of survival Pre-HAART (1995–1996) Early HAART (1997–1999) Survival From Age 25 Years N=3,990 1 0.75 0.5 0.25 25 30 35 40 45 50 55 60 65 70 Age, years Let’s return to the same study from our earlier slide, which presented information on dramatically improved survival in the early HAART era and even greater survival in the late HAART era. Adapted from Lohse N, et al. Ann Intern Med. 2007;146:87–95. 7. 23. 2012 6 6

Late HAART Era Extended Life Expectancy Even Further Probability of survival Pre-HAART (1995–1996) Early HAART (1997–1999) Survival From Age 25 Years N=3,990 1 0.75 0.5 0.25 25 30 35 40 45 50 55 60 65 70 Age, years Late HAART (2000–2005) HIV infection reduces life expectancy even in the highly active antiretroviral therapy (HAART) era. This figure shows the cumulative survival curves for HIV-infected persons in the pre-HAART era (pink) and in early (1997 to 1999, dark orange) and late (light orange) HAART era. Adapted from Lohse N, et al. Ann Intern Med. 2007;146:87–95. 7. 23. 2012 7 7

Probability of survival Survival From Age 25 Years N=3,990 Late HAART Era Patients Still Have a 10-Year Shorter Life Expectancy Than HIV–Controls Probability of survival Pre-HAART (1995–1996) Early HAART (1997–1999) Survival From Age 25 Years N=3,990 1 0.75 0.5 0.25 25 30 35 40 45 50 55 60 65 70 Age, years Late HAART (2000–2005) Population controls Survival probability has improved considerably with the introduction of HAART and the subsequent expansion and improvement of available treatment options; however, HIV-infected patients still have a 10-year shorter expected survival compared with uninfected matched controls. This is a huge difference considering even though most of these patients are achieving and maintaining viral suppression, they’re still living on average a decade shorter than their HIV-uninfected counterparts. Adapted from Lohse N, et al. Ann Intern Med. 2007;146:87–95. (See Also: ART-CC, Lancet. 2008; Lewden, JAIDS. 2007.) 7. 23. 2012 8 8

Violence, substance abuse 15.4 % Non-AIDS Diseases Were Shown to Account for ~50% of Deaths in HIV (1996-2006) 1,876 deaths among 39,727 patients Non-AIDS–related deaths accounted for 50.5% Only 1,597 had a definitive cause of death assigned Relative Causes of Non-AIDS Deaths Renal 3.0% Respiratory 3.1%% Non-AIDS malignancy 23.5% Violence, substance abuse 15.4 % What are patients dying of in the modern HAART era? Studies have shown that non-AIDS diseases account for about half of deaths in HIV. ART Cohort Collaboration, CID. 2010. Antiretroviral Therapy Cohort Collaboration (ART-CC). Clin Infect Dis. 2010;50:1387-1396. 7. 23. 2012 9

Cardiovascular Disease1-3 Cancer (Non-AIDS)4 Many Morbidities Associated with Aging Also Have Been Reported to be Increased in HIV Patients Being Treated Cardiovascular Disease1-3 Cancer (Non-AIDS)4 Bone Fractures/Osteoporosis5,6 Liver Disease7 Kidney Disease8 Cognitive Decline9 Pneumonia Requiring Hospitalization10 [Slide is self-explanatory] 1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2. Hsue P, et al. Circulation. 2004;109:316-319. 3. Grinspoon SK, et al. Circulation. 2008;118:198-210. 4. Patel P, et al. Ann Int Med. 2008;148:728-736. 5. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8. Choi A, et al. AIDS. 2009;23(16):2143-2149. 9. McCutchan JA, et a. AIDS.2007;21:1109-1117. 10. Sogaard OS, et al. Clin Infect Dis. 2008; 47(10):1345-1353. 7. 23. 2012 10

The HIV-infected Population in United States Is Getting Older By 2015, it’s estimated that more than 50% will be over the age of 50! [Slide is self-explanatory] Effros, CID, 2008: reprint of Luther, Clin Geriatr Med. 2007. 7. 23. 2012 11

The HIV-infected Population Is Also Aging in Sub-Saharan Africa 50 Years of Age ≥ [Slide is self-explanatory] Mills, et al. NEJM. 2012 7. 23. 2012 12

Another Kind of AIDS Crisis Accumulation of multiple co-morbidities “A striking number of HIV patients are living longer but getting older faster—showing early signs of dementia and bone weakness usually seen in the elderly…” (David France, Published Nov 1, 2009)   In 2009, New York Magazine ran a feature about this very issue, highlighting “another kind of AIDS crisis,” as people aging with HIV experience diseases – ranging from dementia to bone loss – generally associated with the elderly at earlier ages. 7. 23. 2012 13

HIV and Frailty Frailty: Vulnerability to health threats Accumulated functional defects Cognitive, physical, social Exhaustion, muscle weakness, slow gait, weight loss, decreased physical activity Can be measured Fried’s Frailty Phenotype Short Physical Performance Battery 400m Walk Time We’re also seeing an increased risk of frailty in HIV-infected populations that have been infected for quite some time. Compared to the general population, these risks are much higher. Fried. J Gerontol A, Biol Sci Med Sci. 2001. 7. 23. 2012 14

Increased Frailty-related Phenotype in HIV Infection (MACS Cohort) 3-fold higher prevalence of frailty in HIV+ vs HIV– Occurs ~20 years earlier in HIV+s Associated with lower CD4+ count CD4+ T-cell count (cells/mm3) This slide demonstrates the link between frailty and HIV+ status. Studies have shown that people living with HIV are at a higher risk of frailty at earlier ages than HIV uninfected individuals. Desquilbet, JAIDS. 2009. 7. 23. 2012 15

ART Toxicity Premature Aging Lifestyle In ARV-Treated Patients, Premature Development of Complications Normally Associated with Aging is Likely Multifactorial Normal Aging (average age in many clinics now around 50) ART Toxicity Premature Aging Lifestyle (smoking, etc) So why are HIV-infected patients at increased risk for diseases associated with aging? Several lifestyle factors may contribute to this increased risk, including smoking, as well as the HIV medications themselves, and the normal course of aging. Even after you adjust for these factors, you still see that HIV is independently associated with premature aging. Deeks and Phillips, BMJ. 2009. ARV: Anti-retroviral ART: Anti-retroviral Therapy 7. 23. 2012 16

Persistent Inflammation HIV Itself Appears to Increase the Risk of Several Age-associated Diseases ART Toxicity Premature Aging Lifestyle Persistent Inflammation This has led to the concept that persistent inflammation during ART might be contributing to premature aging and aging-related morbidities in this population. Deeks and Phillips, BMJ. 2009. 7. 23. 2012 17

Time Magazine, February 23, 2004 This cover story from an issue of TIME magazine from 2004 illustrated the potential link between inflammation and disease. Time Magazine, February 23, 2004 7. 23. 2012 18

An Important Clue From Nature Sooty Mangabey Infect with SIV High levels of viral replication No AIDS, normal life span Minimal immune activation Rhesus Macaque Infect with SIV High levels of viral replication AIDS and death Massive immune activation So why do we think this? We do get an important clue from nature. On the left is the Sooty Mangabey, the natural host of the Simian Immunodeficiency Virus (SIV). This animal, when infected with SIV, experiences high levels of viral replication, comparable to what we see in HIV-infected people. But interestingly, this animal rarely if ever experiences AIDS and lives a normal lifespan. However, if you put the same virus in a different monkey – in this case a Rhesus Macaque – the opposite occurs. So what’s the difference? It’s the inflammatory response to the virus that seems to be causing these divergent outcomes. The Mangabey has minimal immune activation, while the Macaque, just like HIV-infected people, experiences massive amounts of immune activation. The more immune activation that occurs, the more rapidly HIV progressions occurs. Silvestri, Immunity. 2003. 7. 23. 2012 19

T Cell Activation Declines With ART –P<0.001– People on antiretroviral therapy experience reductions in the extent of immune activation in the body. Hunt et al, JID. 2003 and 2008. Hunt et al, PLoS One. 2011. VL: Plasma HIV RNA Level 7. 23. 2012 20

But Remains Abnormally High During ART-mediated Viral Suppression However, even these patients who have been suppressed on antiretroviral therapy have abnormally high levels of immune activation when compared to HIV-uninfected individuals. Hunt et al, JID. 2003 and 2008. Hunt et al, PLoS One. 2011. 7. 23. 2012 21

Inflammatory Markers Also Higher In Treated HIV Infection vs Inflammatory Markers Also Higher In Treated HIV Infection vs. HIV Negatives Participants 45-76 years of age N=5,880 Percentage difference vs General population Others have established that inflammatory biomarkers in the blood are higher in treated HIV disease compared to HIV-uninfected individuals. Neuhaus J, et al. JID. 2010. (also see: French, JID. 2009.) 7. 23. 2012 22 22

Inflammation Predicts Disease and Mortality in Treated HIV Infection Cardiovascular Disease Lymphoma Venous Thromboembolism Type II Diabetes Cognitive Dysfunction Frailty Inflammation may be a much greater mediator of cardiovascular risk and risk of other causes of mortality in the HIV-infected population than they are in the HIV-uninfected population. Kuller, PLoS Med. 2008; Duprez, Atherosclerosis. 2009; Breen, Cancer Epi Bio Prev. 2010; Musselwhite, AIDS. 2011; Brown, Diabetes Care. 2010; CROI 2012: Burdo, Abs#81; Letendre Abs#82; Erlandson, IAS, 2011, Abstract #TULBPE029. 7. 23. 2012 23

Inflammation persists during suppressive ART, which may blunt CD4 recovery and increase risk of chronic diseases and mortality. Inflammation persists during suppressive ART which may blunt CD4+ cell recovery and increase the risk of non-AIDS associated morbidities. Hunt, Curr HIV/AIDS Rep. 2012. 7. 23. 2012 24

What is Causing Persistent Inflammation During Suppressive ART? HIV itself (leeching out of infected cells) ART “intensification” doesn’t seem to help Might decreasing inflammatory response to HIV with ASA, statins, etc, help? Microbial translocation (leaky gut) Bovine colostrum, prebiotics, probiotics, rifaximin, sevelamer, chloroquine, mesalamine all being studied Co-infections (HCV, CMV, etc) Others? One obvious potential hypothesis is that there’s still low level HIV being released or replicated below the limit of testing of commercially available assays. Hunt, Curr HIV/AIDS Rep. 2012. 7. 23. 2012 25

Does initiating ART early prevent persistent inflammation and morbidity during ART? [Slide is self-explanatory] 7. 23. 2012 26

Early ART Appears to Reduce Residual T Cell Activation During ART This slide illustrates that early HIV treatment may reduce immune activation. Pre-ART 3 mos ART Pre-ART 3 mos ART Burdo, JID. 2011. 7. 23. 2012 27

Earlier HAART May Decrease Risk of Serious Non-AIDS Events (SMART) Median CD4 still >350 Deferred ART Early ART This slide includes information on a study in which 477 subjects entered SMART off ART with a median CD4 count of 447 and were randomized to immediate (VS) or intermittent ART (DC) once CD4 <250. Deferred ART was associated with a 7-fold increase in non-AIDS events or death. Most events (57%) occurred when CD4 still >350. Median CD4 count=447 at enrollment Emery, JID. 2008. 7. 23. 2012 28

Primary Clinical Events Effects of Early Versus Delayed Initiation of ART on HIV Clinical Outcomes Study Found That Early ART Decreases Risk of TB by 47% Primary Clinical Events Immediate Delayed Total (N=129) 53 76 Tuberculosis 17 33 Severe bacterial infection 16 11 Death 10 13 Chronic herpes simplex 3 7 Bacterial pneumonia (recurrent) 2 Esophageal candidiasis N=105 had primary clinical endpoint* Immediate: 40 Delayed: 65 HR: 0.6 (0.4,0.9) P=0.01 Extrapulmonary TB: largest difference favoring early treatment (P<0.002) Adverse events: Immediate: 14% Delayed: 14% This slide summarizes a study in which 17 subjects experienced >1 clinical event. - 8 immediate arm - 9 delayed arm *Some pts had >1 event Grinstein B, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. MOAX0105, 2011. 7. 23. 2012 29

What About Diet and Exercise? High fat or high carbohydrate meal increases inflammation in healthy volunteers Diet-induced weight loss has been proven to decrease inflammation in elderly Exercise in elderly is proven to: Decrease inflammation Increase functional status Improve glycemic control Prevent cognitive decline Studies in HIV? [Slide is self-explanatory] Deopurkar, Diabetes Care. 2010; Nicklas, Am J Clin Nut. 2004; Nicklas, J Am Ger Soc. 2008; McMurdo, Geriatrics. 1992; Diabetes Care. 2002; Muscari, Int J Ger Psych. 2010. 7. 23. 2012 30

Summary Despite optimal ART, HIV is associated with shorter life expectancy and an increase in chronic diseases associated with aging Immune activation/inflammation persist despite ART and predict many of these morbidities Earlier initiation of ART may decrease both residual immune activation and clinical events Diet / exercise may improve these key pathways of interest Targeted interventions directed at the underlying causes of inflammation may hold promise [Slide is self-explanatory] 7. 23. 2012 31

What Does This Mean for HIV+ Patients? They need to be an active participant in their medical care Ask their provider lots of questions! Consider starting ART earlier Regular clinic follow up and age-appropriate screening Encourage patients to take control of the situation Smoking cessation Healthy diet Regular exercise Encourage participation in research studies [Slide is self-explanatory] 7. 23. 2012 32

What Does This Mean for the Clinical Care of HIV+ Patients? Need to get more people tested and engaged in care to start ART earlier on course of disease With increasing age and burden of chronic diseases, need more multidisciplinary care No longer just about treating HIV itself Need comprehensive primary care, screening, involvement of disease-specific subspecialists Consideration of some disease specific toxicities that may be patient specific when constructing regimens [Slide is self-explanatory] 7. 23. 2012 33

What Does This Mean for Research and New Therapies? Focus on understanding the causes and consequences of inflammation in HIV Lead to new interventions to block inflammation and improve immune function during ART Focusing on specific causes of inflammation might lead to more targeted therapies with less toxicity Clinical trials will become a bit more complicated Additional testing (blood vessel function, bone density) Tissue biopsies (gut, lymph nodes) [Slide is self-explanatory] 7. 23. 2012 34

Thank You! 7. 23. 2012 35