HIV/AIDS and the Older Crowd

1. HIV/AIDS and the Older Crowd Victor G. Valcour MD FACP University of Hawaii Department of Geriatric Medicine and Division of Neuroscience

2. Overview • Understanding HIV and aging is in its infancy • Review of literature • Outcomes, toxicities, response to HAART • Presentation of Hawaii data concerning neurocognitive and neurological outcomes

3. The Magnitude of the Issue

5. Magnitude of the Problem • As of December 2001, 90,513 cases of AIDS were reported in individuals 50+ • Cumulative frequency of about 11% of the population

6. Where in the US are older HIV+ individuals living Retirement phenomenon?

7. Where in the US are older HIV+ individuals living

8. Age and HIV-1 Infection in Miami-Dade County • Percentages of AIDS cases over age 50 increase consecutively from USA to State of Florida to Miami-Dade County • Total AIDS cases 26,050 • Total over age 50 3,935 (15.1%) source: K Goodkin MD

9. AIDS Cases Reported in Hawaiipercent 50+ years old 19% Source: State of Hawaii quarterly surveillance

10. Magnitude of the Problem • Increase in non-HIV morbidity with aging • Vascular disease: heart attacks, stroke • Metabolic and degenerative disease: Osteoporosis, osteoarthritis, dementia • Malignancies: prostate cancer • Immunological changes: Involution of thymus, change in delayed-type hypersentitivity

11. Issues related to aging and HIV • Will there be additional complications in older people with HIV? • Will it be in excess of an additive effect of aging related changes and HIV-related changes? Or synergistic? • Will medications work as well in older people with age-related changes in immune function?

12. Outcomes for Older Individuals:Survival

13. Outcomes for Older Individuals:Survival • Prior to combination ART • Age at AIDS diagnosis accounted for about 12% of added risk for 1 and 5-year survival in a NYC cohort Rothenberg, NEJM 1987 ;317:1297 • Older age was a strong predictor of AIDS diagnosis and survival in hemophiliacs with know HIV conversion dates Goedert, NEJM 1989;321:1141 and Darby,Lancet 1996;347:1573

14. Outcomes for Older Individuals:Survival • After widespread use of combination ARV • Probability of survival for people with AIDS in NYC is inversely proportional to age Fordyce, JAIDS 2002;30:111 • Of patients diagnosed between 1996-1998: 87% survival at 24 months for 13-24 years old decreasing to 59% for people over 55. • A combined analysis of individuals starting first ART regimen, adjusted for baseline CD4 and viral load • Hazard ratio for death increased to 3.09 for people over 50 compared to people 17 to 29 years old (defined HR pf 1) • This effect is less than that seen before ART Egger, Lancet 2002;360:119

15. Outcomes for Older Individuals:Survival • This finding persists into age over 60 • Hazard ratio is 1.70 for people 60+ years old compared to people < 60 years old (n = 58) Adeel South Med J 2001:94(4):397 • Is this due to background mortality? • e.g.: Does the rate disappear when you subtract out the mortality that would be expected for people without HIV at the same given age? • Finding remains even after adjustment Babiker J Clin Epi 2001; 54: S16

16. Outcomes for Older Individuals:Survival • Is this due to a diagnostic lag bias? • Rationale • HIV/AIDS is diagnosed later in older individuals El-Sadr Arch Intern Med 1995; 155: 184 • An increased risk for AIDS progression is seen in older people enrolled in inception cohorts Belanger Int J Epi 1997; 26(6):1340 • However, some data suggest access to care may be an issue

17. Outcomes for Older Individuals:Survival • Moore clinic, Baltimore • 259 older patients (n=259) compared to younger (n=538) • Median follow-up of 39.5 months • Being on ARV was the only predictor within groups • There was no difference in survival between the older compared to younger groups that were on ARV, when adjusted for baseline CD4 and gender Perez 9th Conference on Retroviruses and Opportunistic Infections 2002

18. Outcomes for Older Individuals:Survival • Summary • Mortality among patients with AIDS appears to increase with age, even when adjusted for background mortality • It is not clear that this it due to age alone as differences are not significance among patients treated. • Length of infection may be an emerging issue regarding survival • Older people with HIV have typically been infected longer (“chronic infection” in older people vs. “newly infected” older people)

19. Outcomes for Older Individuals:Adherence

20. Regimen 1 • Nelfinavir (Viracept) • Stavudine (Zerit) • Didanosine (Videx) • Regimen 2 • Ritonavir (Norvir) • Saquinavir (Fortivase) • Zidovudine (Retrovir) • Lamivudine (Epivir) Antiretroviral Medications (ARV)Overview – HAART Regimens

21. Both are not significance Outcomes for Older Individuals:Adherence Adherence to ARV may be better in older persons Valcour 2002 JAGS

22. Outcomes for Older Individuals:ARV Adherence • In a controlled study of protease inhibitor treatment Paterson Ann Int Med 2000;133:21 • Older age predicted greater adherence [OR 1.1 (1.0 –1.2)] • These findings are true even though older patients have more side effects • In a controlled study of first HAART regimen Mocroft AIDS 2001;15:185 • Older patients were are less likely to modify HAART [RH per 10 years: 0.73] • Among older patients who modified, toxicities and compliance was less often the issue than immunological/virological failure Mocroft AIDS 2001;15:185

23. Outcomes for Older Individuals:ARV Adherence • Summary • Older patients appear to be more adherent to ARV regimens than younger patients • When older patients change ARV regimens, it is less often due to compliance issues than is noted in younger patients

24. Outcomes for Older Individuals:Virological response to ARV

25. Outcomes for Older Individuals:Virological response to ARV • Prior to HAART • In HIV positive hemophilia patients prior to HAART, rate of viral load rise was higher in patients who were older at the time of seroconversion (although all patients in this sample were relatively young) Sabin,JAIDS 2000; 23:172-77

26. Outcomes for Older Individuals:Virological response to ARV • Since widespread use of HAART • Retrospective analysis at 12 months (n = 21 patients at 55+) • Viral load response was inferior at 6 months but equal to those <35 years old at 12 months Manfredi R, AIDS 2000, 14 (10): 1475-1477 • Retrospective analysis at 24 month (n = 28 patients at 60+) • Older patients had better adherence, more favorable VL outcome (undetectable VL at 24 months), more toxicities to medications, and more self-reported lipodystrophy Kobel, AIDS 2001, 15 (12): 1591-1593]

27. Outcomes for Older Individuals:Virological response to ARV • Summary • Viral load decrease following HAART generally adequate in the older patients • Response at 24 months may be superior, however, studies adjusting for adherence are needed (e.g.: this might be, in part, due to better adherence)

28. Outcomes for Older Individuals:Immunological response to ARV

29. Outcomes for Older Individuals:Immunological response to ARV • Age related changes in the immunological system may have implications for response to HIV and HAART • Involution of the Thymus – critical to “training” new t-cells

30. Outcomes for Older Individuals:Immunological response to ARV • Rationale: Aging and HIV share some common immune dysfunction which include: • Shift from a naïve to a memory T-cell phenotypeDePaoli P, Clin Immunol Immunopathol 1988, 48: 290-296; Lerner A, J Immunol 1989, 19:977-982; Ernst DN, J Immunol 1993, 151: 575-587] • Reduction in T-cell proliferative abilityNegoro S, Mech Aging Dev 1986, 33:313-322; Eylar EH, J AIDS 1994, 7:124-128 • Associated with reduced telomer length (T cell replicative senescence?) Bestilny LJ, AIDS 2000, 14 (7): 771-780 • Increase in CD8 cell population that are CD28 –Choremi-Papadapoulou H, JAIDS 1994, 7:245-253, Fagnoni FF, Immunology 1996, 88:501-507 • Decreased production of IL-2 and IL-2 receptor (involved in T-cell-mediated immune responses) Gillis S, J Clin Invest 1981, 67: 937-942; Eyler EH, Cell Mol Biol 1995, 41:S25-S33

31. Outcomes for Older Individuals:Immunological response to ARV • With some exceptions [Hernando K, AIDS 2001, 15 (12): 1591] most papers show a less favorable CD4 rise in older patients • At 12 months and 24 months in 55+ years old Goetz MB, AIDS 2001, 15 (12): 1576; Operskalski EA, JAIDS 1997, 15 (3): 243 • From 3 to 36 months for maximal CD4 rise, maximal attained CD4 and time to maximum CD4 Viard JID 2001;183:1290 • Is this explained by changes in thymic output? • No significant difference in 1st phase (approx 4 – 8 weeks) response to ARV; thought to be due to redistribution of existing cells; however, a decrease in naïve CD4 rise during the 2nd phase, thought to represent thymic production Lederman MM, AIDS 2000; 14: 2635 • May be due to involution of the thymus with age as naïve cell rise correlates with thymic size Smith KY, JID 2000; 181:141 and thymic output (TRECs) Douek DC, Nature 1998, 396; 690-695

32. Outcomes for Older Individuals:Immunological response to ARV • Summary • CD4 T-cell response does occur in older patients with substantial benefits, however, the magnitude of response appears to be inversely proportional to age • Lack of thymic production may be a significant issue • Adherence to ARV remains a strong predictor of outcome, regardless of age

33. Outcomes for Older Individuals:Co-morbidity and Medication toxicities

34. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Rationale • Co-morbidities potentially impact response to therapy, mortality, and quality of life • Increased co-morbid illnesses are seen in older people with HIV • The presence of co-existing illness could act synergistically in infected patients

35. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Increased co-morbid illnesses are seen in older people with HIV • HIV and non-HIV related hospitalizations • MI, CHF, Peripheral vascular disease, COPD, Ulcer disease, diabetes Skiest, Am J Med 1996;101:605-11 • HIV-related complications • Oral candidiasis, peripheral neuropathy, hyperlipidemia Kilbourne J Clin Epi 2001; 54:S22 • Osteoporosis? Arnsten 2002 9th Conference on Retroviruses and Opportunistic Infections

36. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Psychiatric co-morbidities • One study indicated a lower rate of alcohol use, drug use, depression and mania in older seropositive individuals.Kilbourne J Clin Epi 2001: 54:S22 • Substance abuse • Hawaii Aging with HIV Cohort • Meet criteria for current substance dependence (DSM IV) • 11% of the younger patients and 7% of the older patients

37. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Hepatitis • Retrospective analysis of 222 patients treated with HAART in Spain • Older age was an independent risk for hepatitis (RR, 1.11; 95% CI, 1.04–1.18;p = 0.001).Nunez,JAIDS 2001;27:426 • Metabolic Complications • Diabetes El-Sadr 2001;7th CROI#13 • Asymptomatic hyperlactatemia • Weak correlation with age, r= 0.11, p=0.009 McComsey 2002 9th Conference on Retroviruses and Opportunistic Infections #710-T; Antela2002 9th Conference on Retroviruses and Opportunistic Infections #711-T • Thrombosis • Rate of thrombosis in persons with HIV reported to be 2.6/1000 • Adjusted Odds Ration for age over 45 is 1.9 (1.4 – 2.7) Sullivan AIDS 2000;14:321

38. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Lipodystrophy • Rationale: Redistribution of fat is a typical aspect of aging in HIV- people • Includes an increase in total body fat, thinning of limbs, and increase in waist/hip ratio • Age is a risk factor for lipodystrophy in patients with HIV Mallal, AIDS 2000; Martinez, Lancet 2001;357:592

39. Ten Year Risk of Cardiovascular Events Men Women Egger, 40th ICAAC Egger, 40th ICAAC Abs 1374

40. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • NRTI mediated Mitochondrial Toxicity: Differential Effect on the Elderly? • Induced mitochondrial dysfunction is the postulated mechanism for the toxic side effects of nucleoside reverse transcriptase inhibitors (NRTIs) • Peripheral Neuropathy • Myopathy • Cardiomyopathy • Lactic Acidosis (acidemia) • Hepatic Steatosis • Pancreatitis • Peripheral lipoatrophy

41. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Decline of mitochondrial energy production resulting in increased oxidative stress and apoptosis play a significant role in degenerative diseases and aging Wallace DC, Novartis Foundation Symposium 235: 247-63 • Age is an independent risk factor for the occurrence of peripheral neuropathy in the Era of HAART Watters, Valcour Amer Acad Neurol 2003, Cherry C, 9th CROI Abs 69 • Lipoatrophy is in part a NRTI mediated mitochondrial toxicity issue • Age is a consistent risk factor for its development Lichtenstein K, AIDS 2001; 14:F25-32 • Lipoatrophy is independently associated with insulin resistance

42. A Phase II Exploratory Study Examining Immunologic and Virologic Indicies of HIV-Infected Subjects to Explore the Basis of Accelerated HIV Disease Progression ACTG 5015

43. Study Design • Prospective, multicenter, cohort study ofolder (³ 45yrs)and younger(£30 yrs) HIV-infected subjects: • Naive to ARV • CD4 cell counts < 600/mL • HIV-RNA > 2,000 copies/mL All received: LPV/r, d4T and FTC • A5113: Companion, age-matched, healthy volunteers.

44. Endpoints Primary: • 5015: Naïve CD4 cell changes at 48 wks. • 5113: Baseline comparison naïve CD4 cell counts. Secondary (5015): • Changes in CD4, CD8 and HIV-RNA • Expanded T cell phenotypes, B cells, NK cells • DTH • Onset of Co-morbidities Secondary (5113): • Baseline comparison of other immune indicies.

45. Outcomes for Older Individuals:Co-morbidity and Medication toxicities • Summary • Aging is associated with an increased risk for co-morbid conditions and toxicities associated with HAART • Despite this finding, adherence appears superior in older patients and virological outcomes appear adequate • Older patients started on HAART should be monitored closely for possible side effects • To date, there are no age-specific treatment recommendations regarding HAART

46. Neurological and Neurocognitive endpoints

48. The Hawaii Aging with HIV Cohort • What are fundamental neuro-epidemiological characteristics of HIV cognitive impairment in older seropositive individuals. • Prevalence, clinical presentation, progression • What are the determinants of increased neuro-cognitive dysfunction, if present, in older people infected with HIV? • co-morbidities • host factors • treatment toxicities • immune reconstitution

49. The Cohort • Goal: 150 Younger (<40) and 150 Older (50+) seropositive individuals • community-based broad recruitment strategies • Matched seronegative controls • Annual neurological and neuropsychological evaluations • Risk profiles including immunologic parameters.