1. Laura Armas-Kolostroubis, MD University of Florida-Jacksonville Aging Issues Among Women Living with HIV

2. Disclosure of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. This speaker will not discuss any off-label use or investigational product during the program. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

3. Objectives Discuss the concept of early aging in HIV ‐ infected females Review two features of immunological senescence and menopause Implement one practice change for screening HIV infected females for osteopenia/osteoporosis, cardiovascular disease and other age related conditions

4. CASE: Sandy 46 y/o AAF with asymptomatic HIV, diagnosed during pregnancy 20 years ago. Nadir CD4 was 356 and has been on HAART for 6 years with TDF/FTC FDC + ATV/RTV. She has an associate degree and works at an insurance company. She read on the internet that HIV infected individuals age more rapidly and she is concerned, particularly about neurocognitive changes and osteoporosis. Her grandmother had Alzheimer’s at the age of 82 and her mother is on medication for osteoporosis. She is premenopausal and still has regular menses every 28 days. No vasomotor symptoms.

5. The following statement is true about aging and HIV: A.HIV itself leads to premature aging, as it integrates into host DNA and programs it for early apoptosis. B.Inflammatory changes, known as immunosenescence, increase the release of cytokines such as IL-6 and TNF associated with aging. C.Other markers of aging (like hearing loss) is associated with HIV infection. D.Menopause does not affect changes associated with aging in women. E.None of the above

6. Aging Gradual change in an organism that leads to increased risk of weakness, disease, and death –Takes place in a cell, an organ, or the total organism over the entire adult life span of any living thing –Decline in biological functions and in the ability to adapt to metabolic stress –Changes in organs include the replacement of functional cardiovascular cells with fibrous tissue Overall effects of aging include –Reduced immunity –Loss of muscle strength –Decline in memory and other cognitive functions –Loss of color in the hair and elasticity in the skin –In women, the process accelerates after menopause Merriam-Webster Dictionary

7. HIV and Aging HAART increases survival but lifespan is shorter than in non-infected individuals. Increased risk of non-communicable diseases (NCD) such as CVD, dementia and frailty. Many of the degenerative changes in immunity seen with aging are common in HIV-infected patients who are either untreated or fail to fully respond to treatment. Jenny NS; Discov Med. 2012 Jun;13(73):451-60

8. HIV and Aging – Mortality WIHS Cohort 1995-2004 Predictors of mortality in women (HR): –Age: CV (1.10) Non AIDS malignancies (1.08) –CD4 <200: No difference –VL: Overdose/trauma (1.52) –HCV RNA: Liver (9.51) –HBsAg + : Liver (5.47) –Depression: CV (4.61) Non-AIDS malignancies (3.01) –BMI <18.5: Liver (6.31) Non AIDS malignancies (5.96) French A, et.al; PLoS One. 2012; 7(7): e39266

9. Aging Accumulation of detrimental changes at the molecular and cellular levels, resulting in disease and ultimately in morbidity and mortality AGING INFLAMMATION Jenny NS; Discov Med. 2012 Jun;13(73):451-60

10. Inflammation TRAUMA & INFECTIONCYTOKINES (TNFα, IL-6, ETC) PATHOGEN DESTRUCTION & TISSUE REPAIR HOMEOSTASIS Jenny NS; Discov Med. 2012 Jun;13(73):451-60

11. Aging and Inflammation Redox stress Mitochondrial damage Immunosenescence Endocrinosenescence Telomere attrition and cellular senescence Epigenetic modifications Inflammatory diseases Frailty Jenny NS; Discov Med. 2012 Jun;13(73):451-60

12. Immunosenescence Accumulation of molecular and cellular defects due to oxidative damage Thymic involution –Reduced levels of naïve T cells impairs response to new infection –Reduced capacity of adaptive responses to previously seen antigens (memory T cells) Chronic inflammation from poor immune function and continued exposure to new antigens –Increased cytokine production by senescent cells Jenny NS; Discov Med. 2012 Jun;13(73):451-60

13. HIV and Aging Increased mtDNA mutations in HIV infected mothers exposed to ART Shorter lymphocyte telomere length in uncontrolled viremia (2) Cochlear dysfunction (marker of aging) not related to HIV, ARV, nadir CD4 or VL (3) Greater number of co-morbidities and their complications in HIV infected individuals: –HIV = chronic inflammatory state –ARV= chronic adverse events –Traditional risk factors (4) 1.Jitratkosol MH, et.al; AIDS. 2012 Mar 27;26(6):675-83 2.Cote H; PLoS One. 2012; 7(7): e39266 3.Torre III P, et,al; [TuPe 138]; 6 th IAS; Rome 2011 4.Aberg JA; Topics in Antiviral Med Sept 2012; 20(3): 101-105

14. Two years later she comes for her regular visit. She is still undetectable but now she is complaining of hot flashes, her menses are irregular with decreased flow, and she wants to know if she is going through “the change”. You: A.Check an FSH on day 15 of her menstrual cycle. B.Check Anti-Mullerian Hormone. C.Tell her not to worry, she will know when it’s here. D.Check an estradiol level and FSH on day 2-5 of menstrual cycle. E.Both answers b and d.

15. Endocrino-senescence Decreased sex steroid hormones, DHEA, DHEAS and growth hormone Increased cortisol production due to over-stimulation of the hypothalamic pituitary-adrenal axis (HPA) Sex hormones modulate inflammatory cytokine production –IL-6 gene transcription and secretion inhibited by estrogen and androgen Jenny NS; Discov Med. 2012 Jun;13(73):451-60

16. Menopause At least 12 consecutive months of amenorrhea not caused by surgery or another obvious cause. Age at which natural menopause occurs is a marker of aging. Later age at natural menopause associated with: –Longer overall survival and greater life expectancy –Reduced all-cause mortality –Reduced risk of CV disease, stroke, angina after MI and atherosclerosis –Preserved bone density and reduced risk of osteoporosis and fracture –Increased risk of breast, endometrial and ovarian cancers Santoro N, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 417–423

17. Menopause Consistent factors related to earlier age at menopause: Low socioeconomic status, low parity, not using contraceptives, active smoking, HIV (1) Inconsistent factors: Race, ethnicity, BMI or body composition, physical activity, diet (1) Adiposity and menopause: Inconclusive, symptoms are more related to higher BMI but difficult to distinguish if increased morbidity due to obesity versus menopause (2) 1.Gold EB; Obstet Gynecol Clin North Am. 2011 Sep; 38(3): 425-440 2.Wildman R, Sowers M; Obstet Gynecol Clin North Am. 2011 Sep; 38(3): 441-454

18. Evaluation of Reproductive Aging and Predictors of Ovarian Function Follicle Stimulating Hormone (FSH) –Sustained rise in late menopausal transition, and precipitous around the final menstrual period –Early follicular phase between cycle days 2 and 5 (more sensitive) Estradiol (E2) –Early follicular levels are the last biomarker of the transition to change with rapid decline 2 years before the FMP Inhibin B –Early predictor of menopausal transition Anti-Mullerian Hormone(AMH)/ Mullerian Inhibitin Substance (MIS) –Concentrations decline through reproductive life –Earliest and most effective way to measure a woman’s progress toward menopause 1.Santoro N; Obstet Gynecol Clin North Am. 2011 Sep; 38(3): 425-440

19. Biologic Markers of Ovarian Reserve in the WIHS cohort Cross-sectional study 263 participants of the Women's Interagency HIV Study –187 HIV infected and 76 uninfected –Reported menstrual bleeding during the preceding 6 months –Not taking exogenous hormones Early follicular FSH, E2, Inhibin B, and MIS Increased FSH, lower E2 and Inhibin B levels correlated with lower MIS levels (r=0.93) No difference between HIV status MIS predicts ovarian reserve in HIV infected women Selfer, et.al; Fertil Steril. 2007 Dec;88(6):1645-52. Epub 2007 Apr 5

20. Study of Women’s Health Across the Nation SWAN Study Survey Cross Sectional Survey (Sampling Frame) N=16,065 Cohort Longitudinal Cohort N=3,302 Nested Sub-studies SWAN Heart, N=559 SWAN Bone, N= 1,902 SWAN Daily Hormone Study, N=848 SWAN Sleep, N=365 SWAN Psychiatric, N=589 Santoro N, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 417–423

21. SWAN Study Multicenter, multi-ethnic longitudinal study to characterize the psychological and physiological changes that occur during the menopausal transition, and observe their effects on subsequent health and risk factors for age related diseases. 28% AA, 47% W, 8% Chinese, 8% Hispanic, 9% Japanese Followed annually for 10 years, then every other year. 2011 is year 14 of the study Santoro N, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 417–423

22. HIV infection is associated with early onset menopause: A.True B.False C.Nobody knows D.Nobody cares

23. Age at Onset of Menopause Ethnicity: –AA and Hispanic: two of the highest BMI More frequent and severe hot flashes. Challenging to determine if BMI or ethnicity related. SES: –Low SES more likely to experience early menopause. –Factors associated with low SES (financial strain, adverse life events, poor social support) are also related to increased depressive symptoms and to menopausal symptoms. HIV infection and immunosuppression are associated with earlier age at the onset of menopause. –571 women: 302 (52.9%) HIV infected and 269 (47.1%) non-HIV infected Santoro N, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 417–423

24. Ms Study HIV infection and immunosuppression are associated with earlier age at the onset of menopause –HIV infection –Drug use –Physical activity Degree of immunosuppression plays an important role

25. Factors Associated with Menopause, by Logistic Regression Analysis of All Women Enrolled in the Ms Study (n = 571) Schoenbaum E E et al. Clin Infect Dis. 2005;41:1517-1524 © 2005 by the Infectious Diseases Society of America

26. Factors Associated with Onset of Menopause by Logistic Regression Limited to HIV-infected Women (n = 302). Schoenbaum E E et al. Clin Infect Dis. 2005;41:1517-1524 © 2005 by the Infectious Diseases Society of America

27. Estrogen has significant cardiovascular effects, which include: A.Vasodilatation B.Prevention of smooth muscle cell proliferation C.Inhibition of LDL deposition in the vascular wall D.Inhibition of platelet aggregation and stress-induced endothelial injury E.All of the above

28. Cardiovascular Lipids –SWAN and Healthy Women Study cohorts had lipid changes within 1-year interval of final menstrual period (FMP) Increases in total cholesterol and LDL and TG Decrease in HDL Blood Pressure –Related to chronologic aging Glucose, insulin and metabolic syndrome –Increased rates of metabolic syndrome in the MT –SWAN risk related to increase in bioavailable testosterone or SHBG Subclinical Atherosclerosis –Estrogen has vasodilatory effects, impedes smooth muscle cell proliferation, inhibits deposition of LDL cholesterol in the vascular wall, inhibits platelet aggregation and stress-induced endothelial injury –Atherosclerosis accelerates in women at menopause (with age in men) Chae CU, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 477-488

29. Cardiovascular Hot flashes are associated with endothelial dysfunction –Decreased flow-mediated dilation –Higher levels of aortic calcification and intima media thickness of the common carotid artery Experienced by most midlife women Racial/ethnic differences Risk factors: –Low education, smoking, negative affect, obesity Decrease QOL Sleep disturbances Negative mood Chae CU, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 477-488

30. Vasomotor Symptoms Experienced by most midlife women Racial/ethnic differences Risk factors: –Low education –Smoking –Negative affect –Obesity Decreased QOL Sleep disturbances Negative mood Thurston, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 489-501

31. HIV and Metabolic Syndrome 30% prevalence, but increases to 42.5 after 50 years of age Lower viral load Abdominal obesity: –Women - 59.5% –Men – 20.7 % Higher plasma glucose in women (37.2 vs. 16.9; P<0.004) Low HDL and elevated BP similar in both sexes High TG < in AA In <50 years old men had double the 10 year CVD risk score than women (6.2 vs. 2.7, P<0.001 Similar scores in older ~10% P <0.001 Pullinger C, et.al; Metab Syndr Relat Disord. 2010 June; 8(3): 279–286

32. Lipodystrophy Lipoatrophy –Diffuse loss of SQ tissue (extremities, face) –Increased insulin resistance, inflammation and dyslipidemia – Affects ~30% of HAART treated patients NRTIs d4T, ddI, AZT Lipohypertrophy –Excess deposition Abdominal Breast Liver, pericardium, muscle –Associated with insulin resistance –Women have more body fat Mixed lipodystrophy

33. The International Antiviral Society recommends: A.Screening for osteoporosis all men >50 with Bone densitometry (DEXA Scan). B.Screening with DEXA scan all HIV infected postmenopausal women. C.Screening with DEXA all HIV infected who are receiving tenofovir. D.Screening with DEXA only if evidence of vitamin D deficiency.

34. Bone and Menopause CopyrightCopyright © 2008 by The Endocrine Society Finkelstein J, et.al; J Clin Endocrinol Metab. 2008 March; 93(3): 861–868 Bone loss accelerates substantially in late peri-menopause and the initial postmenopausal years. Body weight is a major determinant.

35. Osteoporosis screening General population screening –Frailty fracture –Women >65 –Men >70 HIV infected –Postmenopausal women –Men >50 McComsey, et.al; Clin Infect Dis. 2010 Oct 15;51(8):937-46. Review

36. Vitamin D 74-78% of women have low Vit D (25 OHD) levels. Lower in AA women. Higher if supplements or MVI use. In HAART treated women 25 OHD level directly associated with current CD4. AA HIV+ Stein, et.al; Osteoporosis Int; 2011 Feb; 22(2): 477-487 HIV+

37. Cognition No relationship with symptoms. Effects of estrogen on depression and anxiety largely mediated by estrogen receptor-β effects on serotonin and hypothalamic-pituitary-adrenal (HPA) axis function. Long term cognitive consequences may stem directly from the decline in E2. –Changes in cholinergic and serotonergic function. Increased CV risks lead to increased risk of dementia. Cognitive complaints may be the result of peri- menopausal anxiety or depressive symptoms: the memory-mood link. Greendale GA, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 519-535

38. HIV and Neurocognitive Deficit 104 HIV infected: H&P, neuropsychological and functional assessments Frascati, American Academy of Neurology (AAN) and Memorial Sloan Kettering (MSK) scores Predictors of progression –Age older than 50 years (odds ratio: 5.57; p = 0.013) –Female gender (odds ratio: 3.13; p = 0.036). Nishiena S Gandhi, et al. HIV Ther. 2010 May;4(3):371-379

39. Distribution of neurocognitive diagnoses according to Frascati, asymptomatic neurocognitive impairment and Memorial Sloan Kettering ratings MSK 1: Mild Dementia (Memorial Sloan Kettering- MSK) MSK 2: Moderate dementia ANI: Asymptomatic neurocognitive impairment HAD: HIV Associated dementia (American Academy of Neurology- AAN) MCMD: Minor cognitive motor disorder MND: Mild neurocognitive Disorder Nishiena S Gandhi, et al. HIV Ther. 2010 May;4(3):371-379 K2

40. Interventions Environmental –Eliminate cigarette smoking exposure. –Control pollution exposure. Lifestyle –Regular physical activity. –Type of diet: Western vs. Mediterranean. –Caloric restriction. –Stress: socio-economic status, caregiving, pessimism. Hormone replacement: Controversial. Anti-inflammatory mediators: Statins.

41. Physical Activity Conflicting data in the protective effect of physical activity and vasomotor symptoms (VMS). Moderate intensity 60 min/day activity associated with weight maintenance. Weight bearing endurance (walking and running) and resistance exercises attenuate age related bone loss. Amelioration of somatic and mood complaints. Decreased breast cancer risk 25-30%. Sternfeld B, et.al; Obstet Gynecol Clin North Am. 2011 Sept; 38(3): 537-66