Aging, HIV and Women

1. Aging, HIV and Women Kathryn Anastos MD Professor of Medicineand Epidemiology Albert Einstein College of Medicine

2. Projected *Data from 2008, onward projected based on 2001-2007 trends (calculated by Justice, AC), 2001-2007 data from CDC Surveillance Reports 2007

3. 84.4% of women living with HIV are African Photo Jonathan Wallen

4. Photo Jonathan Wallen

5. Our brief foray into aging in HIV+ women • Menopause as an inflammatory state • HIV as an inflammatory state • 3 clinical conditions • Cardiovascular disease • Bone disease • Neurocognition • Research agenda

6. Women’s Interagency HIV Study (WIHS) Sites Bronx, NY Chicago, IL Brooklyn, NY San Francisco, CA Baltimore, MD Washington, D.C. (Data Center) Los Angeles, CA

7. WIHS Cohort 3818 Seroprevalent: 2843 (74%) Seronegative: 975 (26%) a AIDS-free baseline AIDS baseline Seroconverter Seronegative 719 (25%) 2124 (75%) 23 (2%) 952 (98%) AIDS AIDS AIDS-free AIDS-free 772 (36%) 14 (61%) 1352 (64%) 9 (39%) Deadb Dead Dead Dead Dead Dead 3 (21%) 5 (56%) 423 (59%) 64 (7%) 212 (16%) 323 (42%)

8. Baseline Characteristics(Barkan, Melnick, . . . , Feldman, Epidemiology 1998; 9:117-125)a a 01/02 cohort data added. b Transfusion risk not assessed in 01/02 cohort.

9. Cytokine changes in menopause and HIV infection • Menopause causes increased levels of pro-inflammatory cytokines: IL-6, IL-1, TNF alpha • Untreated HIV infection causes high levels of circulating pro-inflammatory cytokines: IL-6, IL-1, TNF alpha

12. Cardiovascular Disease

20. Bone Disease

21. Bone Strength Bone Density Bone Quality Bone strength: a major determinant of fracture risk Rate of Remodeling Microarchitecture Bone size and shape Mineralization Matrix quality

22. Evolution of bone mass: declines with age and sex hormones Men: 0.5-1.0% reduction in BMD/yr Women: 1.0-2.0% reduction in BMD/yr Peak 1.2 1.0 Men 0.8 BMD 0.6 0.4 Women 0.2 0 0 10 20 30 40 50 60 70 80 Age (Yrs) Orwoll ES et al. Endocr Rev. 1995;16(1):87-116.

23. Hypothetical evolution of bone mass with HIV infection HIV infection ART initiation Peak 1.2 1.0 0.8 Men BMD 0.6 HIV+ Men 0.4 Women 0.2 HIV+ Women 0 0 10 20 30 40 50 60 70 80 Age (Yrs) Adapted from Orwoll ES et al. Endocr Rev. 1995;16(1):87-116.

24. Tibial cortical thickness 12% lower in HIV+ postmenopausal women HIV- Age=61 HIV+ Age=61 Yin, IOF-ECCEO 2012

25. Higher prevalence of fracture in HIV+ Female Male Triant, JCEM, 2008

26. Higher incidence of fracture in HIV+ * fracture per 1000 person-years HIV+ 1728 5826 40115 5306 HIV- 663 NA 79203 26530 Increased fracture in multivariate models: Age, weight, caucasian, smoking, ETOH, glucocorticoids, PPI, HCV Yin, 2010; Young, 2011; Womack, 2011; Hansen, 2011

27. Multifactorial etiology of bone loss in HIV Host Virus ART Smoking/alcohol Glucocorticoids HCV infection Lipodystrophy CKD Vitamin D deficiency Weight loss Hypogonadism Decreased activity Direct effect on bone cells Inadequate mineralization Immune reconstitution Direct effect of viral proteins on bone cells Immune activation

28. Neurocognitive Function and Menopause in HIV-infected women

29. Understanding menopausal symptoms in HIV-infected women:Cross-sectional findings from the WIHS

30. Specific Questions Addressed Are HIV-infected women at increased risk for menopausal symptoms? Does menopausal stage influence depressive symptoms in HIV-infected women? Do menopausal symptoms influence cognitive function in HIV-infected women?

31. *P<0.05. As expected, menopausal symptoms are more common in peri- and postmenopausal stages compared to premenopausal stage Symptom Domains Mood Sleep Vasomotor Somatic Vaginal Increased Likelihood * 10 * * 7 Odds Ratio * * * * * 4 1 Decreased Likelihood Early Peri Late Peri Post Early Peri Late Peri Post Early Peri Late Peri Post Early Peri Late Peri Post Early Peri Late Peri Post Reproductive Stage Note: Referent reproductive stage was premenopausal. Adjusted for relevant sociodemographic, clinical and behavioral variables. 55% premenopausal,15% early perimenopausal, 5% late perimenopausal, 25% postmenopausal.

32. The only menopausal symptom that was increased in HIV+ women compared to HIV-women was night sweats • After adjusting for relevant sociodemographic, clinical, and behavioral variables: * * *P<0.05.

33. Results: Depressive Symptoms on CES-D Are Increased During Early Perimenopause Increased Likelihood 5 * 4 * * * 3 * * Odds Ratio 2 1 Decreased Likelihood 0 Post HIV+ Current Smoking 2 Sexual Partners Income 12,000/yr Late Peri Early Peri Recent Use of Antidepressant Meds Unemployed *P <0.05. Predictors Odds Ratio and 95% CI Note: HIV-infected women (N = 835) and at-risk HIV-uninfected women (N =335). Referent for early peri, late peri, and post was premenopausal. “Recent Use” refers to in the past 6 months. CD4 count was an additional predictor in HIV-infected women. Maki et al. (in press) Menopause

34. Results: Depressive Symptoms on CES-D Are Increased During Early Perimenopause in HIV-infected women who are ART naïve Increased Likelihood Odds Ratio Decreased Likelihood Odds Ratio and 95% CI Note. *p< .01. HAART use refers to use in the previous six months. Model is adjusted for age, race/ethnicity, site, education, employment, past history of probable depression, former menopausal hormone therapy use, persistent vasomotor symptoms, self-reported former and recent antidepressant medication use, and CD4 count. Maki et al. (in press) Menopause

35. Menopause-related anxiety symptoms impact verbal learning more in HIV+ vs. HIV- women * Better Learning Worse Learning Note:*p=0.001. Adjusted for relevant sociodemographic, clinical, and behavioral variables.

36. Summary • Midlife women with HIV were at risk for (compared to premenopausal women) but not differentially at risk for (compared to HIV- women): • Any menopausal symptom except night sweats • Depression during the perimenopausal period • Worsening of mood during the menopausal transition may lower ability of HIV+ women to learn and remember verbal material (i.e., word lists)

37. Dimeric glycoprotein growth factor that in females is produced by ovarian granulosa cells of primary follicles Indicative of total ovarian primary follicle pool, expression decreases in late follicular maturation, so levels are not a factor of follicular development, and thus can be measured when ovulation is not occurring AMH: AntiMüllerian Hormone ALL Durlinger, et al. Reproduction. 124:601, 2002.

39. Summary • Studies of men do not inform us adequately about disease in women

41. Summary and Research Needs • Are there sex differences in HIV-induced inflammation: We need to define the inflammatory state in HIV+ women • Must conduct studies • in African women—carry the greatest burden of HIV infection— • and in countries where the metabolic and CV disease burden is high • Must conduct clinical and translational studies across the full age range of women, with focus on menopause when studying aging

42. WIHS Sites and Principal Investigators • Consortia: • Bronx, New York (K. Anastos) • Brooklyn, New York (H. Minkoff) • Chicago, Illinois (M. Cohen) • Los Angeles, California (A. Levine) • Northern California (R. Greenblatt) • Washington, D.C. (M. Young) • Data Coordinating Center (WDMAC): • Johns Hopkins University, Baltimore, Maryland (S. Gange)

43. WIHS Sponsoring Institutions (Program Officers) • National Institute of Allergy and Infectious Diseases (J. Roe) • National Cancer Institute (G. Dominguez) • Eunice Kennedy Shriver National Institute of Child Health and Human Development (H. Watts) • National Institute on Drug Abuse (K. Davenny)

44. Thanks • WIHS collaborators • Robert Kaplan • Pauline Maki • Michael Yin • Ruth Greenblatt • WIHS participants

45. Photo Jonathan Wallen