Routine Health Monitoring in the Peri-Post Menopausal HIV+ WomanRUTH GREENBLATT

UCSF/WIHS

Focus of talk

HIVsex

differences

aging • Physiology

• Contribution of HIV

• Intervention options

smoking

Menopause and HIV General sense that menopause occurs slightly early among

HIV+ • But level of morbidity and other factors may be difficult to isolate

Amenorrhea is common among WLHIV• Energy imbalance• Medication and drug associated• In WIHS approx. 35% of WLHIV with 24 months of amenorrhea

subsequently resume menses

Biomarkers• FSH (in early perimenopause, cycle phase effect, smoking)• Estradiol, inhibin B (cycle phase specific)• Anti-Müllerian hormone

WIHS: AMH levels in HIV+, HIV- women CD4 cell count is a statistically

significant independent predictor of AMH level in HIV+ and HIV-women

HIV+ with CD4 expansion demonstrate a leveling of age related decline in AMH

Importance of lymphocytes and CD4 cells to ovarian follicular function mirrored in animal and other human studies

Scherzer R, Am J Repro Immunol, 2015, 79:273Unadjusted association of age with AMH level by HIV group

AMH level at age 40 in HIV+ predicts age at final menstrual period

Scherzer R, et al. Am J Obstet Gynecol. 2017, 216:electronic

1.49 years per doubling AMH

Other significant predictors:• Current smoking (-)

• CD4>500 (+)

• HCV (-)

• Hx Clin AIDS (-)

Gonadal aging and menopause CD4 cell count influences AMH level, and likely influences

ovarian follicular function• Clinicians should consider CD4 cell count in interpreting ovarian

capacity and menopausal status;

• Restoration of CD4 cell counts may improve ovarian function.

HIV+ women may experience prolonged amenorrhea and resume menses• Consider medications, wasting, and status of viremic control

Even if not due to menopause, amenorrhea may indicate low estrogen exposure, and increased risk of bone and other clinical complications

Aging: Loss of immune function is an essential feature

All hematopoietic cell lines impacted• Lymphocytes

Reduced naïve cell production

Loss less marked in memory population

Loss of B cells

Innate: increased NK cells but reduced function and dysregulated chemotaxis and phagocytosis, dysregulated signaling

• Proinflammatory changes “Inflammaging”

Ghosh M, et al. J Steroid Biochem Mol Biol. 2014, 0:171 Morgado Gameiro C, et al. Maturitas. 2010; 67:316

some improvement with estrogen tx

Sex differences in immune function F>M response to vaccines

• Aging lessens female advantage Estrogen therapy may improve responses

M>F infection mortality

Sex steroid modulation• Estrogen receptors expressed in most cells of the innate and

adaptive immune systems including T, B, NK, DC, macrophages

• Effects vary over the ovulatory cycle and in pregnancy

• Pubertal impact on thymic function

George VK, et al. JID, 2015; 211:1959.Engelmann F. et al. PLOS One. 2016; Feb 9

Pred

icto

rs o

f CD

4 re

cove

ry o

n cA

RTPredictor of Rapid Response

CD4 RESPONSE GROUPS RESULT

Good Poor OR for rapid

response p-value

mean/Std Dev (n) mean/Std Dev (n) OR (95% CI)

Age at start of response period 39.2 ± 7.5 (n=48) 45.5 ± 8.2 (n=42)0.894 (0.838-0.955)

per year 0.0009

CD4 T cell count nadir cells/ml 255.3 ± 189.4 (n=48) 127.5 ± 81.8 (n=42) 1.007 (1.003-1.011) 0.0008

Maximum plasma HIV RNA before cART initiation (log10) 4.4 ± 0.9 (n=48) 4.5 ± 0.9 (n=42) 0.985 (0.616-1.574) 0.95#(%) #(%)

Self-Reported Race♦: White (non-Hispanic)White (Hispanic)

African-American (non-Hispanic)Other

12(25.0%)7(14.6%)16(33.3%)13(27.1%)

12(28.6%)5(11.9%)

12(28.6%)13(31.0%)

Matching variable

AMH▲during phenotype: Not availableBelow detection (≤0.09ng/ml) 1(2.1%)

10(20.8%)2 (4.8%)

22 (52.4%)0.221 (0.087-0.564) 0.0016

Clinical AIDS occurred prior to CD4 response phenotype 17(35.4%) 24(57.1%) 0.411 (0.176-0.963) 0.041HCV RNA positive at the time of cART initiation 11(22.9%) 18(42.9%) 0.396 (0.160-0.984) 0.046

Reported receiving ddI or d4T prior to CD4 response phenotype 32(66.7%) 36(85.7%) 0.333 (0.116-0.955) 0.041Reported adherence to prescribed cART regimen during phenotype:

Not available>95%≤95%

5(10.4%)33(68.8%)10(20.8%)

2 (4.8%)20(47.6%)20(47.6%)

3.300 (1.288-8.5) 0.013

Was a tobacco smoker prior to start of response phenotype 15(31.3%) 22(52.4%) 0.413 (0.175-0.976) 0.044OR=Odds Ratio Chi Square Test ; ♦ participants in the two outcome groups were matched by race/ethnicity; ▲AMH= antiMüllerian hormone measured in plasma

Postmenopausal changes in immune function

Post menopausal changes occur:• Attributed to loss of estrogen

• Increase pro-inflammatory mediators IIL1, IL6, TNF-α

• Decrease CD4 T, NK, B cell functions

• Decreased total B and CD4+ lymphocytes

Summarized in: Gametro CM, et al. Maturatas 2010, 67:316. Giefing-Kroll C, et al, Aging Cell, 2015, 14: 309.

Major factors driving adverse outcomes

Cerebrovascular disease Under-studied in cART

Likely increase in risk:• IDU

• Pro-thrombotic state

• HIV vasculopathy Direct injury from viral

products

Contact with infected monocytes

Altered cell adhesion

Attraction of leukocytes

Benjamin LA, et al. Lancet Neurol. 2012, 11:878Singer EJ, et al. Ther Adv Chronic Dis. 2013, 4: 61Gurbel PA, et al. Eur Heart J. 2017, 0:1-3Kulkarni M, et al. Open Forum ID. 2016; 1

Alzheimer’s Disease F>M

• Longer survival

• Age independent increased risk?

Pathogenesis• Metabolic stress

• Mitochondrial dysfunction – potential interaction with ARV

• ? Protective effect of estrogen Mitochondria have estrogen receptors

CNS tissues produce estrogen

Early menopause is linked with AD risk

Best evidence HRT in early surgical menopause

Henderson and Diaz Brinton, Progress in Brain Res. 2010, 182:77.

Respiratory disease Tobacco use and the residual impact of lung infections are

likely contributors to pulmonary morbidity among HIV+ women.

History of past pulmonary infections and low CD4/CD8 cell counts are risk factors for lung cancer among HIV+ persons, including women.

Impaired DLCO common among women with chronic respiratory symptoms

Sleep apnea was twice as probable to occur among HIV+ women than HIV uninfected women.

Gingo MR, et al. BMC Pulm Med, 2014, 14:75. Fitzpatrick ME, et al. JAIDS. 2013 63

Bone Disease Osteoporosis and osteopenia are common among WLHIV

• 7-84% depending on study• Lower BMI, smoking, substance use, Caucasians• Underlying process is consistent with “inflammaging”• ? Direct effects of HIV proteins• Kyphosis may exacerbate HIV associated respiratory abnormalities

Bone loss is common after initiation of ART • Regardless of the specifics of the regimen• ? Altered metabolism of Vit D

Avoidance of TDF regimens could be considered in women with osteopenia or osteoporosis:• Early menopause, or frequent amenorrhea• Tobacco smoking• Other mineral loss risk factors

Finnerty F, et al. Maturitas, 2017, 95:50 Triant VA, et al. J Clin Endocrinol Metab. 2008, 93:3499

Diagnosis and treatment of bone disease Bone densitometry for all postmenopausal WLHIV

• FRAX instrument may under-estimate fracture risk

Measure 25-hydroxyvitamin D levels and recheck Smoking cessation, Vit D and calcium replacement Consider non-TDF regimen HRT

• Women with early menopause should consider

• Regimen consistent with CVD

Bisphosphonate therapy in marked osteopenia or rapid demineralization• ? Increased risk of osteonecrosis of the jaw and atypical femur

fractures

• Pinzone MR, et al. AIDS Rev. 2014, 16K213.

• Negredo E, Warriner AH, Curr Op HIV/AIDS, 2016, 11:351

• Vescini F, Grimaldi F, Endocrine 2015, 48:358

WIHS talk

WIHS: long term incidence of ICC in HIV+ women

Massad LS, et al. Cancer, 2009, 115:524.

characteristic cases incidence / 100,000 PYs p-valueall 3 16.5 (3.4-48.1)

HIV negativepositive

03

0 (0-88.4)21.4 (4.4-62.4)

0.59

Age <3030-3940-49

50+

0120

0 (0-205.5)14.1 (0.4-78.4)

27.7 (3.4-100.2)0 (0-756.2)

1.00

Race/ethnicitynon-Hispanic Black

non-Hispanic WhiteHispanic

Other

2010

20.2 (2.4-73.1)0 (0-116.5)

21.4 (0.5-119.2)0 (0-756.2)

1.00

WIHS: suppressive cART- HPV detection

Minkoff H et al. JID, 2010, 201:681.

Cervical Cancer Screening in HIV Infection

Screening should continue through lifetime (not end at age 65); Women ≥30 years of age should have a cervical cytology exam at the time of

HIV diagnosis.• If cytology is normal, then repeat in 12 months

Alternative recommendation is one cytology at 6 months, then if 3 consecutive cytologies are normal, then repeat every 3 years.

• If cytology is coupled with HPV testing, and if both are negative (HPV negative for oncogenic types), then screen every 3 years.

• If cytology is normal but HPV+ at all then repeat at 1 year, if that is positive, colposcopy.

• If an HPV test is positive for types 16/18, then colposcopy.

• If cytology result is ASCUS, then perform HPV testing, if positive, then perform colposcopy.

• If cytology result is LSIL or higher, then colposcopy.

Women ≥ 30 years of age

Other considerations with aging Regular eye exams

• Possible increase in macular degeneration “inflammaging” Probably increased risk among individuals with low CD4 nadir, or clinical

AIDS, but OI of eye is not implicated

Prevalence reaches >20% in persons over 60 years

• Early cataracts also possible

• Smoking also a consideration

Jabs DA, et al. Am J Ophthalmol. 2015, 159:1115 Kempen JH, et al. Ophthalmol. 2014, 121:2317

Clinical approach Smoking cessation

• HIV providers should exceed standard of care and offer services directly

Attend to hypertension and other vascular risks Vaccinate as early as possible Note that colonoscopy is indicated 5 years earlier for African Americans

and individuals with risk factors ?? Imaging screening for lung CA

• Risk increased in smokers with history of multiple pneumonias or bronchiectasis

Consider AMH measurement to assess amenorrhea or to estimate timing of ovarian follicle depletion

Bone densitometry for women with early loss of ovarian function and at menopause• Vit D and calcium• HRT or bisphosphonates for severe demineralization depending on specifics