HIV IN THE OLDER WOMAN

PROFESSOR MARGARET JOHNSON

HIV infection acquired at older age is associated with more rapid HIV disease progression

CASCADE, Lancet 2000Progression to CDC stage C by age at seroconversion, before introduction of HAART

100

75

50

25

0

Proportion developing AIDS (%)

0 5 10 15Time since seroconversion (years)

<55–14 15–2425–3435–4445–5455–64≥65

Age (years)

UK CHIC: Life expectancy according to CD4 count compared to the general population

*People who started ART in 2000–8 by CD4 cell count group atstart of ART compared with that of UK population (2000–6 women and men)

60

50

40

30

20

10

Life expectancy (years)

20 25 30 35 40 45 50 55 60 65Age (years)

Female UKMale UKCD4 200–350*CD4 100–199*CD4 <100*

70

May et al, BMJ 2011

With permission from the Health Protection Agency, 2011

New HIV diagnoses among adults ≥50 years

200020012002200320042005200620072008200920102011(to June)

70+60–6950–59

0

100

200

300

400

500

600

700

800

900

Numbers diagnosed

Smith et al, AIDS 2010

High rates of late diagnosis among adults ≥50 years in the UK

0

10

20

30

40

50

60

70

Percentage diagnosed late

≥50 years 15–49 years

Overall

48%

33%

MSM

40%

21%

Heterosexualmale

53%45%

Heterosexualfemale

51%

36%

Other

58%

33%

Smith et al, AIDS 2010

Short-term (6 months) mortality is higher among adults ≥50 years with a late diagnosis

02468

12

16

20

Numbers diagnosed (%)

Prompt diagnosis

Late diagnosis

2000

10

14

18

2001 2002 2003 2004 2005 2006 2007

7

Significance of age at diagnosis

• HIV testing is often delayed in older individuals1 – Older individuals may not perceive themselves as being

at risk for HIV infection – HCPs may fail to consider HIV as a potential cause of

illness• Delayed treatment and diagnosis may have more adverse

consequences in older individuals compared with younger people2,3

• However, older patients derive a similar level of benefit form ART as younger patients4

1. Rotily M et al (2000) Int J STD AIDS 2. Kirk (2006) J Am Geriatr Soc

3. COHERE Study Group (2008) AIDS 4. Perez JL et al (2003) Clin Infect Dis

FDA meta-analysis: age differences in the response to initial HAART in women

• CD4 cell count improvementCD4 Overall: consistently no significant difference– NRTI/PI group: consistently no significant

difference– NRTI/NNRTI group: greater improvement in

women ≤ 35 years consistently significant or nearly significant

• HIV-1 RNA viral suppression (< 400 copies at week 24)– Overall and both drug class groups: consistently

significantly greater success in women ≥ 50 years

1. Yan et al. IWHW 2013, oral presentation 19.

Datasets: registrational ART trials submitted to the FDA in 2000–2010: 4414 HIV-infected naive women, 32 RCTs, 66 study arms Methods: Meta-analysis on age group (≤ 35 vs ≥ 50) differences in week 24/48 responses in virologic (HIV-RNA < 400 c/mL) and immunological measures (CD4 count change from baseline)

2013 2039

HIV and ageing

Adapted from Deeks SG, Phillips AN. Br Med J 2009

Normal ageing

(average age in many

clinics now around 50)

Lifestyle risk

factors(smoking, drug and

alcohol use)

Drug toxicity

(for example tenofovir and renal disease)

Persistentimmune

dysfunction andinflammation

? Prematureageing

Menopause

11

Onset of early menopause in women with HIV

26%

10%

0%5%

10%15%20%25%30%

HIV infected HIV uninfected% o

f wom

en e

xper

ienc

ing

early

on

set o

f men

opau

se (<

40 y

ears

)

11

P=0.04

Schoenbaum et al (2005) Clin Infect Dis

• Women living with HIV were 73% more likely to experience early onset of menopause, compared with HIV-uninfected women (P=0.024)

n=303 n=268

12

Potential contributors to early onset of menopause in women with HIV

Smoking Socioeconomic status

Menopause can occur up to 1–2 years earlier in

smokers, compared with non-smokers

Markers of low socioeconomic

status (e.g. lower level of

education, unemployment and poverty)

have been associated with

early menopause onset

Lower CD4+ count has been associated with

early menopause onset

Immunosuppression

13

The menopause• The menopause is marked by the ending of

menstruation and ovulation– Falling levels of the female sex hormone, oestrogen

• Onset of the menopause is associated with an increased risk of:– cardiovascular disease (CVD)– diabetes – osteopenia / osteoporosis

• Early onset menopause (before 46 years):– increases the risk of these diseases– may be linked to increased mortality

14

Managing the menopause in women with HIV

• Strategies to offset effects associated with menopause include:– Healthy lifestyle choices

– Smoking cessation

– Adherence to effective ART

– HRT

– Symptom management

– Alternative therapies

Hormone replacement therapy in women living with HIV

• HRT may be useful for some women with HIV• Risks may outweigh the benefits if they:

– smoke

– are overweight

– have had blood clots, breast cancer, diabetes, high cholesterol levels, liver problems, or a family history of heart disease

• Oestrogen and/or progesterone have been shown to interact with many HIV drugs

15

16

Consequences of ageing as a woman with HIV

• Women living with HIV face all the challenges that the general population faces when growing older PLUS:

16

Conditions with increased incidence in women living with HIV: • Hormonal changes• Cardiovascular events• Non-AIDS-defining

infections• Renal disease• Non-AIDS-defining

cancers/malignancy• Muscular and skeletal

changes• Non-AIDS-dementias,

neurocognitive changes, mood and CNS disorders

The consequences of living longer

with HIV

The consequences of longer exposure to HIV treatment

regimens

Co-morbidities in HIV

1. Clifford, Top HIV Med 2008; 2. Brown et al, J Clin Endocrinol Metab. 2004; 3. Triant et al, J Clin Endocrinol Metab 2007; 4. Gupta et al, Clin Infect Dis 2005; 5. Patel et al, Ann Intern Med 2008 6. Terzian et al, J Women’s Health 2009

Reduced bone mineral densityIncreased prevalence of osteoporosis or osteopenia in spine, hip or forearm:63% of HIV+ patients2

Neurocognitive dysfunctionNeurological impairment present in ≥50% HIV+ patients1

Cardiovasculardisease75% increase in risk of acute MI3

Renal dysfunctionSome HIV+ patients have abnormal kidney function4

FrailtyIncreased frailty phenotype in HIV; Associated with CD4 count6

CancerIncreased risk of non-AIDS-defining cancerse.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal5

Co-morbidities

Reduced bone mineral

density

Emotional challenges

Cardiovasculardisease

Renal dysfunction

Cancer

Risk factors for decreased bone mineral density in women

• Female sex• White race• Family history• Increasing age• Amenorrhoea

/premature menopause

• Decreased physical activity

• Smoking • Alcohol• Decreased

bone acquisition

Classic

HAART-related

• Nucleoside analogues /mitochondrial dysfunction

• Protease inhibitors• Lipodystrophy

HIV-related

• Cytokines (e.g. TNFa, IL6)

• Decreased muscle mass

• Decreased fat mass

• Fat deposition in marrow

• Chronic diseases (e.g. hyperthyroidism, hyperparathyroidism, liver

disease, rheumatological conditions, eating disorders, etc.)

• Hypogonadism

• Renal dysfunction

• Malnutrition/low BMI

• Medications (e.g. corticosteroids, anticonvulsants, anticoagulants)

Secondary

Adapted from Glesby, 2003 Clin Infect Dis

Prevalence of osteoporosis in HIV+ patients vs HIV- controls: a meta-analysis

Brown & Qaqish, AIDS 2006

• Overall prevalence of osteoporosis in people living with HIV: 15%

Odds ratio.01 1 100

Amiel (2004)Brown (2004)Bruera (2003)Dolan (2004)

Huang (2002)Knobel (2001)

Loiseau-Peres (2002)Madeddu (2004)

Tebas (2000)Teichman (2003)

Yin (2005)

Overall (95% CI)

5.03 (1.47,17.27)4.26 (0.22,82.64)4.51 (0.26,79.27)2.11 (0.54,8.28)3.52 (0.15,81.92)5.13 (1.80,14.60)4.28 (0.46,39.81)29.84 (1.80,494.92)3.40 (0.19,61.67)17.41 (0.97,313.73)2.37 (1.09,5.16)

3.68 (2.31,5.84)

Study Odds ratio

(95% CI)

• Prevalence of osteoporosis is estimated to be approximately 3-fold higher in those living with HIV, than HIV- individuals

Increased fractures in women living with HIV

Fracture prevalence in women/100 persons

Healthcare registry study:• 8,525 HIV-positive patients• 2,208,792 HIV-negative patients

Overall comparison p=0.002

HIV+

HIV-

30–39 40–49 50–59 60–69 70–79 Years

7

6

5

4

3

2

1

0

Triant et al, J Clin Endocrinol Metab 2008

Switch from Tenofovir to Abacavir and BMD Change: Multicenter RCT (Abs:824)

• 54 patients on TDF regimen for at leats12 months suppressed VL• Patients have loss of BMD (DEXA)• Switched to ABC (n=26) and continued with TDF (n=28)• Significant improvement in BMD particularly at femur in ABC arm

BMD Changes at 48 weeks

WIHS: vitamin D insufficiency may impair CD4 recovery among participants with advanced disease on HAART

• Substudy of 204 HIV-infected women with advanced disease (CD4 < 200 cells/μL), who started HAART after enrolment in the Women’s Interagency HIV Study (WIHS)

• Majority were non-Hispanic black (60%) and had insufficient vitamin D levels (89%)

• In adjusted analyses, at 24 months after HAART, insufficient vitamin D (OR 0.20, 95% CI 0.05–0.83) was associated with decreased odds of CD4 recovery

• Average immune reconstitution attenuated significantly (p < 0.01) over time among those with insufficient vitamin D levels compared with those with sufficient vitamin D levels

Aziz et al. AIDS 2013;27:573–78.

Mean CD4 count (cells/mL) among women with normal (> 30 ng/mL) and insufficient or deficient vitamin D (≤ 30 ng/mL), before HAART initiation and 6, 12, and 24 months post HAART initiation. In univariate analysis of variance (ANOVA), difference in mean CD4 by vitamin D status is non-significant (F = 0.639, p = 0.424); difference in mean CD4 by time point is significant (ANOVA F = 14.92, p < 0.001), and vitamin D by time interaction is non-significant (F = 0.358, p = 0.783).

24

No. of Patients With EventsParameter RR (95% CI)

Severe complications 1141.5

CVD, liver, or renal deaths

Nonfatal CVD events

31

63

1.4

1.5

Nonfatal hepatic events

Nonfatal renal events

14

7

1.4

2.5

1.0 10.00.1

Risk of

Com

plicationsSMART: Higher CVD incidence with interruption vs. continuous HAART

• CD4-guided drug conservation strategy was associated with significantly greater disease progression or death, compared with continuous viral suppression RR 2.5 (95% CI: 1.8-3.6; P<0.001)

El-Sadr W, et al. CROI 2006. Abstract 106 LB.

Increased risk of myocardial infarction in women with HIV

Large data registry 3,851 HIV-positive patients1,044,589 HIV-negative patients

HIV+

HIV-

Triant et al, J Clin Endocrinol Metab 2007

26

Renal disease in women living with HIV

• Women living with HIV may be at an increased risk for acute renal failure or CKD– risk of HIV-associated nephropathy and/or ART induced

renal dysfunction– renal complications can increase mortality among

women living with HIV P<0.0001

Gardner LI et al (2003) J Acquir Immune Defic Syndr

Co-morbidities

Reduced bone mineral

density

Emotional challenges

Cardiovasculardisease

Renal dysfunction

Cancer

Shiels et al, JAIDS 2009

Meta-analysis of incidence of non-AIDS cancers in people with HIV by gender

Includes 18 studies; SIR = standardised incidence ratio

29

Neurological function in women with HIV

• Neurological impairment present in ≥50% of people living with HIV

• Neurological dysfunction, including memory impairment and psychomotor function, has been shown to be increased in women with HIV

• Risk increases with age

Clifford DB (2008) Top HIV Med

CDC: Centers for Disease Control and Prevention; A = asymptomatic; B = Symptomatic; C = AIDS indicator

conditions

CRANIum study: Women have a higher rate of depression compared with men

• Prevalence of depressive symptoms in women in the study is twice as high as the general population in Europe

Bayon et al, 2nd International Workshop on HIV and Women, Abst 0_1. 2012

15.714.3

17.9

13.3

10.6

20.8

16.816.517.2

p<0.0001

p<0.01

HIV-positive patients aged ≥ 18 years; Depression = HADS-D ≥ 8

All patients (n=2862)Male (n=1766)Female (n=1096)

CRANIum study: Treatment-naïve women have a higher rate of anxiety compared with

men

p=0.07p=0.02

p=0.51

35.332.8

39.1

33.332.0 32.930.6

33.5 34.3

All patients (n=2862)Male (n=1766)Female (n=1096)

Bayon et al, 2nd International Workshop on HIV and Women, Abst 0_1. 2012HIV-positive patients aged ≥ 18 years; Anxiety = HADS-A ≥ 8

EVhA: quality of life in women living with HIV in Spain

Cabrero et al. IWHW 2013, abstract 13.

Cross-sectional single-visit

studies

• Sign and date informed consent• Sociodemographics• Clinical data for women living

with HIV• Sexual sphere

Young women living with HIV vs control

cohort (EVhA1)

Mature women living with HIV vs control

cohort (EVhA3)

Inclusion criteria• Aged 16–22 years• HIV• On stable ART ≥ 3 months

Inclusion criteria (controls)*• Aged 16–22 years• No HIV or high-risk

behaviour• Similar education and

employment

Inclusion criteria• Aged 35–60 years• HIV• On stable ART ≥ 3 months

Inclusion criteria (controls)*• Aged 35–60 years• No HIV or high-risk

behaviour• Similar education and

employment

*Protocol suggested possible sources of controls: relatives, friends, hospital employees. †Paired women HIV/no HIV; EVhA: Epidemiology study of women living with HIV

Outcomes†

• Quality of life• Mood stages• Neurocognitive

function

Young vs mature women in Spain: EVhA1 vs EVhA3 sub-analysis (= EVhA2)

EVhA: young women living with HIV less impaired QoL than mature women

Transient health

QoL

Cognitive function

Health problems

Mental health

Energy

Social function

Role functional

Physical function

Pain

Global health

• The MOS-HIV revealed mean scores were lower in mature women living with HIV compared to younger women

• Only one dimension, cognitive function, showed similar values for younger and mature women

• All other dimensions favoured younger women, with significant differences in social function, transitory health and global health

Cabrero et al. IWHW 2013, abstract 13.

EVhA: overall conclusions

• Young women living with HIV show less damage in their sexual sphere, better mood stage and neurocognitive function, and higher QoL scores than their mature counterparts

• For mature women, both anxiety and depression positive screening were related factors with lower QoL risk scores

• Further work is needed to investigate how clinical-demographic differences (e.g. HCV co-infection) between groups affect these findings

• Multidimensional care with a special focus on mental health and mood may be critical to improving the wellbeing of older and aging women living with HIV

Cabrero et al. IWHW 2013, abstract 13.

35

Definition of frailty

• In attempting to define frailty as an independent syndrome (or phenotype), three of the following criteria need to be present:

Unintentional weight loss

Self-reported exhaustion

Low physical activity

Slowness – measured by time taken to walk 3m

Weakness – grip strength

Fugate Woods N et al (2005) J Am Geri Soc

Prevalence of age-related co-morbidities in people living with HIV

• Co-morbidities analysed: hypertension, type 2 diabetes mellitus, cardiovascular disease and osteoporosis

100%

75%

50%

25%

4%

0%≤40 yrs

N=542

41–50 yrs

N=1724

51–60 yrs

N=452

>60 yrs

N=136

80%60%

42%21%

16%1%3%

1%8%

0%6%

31%

35%

17%

31%

29%

15%

HIV-positive

¼%2¾%

HIV-negative

No age-related diseases 1 co-morbidity 2 co-morbidities 3 co-morbidities 4 co-morbidities

Guaraldi et al, Clin Infect Diseases 2011

100%

75%

50%

25%

0%≤40 yrs

N=1626

41–50 yrs

N=5172

51–60 yrs

N=1356

>60 yrs

N=408

90% 80%65%

40%

9%0%1%

0%2%

1%6%17%

28%

42%

15%

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