HIV IN THE OLDER WOMAN PROFESSOR MARGARET JOHNSON

HIV infection acquired at older age is associated with more rapid HIV disease progression CASCADE, Lancet 2000 Progression to CDC stage C by age at seroconversion, before introduction of HAART Proportion developing AIDS (%) Time since seroconversion (years) <5 5–14 15–24 25–34 35–44 45–54 55–64 ≥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 at start of ART compared with that of UK population (2000–6 women and men) Life expectancy (years) Age (years) Female UK Male UK CD4 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 (to June) –69 50– Numbers diagnosed

Smith et al, AIDS 2010 High rates of late diagnosis among adults ≥50 years in the UK Percentage diagnosed late ≥50 years15–49 years Overall 48% 33% MSM 40% 21% Heterosexual male 53% 45% Heterosexual female 51% 36% Other 58% 33%

Smith et al, AIDS 2010 Short-term (6 months) mortalit y is higher among adults ≥50 years with a late diagnosis Numbers diagnosed (%) Prompt diagnosis Late diagnosis

7 Significance of age at diagnosis HIV testing is often delayed in older individuals 1 – 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 people 2,3 However, older patients derive a similar level of benefit form ART as younger patients 4 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 improvement CD4 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)

HIV and ageing Adapted from Deeks SG, Phillips AN. Br Med J 2009 Normal ageing (average age in many clinics now around 50) Normal ageing (average age in many clinics now around 50) Lifestyle risk factors (smoking, drug and alcohol use) Lifestyle risk factors (smoking, drug and alcohol use) Drug toxicity (for example tenofovir and renal disease) Drug toxicity (for example tenofovir and renal disease) Persistent immune dysfunction and inflammation ? Premature ageing

Menopause

11 Onset of early menopause in women with HIV 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=303n=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 Terzian et al, J Women’s Health 2009 Reduced bone mineral density Increased prevalence of osteoporosis or osteopenia in spine, hip or forearm: 63% of HIV+ patients 2 Neurocognitive dysfunction Neurological impairment present in ≥50% HIV+ patients 1 Cardiovascular disease 75% increase in risk of acute MI 3 Renal dysfunction Some HIV+ patients have abnormal kidney function 4 Frailty Increased frailty phenotype in HIV; Associated with CD4 count 6 Cancer Increased risk of non-AIDS-defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal 5

Co-morbidities Reduced bone mineral density Emotional challenges Cardiovascular disease 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 ClassicHAART-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 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) (1.80,494.92) 3.40 (0.19,61.67) (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 50–5960–69 70–79 Years 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 EventsParameterRR (95% CI) Severe complications CVD, liver, or renal deaths Nonfatal CVD events Nonfatal hepatic events Nonfatal renal events Risk of Complications SMART: 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: ; P<0.001) El-Sadr W, et al. CROI Abstract 106 LB.

Increased risk of myocardial infarction in women with HIV Large data registry 3,851 HIV-positive patients 1,044,589 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< Gardner LI et al (2003) J Acquir Immune Defic Syndr

Co-morbidities Reduced bone mineral density Emotional challenges Cardiovascular disease 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, 2 nd International Workshop on HIV and Women, Abst 0_ p< 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=0.07 p=0.02 p= All patients (n=2862) Male (n=1766) Female (n=1096) Bayon et al, 2 nd International Workshop on HIV and Women, Abst 0_ HIV-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= –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-morbidity2 co-morbidities3 co-morbidities4 co-morbidities Guaraldi et al, Clin Infect Diseases % 75% 50% 25% 0% ≤40 yrs N= –50 yrs N= –60 yrs N=1356 >60 yrs N=408 90% 80% 65% 40% 9% 0% 1% 0% 2% 1% 6% 17% 28% 42% 15%

AL FLIXOTIDE INHALER SIMVASTATIN OMEPRAZOLE TAMOXIFEN AMLODIPINE LOSARTAN

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