HIV IN THE OLDER WOMAN

1. HIV IN THE OLDER WOMAN PROFESSOR MARGARET JOHNSON

2. HIV infection acquired at older age is associated with more rapid HIV disease progression Proportion developing AIDS (%) 100 Age (years) <5 5–14 75 15–24 25–34 50 35–44 45–54 55–64 25 ≥65 0 0 5 10 15 Time since seroconversion (years) Progression to CDC stage C by age at seroconversion, before introduction of HAART CASCADE, Lancet 2000

3. UK CHIC: Life expectancy according to CD4 count compared to the general population 70 Female UK Life expectancy (years) Male UK 60 CD4 200–350* CD4 100–199* 50 CD4 <100* 40 30 20 10 Age (years) 20 25 30 35 40 45 50 55 60 65 *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) May et al, BMJ 2011

4. New HIV diagnoses among adults ≥50 years Numbers diagnosed 900 50–59 60–69 800 70+ 700 600 500 400 300 200 100 0 2011(to June) 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 With permission from the Health Protection Agency, 2011

5. High rates of late diagnosis among adults ≥50 years in the UK Percentage diagnosed late 70 58% 53% 51% 60 48% 45% 50 40% 36% 33% 33% 40 30 21% 20 10 0 Overall MSM Heterosexualmale Heterosexualfemale Other ≥50 years 15–49 years Smith et al, AIDS 2010

6. Short-term (6 months) mortality is higher among adults ≥50 years with a late diagnosis Numbers diagnosed (%) Late diagnosis 20 18 16 14 12 10 8 6 Prompt diagnosis 4 2 0 2000 2001 2002 2003 2004 2005 2006 2007 Smith et al, AIDS 2010

7. Significance of age at diagnosis • Rotily M et al (2000) Int J STD AIDS • Kirk (2006) J Am Geriatr Soc • 3. COHERE Study Group (2008) AIDS • 4. Perez JL et al (2003) Clin Infect Dis • 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 7

8. FDA meta-analysis: age differences in the response to initial HAART in women 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) 2039 2013 • 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.

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

10. Menopause

11. Onset of early menopause in women with HIV P=0.04 n=303 n=268 • Women living with HIV were 73% more likely to experience early onset of menopause, compared with HIV-uninfected women (P=0.024) 11 11 Schoenbaum et al (2005) Clin Infect Dis

12. Potential contributors to early onset of menopause in women with HIV Smoking Socioeconomic status Immunosuppression 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 Menopause can occur up to 1–2 years earlier in smokers, compared with non-smokers 12

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 13

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 14

15. 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 • 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 Women living with HIV face all the challenges that the general population faces when growing older PLUS: 16 16

17. Cardiovasculardisease Renal dysfunction 75% increase in risk of acute MI3 Some HIV+ patients have abnormal kidney function4 Co-morbidities in HIV Neurocognitive dysfunction Neurological impairment present in ≥50% HIV+ patients1 Reduced bone mineral density Increased prevalence of osteoporosis or osteopenia in spine, hip or forearm: 63% of HIV+ patients2 Frailty Increased frailty phenotype in HIV; Associated with CD4 count6 Cancer Increased risk of non-AIDS-defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal5 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

18. Renal dysfunction Co-morbidities Cardiovasculardisease Emotional challenges Reduced bone mineral density Cancer

19. Risk factors for decreased bone mineral density in women Secondary • 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) Classic • Female sex • White race • Family history • Increasing age • Amenorrhoea/premature menopause • Decreased physical activity • Smoking • Alcohol • Decreased bone acquisition HIV-related HAART-related • Cytokines (e.g. TNFa, IL6) • Decreased muscle mass • Decreased fat mass • Fat deposition in marrow • Nucleoside analogues /mitochondrial dysfunction • Protease inhibitors • Lipodystrophy Adapted from Glesby, 2003 Clin Infect Dis

20. Prevalence of osteoporosis in HIV+ patients vs HIV- controls: a meta-analysis • Overall prevalence of osteoporosis in people living with HIV: 15% Odds ratio (95% CI) Study 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) .01 Odds ratio 100 1 • Prevalence of osteoporosis is estimated to be approximately 3-fold higher in those living with HIV, than HIV- individuals Brown & Qaqish, AIDS 2006

21. Increased fractures in women living with HIV Healthcare registry study: • 8,525 HIV-positive patients • 2,208,792 HIV-negative patients Fracture prevalence in women/100 persons HIV+ HIV- 7 6 Overall comparison p=0.002 5 4 3 2 1 0 40–49 70–79 50–59 60–69 30–39 Years Triant et al, J Clin Endocrinol Metab 2008

22. 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

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

24. 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: 1.8-3.6; P<0.001) Parameter No. of Patients With Events RR (95% CI) 1.5 Severe complications 114 1.4 CVD, liver, or renal deaths 31 1.5 Risk of Complications Nonfatal CVD events 63 1.4 Nonfatal hepatic events 14 2.5 Nonfatal renal events 7 0.1 1.0 10.0 24 El-Sadr W, et al. CROI 2006. Abstract 106 LB.

25. 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 P<0.0001 • 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 26 Gardner LI et al (2003) J Acquir Immune Defic Syndr

27. Renal dysfunction Co-morbidities Cardiovasculardisease Emotional challenges Reduced bone mineral density Cancer

28. Meta-analysis of incidence of non-AIDS cancers in people with HIV by gender Shiels et al, JAIDS 2009 Includes 18 studies; SIR = standardised incidence ratio

29. Neurological function in women with HIV CDC: Centers for Disease Control and Prevention; A = asymptomatic; B = Symptomatic; C = AIDS indicator conditions 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 29 Clifford DB (2008) Top HIV Med

30. CRANIum study: Women have a higher rate of depression compared with men All patients (n=2862) Male (n=1766) • Prevalence of depressive symptoms in women in the study is twice as high as the general population in Europe Female (n=1096) p<0.0001 p<0.01 20.8 17.9 17.2 16.8 16.5 15.7 14.3 13.3 10.6 Bayon et al, 2nd International Workshop on HIV and Women, Abst 0_1. 2012 HIV-positive patients aged ≥ 18 years; Depression = HADS-D ≥ 8

31. p=0.51 39.1 p=0.07 p=0.02 35.3 34.3 33.5 33.3 32.8 32.9 32.0 30.6 CRANIum study: Treatment-naïve women have a higher rate of anxiety compared with men All patients (n=2862) Male (n=1766) Female (n=1096) Bayon et al, 2nd International Workshop on HIV and Women, Abst 0_1. 2012 HIV-positive patients aged ≥ 18 years; Anxiety = HADS-A ≥ 8

32. EVhA: quality of life in women living with HIV in Spain Cross-sectional single-visit studies Young women living with HIV vs control cohort (EVhA1) Mature women living with HIV vs control cohort (EVhA3) • Inclusion criteria • Aged 35–60 years • HIV • On stable ART ≥ 3 months • Sign and date informed consent • Sociodemographics • Clinical data for women living with HIV • Sexual sphere • 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 (controls)* • Aged 35–60 years • No HIV or high-risk behaviour • Similar education and employment • Outcomes† • Quality of life • Mood stages • Neurocognitive function Young vs mature women in Spain: EVhA1 vs EVhA3 sub-analysis (= EVhA2) *Protocol suggested possible sources of controls: relatives, friends, hospital employees. †Paired women HIV/no HIV; EVhA: Epidemiology study of women living with HIV Cabrero et al. IWHW 2013, abstract 13.

33. EVhA: young women living with HIV less impaired QoL than mature women • 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 Transient health QoL Cognitive function Health problems Mental health Energy Social function Role functional Physical function Pain Global health Cabrero et al. IWHW 2013, abstract 13.

34. 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 Unintentional weight loss Self-reported exhaustion Low physical activity Slowness – measured by time taken to walk 3m Weakness – grip strength • In attempting to define frailty as an independent syndrome (or phenotype), three of the following criteria need to be present: 35 Fugate Woods N et al (2005) J Am Geri Soc

36. Prevalence of age-related co-morbidities in people living with HIV HIV-positive HIV-negative • Co-morbidities analysed: hypertension, type 2 diabetes mellitus, cardiovascular disease and osteoporosis ¼%2¾% 1%3% 1%8% 0% 6% 4% 100% 0%1% 0%2% 1% 6% 100% 9% 16% 15% 15% 17% 17% 28% 31% 75% 75% 29% 42% 35% 50% 50% 90% 80% 80% 65% 31% 60% 25% 25% 40% 42% 21% 0% 0% ≤40 yrs N=1626 41–50 yrs N=5172 51–60 yrs N=1356 >60 yrs N=408 ≤40 yrs N=542 41–50 yrs N=1724 51–60 yrs N=452 >60 yrs N=136 1 co-morbidity 2 co-morbidities 3 co-morbidities 4 co-morbidities No age-related diseases Guaraldi et al, Clin Infect Diseases 2011

37. AL • FLIXOTIDE INHALER • SIMVASTATIN • OMEPRAZOLE • TAMOXIFEN • AMLODIPINE • LOSARTAN

38. ANY QUESTIONS?