Women's Health and HIV/AIDS: Aging Issues and Quality of Life

Saturday, May 13, 2011 11:00 am – 12:30pm

Carmen D. Zorrilla, MD

Professor OB-GYN, UPR School of Medicine

Principal Investigator: PR-CCHD, UPR-CTU, PR HVTU, Maternal-Infant Studies Center (CEMI)

carmen.zorrilla@upr.edu

Disclosure of Financial Relationships

This speaker has the following significant financial relationships with commercial entities to disclose:

• Research support from: • Pfizer, Tibotec, BMS, Salix (Avent),

Bavaria-Nordic, Avexa • Advisory board: Tibotec

This slide set has been peer-reviewed to ensure that there areno conflicts of interest represented in the presentation.

At the conclusion of this activity, participants should be able to:

• Describe gender related co-morbidities that are accelerated in chronic HIV infection

• Discuss the implications for symptom management• Formulate an action plan that will promote quality of

life for women throughout the lifespan • Evaluate current guidelines and literature regarding

recommendations for the gynecologic care of women living with HIV

Activity Objectives:

Epidemiology and Natural History of Aging in People Living with HIV

• In the US annual rates of new cases in persons over 50 yrs. were steady at 9-10% from 1985 to 1995 and increased to 20% by 2008

• By 2015 an estimated 50% of people living with HIV/AIDS in the US will be over 50 yrs. (CDC Surveillance report)

• A newly diagnosed 20-yr-old with a CD4 >200 cells/mm3 will live to age 70 (a 14% decrease in remaining life) Lancet 2008; 372: 293-299

Estimated Numbers of Cases of HIV/AIDS, by Age—2005

Epidemiology and Natural History of Aging in Women Living with HIV

• Observational studies have shown blunted CD4 responses with HAART initiated in older age.

• The NA-ACCORD demonstrated decreasing immune response in older persons on HAART (Althoff et al, AIDS 2010; 24: 2469-79)

• Older patients have higher adherence rates compares with younger ones in some studies (Hinkin et al, AIDS 2004;18:19-25)

• Prevalence of obesity, cigarette smoking, drug and alcohol use and sedentary lifestyles are higher among groups with HIV.

HIV Infection, Inflammation, Immunosenescence and AgingSteven Deeks Annu. Rev. Med. 2011. 62: 141-155

• Long-term treated patients remain at higher than expected risk of complications typically associated with aging including cardiovascular disease, cancer, osteoporosis and other end-organ diseases.

• These changes are seen in the adaptive immune system in the “very old” (immunosenescence) and are likely related in part to persistent inflammation.

Cardiovascular System

• Increased morbidity and mortality are seen due to cardiovascular disease (CVD)

• Risk factors are more prevalent among people with HIV (cigarette smoking, obesity, hypertension, dyslipidemia, diabetes)

• The impact of HIV disease on CVD is comparable to that of DM or cigarette smoking (Grunfeld et al. AIDS 2009; 23: 1841-1849)

• Cumulative HAART toxicities, pro-atherogenic state induced by chronic immune activation, and lifestyle factors make people with HIV vulnerable to increased risk of CVD.

• The HIV heart is 5-15 years older than the patient’s age. (Patel & Crane Curr Infect Dis Rep 2011, 13: 75-82)

Neurologic System

• More than half of people with HIV will develop some type of neuro-cognitive decline during the course of their disease (Bloom, Journal of Neurovirology 1997; 3: 102-109)

• Asymptomatic neurocognitive impairment, HIV-associated mild neuro-cognitive disorder and HIV-associated dementia are examples (Antinori, neurology 2007; 69:1789-1799)

• Cerebral blood flow in HIV-infected individuals appears similar to that of HIV-negative who are 10-15 years older (Patel & Crane Curr Infect Dis Rep 2011, 13: 75-82)

Bone Disease

• Reduced bone density has been reported for people living with HIV

• A recent meta-analysis on ART and the prevalence of osteoporosis/osteopenia reported a prevalence of 15% of osteoporosis among people living with HIV.

• This is threefold greater than that for HIV-controls (Brown and Qaqish, AIDS 2006; 20:2165-2174)

Cancer

• People living with HIV are at increased risk of certain cancers such as: Kaposi sarcoma, intermediate and high-grade B-cell Non-Hodgkin’s lymphoma, CNS lymphoma and invasive cervical cancer

• Each of them is associated with infection with other viruses (Human Herpes 8, EBV,HPV)

• Some studies have shown that lung, liver, anal and colorectal cancer occurred 10-20 years younger among people with HIV compared with the general population (Shiels al. Ann Intern med 2010; 153: 452-460)

Health Maintenance

• The care of women with HIV infection must incorporate primary care into their state-of-the-art HIV care.

• As women survive longer with HIV, other co-morbid conditions will increase with age, including cardiac disease, diabetes, and breast cancer.

• Medical care must include routine medical screening (mammograms, breast self-examination, nutritional counseling for osteoporosis, smoking cessation, etc) and a recognition that not all complaints are necessarily HIV-related.

• The complex psychosocial needs of many women with HIV often requires a multidisciplinary team to address issues such as housing, substance abuse, and mental illness, either on-site or by linkage with other institutions or community-based organizations.

• One group found that case management significantly improved care and use of HIV therapies for individuals with HIV.

• Katz, MH, Cunningham, WE, Fleishman, JA, et al. Effect of case management on unmet needs and utilization of medical care and medications among HIV-infected persons. Ann Intern Med 2001; 135:557

Health Maintenance

Suggested Management Adapted from (Patel & Crane Curr Infect Dis Rep 2011, 13: 75-82)

• Early HAART• Avoid agents that alter lipids• Select agents with high CNS penetration• Anti-inflammation therapies: statins, aspirin, suppress

other viral co-infections (HSV, HCV, CMV)• Manage hypertension, DM, dyslipidemia• Aggressively encourage lifestyle changes (smoking

cessation, exercise, drug, alcohol use reduction)• DEXA screens at 50• Follow USPHS guidelines for cancer screening

American College of Obstetrics and Gynecology (ACOG)

Gynecologic Care for Women With HIV

Practice Bulletin Number 117, December 2010

Menopause

• As the population with HIV infection ages, the number of women approaching and experiencing menopause is growing.

• The risk-benefit ratio of hormonal replacement for these women remains to be described, as well as potential pharmacologic interactions between protease inhibitors and estrogen replacement.

• The decision about hormonal replacement should be made individually after education and counseling of the woman and determination of risk factors for cardiac disease, osteoporosis, cancer, and other conditions

Diagnosis and Treatment of Menopausal Symptoms Gynecologic Care for Women With HIV; ACOG Practice Bulletin; Number

117, December 2010

• Studies suggest that the mean age at menopause for HIV-infected women is 3–4 years younger than that for uninfected women.

• A variety of factors associated with earlier menopause, including current smoking, substance abuse, African American race, lower socioeconomic level, and low relative body weight, are common among women with HIV and may be a basis for the occurrence of menopause at an earlier age

• Baseline data from a prospective study showed that HIV infection and immunosuppression were associated with an earlier age at the onset of menopause

Diagnosis and Treatment of Menopausal Symptoms Gynecologic Care for Women With HIV; ACOG Practice Bulletin; Number

117, December 2010

• In the Women’s Interagency HIV Study cohort, the age at menopause was not affected by HIV status, but prolonged amenorrhea (lasting longer than 12 months) was more common among HIV-infected women than among non–HIV-infected women.

• Serum follicle-stimulating hormone levels in approximately one half of the HIV-infected women with prolonged amenorrhea did not necessarily indicate menopausal status, and HIV-infected women were more than three times more likely than non–HIV-infected women to have prolonged amenorrhea without ovarian failure

CROI 2011Abstracts on Menopause

• Pharmacokinetics of TDF in Blood Plasma and Cervico-vaginal Fluid of HIV+ Post-menopausal Compared with Pre-menopausal Women• In post-menopausal women, blood plasma AUC and blood plasma C24h

exceed standard pharmacokinetic parameters by 160% and 125%, respectively (abstract 32)

• Healthy Post-menopausal Women Have Higher Percentages of CCR5+ Cervical CD4+ T Cells Compared to Pre-menopausal Women: Implications for HIV Transmission (abstract 33)• Elevated percentages of R5+CD4+ T lymphocytes in cervix may increase

the risk for HIV acquisition in post-menopausal vs. pre-menopausal women• Enhanced HIV-1 Replication in ex vivo Ectocervical Tissues from Post-

menopausal Women Correlates with Increased Inflammatory Responses (abstract 776)• Enhanced mucosal inflammation during post-menopause may facilitate

immune activation of HIV-1 target cells and enhance the likelihood of HIV-1 infection and spread at mucosal sites.

Osteopenia/Osteoporosis• Osteoporosis is a common disease that is characterized by

• low bone mass with • micro-architectural disruption and • skeletal fragility, • resulting in an increased risk of fracture

• The WHO has defined diagnostic thresholds for low bone mass and osteoporosis based upon bone mineral density (BMD) measurements compared with a young adult reference population (T-score). • T-score ≤-2.5 is consistent with osteoporosis • T-score between -1.0 and -2.5 is osteopenia.

• In addition, low Z-scores (age-matched comparison) identify individuals requiring further evaluation for secondary causes of osteoporosis.

Osteopenia

• A meta-analysis, which included 20 cross-sectional studies reporting bone mineral density (BMD) measurements among 884 HIV-infected patients, demonstrated that 67 percent had reduced BMD with 15 percent meeting criteria for osteoporosis .

• Studies performed in ART-naïve patients also indicate a higher prevalence of osteopenia than would be expected in age- and sex-matched sero-negative adults.

• Brown, TT, Qaqish, RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165.

Osteopenia

• The clinical significance of osteopenia is unclear, since an elevated fracture risk has not yet been prospectively demonstrated in this population

• On the other hand, a retrospective analysis comparing 8525 patients with HIV and 2,208,792 patients without HIV found an increased fracture prevalence based on ICD-9 coding (2.9 versus 1.9 per 100 persons, p<0.0001)

• Triant, VA, Brown, TT, Lee, H, Grinspoon, SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab 2008; 93:3499

Osteoporosis

• No clinical manifestations until fractures• Vertebral fracture is the most common clinical

manifestation of osteoporosis. • Most of these fractures (about two-thirds) are

asymptomatic; they are diagnosed as an incidental finding on chest or abdominal x-ray.

• Hip fractures are relatively common in osteoporosis, affecting 15% of women and 5% of men by 80 years of age.

Osteoporosis

• A history of a fracture is an important risk factor for a subsequent fracture

• A meta-analysis of 11 cohorts (15,259 men and 44,902 women) showed that a previous fracture was associated with an increased risk of any fracture compared with those without a prior fracture (RR 1.86, 95% CI 1.75-1.98)*

• Bone mineral density (BMD) assessment is the gold standard to diagnose osteoporosis.

*A meta-analysis of previous fracture and subsequent fracture risk.Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, Eisman J, Fujiwara S, Garnero P, Kroger H, McCloskey EV, Mellstrom D, Melton LJ, Pols H, Reeve J, Silman A, Tenenhouse A Bone. 2004;35(2):375.

Question 1Select the correct statement regarding

osteopenia/osteoporosis1. Osteopenia predicts fractures

on 88% of cases

2. There is no proven significance to the finding of osteopenia among people living with HIV

3. Osteoporosis is a clinical finding usually associated with low back pain

4. A previous accidental fracture of the pelvis ( iliac crest) is predictive of osteoporotic fracture of the femur head

Low BMD (T-score below -2.5)

• Lifestyle factors which contribute to bone loss, including smoking, excessive alcohol, physical inactivity, and poor nutrition should be addressed

• Biochemistry profile (especially calcium, phosphorous, albumin, total protein, creatinine, liver enzymes including alkaline phosphatase, electrolytes)

• 25-hydroxyvitamin D• Complete blood count• Urinary calcium excretion

Question 2Select the correct statement regarding osteopenia and

HIV1. Some cohort studies and

observational data have shown increased prevalence of osteopenia among people living with HIV

2. A person with HIV needs immediate treatment with alendronate after a diagnosis of osteopenia

3. More men than women with HIV have osteopenia

4. The osteopenia associated with HIV is related to a specific HAART agent

Low Bone Mineral Density (BMD)Gynecologic Care for Women With HIV; ACOG Practice Bulletin; Number

117, December 2010

• Low BMD has been found to be more prevalent among women with HIV approaching menopause than those without HIV.

• Even among women with normal BMD, a case–control population-based study showed that HIV-infected women reported significantly more osteoporotic fractures than women in the control group.

• Data on treatment of osteoporosis for HIV-infected women are lacking. • Standard suggestions for treatment and prevention can be made:

• including increasing physical activity, • stopping smoking, and • taking calcium and • vitamin D supplements

• Small studies confirm the benefits and safety of alendronate therapy in HIV-infected patients.

Fracture Risk Assessment Tool (FRAX)

• In 2008, a WHO task force introduced a Fracture Risk Assessment Tool (FRAX), which estimates the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, spine, shoulder, or wrist) for an untreated woman or man using easily obtainable clinical risk factors for fracture with or without information on bone mineral density.

• FRAX has been validated in 11 cohorts (over one million patient years).

WHO Fracture Risk Assessment Tool

(FRAX)• For USA use only• http://www.shef.ac.uk/FRAX/tool/jsp?country=9• Consider FDA-approved medical therapies in postmenopausal

women and men aged 50 years and older, based on the following:• A hip or vertebral (clinical or morphometric) fracture• T-score ≤ -2.5 at the femoral neck or spine after appropriate

evaluation to exclude secondary causes• Low bone mass (T-score between -1.0 and -2.5 at the femoral

neck or spine) and a 10-year probability of a hip fracture ≥ 3% or a 10-year probability of a major osteoporosis-related fracture ≥ 20% based on the US-adapted WHO algorithm

• Clinical judgment and/or patient preferences may indicate treatment for people with 10-year fracture probabilities above or below these levels

FRAX Criteria• Advancing age • Previous fracture • Glucocorticoid therapy • Parental history of hip fracture • Low body weight • Current cigarette smoking • Excessive alcohol consumption • Rheumatoid arthritis • Secondary osteoporosis (eg, hypogonadism or

premature menopause, malabsorption, chronic liver disease, inflammatory bowel disease

A 55 y/o woman has a DEXA reported with the following values for bone mineral density (BMD): T-score ≤-2.5

Recommendations include:

1. 1,200-1,400mg Calcium daily

2. Weight bearing exercises

3. testing for 25-hydroxyvitamin D, CBC and urinary calcium excretion

4. Alendronate or equivalent

5. All of the above

• Calcium and Vitamin D supplementation could protect bone by preventing bone loss and by healing subclinical osteomalacia.

• The optimal serum 25OHD concentration to maintain skeletal health is not firmly established, serum values exceeding 19 to 24 ng/mL (47.5 to 60 nmol/L) are supported by observational studies .

• Ensrud, KE, Taylor, BC, Paudel, ML, et al. Serum 25-hydroxyvitamin D levels and rate of hip bone loss in older men. J Clin Endocrinol Metab 2009; 94:2773. Cauley, JA, Lacroix, AZ, Wu, L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008; 149:242.

• Looker, AC, Mussolino, ME. Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. white adults. J Bone Miner Res 2008; 23:143.

• Gerdhem, P, Ringsberg, KA, Obrant, KJ, et al. Association between 25-hydroxyvitamin D levels, physical activity, muscle strength, and fractures in the. prospective population-based OPRA study of elderly women. Osteoporos Int 2005; 16:1425

Therapeutic InterventionsIn a cross-sectional study of adults (>50 years) participating

in the NHANES III survey, higher 25-OH-D concentrations were associated with greater BMD measurements throughout the reference range, plateauing in the range of 36 to 40 ng/ml (90 to 100 nmol/L) Bischoff-Ferrari, HA, Dietrich, T, Orav, EJ, Dawson-Hughes, B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med 2004; 116:634

Another approach would be to maintain serum levels >30 to 40 ng/mL (75 to 100 nmol/L), recognizing that some patients need more than 800 international units daily . Dawson-Hughes B. Estimates of optimal vitamin D status. Osteoporos Int 2005; 16:713.

Dosage Recommendations

• Based upon the HANES and other studies, we recommend 1200 to 1500 mg of calcium and 800 international units of vitamin D daily in most individuals with osteoporosis with a target serum 25-hydroxyvitamin D (25-OH-D) concentration >20 ng/mL (50 nmol/L).

• Calcium supplementation in excess of 500 mg/day should be given in divided doses

Fish Oil (Omega 3)•  Fish oil contains two medically relevant long-

chain polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), collectively known as omega-3 fatty acids.

• Omega-3 fatty acids are successfully employed to treat hypertriglyceridemia in HIV-negative individuals .

• They are dosed at 4 grams per day either singly or in a divided dose. Kris-Etherton, PM, Harris, WS, Appel, LJ, et al. Fish consumption, Fish oil, omega-3 fatty acids, and cardiovascular

disease. Circulation 2002; 106:2747.

• One study randomly assigned 52 HIV-infected patients with hypertriglyceridemia to receive lifestyle modification counseling with or without fish oil supplementation for 16 weeks

• After four weeks, mean triglyceride levels significantly declined from 461 to 306 mg/dL in the supplementation group and remained low. It was well tolerated when taken daily with food.

• Wohl, DA, Tien, HC, Busby, M, et al. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41:1498.

• Since fish oil has antiplatelet effects, patients concomitantly using drugs that affect bleeding time should be monitored for adverse effects.

Fish Oil (Omega 3)

Other Lifestyle Changes and Recommendations

• Exercise• Smoking cessation• Balanced diet• Stress management• Regular medical interventions and screenings

such as mammography, Pap smear, colonoscopy, etc

• Vaccines • Screening for violence/abuse, depression