Primary Care of the HIV-infected Adult: If I Can Do It, You Can Do It

Primary Care of the HIV-infected Adult: If I Can Do It, You Can Do It Howard Libman, MD Professor of Medicine, Emeritus Harvard Medical School Boston, Massachusetts Learning Objectives After attending this presentation, learners will be able to: Explain the role of primary care in HIV management Describe the general effects of aging on HIV infection Manage specific comorbidities in the HIV-infected patient Implement relevant healthcare maintenance issues Slide 3 of 51 Role of Primary Care Slide 4 of 51

Slide 5 of 51 Increased HIV Screening of Population Increased Survival of HIV-Infected Patients Increased Number of Patients, Many on Antiretroviral Therapy, Requiring HIV Care Aging of Patient Population and Development of Long-Term Treatment Complications and Comorbid Medical Conditions Need for Increased Primary Care Services Decreased Capacity for Provision of Primary Care Decreased Number of Medical Residents Pursuing Primary Care Inadequate Training of Medical Residents in HIV Outpatient Medicine First Generation of HIV Practitioners Nearing Retirement in Next 10 Years Slide 6 of 51 New HIV Diagnoses by Age United States, 2015 Slide 7 of 51 http://www.cdc.gov/hiv/group/age/olderamericans/index.html

Slide 8 of 51 People Living with HIV by Age United States, 2014 http://www.cdc.gov/hiv/group/age/olderamericans/index.html Primary Care Responsibilities Universal HIV screening and prevention Antiretroviral therapy* and medication adherence Prophylaxis of opportunistic infections Management of comorbid conditions Immunizations Other HIV-related healthcare maintenance issues Age- and sex-related healthcare maintenance issues * Involvement may vary depending upon interest and experience of primary care practitioners and availability of HIV specialists Slide 9 of 51 Overview of HIV Care and Treatment in the US https://www.hiv.gov/federal-response/policies-issues/hiv-aids-care-continuum Slide 10 of 51

Slide 11 of 51 Effects of Aging Normal Aging and Health Taffet GE. Normal Aging. UpToDate. Slide 13 of 51 Chronic Complications by Age and HIV Status Retrospective analysis of HIV-infected outpatients compared to seronegative persons (case-control study) from 2002 through 2009 Examined cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure Independent predictors of polypathology (p < 0.001) included older age (OR 1.11), male gender (OR 1.77), CD4 nadir below 200 (OR 4.46), and duration of antiretroviral therapy (OR 1.01) Guaraldi G et al. Clin Infect Dis 2011;53:1120. Slide 14 of 51

Slide 15 of 51 Chronic Complications by Age and HIV Status 3% 1% 8% 6% 4% 1% 2% 9% 6% 16% 17% 17% 28% 2% 15% 15% 31% 35% 29% 42% 80% 60% 31% 90% 80% 65% 42% 40% 21% Guaraldi G et al. Clin Infect Dis 2011;53:1120. Distribution of Age-related Comorbidities Stratified by Age Schouten et al. Clin Infect Dis 2014;59:1787. Slide 16 of 51 Prevalence of Different Age-related Comorbidities P<.0001 HIV-uninfected HIV-infected P<.018 P=.008 P=.044 Schouten et al. Clin Infect Dis 2014;59:1787. Slide 17 of 51

Slide 18 of 51 Comorbidity Trends in HIV-infected Patients Gallant J et al. J Infect Dis 2017;216(12):1525. doi:10.1093/infdis/jix518. Case Presentation The patient is a 50 year old man who was diagnosed with HIV infection 24 years ago. His risk behavior is sex with other men. He is asymptomatic and currently on TAF/FTC/cobi/EVG with a CD4 count of 728/mm3 and viral load < 20 copies/ml. He has a family history of coronary artery disease and smokes one pack of cigarettes per day. His BP reading is 138/86, BMI=32, and the remainder of his physical examination is unremarkable. His cholesterol level of 200 mg/dl with LDL component of 130, and his HgbA1c level is 6.2%. Slide 19 of 51 Case Questions How should his blood pressure be further evaluated, and does it require treatment? How should his cigarette smoking be managed? Should he be started on a statin for hypercholesterolemia? Should he be started on metformin for glucose intolerance? What healthcare preventive measures should be implemented? What healthcare screening measures should be implemented? Slide 20 of 51

Slide 21 of 51 Specific Comorbidities HIV Infection and Coronary Artery Disease (1) Incidence of CAD is relatively low but higher than that in HIV-negative patients matched for age and gender Studies have demonstrated an increase in subclinical atherosclerosis (e.g., carotid intima media thickness) and clinical endpoints (e.g., acute myocardial infarction) HIV infection is associated with increased soluble and cellular markers of inflammation, endothelial dysfunction, and altered coagulation, all of which have been shown to contribute to cardiovascular disease Slide 23 of 51 HIV Infection and Coronary Artery Disease (2) Degree to which HIV infection itself, antiretroviral therapy, and traditional risk factors contribute to increased risk in this population is unknown Protease inhibitor class appears to be associated with higher risk of CAD; data regarding abacavir are inconsistent Discontinuation of ART is associated with a higher risk of CAD High prevalence of traditional risk factors in this population Slide 24 of 51

Slide 25 of 51 The Risk of Coronary Artery Disease in HIV-infected Patients Freiberg MS et al. JAMA Intern Med 2013;173:614. Slide 26 of 51 Hypertension Use of ambulatory BP monitoring for diagnosis Newly redefined: Stage 1 Systolic 130-139 mmhg or diastolic 80-89 mmhg Stage 2 Systolic 140 mmhg or diastolic 90 mmhg In the absence of history or physical exam pointing to secondary hypertension, baseline evaluation should include renal function, potassium, urinalysis, and electrocardiogram Nonpharmacologic management consists of modest salt restriction, increased physical activity, and weight reduction Initial drug therapy should consist of thiazide diuretic, ACE inhibitor or receptor blocker, or calcium channel blocker in most patients For those who are more than 20/10 mmhg above goal, ACE inhibitor or receptor blocker plus calcium channel blocker is recommended Lower target BP readings (130/80) on treatment for most patients No important ART interactions for commonly used drugs ACC/AHA Hypertension Guideline. J Am Coll Cardiol 2017. doi: 10.1016/j.jacc.2017.11.006. Diabetes Mellitus HIV infection probably increases risk of DM (BMJ Open Diabetes Res Care http://dx.doi.org/10.1136/bmjdrc-2016-000304) Diagnosis is often based upon fasting glucose 126 mg/dl or HgbA1c 6.5% Treatment goals include prevention of symptomatic hyperglycemia and vascular complications; HgbA1c target 7.0% Nonpharmacologic management consists of weight reduction through dietary modification and increased physical activity Initial drug therapy generally consists of metformin with sulfonylurea (e.g., glipizide) added as the second agent Metformin may cause lactic acidemia as do older NRTI drugs Dolutegravir increases metformin AUC (do not exceed 1000 mg/d) DM and HIV have particularly detrimental effect on renal function (J Acquir Immune Defic Syndr 2012;60:393) Slide 27 of 51

Slide 28 of 51 Hyperlipidemia Dyslipidemia is common in HIV-infected patients on ART; it may be isolated or seen in combination with other features of LDS HIV-infected patients should be evaluated and treated for dyslipidemia in a similar fashion to seronegative persons; efficacy data are limited Cardiac risk factor assessment should be considered when designing an initial ART regimen; avoid protease inhibitors (except possibly atazanavir) and abacavir if there are other risks Protease inhibitors, particularly ritonavir, increase most statin levels Simvastatin and lovastatin are contraindicated with protease inhibitors and cobicistat; atorvastatin, rosuvastatin, and pitavastatin can be used as alternatives Prudent to start with low dose and to monitor LFTs and CPK on treatment ACC/AHA CV Risk Calculator Uses data primarily from non-hispanic whites and African Americans in the United States. Concerns about accuracy of results have been made (statin recommendations, DM yes vs. no categorization, FMH of premature CAD not included). Slide 29 of 51 Slide 30 of 51 Cigarette Smoking HIV-infected patients are more likely to smoke and less likely to quit compared to general population (Ann Intern Med 2015;162:335) HIV-infected smokers lose more life-years to smoking than to HIV-related conditions (Clin Infect Dis 2013;56:727) No evidence that specific smoking cessation approaches are more or less effective Management includes behavioral intervention and/or pharmacologic therapy; evidence suggests that combination approach works better than either alone Drug options include nicotine replacement (e.g., patch, gum, lozenge), bupropion, and varenicline, which can be used alone or in combination No important ART interactions for commonly used drugs

Slide 32 of 51 Premature Bone Loss (1) Osteopenia, osteoporosis, and pathological fractures have been described Osteopenia is usually asymptomatic Osteoporosis may present with fractures of vertebrae, forearms, or hips HIV infection itself, TDF, protease inhibitors, alterations in vitamin D metabolism, and lactic acidemia related to older NRTI drugs may be contributing factors to premature bone loss Premature Bone Loss (2) Immobility, cigarette smoking, excessive alcohol use, chronic renal disease, hypogonadism, hyperparathyroidism, hyperthyroidism, and steroid use accentuate bone loss Optimal use of bone densitometry as screening test in this population is uncertain; HIVMA advises baseline in postmenopausal women and men 50 years of age Calcium and vitamin D should be given in highrisk patients; regular exercise and smoking cessation should be advised Slide 33 of 51 Antiretroviral Exposure and Risk of Osteoporotic Fractures Bedino R et al. AIDS 2012;26:825. Slide 34 of 51

Slide 35 of 51 Malignancies Observational studies suggest that lung, hepatic, and anal cancers occur at younger age in HIVinfected adults compared to seronegative persons Using 15 HIV and cancer registry databases in the US, including 212,055 persons with AIDS, the age of diagnosis of non-aids-defining cancers was examined Only lung and anal cancers were seen in AIDS patients at younger age (median 50 years old vs. 54; p < 0.001) than expected Shiels MS et al. Ann Intern Med 2010;153:452. Pulmonary Diseases Veterans Aging Cohort Study consisting of 33,420 HIV-infected patients and 66,840 seronegative controls Subjects were matched by age, sex, race, and ethnicity Incidence of chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis was significantly higher in the HIV-infected group Crothers K et al. Am J Respir Crit Care Med 2011;183:388. Slide 36 of 51 Cognitive Dysfunction Epidemiologic findings suggest that increasing age is risk factor for HIV-associated dementia, although the studies are small There are still many unanswered questions Longitudinal study comparing 106 HIV-infected patients over 50 years of age to 96 patients between 20-39 years of age showed a three-fold higher risk of dementia on multivariate analysis Study adjusted for race, education, depression, substance abuse, ART, CD4 count, and viral load Valcour V et al. Neurol 2004;63:822. Sacktor N et al. Neurovirol 2007;13:203. Wendelken LA et al. J Neurovirol 2012;18:256. Slide 37 of 51

Slide 38 of 51 Healthcare Maintenance Slide 40 of 51 Cancer Screening (1) Breast Cancer: Biannual mammography in women aged 50 to 74 years; individualize for younger ages Cervical Cancer: Annual Pap test in women after 2 normal Pap tests documented; role of HPV testing in HIV-infected patients is unclear Colon Cancer: Colonoscopy every 10 years starting at age 50; earlier and more often screening if history of polyps or inflammatory bowel disease Prostate Cancer: Discuss the benefits and risks of prostate-specific antigen (PSA) testing in males aged 55 to 69 years and in patients with family history Slide 41 of 51 US Preventive Services Task Force and other recommendations

Slide 42 of 51 Algorithm for Cervical Cancer Screening in HIV-infected Women Adapted from content in Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Cancer Screening (2) Lung Cancer: Annual screening for lung cancer with low-dose CT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or ability or willingness to have curative lung surgery. Slide 43 of 51 US Preventive Services Task Force Anal Cancer ART has not altered the prevalence of anal SIL and may be associated with an increased incidence of progression to anal cancer because of the longer life expectancy of HIV-infected persons. It not inappropriate to screen this population with anal cytology without local expertise in interpretation and availability of a referral structure for highresolution anoscopy with biopsy, as well as access to ablative treatment. HPV vaccine can decrease the incidence of infection with the types associated with anal cancer. Slide 44 of 51

Slide 45 of 51 Algorithm for the Management of Anal Pap Smear Results ANAL PAP SMEAR NORMAL ASCUS or LSIL HSIL continue screening schedule yearly for HIV+ MSM, every 2 years for HIV- MSM HRA LESION NOT FOUND LESION FOUND REPEAT PAP in 6 months BIOPSY AIN1 AIN2 or AIN3 REPEAT PAP and HRA in 6 months, if stable x 2 exams, PAP and HRA every 12 months ABLATE REPEAT PAP and HRA in 4-6 months LSIL, low -grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion; AIN, anal intraepithelial neoplasia; HRA, high resolution anoscopy. Panther L, Schlect H, Dezube B. AIDS Reader 2005;15:79. Infectious Diseases Screening Sexually Transmitted Diseases: Annual chlamydia, gonorrhea, and syphilis testing in adults at ongoing risk for STDs Tuberculosis: Annual PPD or interferon-gamma release assay testing in adults at ongoing risk for tuberculosis Aberg JA, Gallant JE, Ghanem KG et al. Clin Infect Dis 2013;doi:10.1093/cid/cit665. Slide 46 of 51 Cardiovascular Disease Hypertension: Regular blood pressure checks Abdominal Aortic Aneurysm: One-time ultrasound in men ages 65-75 who ever smoked Aspirin Prophylaxis (CVD and colon cancer): Adults aged 50 to 69 years who have a 10% or greater 10- year CVD risk, are not at increased risk for bleeding, and have a life expectancy of at least 10 years US Preventive Services Task Force Slide 47 of 51

Slide 48 of 51 Case Presentation The patient is a 50 year old man who was diagnosed with HIV infection 24 years ago. His risk behavior is sex with other men. He is asymptomatic and currently on TAF/FTC/cobi/EVG with a CD4 count of 728/mm3 and viral load < 20 copies/ml. He has a family history of coronary artery disease and smokes one pack of cigarettes per day. His BP reading is 138/86, BMI=32, and the remainder of his physical examination is unremarkable. His cholesterol level of 200 mg/dl with LDL component of 130, and his HgbA1c level is 6.2%. Slide 49 of 51 Case Questions How should his blood pressure be further evaluated, and does it require treatment? - Use of ambulatory BP monitoring; lower thresholds for diagnosis and treatment How should his cigarette smoking be managed? - Individualize based upon method(s) that are most likely to succeed Should he be started on a statin for hypercholesterolemia? - ACC/AHA risk calculation of 10.9% without adjustment for HIV infection; start atorvastatin Should he be started on metformin for glucose intolerance? - Concerted effort at weight reduction; if not successful or no improvement in HgbA1c, start metformin What healthcare preventive measures should be implemented? - HAV (if seronegative), HBV (if seronegative), meningococcal conjugate, and pneumococcal vaccines; and Td booster every 10 years What healthcare screening measures should be implemented? - Low-dose aspirin for CAD and colon cancer prophylaxis; colonoscopy, bone densitometry, and anal cytology (if local expertise is available); and screening for STDs and TB as warranted Summary There is an increased need for primary care services for HIV-infected patients at the same time that there is potentially decreased capacity to provide them Both generalist and infectious disease practitioners have important contributions to make in providing high quality primary care to this patient population HIV-infected patients may develop age-related diseases at a younger chronological age Incidence of coronary artery disease (CAD) is higher than that in HIV-negative patients matched for age and gender CAD risk calculator results need to be interpreted in context of increased risk in the HIVinfected population HIV infection and its treatment and comorbidities are associated with premature bone loss Lung, hepatic, and anal cancers may occur at a younger age in HIV-infected patients Appropriate immunizations and age- and sex-related healthcare maintenance issues should be routinely addressed as part of comprehensive care Slide 50 of 51