HIV in Aging Patients eHealth Source by Integritas Communications

Faculty

Chris Longenecker, MD Adult Cardiologist Director, HIV Cardiometabolic Risk Clinic University Hospitals Harrington Heart & Vascular Institute Associate Professor of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio Dr. Chris Longenecker is Medical Director of the Harrington Heart & Vascular Institute Research and Innovation Center and a noninvasive cardiologist who is a leading expert on the cardiovascular complications of HIV infection in the era of combination antiretroviral therapy. Dr. Longenecker graduated from The Ohio State University School of Medicine, Columbus, and completed internal medicine training at the University of California, San Francisco. He returned to Ohio in 2009 for a cardiology fellowship at University Hospitals Cleveland Medical Center, where he served as Chief Fellow. In July 2013, he joined the faculty of the Harrington Heart & Vascular Institute, where he started an innovative and multidisciplinary HIV Cardiometabolic Risk Clinic. His research program focuses on the effect of chronic inflammation on cardiovascular risk in HIV and on practical approaches to cardiovascular disease prevention in this special population, both in Cleveland and in sub-Saharan Africa. His work is supported by multiple National Institutes of Health and private foundation grants, including a multisite study to improve blood pressure and cholesterol management in the HIV specialty clinic context.

Paul E. Sax, MD Professor of Medicine Harvard Medical School Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women’s Hospital Boston, Massachusetts

Dr. Paul E. Sax is Clinical Director of the Division of Infectious Diseases and the HIV Program at Brigham and Women’s Hospital (BWH), and Professor of Medicine at Harvard Medical School. Dr. Sax received his medical degree from Harvard Medical School, then did his residency in Internal Medicine at BWH, while continuing his postdoctoral education with a fellowship in Infectious Diseases at Massachusetts General Hospital. He is Editor-in-Chief of Open Forum Infectious Diseases, Section Editor of HIV/AIDS in UpToDate, on the Editorial Board of NEJM Journal Watch Infectious Diseases (where he writes the HIV and ID Observations blog), and on the editorial advisory board of Medscape HIV/AIDS. Dr. Sax is also on the core faculty of the International AIDS Society–USA. In addition to his clinical practice and teaching, Dr. Sax’s ongoing areas of research include clinical trials of antiretroviral therapies, cost-effectiveness of management strategies for HIV, and toxicity of antiretroviral therapy. He is presently the principal investigator at the BWH AIDS Clinical Trials Unit and a member of the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Research Group.

Preamble Target Audience This activity is intended for infectious diseases and infectious disease and HIV specialist physicians and other clinicians involved in the care of patients with HIV infection.

Educational Objectives After completing this activity, the participant should be better able to: • Review the role of inflammation in the comorbidities commonly associated with HIV in aging patients • Tailor screening and treatment for common age-related HIV comorbidities, such as decreased bone mineral density and renal disease • Address CV risk in aging patients with HIV through selection of appropriate ART regimens and incorporation of recommended therapies to prevent cardiovascular disease (CVD) • Utilize knowledge of virus-related cancers to appropriately screen patients with HIV • Implement screening and appropriate treatment strategies for depression and HIV-associated neurocognitive disorders (HAND) in aging patients with HIV

Program Overview People with HIV (PWH) have a life expectancy that is only slightly shorter than that of the general population. In the United States, more than half of the 1.3 million PWH are older than 50 years—and the average age is rising.1 As PWH age, the risk of comorbidities and multimorbidity increases.2 The age-related multimorbidity seen in PWH is believed to be caused by HIV-associated chronic inflammation, immune dysregulation, and immune cell senescence.1 Comorbidity burden in aging PWH has a substantial negative effect on quality of life. Comorbidities of particular concern are cardiovascular disease, decreased bone mineral density, cancer, neurocognitive impairment and depression, and renal disease. These comorbidities may be influenced both by antiretroviral therapy (ART) and by HIV itself. There is a need for clinicians to better understand these comorbidities and form multidisciplinary teams to appropriately care for their aging patients with HIV. This HIV eHealth program includes epidemiology, pathophysiology, diagnosis, and management strategies for common comorbidities seen in aging PWH, including effect of ART on comorbidities and how each comorbidity may influence ART selection.

References 1. 2.

Wing EJ. HIV and aging. Int J Infect Dis. 2016;53:61-68. Kendall CE, Wong J, Taljaard M, et al. A cross-sectional, population-based study measuring comorbidity among people living with HIV in Ontario. BMC Public Health. 2014;14:161.

Disclosure of Conflicts of Interest Global Education Group (Global) requires instructors, planners, managers, and other individuals and their spouses/life partners who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Chris Longenecker, MD

Grant/Research Support: Gilead Sciences, Inc.

Paul E. Sax, MD

Consultant/Independent Contractor: AbbVie Inc., Bristol-Myers Squibb, Gilead Sciences, Inc., GlaxoSmithKline/ViiV Healthcare, Janssen Pharmaceuticals, Inc., Merck & Co., Inc.; Grant/ Research Support: Bristol-Myers Squibb, Gilead Sciences, Inc., GlaxoSmithKline/ViiV Healthcare, Merck & Co., Inc.

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Lindsay Borvansky

Nothing to disclose

Andrea Funk

Nothing to disclose

Liddy Knight

Nothing to disclose

Ashley Cann

Nothing to disclose

Gena Dolson, MS

Nothing to disclose

Celeste Collazo, MD

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Physician Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Creditâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturerâ&#x20AC;&#x2122;s product information, and comparison with recommendations of other authorities.

Instructions to Receive Credit In order to receive credit for this activity, the participant must complete the posttest and program evaluation. Your posttest will automatically be graded. If you successfully complete the posttest (score of 80% or higher), your statement of participation will be made available immediately. Click on the View Statement of Participation link and print the statement for your records. If you receive a score lower than 80%, you will receive a message notifying you that you did not pass the posttest. You will have 2 opportunities to pass the posttest. For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Introduction: HIV in the Aging Patient

Chris Longenecker, MD Over the past several decades, HIV has shifted from a fatal diagnosis to a chronic condition that can be managed with antiretroviral therapy (ART). Today, people with HIV (PWH) have a life expectancy that is only slightly shorter than that of the general population. In the United States, more than half of the 1.3 million PWH are older than 50 years—and the average age is rising. By 2030, 70% of PWH are expected to be older than 50 years.1 As the life expectancies of PWH extend, and as people are diagnosed with HIV at older ages, the effects of the infection on aging are becoming important clinical considerations (see link to supplementary video 1).2

VIDEO 1: Introduction  Chris Longenecker, MD

Multimorbidity appears to occur in PWH in their 40s at the same rate that it occurs in the general population in their 50s.3 Furthermore, as PWH age, the risk of comorbidities and multimorbidity increases.4 The agerelated multimorbidity seen in PWH is believed to be caused by HIV-associated chronic inflammation, immune dysregulation, and immune cell senescence—so-called inflammaging or inflammAIDS. Inflammatory biomarkers of inflammaging are reported in PWH regardless of whether HIV levels are suppressed on ART. Although there are multiple mechanisms leading to chronic inflammation in PWH, a key mediator is believed to be low-level HIV replication in tissues despite undetectable levels of HIV in the serum. Furthermore, immune dysregulation and senescence occurs at a younger age among PWH, potentially due to depletion of CD4+ T cells prior to initiation of ART.1,2

Comorbidity burden in an aging HIV-positive population has a substantial negative effect on quality of life. PWH who have chronic conditions such as diabetes, neurocognitive impairment, cancer, depression, hypertension, chronic pain, hepatitis, or arthritis typically have lower scores on quality of life assessments than PWH who do not have these comorbidities.5,6 Currently, PWH are dying more often from noninfectious causes than from AIDS.7 As such, the clinical conversation surrounding aging PWH has shifted, and clinicians must focus on providing comprehensive health care for PWH who have multiple comorbidities.

References 1. 2. 3. 4. 5. 6. 7.

Wing EJ. HIV and aging. Int J Infect Dis. 2016;53:61-68. Nasi M, De Biasi S, Gibellini L, et al. Ageing and inflammation in patients with HIV infection. Clin Exp Immunol. 2017;187(1):44-52. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53(11):1120-1126. Kendall CE, Wong J, Taljaard M, et al. A cross-sectional, population-based study measuring comorbidity among people living with HIV in Ontario. BMC Public Health. 2014;14:161. Balderson BH, Grothaus L, Harrison RG, McCoy K, Mahoney C, Catz S. Chronic illness burden and quality of life in an aging HIV population. AIDS Care. 2013;25(4):451-458. Rodriguez-Penney AT, Iudicello JE, Riggs PK, et al. Co-morbidities in persons infected with HIV: increased burden with older age and negative effects on health-related quality of life. AIDS Patient Care STDS. 2013;27(1):5-16. Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: collaborative analysis of 13 HIV cohort studies. Clin Infect Dis. 2010;50(10):1387-1396.

Inflammation and Cardiovascular Disease Risk in HIV

Chris Longenecker, MD People with HIV (PWH) are at elevated risk for a variety of heart and blood vessel conditions, including atherosclerosis, coronary artery disease, thromboembolism, atrial fibrillation, heart failure, and pulmonary arterial hypertension. These diseases are collectively known as cardiovascular disease (CVD). In a systematic review and meta-analysis, researchers reported that PWH who are receiving antiretroviral therapy (ART) are at a 2-fold elevated risk of CVD compared with people who are not infected with HIV.1 Other common cardiovascular conditions associated with HIV infection include left ventricular systolic and diastolic dysfunction, myocardial fibrosis, and cardiac fat infiltration.2-5 In a database review of people undergoing carotid endarterectomy, PWH received carotid intervention 9 years earlier, on average, than people without HIV.6 Similarly, the Veterans Aging Cohort Study (VACS) has shown that ischemic stroke occurs at an increased rate among younger PWH relative to HIV-uninfected individuals. The VACS also showed that the risk of myocardial infarction (MI) is higher among PWH in all age groups; however, the mean age at the time of MI is similar regardless of HIV status.7 Furthermore, in a longitudinal study, the risk of MI or stroke did not rise with increasing duration of HIV infection.8 On the basis of these study results, HIV could lead to either accelerated aging or accentuated aging (Figure 1.1). The two models of HIV-influenced aging may be reconciled if one considers that HIV-associated risk factors (eg, ART use) may be more important for CVD risk at younger ages, and traditional risk factors (eg, hypertension and cholesterol) may become more important at older ages among PWH.9

Atherosclerotic Cardiovascular Disease Among PWH Pathophysiology Damage leading to atherosclerotic cardiovascular disease (ASCVD) appears to be mediated by chronic inflammation and immune activation (Figure 1.2). Inflammation in PWH is caused in large part by the alteration of immune cell subsets, including lowered CD4+ T-cell counts and activation of monocytes. Low current CD4+

T-cell counts have been associated with increased risk of carotid intima-media thickening, atherosclerosis, incident CVD, and acute MI.10-14 Low nadir CD4+ counts have also been associated with inflammation and cardiovascular risk.15,16 The activation of monocytes can lead to monocyte and macrophage infiltration of endothelial tissue, which is a risk factor for vulnerable atherosclerotic plaque.17 Markers of monocyte activation have been linked to higher rates of all-cause mortality among PWH.18,19

ART ART contributes to the risk of CVD among PWH (Table 1.1). By 2007, protease inhibitors (PIs) were identified as a primary contributor to MI risk, due in part to associated dyslipidemia. Even after adjustment for cholesterol levels, however, the risk of MI was increased by 10% among people who received ritonavir and other firstgeneration PIs.21 According to recent results from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, atazanavir appears to be the only PI that is not associated with an increased risk of CVD.22

Nonetheless, the cardiovascular risk of ART should be balanced against the risks of leaving HIV untreated. According to the results of the Strategic Timing of AntiRetroviral Treatment (START) trial, early initiation of ART among PWH is the standard of care and reduces the risk of both AIDS-related and non-AIDS-related adverse events.23

Anti-inflammatory Therapies Canakinumab, an anti-inflammatory antibody treatment that targets interleukin (IL)-1β, was tested in the CANTOS clinical trial, which included more than 10,000 HIV-negative patients with previous MI and highsensitivity C-reactive protein (CRP) level of ≥2 mg/L. Canakinumab 150 mg was shown to significantly reduce the risk of the primary endpoint—which was nonfatal MI, nonfatal stroke, or cardiovascular death—by 15% (P=0.02).44 In a smaller study of adults with treated HIV infection and established CVD or at least 1 cardiovascular risk factor, canakinumab reduced the levels of CRP and IL-6 among PWH and also reduced arterial inflammation by 10% and bone marrow metabolic activity by 11%.45 Canakinumab appears to mediate its effects solely through inflammatory pathways.44 Yet other studies have revealed that treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of MI and other cardiovascular adverse events.46,47 Furthermore, results from the CIRT study demonstrated that methotrexate did not reduce inflammatory markers among people from the general population with stable atherosclerosis or among PWH who were at risk for CVD.48,49

Lipid-Lowering Therapies Among PWH, statin therapy has been shown to reduce plaque volume and decrease inflammatory biomarkers50,51; however, a direct correlation between mortality reduction and statin therapy has not been established among PWH.52 Lipid-lowering therapies are currently used at a lower rate among PWH than among people without HIV infection (see link to supplementary video 2).

VIDEO 2: Statin Use in PWH  Chris Longenecker, MD

Diagnosing & Managing ASCVD

Ideally, PWH will be evaluated for risk of CVD at every visit. Common risk calculators that use conventional risk factors to calculate the 10-year risk of heart disease, such as the ASCVD Risk Estimator Plus, do not account for HIV-associated risk factors, and, therefore, underestimate CVD risk among PWH.53 The D:A:D risk equation does incorporate HIV-specific factors, such as exposure to abacavir, indinavir, or lopinavir/r, but does not significantly improve risk estimation for PWH.54 Because of the association between PIs and CVD, combinations containing integrase inhibitors may be preferable options for PWH who are at high risk for CVD. Other ART agents that have been shown to have a neutral lipid profile include nonnucleoside reverse transcriptase inhibitors (NNRTIs) and CCR5 antagonists.20 Unfortunately, many ART agents interact with statins. Pitavastatin is a newer statin with fewer interactions than other statin therapies.55

Heart Failure Among PWH HIV infection is often traditionally associated with ASCVD but many PWH—especially older PWH—are at risk for heart failure (HF) independent of increased risk for MI.56 Although PWH have elevated risk for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), the epidemiology of HF in PWH has changed with the advent of ART.57,58 In the pre-ART era, HFrEF was more common. With the introduction of effective ART and a lower number of PWH progressing to AIDS, HFpEF has become more common.58 HF is mediated and characterized by high levels of inflammatory markers and immune activation.59 Antiinflammatory drugs, however, may result in worse clinical outcomes among patients with HF. Some biologic drugs that block inflammation have been associated with an increased risk of HF.60,61 In contrast, canakinumab has been shown to decrease the risk for hospitalization for HF.62

ART In a retrospective single-center study of PWH who were hospitalized with HF, the use of PIs was associated with increased odds of cardiovascular adverse events: dyslipidemia, diabetes, coronary artery disease, lower left ventricular ejection fraction, and higher pulmonary artery systolic pressure.39 In contrast, tenofovir disoproxil fumarate (TDF) has been associated with a lower risk of incident HF.32

Diagnosing & Managing HF HF is frequently asymptomatic in PWH, especially with the advent of effective ART. In a meta-analysis of more than 2000 PWH who were asymptomatic, diastolic dysfunction was evident in 43%.2 Similarly, pericardial effusions and valvular heart disease are often diagnosed incidentally with echocardiography.63 As such, consideration should be given to echocardiogram testing among asymptomatic individuals with multiple risk factors for HF. No randomized controlled trials have been performed to determine the best treatment for PWH who have HF VIDEO 3: HF Treatment in PWH  (see link to supplementary video 3). It is nonetheless Chris Longenecker, MD reasonable to use standard HF therapies such as cardioverter-defibrillator implantation, cardiac resynchronization therapy, and pharmacologic management. PWH who have HF should continue to receive ART, but regimens containing zidovudine should be switched to another option because of the association of zidovudine with myocyte mitochondrial damage.64

Key Clinical Highlights • CVD is a proinflammatory disease, but the relationship among inflammation, immune activation, HIV infection, and CVD is complex and warrants further investigation • PIs are associated with an increased risk of MI and HF, whereas integrase inhibitors are associated with a more favorable cardiac risk profile • Statins and other lipid-lowering and cardioprotective therapies should be prescribed to PWH who are at risk for CVD according to current guidelines 12

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Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med. 2012;13(8):453-468. Cerrato E, D'Ascenzo F, Biondi-Zoccai G, et al. Cardiac dysfunction in pauci symptomatic human immunodeficiency virus patients: a meta-analysis in the highly active antiretroviral therapy era. Eur Heart J. 2013;34(19):1432-1436. Thiara DK, Liu CY, Raman F, et al. Abnormal myocardial function is related to myocardial steatosis and diffuse myocardial fibrosis in HIV-infected adults. J Infect Dis. 2015;212(10):1544-1551. Nelson MD, Szczepaniak LS, LaBounty TM, et al. Cardiac steatosis and left ventricular dysfunction in HIV-infected patients treated with highly active antiretroviral therapy. JACC Cardiovasc Imaging. 2014;7(11):1175-1177. Holloway CJ, Ntusi N, Suttie J, et al. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. Circulation. 2013;128(8):814-822. Lin TC, Burton BN, Barleben A, Hoenigl M, Gabriel RA. Association of HIV infection with age and symptomatic carotid atherosclerotic disease at the time of carotid intervention in the United States. Vasc Med. 2018;23(5):467-475. Althoff KN, McGinnis KA, Wyatt CM, et al. Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults. Clin Infect Dis. 2015;60(4):627-638. Rasmussen LD, May MT, Kronborg G, et al. Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. Lancet HIV. 2015;2(7):e288-298. Longenecker CT. Vascular disease and aging in HIV: time to extend the treatment cascade. Vasc Med. 2018;23(5):476-477. Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis. 2010;51(4):435-447. Triant VA, Regan S, Lee H, Sax PE, Meigs JB, Grinspoon SK. Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. J Acquir Immune Defic Syndr. 2010;55(5):615-619. Kaplan RC, Kingsley LA, Gange SJ, et al. Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men. AIDS. 2008;22(13):1615-1624. Hsue PY, Lo JC, Franklin A, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109(13):1603-1608. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008;22(7):841-848. Ho JE, Deeks SG, Hecht FM, et al. Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals. AIDS. 2010;24(12):1897-1905. Longenecker CT, Jiang Y, Yun CH, et al. Perivascular fat, inflammation, and cardiovascular risk in HIV-infected patients on antiretroviral therapy. Int J Cardiol. 2013;168(4):4039-4045. Alsheikh-Ali AA, Kitsios GD, Balk EM, Lau J, Ip S. The vulnerable atherosclerotic plaque: scope of the literature. Ann Intern Med. 2010;153(6):387-395. Knudsen TB, Ertner G, Petersen J, et al. Plasma soluble CD163 level independently predicts all-cause mortality in HIV-1-infected individuals. J Infect Dis. 2016;214(8):1198-1204. Wada NI, Bream JH, Martinez-Maza O, et al. Inflammatory biomarkers and mortality risk among HIV-suppressed men: a multisite prospective cohort study. Clin Infect Dis. 2016;63(7):984-990. Vachiat A, McCutcheon K, Tsabedze N, Zachariah D, Manga P. HIV and ischemic heart disease. J Am Coll Cardiol. 2017;69(1):73-82. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17): 1723-1735. Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV. 2018;5(6):e291-e300. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. â&#x20AC;¨ N Engl J Med. 2015;373(9):795-807. Maraviroc (Selzentry) [package insert]. Research Triangle Park, NC: ViiV Healthcare; July 2018. Raltegravir (Isentress) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc; January 2019. Abacavir sulfate (Ziagen) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; July 2008. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis. 2010;201(3):318-330. Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011;25(10):1289-1298. Stavudine (Zerit) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2018. Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIVinfected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417-1426. Tenofovir disoproxil fumarate (Viread) [package insert]. Foster City, CA: Gilead Sciences, Inc; August 2012. Chen R, Scherzer R, Hsue PY, et al. Association of tenofovir use with risk of incident heart failure in HIV-infected patients. J Am Heart Assoc. 2017;6(4). Zidovudine (Retrovir) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; September 2008. Efavirenz (Sustiva) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; October 2017.

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Etravirine (Intelence) [package insert]. Titusville, NJ: Janssen Therapeutics; November 2018. Nevirapine (Viramune) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; September 2018. Atazanavir (Reyataz) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; March 2018. Chow D, Shikuma C, Ritchings C, Guo M, Rosenblatt L. Atazanavir and cardiovascular risk among human immunodeficiency virusinfected patients: a systematic review. Infect Dis Ther. 2016;5(4):473-489. Alvi RM, Neilan AM, Tariq N, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV and heart failure. J Am Coll Cardiol. 2018;72(5):518-530. Darunavir (Prezista) [package insert]. Titusville, NJ: Janssen Therapeutics; January 2019. Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet. 2002;360(9347):1747-1748. Fosamprenavir calcium (Lexiva) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; September 2009. Lopinavir and ritonavir (Kaletra) [package insert]. North Chicago, IL: AbbVie Inc; November 2016. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. Hsue PY, Li D, Ma Y, et al. IL-1Î˛ inhibition reduces atherosclerotic inflammation in HIV infection. J Am Coll Cardiol. 2018;72(22): 2809-2811. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclooxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365(9458):475-481. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018;380(8):752-762. Hsue P, Ribaudo H, Deeks S, et al. Safety and impact of LDMTX on immune activation and endothelial function in treated HIV: ACTG 5314. Conference on Retroviruses and Opportunistic Infections; 2018; Boston, MA. Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIVinfected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;68(4):396-404. Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIVinfected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2(2):e52e63. Rasmussen LD, Kronborg G, Larsen CS, Pedersen C, Gerstoft J, Obel N. Statin therapy and mortality in HIV-infected individuals; a Danish nationwide population-based cohort study. PloS One. 2013;8(3):e52828. American College of Cardiology, American Heart Association. ASCVD Risk Estimator Plus. http://tools.acc.org/ascvd-risk-estimatorplus/#!/calculate/estimate/. Accessed May 23, 2019. Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil. 2010;17(5):491-501. Wiggins BS, Lamprecht DG, Jr., Page RL, 2nd, Saseen JJ. Recommendations for managing drug-drug interactions with statins and HIV medications. Am J Cardiovasc Drugs. 2017;17(5):375-389. Al-Kindi SG, ElAmm C, Ginwalla M, et al. Heart failure in patients with human immunodeficiency virus infection: epidemiology and management disparities. Int J Cardiol. 2016;218:43-46. Freiberg MS, Chang CH, Skanderson M, et al. Association between HIV infection and the risk of heart failure with reduced ejection fraction and preserved ejection fraction in the antiretroviral therapy era: results from the Veterans Aging Cohort Study. JAMA Cardiol. 2017;2(5):536-546. Erqou S, Lodebo BT, Masri A, et al. Cardiac dysfunction among people living with HIV: a systematic review and meta-analysis. JACC Heart Fail. 2019;7(2):98-108. Dick SA, Epelman S. Chronic heart failure and inflammation: what do we really know? Circ Res. 2016;119(1):159-176. Ungprasert P, Srivali N, Thongprayoon C. Nonsteroidal anti-inflammatory drugs and risk of incident heart failure: a systematic review and meta-analysis of observational studies. Clin Cardiol. 2016;39(2):111-118. Arfe A, Scotti L, Varas-Lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ. 2016;354:i4857. Everett BM, Cornel JH, Lainscak M, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139(10):1289-1299. Manga P, McCutcheon K, Tsabedze N, Vachiat A, Zachariah D. HIV and nonischemic heart disease. J Am Coll Cardiol. 2017;69(1):83. Lewis W. Mitochondrial DNA replication, nucleoside reverse-transcriptase inhibitors, and AIDS cardiomyopathy. Prog Cardiovasc Dis. 2003;45(4):305-318.

Bone Density and Osteoporosis Screening and Management

Paul E. Sax, MD As with cardiovascular disease (CVD) and other age-related comorbidities, bone mineral density (BMD) loss appears to occur at an earlier age and a higher frequency among people with HIV (PWH). Fracture incidence in PWH in their 50s was comparable to the fracture incidence of HIV-negative individuals who were a decade older.1 Compared with the general population, PWH have accelerated BMD loss, an increased incidence of osteopenia and osteoporosis, and an increased risk of fracture.2-4 A large case-control study estimated a substantially increased risk for hip fractures (9-fold), spinal fractures (9-fold), and forearm fracture (4-fold).5 Any fracture type is associated with a high level of morbidity, and hip fractures are associated with a 30% mortality rate within the first year.6,7

Causes of BMD Loss Among PWH The high rate of BMD loss among PWH has been attributed to both traditional risk factors and HIV-associated risk factors (Table 2.1). Smoking, low body weight, low vitamin D levels, and corticosteroid use are of particular concern in PWH.8,9 The risk of fracture among PWH may be compounded because of the many classical risk factors that occur at a higher rate among PWH. The association of traditional risk factors with low BMD among PWH is further supported by findings that HIV-negative men have low BMD prior to initiation of pre-exposure prophylaxis.10

Inflammation and Immune Dysregulation The primary risk factors for BMD loss associated with HIV infection are inflammation, immune reconstitution, and ART use. The chronic inflammation experienced by PWH may be analogous to the inflammation and immune dysregulation experienced by postmenopausal women as estrogen levels decline.12,13 To maintain skeletal homeostasis, osteoclasts and osteoblasts simultaneously destroy and synthesize bone cells, respectively. Osteoclast differentiation is mediated by the receptor activator of NF-ÎşB (RANK), RANK ligand (RANKL), and osteoprotegerin, a decoy receptor for RANKL. The production of RANKL and osteoprotegerin is mediated by B cells and T cells; therefore, immune dysregulation leads to overproduction of RANKL, underproduction of osteoprotegerin, and a resultant increase in osteoclastic bone resorption.13-15 Inflammation and immune dysregulation in PWH can occur in a variety of ways. Among those who are not receiving ART, low CD4+ T-cell counts and high levels of viremia are associated with chronic inflammation. Furthermore, in PWH who recently initiated ART, immune reconstitution appears to paradoxically increase BMD loss. Within 12 weeks of starting ART, RANKL and other markers of bone resorption increased by 200% in parallel with CD4+ T-cell recovery and increased levels persisted through 24 weeks.16 A compensatory increase in bone formation was also noted after ART initiation.

Effect of ART on BMD The effect of ART on BMD is unique in that ART appears to be associated with worse bone-related clinical outcomes than HIV replication itself. In the Strategic Timing of AntiRetroviral Treatment (START) Bone Mineral Density substudy, immediate ART resulted in worse BMD loss in the hip and spine compared with deferred ART over a median follow-up of 2.2 years (Figure 2.1).17 Despite these results, guidelines do recommend early initiation of ART in PWH. 16

Similarly, in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy, more ART exposure was correlated with increased BMD loss. PWH who received continuous ART had more BMD loss in the hip and spine than people who received intermittent ART.18 In both the START and SMART studies, no drug-specific association was found for BMD loss.17,18 In randomized clinical comparative studies, however, tenofovir disoproxil fumarate (TDF) has been associated with substantially more bone loss than other ART agents.19 The prodrug of TDF, tenofovir alafenamide (TAF), has less effect on BMD. After 144 weeks of treatment, hip BMD loss and spine BMD loss were significantly greater among participants receiving TDF than among those given TAF (Figure 2.2).

Moreover, more participants receiving TAF recovered from osteopenia and osteoporosis than participants receiving TDF.20 Boosted protease inhibitors are another drug class associated with a higher rate of BMD loss than nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs).21 Regimens containing boosted atazanavir were associated with a greater decrease in lumbar spine BMD than efavirenz-containing regimens.22

Managing Low BMD Among PWH Screening for Low BMD Recommendations for screening, assessing, managing, and monitoring BMD are outlined in Figure 2.3. Briefly, patients with major risk of fragility fracture are assessed by the Fracture Risk Assessment Tool (FRAX) score every 2 to 3 years to determine whether patients should be screened by dual-energy X-ray absorptiometry (DXA) for low BMD (see link to supplementary video 4).

VIDEO 4: Screening for Low BMD in PHW  Paul E. Sax, MD

Tailoring ART Regimens Among PWH With Low BMD

Switching from TDF to TAF is the most important change for people with low BMD who are currently receiving TDF. Switching from a TDF-containing regimen to a TAF-containing regimen resulted in a 2.2% increase in spine BMD and a 2.9% increase in hip BMD over 96 weeks. Moreover, in nearly one quarter of participants, osteoporosis or osteopenia was reversed after the switch.23 Another important consideration for people with low BMD is to avoid protease inhibitor–based regimens in favor of integrase inhibitor–based regimens to decrease BMD loss and optimize the chance for osteoporosis reversal.

Treating Low BMD Low BMD can be treated among PWH in a similar fashion to the general population. Calcium and vitamin D supplements should be considered. Because calcium supplements can interfere with integrase inhibitor absorption, patients receiving both calcium inhibitors and integrase inhibitors should be coached to take the integrase inhibitor at least 2 hours prior to calcium supplementation and at meal time.24 For PWH who are at high risk for fracture, bisphosphonates should be considered. Among PWH, bisphosphonates are generally well tolerated and have been shown to increase BMD in the lumbar spine and hip.25

Key Clinical Highlights • PWH are at high risk for low BMD because of HIV infection, ART toxicity, and non-HIV–related risk factors • BMD loss is associated with a high risk of morbidity and mortality, and PWH older than 40 years should be evaluated for risk for BMD using FRAX • TDF in particular and some protease inhibitors are associated with higher risk of BMD loss; switch to nonTDF containing regimens should be initiated among PWH who have low BMD

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13. 14. 15. 16. 17.

18. 19. 20.

21. 22.

23.

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Gonciulea A, Wang R, Althoff KN, et al. An increased rate of fracture occurs a decade earlier in HIV+ compared with HIV- men. AIDS. 2017;31(10):1435-1443. Tebas P, Powderly WG, Claxton S, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000;14(4):F63-67. Hansen A-BE, Gerstoft J, Kronborg G, et al. Incidence of low and high-energy fractures in persons with and without HIV infection: a Danish population-based cohort study. AIDS. 2012;26(3):285-293. Arnsten JH, Freeman R, Howard AA, Floris-Moore M, Lo Y, Klein RS. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS. 2007;21(5):617-623. Prieto-Alhambra D, Guerri-Fernandez R, De Vries F, et al. HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study. J Acquir Immune Defic Syndr. 2014;66(1):90-95. Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int. 2006;17(12):1726-1733. Lewis JR, Hassan SKZ, Wenn RT, Moran CG. Mortality and serum urea and electrolytes on admission for hip fracture patients. Injury. 2006;37(8):698-704. Wing EJ. HIV and aging. Int J Infect Dis. 2016;53:61-68. Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015;60(8):1242-1251. Liu AY, Vittinghoff E, Sellmeyer DE, et al. Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco. PloS One. 2011;6(8):e23688. Premaor MO, Compston JE. The hidden burden of fractures in people living with HIV. JBMR Plus. 2018;2(5):247-256. Koh J-M, Khang Y-H, Jung C-H, et al. Higher circulating hsCRP levels are associated with lower bone mineral density in healthy preand postmenopausal women: evidence for a link between systemic inflammation and osteoporosis. Osteoporos Int. 2005;16(10): 1263-1271. Vikulina T, Fan X, Yamaguchi M, et al. Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats. Proc Natl Acad Sci. 2010;107(31):13848-13853. Seminari E, Castagna A, Soldarini A, et al. Osteoprotegerin and bone turnover markers in heavily pretreated HIV-infected patients. HIV Med. 2005;6(3):145-150. Brown TT, Chen Y, Currier JS, et al. Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2013;63(3):323-330. Ofotokun I, Titanji K, Vunnava A, et al. Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS. 2016;30(3):405-414. Hoy JF, Grund B, Roediger M, et al. Immediate initiation of antiretroviral therapy for HIV infection accelerates bone loss relative to deferring therapy: findings from the START bone mineral density substudy, a randomized trial. J Bone Miner Res. 2017;32(9): 1945-1955. Grund B, Peng G, Gibert CL, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS. 2009;23(12):1519-1529. Stellbrink H-J, Rizzardini G, Sprenger HG, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963-972. Arribas JR, Thompson M, Sax PE, et al. Brief report: randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: week 144 results. J Acquir Immune Defic Syndr. 2017;75(2):211-218. Duvivier C, Kolta S, Assoumou L, et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naive patients. AIDS. 2009;23(7):817-824. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011;203(12):1791-1801. DeJesus E, Haas B, Segal-Maurer S, et al. Superior efficacy and improved renal and bone safety after switching from a tenofovir disoproxil fumarate- to a tenofovir alafenamide-based regimen through 96 weeks of treatment. AIDS Res Hum Retroviruses. 2018;34(4):337-342. Song I, Borland J, Arya N, Wynne B, Piscitelli S. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol. 2015;55(5):490-496. Pinzone MR, Moreno S, Cacopardo B, Nunnari G. Is there enough evidence to use bisphosphonates in HIV-infected patients? A systematic review and meta-analysis. AIDS Reviews. 2014;16(4):213-222.

HIV and Related Cancers

Paul E. Sax, MD People with HIV (PWH) are at increased risk for developing cancer. As with most of the aging-related comorbidities among PWH, the presentation and incidence of cancers has shifted with the introduction of antiretroviral therapy (ART). The incidence of AIDS-defining cancers (eg, Kaposiâ&#x20AC;&#x2122;s sarcoma) has decreased in conjunction with the decline in AIDS diagnoses and AIDS-related deaths.1,2 During the same time period, the incidence of non-AIDSâ&#x20AC;&#x201C;defining cancers has increased (Figure 3.1).3,4 Cancer now accounts for one third of all deaths among PWH.5

Compared with the general population, PWH are at greater risk for cancers caused by viruses (eg, anal cancer) and other types of cancers (eg, lung cancer) (Table 3.1). Furthermore, AIDS-defining cancers continue to occur at an elevated rate among PWH. The standardized incidence ratios for Kaposi sarcoma and non-Hodgkin lymphoma are 192 and 76.4, respectively.3

Causes of Malignancy Among PWH A total of 40% of cancers among PWH are attributable to viral infections compared with 5% of cancers among the general population.8 The shared transmission modalities among HIV and oncogenic viruses may be one of the reasons for the increased number of virus-related malignancies among PWH. The rates of human papillomavirus, hepatitis B, and hepatitis C infection are all far higher among PWH (Table 3.2). It is also likely that the HIV-mediated immune dysregulation impacts the high rate of malignancy.9,10 By combating this dysregulation, use of ART and viral suppression decreases the risk of cancer.11 Oncogenic viruses typically cause cancer by interfering with host cell regulation of apoptosis and proliferation. Because HIV infection impairs immune function, the replication of oncogenic viruses may go unchecked.13,14 Furthermore, PWH often have chronic inflammation, which has long been linked to oncogenesis (see link to supplementary video 5).15 Cancers with no identified viral etiology are also more common among PWH, but the reason for this is controversial. It is possible that immune dysregulation and chronic inflammation lead to an increase in cancers among PWH; however, it is also undeniable that risk factors for various cancers are far more prevalent among PWH (Table 3.2).12

VIDEO 5: Immune Dysregulation and Malignancyâ&#x20AC;¨ Paul E. Sax, MD

Cancer Screening for PWH The approach to cancer screening for PWH is similar to the approach for the general population. When considering screening PWH for cancer, one must balance cancer risk and the benefits of screening with the harms of overdiagnosis and unnecessary testing. As shown in Table 3.3, many of the recommendations from the New York State Department of Health AIDS Institute and the Infectious Diseases Society of America mirror those from other agencies for the general population. However, the majority of these recommendations are based on weak or moderate evidence, many are outdated, and some cancer types have no HIV-specific recommendations. For example, no HIV-specific recommendation for lung cancer is available, but a recent study has demonstrated that lung cancer screening for PWH would reduce mortality related to lung cancer for PWH with CD4+ T-cell counts of at least 500 cells/µL, and widening the screening age from 45 to 77 years (compared with 55 to 80 years in the general population) would result in the greatest reduction in mortality—but also the most overdiagnosis.16

Tailoring ART Among PWH Diagnosed With Cancer PWH who have cancer can—and should—continue to receive ART during chemotherapy; however, modifications to the regimen may be necessary.28 Continuation of ART during chemotherapy is associated with improved tolerance of chemotherapy, better response rates, and increased survival.29,30 The potential for drug-drug interactions between ART and chemotherapy stem from the metabolism of the agents and overlapping adverse events (see link to supplementary video 6). Like many ART agents, many chemotherapy agents are metabolized by enzymes in the cytochrome P450 pathway of the liver. Competition for this pathway could directly impact efficacy and tolerability of both ART and chemotherapy; therefore, avoiding the pharmacokinetic boosters ritonavir and cobicistat is important. In a retrospective study of ART regimens, nonnucleoside reverse transcriptase

VIDEO 6: Multidisciplinary Care in Cancer in PWH  Paul E. Sax, MD

inhibitors (NNRTIs) and integrase inhibitors were better tolerated and more efficacious among patients receiving chemotherapy than protease inhibitors (Figure 3.2).31

Key Clinical Highlights • The incidence of AIDS-defining cancers is decreasing, but the incidence of non–AIDS-defining cancers is increasing • Screening for cancer should usually follow the recommendations available for the general population; screening for cervical cancer should start earlier and continue past the age of 65 years • PWH should receive ART during chemotherapy • Regimens that include the pharmacokinetic boosters ritonavir or cobicistat may interfere with the efficacy and tolerability of ART and chemotherapy

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Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ. Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst. 2002;94(16):1204-1210. Palella FJ, Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853-860. Clifford GM, Rickenbach M, Polesel J, et al. Cancer risk in the Swiss HIV cohort study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst. 2005;97(6):425-432. Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762. Morlat P, Roussillon C, Henard S, et al. Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000. AIDS. 2014;28(8):1181-1191. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728-736. Rubinstein PG, Aboulafia DM, Zloza A. Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. AIDS (London, England). 2014;28(4):453. de Martel C, Shiels MS, Franceschi S, et al. Cancers attributable to infections among adults with HIV in the United States. AIDS. 2015;29(16):2173-2181. Gerstoft J, Obel N, Helleberg M, et al. CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV. Clin Infect Dis. 2013;57(2):314-321. Kowalkowski MA, Mims MP, Amiran ES, Lulla P, Chiao EY. Effect of immune reconstitution on the incidence of HIV-related Hodgkin lymphoma. PloS One. 2013;8(10):e77409. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795-807. Park LS, Hernández-Ramírez RU, Silverberg MJ, Crothers K, Dubrow R. Prevalence of non-HIV cancer risk factors in persons living with HIV/AIDS: a meta-analysis. AIDS. 2016;30(2):273-291. Corallini A, Altavilla G, Pozzi L, et al. Systemic expression of HIV-1 tat gene in transgenic mice induces endothelial proliferation and tumors of different histotypes. Cancer Res. 1993;53(22):5569-5575. Borges Á H, Silverberg MJ, Wentworth D, et al. Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS. 2013;27(9):1433-1441. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860. Kong CY, Sigel K, Criss SD, et al. Benefits and harms of lung cancer screening in HIV-infected individuals with CD4+ cell count at least 500 cells/µl. AIDS. 2018;32(10):1333-1342. Moscicki AB, Darragh TM, Berry-Lawhorn JM, et al. Screening for anal cancer in women. J Low Genit Tract Dis. 2015;19(3 suppl 1):S27S42. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2013;58(1):e1-e34. Siu AL, Force obotUSPST. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164(4):279-296. Committee on Practice Bulletins—Gynecology. Practice Bulletin Number 179: Breast cancer risk assessment and screening in average-risk women. Obstet Gynecol. 2017;130(1):e1-e16. Qaseem A, Lin JS, Mustafa RA, Horwitch CA, Wilt TJ, Clinical Guidelines Committee of the American College of Physicians. Screening for breast cancer in average-risk women: a guidance statement from the American College of Physicians. Ann Intern Med. 2019. [Epub ahead of print] Medical Care Criteria Committee. Preventive medicine. https://www.hivguidelines.org/hiv-care/primary-care-approach/#tab_5. March 2011. Accessed April 10, 2019. US Preventative Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320(7):674-686.

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American College of Obstetricians and Gynecologistsâ&#x20AC;&#x2122; Committee on Practice Bulletinsâ&#x20AC;&#x201C;Gynecology. Practice bulletin no. 167: gynecologic care for women and adolescents with human immunodeficiency virus. Obstet Gynecol. 2016;128(4):e89-e110. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2016;315(23):2564-2575. Moyer VA. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(5): 330-338. US Preventative Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(18):1901-1913. Reid E, Suneja G, Ambinder RF, et al. Cancer in people living with HIV, version 1.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(8):986-1017. Hessol NA, Pipkin S, Schwarcz S, Hessol NA, Pipkin S, Schwarcz S. The impact of highly active antiretroviral therapy on non-AIDSdefining cancers among adults with AIDS. Amer J Epidemiol. 2007;165:1143-1153. Gerard L, Galicier L, Maillard A, Gerard L, Galicier L, Maillard A. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. J Acquir Immune Defic Syndr. 2002;30:478-484. Torres HA, Rallapalli V, Saxena A, et al. Efficacy and safety of antiretrovirals in HIV-infected patients with cancer. Clin Microbiol Infect. 2014;20(10):O672-O679.

Neurocognitive Impairment and Depression in HIV

Paul E. Sax, MD HIV infection is associated with a collection of neuropsychiatric disorders that include behavioral abnormalities, motor dysfunction, dementia, and executive function impairment. Collectively, these clinical manifestations are known as HIV-associated neurocognitive disorders (HAND). Although the presentation and severity of HAND has changed since the introduction of antiretroviral therapy (ART), the overall prevalence has remained steady at about 50%.1,2 In the pre-ART era, the most severe form of HAND was more common. In contrast, the asymptomatic form of HAND has become more common since the introduction of ART (Figure 4.1).2 The criteria for classifying HAND subtypes are shown in Table 4.1. In addition to HAND, people with HIV (PWH) often have comorbid depression and anxiety.3

Aging appears to play an important role in neurocognitive decline among PWH.6,7 HIV-associated dementia (HAD) occurs 3 times more frequently in PWH who are 50 years or older compared with those aged 20 to 39 years.8 Relative to the general population, the neurocognitive changes seem to be amplified among PWH. The rate of verbal memory decline is greater among PWH than in the general populationâ&#x20AC;&#x201D;so much so that middleaged PWH may be cognitively similar to people without HIV who are 70 years or older.9 Even among PWH using ART with continued virologic suppression, the odds of neurocognitive impairment increases by 20% with each decade of increased age.10

Pathophysiology of HAND Prior to the introduction of ART, HAND was associated with encephalitis and neuronal loss. In the pre-ART era, 54% of autopsies revealed encephalitis compared with 15% in the ART era.11 Encephalitis and neuronal loss are no longer common and do not explain the high level of mild neurocognitive disorder (MND) and ANI reported today. It is likely that neuropsychiatric dysfunction stems from functional impairment of the neurons due to subtler changes in the brain.12,13 Chronic inflammation appears to be an important trigger for neuropsychiatric decline among PWH. Activated monocytes facilitate the virus crossing the blood-brain barrier and establishing infection within central nervous system (CNS) cells, including macrophages, microglia, and astrocytes.14 Altered blood-brain barrier permeability occurs early in HIV infection and has been associated with markers of neuronal damage and astrocytosis.15,16 Furthermore, viral proteins secreted by infected cells can circulate within the CNS, resulting in the release of cytokines. Proinflammatory cytokines then activate microglia and astrocytes, leading to a feedback loop of immune activation and inflammation. Activated immune cells within the CNS further contribute to neuroinflammation by releasing neurotoxic proteins that can lead to neuropsychiatric dysfunction.17 Prompt initiation of ART appears to be associated with a lower risk of HAND.18 As can be seen in Table 4.2, in addition to HIV-associated risk factors, many of the conditions that can cause cognitive dysfunction on their own are risk factors for HAND.

ART and HAND It is unclear whether the extent of ART penetration into the CNS impacts clinical outcomes among PWH. ART regimens with high CNS penetration have been associated with lower viral loads in the cerebrospinal fluid (CSF)20; however, viral suppression in the CSF has not been linked to reduced HAND independent of viral suppression in the plasma. Furthermore, in a randomized controlled study that optimized ART regimens based on high CNS penetration, no neurocognitive benefit was reported.21 Given the lack of benefit for using highly penetrant ART regimens, the current recommendation is to use the simplest, most potent, and least toxic ART regimens for patients with or without HAND.19 There is also some concern that highly penetrant ART may lead to worse neurocognitive function because of the potential for neurotoxic adverse events. Efavirenz, which is highly penetrant into the CNS, has been associated with neurotoxic effects in vitro and negative neurocognitive effects among patients.22-25 If patients are exhibiting neuropsychiatric decline, a switch away from efavirenz may be warranted. Other ART regimens have fewer neuropsychiatric adverse events; doravirine has demonstrated a lower rate of treatment-emergent adverse events compared with efavirenz, and doravirine and darunavir demonstrated a similar rate of neuropsychiatric adverse events.26,27

Depression and HIV Comorbid depression is the most common neuropsychiatric condition among PWH. Compared with the general population, PWH have up to a 5-fold higher prevalence of depression.28 Socioeconomic and demographic factors overlap considerably among PWH and people with clinical depression, so it is unsurprising that the prevalence of depression is high among PWH.3 Depression can negatively impact the efficacy of HIV treatment and substantially impair quality of life.29 PWH with clinical depression are 1.8-times more likely to be nonadherent to ART than those without depression.30 Indeed, treating depression with antidepressants not only reduces symptoms of depression but also has been shown to improve viral suppression by 16% and increase CD4+ T-cell levels by a mean of 39 cells/ÂľL.31 Therefore, PWH should be screened for depression at each visit using validated screening questionnaires. Those patients with clinical depression should be treated with evidence-based therapy, including antidepressants and cognitive behavioral therapy where appropriate. In the absence of a response,

psychiatric referral may be appropriate (see link to supplementary video 7).

Key Clinical Highlights • Aging plays a significant role in HAND • Chronic inflammation may trigger neuropsychiatric decline in PWH • The extent of ART penetration into the CNS may or may not play a role in neurocognitive decline; there may be a risk of increased neurocognitive symptoms with certain neurotoxic ART agents, specifically efavirenz

VIDEO 7: Multidisciplinary Care for Depression in PWH  Paul E. Sax, MD

• Depression is common in PWH and can affect both treatment efficacy and adherence

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Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17(1):3-16. Heaton RK, Clifford DB, Franklin DR Jr, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology. 2010;75(23):2087-2096. Nanni MG, Caruso R, Mitchell AJ, Meggiolaro E, Grassi L. Depression in HIV infected patients: a review. Curr Psychiatry Rep. 2015;17(1): 530. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol. 2010;67(6):699-714. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799. Goodkin K, Miller EN, Cox C, et al. Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study. Lancet HIV. 2017;4(9):e411-e422. Komatsu K, Kinai E, Sakamoto M, et al. Various associations of aging and long-term HIV infection with different neurocognitive functions: detailed analysis of a Japanese nationwide multicenter study. J Neurovirol. 2019. Valcour V, Shikuma C, Shiramizu B, et al. Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort. Neurology. 2004;63(5):822-827. Seider TR, Luo X, Gongvatana A, et al. Verbal memory declines more rapidly with age in HIV infected versus uninfected adults. J Clin Exp Neuropsychol. 2014;36(4):356-367. Coban H, Robertson K, Smurzynski M, et al. Impact of aging on neurocognitive performance in previously antiretroviral-naive HIVinfected individuals on their first suppressive regimen. AIDS. 2017;31(11):1565-1571. Vago L, Bonetto S, Nebuloni M, et al. Pathological findings in the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies. AIDS. 2002;16(14):1925-1928. Chang L, Wong V, Nakama H, et al. Greater than age-related changes in brain diffusion of HIV patients after 1 year. J Neuroimmune Pharmacol. 2008;3(4):265-274. Seider TR, Gongvatana A, Woods AJ, et al. Age exacerbates HIV-associated white matter abnormalities. J Neurovirol. 2016;22(2): 201-212. Burdo TH, Lackner A, Williams KC. Monocyte/macrophages and their role in HIV neuropathogenesis. Immunol Rev. 2013;254(1):102-113. Calcagno A, Romito A, Atzori C, et al. Blood brain barrier impairment in HIV-positive naive and effectively treated patients: immune activation versus astrocytosis. J Neuroimmune Pharmacol. 2017;12(1):187-193. Calcagno A, Atzori C, Romito A, et al. Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients. J Neurovirol. 2016;22(1):88-92. Hong S, Banks WA. Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun. 2015;45:1-12. Crum-Cianflone NF, Moore DJ, Letendre S, et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIVinfected persons. Neurology. 2013;80(4):371-379. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(4):234-248.

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Letendre SL, Mills AM, Tashima KT, et al. ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects. Clin Infect Dis. 2014;59(7):1032-1037. Ellis RJ, Letendre S, Vaida F, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder. Clin Infect Dis. 2014;58(7):1015-1022. Tovar-y-Romo LB, Bumpus NN, Pomerantz D, et al. Dendritic spine injury induced by the 8-hydroxy metabolite of efavirenz. J Pharmacol Exp Ther. 2012;343(3):696-703. Ciavatta VT, Bichler EK, Speigel IA, et al. In vitro and ex vivo neurotoxic effects of efavirenz are greater than those of other common antiretrovirals. Neurochem Res. 2017;42(11):3220-3232. Brown LA, Jin J, Ferrell D, et al. Efavirenz promotes Î˛-secretase expression and increased AÎ˛1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND). PLoS One. 2014;9(4):e95500. Ma Q, Vaida F, Wong J, et al. Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol. 2016;22(2):170-178. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVEFORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018; 5(5):e211-e220. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc. 2014;17(4 Suppl 3):19532. Feuillet P, Lert F, Tron L, Aubriere C, Spire B, Dray-Spira R. Prevalence of and factors associated with depression among people living with HIV in France. HIV Med. 2017;18(6):383-394. Millar BM, Starks TJ, Gurung S, Parsons JT. The impact of comorbidities, depression, and substance use problems on quality of life among older adults living with HIV. AIDS Behav. 2017;21(6):1684-1690. Grenard JL, Munjas BA, Adams JL, et al. Depression and medication adherence in the treatment of chronic diseases in the United States: a meta-analysis. J Gen Intern Med. 2011;26(10):1175-1182. Mills JC, Harman JS, Cook RL, et al. Comparative effectiveness of dual vs. single-action antidepressants on HIV clinical outcomes in HIV-infected people with depression. AIDS. 2017;31(18):2515-2524.

Renal Disease in Aging Patients With HIV

Chris Longenecker, MD People with HIV (PWH) are at elevated risk for renal disease, which can manifest in a variety of ways, from acute kidney injury (AKI) to chronic kidney disease (CKD). Other HIV-associated kidney disorders include HIVassociated nephropathy and antiretroviral-associated kidney toxicity (Table 5.1).

HIV-associated nephropathy was the first kidney manifestation of HIV that was identified and is associated with proteinuria and renal dysfunction. Since the introduction of effective antiretroviral therapy (ART), the prevalence of HIV-associated nephropathy has decreased by about 60%.2 As the prevalence of HIVassociated nephropathy has declined and then plateaued, so too has the incidence of HIV-associated endstage renal disease (ESRD); however, the prevalence of ESRD in this population is now increasing as PWH live longer.1 Furthermore, the incidences of other types of renal disease, such as AKI, are increasing during the ART era; some ART regimens are known to be nephrotoxic (Figure 5.1).3

Pathophysiology of Renal Disease in HIV The pathophysiology of renal disease among PWH is multifactorial and dependent on the interplay of HIV replication, ART, traditional risk factors, and genetics. For example, polymorphisms in the APOL1 gene increase the risk of renal disease among PWH. APOL1 is a protein constituent of high-density lipoprotein and plays a role in innate immunity. APOL1 risk variants confer protection against the parasitic infection African trypanosomiasis and are more common among West Africans and African Americans than among people of European descent.4,5 Although ART is known to extend the life expectancy of PWH, these drugs often have adverse effects on the kidneys. Indinavir, darunavir, and atazanavir have been associated with crystal nephropathy caused by poor drug solubility in alkaline urine.6,7 Tenofovir disoproxil fumarate (TDF) has been associated with renal tubular dysfunction leading to Fanconi syndrome, nephrogenic diabetes insipidus, acute tubular necrosis, and, eventually, CKD.8,9 In contrast, the prodrug of TDF, tenofovir alafenamide (TAF) is associated with substantially less renal toxicity than TDF.10 Additional HIV-related risk factors for kidney disease have been identified. Uncontrolled HIV infection with low CD4+ T-cell count or high viral load has been implicated in renal disease.11 Because ART can control HIV infection and reduce these risk factors, ART is still associated with an overall reduced risk of kidney disease despite the known nephrotoxic effects of some agents. In parallel with decreasing incidence of HIVassociated nephropathy, HIV-associated immune-mediated kidney disease is becoming more common. The precise mechanisms of this disease are unclear, but research suggests that antibody responses to HIV

epitopes and B-cell activation leads to the formation of immune complexes that are deposited in glomerular capillaries.12 Traditional risk factors for kidney disease are important contributors to the high prevalence of renal disease among PWH. Examples of these risk factors include diabetes, hypertension, and drug use; these various factors can greatly impact whether PWH develop renal disease. As with the general population, CVD is often comorbid with CKD and is another risk factor for developing renal dysfunction (Figure 5.2; see link to supplementary video 8).13

VIDEO 8: Cardio-Renal Axisâ&#x20AC;¨ Chris Longenecker, MD

Management of Renal Disease in PWH CKD Diagnostic Criteria and Testing Diagnosing renal impairment in PWH requires familiarity with the various diagnostic and classification criteria available for kidney disease. The criteria for CKD are outlined in Table 5.2 and must be present for more than 3 months and have implications for patient health.14 Glomerular filtration rate (GFR) is challenging to accurately estimate among PWH. GFR is typically calculated using mathematic formulas validated in the general population. These formulas rely heavily on serum creatinine levels.15,16 In PWH, however, creatinine levels may not be a good measure of GFR, as newer ART (eg, dolutegravir, cobicistat) interfere with the secretion of creatinine in the proximal tubule, increasing serum creatinine levels without affecting the actual GFR.17 There has been some interest in considering cystatin C levels to estimate GFR, but studies have had mixed results on whether cystatin Câ&#x20AC;&#x201C;based estimations are more accurate than creatinine-based estimations.18-20 One option for clinicians attempting to estimate GFR in PWH receiving ART is to follow serum creatinine trends over time to determine the impact of ART on GFR estimations.

Monitoring for Renal Function Because of the elevated risk for renal disease, PWH should be monitored for renal function every 3 to 12 months, depending on baseline function, risk factors, and ART regimen. Risk for CKD among PWH can be calculated using the D:A:D (Data collection on Adverse events of Anti-HIV Drugs) Full or Short Risk Score models (Table 5.3). The scores from D:A:D risk models range from low risk (score <0) to high risk (score >5) and calculators can be found online.21

Selecting and Modifying ART for Renal Insufficiency For people with renal insufficiency or a high risk of CKD, TAF may be preferable to TDF to ensure efficacy and reduce the risk of renal damage. Similarly, atazanavir and indinavir may be avoided in people at high risk for kidney disease. Suggestions for other dosage adjustments among PWH who have renal insufficiency are outlined in Table 5.4.22

Considering ART dosage adjustments among PWH with renal insufficiency is particularly important in the context of the aging HIV-infected population. As PWH age, the proportion of comorbidities increases substantially, necessitating consideration of multimorbidity, polypharmacy, and the adherence and pill fatigue issues that accompany these issues.22-25

Key Clinical Highlights • The incidence of renal disease has decreased with ART use, but the prevalence is rising • The D:A:D risk models can be used to estimate risk of kidney disease among PWH • PWH should be screened for renal function every 3 to 12 months depending on the results of the D:A:D risk assessment, baseline kidney function, and ART regimen • Estimated GFR may not accurately reflect actual GFR; longitudinal trends in estimated GFR may be more informative • Switching from TDF to TAF may reduce the risk of renal damage

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Cohen SD, Kopp JB, Kimmel PL. Kidney diseases associated with human immunodeficiency virus infection. N Engl J Med. 2017;377(24):2363-2374. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD. Highly active antiretroviral therapy and the incidence of HIV-1associated nephropathy: a 12-year cohort study. AIDS. 2004;18(3):541-546. Nadkarni GN, Patel AA, Yacoub R, et al. The burden of dialysis-requiring acute kidney injury among hospitalized adults with HIV infection: a nationwide inpatient sample analysis. AIDS. 2015;29(9):1061-1066. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010;329(5993):841-845. Kopp JB, Nelson GW, Sampath K, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol. 2011;22(11):2129-2137. Martinez F, Mommeja-Marin H, Estepa-Maurice L, et al. Indinavir crystal deposits associated with tubulointerstitial nephropathy. Nephrol Dial Transplant. 1998;13(3):750-753. de Lastours V, Ferrari Rafael De Silva E, Daudon M, et al. High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients. J Antimicrob Chemother. 2013;68(8):1850-1856. Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis. 2005;40(8):1194-1198. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. 2010;51(5):496-505. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014;67(1):52-58. Krawczyk CS, Holmberg SD, Moorman AC, Gardner LI, McGwin GJ, HIV Outpatient Study Group. Factors associated with chronic renal failure in HIV-infected ambulatory patients. AIDS. 2004;18(16):2171-2178. Nobakht E, Cohen SD, Rosenberg AZ, Kimmel PL. HIV-associated immune complex kidney disease. Nat Rev Nephrol. 2016;12:291. Boyd MA, Mocroft A, Ryom L, et al. Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study. PLoS Med. 2017;14(11):e1002424. Eknoyan G, Lameire N, Eckardt K, et al. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013;3(1):5-14. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-254. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61(1):32-40. Inker LA, Wyatt C, Creamer R, et al. Performance of creatinine and cystatin C GFR estimating equations in an HIV-positive population on antiretrovirals. J Acquir Immune Defic Syndr. 2012;61(3):302-309. Gagneux-Brunon A, Delanaye P, Maillard N, et al. Performance of creatinine and cystatin C-based glomerular filtration rate estimating equations in a European HIV-positive cohort. AIDS. 2013;27(10):1573-1581. Palich R, Tubiana R, Abdi B, et al. Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in HIV-1-infected patients treated with dolutegravir-based ART. J Antimicrob Chemother. 2018;73(7):1935-1939.

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Mocroft A, Lundgren JD, Ross M, et al. Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study. PLoS Med. 2015;12(3):e1001809. Burgess MJ, Zeuli JD, Kasten MJ. Management of HIV/AIDS in older patients-drug/drug interactions and adherence to antiretroviral therapy. HIV AIDS. 2015;7:251-264. Gleason LJ, Luque AE, Shah K. Polypharmacy in the HIV-infected older adult population. Clin Interv Aging. 2013;8:749-763. Halloran MO, Boyle C, Kehoe B, et al. Polypharmacy and drug-drug interactions in older and younger people living with HIV: the POPPY study. Antivir Ther. 2019. [Epub ahead of print]. Claborn KR, Meier E, Miller MB, Leffingwell TR. A systematic review of treatment fatigue among HIV-infected patients prescribed antiretroviral therapy. Psychol Health Med. 2015;20(3):255-265.

Clinical Resource Center™

Clinical Practice Guidelines Recommendations for evaluation and management of bone disease in HIV. Brown TT, Hoy J, Borderi M, et al. Clin Infect Dis. 2015;60(8):1242-1251. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400413/

Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA. Clin Infect Dis. 2013;58(1):e1-e34. https://academic.oup.com/cid/article/58/1/e1/374007

Preventive medicine. Medical Care Criteria Committee. https://www.hivguidelines.org/hiv-care/primary-care-approach/#tab_5

Practice bulletin no. 167: gynecologic care for women and adolescents with human immunodeficiency virus. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Gynecology. Obstet Gynecol. 2016;128(4):e89-e110. https://www.acog.org/Clinical-Guidance-and-Publications/Practice-Bulletins/Committee-on-Practice-Bulletins-Gynecology/ Gynecologic-Care-for-Women-and-Adolescents-With-Human-Immunodeficiency-Virus?IsMobileSet=false

Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. US Department of Health and Human Services. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0

KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Eknoyan G, Lameire N, Eckardt K, et al. Kidney Int. 2013;3(1):5-14. https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf 39

Patient and Caregiver Resources AIDS Map Resources NAM Publications https://www.aidsmap.com/resources

Resources for Persons Living with HIV Centers for Disease Control and Prevention https://www.cdc.gov/hiv/basics/livingwithhiv/resources.html

HIV Resources National Institutes of Health https://www.oar.nih.gov/hiv-resources/public

Suggested Readings Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults. Althoff KN, McGinnis KA, Wyatt CM, et al. Clin Infect Dis. 2015;60(4):627-638. https://academic.oup.com/cid/article/60/4/627/2895648

Brief report: randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/ C/F) for initial HIV-1 treatment: week 144 results. Arribas JR, Thompson M, Sax PE, et al. J Acquir Immune Defic Syndr. 2017;75(2):211-218. https://journals.lww.com/jaids/fulltext/2017/06010/Brief_Report___Randomized,_Double_Blind_Comparison.10.aspx

Cardiovascular disease (CVD) and chronic kidney disease (CKD) event rates in HIV-positive persons at high predicted CVD and CKD risk: A prospective analysis of the D:A:D observational study. Boyd MA, Mocroft A, Ryom L, et al. PLoS Med. 2017;14(11):e1002424. https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002424

Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals. Brown TT, Chen Y, Currier JS, et al. J Acquir Immune Defic Syndr. 2013;63(3):323-330. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693854/

Management of HIV/AIDS in older patients-drug/drug interactions and adherence to antiretroviral therapy. Burgess MJ, Zeuli JD, Kasten MJ. HIV AIDS. 2015;7:251-264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629973/

Kidney diseases associated with human immunodeficiency virus infection. Cohen SD, Kopp JB, Kimmel PL. N Engl J Med. 2017;377(24):2363-2374. https://www.nejm.org/doi/full/10.1056/NEJMra1508467

Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIVinfected patients. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Clin Infect Dis. 2010;51(5):496-505. https://academic.oup.com/cid/article/51/5/496/332916

Superior efficacy and improved renal and bone safety after switching from a tenofovir disoproxil fumarate- to a tenofovir alafenamide-based regimen through 96 weeks of treatment. DeJesus E, Haas B, Segal-Maurer S, et al. AIDS Res Hum Retroviruses. 2018;34(4):337-342. https://www.liebertpub.com/doi/abs/10.1089/AID.2017.0203

Cardiac dysfunction among people living with HIV: a systematic review and meta-analysis. Erqou S, Lodebo BT, Masri A, et al. JACC Heart Fail. 2019;7(2):98-108. https://www.sciencedirect.com/science/article/pii/S2213177918307649

Immediate initiation of antiretroviral therapy for HIV infection accelerates bone loss relative to deferring therapy: findings from the START bone mineral density substudy, a randomized trial. Hoy JF, Grund B, Roediger M, et al. J Bone Miner Res. 2017;32(9):1945-1955. https://onlinelibrary.wiley.com/doi/full/10.1002/jbmr.3183

Initiation of antiretroviral therapy in early asymptomatic HIV infection. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. N Engl J Med. 2015;373(9):795-807. https://www.nejm.org/doi/full/10.1056/NEJMoa1506816

Factors associated with chronic renal failure in HIV-infected ambulatory patients. Krawczyk CS, Holmberg SD, Moorman AC, et al; HIV Outpatient Study Group. AIDS. 2004;18(16):2171-2178. https://journals.lww.com/aidsonline/Fulltext/2004/11050/Factors_associated_with_chronic_renal_failure_in.9.aspx

Vascular disease and aging in HIV: time to extend the treatment cascade. Longenecker CT. Vasc Med. 2018;23(5):476-477. https://journals.sagepub.com/doi/full/10.1177/1358863X18789767

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. Ma Q, Vaida F, Wong J, et al. J Neurovirol. 2016;22(2):170-178. https://link.springer.com/article/10.1007%2Fs13365-015-0382-7

Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. McArthur JC, Steiner J, Sacktor N, Nath A. Ann Neurol. 2010;67(6):699-714. https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.22053

Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVEFORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Molina JM, Squires K, Sax PE, et al. Lancet HIV. 2018;5(5):e211-e220. https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(18)30021-3/fulltext

Screening for anal cancer in women. Moscicki AB, Darragh TM, Berry-Lawhorn JM, et al. J Low Genit Tract Dis. 2015;19(3 Suppl 1):S27-42. https://journals.lww.com/jlgtd/fulltext/2015/07002/Screening_for_Anal_Cancer_in_Women.1.aspx

Ageing and inflammation in patients with HIV infection. Nasi M, De Biasi S, Gibellini L, et al. Clin Exp Immunol. 2017;187(1):44-52. https://onlinelibrary.wiley.com/doi/full/10.1111/cei.12814

Prevalence of non-HIV cancer risk factors in persons living with HIV/AIDS: a meta-analysis. Park LS, HernĂĄndez-RamĂrez RU, Silverberg MJ, Crothers K, Dubrow R. AIDS. 2016;30(2):273-291. https://journals.lww.com/aidsonline/fulltext/2016/01140/Prevalence_of_non_HIV_cancer_risk_factors_in.14.aspx

The hidden burden of fractures in people living with HIV. Premaor MO, Compston JE. JBMR Plus. 2018;2(5):247-256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139727/

Time trends for risk of severe age-related diseases in individuals with and without HIV infection in Denmark: a nationwide population-based cohort study. Rasmussen LD, May MT, Kronborg G, et al. Lancet HIV. 2015;2(7):e288-298. https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(15)00077-6/fulltext

Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. Sax PE, Zolopa A, Brar I, et al. J Acquir Immune Defic Syndr. 2014;67(1):52-58. https://journals.lww.com/jaids/fulltext/2014/09010/Tenofovir_Alafenamide_Vs__Tenofovir_Disoproxil.9.aspx

HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Saylor D, Dickens AM, Sacktor N, et al. Nat Rev Neurol. 2016;12(4):234-248. https://www.nature.com/articles/nrneurol.2016.27

Efficacy and safety of antiretrovirals in HIV-infected patients with cancer. Torres HA, Rallapalli V, Saxena A, et al. Clin Microbiol Infect. 2014;20(10):O672-O679. https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)65405-7/fulltext

HIV and ischemic heart disease. Vachiat A, McCutcheon K, Tsabedze N, Zachariah D, Manga P. J Am Coll Cardiol. 2017;69(1):73-82. https://www.sciencedirect.com/science/article/pii/S0735109716369674

Recommendations for Managing Drug-Drug Interactions with Statins and HIV Medications. Wiggins BS, Lamprecht DG, Jr., Page RL, 2nd, Saseen JJ. Am J Cardiovasc Drugs. 2017;17(5):375-389. https://link.springer.com/article/10.1007%2Fs40256-017-0222-7

HIV and aging. Wing EJ. Int J Infect Dis. 2016;53:61-68. https://www.ijidonline.com/article/S1201-9712(16)31187-0/fulltext

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