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2 John G. Bartlett, MD Program Chair Professor of Medicine Johns Hopkins University School of Medicine Baltimore, MD

3 Educational Objectives Discuss the epidemiology of HIV, particularly in minority populations Identify special issues related to HIV testing and treatment Outline the risks and benefits of earlier ART initiation and its role in reducing HIV transmission Summarize the latest data on the newer HIV agents, including those in clinical development, and how they may fit into HIV treatment paradigms Define the most important concerns in the long-term management of patients with HIV Discuss critical factors for aging patients with HIV

4 Program Agenda 7:30 PM – 7:35 PM Welcome and Introduction John G. Bartlett, MD, Program Chair 7:35 PM – 8:00 PM Testing & Access to Care: Where Have We Been, Where Do We Need to Be, and How Can We Get There? John G. Bartlett, MD, Moderator Harold W. Jaffe, MD Valerie E. Stone, MD, MPH 8:00 PM – 8:10 PM Panel Discussion & Audience Q & A

5 Program Agenda (Continued) 8:10 PM – 8:35 PM Hit Hard, Hit Early: When to Treat and With What? Professor Brian G. Gazzard, MD, Moderator Calvin J. Cohen, MD, MS Julio Montaner, MD 8:35 PM – 8:45 PM Panel Discussion/Audience Q & A 8:45 PM – 9:10 PM Long-Term Consequences of Immune Activation and ART William G. Powderly, MD, Moderator Sally L. Hodder, MD Jens Lundgren, MD 9:10 PM – 9:25 PM Panel Discussion/Audience Q & A 9:25 PM – 9:30 PM Concluding Remarks and Program Adjournment John G. Bartlett, MD, Program Chair

6 FACULTY Program Chair John G. Bartlett, MD Professor of Medicine Johns Hopkins University School of Medicine Baltimore, MD Faculty Calvin J. Cohen, MD, MS Clinical Instructor Harvard Medical School Research Director CRI New England Boston, MA Brian G. Gazzard, MA, MD, FRCP Consultant Physician and Research Director, HIV/GUM Chelsea & Westminster Hospital London, UK Sally L. Hodder, MD Professor of Medicine New Jersey Medical School University of Medicine and Dentistry of New Jersey Newark, NJ Harold W. Jaffe, MA, MD, FFPH Professor of Public Health University of Oxford Oxford, UK Jens D. Lundgren, MD Professor, Viral Diseases University of Copenhagen Copenhagen, Denmark

7 FACULTY (Continued) Julio Montaner, MD Professor of Medicine Chair in AIDS Research The University of British Columbia Vancouver, BC William G. Powderly, MD Dean of Medicine Head, University College Dublin School of Medicine and Medical Science Dublin, Ireland Valerie E. Stone, MD, MPH Associate Professor of Medicine Director, Womens HIV/AIDS Program Massachusetts General Hospital Boston, MA

8 Physician CME Information Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and HealthmattersCME. PIM is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity.

9 Nursing CE Information Credit Designation This educational activity for 2.0 contact hours is provided by Postgraduate Institute for Medicine (PIM). Accreditation Statements Postgraduate Institute for Medicine is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centers Commission on Accreditation. California Board of Registered Nursing Postgraduate Institute for Medicine is approved by the California Board of Registered Nursing, Provider Number 13485, for 2.4 contact hours

10 Program Sponsorship This activity is jointly sponsored by Postgraduate Institute for Medicine and HealthmattersCME

11 Financial Support This activity is supported by an independent educational grant from Gilead Sciences Medical Affairs

12 Estimated Rates for Adults and Adolescents Living With HIV Infection (not AIDS) 34 States and 5 U.S. Dependent Areas, 2007 Estimated HIV Rate per 100,000 Confidential name-based HIV infection reporting not implemented as of – – – – Data classed using quartiles Total rate: per 100,000 Note: Rates have been adjusted for reporting delays. Inset maps not to scale. HIV/AIDS Surveillance Report, Vol 19, table 11. U.S. Virgin Islands AK HI Puerto Rico American Samoa Northern Mariana Islands Guam DC

13 Awareness of HIV Status in the US 1 CDC. HIV prevalence estimateUnited States, MMWR. 2008;57(39): Hall HI, et al. Estimation of HIV incidence in the United States of America. JAMA. 2008;300: CDC. HIV/AIDS surveillance reportcases of HIV infection and AIDS in the United States and dependent areas, 2007;19. Accessed July 23, HIV estimated prevalence 1 1,056, ,156,400 Undiagnosed 1 232,700 Estimated new annual infections (2006) 2 56,300 From 2004 to 2007, the estimated number of newly diagnosed HIV/AIDS cases increased 15% 3

14 US Population Demographics: Total Population and HIV/AIDS Cases by Race/Ethnicity White 66% Other 6% Black 12% Hispanic 15% Total US Population (2007) (N = million) 1 1 Kaiser Family Foundation, based on Table 3: Annual Estimates of the Population by Sex, Race and Hispanic Origin for the United States: April 1, 2000 to July 1, 2007 (NC-EST ). Population Division, U.S. Census Bureau. 2 CDC. HIV Incidence. Available at Estimated HIV/AIDS Prevalence by Race/Ethnicity (2006) (N = 1,106,400) 2 Black 46% White 35% Hispanic/ Latino 18% Other <2%

15 HIV Testing: Efforts to Change Maryland Law and Practice Maryland Law: –Teams of providers and advocates, but the main lesson is power of the anecdote Maryland Practice: – to 155 Maryland infectious disease (ID) physicians –Lectures – general ID talks –Medscape –Emergency room workers (0.5% test)

16 AUDIENCE RESPONSE QUESTION

17 Which of the following do you most favor regarding testing adults for HIV? 1.Require signed consent 2.Require pre-test & post test counseling (+/- signed consent) 3.Require notification that you are doing the test 4.No requirements

18 You have newly detected HIV, asymptomatic and VL 50,000 c/mL. When would you want HAART to be started based on CD4 count? 1.> <350

19 You would start on 2NRTIs plus? 1.Efavirenz 2.Lopinavir/ritonavir 3.Atazanavir/ritonavir 4.Darunavir/ritonavir 5.Raltegravir

20 HAART is effective for improved outcome with? 1.HIV dementia 2.Cardiovascular events 3.Premature aging

21 Testing and Access to Care: Where Have We Been, Where Do We Need to Be, and How Can We Get There? John G. Bartlett, MD, Moderator Harold W. Jaffe, MA, MD, FFPH Valerie E. Stone, MD

22 Faculty Disclosures John G. Bartlett, MD Consulting fees: Merck, Tibotec Harold W. Jaffe, MA, MD, FFPH Fees for non-CME services: Merck Valerie E. Stone, MD Consulting fees: Abbott, Gilead Sciences, Tibotec Fees for non-CME services: Abbott, Gilead Sciences

23 Whats New in HIV Testing, Access and Linkage to Care? Valerie E. Stone, MD, MPH Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School Boston, MA

24 Case Presentation Imagine that you are a primary care provider… You are seeing a new 35-year-old female patient for her initial annual physical exam. She feels completely well and has no complaints She has a history of depression for which she has taken citalopram in the past. Denies history of other medical problems including HTN, DM, asthma, high lipids Social history is essentially unremarkable – she is an attorney, has a long-term boyfriend with whom she lives, no smoking hx, 5-7 alcoholic drinks per wk, no hx of illicit drug use. FH notable only for breast ca in her mother last year at age 65 You do a complete history and physical including pap/pelvic. Exam is completely normal except that she is a bit overweight (BMI 26.5)

25 AUDIENCE RESPONSE QUESTION

26 Question 1 What other screening tests should you order on this patient? A. Fasting lipids B. HIV antibody test C. Both of the above tests D. Mammogram E. All of the above tests

27 Question 1 – Response What other screening tests should you order on this patient? A. Fasting lipids B. HIV antibody test C. Both of the above tests D. Mammogram E. All of the above tests

28 Question 2 If you responded that you should obtain an HIV antibody test…why? A.This patients sexual history B.This patients age group C.Would suggest routinely for all patients at their annual physical D.Given the topic of this presentation, it seemed like the right response!

29 Question 2 – Response If you responded that you should obtain an HIV antibody test…why? A.This patients sexual history B.This patients age group C.Would suggest routinely for all patients at their annual physical D.Given the topic of this presentation, it seemed like the right response!

30 September 22, 2006 CDC Recommendations: Routine Testing for HIV ROUTINE voluntary screening for patients aged in health care settings OPT-OUT testing NO separate consent Pretest counseling NOT required Goal is to make HIV testing Less exceptional Universal and routine Not based on RISK

31 Opt-Out Testing Has Become More Feasible Legislatively Since 2006 At the time of CDCs 2006 recommendations, 20 states had laws or regulations that required written consent for HIV testing Currently, laws in 40 states and DC are compatible with the CDC recommendations 1 States that still have laws requiring signed consent are: Alabama, Hawaii, Massachusetts, Michigan, New York, Nebraska, Pennsylvania, Wisconsin, and Rhode Island 1. Branson BM National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA.

32 High Acceptance of Testing and Increasing Percentage Have Been Tested HIV testing has a high rate of acceptance in the US As of 2006 in US, 71 million reported that they had ever had an HIV test -- 40% of target population aged Data show modest increase in number tested in 2006 compared with Most of the testing was done in physicians offices (53%) or hospital setting (22% ERs or hospital based clinics) 1 PCPs cite many barriers to routine HIV screening 2 1. Branson BM National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA. 2. Bashook PG et al. Society of General Internal Medicine Annual Meeting, April 2008.

33 Views on Routine HIV Testing HIV testing should be: 65% say treated just like routine testing for any other disease and should be included as part of regular check-ups 27% say it is different from screening for other diseases and should require written permission from the patient 65% 27% Kaiser Family Foundation. Survey of Americans on HIV/AIDS; May 8, Available at: Neither Dont know

34 Trends in HIV Testing in the US, Percent Ever tested Preceding 12 months Branson BM National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA.

35 Location of HIV Testing Summary health statistics for US adults: National Health Interview Survey, Private doctor/HMO44%53% Hospital, ED, Outpatient22%18% Community clinic (public)9% HIV counseling/testing5% Correctional facility0.6%0.4% STD clinic0.1% Drug treatment clinic0.7%0.4%

36 Reasons for HIV Testing 0% 20% 40% 60% 80% 100% IllnessSelf/partner at risk Wanted to know Routine check up RequiredOther Late (Tested <1 y before AIDS dx) Early (Tested >5 y before AIDS dx) Supplement to HIV/AIDS Surveillance,

37 Primary Care Physicians Cite Many Barriers to Routine HIV Testing Focus groups of primary care physicians regarding routine HIV testing at SGIM Annual Meeting in 2007 Numerous perceived barriers to implementing routine HIV screening cited: State and local laws and regulations Concerns about stigma and stereotyping Belief that pre-test counseling is essential Time constraints Concerns about how and when to give results Reimbursement concerns Rapid test preferred but not available at their site Bashook PG et al. Society of General Internal Medicine Annual Meeting, April 2008.

38 Late HIV Diagnosis Is Common In 1 state, 45% of patients diagnosed with HIV within 1 year of AIDS diagnosis (late testers) Late testers compared with early testers (>5 y prior to AIDS dx) are more likely to be: Younger (18-29 y) Heterosexual Less educated African American or Hispanic CDC. HIV/AIDS Surveillance, MMWR Morbid Mortal Wkly Rep. 2003;52(25):

39 Late Testing in 34 States, Method: CDC review of AIDS diagnosis within 1 year of first positive test in 34 states with named reporting Results: 38% of 281, – 43%2001 – 36% 1998 – 42%2003 – 38% 2000 – 40%2005 – 36% CDC. MMWR Morbid Mortal Wkly Rep. 2009;58(24):

40 Awareness of Serostatus Among People With HIV and Estimates of Transmission ~25% Unaware of Infection ~75% Aware of Infection People Living with HIV/AIDS: ~1,000,000 New Sexual Infections Each Year: ~32,000 Accounting for ~54% of New Infections ~46% of New Infections Marks G et al. AIDS. 2006;20(10):

41 Knowledge of HIV Infection and Behavior Meta-analysis of 11 HIV risk-behavior studies: Unprotected anal/vaginal sex with HIV-negative partners was 68% lower in people aware vs unaware they were HIV positive Marks G et al. J Acquir Immune Defic Syndr. 2005;39(4):

42 Critical Challenge: Linkage to Care Mean time from diagnosis to first HIV primary care visit 2.5 years in cohort of 203 consecutive outpatients presenting for HIV care in Boston 1 HIV Cost and Services Utilization Study (HCSUS): 1/3 of people delayed >3 months before getting HIV care 2 Delay more common in: African American, Latino Women (esp children at home) 3 Uninsured Low trust in doctors 1 Samet JH. AIDS. 2001;15(1):77-85; 2 Turner BJ. Arch Intern Med. 2000;160(17): Stein MD. Am J Public Health. 2000;90(7):

43 HIV Provider-Cited Challenges to Early Linkage to Care Manpower issues: number of HIV providers is insufficient and decreasing Productivity is lower in HIV-focused practices than in other primary care practices Numerous hidden costs of care that negatively impact the cost-effectiveness of HIV care All of these factors result in each additional patient who is newly linked to care contributing further to the challenging financial situation of HIV-focused practices Saag M, Weddle A, Carmichael JK. National Summit on HIV Diagnosis, Prevention and Access to Care; November 19-21, 2008; Arlington, VA.

44 Interventions to Reduce Delay Rapid testing – more patients get results Case management Improve physician training in posttest counseling – Attention to social situation and need for support Immediate referral and specifics about accessible HIV providers and sites No show follow-up by HIV providers Address drug, alcohol use, and mood disorders

45 Summary 3 years have passed since the new CDC Recommendations for HIV Testing were released There has been legislative progress; now 40 states have laws that support opt-out testing More people have been tested at least once in the USwas 40% as of 2006 Primary care physicians cite numerous barriers to enacting these guidelines Linkage to care for those found to be HIV positive is critical and remains challenging

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47 Testing and Access to Care Harold W. Jaffe, MA, MD, FFPH Professor of Public Health University of Oxford Oxford, UK

48 Overview of Talk HIV rapid tests Screening for acute infection Test and treat strategy

49 HIV Rapid Tests Point-of-contact testing Three tests CLIA-waived in the US Whole blood (finger stick) or oral fluid (OraQuick) Results in 10 to 20 min

50 PositiveNegative Reactive Control HIV Rapid Testing of Oral Fluid Positive HIV-1/2

51 HIV Rapid Test Screening in Emergency Departments Site Screened (N) HIV Prevalence (%) Brigham and Womens Hospital, Boston Columbia University Medical Center, NYC Stroger Hospital, Chicago Walensky RP, et al. Ann Intern Med. 2008;149: Christopoulos K, et al. CROI 2009, Abstract # Lyss SB, et al. J Acquir Immune Defic Syndr. 2007;44:

52 Confirmation of Reactive HIV Rapid Tests: Standard Algorithm Screening TestConfirmatory TestTie Breaker Rapid (oral fluid or blood) WBNone Rapid (oral fluid or blood) IFANone Rapid (oral fluid or blood) NAT*Additional test *APTIMA RNA Qualitative Assay (Gen-Probe) is only FDA-approved NAT test for confirmation of HIV infection. WB, Western blot; IFA, indirect fluorescent antibody; NAT, nucleic acid test.

53 Confirmation of Reactive HIV Rapid Tests: Proposed Algorithms Screening TestConfirmatory TestTie Breaker Rapid (oral fluid or blood) Rapid (blood)*WB/IFA/NAAT Rapid (blood)Rapid (blood)*Rapid (blood) *Second manufacturer Third manufacturer From: APHL and CDC. HIV testing algorithms: a status report. April Available at: WB, Western blot; IFA, indirect fluorescent antibody; NAAT, nucleic acid amplification test.

54 Screening for Early HIV Infection by Pooled NAT Testing 1 Screening Pool 10 Pools of 10 A B C D E F G H I J A B C D E F G H I J 100 Individual specimens (HIV antibody negative)

55 Resolution Testing A Individual NAT testing on 10 specimens 10 Pools of 10 tested with NAT Screening Pools of 100 specimens tested with NAT

56 Screening for Early HIV Infection NAT testing Detects infection as early as 10 to 12 days Increases detection rate by 2%-8% in public health settings Fourth-generation immunoassay* Simultaneous detection of antibody/p24 antigen in single sample Detects 60%-90% of EIA-/NAAT+ acute infections EIA, enzyme immunoassay; NAAT, nucleic acid amplification test. * ARCHITECT HIV Combo Assay; Abbott Laboratories. Available for sale outside of the United States only.

57 Test and Treat Strategy Our model suggests that massive scale-up of universal voluntary HIV testing with immediate initiation of ART could nearly stop transmission and drive HIV into an elimination phase in a high-burden setting within 1-2 years of reaching 90% of programme coverage. Granich RM et al. Lancet. 2009;373:48-57.

58 Obstacles to Test and Treat In sub-Saharan Africa, 60%-95% of infected persons have not been diagnosed Of ~33 million HIV-infected persons worldwide, only ~3 million receiving ART Primary infection accounts for 9%-31% of sexual transmission of HIV 1 Risks and benefits of early treatment unclear 1 Hollingsworth TD et al. J Infect Dis. 2008;198:

59 A Hypothetical Conversation Doctor:Youre doing very well. Youve had no complications of your HIV infection and your CD4 cell count is high. But I think you should be treated. Patient: Why? Doctor: To decrease the likelihood that youll infect someone else. Patient: Will I benefit from the treatment? Doctor: I dont know.

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61 Hit Hard, Hit Early: When to Treat and With What? Brian G. Gazzard, MD, Moderator Julio Montaner, MD Calvin J. Cohen, MD, MS

62 Faculty Disclosure Brian G. Gazzard, MD No real or apparent conflicts of interest to report. Julio Montaner, MD Research grants, advisory boards, speakers bureaus: Abbott, Argos Therapeutics, Bioject Inc, Boehringer Ingelheim, Bristol- Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Janssen-Ortho, Merck Frosst, Panacos, Pfizer, Schering Serono Inc. TheraTechnolgies, Tibotec (J&J), Trimeris Calvin J. Cohen, MD Consulting fees, fees for non-CME services, contracted research: Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Pfizer, Tibotec

63 Hit Hard, Hit Early: When to Treat and With What? Brian G. Gazzard, MA, MD, FRCP Consultant Physician and Research Director, HIV/GUM Chelsea & Westminster Hospital London, UK

64 Cumulative Mortality Estimates Calculated Using Extended Kaplan-Meier Survival Estimates CD4 >500 & defer HAART (n=6539) CD4 >500 & initiate HAART (n=2616) Years After Kitahata M et al. 16th CROI; 2009; Montreal. Abstract 71.

65 CD4 Threshold (cells/mm 3 ) Hazard Ratio Note that successive comparisons are not statistically independent Sterne J et al. 16 th CROI; 2009; Montreal. Oral Abstract 72LB. Hazard Ratios for AIDS or Death, Adjusted for Lead Times and Unseen Events

66 AUDIENCE RESPONSE QUESTION

67 Assume you are HIV positive and have a CD4 count of 500 cc/mL. You have two options. Which would you choose? 1. $10,000 in the bank annually earning compound interest until your CD4 count is 350 cc/mL 2. Start ART immediately

68 Hit Early? At what CD4 cell count would you start for the benefit of the patient?

69 STARTMRK: Percent of Patients With HIV RNA <50 Copies/mL (95% CI) (Non-Completer = Failure) Raltegravir 400 mg bid a Efavirenz 600 mg qhs a Number of Contributing Patients Weeks Percent of Patients % Noninferiority P Value < % a In combination with tenofovir/emtricitabine. Lennox J et al. 48 th ICAAC–46 th IDSA; 2008; Washington, DC. Abstract H-896a.

70 MERIT-ES Re-analysis: Kaplan-Meier Plot of Time to Virologic Failure (50 Copies/mL) Only patients with an R5 screening result by enhanced Trofile assay are included. Nonresponders (failure, rebound, discontinuation) were censored. MVC + ZDV /3TC EFV + ZDV /3TC Survival Estimate Days Heera J et al. 5 th IAS; 2009; Capetown. Abstract TUAB TC, lamivudine; EFV, efavirenz; MVC, maraviroc; ZDV, zidovudine.

71 Time to Virologic Failure (Plasma HIV RNA >200 log 10 copies/mL) No shorter time to undetectable viral load, but significantly shorter time to virologic failure. Consistent for other HIV RNA thresholds ZDV/ABC + TDF/FTC ATV/r + TDF/FTC EFV/TDF/FTC Number at risk Weeks EFV/TDF/FTC ATV/r + TDF/FTC ZDV/ABC + TDF/FTC ArmHRP EFV/TDF/FTC1 ATV/r + TDF/FTC ZDV + ABC + TDF/FTC * ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; ZDV, zidovudine. Cooper D. 5 th IAS; 2009; Capetown. Abstract LBPEB09.

72 Hit hard? What agent would you start with? Why would you no longer start with efavirenz?

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74 Long-Term Consequences of Immune Activation and ART William G Powderly, MD, Moderator Sally L. Hodder, MD Jens Lundgren, MD

75 Faculty Disclosures William G. Powderly, MD Consulting fees: Boehringer Ingelheim Other: Member of DSMB: Tibotec Sally L. Hodder, MD Consulting fees: Gilead Sciences Jens Lundgren, MD Consulting fees, contracted research: Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Pfizer, Roche, Tibotec

76 Long-Term Consequences of Immune Activation and ART William G. Powderly, MD Dean of Medicine Head, University College Dublin School of Medicine and Medical Science Dublin, Ireland

77 Immune Activation in HIV Chronic untreated HIV infection is associated with immune activation In established infection, 50% of peripheral CD8+ T cells appear to be activated, compared with <10% in HIV-uninfected persons Similar trends in the CD4+ T-cell population Frequency of activated T cells predicts disease progression, independent of HIV-1 RNA Antiretroviral therapy reduces HIV-associated T-cell activation, although often incompletely Markers of inflammation elevated in untreated HIV infection Only partially reversed with effective ART

78 Mechanism of Immune Activation Partially a direct effect of HIV Decrease in markers of inflammation and immune activation during ART Likely to be indirect effects also Most activated T cells are not HIV specific Markers of inflammation do not return to normal with sustained effective ART suppression Other putative mechanisms of persistent immune activation have been postulated Microbial translocation Irreversible damage to lymphoid infrastructure, Irreversible thymic dysfunction Increased prevalence of coinfections (eg, CMV) Persistent low-level HIV replication

79 Significance of Immune Activation Constant T-cell proliferation and death in uncontrolled HIV may result in eventual immunologic exhaustion Even with treatment, persistent immune activation may lead to immune senescence and premature aging of the immune system Full immune recovery (with reversal of activation) may not be seen with effective ART, especially in patients with low CD4+ T-cell count nadir (<200 cells/mm³) prior to treatment Is there a relationship between persistent immune activation, immune senescence and diseases associated with aging?

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81 Long-Term Consequences of Immune Activation and ART Jens D. Lundgren, MD, DMSc Professor, Faculty of Health Sciences University of Copenhagen Head, Centre for Viral Diseases/KMA, Rigshospitalet Head, Copenhagen HIV Programme, Denmark

82 Discussion Questions Related to CVD What is the evidence that HIV infection is associated with an increased risk of cardiovascular disease? What are the possible causes of this increased risk? Is immune activation a possible cause?

83 Principal factors affecting risk of CVD in HIV Traditionalriskfactors HIV ART + + +

84 % With a Major CVD Event Years from randomization DC VS VS DC No. at risk Relative hazard: 1.57 (1.00 – 2.46) p = 0.05 SMART/CVD: Phillips et al, AVT 2008 * Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure Risk of Major CVD Events* by Treatment Arm DC = Drug Conservation VS = Viral Suppression

85 Change in Log IL-6 (pg/mL) and HDL Cholesterol Concentration (μmol/L) from Baseline to 1 Month* ,00010,000-50,000>50,000 Month 1 HIV RNA Level (copies/mL) IL-6 (pg/mL) P< for trend HDL (μmol/L) * DC patients on ART at baseline with HIV RNA 400 copies/mL IL-6 HDL P= for trend SMART/INSIGHT: Duprez et al, CROI,

86 Time-Course for Association Between ARV Drug Exposure and Risk of MI Start ABC MI risk Some PI: progressive risk with cumulative exposure Stop ABC

87 * Recent = still using or stopped within last 6 months OverallLow Moderate High Not known Rate (per 1000 PY) Predicted 10-year CHD risk No recent abacavir D:A:D study: Sabin et al, Lancet, 2008 Rates of MI For Recent* Use of Abacavir by Predicted 10-Year CHD Risk Recent abacavir

88 Long-Term Consequences of Immune Activation and ART Sally L. Hodder, MD Professor of Medicine New Jersey Medical School University of Medicine and Dentistry of New Jersey Newark, NJ

89 Discussion Questions Are HIV-infected patients at a greater risk for bone disease? Is HIV- associated bone disease related to virus or to treatment?

90 Bone Mineral Density in HIV-Infected Persons Multiple studies have found increased prevalence of osteoporosis and osteopenia in HIV-infected persons compared with uninfected persons Meta-analytical review of studies –67% HIV infected persons had reduced BMD (OR 6.4) –15% HIV+ had osteoporosis (OR 3.7) Brown et al AIDS 2006;20:

91 Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502. WomenMen Fracture Prevalence Higher in HIV Patients Fracture Prevalence/100 Persons HIV Non-HIV P=0.002 P=0.01 P=0.53 P=0.01 AnyVertebralHipWrist Fracture Prevalence/100 Persons HIV Non-HIV P< P=0.001 AnyVertebralHipWrist Population: 8,525 HIV+ and 2, HIV- Patients with fracture: 245 HIV+ and 39,073 HIV- Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV-

92 Changes in Hip Bone Mineral Density with Antiretroviral Therapy Intermittent (Fracture 0.03/100 PY) Continuous (Fracture 0.13/100 PY) n = n = Est. diff.: P values: Gallant et al. JAMA 2004, 292:191.Grund B et al. ICAAC/IDSA Abstract 2312a. d4T + 3TC + EFV TDF + 3TC + EFV n= n= Years Change From Baseline (%) 2 Gilead 903 StudySMART Study Baseline Weeks P=0.06

93 Association of Osteoporosis with Antiretroviral Therapy Brown TT et al. AIDS. 2006, 22:2168. Antiretroviral Therapy OverallProtease Inhibitor Therapy Odds ratio Study Amiel (2004) Bruera (2003) Garcia (2001) Knobel (2001) Knishi (2005) Mededdu (2004) Vescini (2003) Overall (95%CI) Odds ratio (95%CI) 2.41 (0.77, 7.58) 4.81 (0.60, 38.74) 1.60 (0.13, 19.84) 2.68 (0.70, 10.33) 0.84 (0.03, 22.43) (0.65, ) 0.54 (0.05, 5.68) 2.38 (1.20, 4.75) Odds ratio Odds ratio (95%CI) 0.61 (0.21, 1.72) (0.57, ) 1.18 (0.37, 3.78) 0.71 (0.11, 4.51) 1.57 (0.05, 43.79) 1.97 (0.47, 8.27) 2.63 (1.13, 7.03) 1.89 (0.23, 15.81) 3.25 (2.08, 9.83) 1.83 (0.35, 9.62) 1.24 (0.34, 4.52) 0.77 (0.15, 2.34) 1.57 (1.05, 2.34) Study Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Mededdu (2004) Mondy (2003) Nolan (2001) Tebas (2000) Vescini (2003) Yiu (2005) Overall (95%CI) Caveat: Few studies adjusted for age or duration of infection

94 Effects of HIV on Bone Metabolism HIV-1 p55 gag and gp120 –Significantly decrease calcium deposition in vitro 1 –Reduce RUNX-2 activity in vitro 1 gp120 increases PPARγ activity 1 gp120 (100 ng/ml) induces RANKL 2 1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12): Fakruddin JM et al. J Biol Chem. 2003;278: RUNX-2 (Runt-related transcription factor-s) promotes osteoblast differentiation. PPARγ (Peroxisome proliferator-activated receptor gamma) promotes adipogenesis. RANKL (Receptor Activator for Nuclear Factor κ B Ligand), activates osteoclasts.

95 25-OH Vitamin D Deficiency Prevalent in HIV-Infection 1.Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1): Seminari E et al. HIV Med. 2005;6: Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4): % Boston outpatient HIV clinic (n=57) 1 –Low Vitamin D intake in 31% < 50 years and 76% years –Low calcium intake in in 37% < 50 years and 71% years 81% Italian HIV treatment-experienced patients (n=48) 2 86% in Spanish cohort of men (n=30) 3 –Mean 25,OH Vitamin D level 14.3 ng/ml in healthy controls vs.11.4 ng/ml (p=0.044)

96 All Inflammatory markerQ1Q2Q3Q4 CRP IL TNF IL-2sR § IL-6sR § TNF sRI § TNF sRII Cauley JA et al. J Bone Miner Res. 2007;22:1091. Inflammatory Biomarkers Associated With Bone Fracture P<.05 from trend test. P<.01 from trend test. § P<.001 from trend test. Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory

97 Cauley JA et al. J Bone Miner Res. 2007;22:1092. Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers* Years % With Non-spine Fracture or 1 P = (log rank test) *CRP, IL-6, TNFα

98 Discussion Questions Are there important long-term CNS consequences of HIV in adequately treated patients? Is CNS penetration of antiviral drugs important?

99 HIV-1 Infection and the CNS Mean Incidence HIV Dementia MACS Cohort Number/1000 person years Antinori A et al. Neurology. 2007;69: Sacktor N et al. Neurology. 2001;56: HIV-Associated Neurocognitive Disorder –Asymptomatic neurocognitive impairment –Minor neurocognitive disorder –Dementia Mean Incidence HIV Dementia MACS Cohort

100 Does CNS Antiretroviral Agent Penetration Matter? Letendre S et al. Arch Neurol. 2008;65(1): Proportion of Subjects With Detectable CSF Viral Load CPE Score Proportion of Subjects With Detectable CSF Viral Load (n=25) 0.5 (n=38) 1 (n=128) 1.5 (n=100) 2 (n=100) 3 (n=13) 2.5 (n=63) CPE Score N=31 (24 ART naïve) CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV

101 Does CSF HIV RNA Affect Neurocognitive Function? Letendre S et al. Ann Neurol. 2004;56:419. Reduction in GDS at Follow-up CSF HIV RNA Suppression at Follow-up Not SuppressedSuppressed N=14N=17 2 =6.25 P=.01

102 Sinclair E et al. JAIDS. 2008;47:548. ART Affects CNS Immune Activation % CSFCD8 CD38+DR+ Off Failure Success HIV–

103 Long-Term Consequences of Immune Activation and ART Jens D. Lundgren, MD, DMSc Professor, Faculty of Health Sciences University of Copenhagen Head, Centre for Viral Diseases/KMA, Rigshospitalet Head, Copenhagen HIV Programme, Denmark

104 Discussion Question Related to Cancers Will we see more cancers in HIV infected patients in the next 10 years?

105 AIDS and Non-AIDS Defining Cancers in Baltimore Cohort Long et al, AIDS 2008

106 Incidence of non-AIDS defining cancers in HIV-infected and uninfected persons in VA Bedimo et al, JAIDS 2009.

107 Why Will Incidence of Cancers Increase in the Next 10 Years Risk of AIDS-related cancers decreased due to benefit of ART Except HPV-induced genital cancers HIV-infected population is aging Risk of fatal non-AIDS-defining cancers increases 47% per 5 year older age (i.e. >2-fold increase over a 10 year period Secondary cancers - may further increase the 47% estimate 1 Immunodeficiency Chronic pro-oncogenic viral infections e.g. HPV, EBV, viral hepatitis Other cancers (and associated therapy hereof) e.g. bladder cancer after prostate cancer 2 ; leukemia after NHL 3 ART ? 1 D:A:D study group, AIDS Shirodkar et al, Curr Opin Urol Mudie et al, J Clin Oncol 2006

108 For 20 / 28 cancers examined there was significantly increased incidence in both groups – strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung Leukaemia Kidney Oesophagus Stomach Meta-analysis: 444,172 people with HIV, 31,977 transplant patients Grulich et al, Lancet HIV and Risk of Non-AIDS Malignancies

109 HPV Cancers and HIV Transmission Temporal trends in US cohort - incidence of anal cancer (/100,000 PYs) 19 ( ), 48.3 ( ), 78.2 ( ) Impact of ART on risk of malignant transformation ART was not associated with altered risk of cytological progression or regression Oral HPV infection in HIV may enhance smoking induced risk of oropharyngeal cancer Anal HPV infection may increase risk of HIV transmission Patel et al, Ann Intern Med 2008; Paramsothy et al, Obstet and Gynecol 2009; Chin-Hong et al, AIDS 2009; Gillison, Curr Opin Oncol 2009.

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