John G. Bartlett, MD Program Chair

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

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

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

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 9:25 pm– 9:30 pm Concluding Remarks and Program Adjournment John G. Bartlett, MD, Program Chair

FACULTY John G. Bartlett, MD Sally L. Hodder, MD
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

FACULTY (Continued) Julio Montaner, MD William G. Powderly, 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, Women’s HIV/AIDS Program Massachusetts General Hospital Boston, MA

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.

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 Center’s 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

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

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

34 States and 5 U.S. Dependent Areas, 2007
Estimated Rates for Adults and Adolescents Living With HIV Infection (not AIDS) 34 States and 5 U.S. Dependent Areas, 2007 American Samoa Northern Mariana Islands Guam DC Estimated HIV Rate per 100,000 Slide 1: Estimated rates (per 100,000 population) for adults and adolescents living with HIV infection (not AIDS), states and 5 U.S. dependent areas At the end of 2007, in the 39 areas with confidential name-based HIV infection reporting since at least 2003, the prevalence rate of HIV infection (not AIDS) among adults and adolescents was estimated to be per 100,000. The estimated prevalence rate for adults and adolescents living with HIV infection (not AIDS) ranged from 2.2 per 100,000 (American Samoa) to per 100,000 (New York). Confidential name-based HIV infection reporting not implemented as of 2003 2.2 – 51.7 AK HI 51.8 – 103.8 103.9 – 170.5 Puerto Rico 170.6 – 282.0 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 12 12

Awareness of HIV Status in the US
HIV estimated prevalence1 1,056, ,156,400 Undiagnosed1 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 This data will need to be updated in January, 2008 when the CDC is slated to announce results from their new STAHRS reporting system. HIV Prevalence: includes Undiagnosed and Estimated New Annual infections # of people aware of HIV status: HIV estimated Prevalence—undiagnosed = those who are aware. This is approximately 900K of the estimated prevalence are diagnosed. 57% are in care but not necessarily treated. This leaves approximately 400K who are aware but not in treatment. 1CDC. HIV prevalence estimate—United States, MMWR. 2008;57(39): 2Hall HI, et al. Estimation of HIV incidence in the United States of America. JAMA. 2008;300: 3CDC. HIV/AIDS surveillance report—cases of HIV infection and AIDS in the United States and dependent areas, 2007;19. Accessed July 23, 2009. 13 13

US Population Demographics: Total Population and HIV/AIDS Cases by Race/Ethnicity
Total US Population (2007) (N = million)1 Estimated HIV/AIDS Prevalence by Race/Ethnicity (2006) (N = 1,106,400)2 Other <2% Other 6% Hispanic/ Latino 18% White 66% Black 46% Black 12% White 35% Hispanic 15% 1Kaiser 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. 2CDC. HIV Incidence. Available at 14

HIV Testing: Efforts to Change Maryland Law and Practice
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) 15

AUDIENCE RESPONSE QUESTION

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

You have newly detected HIV, asymptomatic and VL 50,000 c/mL
You have newly detected HIV, asymptomatic and VL 50,000 c/mL. When would you want HAART to be started based on CD4 count? >700 <350

You would start on 2NRTIs plus?
Efavirenz Lopinavir/ritonavir Atazanavir/ritonavir Darunavir/ritonavir Raltegravir

HAART is effective for improved outcome with?
HIV dementia Cardiovascular events Premature aging

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 21

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 22

What’s 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 23

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) 24

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

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

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

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

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 30

Opt-Out Testing Has Become More Feasible Legislatively Since 2006
At the time of CDC’s 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 recommendations1 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. 31

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 13-64 Data show modest increase in number tested in compared with 20021 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 screening2 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. 32

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 Don’t know Neither 27% 65% Kaiser Family Foundation. Survey of Americans on HIV/AIDS; May 8, Available at: 33

Trends in HIV Testing in the US, 2002-2006
Ever tested Preceding 12 months Percent Branson BM National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA. 34

Location of HIV Testing
2002 2006 Private doctor/HMO 44% 53% Hospital, ED, Outpatient 22% 18% Community clinic (public) 9% HIV counseling/testing 5% Correctional facility 0.6% 0.4% STD clinic 0.1% Drug treatment clinic 0.7% Summary health statistics for US adults: National Health Interview Survey, 2006. 35

Reasons for HIV Testing
100% Late (Tested <1 y before AIDS dx) Early (Tested >5 y before AIDS dx) 80% 60% 40% And most of those who were tested late were tested because they were ill – they had already developed symptoms. This chart shows the reasons people said they were tested – late testers in red, and early testers in blue. Part of CDC’s intention, through the new strategies to make testing a routine part of medical care, is to shift <click> this curve, so that more people are tested as part of routine check-ups, and more infections are diagnosed earlier. 20% 0% Illness Self/partner Wanted to Routine Required Other at risk know check up Supplement to HIV/AIDS Surveillance, 36 36

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. 37

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 Unfortunately, however, many people with HIV do not find out until late in the course of their disease. 40% to 45% of persons with HIV are first tested within one year of being diagnosed with AIDS. Many of them have already developed AIDS (which takes an average of 10 years after becoming infected) before they are tested for HIV. Persons tested late (compared with those tested early, >5 years before developing AIDS) were more likely to be younger, heterosexual, less educated, and African American or Hispanic. In other words, people who were less likely to think they were at risk, and less likely to be identified through targeted testing. CDC. HIV/AIDS Surveillance, MMWR Morbid Mortal Wkly Rep. 2003;52(25): 38 38

Late Testing in 34 States, 1996-2005
Method: CDC review of AIDS diagnosis within 1 year of first positive test in 34 states with named reporting Results: 38% of 281,421 1996 – 43% – 36% 1998 – 42% – 38% 2000 – 40% – 36% CDC. MMWR Morbid Mortal Wkly Rep. 2009;58(24): 39

Awareness of Serostatus Among People With HIV and Estimates of Transmission
Accounting for ~25% Unaware of Infection ~54% of New Infections ~75% Aware of Infection ~46% of New Infections It is estimated that sexual transmission accounts for 32,000 of the 40,000 new infections each year. Conservative estimates based on the changes in behavior observed once people find out they are infected with HIV indicate that the 25% of people who are unaware that they are infected account for at least 54%, and potentially as much as 70%, of the new sexually transmitted infections each year. The transmission rate among those who don’t know they are infected is 3.5 times higher than for people who know about their HIV infection. The importance of getting these individuals tested and into care that includes both treatment and prevention interventions is critical. People Living with HIV/AIDS: ~1,000,000 New Sexual Infections Each Year: ~32,000 Marks G et al. AIDS. 2006;20(10): 40 40

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 In addition to the benefits of treatment for the individual patient, Screening has significant potential prevention benefits. In a meta-analysis of 11 studies, after people become aware they are infected with HIV, there is 68% less unprotected anal or vaginal intercourse with HIV-negative partners among people who are aware they are HIV-infected, compared with those who are not. These studies included people with long-term HIV infection, as well as those who were recently diagnosed; some were conducted before, and others, after the availability of Highly Active Antiretroviral Therapy. Thus, the finding of reduced risk behavior was not based only on persons who had known of their HIV-positive status for a short time. Marks G et al. J Acquir Immune Defic Syndr ;39(4): 41 41

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 Boston1 HIV Cost and Services Utilization Study (HCSUS): 1/3 of people delayed >3 months before getting HIV care2 Delay more common in: African American, Latino Women (esp children at home)3 Uninsured Low trust in doctors 1Samet JH. AIDS. 2001;15(1):77-85; 2Turner BJ. Arch Intern Med. 2000;160(17): 3Stein MD. Am J Public Health. 2000;90(7): 42 42

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. 43 43

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 44 44

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 US—was 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 45

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

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

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 49

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

HIV Rapid Test Screening in Emergency Departments
Site Screened (N) HIV Prevalence (%) Brigham and Women’s Hospital, Boston1 849 0.6 Columbia University Medical Center, NYC2 2569 0.9 Stroger Hospital, Chicago3 2824 1.2 1Walensky RP, et al. Ann Intern Med. 2008;149: 2Christopoulos K, et al. CROI 2009, Abstract #1040. 3Lyss SB, et al. J Acquir Immune Defic Syndr. 2007;44: 51

Confirmation of Reactive HIV Rapid Tests: Standard Algorithm
Screening Test Confirmatory Test Tie Breaker Rapid (oral fluid or blood) WB None IFA NAT* Additional test WB, Western blot; IFA, indirect fluorescent antibody; NAT, nucleic acid test. *APTIMA RNA Qualitative Assay (Gen-Probe) is only FDA-approved NAT test for confirmation of HIV infection. 52

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

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

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

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. 56

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. 57

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 HIV1 Risks and benefits of early treatment unclear 1Hollingsworth TD et al. J Infect Dis. 2008;198: 58

A Hypothetical Conversation
Doctor: You’re doing very well. You’ve 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 you’ll infect someone else. Patient: Will I benefit from the treatment? Doctor: I don’t know. 59

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

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

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

Cumulative Mortality Estimates
Calculated Using Extended Kaplan-Meier Survival Estimates 0.20 CD4 >500 & defer HAART (n=6539) CD4 >500 & initiate HAART (n=2616) 0.15 0.10 0.05 0.00 2 4 6 8 10 Years After 1996 Kitahata M et al . 16th CROI; 2009; Montreal. Abstract 71. 64

Hazard Ratios for AIDS or Death, Adjusted for Lead Times and Unseen Events
4 2 Hazard Ratio 1 0.5 500 400 300 200 100 CD4 Threshold (cells/mm3) Note that successive comparisons are not statistically independent Sterne J et al . 16th CROI; 2009; Montreal. Oral Abstract 72LB. 65

Assume you are HIV positive and have a CD4 count of 500 cc/mL
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

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

STARTMRK: Percent of Patients With HIV RNA <50 Copies/mL (95% CI) (Non-Completer = Failure)
100 86% 80 82% 60 Percent of Patients Noninferiority P Value <.001 40 20 2 4 8 12 16 24 32 40 48 Weeks Number of Contributing Patients Raltegravir 400 mg bida 281 279 281 279 281 279 278 280 280 Efavirenz 600 mg qhsa 282 282 282 282 281 282 280 281 281 aIn combination with tenofovir/emtricitabine. Lennox J et al. 48th ICAAC–46th IDSA; 2008; Washington, DC. Abstract H-896a. 69

MERIT-ES Re-analysis: Kaplan-Meier Plot of Time to Virologic Failure (≥50 Copies/mL)
1.0 EFV + ZDV /3TC 0.9 MVC + ZDV /3TC 0.8 0.7 0.6 Survival Estimate 0.5 0.4 0.3 0.2 Only patients with an R5 screening result by enhanced Trofile assay are included. Nonresponders (failure, rebound, discontinuation) were censored. 0.1 0.0 100 200 300 400 500 600 700 Days 3TC, lamivudine; EFV, efavirenz; MVC, maraviroc; ZDV, zidovudine. Heera J et al. 5th IAS; 2009; Capetown. Abstract TUAB 103. 70

Time to Virologic Failure (Plasma HIV RNA >200 log10 copies/mL)
1.00 Arm HR P EFV/TDF/FTC 1 ATV/r + TDF/FTC 0.88 0.840 ZDV + ABC + TDF/FTC 3.30 0.012* 0.75 0.50 EFV/TDF/FTC 0.25 ATV/r + TDF/FTC ZDV/ABC + TDF/FTC 0.00 4 12 24 36 48 Number at risk Weeks EFV/TDF/FTC 111 111 111 109 109 108 ATV/r + TDF/FTC 105 105 105 104 103 102 ZDV/ABC + TDF/FTC 97 97 97 93 91 89 No shorter time to undetectable viral load, but significantly shorter time to virologic failure. Consistent for other HIV RNA thresholds ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; ZDV, zidovudine. Cooper D. 5th IAS; 2009; Capetown. Abstract LBPEB09. 71 71

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

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

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

William G. Powderly, MD Dean of Medicine Head, University College Dublin School of Medicine and Medical Science Dublin, Ireland

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

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

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?

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

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?

Principal factors affecting risk of CVD in HIV
+ HIV Traditional risk factors + + ART

Risk of Major CVD Events* by Treatment Arm
Relative hazard: 1.57 (1.00 – 2.46) p = 0.05 DC VS % With a Major CVD Event DC = Drug Conservation VS = Viral Suppression This shows Kaplan Meier estimates of the risk of major CVD events according to treatment arm. Contrary to the original hypothesis, there was a raised risk in the DC arm. The relative hazard was 1.57 which was of borderline statistical significance. The breakdown of the types of events are shown. Note that there were 48 events in the DC arm and 31 in the VS arm, so power for some of the following analyses is limited. No. at risk Years from randomization DC VS * Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure SMART/CVD: Phillips et al, AVT 2008

Month 1 HIV RNA Level (copies/mL)
Change in Log IL-6 (pg/mL) and HDL Cholesterol Concentration (μmol/L) from Baseline to 1 Month* ∆ IL-6 0.4 0.4 ∆ HDL P= for trend 0.3 0.3 0.2 0.2 0.1 0.1 ∆ IL-6 (pg/mL) ∆ HDL (μmol/L) -0.1 -0.1 -0.2 -0.2 P< for trend -0.3 -0.3 ≤ 400 401-10,000 10,000-50,000 >50,000 -0.4 -0.4 Month 1 HIV RNA Level (copies/mL) * DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL SMART/INSIGHT: Duprez et al, CROI, 2009

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

Rates of MI For Recent* Use of Abacavir by Predicted 10-Year CHD Risk
No recent abacavir Recent abacavir 35 30 25 20 15 10 5 Rate (per 1000 PY) Overall Low Moderate High Not known Predicted 10-year CHD risk * Recent = still using or stopped within last 6 months D:A:D study: Sabin et al, Lancet, 2008

Sally L. Hodder, MD Professor of Medicine New Jersey Medical School University of Medicine and Dentistry of New Jersey Newark, NJ 88

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

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:

Fracture Prevalence Higher in HIV Patients
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- Women Men 3.0 3.0 P=0.002 HIV Non-HIV P<0.0001 HIV Non-HIV 2.5 2.5 2.0 2.0 Fracture Prevalence/100 Persons Fracture Prevalence/100 Persons 1.5 P=0.01 1.5 P=0.001 1.0 P=0.01 1.0 P<0.0001 P=0.001 P=0.53 0.5 0.5 Any Vertebral Hip Wrist Any Vertebral Hip Wrist Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502. 91

Changes in Hip Bone Mineral Density with Antiretroviral Therapy
Gilead 903 Study SMART Study d4T + 3TC + EFV Intermittent (Fracture 0.03/100 PY) 8 TDF + 3TC + EFV Continuous (Fracture 0.13/100 PY) 6 1 4 2 -1 Change From Baseline (%) -2 -3 -2 P=0.06 -4 -6 1 2 3 4 -8 Years Baseline 24 48 72 96 120 144 n = n = Weeks n= n= Est. diff.: P values: Gallant et al. JAMA 2004, 292:191. Grund B et al. ICAAC/IDSA Abstract 2312a. 92

Association of Osteoporosis with Antiretroviral Therapy
Antiretroviral Therapy Overall Protease Inhibitor Therapy 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) 11.00 (0.65, ) 0.54 (0.05, 5.68) 2.38 (1.20, 4.75) 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) Odds ratio (95%CI) 0.61 (0.21, 1.72) 11.09 (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) Odds ratio 0.01 100 Odds ratio 0.01 100 Caveat: Few studies adjusted for age or duration of infection Brown TT et al. AIDS. 2006, 22:2168. 93

Effects of HIV on Bone Metabolism
HIV-1 p55 gag and gp120 Significantly decrease calcium deposition in vitro1 Reduce RUNX-2 activity in vitro1 gp120 increases PPARγ activity1 gp120 (100 ng/ml) induces RANKL2 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. 1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12): 2. Fakruddin JM et al. J Biol Chem. 2003;278: 94

25-OH Vitamin D Deficiency Prevalent in HIV-Infection
47% 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) Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14. Seminari E et al. HIV Med. 2005;6: Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4): 95

Inflammatory Biomarkers Associated With Bone Fracture
Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory All Inflammatory marker Q1 Q2 Q3 Q4 CRP 13.5 13.7 16.5 17.4 IL-6 14.2 15.6 13.0 17.5 TNF 12.5 15.1 14.6 20.8† IL-2sR 10.9 13.8 15.9 25.4§ IL-6sR 12.0 13.6 17.6 22.3‡§ TNF sRI 14.0 10.5 14.8 26.7‡§ TNF sRII 8.6 17.9 22.3 † P<.05 from trend test. ‡ P<.01 from trend test. § P<.001 from trend test. Cauley JA et al. J Bone Miner Res. 2007;22:1091. 96

Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers*
20 *CRP, IL-6, TNFα 18 16 2+ 14 12 10 0 or 1 % With Non-spine Fracture 8 6 4 P = (log rank test) 2 1 2 3 4 5 6 7 8 Years Cauley JA et al. J Bone Miner Res. 2007;22:1092. 97

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

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

Does CNS Antiretroviral Agent Penetration Matter?
N=31 (24 ART naïve) CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV Proportion of Subjects With Detectable CSF Viral Load 0.1 0.2 0.3 0.4 0.5 ≥3.5 (n=25) ≤0.5 (n=38) 1 (n=128) 1.5 (n=100) 2 (n=100) 3 (n=13) 2.5 (n=63) Proportion of Subjects With Detectable CSF Viral Load CPE Score CPE Score Letendre S et al. Arch Neurol. 2008;65(1):65-70. 100

Does CSF HIV RNA Affect Neurocognitive Function?
1.0 0.5 Reduction in GDS at Follow-up 0.0 2=6.25 P=.01 -0.5 N=14 N=17 Not Suppressed Suppressed CSF HIV RNA Suppression at Follow-up Letendre S et al. Ann Neurol. 2004;56:419. 101

ART Affects CNS Immune Activation
Blood CD8 Activation Off Failure Success HIV– % Bld CD8 CD38+DR+ 100 40 80 60 20 CSF CD8 Activation Off Failure Success HIV– 100 40 80 60 20 Off Failure Success HIV– % CSFCD8 CD38+DR+ Sinclair E et al. JAIDS. 2008;47:548. 102

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

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

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

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

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% estimate1 Immunodeficiency Chronic pro-oncogenic viral infections e.g. HPV, EBV, viral hepatitis Other cancers (and associated therapy hereof) e.g. bladder cancer after prostate cancer2; leukemia after NHL3 ART ? 1 D:A:D study group, AIDS 2008 2 Shirodkar et al, Curr Opin Urol 2009 3 Mudie et al, J Clin Oncol 2006

HIV and Risk of Non-AIDS Malignancies
Meta-analysis: 444,172 people with HIV, 31,977 transplant patients 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 Grulich et al, Lancet 2007.

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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