John G. Bartlett, MDProgram ChairProfessor of MedicineJohns Hopkins University School of MedicineBaltimore, 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 IntroductionJohn 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, ModeratorHarold W. Jaffe, MDValerie 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, ModeratorCalvin J. Cohen, MD, MSJulio 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 ARTWilliam G. Powderly, MD, ModeratorSally L. Hodder, MDJens Lundgren, MD

9:10 PM– 9:25 PM Panel Discussion/Audience Q & A

9:25 PM– 9:30 PM Concluding Remarks and Program AdjournmentJohn G. Bartlett, MD, Program Chair

FACULTYProgram Chair

John G. Bartlett, MDProfessor of Medicine

Johns Hopkins University School of Medicine

Baltimore, MD

Faculty

Calvin J. Cohen, MD, MSClinical Instructor

Harvard Medical School

Research Director

CRI New England

Boston, MA

Brian G. Gazzard, MA, MD, FRCPConsultant Physician and Research Director,

HIV/GUM

Chelsea & Westminster Hospital

London, UK

Sally L. Hodder, MDProfessor of Medicine

New Jersey Medical School

University of Medicine and Dentistry of New Jersey

Newark, NJ

Harold W. Jaffe, MA, MD, FFPHProfessor of Public Health

University of Oxford

Oxford, UK

Jens D. Lundgren, MDProfessor, Viral Diseases

University of Copenhagen

Copenhagen, Denmark

FACULTY (Continued)

Julio Montaner, MDProfessor of Medicine

Chair in AIDS Research

The University of British Columbia

Vancouver, BC

William G. Powderly, MDDean of Medicine

Head, University College Dublin

School of Medicine and Medical Science

Dublin, Ireland

Valerie E. Stone, MD, MPHAssociate Professor of Medicine

Director, Women’s HIV/AIDS Program

Massachusetts General Hospital

Boston, MA

Physician CME Information

Accreditation StatementThis 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 DesignationPostgraduate 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 DesignationThis educational activity for 2.0 contact hours is provided by Postgraduate Institute for Medicine (PIM).

Accreditation StatementsPostgraduate 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 NursingPostgraduate 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

Estimated Rates for Adults and Adolescents Living With HIV Infection (not AIDS)

34 States and 5 U.S. Dependent Areas, 2007

Estimated HIV Rateper 100,000

Confidential name-basedHIV infection reporting not implemented as of 2003

2.2 – 51.7

51.8 – 103.8

103.9 – 170.5

170.6 – 282.0Data classed using quartilesTotal rate: 154.2 per 100,000

Note: Rates have been adjusted for reporting delays. Inset maps not to scale. HIV/AIDS Surveillance Report, 2007. Vol 19, table 11.

U.S. Virgin Islands

AKHI

Puerto Rico

American Samoa

NorthernMarianaIslands

Guam

DC

Awareness of HIV Status in the US

1CDC. HIV prevalence estimate—United States, 2006. MMWR. 2008;57(39):1073-1076.2Hall HI, et al. Estimation of HIV incidence in the United States of America. JAMA. 2008;300:520-529.

3CDC. HIV/AIDS surveillance report—cases of HIV infection and AIDS in the United States and dependent areas, 2007;19.http://www.cdc.gov/hiv/topics/surveillance/resources/reports/2007report/default.htm. Accessed July 23, 2009.

HIV estimated prevalence1 1,056,400 - 1,156,400

Undiagnosed1 232,700

Estimated newannual infections (2006)2

56,300

From 2004 to 2007, the estimated number of newly diagnosed HIV/AIDS cases increased 15%3

US Population Demographics: Total Population and HIV/AIDS Cases by Race/Ethnicity

White66%

Other6%

Black12%

Hispanic15%

Total US Population (2007)(N = 301.6 million)1

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-EST2007-03). Population Division, U.S. Census Bureau.2CDC. HIV Incidence. Available at http://www.cdc.gov/hiv/topics/surveillance/incidence.htm.

Estimated HIV/AIDS Prevalence by Race/Ethnicity (2006)

(N = 1,106,400)2

Black46%

White35%

Hispanic/Latino18%

Other<2%

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:– Email to 155 Maryland infectious disease (ID)

physicians– Lectures – general ID talks– Medscape– Emergency room workers (0.5% test)

AUDIENCERESPONSEQUESTION

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

Faculty Disclosures

John G. Bartlett, MDConsulting 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

What’s New in HIV Testing, Access and Linkage to Care?Valerie E. Stone, MD, MPH

Massachusetts General HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA

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)

AUDIENCERESPONSEQUESTION

September 22, 2006 CDC Recommendations: Routine Testing for HIV

• ROUTINE voluntary screening for patients aged 13-64 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

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. 2008 National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA.

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 2006 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. 2008 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.

Views on Routine HIV TestingHIV 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, 2006. Available at: http://www.kff.org/kaiserpolls/pomr050806pkg.cfm.

NeitherDon’t know

Trends in HIV Testing in the US, 2002-2006

Per

cen

t

Ever testedPreceding 12 months

Branson BM. 2008 National Summit on HIV Diagnosis, Prevention and Access to Care. November 19-21, 2008; Arlington, VA.

Location of HIV Testing

Summary health statistics for US adults: National Health Interview Survey, 2006.

2002 2006

Private doctor/HMO 44% 53%

Hospital, ED, Outpatient 22% 18%

Community clinic (public) 9% 9%

HIV counseling/testing 5% 5%

Correctional facility 0.6% 0.4%

STD clinic 0.1% 0.1%

Drug treatment clinic 0.7% 0.4%

Reasons for HIV Testing

0%

20%

40%

60%

80%

100%

Illness Self/partnerat risk

Wanted toknow

Routinecheck up

Required Other

Late (Tested <1 y before AIDS dx)

Early (Tested >5 y before AIDS dx)

Supplement to HIV/AIDS Surveillance, 2000-2003.

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.

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, 2000-2003. MMWR Morbid Mortal Wkly Rep. 2003;52(25):581-586.

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% 2001 – 36% 1998 – 42% 2003 – 38% 2000 – 40% 2005 – 36%

CDC. MMWR Morbid Mortal Wkly Rep. 2009;58(24):661-665.

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):1447-1450.

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):446-453.

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):2614-2622. 3Stein MD. Am J Public Health. 2000;90(7):1138-1140.

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.

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

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

Testing and Access to CareHarold W. Jaffe, MA, MD, FFPH

Professor of Public HealthUniversity of OxfordOxford, UK

Overview of Talk

• HIV rapid tests

• Screening for acute infection

• Test and treat strategy

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

Positive Negative

Reactive Control

HIV Rapid Testing of Oral Fluid

Positive HIV-1/2

HIV Rapid Test Screening in Emergency Departments

SiteScreened

(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;149:153-160.2Christopoulos K, et al. CROI 2009, Abstract #1040.3Lyss SB, et al. J Acquir Immune Defic Syndr. 2007;44:435-442.

Confirmation of Reactive HIV Rapid Tests: Standard Algorithm

Screening Test Confirmatory Test Tie Breaker

Rapid (oral fluid or blood)

WB None

Rapid (oral fluid or blood)

IFA None

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.

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)* Rapid (blood)†

*Second manufacturer †Third manufacturer

From: APHL and CDC. HIV testing algorithms: a status report. April 2009. Available at: http://www.aphl.org/aphlprograms/infectious/hiv/Pages/HIVStatusReport.aspx

WB, Western blot; IFA, indirect fluorescent antibody; NAAT, nucleic acid amplification test.

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)

Resolution Testing

A

Individual NAT testing on 10 specimens

10 Pools of 10 tested with NAT

Screening Pools of 100 specimens tested with NAT

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.

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.

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;198:687-693.

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.

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, FRCPConsultant Physician and Research Director, HIV/GUMChelsea & Westminster HospitalLondon, UK

Cumulative Mortality Estimates

Calculated Using Extended Kaplan-Meier Survival Estimates

CD4 >500 & defer HAART (n=6539)

CD4 >500 & initiate HAART (n=2616)

Years After 1996

0.00

0.05

0.10

0.15

0.20

0 2 4 6 8 10

Kitahata M et al . 16th CROI; 2009; Montreal. Abstract 71.

CD4 Threshold (cells/mm3)

0.5

1

2

4

H

azar

d R

atio

0 100 200 300 400 500

Note that successive comparisons are not statistically independent

Sterne J et al . 16th CROI; 2009; Montreal. Oral Abstract 72LB.

Hazard Ratios for AIDS or Death, Adjusted for Lead Times and Unseen Events

AUDIENCERESPONSEQUESTION

Hit Early?

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

STARTMRK: Percent of Patients With HIV RNA <50 Copies/mL (95% CI) (Non-Completer = Failure)

281 279 281 279 281 279 278 280 280282 282 282 282 281 282 280 281 281

Raltegravir 400 mg bida

Efavirenz 600 mg qhsa

Number of Contributing Patients Weeks

Per

cen

t o

f P

ati

en

ts

0 2 4 8 12 16 24 32 40 48

0

20

40

60

80

100

82%

NoninferiorityP Value <.001

86%

aIn combination with tenofovir/emtricitabine.Lennox J et al. 48th ICAAC–46th IDSA; 2008; Washington, DC. Abstract H-896a.

MERIT-ES Re-analysis: Kaplan-Meier Plot of Time to Virologic Failure (≥50 Copies/mL)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 100 200 300 400 500 600 700

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

Su

rviv

al E

stim

ate

Days

Heera J et al. 5th IAS; 2009; Capetown. Abstract TUAB 103.

3TC, lamivudine; EFV, efavirenz; MVC, maraviroc; ZDV, zidovudine.

Time to Virologic Failure (Plasma HIV RNA >200 log10 copies/mL)

No shorter time to undetectable viral load, but significantly shorter time to virologic failure. Consistent for other HIV RNA thresholds

0.00

0.25

0.50

0.75

1.00

97 97 97 93 91 89ZDV/ABC + TDF/FTC105 105 105 104 103 102ATV/r + TDF/FTC111 111 111 109 109 108EFV/TDF/FTC

Number at risk

0 4 12 24 36 48

Weeks

EFV/TDF/FTC

ATV/r + TDF/FTC

ZDV/ABC + TDF/FTC

Arm HR P

EFV/TDF/FTC 1

ATV/r + TDF/FTC 0.88 0.840

ZDV + ABC + TDF/FTC 3.30 0.012*

ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; ZDV, zidovudine.

Cooper D. 5th IAS; 2009; Capetown. Abstract LBPEB09.

Hit hard?

What agent would you start with?

Why would you no longer start with efavirenz?

Long-Term Consequences of Immune Activation and ART

William G Powderly, MD, ModeratorSally L. Hodder, MDJens Lundgren, MD

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

Long-Term Consequences of Immune Activation and ARTWilliam 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?

Long-Term Consequences of Immune Activation and ARTJens D. Lundgren, MD, DMSc

Professor, Faculty of Health SciencesUniversity 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

TraditionalTraditionalriskrisk

factorsfactors

HIVHIV

ARTART

++

++

++

0

1

2

3

4

5

0 0.5 1 1.5 2 2.5 3 3.5 4

% W

ith a

Maj

or C

VD

Eve

nt

Years from randomization

DC 2752 1306 713 379 10

VS 2720 1292 696 377 10

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* Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure

Risk of Major CVD Events* by Treatment Arm

DC = Drug ConservationVS = Viral Suppression

Change in Log IL-6 (pg/mL) and HDL Cholesterol Concentration (μmol/L) from Baseline to 1 Month*

≤ 400 401-10,000 10,000-50,000 >50,000

Month 1 HIV RNA Level (copies/mL)

∆ IL

-6 (

pg

/mL

)

P<0.0001 for trend

∆ H

DL

(μ

mo

l/L)

* DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL

∆ IL-6

∆ HDL P=0.0003 for trend

SMART/INSIGHT: Duprez et al, CROI, 2009

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

Time-Course for Association Between ARV Drug Exposure and Risk of MI

Start ABC

MIrisk

Some PI: progressive riskwith cumulative exposure

Stop ABC

* Recent = still using or stopped within last 6 months

35

30

25

20

15

10

5

0

Overall Low Moderate High Not known

Rat

e (p

er

100

0 P

Y)

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

Long-Term Consequences of Immune Activation and ART

Sally L. Hodder, MDProfessor of MedicineNew Jersey Medical SchoolUniversity of Medicine and Dentistry of New JerseyNewark, NJ

Discussion Questions

Are HIV-infected patients at a greater risk for bone disease?

Is HIV- associated bone disease related to virus or to treatment?

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;20:2165-2174

Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502.

Women Men

Fracture Prevalence Higher in HIV Patients

Fra

ctu

re P

reva

len

ce/1

00 P

erso

ns

0.5

1.0

1.5

2.0

2.5

3.0

0

HIVNon-HIV

P=0.002

P=0.01

P=0.53

P=0.01

Any Vertebral Hip Wrist

Fra

ctu

re P

reva

len

ce/1

00 P

erso

ns

0.5

1.0

1.5

2.0

2.5

3.0

0

HIVNon-HIV

P<0.0001

P<0.0001P=0.001

P=0.001

Any Vertebral Hip Wrist

• Population: 8,525 HIV+ and 2,208792 HIV-• Patients with fracture: 245 HIV+ and 39,073 HIV-• Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV-

Changes in Hip Bone Mineral Density with Antiretroviral Therapy

Intermittent (Fracture 0.03/100 PY)Continuous (Fracture 0.13/100 PY)

n = 109 86 51 9 n = 95 75 47 15

Est. diff.: 1.3 1.7 1.0 2.5P values: .002 .005 .27 .21

Gallant et al. JAMA 2004, 292:191. Grund B et al. ICAAC/IDSA 2008. Abstract 2312a.

d4T + 3TC + EFVTDF + 3TC + EFV

n=301 267 246 226 205 185 181 n=299 261 234 221 209 193 185

-4

-3

-2

-1

0

1

0 1 3 4Years

Ch

ang

e F

rom

B

asel

ine

(%)

2

Gilead 903 Study SMART Study

-8

-6

-2

0

4

8

2

6

Baseline 24 48 72 96 120 144

Weeks

P=0.06

Association of Osteoporosis with Antiretroviral Therapy

Brown TT et al. AIDS. 2006, 22:2168.

Antiretroviral Therapy Overall Protease Inhibitor Therapy

Odds ratio0.01 100

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, 187.76)

0.54 (0.05, 5.68)

2.38 (1.20, 4.75)

Odds ratio0.01 100

Odds ratio (95%CI)

0.61 (0.21, 1.72)

11.09 (0.57, 217.66)

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

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

1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12):1521-1529.2. Fakruddin JM et al. J Biol Chem. 2003;278:48251-48258.

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.

25-OH Vitamin D Deficiency Prevalent in HIV-Infection

1. Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14.2. Seminari E et al. HIV Med. 2005;6:145-150.3. Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):537-539.

• 47% Boston outpatient HIV clinic (n=57)1

– Low Vitamin D intake in 31% < 50 years and 76% 51-70 years

– Low calcium intake in in 37% < 50 years and 71% 51-70 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)

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 15.9 17.9 22.3

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

Cauley JA et al. J Bone Miner Res. 2007;22:1092.

Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers*

Years

0

4

8

12

16

20

% W

ith

No

n-s

pin

e F

ract

ure

0 81 2 3 4 65 7

2

6

10

14

18

2+

0 or 1

P = 0.0093 (log rank test)

*CRP, IL-6, TNFα

Discussion Questions

Are there important long-term CNS consequences of HIV in adequately treated patients?

Is CNS penetration of antiviral drugs important?

HIV-1 Infection and the CNS

21.1

17.8

10.5

0

5

10

15

20

25

1990-1992 1993-1995 1996-1998

Mean Incidence HIV DementiaMACS Cohort 1990-1998

Nu

mb

er/1

000

per

son

yea

rs

Antinori A et al. Neurology. 2007;69:1789-1799Sacktor N et al. Neurology. 2001;56:257-260

• HIV-Associated Neurocognitive Disorder– Asymptomatic

neurocognitive impairment

– Minor neurocognitive disorder

– Dementia

Mean Incidence HIV DementiaMACS Cohort 1990-1998

Does CNS Antiretroviral Agent Penetration Matter?

Letendre S et al. Arch Neurol. 2008;65(1):65-70.

Pro

po

rtio

n o

f S

ub

ject

s W

ith

D

etec

tab

le C

SF

Vir

al L

oad

CPE Score

Pro

po

rtio

n o

f S

ub

ject

s W

ith

Det

ecta

ble

C

SF

Vir

al L

oa

d

0

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)

CPE Score

N=31 (24 ART naïve)CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV

Does CSF HIV RNA Affect Neurocognitive Function?

Letendre S et al. Ann Neurol. 2004;56:419.

Red

uct

ion

in G

DS

at

Fo

llow

-up

CSF HIV RNA Suppression at Follow-up

Not Suppressed Suppressed

1.0

0.5

0.0

-0.5

N=14 N=17

2=6.25 P=.01

Sinclair E et al. JAIDS. 2008;47:548.

ART Affects CNS Immune Activation

% C

SF

CD

8 C

D38

+D

R+

Blood CD8 Activation

Off Failure Success HIV–

% B

ld C

D8

CD

38+

DR

+

100

40

80

60

20

0

CSF CD8 Activation

Off Failure Success HIV–

100

40

80

60

20

0

Off

Failure

Success

HIV–

Long-Term Consequences of Immune Activation and ARTJens D. Lundgren, MD, DMScProfessor, Faculty of Health SciencesUniversity 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 20082 Shirodkar et al, Curr Opin Urol 20093 Mudie et al, J Clin Oncol 2006

For 20 / 28 cancers examined there was significantly increased incidencein both groups – strongly suggesting a link with immunodeficiency

Standardized Incidence Ratio

HIV/AIDS Transplant

Lung 2.7 2.2Leukaemia 3.2 2.4Kidney 1.5 6.8Oesophagus 1.6 3.1Stomach 1.9 2.0

Meta-analysis: 444,172 people with HIV, 31,977 transplant patients

Grulich et al, Lancet 2007.

HIV and Risk of Non-AIDS Malignancies

HPV Cancers and HIV Transmission

• Temporal trends in US cohort - incidence of anal cancer (/100,000 PYs) 19 (1992-95), 48.3 (1996-99), 78.2 (2000-2003)

• 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.