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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

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John g bartlett md program chair l.jpg

John G. Bartlett, MDProgram Chair

Professor of MedicineJohns Hopkins University School of MedicineBaltimore, MD


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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


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Program Agenda


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Program Agenda (Continued)


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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


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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, Women’s HIV/AIDS Program

Massachusetts General Hospital

Boston, MA


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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.


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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


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Program Sponsorship

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


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Financial Support

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


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

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

American Samoa

NorthernMarianaIslands

Guam

DC

Estimated HIV Rateper 100,000

Confidential name-basedHIV 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: 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


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

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.


Us population demographics total population and hiv aids cases by race ethnicity l.jpg

Total US Population (2007)

(N = 301.6 million)1

Estimated HIV/AIDS Prevalence by Race/Ethnicity (2006)(N = 1,106,400)2

Other<2%

Other

6%

Hispanic/Latino18%

White

66%

Black46%

Black

12%

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

White35%

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


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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)


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AUDIENCE

RESPONSE

QUESTION


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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


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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


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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


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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)


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AUDIENCE

RESPONSE

QUESTION


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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 NOTrequired

Goal is to make HIV testing

Less exceptional

Universal and routine

Not based on RISK


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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.


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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.


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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, 2006. Available at: http://www.kff.org/kaiserpolls/pomr050806pkg.cfm.


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Trends in HIV Testing in the US, 2002-2006

Ever tested

Preceding 12 months

Percent

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


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Location of HIV Testing

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


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Reasons for HIV Testing

100%

Late (Tested <1 y before AIDS dx)

Early (Tested >5 y before AIDS dx)

80%

60%

40%

20%

0%

Illness

Self/partner

Wanted to

Routine

Required

Other

check up

at risk

know

Supplement to HIV/AIDS Surveillance, 2000-2003.


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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.


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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.


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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.


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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

People Living with HIV/AIDS: ~1,000,000

New Sexual Infections Each Year: ~32,000

Marks G et al. AIDS. 2006;20(10):1447-1450.


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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.


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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.


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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.


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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


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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


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Testing and Access to Care

Harold W. Jaffe, MA, MD, FFPH

Professor of Public HealthUniversity of OxfordOxford, UK


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Overview of Talk

HIV rapid tests

Screening for acute infection

Test and treat strategy


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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


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HIV Rapid Testing of Oral Fluid

Reactive Control

Positive HIV-1/2

Positive

Negative


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HIV Rapid Test Screening in Emergency Departments

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.


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Confirmation of Reactive HIV Rapid Tests: Standard Algorithm

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.


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Confirmation of Reactive HIV Rapid Tests: Proposed Algorithms

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 2009. Available at: http://www.aphl.org/aphlprograms/infectious/hiv/Pages/HIVStatusReport.aspx


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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


Resolution testing l.jpg

Resolution Testing

A

Individual NAT testing on 10 specimens

10 Pools of 10 tested with NAT

Screening Pools of 100 specimens tested with NAT


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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.


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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.


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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.


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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.


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Hit Hard, Hit Early: When to Treat and With What?

Brian G. Gazzard, MD, Moderator

Julio Montaner, MD

Calvin J. Cohen, MD, MS


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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


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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


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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

0

2

4

6

8

10

Years After 1996

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


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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

0

CD4 Threshold (cells/mm3)

Note that successive comparisons are not statistically independent

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


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AUDIENCE

RESPONSE

QUESTION


Hit early l.jpg

Hit Early?

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


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

86%

100

80

82%

60

Percent of Patients

Noninferiority

P Value <.001

40

20

0

0

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.


Merit es re analysis kaplan meier plot of time to virologic failure 50 copies ml l.jpg

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

700

0

100

200

300

400

500

600

Days

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

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


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

1.00

0.75

0.50

EFV/TDF/FTC

0.25

ATV/r + TDF/FTC

ZDV/ABC + TDF/FTC

0.00

0

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.


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Hit hard?

What agent would you start with?

Why would you no longer start with efavirenz?


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Long-Term Consequences of Immune Activation and ART

William G Powderly, MD, Moderator

Sally L. Hodder, MD

Jens Lundgren, MD


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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


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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


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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


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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


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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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Long-Term Consequences of Immune Activation and ART

Jens D. Lundgren, MD, DMSc

Professor, Faculty of Health SciencesUniversity of Copenhagen

Head, Centre for Viral Diseases/KMA, Rigshospitalet

Head, Copenhagen HIV Programme,

Denmark


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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?


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Principal factors affecting risk of CVD in HIV

HIV

+

Traditional

risk

factors

+

+

ART


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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

Years from randomization

No. at risk

DC 2752 1306 713 379 10

VS 2720 1292 696 377 10

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

SMART/CVD: Phillips et al, AVT 2008


Change in log il 6 pg ml and hdl cholesterol concentration mol l from baseline to 1 month l.jpg

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

∆ IL-6

0.4

0.4

P=0.0003 for trend

∆HDL

0.3

0.3

0.2

0.2

0.1

0.1

∆ IL-6 (pg/mL)

∆ HDL (μmol/L)

0

0

-0.1

-0.1

-0.2

-0.2

P<0.0001 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


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Some PI: progressive risk

with cumulative exposure

Start ABC

Stop ABC

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

MI

risk


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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

0

Rate (per 1000 PY)

OverallLow 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


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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


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Discussion Questions

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

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


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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


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Fracture Prevalence Higher in HIV Patients

  • 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-

Women

Men

3.0

3.0

P=0.002

P<0.0001

HIVNon-HIV

HIVNon-HIV

2.5

2.5

2.0

2.0

Fracture Prevalence/100 Persons

Fracture Prevalence/100 Persons

P=0.01

P=0.001

1.5

1.5

P=0.01

P<0.0001

1.0

1.0

P=0.001

P=0.53

0.5

0.5

0

0

Any

Vertebral

Hip

Wrist

Any

Vertebral

Hip

Wrist

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


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Changes in Hip Bone Mineral Density with Antiretroviral Therapy

d4T + 3TC + EFV

TDF + 3TC + EFV

Gilead 903 Study

SMART Study

Intermittent (Fracture 0.03/100 PY)

8

Continuous (Fracture 0.13/100 PY)

1

6

0

4

-1

2

Change From Baseline (%)

-2

0

-3

-2

P=0.06

-4

-6

0

1

2

3

4

Years

-8

Baseline

24

48

72

96

120

144

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

Weeks

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

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.


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Association of Osteoporosis with Antiretroviral Therapy

Antiretroviral Therapy Overall

Protease Inhibitor Therapy

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, 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)

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)

0.01

Odds ratio

100

0.01

Odds ratio

100

Caveat: Few studies adjusted for age or duration of infection

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


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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):1521-1529.

2. Fakruddin JM et al. J Biol Chem. 2003;278:48251-48258.


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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% 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)

  • Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14.

  • Seminari E et al. HIV Med. 2005;6:145-150.

  • Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):537-539.


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Inflammatory Biomarkers Associated With Bone Fracture

Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory

† 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.


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Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers*

*CRP, IL-6, TNFα

20

18

16

2+

14

12

0 or 1

10

% With Non-spine Fracture

8

6

4

P = 0.0093 (log rank test)

2

0

0

1

2

3

4

5

6

7

8

Years

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


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Discussion Questions

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

Is CNS penetration of antiviral drugs important?


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HIV-1 Infection and the CNS

Mean Incidence HIV Dementia

MACS Cohort 1990-1998

Mean Incidence HIV Dementia

MACS Cohort 1990-1998

  • HIV-Associated Neurocognitive Disorder

    • Asymptomatic neurocognitive impairment

    • Minor neurocognitive disorder

    • Dementia

Number/1000 person years

Antinori A et al. Neurology. 2007;69:1789-1799

Sacktor N et al. Neurology. 2001;56:257-260


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Does CNS Antiretroviral Agent Penetration Matter?

N=31 (24 ART naïve)

CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV

0.5

0.4

0.3

Proportion of Subjects With Detectable CSF Viral Load

Proportion of Subjects With Detectable CSF Viral Load

0.2

0.1

0

≤0.5(n=38)

1(n=128)

≥3.5(n=25)

1.5(n=100)

2(n=100)

2.5(n=63)

3(n=13)

CPE Score

CPE Score

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


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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.


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ART Affects CNS Immune Activation

Off

Failure

Success

HIV–

Blood CD8 Activation

CSF CD8 Activation

100

100

80

80

60

60

% Bld CD8 CD38+DR+

40

40

% CSFCD8 CD38+DR+

20

20

0

0

Off

Failure

Success

HIV–

Off

Failure

Success

HIV–

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


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Long-Term Consequences of Immune Activation and ART

Jens D. Lundgren, MD, DMSc

Professor, Faculty of Health SciencesUniversity of Copenhagen

Head, Centre for Viral Diseases/KMA, Rigshospitalet

Head, Copenhagen HIV Programme,

Denmark


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Discussion Question Related to Cancers

Will we see more cancers in HIV infected patients in the next 10 years?


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AIDS and Non-AIDS Defining Cancers in Baltimore Cohort

Long et al, AIDS 2008


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Incidence of non-AIDS defining cancers in HIV-infected and uninfected persons in VA

Bedimo et al, JAIDS 2009.


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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


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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 2.72.2

Leukaemia 3.22.4

Kidney 1.56.8

Oesophagus 1.63.1

Stomach 1.92.0

Grulich et al, Lancet 2007.


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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.


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