John G. Bartlett, MD Program Chair

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(No Transcript)
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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
730 pm 735 pm Welcome and Introduction John G. Bartlett, MD, Program Chair
735 pm 800 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
800 pm 810 pm Panel Discussion Audience Q A
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Program Agenda (Continued)
810 pm 835 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
835 pm 845 pm Panel Discussion/Audience Q A
845 pm 910 pm Long-Term Consequences of Immune Activation and ARTWilliam G. Powderly, MD, Moderator Sally L. Hodder, MD Jens Lundgren, MD
910 pm 925 pm Panel Discussion/Audience Q A
925 pm 930 pm Concluding Remarks and Program Adjournment John G. Bartlett, MD, Program Chair
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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, Womens 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 Centers
  Commission on Accreditation.
• California Board of Registered Nursing
• Postgraduate Institute for Medicine is approved
  by the California Board of Registered Nursing,
  Provider Number 13485, for 2.4 contact hours

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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
13
Awareness of HIV Status in the US
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 153
1CDC. HIV prevalence estimateUnited States,
2006. MMWR. 200857(39)1073-1076. 2Hall HI, et
al. Estimation of HIV incidence in the United
States of America. JAMA. 2008300520-529. 3CDC.
HIV/AIDS surveillance reportcases of HIV
infection and AIDS in the United States and
dependent areas, 200719.http//www.cdc.gov/hiv/t
opics/surveillance/resources/reports/2007report/de
fault.htm. Accessed July 23, 2009.
14
US Population Demographics Total Population and
HIV/AIDS Cases by Race/Ethnicity
Total US Population (2007) (N 301.6 million)1
Estimated HIV/AIDS Prevalence by Race/Ethnicity
(2006) (N 1,106,400)2
Otherlt2
Other 6
Hispanic/Latino18
White 66
Black46
Black 12
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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Which of the following do you most favor
regarding testing adults for HIV?

1. Require signed consent
2. Require pre-test post test counseling (/-
   signed consent)
3. Require notification that you are doing the test
4. No requirements

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

1. gt700
2. 550-700
3. 400-550
4. 350-400
5. lt350

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You would start on 2NRTIs plus?

1. Efavirenz
2. Lopinavir/ritonavir
3. Atazanavir/ritonavir
4. Darunavir/ritonavir
5. Raltegravir

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HAART is effective for improved outcome with?

1. HIV dementia
2. Cardiovascular events
3. Premature aging

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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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Whats 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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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

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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

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Question 2

• If you responded that you should obtain an HIV
  antibody testwhy?
• This patients sexual history
• This patients age group
• Would suggest routinely for all patients at their
  annual physical
• Given the topic of this presentation, it seemed
  like the right response!

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Question 2 Response

• If you responded that you should obtain an HIV
  antibody testwhy?
• This patients sexual history
• This patients age group
• Would suggest routinely for all patients at their
  annual physical
• Given the topic of this presentation, it seemed
  like the right response!

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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 NOT required
• 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 CDCs 2006 recommendations, 20
  states had laws or regulations that required
  written consent for HIV testing
• Currently, laws in 40 states and DC are
  compatible with the CDC 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

Dont 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.
34
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
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
Summary health statistics for US adults National
Health Interview Survey, 2006.
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Reasons for HIV Testing
100
Late (Tested lt1 y before AIDS dx)
Early (Tested gt5 y before AIDS dx)
80
60
40
20
0
Illness
Self/partner
Wanted to
Routine
Required
Other
at risk
know
check up
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.
38
Late HIV Diagnosis Is Common

• In 1 state, 45 of patients diagnosed with HIV
  within 1 year of AIDS diagnosis (late testers)
• Late testers compared with early testers (gt5 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. 200352(25)581-586.
39
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.
200958(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. 200620(10)1447-1450.
41
Knowledge of HIV Infection and Behavior

• Meta-analysis of 11 HIV risk-behavior studies
• Unprotected anal/vaginal sex with HIV-negative
  partners was 68 lower in people aware vs unaware
  they were HIV positive

Marks G et al. J Acquir Immune Defic Syndr.
200539(4)446-453.
42
Critical Challenge Linkage to Care

• Mean time from diagnosis to first HIV primary
  care visit 2.5 years in cohort of 203 consecutive
  outpatients presenting for HIV care in Boston1
• HIV Cost and Services Utilization Study (HCSUS)
  1/3 of people delayed gt3 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. 200115(1)77-85 2Turner BJ.
Arch Intern Med. 2000160(17)2614-2622. 3Stein
MD. Am J Public Health. 200090(7)1138-1140.
43
HIV Provider-Cited Challenges to Early Linkage to
Care

• Manpower issues number of HIV providers is
  insufficient and decreasing
• Productivity is lower in HIV-focused practices
  than in other primary care practices
• Numerous hidden costs of care that negatively
  impact the cost-effectiveness of HIV care
• All of these factors result in each additional
  patient who is newly linked to care
  contributing further to the challenging financial
  situation of HIV-focused practices

Saag M, Weddle A, Carmichael JK. National Summit
on HIV Diagnosis, Prevention and Access to Care
November 19-21, 2008 Arlington, VA.
44
Interventions to Reduce Delay

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

45
Summary

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

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Testing and Access to Care

• Harold W. Jaffe, MA, MD, FFPH
• Professor of Public HealthUniversity of
  OxfordOxford, UK

48
Overview of Talk

• HIV rapid tests
• Screening for acute infection
• Test and treat strategy

49
HIV Rapid Tests

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

50
HIV Rapid Testing of Oral Fluid
Reactive Control
Positive HIV-1/2
Positive
Negative
51
HIV Rapid Test Screening in Emergency Departments
Site Screened(N) HIV Prevalence ()
Brigham and Womens 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.
2008149153-160. 2Christopoulos K, et al. CROI
2009, Abstract 1040. 3Lyss SB, et al. J Acquir
Immune Defic Syndr. 200744435-442.
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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
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
Screening Test Confirmatory Test Tie Breaker
Rapid (oral fluid or blood) Rapid (blood) WB/IFA/NAAT
Rapid (blood) 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 2009. Available at
http//www.aphl.org/aphlprograms/infectious/hiv/Pa
ges/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
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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.
57
Test and Treat Strategy

• Our model suggests that massive scale-up of
  universal voluntary HIV testing with immediate
  initiation of ART could nearly stop transmission
  and drive HIV into an elimination phase in a
  high-burden setting within 1-2 years of reaching
  90 of programme coverage.

Granich RM et al. Lancet. 200937348-57.
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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.
2008198687-693.
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A Hypothetical Conversation

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

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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 (JJ), 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 gt500 defer HAART (n6539)
CD4 gt500 initiate HAART (n2616)
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
0
100
200
300
400
500
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
67
Assume you are HIV positive and have a CD4 count
of 500 cc/mL. You have two options. Which would
you choose?

• 1. 10,000 in the bank annually earning compound
  interest until your CD4 count is 350 cc/mL
• 2. Start ART immediately

68
Hit Early?

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

69
STARTMRK Percent of Patients With HIV RNA lt50
Copies/mL (95 CI) (Non-Completer Failure)
86
100
80
82
60
Percent of Patients
Noninferiority P Value lt.001
40
20
0
0
2
4
8
12
16
24
32
40
48
Weeks
Number of Contributing Patients
281
279
281
279
281
279
278
280
280
Raltegravir 400 mg bida
282
282
282
282
281
282
280
281
281
Efavirenz 600 mg qhsa
aIn combination with tenofovir/emtricitabine. Lenn
ox J et al. 48th ICAAC46th IDSA 2008
Washington, DC. Abstract H-896a.
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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
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.
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Time to Virologic Failure (Plasma HIV RNA gt200
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
0
4
12
24
36
48
Number at risk
Weeks
111
111
111
109
109
108
EFV/TDF/FTC
105
105
105
104
103
102
ATV/r TDF/FTC
97
97
97
93
91
89
ZDV/ABC TDF/FTC
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.
72
Hit hard?

• What agent would you start with?
• Why would you no longer start with efavirenz?

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74
Long-Term Consequences of Immune Activation and
ART

• William G Powderly, MD, Moderator
• Sally L. Hodder, MD
• Jens Lundgren, MD

75
Faculty Disclosures

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

76
Long-Term Consequences of Immune Activation and
ART
William G. Powderly, MD Dean of Medicine Head,
University College Dublin School of Medicine and
Medical Science Dublin, Ireland
77
Immune Activation in HIV

• Chronic untreated HIV infection is associated
  with immune activation
• In established infection, 50 of peripheral CD8
  T cells appear to be activated, compared with
  lt10 in HIV-uninfected persons
• Similar trends in the CD4 T-cell population
• Frequency of activated T cells predicts disease
  progression, independent of HIV-1 RNA
• Antiretroviral therapy reduces HIV-associated
  T-cell activation, although often incompletely
• Markers of inflammation elevated in untreated HIV
  infection
• Only partially reversed with effective ART

78
Mechanism of Immune Activation

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

79
Significance of Immune Activation

• Constant T-cell proliferation and death in
  uncontrolled HIV may result in eventual
  immunologic exhaustion
• Even with treatment, persistent immune activation
  may lead to immune senescence and premature aging
  of the immune system
• Full immune recovery (with reversal of
  activation) may not be seen with effective ART,
  especially in patients with low CD4 T-cell count
  nadir (lt200 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
82
Discussion Questions Related to CVD

• What is the evidence that HIV infection is
  associated with an increased risk of
  cardiovascular disease?
• What are the possible causes of this increased
  risk?
• Is immune activation a possible cause?

83
Principal factors affecting risk of CVD in HIV
HIV

Traditional risk factors


ART
84
Risk of Major CVD Events by Treatment Arm
DC
Relative hazard 1.57 (1.00 2.46) p 0.05
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
85
Change in Log IL-6 (pg/mL) and HDL Cholesterol
Concentration (µmol/L) from Baseline to 1 Month
? IL-6
0.4
0.4
P0.0003 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
Plt0.0001 for trend
-0.3
-0.3
400
401-10,000
10,000-50,000
gt50,000
-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
86
Time-Course for Association Between ARV Drug
Exposure and Risk of MI
MI risk
87
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)
Overall Low Moderate High Not known
Predicted 10-year CHD risk
Recent still using or stopped within last 6
months
DAD study Sabin et al, Lancet, 2008
88
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

89
Discussion Questions

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

90
Bone Mineral Density in HIV-Infected Persons

• Multiple studies have found increased prevalence
  of osteoporosis and osteopenia in HIV-infected
  persons compared with uninfected persons
• Meta-analytical review of studies
• 67 HIV infected persons had reduced BMD (OR 6.4)
• 15 HIV had osteoporosis (OR 3.7)

Brown et al AIDS 2006202165-2174
91
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
P0.002
Plt0.0001
HIVNon-HIV
HIVNon-HIV
2.5
2.5
2.0
2.0
Fracture Prevalence/100 Persons
Fracture Prevalence/100 Persons
P0.01
P0.001
1.5
1.5
P0.01
Plt0.0001
1.0
1.0
P0.001
P0.53
0.5
0.5
0
0
Any
Vertebral
Hip
Wrist
Any
Vertebral
Hip
Wrist
Triant VA et al. J Clin Endocrinaol Metab.
200893(9)3502.
92
Changes in Hip Bone Mineral Density with
Antiretroviral Therapy
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
P0.06
-4
-6
0
1
3
4
2
Years
-8
Baseline
24
48
72
96
120
144
n 109 86
51 9 n 95
75 47 15
Weeks
n301 267 246 226 205 185
181 n299 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, 292191.
Grund B et al. ICAAC/IDSA 2008. Abstract 2312a.
93
Association of Osteoporosis with Antiretroviral
Therapy
Antiretroviral Therapy Overall
Protease Inhibitor Therapy
Odds ratio (95CI) 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 (95CI)
Study Amiel (2004) Bruera (2003) Garcia
(2001) Knobel (2001) Knishi (2005) Mededdu
(2004) Vescini (2003) Overall (95CI)
Odds ratio (95CI) 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)
Caveat Few studies adjusted for age or duration
of infection
Brown TT et al. AIDS. 2006, 222168.
94
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 PPAR? activity1
• gp120 (100 ng/ml) induces RANKL2

RUNX-2 (Runt-related transcription factor-s)
promotes osteoblast differentiation. PPAR?
(Peroxisome proliferator-activated receptor
gamma) promotes adipogenesis. RANKL (Receptor
Activator for Nuclear Factor ? B Ligand),
activates osteoclasts.
1. Cotter EJ et al. AIDS Res Hum Retroviruses.
200723(12)1521-1529. 2. Fakruddin JM et al. J
Biol Chem. 200327848251-48258.
95
25-OH Vitamin D Deficiency Prevalent in
HIV-Infection

• 47 Boston outpatient HIV clinic (n57)1
• Low Vitamin D intake in 31 lt 50 years and 76
  51-70 years
• Low calcium intake in in 37 lt 50 years and 71
  51-70 years
• 81 Italian HIV treatment-experienced patients
  (n48)2
• 86 in Spanish cohort of men (n30)3
• Mean 25,OH Vitamin D level 14.3 ng/ml in healthy
  controls vs.11.4 ng/ml (p0.044)

1. Rodriguez M et al. AIDS Res Hum Retroviruses.
   200925(1)9-14.
2. Seminari E et al. HIV Med. 20056145-150.
3. Garcia Aparicio AM et al. Clin Rheumatol.
   200625(4)537-539.

96
Inflammatory Biomarkers Associated With Bone
Fracture
Incidence Rate (per 1000 Person-Years) of
Fracture by Quartiles of Inflammatory
All All All 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
Plt.05 from trend test. Plt.01 from trend
test. Plt.001 from trend test.
Cauley JA et al. J Bone Miner Res. 2007221091.
97
Cumulative Nonspine Fracture by Highest Quartile
Inflammatory Markers
CRP, IL-6, TNFa
20
18
16
2
14
12
10
0 or 1
With Non-spine Fracture
8
6
4
P 0.0093 (log rank test)
2
0
0
8
1
2
3
4
6
5
7
Years
Cauley JA et al. J Bone Miner Res. 2007221092.
98
Discussion Questions

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

99
HIV-1 Infection and the CNS
Mean Incidence HIV Dementia MACS Cohort 1990-1998

• HIV-Associated Neurocognitive Disorder
• Asymptomatic neurocognitive impairment
• Minor neurocognitive disorder
• Dementia

Mean Incidence HIV Dementia MACS Cohort 1990-1998
Number/1000 person years
Antinori A et al. Neurology. 2007691789-1799 Sac
ktor N et al. Neurology. 200156257-260
100
Does CNS Antiretroviral Agent Penetration Matter?

N31 (24 ART naïve) CSF penetrating drugs
d4T,AZT, ABC, EFV, NVP IDV
Proportion of Subjects With Detectable CSF Viral
Load
CPE Score
CPE Score
Letendre S et al. Arch Neurol. 200865(1)65-70.
101
Does CSF HIV RNA Affect Neurocognitive Function?
1.0
0.5
Reduction in GDS at Follow-up
0.0
??26.25 P.01
-0.5
N14
N17
Not Suppressed
Suppressed
CSF HIV RNA Suppression at Follow-up
Letendre S et al. Ann Neurol. 200456419.
102
ART Affects CNS Immune Activation
CSFCD8 CD38DR
Sinclair E et al. JAIDS. 200847548.
103
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
104
Discussion Question Related to Cancers

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

105
AIDS and Non-AIDS Defining Cancers in Baltimore
Cohort
Long et al, AIDS 2008
106
Incidence of non-AIDS defining cancers in
HIV-infected and uninfected persons in VA
Bedimo et al, JAIDS 2009.
107
Why Will Incidence of Cancers Increase in the
Next 10 Years

• Risk of AIDS-related cancers decreased due to
  benefit of ART
• Except HPV-induced genital cancers
• HIV-infected population is aging
• Risk of fatal non-AIDS-defining cancers increases
  47 per 5 year older age (i.e. gt2-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 DAD study group, AIDS 2008 2 Shirodkar et
al, Curr Opin Urol 2009 3 Mudie et al, J Clin
Oncol 2006
108
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 2.7 2.2 Leukaemia
3.2 2.4 Kidney 1.5 6.8 Oesophagus
1.6 3.1 Stomach 1.9 2.0
Grulich et al, Lancet 2007.
109
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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