1. health and fitness
2. disease
3. aids and hiv

2009
Improving the Management of HIV Disease ®
AN ADVANCED CME COURSE IN HIV
PATHOGENESIS, ANTIRETROVIRALS, AND
OTHER SELECTED ISSUES IN HIV DISEASE
MANAGEMENT
Friday, May 8, 2009
JW Marriott Hotel
1331 Pennsylvania Avenue
Washington, DC 20004
COURSE CHAIR
Henry Masur, MD
Clinical Professor of Medicine
George Washington University School of Medicine
Bethesda, Maryland
COURSE VICE-CHAIR
Michael S. Saag, MD
Member, Board of Directors (Volunteer)
International AIDS Society–USA
Professor of Medicine
Director, Division of Infectious Diseases and
The William C. Gorgas Center for
Georgraphic Medicine
University of Alabama at Birmingham
Birmingham, Alabama
The International AIDS Society–USA is accredited
by the Accreditation Council for Continuing
Medical Education to sponsor continuing medical
education for physicians.
The International AIDS Society–USA designates
this educational activity for a maximum of 6.5 AMA
PRA Category 1 Credits™. Physicians should only
claim credit commensurate with the extent of their
participation in the activity.
©2009 International AIDS Society–USA
CONTENTS
The International AIDS Society–USA ...........................................................................2
Course Faculty ...............................................................................................................4
Course Agenda ..............................................................................................................5
CME Credits, American Academy of Family Physician Credits, Claiming CME
Credits, and Nursing Continuing Education Contact Hours ........................................6
Needs Statement and Course Objectives ....................................................................8
Educational Format........................................................................................................8
Relevant Policy on Disclosure, Conflicts of Interest, and Proximate Activities ...........9
Grant Support...............................................................................................................10
Disclosure Information .................................................................................................11
Audience Response System Instructions...................................................................14
International AIDS Society–USA CME Programs ......................................................15
Topics in HIV Medicine® Subscription Form ...............................................................18
Presentation Summaries
♦ Early Events in HIV Infection: Implications for Pathogenesis,
Treatment, and Prevention
Anthony S. Fauci, MD.....................................................................................19
♦ New Issues in Antiretroviral Drug Resistance
Daniel R. Kuritzkes, MD..................................................................................23
♦ Cardiovascular Risk: HAART to HEART
Judith A. Aberg, MD ........................................................................................35
♦ Malignancies in HIV: A Growing Problem
Ronald T. Mitsuyasu, MD................................................................................47
♦ Addictions in the HIV Clinic
Glenn J. Treisman, MD, PhD .........................................................................57
♦ Methicillin-Resistant Staphylococcus aureus
John G. Bartlett, MD........................................................................................71
♦ Strategies for Antiretroviral Therapy: Case-Based Panel Discussion
Michael S. Saag, MD......................................................................................91
♦ HIV and Hepatitis C Virus Coinfection
Kenneth E. Sherman, MD, PhD.....................................................................99
Frequently Asked Questions About IAS–USA CME Courses .................................101
Common Abbreviations .............................................................................................103
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
THE INTERNATIONAL AIDS SOCIETY–USA
The International AIDS Society–USA (IAS–USA) is a 501(c)(3) not-for-profit organization that provides cuttingedge, clinically relevant, unbiased education and information for clinicians who are actively involved in HIV care.
The educational activities are particularly intended to bridge clinical research and patient care.
Non-Staff Board Members serve in a volunteer capacity and are not compensated for their roles in oversight and
governance of the organization. As part of its duties, the Board oversees the development of the educational
programs along with the Program Committee Liaisons.
Board of Directors
Paul A. Volberding, MD
Marvin Sleisenger Professor of Medicine
Vice-Chair, Department of Medicine
University of California San Francisco
Chief of Medical Service
San Francisco Veterans Affairs Medical Center
San Francisco, California
Joel E. Gallant, MD, MPH
Professor of Medicine and Epidemiology
The Johns Hopkins University
Associate Director
Johns Hopkins AIDS Service
Baltimore, Maryland
Roy M. Gulick, MD, MPH
Professor of Medicine
Chief of the Division of Infectious Diseases
Weill Medical College of Cornell University
New York, New York
Constance A. Benson, MD
Professor of Medicine
Division of Infectious Diseases
University of California San Diego
San Diego, California
Donna M. Jacobsen
Founding Executive Director/President
International AIDS Society–USA
San Francisco, California
Peter C. Cassat, JD
Member
Dow, Lohnes & Albertson, PLLC
Washington, DC
Douglas D. Richman, MD
Professor of Pathology and Medicine
University of California San Diego and
Veterans Affairs San Diego Healthcare System
San Diego, California
Judith S. Currier, MD
Professor of Medicine
University of California Los Angeles (UCLA)
Associate Director
UCLA Center for Clinical AIDS Research
and Education
Los Angeles, California
Michael S. Saag, MD
Professor of Medicine
Director, Division of Infectious Diseases and The
William C. Gorgas Center for Geographic Medicine
University of Alabama at Birmingham
Birmingham, Alabama
Carlos del Rio, MD
Professor of Medicine
Emory University
Chief of Medical Services
Grady Memorial Hospital
Atlanta, Georgia
Robert T. Schooley, MD
Professor of Medicine
Head, Division of Infectious Diseases
University of California San Diego
San Diego, California
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
2
THE INTERNATIONAL AIDS SOCIETY–USA
CME Courses
Drug Resistance Mutations Project
IAS–USA Continuing Medical Education (CME)
courses present state-of-the-art lectures and
discussion of current issues in clinical
management of HIV disease. The CME courses
promote interaction between faculty and attendees
via an audience-response touchpad system and
question-and-answer periods. These courses,
®
along with our journal, Topics in HIV Medicine ,
and the interactive activities on our Web site
(Cases on the Web), are a comprehensive set of
core educational activities. The IAS–USA also
offers Webcasts of the live courses. Those who
cannot attend courses can access these cuttingedge presentations online.
Through the Drug Resistance Mutations Project, the
IAS–USA provides regular updates on the mutations
associated with resistance to antiretroviral drugs.
The information on relevant mutations is collected
and reviewed by a panel of acknowledged leaders in
the field. This information is made available in Topics
®
in HIV Medicine, on a laminated pocket-reference
card, and on the IAS–USA Web site at
www.iasusa.org.
Topics in HIV Medicine
Core Faculty Lecture Series
The Core Faculty Lecture Series is a live CME
activity. IAS–USA Core Faculty present topics
selected from a menu of key HIV issues at local
venues to those practitioners who may be located
outside major HIV epicenter areas and unable to
attend regional CME programs. Session topics for
2009 have been designed for experienced
providers: 1) management of antiretroviral failure
including use of resistance testing, investigational
new antiretroviral drugs, and 2) managing the
complications of HIV and its therapy. More
information about the IAS–USA Core Faculty
Lecture Series and how to request a program in
you area is available on the IAS–USA Web site at
www.iasusa.org.
®
®
The IAS–USA journal, Topics in HIV Medicine , is
a peer-reviewed publication and respected
scientific resource. The journal is published 4 to 6
times each year and is indexed in Index
Medicus/MEDLINE. To be added to our mailing
list, please complete a subscription form, available
in your syllabus book on page 17 and on the IAS–
USA Web site at www.iasusa.org.
Treatment and Testing Guidelines
The IAS–USA sponsors the development of
clinical practice guidelines on HIV-related subjects.
The guidelines are written by independent panels
of researchers and clinicians from around the
world and focus on management issues about
which definitive evidence is lacking. Guidelines for
viral load testing, antiretroviral therapy, HIV drug
resistance testing, CMV infection, and metabolic
complications have been published.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
3
COURSE FACULTY
CHAIRS
Henry Masur, MD
Michael S. Saag, MD
Course Chair
Clinical Professor of Medicine
George Washington University School of Medicine
Bethesda, Maryland
Course Vice-Chair
Member, Board of Directors (Volunteer)
International AIDS Society–USA
Professor of Medicine
Director, Division of Infectious Diseases and
The William C. Gorgas Center for
Georgraphic Medicine
University of Alabama at Birmingham
Birmingham, Alabama
SPEAKERS
Judith A. Aberg, MD
Ronald T. Mitsuyasu, MD
Associate Professor of Medicine
New York University Medical Center
Division of Infectious Diseases and Immunology
Director of Virology
Director, AIDS Clinical Trials Unit
Bellevue Hospital Center
New York, New York
Professor of Medicine
University of California Los Angeles
Director, UCLA Center for Clinical AIDS
Research and Education
Los Angeles, California
Kenneth E. Sherman, MD, PhD
Gould Professor of Medicine
Director, Division of Digestive Diseases
University of Cincinnati College of Medicine
Cincinnati, Ohio
John G. Bartlett, MD
Professor of Medicine
Founder and Director of HIV Care Service
Johns Hopkins University School of Medicine
HIV Care Service
Baltimore, Maryland
Glenn J. Treisman, MD, PhD
Professor
Director of AIDS Psychiatry Services
Johns Hopkins Medical Institutions
School of Medicine
Department of Psychiatry
Baltimore, Maryland
Anthony S. Fauci, MD
Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland
Daniel R. Kuritzkes, MD
Professor of Medicine
Harvard Medical School
Director of AIDS Research
Brigham and Women’s Hospital
Cambridge, Massachusetts
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
4
COURSE AGENDA
7:30 AM
Registration
12:05 PM
8:15
Welcome and Introduction
Henry Masur, MD
Michael S. Saag, MD
Hosted Working Lunch⎯Addictions in the HIV Clinic
Glenn J. Treisman, MD, PhD
12:50
Question-and-Answer Period
1:00
Afternoon Break
1:15
Methicillin-Resistant
Staphylococcus aureus
John G. Bartlett, MD
1:45
Question-and-Answer Period
1:55
Strategies for Antiretroviral
Therapy: Case-Based Panel
Discussion
Michael S. Saag, MD
8:30
Early Events in HIV Infection:
Implications for Pathogenesis,
Treatment, and Prevention
Anthony S. Fauci, MD
9:00
Question-and-Answer Period
9:10
New Issues in Antiretroviral
Drug Resistance
Daniel R. Kuritzkes, MD
9:40
Question-and-Answer Period
9:50
Morning Break
2:55
10:20
Cardiovascular Risk: HAART to
HEART
Judith A. Aberg, MD
HIV and Hepatitis C Virus
Coinfection
Kenneth E. Sherman, MD, PhD
3:25
Question-and-Answer Period
10:50
Question-and-Answer Period
3:40
11:00
Malignancies in HIV:
A Growing Problem
Ronald T. Mitsuyasu, MD
Summary of Afternoon
Presentations
Henry Masur, MD
Michael S. Saag, MD
11:30
3:45
Closing Remarks
Question-and-Answer Period
11:40
Summary of Morning
Presentations
Henry Masur, MD
Michael S. Saag, MD
11:45
Break for Lunch
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
5
CME CREDITS, AMERICAN ACADEMY OF FAMILY PHYSICIAN CREDITS,
CLAIMING CME CREDITS, AND NURSING CONTINUING EDUCATION
CONTACT HOURS
CME CREDITS
CLAIMING CME CREDITS
Physicians (MD, DO, and international
equivalents) are eligible to receive CME credit for
their participation in this course. See the
instructions below for claiming CME credit. Nonphysicians receive a certificate of attendance,
verifying their participation. Please keep this
certificate at the end of the course for your records.
CME-accredited providers are required to
document the number of CME credits that each
registered physician intends to claim for a CME
activity. The CME claim form that you received at
registration must be returned to the IAS–USA for
you to receive your CME certificate. When
completing your form, note the actual number of
hours that you participated in this CME activity. If
you did not receive the claim form, stop by the
registration desk prior to leaving today. As of 2009,
a PDF of your CME certificate will be e-mailed to
you within 14 days of receipt of the CME claim
form. You may hand in your completed form to an
IAS–USA staff member at the end of the course,
send it by fax to (415) 544-9402, or mail it to:
International AIDS Society–USA, 425 California
Street, Suite 1450, San Francisco, CA 941042120.
The International AIDS Society–USA is accredited
by the Accreditation Council for Continuing
Medical Education to sponsor continuing medical
education for physicians.
The International AIDS Society–USA designates
this educational activity for a maximum of 6.5 AMA
PRA Category 1 Credits™. Physicians should only
claim credit commensurate with the extent of their
participation in the activity.
To determine the CME credits that you may claim,
count the time you spent attending presentations,
panel discussions, and question-and-answer
sessions. For example, if you attended 5
presentations at 30 minutes each, 4 question-andanswer sessions at 15 minutes each, and a panel
discussion for 60 minutes, for a total of 4.5 hours,
you would claim 4.5 CME credits. You may claim a
maximum of 6.5 credits for this activity.
AMERICAN ACADEMY OF FAMILY PHYSICIAN
CREDITS
Program Development Committee Liaison to
the American Academy of Family Physician:
J. Kevin Carmichael, MD
Chief of Service
El Rio Special Immunology Associates
Tucson, Arizona
If the number of CME credits you actually claim is
different from the number you noted as intending
to claim, contact the IAS–USA to ensure that your
records match ours.
This program has been reviewed and is
acceptable for up to 6.25 prescribed credit hours
by the American Academy of Family Physicians.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
6
Calculate CME credits:
Maximum allowed
Morning session
3.0 hours
___________
Working Lunch
1.0 hour
___________
Afternoon Session
2.5 hours
___________
Maximum Total
6.5 hours
___________ CME credits I will claim
NURSING CONTINUING EDUCATION CONTACT HOURS
Southeast AIDS Training and Education Center is
an approved provider of continuing nursing
education by the Georgia Nurses Association, an
accredited approver by the American Nurses
Credentialing Center’s Commission on
Accreditation.
The IAS–USA offers nursing continuing education
contact hours at live medical education courses
through a collaboration with the Southeast AIDS
Training and Education Center (SEATEC). We are
grateful to SEATEC and Emory University School
of Medicine for joining us in this partnership. In
particular, we thank Ira K. Schwartz, MD, Dianne
H. Weyer, RN, MS, CFNP, and Elizabeth Fullerton
for their key roles in the development of this
component of our educational program.
Contact hours will be awarded based on
attendance at the entire training program and
submission of a completed evaluation form. This
course is approved for 6.4 contact hours.
Program Development Committee Liaison to
the Georgia Nurses Association:
Dianne H. Weyer, RN, MS, CFNP
Senior Clinical Instructor
Southeast AIDS Training and Education Center
Atlanta, Georgia
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
7
NEEDS STATEMENT AND COURSE OBJECTIVES
This program offers a dynamic course agenda, with expert faculty speaking on timely and clinically relevant
issues in HIV disease management. New insights arise continuously in the areas of HIV disease
pathogenesis, antiretroviral drugs and monitoring tools, HIV resistance to antiretroviral drugs, and
complications of HIV disease and its therapies. Clinicians involved in HIV and AIDS care require ongoing, upto-date reviews of these data presented in an unbiased setting.
Case presentations outline patient histories,
and attendees use an audience-response
touchpad system to register their diagnostic or
treatment choices. Faculty members use
clinical-decision points in case presentations
as springboards for discussion of new data
and current diagnostic and therapeutic issues
in HIV management.
Upon completion of the course, learners will be
able to:
Design antiretroviral strategies that consider
data on:
− HIV pathogenesis as it impacts clinical
treatment strategies
− Cardiovascular risk of HIV and its
therapies
− Managing treatment failure
− Antiretroviral drug resistance and the use
of newer agents
Describe the incidence of non-AIDS-defining
cancers in HIV
Formulate appropriate management strategies
for HIV and hepatitis C virus coinfection
Manage methicillin-resistant Straphylococcus
aureus (MRSA) in HIV-infected patients
Formulate appropriate management strategies
for substance users
We encourage you to provide your comments and
suggestions on the course evaluation form. Please
complete the evaluation form and return it to the
registration desk at the end of the course.
Please note that photographing, videotaping, or
audio recording presentations is not permitted.
Webcasts of the lectures are available at
www.iasusa.org/webcast.
LIVE WEBCAST RECORDING
This course will be recorded live for broadcast on
the internet. By actively participating in the course
and asking questions at the microphone, you
agree to having your voice and comments used for
the broadcast. If you would like to make a
comment but do not wish to be recorded, please
submit a question card.
EDUCATIONAL FORMAT
In this course, information is presented through
lectures and clinically relevant case studies
developed by a distinguished faculty of expert HIV
clinicians and researchers.
Lectures provide state-of-the-art updates on
timely and clinically relevant issues, such as
new drugs and regimens, use of resistance
testing, and complications of HIV and its
therapies.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
8
RELEVANT POLICY ON DISCLOSURE, CONFLICTS OF INTEREST, AND
PROXIMATE ACTIVITIES
DISCLOSURE AND CONFLICTS OF INTEREST
information will also be provided directly by the
IAS–USA office upon request.
It is the policy of the International AIDS Society–
USA (IAS–USA) to ensure balance,
independence, objectivity, and scientific rigor in all
its educational activities. All parties with control the
content of IAS–USA activities (eg, members of the
Board of Directors, activity chairs, authors, faculty,
and IAS–USA staff) are required to disclose to the
organization and activity audience any financial
interest or other relationship with the
manufacturer(s) of any commercial product(s) or
provider(s) of commercial services with interests
discussed in the activity (eg, presentation, article,
etc) within the past 12 months. Financial interests
or other relationships can include grants or
research support, employee, consultant, stock or
options holder, paid lecturer, paid writer/author,
member of speakers’ bureau, of the party, or of his
or her spouse or partner. The Accreditation
Council for Continuing Medical Education
(ACCME) defines a financial interest as an interest
of any dollar amount.
The date of the disclosure to be documented along
with financial conflict information. As stated above,
the information published will reflect financial
conflicts incurred within the previous 12 months. It
should be understood that other organizations may
have different policies with regard to financial
conflicts and with regard to the time period covered
in the disclosure of financial conflicts.
In collaborative projects (eg, publication of
materials in medical literature), the IAS–USA may
adhere to the disclosure and conflict-of-interest
policies of the collaborating organization..
POLICY ON COMMERCIAL COMPANY
ACTIVITIES IN TEMPORAL OR PHYSICAL
PROXIMITY TO IAS–USA ACTIVITIES
The IAS–USA educational model functions to
protect the integrity of scientific information, the
spirit of open discussion, and effective education
through vigilant oversight of balance,
independence, and objectivity. To protect these
values and to shield participants and faculty in
IAS–USA activities from undue exposure to
commercial interests and marketing objectives, it is
the policy of the IAS–USA that commercial
companies may not host or sponsor educational,
promotional, or social events in temporal or
physical proximity to IAS–USA activities.
IAS–USA policy requires that the IAS–USA
resolve any identified conflict of interest that may
influence the development, content, or delivery of
its educational activity prior to the activity’s being
delivered to learners. The IAS–USA has several
mechanisms for resolving conflicts of interest in
educational activities. If the conflict of interest
cannot be resolved through these mechanisms,
the party will be removed from the activity.
It is the policy of the IAS–USA to publish the
financial interests of all parties in control of the
content of IAS–USA activities on activity materials
or, in cases where space is limited (eg, reprints of
figures), on the IAS–USA Web site through a Web
address printed on the activity material. This
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
9
GRANT SUPPORT
This course is funded through unrestricted educational grants at a national level from commercial
organizations that are committed to supporting independent CME in the field of HIV and AIDS as part of a
®
national effort (live CME courses, Cases on the Web, and in some cases Topics in HIV Medicine ). In the
interest of an objective, unbiased, balanced, and scientifically rigorous program, the IAS–USA seeks and pools
funding from companies with competing products to support the other IAS–USA activities. These companies
have no input into or control over the program content or the selection of faculty. We gratefully acknowledge
the support of the companies listed below.
SUBSTANTIAL GRANT SUPPORT
Bristol-Myers Squibb
Tibotec Therapeutics
Merck & Co, Inc
Gilead Sciences, Inc
Pfizer Inc
GENEROUS GRANT SUPPORT
GlaxoSmithKline
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
10
DISCLOSURE INFORMATION
The International AIDS Society–USA obtains information regarding financial interests that may be perceived as
conflicts of interest from all persons with control activity content (chairs, authors, speakers, Board members,
staff, etc). Any conflicts of interest of those parties are resolved prior to the education activity’s being delivered.
Below are the financial interests that faculty members of this course have had within the last 12 months, as of
04/29/09.
COURSE FACULTY
Dr Masur had no relevant financial affiliations to
disclose. (Updated 04/27/09)
Dr Aberg received grants and research support for
Multi-Center Clinical Trials participation from
Abbott Laboratories, Bristol-Myers Squibb, Gilead
Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc,
Pfizer Inc, Schering-Plough Corp,
Theratechnologies Inc, and Tibotec Therapeutics.
She served a scientific advisor for Abbott
Laboratories, Bristol-Myers Squibb, Boehringer
Ingelheim Pharmaceuticals, Inc, Gilead Sciences,
Inc, GlaxoSmithKline, Merck & Co, Inc, Pfizer Inc,
Schering-Plough Corp, and Tibotec Therapeutics.
(Updated 04/09/09)
Dr Mitsuyasu received research grants awarded to
UCLA from Bionor Immuno, Johnson & Johnson
Research, LTD, and Pfizer, Inc. (Updated
01/07/09)
Dr Saag has received grants and research support
from Achillion Pharmaceuticals, Inc, Boehringer
Ingelheim Pharmaceuticals, Inc, Merck & Co, Inc,
Pfizer Inc, Progenics Pharmaceuticals, Inc, and
Tibotec Therapeutics. He has served as a
consultant to Ardea Biosciences, Inc, Avexa, Ltd,
Boehringer Ingelheim Pharmaceuticals, Inc,
Bristol-Myers Squibb, Gilead Sciences, Inc,
GlaxoSmithKline, Merck & Co, Inc, Monogram
Biosciences, Inc, Pain Therapeutics, Inc, Panacos
Pharmaceuticals, Inc, Pfizer Inc, Progenics
Pharmaceuticals, Inc, Roche Laboratories, Tibotec
Therapeutics, Tobira Therapeutics, and Virco Lab,
Inc. (Updated 02/05/09)
Dr Bartlett received grants and research support
from Gilead Sciences, Inc, or served as a
consultant to Johnson & Johnson, Pfizer Inc, and
Tibotec Therapeutics. He was on a data and safety
monitoring boards for Tibotec Therapeutics, and
was a paid lecturer for Abbott Laboratories.
(Updated 03/11/09)
Dr Fauci had no relevant financial affiliations to
disclose. (Updated 11/11/08)
Dr Sherman grants and research support (to
institution) from Bristol-Myes Squibb, Gilead
Sciences, Inc, GlaxoSmithKline, Human Genome
Sciences, Roche Laboratories, Schering-Plough
Corp, SciClone Pharmaceuticals, and Vertex
Pharmaceuticals Inc. He served as a consultant or
was on the advisory boards of Anadys
Pharmaceuticals, Inc, Bristol-Myers Squibb, Merck
& Co, Inc, SciClone Pharmaceuticals, Valeant
Pharmaceuticals International, and Vertex
Pharmaceuticals Inc. (Updated 05/04/09)
Dr Kuritzkes received grants and research support
from Gilead Sciences, Inc, Human Genome
Sciences, Merck & Co, Inc, and Schering-Plough
Corp. He served as a consultant to Abbott
Laboratories, Avexa Ltd, Boehringer Ingelheim
Pharmaceuticals, Inc, Gilead Sciences, Inc,
GlaxoSmithKline, Human Genome Sciences,
Idenix Pharmaceuticals, Inc, Merck & Co, Inc,
Millenium, Oncolys, Pfizer Inc, Progenics
Pharmaceuticals, Inc, Schering-Plough Corp,
Siemens, Tobira Therapeutics Inc, ViroStatics, and
VirxSys Corp. (Updated 04/10/09)
Dr Treisman received honoraria for speaking from
Abbott Laboratories and Boehringer Ingelheim
Pharmaceuticals, Inc. (Updated 03/23/09)
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
11
IAS–USA BOARD OF DIRECTORS
The non-staff members of the IAS–USA Board of Directors participate in a volunteer capacity. They are
not compensated for their role in governing/overseeing the IAS–USA.
In accordance with IAS–USA policy on disclosure and conflicts of interest, information regarding conflicts
of interest is obtained from all parties with control over activity content (ie, directors, officers, activity
chairs, faculty, authors, and IAS–USA staff), and conflicts of interest of those parties are resolved.
Below are the financial interests that the volunteer members of the Board of Directors have had with
commercial companies within the last 12 months of the date of disclosure (noted next to each):
RAPID Pharmaceuticals, Inc, Schering-Plough
Corp, and Tibotec Therapeutics. He is a member
of data and safety monitoring boards for Abbott
Laboratories, Gilead Sciences, Inc, Koronis
Pharmaceuticals, and VIRxSYS Corp. (Updated
02/05/09)
Dr Benson has received research grants awarded
to the University of California San Diego from
Gilead Sciences, Inc. She has served on advisory
boards for GlaxoSmithKline, Merck & Co, Inc, and
Pfizer Inc, and chaired data and safety monitoring
boards for Johnson & Johnson Research, Ltd
(Australia) and Achillion Pharmaceuticals, Inc.
(Updated 02/12/09)
Dr Gulick has served as a consultant to Boehringer
Ingelheim Pharmaceuticals, Inc, Bristol-Myers
Squibb, Gilead Sciences, Inc, GlaxoSmithKline,
Merck & Co, Inc, Pathway Pharmaceuticals Inc,
Pfizer Inc, Progenics Pharmaceuticals, Inc,
Schering-Plough Corp, Tibotec Therapeutics, and
Virostatics. He also serves as Chair of a data and
safety monitoring board for Koronis
Pharmaceuticals. (Updated 03/25/09)
Dr Currier has received research grants and
research support from Merck & Co, Inc, Schering
Plough Corp, Theratechnologies Inc, and Tibotec
Therapeutics. She has served as a scientific
advisor to Bristol-Myers Squibb, Merck & Co, Inc,
and Tibotec Therapeutics and on a data and safety
monitoring boards for Achillion Pharmaceuticals,
Inc, and Koronis Pharmaceuticals. (Updated
02/05/09)
Ms Jacobsen had no relevant financial affiliations
to disclose. (Updated 02/05/09)
Dr del Rio has received research grants awarded
to Emory University from GlaxoSmithKline, Merck
& Co, Inc, Pfizer Inc, and Sanofi Pasteur. He
served as a consultant or received honoraria from
Bristol-Myers Squibb, Merck & Co, Inc, and Trinity
Biotech Plc. (Updated 02/12/09)
Dr Richman has served as a consultant to Anadys
Pharmaceuticals, Inc, Biota, Bristol-Myers Squibb,
Chimerix, Inc, Gen-Probe, Gilead Sciences, Inc,
Idenix Pharmaceuticals, Merck & Co, Inc,
Monogram Biosciences, Inc, Pfizer Inc, and Roche
Laboratories. (Updated 04/15/09)
Dr Gallant has received grants and research
support from Gilead Sciences, Inc, Merck & Co,
Inc, Pfizer Inc, Roche Laboratories, and Tibotec
Therapeutics. He has received honoraria from
Abbott Laboratories, Gilead Sciences, Inc,
GlaxoSmithKline, and Monogram Biosciences, Inc.
He has served as a consultant to or was on the
advisory boards for Abbott Laboratories, BristolMyers Squibb, Gilead Sciences, Inc,
GlaxoSmithKline, Merck & Co, Inc, Pfizer Inc,
Dr Saag has received grants and research support
from Achillion Pharmaceuticals, Inc, Boehringer
Ingelheim Pharmaceuticals, Inc, Merck & Co, Inc,
Pfizer Inc, Progenics Pharmaceuticals, Inc, and
Tibotec Therapeutics. He has served as a
consultant to Ardea Biosciences, Inc, Avexa, Ltd,
Boehringer Ingelheim Pharmaceuticals, Inc,
Bristol-Myers Squibb, Gilead Sciences, Inc,
GlaxoSmithKline, Merck & Co, Inc, Monogram
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
12
Biosciences, Inc, Pain Therapeutics, Inc, Panacos
Pharmaceuticals, Inc, Pfizer Inc, Progenics
Pharmaceuticals, Inc, Roche Laboratories, Tibotec
Therapeutics, Tobira Therapeutics, and Virco Lab,
Inc. (Updated 02/05/09)
IAS–USA CME STAFF
Ms Jacobsen has no relevant financial affiliations
to disclose (see above).
PROGRAM DEVELOPMENT COMMITTEE
Dr Schooley served as a consultant to Achillion
Pharmaceuticals, Inc, Anadys Pharmaceuticals,
Inc, Ardea Biosciences, Inc, Chimerix, Inc, Gilead
Sciences, Inc, GlaxoSmithKline, Inhibitex, Inc,
iTherX, Inc, Koronis Pharmaceuticals, Merck & Co,
Inc, Monogram Biosciences, Inc, Pfizer Inc,
TaiMed Biologics, Tibotec Therapeutics, and
Vertex Pharmaceuticals. He had stock options for
Achillion Pharmaceuticals, Inc, and Monogram
Biosciences, Inc. (Updated 02/13/09)
Ms Weyer was on the speakers’ bureaus of
Boehringer Ingelheim Pharmaceuticals, Inc, and
Bristol-Myers Squibb. (Updated 02/05/09).
Dr Carmichael was a paid lecturer for
GlaxoSmithKline and Tibotec Therapeutics.
(Updated 01/16/09)
Dr Volberding has served on scientific advisory
boards for Bristol-Myers Squibb, Gilead Sciences,
Inc, Merck & Co, Inc, Pfizer Inc, Schering-Plough
Corp, and Tobira Therapeutics and has been on
an endpoint adjudication committee for ScheringPlough Corp for an ongoing clinical trial. He is a
member of data safety and monitoring boards for
Merck & Co, Inc, and TaiMed Biologics. He served
as a consultant to Pfizer Inc and received an
unrestricted educational grant from
GlaxoSmithKline-Italy. (Updated 02/05/09)
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
13
AUDIENCE RESPONSE SYSTEM INSTRUCTIONS
PLEASE RETURN TOUCHPADS TO THE DESIGNATED BIN
AT THE END OF THE COURSE
Keep these tips in mind when using the touchpads:
Audience response touchpads are handheld
wireless terminals that enable the audience to
respond anonymously to questions asked by the
speaker. Attendees answer questions by pushing a
button on the touchpad. Questions are multiple
choice and the answers are tabulated immediately
and displayed in a bar graph for the speaker and
the audience to analyze.
Before and during the program, audience members
are asked to answer a short series of demographic
questions. These questions help to determine the
knowledge level and professional background of the
audience and whether the audience response
system is working properly. Please use the same
touchpad throughout the day. Answers are linked
only to the touchpad and not to the individual. Your
participation is appreciated.
Participants are urged to choose answers based on
their own experiences and preferences in
treatment. Although some questions have definite
right and wrong answers, many answers reflect
current treatment trends, firsthand clinical or
research experiences, and individual opinions. It is
likely that the speaker will comment on the
audience responses and, if appropriate, compare
them with the approach chosen in the case under
discussion. There is further discussion between the
audience and the faculty in scheduled questionand-answer periods.
–
Answers are anonymous and are not tracked to
individuals in any way.
–
Questions are multiple choice, and answers are
numbered 1 to 10. Use the number 1 for yes
and 2 for no.
–
You have approximately 5 to 10 seconds to
enter an answer choice. A timer on the screen
at the front of the room shows you how much
time remains.
–
Press your selection button firmly and only
once.
–
To cancel an answer and choose a new one,
press another answer: this action deletes the
first response. Answers may be changed only
during the time allowed for each question.
–
For demographic purposes, please note the
number on touchpad, and use the same
touchpad throughout the day.
–
If you think your touchpad is not working
properly, please alert an IAS–USA staff
member, who will try to provide you with
another unit.
Please do not remove the touchpad from its plastic
cover. Responses will transmit through the plastic.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
14
INTERNATIONAL AIDS SOCIETY–USA LIVE CME PROGRAMS
The IAS–USA is sponsoring the following CME courses in 2009. For additional information, visit
www.iasusa.org or call (415) 544-9400.
®
THE SEVENTEENTH YEAR OF CME COURSES: Improving the Management of HIV Disease
Los Angeles, California
Los Angeles Marriott Downtown
Monday, February 23, 2009
Chairs: Ronald T. Mitsuyasu, MD, and Constance A. Benson, MD, FACP
New York, New York
New York Marriott Marquis
Friday, March 13, 2009
Chairs: Gerald H. Friedland, MD, and Paul A. Volberding, MD
Atlanta, Georgia
Hyatt Regency Atlanta
Friday, April 3, 2009
Chairs: Michael S. Saag, MD, and Jeffrey Lennox, MD
San Francisco, California
Grand Hyatt San Francisco
Monday, April 20, 2009
Chairs: Robert T. Schooley, MD, and Stephen E. Follansbee, MD
Washington, DC
JW Marriott Hotel
Friday, May 8, 2009
Chairs: Henry Masur, MD, and Michael S. Saag, MD
Chicago, Illinois
Marriott Chicago Downtown
Tuesday, May 19, 2009
Chairs: John P. Phair, MD, and Paul A. Volberding, MD
Core Faculty Lecture Series
The International AIDS Society–USA has designed interactive and innovative small-group CME workshops for
experienced HIV clinical decision makers, led by HIV experts. These workshops are formatted to enhance
professional development and improve clinical practice in an exclusive setting, and are restricted to a target
audience of roughly 30 attendees. For workshop and registration information, go to
www.iasusa.org/cme/workshop.
Half-Day Intensive Workshops
Antiretroviral Strategies: New Drugs, Antiretroviral Failure, and Resistance Testing
Los Angeles, California
Marriott Los Angeles Downtown
Tuesday, February 24, 2009
8:30 AM – 12:00 PM
Workshop Leaders: Steven J. Deeks, MD, and Andrew R. Zolopa, MD
Melville, New York
Melville Marriott Long Island
Monday, April 1, 2009
9:00 AM – 12:00 PM
Workshop Leader: Roy M. Gulick, MD, MPH
San Francisco, California
Millberry Union Conference Center
University of California San
Francisco
Tuesday, April 21, 2009
8:30 AM – 12:00 PM
Workshop Leaders: Andrew R. Zolopa, MD, and Charles B. Hicks, MD
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
15
Washington, DC
JW Marriott, Pennsylvania Avenue
Thursday, May 7, 2009
1:00 PM – 4:30 PM
Workshop Leaders: Joel E. Gallant, MD, MPH, and Daniel R. Kuritzkes, MD
Chicago, Illinois
Marriott Chicago Downtown
Magnificent Mile
Monday, May 18, 2009
1:00 PM – 4:30 PM
Workshop Leaders: Steven G. Deeks, MD, and Michael S. Saag, MD
Seattle, Washington
Talaris Conference Center
Friday, May 29, 2009
1:00 PM – 4:30 PM
Workshop Leaders: Eric S. Daar, MD, and Joel E. Gallant, MD, MPH
Sacramento, CA
Location to be determined
Friday, June 5, 2009
8:30 AM – 12:00 PM
Workshop Leader: Andrew R. Zolopa, MD
Denver, Colorado
Doubletree Hotel Denver
Tech Center
Thursday, June 11, 2009
9:00 AM – 12:30 PM
Workshop Leaders: Steven C. Johnson, MD, and Jeffrey L. Lennox, MD
Metabolic and Cardiovascular Complications of HIV and Its Therapies
Bronx, New York
Salsa Caterers & Special Events
Friday, January 30, 2009
8:30 AM – 12:00 PM
Workshop Leaders: Marshall J. Glesby, MD, PhD, and David A. Wohl, MD
New York, New York
Griffis Faculty Club
Weill Cornell Medical College
Thursday, March 12, 2009
1:00 PM – 4:30 PM
Workshop Leaders: Marshall J. Glesby, MD, PhD, and David A. Wohl, MD
Atlanta, Georgia
Hyatt Regency Atlanta
Thursday, April 2, 2009
1:00 PM – 4:30 PM
Workshop Leaders: Marshall J. Glesby, MD, PhD, and David A. Wohl, MD
CASES ON THE WEB: www.iasusa.org/cow
Cases on the Web is an ongoing series of case-based, advanced online CME activities. The Cases on the
Web activities are overseen by Cases on the Web Editorial Board members, Michael S. Saag, MD, Meg
Newman, MD, Judith A. Aberg, MD, Roger Bedimo, MD, Marshall J. Glesby, MD, PhD, Steven C. Johnson,
MD, Harry W. Lampiris, MD, and Paul E. Sax, MD.
Current Cases on the Web include:
Initial Evaluation of a Patient with A New HIV
Diagnosis
Michael Melia, MD, and Howard Libman, MD
HIV-Infection and International Travel:
Pretravel Patient Assessment and
Management
Carlos Franco-Paredes, MD, MPH
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
16
Managing Oral Health Problems in People with
HIV Infection
David A. Reznik, DDS
Management of Cryptococcal Meningitis in the
Antiretroviral Therapy Era: More than Just
Antifungals
Anuradha Ganesan, MD, and Henry Masur, MD
Strategies Use of Antiretroviral Drugs in the
Patient with Numerous Treatment Failures and
Multidrug Resistance
Harry W. Lampiris, MD, and Elvin H. Geng, MD
Immune Reconstitution Inflammatory
Syndrome in HIV-Infected Patients: Diagnosis
and Management Challenges
Jaime C. Robertson, MD, and Carl J.
Fichtenbaum, MD
Syphilis in the HIV-Infected Patient
Jeanne M. Marrazzo, MD, MPH
Issues in the Care of HIV and Hepatitis C Viruscoinfected Patients: Antiretroviral
Pharmacokinetics, Drug Interactions, and Liver
Transplantation
David L. Wyles, MD
Using Biomedical Prevention as Part of HIV
Prevention
Raphael J. Landovitz, MD
Severe Mycobacterial Infection in a Patient
with Advanced AIDS
William J. Burman, MD
HIV-associated Cognitive Impairment
Miguel G. Madariaga, MD, and Susan Swindells,
MBBS
Treatment of Hepatitis C Virus and HIV
Coinfection: Selecting Candidates for Hepatitis
C Virus Therapy and Managing Side Effects of
Treatment
Melissa K. Osborn, MD
HIV-Related Renal Disease
Lynda Anne Szczech, MD, MSCE, FASN
HIV-Associated Dyslipidemias: 2008 Update
Roger J. Bedimo, MD, MS
Special Cases in Antiretroviral Therapy
Initiation: Focus on Acute HIV and
HIV/Hepatitis B Virus Coinfection
Charles Hicks, MD, and Elizabeth Reddy, MD
Sexual Addiction in an HIV-infected Patient
Edward R. Hammond, MD, MPH, and Glenn J.
Treisman, MD, PhD
Managing Initiation of Antiretroviral Therapy in
a Patient with Chronic Methamphetamine Use
and Depression
Sara Vazquez, MD, and J. Kevin Carmichael, MD
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
17
Topics in
HIV Medicine
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18
May 8, 2009
EARLY EVENTS IN HIV INFECTION: IMPLICATIONS FOR
PATHOGENESIS, TREATMENT, AND PREVENTION
Anthony S. Fauci, MD
It has become increasingly apparent from studies over the past few years that the early
events in HIV infection are major determinants of the subsequent course of HIV disease. The
precise delineation of these events has served not only as the foundation for greater
understanding of the pathogenesis of HIV disease, but also has provided the scientific basis
for the development of strategies for prevention of infection by topical microbicides, preexposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and vaccines, as well as for
the early treatment of infection.
In most cases when clinicians encounter an acutely infected individual, the patient is
symptomatic with the “Acute HIV Syndrome” that is characterized by a constellation of flu-like
signs and symptoms. This syndrome usually occurs from 3 to 6 weeks following the actual
exposure to the virus and is a reflection of high levels of viremia, at times reaching millions of
copies of HIV RNA/mL. Unfortunately, most of the early events that determine the course and
outcome of HIV infection have already occurred by the time the acute syndrome occurs and
is recognized.
For the purposes of this discussion, we will consider only infection via the mucosa
route, which could either be vaginally, rectally, through the urethra or mucosal-like foreskin, or
rarely, orally. We will use the prototype of the deposition of HIV-infected seminal fluid into the
vaginal vault as the example. A relatively large inoculum of HIV in the form of free virions and
infected cells is deposited in the vaginal vault. Within hours virus or virus-infected cells cross
the cervicovaginal mucosal barrier and infection becomes established at the point of entry.
This occurs either by HIV passing through breaks in the epithelial barrier or by binding to
dendritic cells(DCs) that carry the virus to the sub-epithelial space (lamina propria) where
contact is made with resting and activated CD4+ T cells as well as other DCs and
macrophages. These cells become infected, but the infection may not necessarily be selfpropagating. Only when the virus passes to the more fertile environment of larger numbers of
susceptible CD4+ T cell targets (mainly activated CD4+ T cells) in the lymphoid tissues is the
propagation of infection assured.
Since the process just prior to self-propagation occurs within hours to at most a day,
the window of opportunity for blocking entry or initial infection at this point is narrow, but
crucial. It is at this point that topical microbicides potentially could be effective by blocking the
initial infection at the point of entry. PrEP and PEP could also be effective at this point in
blocking the initial infection as well as the progression toward self-propagation. Immune
activation is critical in driving this early phase of infection towards self-propagation. In this
regard, studies using immunosuppressive agents such as cyclosporine in monkeys and
humans as well as suppressors of immune activation such as glycerol monolaurate in
monkeys during the early phase of infection have shown a beneficial effect in inhibiting
infection. As pointed out by Haase (Nat Rev Immunol, 5(10):783-792, 2005), this earliest
event is a time of great vulnerability for the virus because of the “bottleneck” that is
manifested by the relationship between the relatively large size of the initial inoculum and the
relatively small “founder” population of infected cells that are very few in number and exist in
rare foci. The challenge for the virus is to maintain the basic reproductive rate (R0) of 1 or
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
19
A. S. Fauci, MD
greater by spreading the infection to the relatively small number of susceptible targets in the
mucosa and lamina propria. If the virus fails, the infection will die out.
Intervention by PrEP, PEP, or a vaccine-induced immune response could
successfully suppress the virus so that the founder population is never established or it could
dampen the expansion of infection so that the infection is established but the R0 fails below 1
and the infection indeed “dies out”. If the virus succeeds in spreading locally, the virus will
spread out of the initial microenvironment and undergo a period of exponential growth during
which wide dissemination to lymphoid organs including the largest lymphoid organ, the gutassociated lymphoid tissue (GALT), occurs. In the non-human primate model the time frame
of the spread of infection from the point of entry to the draining lymph nodes ranges from 1
day to 1 week. At this point a latent viral reservoir is established in the resting CD4+ T cell
compartment that no regimen of antiretroviral therapy has thus far been able to eradicate
even in individuals who have received more than a decade of therapy that has maintained the
plasma viral load below detectable levels.
Once the infection spreads to draining lymph nodes, it is too late for intervention
aimed at prevention or eradication. However, there is still the opportunity for therapeutic
benefit. Depletion of CD4+ T cells, particularly memory CD4+ T cells begins during the acute
stage of infection almost immediately after the virus reaches densely packed lymphoid tissue
such as the GALT. Immune activation is intense and considerable levels of apoptosis of
CD4+ T cells occurs via a Fas–Fas ligand mechanism. Although antiviral therapy at this point
will not eradicate HIV, it will suppress virus replication and thus inhibit spread of virus within
lymphoid tissue resulting in preservation of a portion of the memory CD4+ T cell pool. It is for
this reason that it is recommended when patients present with the acute HIV syndrome and
its concurrent high levels of plasma viremia (referred to as the exponential growth phase) that
they be treated with antiretroviral therapy.
It also has been shown that initiation of therapy early in the course of HIV infection
(as close to the acute stage as possible) results in a smaller reservoir of latently infected
resting CD4+ T cells whose slope of decline is steeper on therapy than that for patients in
whom therapy was initiated during the chronic stage of HIV infection. In the absence of
antiretroviral therapy, peak replication of virus occurs within 2 to 3 weeks and then declines
predominantly because of an exhaustion of the substrate of vulnerable CD4+ T cell targets
and the generation of partially effective anti-HIV immune responses. The plasma viremia
usually reaches it steady state “set point” within 6 months and in the absence of treatment,
the level of CD4+ T cells gradually declines at a rate of approximately 100 to 150 cells/μL per
year. It is for this reason that current thinking is leaning toward earlier initiation of therapy in
persons who present with established infection in order to preserve the CD4+ T cell pool and
prevent the onging and relentless replication of virus causing a host of non-immunological
deleterious effects. It is important to point out that although the CD4+ T cell count gradually
declines over years of infection, a major component of the CD4+ T cell depletion, including
HIV-specific CD4+ T cells has already occurred during the early events of HIV infection
described above. And so, from a pathogenesis standpoint and its relevance to prevention
with microbicides, PrEP, PEP, and vaccines, as well as its relevance to therapeutic strategies
for containing the early and massive depletion of memory CD4+ T cells, the early events in
HIV infection are indeed crucial.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
20
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
21
NEW ISSUES IN ANTIRETROVIRAL DRUG RESISTANCE
Daniel R. Kuritzkes, MD
___________________________________
___________________________________
___________________________________
New Issues in Antiretroviral
Drug Resistance
___________________________________
___________________________________
Daniel R. Kuritzkes, MD
___________________________________
Professor of Medicine
Harvard Medical School
___________________________________
International AIDS Society–USA
Slide 2
___________________________________
Novel agents
___________________________________
Q
Etravirine
___________________________________
Q
Integrase inhibitors
Q
CCR5 antagonists
___________________________________
___________________________________
___________________________________
___________________________________
Slide 3
Q
13 BL resistance-associated
mutations (RAMs) correlated with
a decreased response to
etravirine:
– V90I
– K101E/P
– A98G
– V179D/F
– L100I
– G190A/S
– V106I
HIV RNA <50 c/mL (%)
DUET-1 and -2: Virologic response by
ETV resistance mutations—2007
___________________________________
80
___________________________________
60
___________________________________
40
___________________________________
20
___________________________________
– Y181C/I/V
Q
Q
If >3 mutations present, response
similar to PBO
Note: 14% had >3 ETV RAMs
___________________________________
___________________________________
0
0
1
2
3
4
5
Number of ETV RAMs
% = 40
30
16
8
5
0.9
Katlama C, et al. 4th IAS, Sydney 2007, #WESS204:2
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
23
D. R. Kuritzkes, MD
Etravirine Resistance Mutations: 2008
Weighting Algorithm
Individual
Mutation Score
Y181I
Y181V
3
2.5
L100I
2.5
Y181C
2.5
M230L
2.5
E138A
1.5
V106I
1.5
G190S
1.5
V179
1.5
V90I
1
V179D
1
K101E
1
K101H
1
A98G
1
V179T
1
G190A
1
Add Together
___________________________________
___________________________________
___________________________________
Total
Weighted Score
3
K101P
Slide 4
___________________________________
>4
Reduced
Response
2.5-3.5
Intermediate
Response
0-2
Highest
Response
___________________________________
___________________________________
___________________________________
Vingerhoets J, et al. 17th IHIVDRW. Sitges, 2008. Abstract 24.
Etravirine Weighted Score:
Achieving HIV RNA <50 Copies/mL
Intermediate
Response
Reduced
Response
(Mean: 52.0%)
(Mean: 37.7%)
60
40
20
0
1.0
1.5
2.0
80
60
40
20
0
2.5
3.0
___________________________________
___________________________________
___________________________________
___________________________________
100
HIV RNA <50 Copies/mL (%)
80
0
100
HIV RNA <50 Copies/mL (%)
HIV RNA <50 Copies/mL (%)
100
Highest
Response
(Mean: 74.4%)
Slide 5
___________________________________
80
60
___________________________________
40
___________________________________
20
3.5
0
4.0 4.5 5.0 5.5 6.0 6.5 >7.0
Weighted Score for the 17 Etravirine
Resistance-Associated Mutations 2008
Vingerhoets J, et al. 17th IHIVDRW. Sitges, 2008. Abstract 24.
Slide 6
Correlation of week 4 HIV-1 RNA change
and ETR fold-change in IC50
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Coakely E et al 17th Intl HIV Drug Resistance Workshop, Sitges, Spain 2008
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
24
D. R. Kuritzkes, MD
Slide 7
___________________________________
___________________________________
Adjusted Week 4 HIV-1 RNA outcomes
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Peters M et al 17th Intl HIV Drug Resistance Workshop, Sitges, Spain 2008
Slide 8
___________________________________
___________________________________
NAMs and ETR hypersusceptibility
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Benhamida J et al 17th Intl Workshop HIV Drug Resistance, Sitges, 2008 [abstr 22].
Slide 9
Etravirine summary
Q
Q
___________________________________
___________________________________
17 etravirine resistance mutations
Genotype interpretation depends on weighted
score
___________________________________
– Y181C alone gives intermediate resistance
Q
___________________________________
___________________________________
Phenotypic cut-offs now defined
– Lower cutoff 2.9 or 3.0
– Upper cutoff 13 (?)
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
25
D. R. Kuritzkes, MD
Slide 10
Integrase inhibitor resistance
Q
Q
___________________________________
___________________________________
Integrase strand-transfer inhibitors (INSTI) select
for specific resistance mutations in HIV-1 IN
Three pathways identified for raltegravir:
___________________________________
– N155H
– Q148K/R/H
– Y143C/R
Q
___________________________________
___________________________________
Extensive cross-resistance between raltegravir
and elvitegravir
___________________________________
Slide 11
Raltegravir Resistance at Failure (%)
BENCHMRK Combined Analysis:
Raltegravir Resistance at Virologic Failure
___________________________________
Nonresponse (n=13)
Viral rebound (n=81)
___________________________________
80
67%
70
___________________________________
___________________________________
Week 48
100
90
___________________________________
62%
___________________________________
60
50
43%
40
___________________________________
30%
30
23%
23%
15%
20
___________________________________
10%
10
0
155, 148, or 143
155
148
143
Percent With Mutation at Integrase Codons 155, 148 or 143
Includes only patients with virologic failure for whom integrase genotypic data were available (n=89).
Modified from Cooper DA, et al. N Engl J Med. 2008;359:355-365.
Slide 12
BENCHMRK: Longitudinal Data by Mutation
Pathway Among Virologic Failures
___________________________________
___________________________________
70
Number of Patients
60
Mixed
19%
143
148
27%
___________________________________
50
40
10%
___________________________________
Mixed
143
___________________________________
30
155
20
53%
148
18%
155
45%
___________________________________
10
0
___________________________________
First Genotype
(n=64)
Subsequent Genotype
(n=51)
Miller M, et al. 48th ICAAC. Washington, DC, 2008. AbstractH-898.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
26
D. R. Kuritzkes, MD
Slide 13
Fitness of INSTI-resistant HIV-1
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Days post-infection
INSTI = integrase strand transfer inhibitor
Hu et al Intl HIV Drug Resistance Workshop, Sitges, 2008
Slide 14
Conclusions
Q
Q
Q
Q
___________________________________
___________________________________
___________________________________
Virologic failure of integrase inhibitors frequently
associated with drug resistance
INSTI-resistant viruses have reduced replication
Cross-resistance among existing drugs in class
Clinical impact of reduced replication of INSTIresistant viruses uncertain
___________________________________
___________________________________
___________________________________
___________________________________
CCR5 antagonists are allosteric
inhibitors of HIV-1 infection
Slide 15
___________________________________
___________________________________
___________________________________
Free
receptor
wt
gp120
gp120
binding site
on CCR5
___________________________________
High affinity
___________________________________
___________________________________
•
Drug ( )
bound
to CCR5
Binding site
disrupted
by drug
___________________________________
Very low affinity
Adapted from Mosley M et al. 13th CROI 2006; abstract 598.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
27
D. R. Kuritzkes, MD
Slide 16
Inhibition curves for competitive versus noncompetitive inhibitors of HIV-1
___________________________________
___________________________________
___________________________________
___________________________________
Non-competitive inhibitor
___________________________________
% inhibition
% inhibition
Competitive inhibitor
Log drug concentration
___________________________________
___________________________________
Log drug concentration
Slide 17
Change in coreceptor usage in subjects
receiving CCR5 antagonists
Q
___________________________________
___________________________________
The dominant pathway to virologic failure
– 57% of subjects in MOTIVATE-1 and -2
– 35% of subjects in ACTG 5211
– 31% of subjects in MERIT
Q
___________________________________
___________________________________
___________________________________
Origin of CXCR4-using viruses
– Emergence from pre-existing minority population
___________________________________
___________________________________
Fätkenheuer G, et al. N Engl J Med. 2008;359:1442-1455.
Gulick R, et al. J Infect Dis. 2007;196:304-312.
Heera J, et al. 15th CROI. Boston, 2008. Abstract 40LB.
Slide 18
V3 Loop of gp120
Q
Q
___________________________________
___________________________________
One of 5 variable loops in gp120
Averages 35 amino acids in length
___________________________________
– 105 nucleotides
Q
Q
Major determinant of co-receptor usage
Major effect on rate of gp41 conformational
changes
___________________________________
___________________________________
– Can accelerate the rate-limiting step of entry
Q
Q
___________________________________
Immunodominant region of gp120 for humoral
immunity
Protected/obscured by glycan shield
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
28
D. R. Kuritzkes, MD
Slide 19
Subject 07J – Bulk VCV Susceptibilities
___________________________________
___________________________________
___________________________________
___________________________________
Baseline
R5
Week 2
1403977
155
R5
___________________________________
Week 8
2410246
74
R5
321470
89
___________________________________
___________________________________
Week 19 failure confirmation
DM
1015924
Week 24
462
DM
Week 28
1090479
395
DM
938203
235
Tsibris et al J Virol 2009
Slide 20
___________________________________
ACTG A5211: vicriviroc resistance
V3 mutations accrue, VCV activity lost
0
0
1
2
3
100
50
p07Jenv0χgp41
p07Jenv0
0
Percent Inhibition (%)
Percent Inhibition (%)
Percent Inhibition (%)
Week 0
Week 16
Week 19
Week 28
Week 48
50
___________________________________
V3 mutations confer resistance
100
100
___________________________________
p07Jenv0χgp120
p07Jenv0χV1V3
p07Jenv0χV3
50
0
1
2
___________________________________
3
0
-50
-50
-1
VCV (log nM)
0
1
2
3
VCV concentration (log nM)
VCV concentration (log nM)
___________________________________
V3 mutations affect TAK779, HGS and AOP-RANTES activity
___________________________________
100
Percent Inhibition (% )
Percent Inhibition (% )
Week 0
Week 28
Week 48
50
Percent Inhibition (% )
100
100
50
W eek 0
W eek 28
0
50
___________________________________
W eek 0
W eek 28
0
0
0
1
2
-2
3
-1
0
1
2
-1
HGS004 concentration (log nM)
TAK-779 concentration (log nM)
0
1
2
AOP-RANTES (log nM)
Percent Inhibition (% )
100
50
W eek 0
W eek 28
0
Tsibris et al J Virol 2009
0
1
2
3
4
Enfuvirtide concentr ation (log nM)
Slide 21
Conclusions
Q
Q
___________________________________
___________________________________
Resistance to CCR5 antagonists emerges slowly
Mutations in V3 and other regions of envelope
___________________________________
– No canonical mutations or positions identified to date
– Each virus likely to follow unique path to resistance
Q
Q
___________________________________
___________________________________
“Plateau” effect in phenotypic assays
Limited data on cross-resistance
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
29
D. R. Kuritzkes, MD
Slide 22
V3 loop analysis by massively parallel
sequencing (“ultra-deep sequencing”)
Q
___________________________________
___________________________________
454 Life Sciences technology
– Microfabricated picoliter wells
– Emulsion-based PCR
– Pyrosequencing
Q
___________________________________
___________________________________
Unprecedented depth of sequencing
– 100,000 clones
Q
Q
Q
___________________________________
___________________________________
Key Limitation: Amplicon Length
Current maximum length: 200-300 nucleotides
Ideal for V3 loop sequencing
___________________________________
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
Slide 23
Ultra-deep pyrosequencing
___________________________________
___________________________________
___________________________________
Load beads into
PicoTiterPlateTM
Load Enzyme
Beads
___________________________________
___________________________________
Centrifugation
___________________________________
___________________________________
44 μm
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
Slide 24
Pyrosequencing
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
30
D. R. Kuritzkes, MD
Slide 25
___________________________________
Ultradeep Sequencing - Results
___________________________________
Subject No.
07
___________________________________
18
19
47-Control
Week
0
12
19
0
2
16
0
2
17
0
17
18
HIV-1 RNA copy no.
792,750
88,066
660,088
41,152
63,440
25,964
74,533
18,184
28,110
196,425
42,397
33,391
454 coverage
125,299
120,539
135,649
138,681
62,475
98,025
70,391
46,826
25,685
36,889
64,253
28,445
___________________________________
___________________________________
___________________________________
___________________________________
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
Slide 26
Longitudinal Changes in V3 sequence
___________________________________
___________________________________
___________________________________
Subject 07
Subject 18
___________________________________
___________________________________
___________________________________
___________________________________
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
Slide 27
___________________________________
Ultra-deep sequencing: Conclusions
Q
Q
Q
Q
___________________________________
___________________________________
The V3 loop of HIV-1 Env displays extraordinary
sequence diversity
Rapid fluxes in the viral population allow rare
forms to become dominant over short time spans
After expansion, diversification occurs as
variants seek to fill available sequence space
These results also provide data in support of the
quasispecies hypothesis
___________________________________
___________________________________
___________________________________
___________________________________
Tsibris et al 17th Intl HIV Drug Resist Workshop, Sitges, Spain, June, 2008
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
31
D. R. Kuritzkes, MD
Slide 28
Decay of vicriviroc-resistant mutants
PMI†
Clones,
n
0 (Entry)
97.2
17
2
CTRPGNNTRKSTRIGPGQTFFATGDIIGDIRQAHC
-----------I----------R------------
28
0
Study Week
100
6
50
2
Mu tant Pr oportion
Plasma Viral Load
10
20
30
Time (weeks)
40
Proportion of Mutants (%)
4
0
0
___________________________________
___________________________________
Longitudinal Amino Acid Changes
Resistance decay
VCV
HIV-1 RNA (log10copies/mL)
___________________________________
The rate of decay of VCV-resistant V3 loop plasma sequences
was determined following VCV discontinuation in an ACTG
A5211 subject
Q
0
50
Fig. 1. The proportion of VCV-resistant
clones are plotted on the right y-axis and
shown in open red circles and a red line.
Treatment with VCV is shown above the
graph.
Clonal V3 loop sequences
12
---------RPI--------I-RE---------Y-
30
17
5
2
---------RPI--------I-RE---------Y---------RPI--------I-RE-------------------RPI----------RE---------Y-
41
12
7
2
---------RPI--------I-RE---------Y---------R---------------------------------RPI--------I-RE-----------
14
---------R-------------------------
48
90
___________________________________
___________________________________
___________________________________
___________________________________
Fig. 2. Clonal Sequence Analysis. For each study week indicated,
the number and sequence of the isolated V3 loop forms are shown.
PMI=percent maximal inhibition.
A. Tsibris et al CROI 2009
Slide 29
Conclusions
___________________________________
___________________________________
Q
VCV-resistant V3 loop forms were replaced by near-wildtype
sequence within 20 weeks of drug discontinuation
Q
VCV resistance resulted in a 12-19% fitness disadvantage.
Q
Changes in multiple antiretrovirals during the time period
analyzed complicates the correlation of this fitness
disadvantage with changes in the observed plasma viral load.
Q
The presence of the dominant week 48 V3 form at baseline
suggest re-emergence from an archived variant.
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
A. Tsibris et al CROI 2009
Slide 30
Acknowledgments
BWH
Athe Tsibris
Manish Sagar
Francoise Giguel
Kay Leopold
Zixin Hu
HSPH
Zhaohui Su
Michael Hughes
ACTG 5211 Team
Roy M. Gulick
Charles Flexner
___________________________________
___________________________________
Monogram Biosciences
Eoin Coakley
Jeannette Whitcomb
___________________________________
___________________________________
Schering-Plough
Wayne Greaves
Julie Strizki
___________________________________
Los Alamos National Laboratory
Bette Korber
Thomas Leitner
___________________________________
___________________________________
Broad Institute
Ramy Arnout
Carsten Russ
Chien-Chi Lo
Brian Gaschen
Carla Kuiken
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
32
D. R. Kuritzkes, MD
SUGGESTED READING
Coakley E, Chappey C, Benhamida J, et al. Biological and clinical cut-off analyses for etravirine in the
PhenoSense HIV assay. [Abstract 122.] Antivir Ther. 2008;13(Suppl 3):A134.
Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant
HIV-1 infection. N Engl J Med. 2008;359:355-365.
Hazuda DF, Miller MD, Nguyen BY, Zhao J, for the P005 Study Team. Resistance to the HIV-integrase
inhibitor raltegravir: analysis of protocol 005, a phase II study in patients with triple-class resistant HIV-1
infection. Antivir Ther. 2007;12:S10.
Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatmentexperienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind,
placebo-controlled trial. Lancet. 2007;370:39-48.
Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatmentexperienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind,
placebo-controlled trial. Lancet. 2007;370:29-38.
McColl DJ, Fransen S, Parkin S, et al. Resistance and cross-resistance to first generation integrase
inhibitors: insights from a phase II study of elvitegravir (GS-9137). Antivir Ther. 2007;12:S11.
Peters M, Nijs S, Vingerhoets J, et al. Determination of phenotypic clinical cut-offs for etravirine (ETR):
pooled week 24 results of the DUET-1 and DUET-2 trials. Antivir Ther. 2008;13(Suppl 3):A133.
Tsibris AMN, Gulick RM, Su Z, et al. In vivo emergence of HIV-1 resistance to the CCR5 antagonist
vicriviroc: findings from ACTG A5211. Antivir Ther. 2007;12:S15.
Vingerhoets J, Peeters M, Azijn H, et al. An update of the list of NNRTI mutations associated with
decreased virological response to etravirine: multivariate analyses on the pooled DUET-1 and DUET-2
clinical trial data. [Abstract 24.] Antivir Ther. 2008;13(Suppl 3):A26.
Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility
assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound
receptor for entry. J Virol. 2007;81:2359-2371.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
33
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
34
CARDIOVASCULAR RISK: HAART TO HEART
Judith A. Aberg, MD
___________________________________
___________________________________
___________________________________
Cardiovascular Risk:
HAART to HEART
___________________________________
___________________________________
Judith A. Aberg, MD
___________________________________
Associate Professor of Medicine
New York University Medical Center
___________________________________
International AIDS Society–USA
___________________________________
Slide 2
___________________________________
HIV Infection and CV Risk
Included in risk
calculations
•
•
•
•
•
•
•
•
•
Age
Sex
BP
T-chol
LDL
Diabetic status
Smoker status
ECG LVH
History
Not included in
risk calculations
Lipid
abnormalities
⇓ HDL
⇑ LDL Cho
⇑ TG
Insulin
resistance
___________________________________
___________________________________
Evaluated factors associated with MI in 15,000 (MI) patients versus 15,000 case controls
2.4
Odds Ratio (99% CI)
1.9
3.3
(1.7-2.1)
(2.8-3.8)
13.0
42.3
(10.7-15.8) (33.2-54.0)
___________________________________
___________________________________
Slide 3
2.9
___________________________________
Endothelial
dysfunction
INTERHEART Study: In the General Population, Multiple
Traditional Risk Factors Confer Synergistic Increases in
the Risk of MI
(2.6-3.2) (2.1-2.7)
___________________________________
___________________________________
Increased
visceral
fat
Chronic
inflammation
• Insulin resistance
• Microvascular NO
effects
• Particle size
• Endothelial
dysfunction
• Chronic
inflammatory states
___________________________________
68.5
182.9
333.7
(53.0-88.6)
(132.6-252.2)
(230.2-483.9)
512
256
128
64
32
16
8
___________________________________
___________________________________
___________________________________
4
2
1
Smk
(1)
DM
(2)
HTN ApoB/A1 1+2+3
(3)
(4)
All 4
+Ab Obes
+PS
___________________________________
All RFs
Risk Factor (Adjusted for All Others)
Smk=smoking; DM=diabetes mellitus; HTN=hypertension; Obes=abdominal obesity; PS=psychosocial; RF=risk factors.
>90% of total risk can be attributed to these factors
3
Yusuf S, et al. Lancet. 2004;364:937-952.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
35
J. A. Aberg, MD
___________________________________
Slide 4
Prediction of CV risk based on the
Framingham Heart Study
Risk Factor
___________________________________
___________________________________
Units
Gender
Age
Total Cholesterol
HDL
Systolic Blood Pressure
Treatment for Hypertension (Only if SBP >120)
Current Smoker
Time Frame for Risk Estimate
male or female
years
mg/dL
mg/dL
mmHg
yes or no
yes or no
m
46
245
35
125
n
y
10 years
10
0,19
Your Risk
___________________________________
___________________________________
___________________________________
19%
___________________________________
0%
5%
10%
15%
low risk moderate risk
20%
25%
30%
high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
Rates Per Thousand Person Years
8
7
___________________________________
Slide 5
D:A:D Study: Is the Framingham Risk
Estimation Valid in HIV-Infected Patients?
___________________________________
Observed and predicted MI rates according to ART exposure
(D:A:D Study; n=23,468)
___________________________________
Incidence of MIs is low: 345 over 94,469 patient-years’ follow-up (3.7/1,000 patient-years)
Observed
rates
6
Best
estimate of
predicted
rates
5
4
3
2
___________________________________
___________________________________
___________________________________
___________________________________
1
0
None
<1
1–2
2–3
3–4
n=5,973
n=5,292
n=6,805
n=9,050
n=10,574
4+
n=8,890
Duration of cART Exposure (Years)
n=ART exposure
5
Law MG, et al. HIV Med. 2006;7:218-230.
D:A:D Study:
NRTI Use and Risk of MI
• D:A:D study
– 33,347 HIV patients on HAART
• 517 patients developed MI over
157,912 person-years of follow-up
– Recent didanosine use (n=124)
– Recent abacavir use (n=192)
– Recent other NRTI use (n=237)
• Recent use of abacavir and
didanosine (but not cumulative or
past use) associated with increased
risk of MI
– Risk persists regardless of length of
use
– Risk was reversible with
discontinuation of drugs
– Most MIs occurred in patients with
existing cardiovascular risk factors
Recent use
Zidovudine
Stavudine
Lamivudine
Abacavir
Didanosine
___________________________________
Slide 6
___________________________________
Relative Risk
(95% CI)
P
Value
___________________________________
0.97
0.82
___________________________________
1.00
0.98
1.25
0.10
1.90
0.0001
1.49
0.003
(0.76- 1.25)
(0.76-1.32)
(0.96-1.62)
(1.47-2.45)
(1.14-1.95)
___________________________________
___________________________________
___________________________________
Implications:
Use caution in the interpretation of
these preliminary findings and await
further studies
D:A:D Study Group. Lancet. 2008;April 2. Epub ahead of print.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
36
J. A. Aberg, MD
___________________________________
Slide 7
SMART Subgroup Analysis: Association of
Abacavir Use With Increased Risk of CVD Events
___________________________________
• Current use of abacavir without
didanosine was significantly
associated with
___________________________________
Adjusted Hazard Ratio for
Events Based on
Abacavir Use (no ddI)
Versus Use of Other NRTIs
– Increased risk for all types of
cardiovascular events
compared with other NRTIs
– Increased risk for expanded
major CVD events among
patients with >5 CVD risk
factors and among those with
ischemic abnormalities on
ECG
• Hazard ratio versus other NRTIs
was 3.1 for both
– Increased levels of IL-6 and
hs-CRP
___________________________________
MI (n=19)
4.3
Major CVD events
(n=70)
1.8
Expanded major
CVD events
(n=112)
1.9
___________________________________
Minor CVD events
(n=58)
2.7
___________________________________
___________________________________
• Use of didanosine + abacavir
was not associated with an
increased risk for any
cardiovascular endpoint
Lundgren J, et al. 17th IAC. Mexico City, 2008. Abstract ThAB0305.
___________________________________
Slide 8
The Reports on abacavir and its
association with CHD have
___________________________________
___________________________________
1. Altered my prescribing habits and I do not prescribe
abacavir at all
___________________________________
2. Altered my prescribing habits and I do not prescribe to
those with high CHD risk
___________________________________
3. Altered my prescribing of abacavir in naïve patients but not
treatment experienced patients
___________________________________
4. I have switched all my patients on abacavir to another
ARV if available
___________________________________
5. Not affected my practice. I prescribe whatever is best for
the individual
6. Answers 2 and 4
7. Answers 2 and 3
The D:A:D Study
___________________________________
Slide 9
___________________________________
CROI 2009 UPDATE
• Prior analyses* from the D:A:D study showed an
___________________________________
increased risk of MI associated with:
___________________________________
– Cumulative exposure to PIs but not NNRTIs
– Current/recent exposure to abacavir (ABC) or
didanosine (ddI)
___________________________________
• Drugs within PI and NNRTI classes associated with
different metabolic profiles
___________________________________
assess role of tenofovir
___________________________________
• Previous NRTI analyses had insufficient follow-up to
• Aim: Sufficient follow-up has now accrued to explore
associations between a total of 14 drugs from these
classes and MI risk
* D:A:D Study Group, NEJM 2007; D:A:D Study Group, Lancet 2008.
Lundgren JD et al., CROI 2009;
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
37
J. A. Aberg, MD
The D:A:D Study
___________________________________
Slide 10
NRTIs and Risk of MI:
Recent* and Cumulative Exposure
RR
yes/no
95% CI
___________________________________
1.9
___________________________________
1.5
___________________________________
___________________________________
1.2
RR per
year
95% CI
**
1
___________________________________
0.8
___________________________________
0.6
ZDV
ddI
ddC
#PYFU: 138,109 74,407
#MI:
523
d4T
3TC
ABC
TDF
29,676 95,320 152,009 53,300 39,157
331
148
405
554
221
139
*Recent use=current or within the last 6 months. **Not shown (low number of patient currently on ddC)
Lundgren JD et al., CROI 2009;
The D:A:D Study
___________________________________
Slide 11
PIs/NNRTIs and Risk of MI: Cumulative
Exposure to Each Drug
PI
1.2
___________________________________
___________________________________
NNRTI
___________________________________
1.13
___________________________________
RR/year
95% CI
___________________________________
1
0.9
___________________________________
IDV
#PYFU: 68,469
#MI:
298
NFV
LPV/r
SAQ
NVP
EFV
56,529
37,136
44,657
61,855
58,946
197
150
221
228
221
* Approximate test for heterogeneity: P=0.02
Lundgren JD et al., CROI 2009;
Clinical Data Suggest Increased Risk
of MI or CVD Associated with ABC is
(Sub)acute and Reversible
___________________________________
Slide 12
___________________________________
___________________________________
___________________________________
CVD Risk
___________________________________
___________________________________
Some PIs have progressive risk
with cumulative exposure
___________________________________
Start ABC
Stop ABC
Adapted from Reiss P, CROI 2009; 152
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
38
J. A. Aberg, MD
The D:A:D Study
___________________________________
Slide 13
Characteristics of Patients at Time of
MI/Last Follow-up
Number of patients
Male sex; %
Age (years); median
BMI>26 kg/mm²; %
Current smoker; %
Ex-smoker; %
Prior CVD event; %
Family history of CHD; %
Diabetes; %
Any hypertension; %
Latest total cholesterol (mmol/L); median
Latest HDL cholesterol (mmol/L); median
Latest triglycerides (mmol/L); median
Use of lipid-lowering medications; %
Any dyslipidemia; %
Predicted 10-year CHD risk; %
Moderate (10–20%)
High (>20%)
Patients with MI
580
90.7
49
18.8
44.8
29.8
20.0
13.6
16.6
43.5
5.7
1.1
2.2
36.0
74.8
Patients without MI
32728
73.8
44
17.3
28.7
30.1
2.5
8.3
5.3
19.2
4.8
1.2
1.6
12.5
44.3
30.3
18.1
14.5
4.2
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Lundgren JD et al., CROI 2009;
D:A:D
___________________________________
Slide 14
Channelling Bias
___________________________________
Effect observed because persons perceived at risk of CVD
are preferentially prescribed abacavir
___________________________________
Unlikely explanation because:
___________________________________
• Risk of ABC not reduced by adjustment for known CVD risk
factors including those possibly affected by ART
___________________________________
• Risk of ABC no longer present after drug discontinuation
• Risk of ABC specific for MI and other outcomes related to CAD,
___________________________________
but not for stroke which shares many risk factors with MI and
might, to some extent, be expected to be affected by the same
bias
___________________________________
• Same effect not seen with tenofovir which like ABC could be
expected to be preferentially prescribed to avoid metabolic
complications and thereby mitigate CVD risk *
D:A:D study group Lancet 2008
* J Lundgren and D:A:D study group, CROI 2009; LB abst 44
ANRS:
CVD Case Control Study
z
___________________________________
Slide 15
___________________________________
Nested, case-control study to evaluate association between risk
of MI and
z
Cumulative exposure to specific NRTIs
z
Recent (current or within last 6 months) and past exposure (>6 months ago) to specific
NRTIs
z
Cumulative exposure to specific PIs
___________________________________
___________________________________
• Over 115,000 HIV-infected patients enrolled between 1989 and
___________________________________
2006
•
Cases: 289 Patients with a first definite or probable MI prospectively reported between
January, 2000 and December, 2006
•
Matched Controls: For each MI case, up to 5 controls with no history of MI matched for
age, sex and clinical center
___________________________________
• Data collected for cases and controls
•
Cardiovascular risk factors and treatments
•
HIV history and treatment
___________________________________
Lang S, et al .16th CROI; Montreal, Canada; February 8-11, 2009. Abst . 43LB.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
39
J. A. Aberg, MD
Cases (n = 289)
Sex, male, n (% )
___________________________________
Controls (n = 884)
257 (88.9%)
788 (89.1%)
46.9 ± (40.7 – 54.1)
46.3 (40.2 – 53.7)
Hypertension, n (%)
59 (20.6%)
102 (11.8%)
Smoking, n (%)
210 (72.7%)
388 (43.9%)
Age, years, median (IQR )
___________________________________
Slide 16
FHDH Characteristics
___________________________________
___________________________________
Family history of CHD, n (%)
53 (18.5%)
58 (6.7%)
Hypercholesterolemia, n (%)
148 (51.7%)
282 (32.6%)
Intravenous drug use, n (%)
38 (13.3%)
83 (9.5%)
3 (1.0%)
163 (18.4%)
1-2 n, (%)
172 (59.5%)
553 (62.6%)
? 3 n, (%)
114 (39.4%)
168 (19.0%)
127 (50 - 3900)
50 (50 – 1368)
___________________________________
Number of CV risk factors :
0, n (%)
Viral load, copies/mL, median (IQR)
Viral load <50 copies/mL, n (%)
___________________________________
___________________________________
125 (43.3%)
457 (51.7%)
427 (256 - 638)
451 (291 – 634)
CD4/CD8 ratio ≥ 1, n (%)
19 (6.6%)
116 (13.1%)
No treatment before MI, n (%)
11 (3.8%)
55 (6.2%)
210 (72.7%)
677 (76.6%)
CD4 count, cells/mm3 median (IQR)
1st treatment after inclusion in FHDH, n (%)
___________________________________
Slide 17
Exposure to abacavir and risk of MI - II
N exposed
Model 1
Model 2
N exposed
cases
127
___________________________________
OR
[ 95% CI ]
p value
0.97
0.86 - 1.10
0.651
0.88
0.75 - 1.04
0.138
Cumulative exp to abacavir
410
Cumulative exp to abacavir
410
127
No exposure
763
162
1
-
-
Exposure or stop ≤ 6 months
290
88
1.57
0.91 - 2.72
0.107
Stop > 6 months
120
39
1.59
0.89 - 2.83
0.116
___________________________________
___________________________________
___________________________________
For abacavir, there was evidence of an interaction between recent/past and
cumulative exposure, while no such effect was observed for any other NRTI
___________________________________
„A
final model including exposure to abacavir as a five-class variable
and cumulative exposure to all other ART was constructed
___________________________________
„no
exposure
„exposure <= 1 year and last use <= 6 months prior to the MI
„exposure <= 1 year and last use > 6 months prior to the MI
„exposure > 1 year and last use <= 6 months prior to the MI
„exposure > 1 year and last use > 6 months prior to the MI
___________________________________
Slide 18
Exposure to abacavir and other NRTIs
and risk of MI - III
N exposed
cases
OR
[ 95% CI ]
p value
763
162
1
-
-
Final model
No exposure
Expo < 1 year, stop ≤ 6 months
___________________________________
N exposed
72
31
1.97
Expo < 1 year, stop > 6 months
76
24
1.31
0.68 - 2.52
0.415
Expo > 1 year, stop ≤ 6 months
218
57
1.05
0.65 - 1.69
0.844
Expo > 1 year, stop > 6 months
44
15
1.42
0.60 - 3.35
0.420
1.09 - 3.56
___________________________________
___________________________________
0.025
Cum exp to zidovudine
998
256
1.08
0.99 - 1.18
0.086
Cum exp to didanosine
691
186
0.91
0.82 - 1.01
0.071
Cum exp to zalcitabine
314
92
0.99
0.81 - 1.21
0.924
Cum exp to stavudine
718
199
1.09
0.98 - 1.22
0.132
Cum exp to lamivudine
1043
269
0.95
0.85 - 1.07
0.387
Cum exp to tenofovir
238
65
0.97
0.75 - 1.24
0.785
___________________________________
___________________________________
___________________________________
No interaction was found between exposure to abacavir and numbers of CV risk
factors on the risk of MI (p = 0.384)
Similar results were observed when restricting the analysis to patients with first
ART after inclusion in the cohort
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
40
J. A. Aberg, MD
___________________________________
Slide 19
___________________________________
Exposure to PIs and risk of MI
Final model
Cumulative exposure (per
additional year)
N exposed
___________________________________
N exposed
cases
OR
[ 95% CI ]
p value
Saquinavir
324
92
0.96
0.80 – 1.15
0.669
Indinavir
497
146
1.10
0.98 – 1.24
0.117
Nelfinavir
453
131
1.12
0.98 – 1.28
0.110
Lopinavir
290
94
1.37
1.09 – 1.72
0.006
Amprenavir/fos-amp
117
46
1.52
1.19 – 1.95
0.001
N exposed
N exposed
cases
OR
[ 95% CI ]
p value
PI
864
239
1.16
1.07 – 1.26
<0.001
Saquinavir
324
92
0.95
0.83 – 1.10
0.502
Final model
combining
all PIs but SQV
Cumulative exposure
(per additional year)
___________________________________
___________________________________
___________________________________
___________________________________
Similar results were observed when restricting the analysis to
patients with first ART after inclusion in the cohort
___________________________________
Slide 20
GSK: analysis from 54 clinical studies of abacavir
___________________________________
(12 randomized ABC vs no ABC)
CVD Outcomes - Exposure to ABC Compared with No Exposure to ABC
Exposure to
ABC
Events
Frequency
/Patients
Events
Rate
/PersonYears
/1000 Person- (95% CI)
Years
Relative rate
___________________________________
___________________________________
Any Myocardial Infarction or Acute Myocardial Infarction:
None
7/5044
0.139%
11/4653
2.36
ABC CART
11/9639
0.114%
16/7845
2.04
___________________________________
___________________________________
0.863
(0.40,1.86)
___________________________________
Any ischemic Coronary Artery Disease or Disorder:
None
21/5044
0.416%
27/4642
5.82
ABC CART
24/9639
0.249%
27/7832
3.45
0.593
(0.35 ,1.01)
Cutrell A, Hernandez J, Brothers C et al. Lancet 2008; IAC Mexico 2008; JAIDS in press
Median VL > 4 log10copies/mL
___________________________________
Slide 21
ACTG 5001:
ABC Not Associated with CV Risk
___________________________________
___________________________________
• Evaluation of association between ABC and risk of MI or severe CVD after
starting HAART
– Patients randomized to first ART in 5 ACTG studies evaluated for CV risk factors
(N=3,205)
___________________________________
– 63 severe CVD, including 27 MI
___________________________________
• No association of ABC and severe CVD or MI found
Recent ABC
Age (per 10 yrs)
Ever Smoked
HTN
Family CVD Hx
Black, Non-hispanic
Hispanic
MI
Adjusted RR
P
1.2
2.0
3.1
1.3
1.2
0.5
0.5
0.82
<0.001
0.07
0.57
0.89
0.13
0.16
Severe CVD
Adjusted RR
P
0.8
1.9
1.4
2.3
2.5
0.6
0.4
___________________________________
0.50
<0.001
0.27
0.007
0.11
0.11
0.06
___________________________________
Benson C, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 721.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
41
J. A. Aberg, MD
___________________________________
Slide 22
STEAL
Randomized Simplification with fixed-dose TenofovirEmtricitabine or Abacavir-Lamivudine in adults with HIV-RNA<50 c/mL
___________________________________
N = 357 (179 ABC/3TC, 178 TDF/FTC)
HLA-B5701 negative, 96 weeks follow-up
Serious non-AIDS events
___________________________________
ABC-3TC
TDF-FTC
n
Rate
n
Rate
(TDF/
ABC)
95%CI
P
___________________________________
HR
Total *
14
4.4
4
1.2
0.26
0.08, 0.79
0.018
CVD
8
2.2
1
0.3
0.13
0.02, 0.98
0.046
Cancer
5
2.8
2
1.1
Major fracture
0
1.1
1
1.1
Cirrhosis
1
0.6
0
0
Deaths
(all cancer)
3
1.6
1
0.6
___________________________________
___________________________________
___________________________________
A Carr & NCHECR investigators;CROI 2009 abs 576 P session 104
___________________________________
Slide 23
___________________________________
STEAL: Baseline Cardiovascular Risk
Smoking (%)
current
past
never
Diabetes (%)
Hypertension (%)
Ischemic heart disease (%)
Ischemic stroke (%)
Framingham risk score (%)
*n=145
ABC-3TC
N=179
%
40.2
29.1
30.7
5.0
13.4
3.9
0.6
8.5*
___________________________________
TDF-FTC
N=178
%
29.2
29.8
41.0
3.4
11.2
2.3
0.0
7.0**
___________________________________
___________________________________
___________________________________
___________________________________
**n=136
Carr A, NCHECR investigators. CROI 2009. abstract 576, poster session 104.
___________________________________
Slide 24
ACTG 5206 CROI 2009
___________________________________
___________________________________
ƒ Documented HIV infection, ≥ 18 years, dyslipidemia (TG ≥ 200 and
non-HDL ≥ 160) and HIV VL <400 copies/mL
___________________________________
ƒ Subjects randomized to one of the following arms:
• Arm A:
___________________________________
– 12 weeks of tenofovir 300 mg PO QD
___________________________________
– 4 weeks of no study treatment
– 12 weeks of placebo PO QD
___________________________________
• Arm B:
– 12 weeks of placebo PO QD
– 4 weeks of no study treatment
– 12 weeks of tenofovir 300 mg PO QD
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
42
J. A. Aberg, MD
___________________________________
Slide 25
A5206 TDF Intensification
Non-HDL-C
Total Cholesterol
LDL-C
Δ TDF Median (IQR) (mg/dL)
-32 (-51, -7)
-39 (-58, -6)
-12 (-29, 0)
ΔPlacebo Median (IQR) (mg/dL)
-4 (-10, 10)
-6 (-16, 14)
-3 (-17, 25)
Estimated Mediana (mg/dL)
-29.5
-36.5
-20.0
P-valueb
0.01
<0.01
0.06
90% Exact CI Bound (mg/dL)
-14c
-16.5c
-1c
-16% (-26%, -4%)
-18% (-24%, -3%)
-12% (-28%, 0%)
-2% (-7%, 5%)
-3% (-6%, 6%)
-4% (-11%, 25%)
-14%
-14%
-17%
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
% ΔTDF Median (IQR)
% ΔPlacebo Median (IQR)
Estimated Mediana
P-valueb
0.02
0.01
0.04
90% Exact CI Bound
-5%c
-7%c
-3%c
___________________________________
___________________________________
Slide 26
Summary of Studies Assessing Association Between
Abacavir and CVD Risk
___________________________________
___________________________________
N
Effect of Abacavir
Found
Prospective predefined
33347
Yes
___________________________________
Case control in
observ. cohort
Prospect rep. MI retrosp
validated
289 ca
884 ctr
Yes
(1st year exposure)
___________________________________
SMART3
RCT observ.
analysis
Prospective predefined
2752
Yes
___________________________________
STEAL4
RCT
Prospective
357
Yes
GSK Analysis5
RCT (54)
Retrospective, database
search
14174
No
ALLRT ACTG6
LTFU from from 5
RCT
Retrospective by 2
independent reviewers
3205
No
Study
Design
Event Ascertainment
D:A:D1
Prospective
observ. cohort
FHDH2
___________________________________
1. Lundgren J and D:A:D study group, CROI 2009; LB abst 44. 2. Lang S, et al .16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 43LB.
3. Lundgren, IAS 2008. 4. Carr A, NCHECR investigators. CROI 2009. abstract 576, poster session 104.
5. Cutrell A, et al. Lancet 2008; IAC Mexico 2008; JAIDS in press. 6. Benson C, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 721.
___________________________________
Slide 27
In the HEAT and WIHS/MACS Cohort, IL-6
levels
1.
2.
3.
4.
___________________________________
___________________________________
Decreased only in those taking tenofovir
___________________________________
Decreased only in those taking abacavir
Similar increases in those taking any nucleoside
___________________________________
Similar decreases among those taking either
abacavir or tenofovir
___________________________________
5. Remained constant throughout the course of follow
___________________________________
up
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
43
J. A. Aberg, MD
___________________________________
Slide 28
Biomarkers Summary
___________________________________
___________________________________
• SMART (Lundgren, IAS 2008)
___________________________________
– Hs-CRP and IL-6 found to be significantly elevated at
study entry in those on ABC versus “Other NRTI” group
___________________________________
• HEAT (McComsey, CROI 2009)
– Declines in sVCAM, IL-6 and hsCRP observed at Weeks
48 and 96, with no difference in magnitude of reduction
between ABC/3TC and TDF/FTC
___________________________________
___________________________________
• MACS & WIHS (Palella, CROI 2009)
• Biomarker level changes (D-dimer and IL-6 decreases,
hsCRP increases) comparable among persons who
initiated ABC versus non-ABC containing HAART
___________________________________
Slide 29
Abacavir Risk Seems More Pronounced in Those
With Higher Underlying CVD Risk: D:A:D
___________________________________
___________________________________
Rates of MI for Recent* Use of Abacavir by Predicted
10-year Coronary Heart Disease (CHD) Risk
No recent abacavir
Recent abacavir
___________________________________
Rate (per 1000 PY)
Stratified by recent*
abacavir use
35
___________________________________
SMART
&
FHDB
interaction
not significant
30
25
20
15
10
5
0 Overall Low Moderate High
___________________________________
___________________________________
Not known
Predicted 10-year CHD risk
Events
325 192 60
42
79
33 100 68
86
49
PY
126581 31331 57628 14754 13372 4300 6293 2095 49288 10182
Interaction between moderate/high CHD risk and recent abacavir use: p=0.04
* Recent = still using or stopped within last 6 months
D:A:D study group, Lancet 2008
___________________________________
Slide 30
Cardiovascular Risk Summary
___________________________________
• Unclear if and why abacavir is associated with CHD. Need
___________________________________
• Traditional Risk Factors, regardless of the contribution
___________________________________
to understand the pathogenesis
from HIV and its therapies, need to be addressed and
managed
___________________________________
• Insufficient data to recommend using inflammatory
___________________________________
markers and subclinical atherosclerosis imaging studies.
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
44
J. A. Aberg, MD
SUGGESTED READING
Aberg JA. Cardiovascular complications in HIV management: past, present, and future. JAIDS.
2009;50:54-64.
D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and
risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort
collaboration. Lancet. 2008;371:1417-1426.
DAD Study Group, Friis-Moller N, Reiss P, et al. Class of antiretroviral drugs and the risk of myocardial
infarction. N Engl J Med. 2007;356:1723-1735.
El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment.
N Engl J Med. 2006;355:2283-2296.
Kostis JB. The importance of managing hypertension and dyslipidemia to decrease cardiovascular
disease. Cardiovasc Drugs Ther. 2007;21:297-309.
Stein JH. Cardiovascular risks of antiretroviral therapy. N Engl J Med. 2007;356:1773-1775.
Strategies for Management of Antiretroviral Therapy/INSIGHT, DAD Study Groups. Use of
nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients.
AIDS. 2008;22:F17-F24.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
45
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
46
MALIGNANCIES IN HIV: A GROWING PROBLEM
Ronald T. Mitsuyasu, MD
___________________________________
___________________________________
___________________________________
Malignancies in HIV:
A Growing Problem
___________________________________
___________________________________
Ronald T. Mitsuyasu, MD
___________________________________
Professor of Medicine
David Geffen School of Medicine at UCLA
University of California Los Angeles
___________________________________
International AIDS Society–USA
Slide 2
Cancers in HIV Disease
AIDS-Defining
• Kaposi’s Sarcoma
• Non-Hodgkin’s Lymphoma
(systemic and CNS)
• Invasive Cervical Carcinoma
Non-AIDS Defining
• Anal Cancer
• Hodgkin’s Disease
• Leiomyosarcoma (pediatric)
• Squamous Carcinoma (oral)
• Merkel cell Carcinoma
• Hepatoma
___________________________________
___________________________________
Virus
HHV-8
EBV, HHV-8
___________________________________
___________________________________
___________________________________
HPV
___________________________________
HPV
EBV
EBV
HPV
MCV
HBV, HCV
___________________________________
Slide 3
Background
___________________________________
___________________________________
• Early reports in the late 1980s suggested that
malignancies may cause a “second” epidemic of
AIDS1
• KS and NHL initially accounted for the majority
of morbidity and mortality
• HAART resulted in a shift in the proportion of
deaths due to cancer towards NADCs
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
– NADCs as a cause of death increased
from <1% (pre-HAART) to 13% (post-HAART)2,3
1. Monfardini et al AIDS 1989; 3:449-52.
2. Stein et al. Am J Med 1992; 93:387-90.
3. Bonnet et al. Cancer 2004; 101:317-24.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
47
R. T. Mitsuyasu, MD
Slide 4
Change in Incidence of Cancers in
HIV in the HAART Era in USA
•
•
•
•
•
•
•
•
•
•
___________________________________
___________________________________
___________________________________
Kaposi’s sarcoma
CNS Lymphoma
Lymphoma (NHL)
Lymphoma (HD)
Cervical Cancer
Anal Cancer
Lung Cancer
Prostate
Breast
Hepatoma
___________________________________
___________________________________
___________________________________
___________________________________
Patel P et al, Ann Intern Med 2008;148:728-736
CASCADE Collaboration:
Overall Mortality and Causes of Death
35
___________________________________
Pre-HAART (n=1424)
HAART (n=514)
31.7%
Pre-HAART
___________________________________
30
Deaths (%)
Proportion (%)
25
60
40
20
HAART
___________________________________
19.3%
10.0%
5
0
5
10
0
15
9.9%
4.9%
2.5%
0
___________________________________
15
10
20
3.2%
Years Since Seroconversion*
___________________________________
4.3%
2.5%
1.3%
Not
Hepatitis
Specified Liver
OIs
___________________________________
___________________________________
Causes of Death†
Overall Mortality*
80
Slide 5
Malignancy
CVD/
DM
*n=7680 seroconverters, of whom 1938 died (26%; 1424 pre-HAART and 514 during HAART).
†
no change in the following causes of death: AIDS-related malignancy, other infections, organ failure,
and unknown causes.
Smit C, et al. AIDS. 2006;20:741-749.
Breakdown of causes of death: France 2005
Slide 6
___________________________________
___________________________________
AIDS
Cancer
Hepatitis C
CVD
Suicide
Non-AIDS infection
Accident
Hepatitis B
Liver disease
OD / drug abuse
neurologic
renal
pulmonary
digestive
iatrogenic
metabolic
psychiatric
other
unknown
___________________________________
___________________________________
N = 937 deaths
___________________________________
___________________________________
___________________________________
0
ANRS EN19 Mortalité 2005
5
10
15
20
Percent
25
30
35
40
Lewden JAIDS 2008, 48:590-9
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
48
R. T. Mitsuyasu, MD
Slide 7
Pathogenesis of NADC
• Some are virally-induced cancers, but not all
• HIV-tat may transactivate cellular genes or protooncogenes, inhibit tumor suppressor genes
• Microsatellite alterations (MA) due to genetic
instability in HIV (e.g 6 fold higher number of MA in
HIV lung CA over non-HIV)1
• Increase susceptibility to effects of carcinogens
• Endothelial abnormalities and elaboration of
angiogenic factor
• Immune activation and decreased immune
surveillance
• Population differences based on genetics and
exposure to carcinogens
Wistuba, AIDS 1999;13:415-26
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
1
HIV and risk of non-AIDS malignancies
Slide 8
___________________________________
___________________________________
___________________________________
___________________________________
Meta-analysis: 444,172 people with HIV, 31,977 transplant patients
___________________________________
For 20 / 28 cancers examined there was significantly increased incidence
in both groups – strongly suggesting a link with immunodeficiency
___________________________________
Standardized Incidence Ratio
HIV/AIDS
Transplant
Lung
Leukaemia
Kidney
Esophagus
Stomach
2.7
3.2
1.5
1.6
1.9
___________________________________
2.2
2.4
6.8
3.1
2.0
Grulich et al, Lancet 2007
Slide 9
___________________________________
Non-AIDS-defining Cancers
Emerging Epidemiologic Features
1991-1995
___________________________________
1996-2002
___________________________________
Proportion of Cancers in HIV
NADC
31%
58%
___________________________________
Standardized Incidence Ratio
Lung
Hodgkin
lymphoma
Larynx
Pancreas
Liver
2.6
2.6
2.8
6.7
1.8
0.8
0
2.7
2.5
3.7
___________________________________
___________________________________
___________________________________
Engels EA, Int J Cancer. 2008;123:187-194
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
49
R. T. Mitsuyasu, MD
Slide 10
Study Design
___________________________________
___________________________________
___________________________________
• Retrospective analysis of incident malignancies
from 1996 to 2005 among 2,566 patients in the
Johns Hopkins AIDS clinic cohort
___________________________________
• NADC compared with ADC and general cohort
___________________________________
___________________________________
– ADC: KS, NHL, cervical cancer
___________________________________
– NADC: all other malignancies, except
non-melanoma skin cancers
Long JL et al. AIDS. 2008;22:489-496
Slide 11
Results: Demographic and Clinical
Characteristics at Cancer Diagnosis
ADC
155 (45.5)
138 (54.5)
48
38
<.001
Median years of follow-up
Median CD4+ cells/µL
History of OI [No. (%)]
History of ARV
5.2
270
65 (57.4)
83 (72.2)
3.5
60
97 (70.3)
93 (67.4)
.029
<.001
.033
.410
On ARV at cancer dx
On ARV and HIV RNA
<400 copies/mL
68 (59.1)
39 (59.1)
70 (50.7)
23 (35.4)
.181
.007
Median age (yr)
___________________________________
___________________________________
NADC
No (%)
___________________________________
P
___________________________________
___________________________________
___________________________________
___________________________________
Long JL et al. AIDS. 2008;22:489-496
Slide 12
Results: Cancer Incidence Rates
___________________________________
___________________________________
___________________________________
Incidence (per 1000 PY)
Overall
1996-1997
1998-1999
2000-2001
2002-2003
2004-2005
P for trend over time
NADC
5.9
3.9
~6.5
~7.0
~6.0
7.1
.13
ADC
7.1
>12.0
~8.0
~7.0
~7.0
<4.0
<.001
___________________________________
___________________________________
___________________________________
___________________________________
Long JL et al. AIDS. 2008;22:489-496
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
50
R. T. Mitsuyasu, MD
Slide 13
Results
___________________________________
___________________________________
HIV status differences
• Lung, liver, head and neck, anal, bladder, esophageal cancers;
Hodgkin lymphoma; melanoma-incidences are higher in HIVinfected population
• Prostate, breast, colorectal cancer rates similar
Racial differences
• NADC incidence similar, but mortality higher in black patients
• 7 of 10 anal cancer cases in white patients
• 26 of 29 cases of lung cancer and 10 of 13 of liver tumors
in black patients
Transmission group differences
• Most KS and anal cancer in MSM
Sex differences
• KS (91%) and NHL (78%) occur predominately in men
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Long JL et al. AIDS. 2008;22:489-496
Slide 14
Incidence and Risk Factors for ADC and
NADC Among HIV-Infected Individuals
___________________________________
___________________________________
___________________________________
• HIV natural history study among US military
beneficiaries
• 1984-2006, divided by pre- and post-HAART periods
(early and late)
• 311 ADC and 133 NADCs/4566 participants
___________________________________
___________________________________
___________________________________
– ADC more common pre-HAART, NADC post-HAART
– NADC increased from 2.9 to 6.7 per 1000 person-yr
– ADC decreased from 7.6 to 2.7 per 1000 person-yr
___________________________________
• Rates compared to the Surveillance Epidemiology and
End Results (SEER) data
Crum-Cianflone, AIDS 2009;23:41-50
Slide 15
Cancer Incidence Rates by HAART Period
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Crum-Cianflone AIDS 2009, 23:41-50.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
51
R. T. Mitsuyasu, MD
Slide 16
Incidence and Risk Factors for NADCs Among
HIV-Infected Individuals
___________________________________
___________________________________
___________________________________
• Predictors in the multivariate analyses:
– Older Age
___________________________________
• HR 1.99 per 10 yrs (CI 1.67,2.36), p<0.001
___________________________________
– Caucasian/non-Hispanic
• Compared to AA, HR 1.56 (CI, 1.78, 1.22) p=0.02
___________________________________
– HAART was protective for ADC but not NADC
• OR 0.21, p<0.001
___________________________________
• No associations with time-updated CD4 at
diagnosis
– 79% in post-HAART era with CD4>350
Crum-Cianflone AIDS 2009, 23:41-50
Slide 17
Incidence and Risk Factors for NADCs
Among HIV-Infected Individuals
___________________________________
___________________________________
Higher rate of following cancers compared to
general US population:
• Whites
– Skin cancer
• Basal and
squamous
– Melanoma
– Hodgkin’s
– Anal
___________________________________
___________________________________
• African Americans
–
–
–
–
___________________________________
Hodgkin’s
Anal
Lung
Colorectal
___________________________________
___________________________________
Burgi et al, Cancer 2005; 104:1505-11
Incidence and Risk of NADC in a
Large Prospective Cohort
Slide 18
___________________________________
___________________________________
___________________________________
• Incidence of NADCs in 11,112 HIV+ patients seen at
Chelsea-Westminster Hospital 1983-2007
___________________________________
– Pre-HAART (1983-1995) SIR 0.95 (CI 0.58-1.47)
– Early HAART (1996-2001) SIR 2.05 (CI 1.51-2.72)
___________________________________
– Established HAART (2002-2007) SIR 2.49 (CI 2.0-3.07)
___________________________________
• Increased risk in multivariate analyses associated with
___________________________________
– Use of HAART HR 1.64 (CI 1.13-2.39)
– Nadir CD4 <200 HR 1.67 (CI 1.10-2.54)
– Use of NNRTI and HD HR 1.45 (CI 1.01-2.08)
Powles T et al. J Clin Onc 2009, 27:884-890
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
52
R. T. Mitsuyasu, MD
Slide 19
Non-AIDS Endpoint
SMART Study
___________________________________
___________________________________
___________________________________
• Randomized trial of continuous viral suppression (VS) vs
drug conserving, intermittent HAART (DC), CD4 250-350
• N=5472 Study prematurely stopped due to higher deaths
and other endpoints in DC
___________________________________
Number
%
___________________________________
CVD
79
42
___________________________________
Hepatic
17
12
___________________________________
Renal
11
10
NA Cancer
60*
36
Endpoint
*25% Fatal
Silverberg et al. AIDS 2007, 21:1957-1963
HIV RNA and risk of serious non-AIDS
events: SMART
Slide 20
___________________________________
All serious non-AIDS
Non-AIDS malignancy
CVD
Other non-AIDS death
Adjusted hazard ratio
copies/mL
1.0
___________________________________
___________________________________
Liver
0.5
___________________________________
___________________________________
Renal
0.2
___________________________________
___________________________________
1.5
< 400 vs. > 400
Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count
Slide 21
Why does lung CA do so badly?
___________________________________
___________________________________
HIV-
AgeMatched
HIV-
Pre HAART
HIV+
Post HAART
HIV+
___________________________________
Number
192
102
97
18
___________________________________
Age
69
45
42
45
___________________________________
Stage 1-IIIA
32%
10%
25%
6%
PS 0-2
51%
52%
42%
40%
___________________________________
Survival
(months)
>10
4
4.5
4
45%
27%
Adenocarcinoma 28%
66%
___________________________________
Powels, Br J Cancer 2003;89:457-9
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
53
R. T. Mitsuyasu, MD
Slide 22
Efficacy of Treatment
___________________________________
___________________________________
___________________________________
• Are standard treatment for each stage of
each cancer in non-HIV patient similarly
effective in the setting of HIV?
___________________________________
___________________________________
• Do worse prognostic factors in HIV justify
more aggressive therapy?
___________________________________
• Is the rate of relapse higher in HIV? What is
the role of intensification?
___________________________________
• Are molecular and virally-targeted therapies
more or less appropriate in HIV patients?
Slide 23
Side Effects and Complications
___________________________________
___________________________________
• Do HIV pts suffer more with greater toxicities?
___________________________________
• Interactions of HIV meds with anti-CA therapy?
___________________________________
• How do you adjust chemotherapy and HIV therapy
to minimize toxicities and side effects?
___________________________________
– E.g. reduce irinotecan in patients on PIs
___________________________________
– Hold chemotherapy during high dose chemotherapy
___________________________________
• Are standard palliative measures for side effects
effective in HIV patient?
• What is cost/benefit of more aggressive therapy?
Slide 24
Prevention
___________________________________
___________________________________
• Smoking Cessation – Highest priority
• Hepatitis and HPV vaccination
• Yearly cervical and anal Pap tests – Gyn and
HRA
• Maintain high index of suspicion for cancer
• Yearly breast, prostate (incl. PSA) exam
• Advise sunscreen and avoid overexposure
• Complete family history for malignancies
• If Hepatitis B or C positive, follow LFTs and
perhaps AFP periodically
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
54
R. T. Mitsuyasu, MD
Slide 25
Conclusions
___________________________________
___________________________________
• As patients live longer with HIV, morbidity and
mortality from cancers are increasing
• We must be able to quantify and characterize
cancers in HIV, as it may vary in different
populations around the world
• Treatment of malignancies in HIV should be
vigorous and appropriate to the situation
• Side effects associated with HAART and cancer
therapy should be treated/prevented
• Prevention strategies for virally-associated
malignancies need to be investigated
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 26
___________________________________
___________________________________
Thank You
___________________________________
• For information on AMC clinical trials see:
http://pub.emmes.com/study/amc/public/
index.htm
• For information on NCI programs in HIV
cancer see:
http://www.cancer.gov/cancertopics/types/
AIDS/
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
55
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
56
ADDICTIONS IN THE HIV CLINIC
Glenn J. Treisman, MD, PhD
___________________________________
___________________________________
___________________________________
___________________________________
Addictions in the HIV Clinic
___________________________________
Glenn J. Treisman, MD, PhD
___________________________________
Professor
Johns Hopkins Medical Institutions
School of Medicine
___________________________________
International AIDS Society–USA
Slide 2
___________________________________
depression
demoralization
substance abuse
cognitive impairment
Mental Illness
___________________________________
___________________________________
AIDS
___________________________________
___________________________________
impulsivity
depression
demoralization
substance abuse
cognitive impairment
___________________________________
Slide 3
___________________________________
___________________________________
Definition of Addiction
„
___________________________________
___________________________________
One is too many but ten is not enough
___________________________________
– Old alcoholic adage H Kleber
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
57
G. J. Treisman, MD, PhD
Slide 4
___________________________________
___________________________________
Core concepts of addiction
___________________________________
Tolerance
‹ Increasing dose
„ Dependence
‹ Physical withdrawal
„ Reinforcement
‹ Provides behavioral reinforcement
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 5
___________________________________
___________________________________
What is addiction?
___________________________________
What drugs are addictive?
‹ Tolerance
‹ Dependence
‹ Reinforcement
„ Continued increasing repetitive stereotyped
behavior despite mounting consequences
that disrupts function in all realms of life
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 6
___________________________________
___________________________________
Is Addiction a Disorder?
___________________________________
Disordering addictions (use to abuse ratio)
„ Non-disordering addictions
‹ Nicotine
‹ Caffeine
„ Less disordering addictions
‹ Methadone < Heroin
„ Risk and Benefit
„
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
58
G. J. Treisman, MD, PhD
Slide 7
___________________________________
Reinforcing and addictive drugs
___________________________________
Psychomotor stimulants (dopamine)
„ Opiates
„ Sedative-Hypnotics (GABA)
„ Cannabinoids
„ Phencyclidine (NMDA receptor)
„ Hallucinogens?
„ Nicotine and caffeine
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 8
___________________________________
A disease?
„ A result of environment?
„ A problem of the type of person involved?
„ A conditioned behavior that becomes self
sustaining?
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 9
„
___________________________________
___________________________________
The disease model
„
___________________________________
___________________________________
Is substance abuse...
„
___________________________________
___________________________________
Assumes a broken part in the brain
Assets
‹ Removes blame and stigma
‹ Emphasizes medical treatment
Vulnerabilities
‹ Cannot explain data from models or recovery
‹ Removes responsibility from patients
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
59
G. J. Treisman, MD, PhD
Slide 10
___________________________________
Problems with the disease
approach
___________________________________
There is a volitional component to addiction
that is absent from other disease states
„ Treatment needs to emphasize rehabilitation
rather than drugs
„ Behavioral models are better than lesion
models
___________________________________
___________________________________
„
___________________________________
___________________________________
___________________________________
Slide 11
___________________________________
___________________________________
What is behavior?
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 12
___________________________________
___________________________________
___________________________________
Behavior
___________________________________
___________________________________
___________________________________
Goal
___________________________________
Goal directed purposeful action
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
60
G. J. Treisman, MD, PhD
Slide 13
___________________________________
___________________________________
Behavior
___________________________________
increase
___________________________________
positive
___________________________________
environmental response
environmental exposure
Behavior
___________________________________
___________________________________
negative
decrease
Slide 14
Motivated Behavior
___________________________________
___________________________________
___________________________________
environmental response
environmental exposure
___________________________________
Behavior
___________________________________
Internal “drive” (craving)
___________________________________
Reward-Reinforcement
___________________________________
Satiation
Slide 15
___________________________________
___________________________________
Can we measure reinforcement?
___________________________________
How hard will you work to get it?
„ What will you put up with to get it?
„ What will you give up to get it?
„ Which would you rather have?
„
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
61
G. J. Treisman, MD, PhD
Slide 16
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 17
___________________________________
___________________________________
Treatment
___________________________________
Conversion
„ Detoxification
„ Rehabilitation
‹ GROUP
„ Co-morbid Treatment
„ Relapse Prevention
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 18
___________________________________
___________________________________
Conversion
___________________________________
Confrontation with a smile (group)
„ Physician Goals vs. Patient Goals
‹ Quality of Life
‹ Longevity vs Comfort
‹ Function
„ Treatment Contract
„
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
62
G. J. Treisman, MD, PhD
Slide 19
___________________________________
Detoxification
___________________________________
Stop the behavior
„ Prevent withdrawal
„ Diminish craving
„ Treat potential accompanying disorders
„
___________________________________
___________________________________
___________________________________
Wernicke-Korsakoff
‹ Endocarditis
‹ HIV
‹
___________________________________
Slide 20
Rehabilitation
„
Damage control
‹
„
‹
‹
People places and
things that are triggers
Structure
___________________________________
___________________________________
„
Social, occupational
and family intervention
Environmental
change
___________________________________
„
„
„
___________________________________
Occupational
‹ Vocational
‹ Educational
Social
Physical
Psychological
___________________________________
___________________________________
___________________________________
___________________________________
Extinguish the habit
„ Prescribe a new
program
„
Slide 21
___________________________________
___________________________________
Adjunctive Pharmacotherapy
___________________________________
Treatment of Psychiatric Comorbidity
„ Substituted Addiction
„ Blockade of reinforcement
„ Aversive conditioning
„ Drive suppression
„ Symptomatic treatment for withdrawal
„
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
63
G. J. Treisman, MD, PhD
Slide 22
___________________________________
___________________________________
Substituted Addiction
___________________________________
Methadone, LAAM, Buprenorphine
‹ Addiction with Less Disorder
‹ Decreased Reinforcement of Behavior
‹ Other Addictions as models
 Nicotine
 Caffeine
„ Nicotine patch, gum, and inhalers
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 23
___________________________________
___________________________________
Blockade of reinforcement
___________________________________
Naltrexone
‹ Non-addictive
‹ Usually a dismal failure
„ Benzodiazepine blockers
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 24
___________________________________
Aversive conditioning
„
___________________________________
___________________________________
Disulfiram
 Behavioral Aversive Conditioning
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
64
G. J. Treisman, MD, PhD
Slide 25
___________________________________
___________________________________
Drive suppression
___________________________________
Bupropion for nicotine
„ Naltrexone for alcohol
‹ Antidepressants for cocaine?
‹ Buprenorphine for cocaine?
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 26
___________________________________
Pharmacologic treatment for
withdrawal
___________________________________
Active Tapers
Suppression of specific symptoms
‹ Clonidine
‹ Dicyclomine (Bentyl) anticholinergics
‹ NSAID’s
‹ Methocarbamol (Robaxin)
‹ Antihistamines
___________________________________
„
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 27
___________________________________
Treat Comorbid Conditions
„
___________________________________
Attend to Life Story
___________________________________
Psychotherapy and remoralization
‹ Mobilize social supports
‹
„
„
___________________________________
Treat Depression
‹
___________________________________
Medication and therapy
___________________________________
Manage temperament
‹
___________________________________
Practical suggestions and directive advice
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
65
G. J. Treisman, MD, PhD
Slide 28
The Four Perspectives
___________________________________
___________________________________
McHugh and Slavney
___________________________________
„Disease
___________________________________
„Temperament
___________________________________
„Behavior
___________________________________
„Life
___________________________________
Story
Slide 29
___________________________________
___________________________________
Depression
___________________________________
„
Mood
___________________________________
„
Vital Sense
___________________________________
„
Self attitude
„
Anhedonia
___________________________________
___________________________________
Slide 30
___________________________________
___________________________________
___________________________________
It is much more important to
know what sort of patient
has a disease than what sort
of disease a patient has.
___________________________________
___________________________________
___________________________________
___________________________________
William Osler
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
66
G. J. Treisman, MD, PhD
Slide 31
Simplified model of
disposition
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
percent of
population
___________________________________
Introversion
Extroversion
Slide 32
• Population-Disposition
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
StabilityInstability
___________________________________
___________________________________
Introversion-Extroversion
Slide 33
stable
___________________________________
___________________________________
___________________________________
phlegmatic
___________________________________
sanguine
introversion
___________________________________
extroversion
melancholy
___________________________________
choleric
___________________________________
unstable
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
67
G. J. Treisman, MD, PhD
Slide 34
___________________________________
___________________________________
Problems of life story
___________________________________
An “assumptive” world
„ Assumptions provoke experience
„ Experience shapes assumptions
„ We understand these experiences using
“meaning”
„ Provides the “software operating system”
for data and action
„ Can be “rescripted” or rewritten
„
___________________________________
___________________________________
___________________________________
___________________________________
Slide 35
___________________________________
___________________________________
Experience
___________________________________
___________________________________
___________________________________
Meaning
Behavior
___________________________________
___________________________________
Assumption
Slide 36
Poor Compliance
___________________________________
___________________________________
Education
Treatment Plan Induction
Medication Adjustment
___________________________________
___________________________________
Assessment of
Comorbid
Disorders
Engagement of
more
Better Compliance
Improved Self Efficacy aggressive
therapy
___________________________________
___________________________________
___________________________________
Treat Comorbid
Disorders
Collaborative Treatment
Better Outcome
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
68
G. J. Treisman, MD, PhD
Slide 37
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 38
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
SUGGESTED READING
De P, Cox J, Boivin JF, Platt RW, Jolly AM. The importance of social networks in their association to
drug equipment sharing among injection drug users: a review. Addiction. 2007;102:1730-1739.
Khalsa JH, Treisman G, Cance-Katz E, Tedaldi E. Medical consequences of drug abuse and cooccurring infections: research at the National Institute on Drug Abuse. Subst Abus. 2008;29:5-16.
Shoptaw S, Reback CJ. Methamphetamine use and infectious disease-related behaviors in men who
have sex with men: implications for interventions. Addiction. 2007;102(Suppl 1):130-135.
Sullivan LE, Bruce RD, Haltiwanger D, et al. Initial strategies for integrating buprenorphine into HIV care
settings in the United States. Clin Infect Dis. 2006;43(Suppl 4):S191-S196.
Wadland WC, Ferenchick GS. Medical comorbidity in addictive disorders. Psychiatr Clin North Am.
2004;27:675-687.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
69
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
70
Methicillin-Resistant Staphylococcus aureus
John G. Bartlett, MD
___________________________________
___________________________________
___________________________________
MRSA
___________________________________
John G. Bartlett, MD
___________________________________
Professor of Medicine
Johns Hopkins University School of Medicine
___________________________________
___________________________________
International AIDS Society–USA
___________________________________
Slide 2
Disclosure of Financial
Relationships
___________________________________
___________________________________
Pfizer
Advisory Board (2006)
J&J
Policy Board
Tibotec DSMB
Scientific Advisory Board
Merck
International HIV Advisory Board
Abbott Honoraria
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 3
MRSA-USA 300
___________________________________
___________________________________
Magnitude of Problem
History USA 300
Clinical Features
Virulence Factors
Antibiotic selection
Infection Control
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
71
J. G. Bartlett, MD
___________________________________
Slide 4
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 5
PROJECTIONS AND CONCLUSIONS
___________________________________
US burden invasive
MRSA infections
94,360/yr
Mortality
18,650/yr
32/100,000
Incidence
S. pneumonia-----14/100.000
Regional differences
Portland--------------20/100,000
Baltimore------------118/100,00
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 6
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
72
J. G. Bartlett, MD
___________________________________
Slide 7
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 8
USA 100
USA 300
___________________________________
Where
Hospital
Community
___________________________________
When
1983
2000
PVL
Absent
Present
___________________________________
MR element
Mec I-III
Mec IV
Active Abx
Vanc, Lin,
Dapto
TMP-SMX,
Doxy, Clind.
Infections
Wound VAP
Plastic/metal
SSS, CAP
Necrosis
___________________________________
___________________________________
___________________________________
___________________________________
Slide 9
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
73
J. G. Bartlett, MD
___________________________________
Slide 10
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 11
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 12
STAPH AUREUS (USA 300 & 400)
NEW SYNDROMES
___________________________________
___________________________________
Necrotizing skin infections
(Spider bite abscesses)
Necrotizing pneumonia
Necrotizing fasciitis
Septic thrombophlebitis
Pelvic syndromes (Peds): Septic
arthritis hips, pelvic abscess
Waterhouse – Friderichsen syndrome
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
74
J. G. Bartlett, MD
___________________________________
Slide 13
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 14
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
PVL POSITIVE S. AUREUS
PNEUMONIA
___________________________________
Slide 15
___________________________________
(Gillet. Lancet 2002;359:753)
Method: review 1986-98
PVL pos vs PVL neg
PVL +
Results
n=16
Mean age
15 yrs
Flu
12 (75%)
Hypotension
13 (81%)
Mortality
12 (75%)
___________________________________
PVLn=36
70 yrs
3 (8%)
18 (50%)
17 (47%)
INTERNATIONAL AIDS SOCIETY–USA
___________________________________
___________________________________
___________________________________
___________________________________
May 8, 2009
75
J. G. Bartlett, MD
___________________________________
Slide 16
COMMUNITY-ACQUIRED
PNEUMONIA CAUSED BY MRSA
(MMWR 2007;56:325)
___________________________________
___________________________________
Cases: 10 cases LA and GA
Influenza season 2006-7
Cultures: Blood - 6, Sputum – 8
Influenza: 7/8; Vaccine 0/10
Age: 4 mo-43 yrs; median: 18 yrs
Lethal outcome: 6/10
Duration illness: 3.5 days
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 17
MRSA AND HIV
___________________________________
Risk: IDU and MSM
___________________________________
___________________________________
Pyomyositis
___________________________________
___________________________________
Soft tissue infections
___________________________________
MRSA pneumonia (?)
___________________________________
Slide 18
MRSA (USA 300) AND MSM
(Diep. Ann Int Med 2008;148:249)
___________________________________
___________________________________
Method: regional survey – Boston
and San Francisco for MRSA 200406
Results: MSM risk OR 13.2 (p
<0.001)
• Risk independent of HIV
• USA 300: 93% of MRSA
• Favored sites: Buttocks,
perineum, genitals.
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
76
J. G. Bartlett, MD
___________________________________
Slide 19
CONCLUSIONS
___________________________________
1. MRSA epidemic in the community
___________________________________
___________________________________
2. Differed from nosocomial MRSA
___________________________________
3. Diverse and often unique pathology
___________________________________
___________________________________
4. Recognized by PVL (USA 300)
___________________________________
Slide 20
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 21
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
77
J. G. Bartlett, MD
___________________________________
Slide 22
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
PNEUMONIA SCORE FOLLOWING in
CHALLENGE TO MICE AT 48h
___________________________________
Slide 23
___________________________________
(Labandeira-Rey M. Science Express 1/18/07:1)
Challenge
No.
PVL pos
PVL neg
PVL neg
+ PVL plasmid
PVL
5
7
5
Pathology
Necrosis/death*
PMN
Necrosis/death*
6
Focal lesions &
death*
*Mortality 35-80% at 24 hrs.
EVOLUTION OF VIRULENCE
OF CA-MRSA
(Li M, PNAS March 17, 2009)
Mean
score
4.7
2.1
4.6
3.8
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 24
___________________________________
___________________________________
Method: Study virulence and phylogeny
of USA 300 strains in mice
Results:
• USA 500 projenitor of USA 300
• Both had high virulence
1) Abscess size, 2) TNF alpha, 3)
survival, 4, Cytolytic toxins and 5) PMN
lysis
___________________________________
___________________________________
___________________________________
___________________________________
• PVL and mecIV-irrelevant
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
78
J. G. Bartlett, MD
___________________________________
Slide 25
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 26
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 27
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
79
J. G. Bartlett, MD
___________________________________
Slide 28
S. AUREUS AND PVL
___________________________________
Labandeira-Rey M et al: “PVL is a
key virulence factor in pulmonary
infections”
___________________________________
Voyich M et al: PVL may be a
marker for CA-MRSA but “ . . . Is
not the major virulence
determinant”
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 29
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 30
MANAGEMENT OF SKIN AND
SOFT-TISSUE INFECTION
(NEJM 2008;359:1063)
___________________________________
___________________________________
___________________________________
Hx: 20 year old college basketball
player with buttock abscess
PE: T 37.7ºC
3 x 5 cm abscess
Management issue: I & D plus
No antibiotic
Cephalexin/diclox
Clind/TMP-SMX
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
80
J. G. Bartlett, MD
___________________________________
Slide 31
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 32
SOFT TISSUE INFECTION
POLL RESULTS
Area
US
Europe
S. Amer.
___________________________________
(NEJM 2008;359:e20)
___________________________________
No.
___________________________________
Antibacterial
None MSSA MRSA
6,904 29%
18%
53%
1,787 45%
34%
22%
1,013 25%
54%
20%
___________________________________
___________________________________
___________________________________
___________________________________
Slide 33
CLINICAL CURE RATES FOR “MAJOR
ABSCESSES” BASED ON REVIEWS OF 31
PUBLISHED PAPERS 1909-1950
(Spellberg B. CID [in press])
___________________________________
___________________________________
___________________________________
Placebo
Sulfa
Penicillin
Total
254336
60/69
282/293
95% CI 76% (71-80%) 87% (80-94%) 96% (94-98%)
Effect
size
---------11%
21%
___________________________________
___________________________________
___________________________________
I & D without Abx: 99%
I & D plus penicillin: 100%
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
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J. G. Bartlett, MD
MRSA SOFT TISSUE
INFECTIONS
___________________________________
Slide 34
___________________________________
___________________________________
Pus (S. aureus)
• TMP-SMX
• Minocycline
Cellulitis (Strep or S. aureus)
• Clindamycin
Epidemiology
• Cover lesions
• Culture nose, etc?
• Role of mupirocin, bathing, chronic Abx
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 35
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
SCREENING FOR MRSA AND
NOSOCOMIAL SURGICAL INFECTIONS
Slide 36
(Harbath S. JAMA 2008:299:1149)
___________________________________
___________________________________
___________________________________
Method: Randomized surgical pts
1) Rapid screening (PCR for
mecA gene) + Standard
Infection Control
2) Standard Infection Control
Surveillance for MRSA at
surgical site
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
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J. G. Bartlett, MD
INTERVENTION FOR MRSA
CARRIERS
___________________________________
Slide 37
___________________________________
(Harbath S et al.)
___________________________________
• Contact isolation
• Adjusted Abx prophylaxis
• Computerized MRSA alert
• Mupirocin ointment
• Chlorhexidine body wash
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 38
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
RATES OF NOSOCOMIAL MRSA
INFECTION AND ACQUISITION
MRSA infection
Number (%)
Surgical site
Rate/100
MRSA acquisition
Incidence/1000 pd
Control
n=10,910
Intervention
n=10,844
76 (0.7%)
60
0.99
132
1.59
93 (0.9%)
70
1.14
142
1.69
___________________________________
Slide 39
___________________________________
___________________________________
OR
___________________________________
___________________________________
1.2
___________________________________
1.2
___________________________________
1.1
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
83
J. G. Bartlett, MD
___________________________________
Slide 40
UNIVERSAL SURVEILANCE FOR MRSA
IN 3 AFFILIATED HOSPITALS
___________________________________
(Robicsek A et al. Ann Intern Medicine 2008;148:409)
___________________________________
___________________________________
Goal: To determine the effect
of two expanded surveillance
methods on rates of MRSA
infection
___________________________________
___________________________________
___________________________________
___________________________________
Slide 41
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 42
RESULTS
___________________________________
Prevalence of MRSA – 3,926/73,464 (8.3%)
Aggregate MRSA infections
___________________________________
Study period Rate
Compared –
(/10,000 pt d) baseline
Control
8.9
----ICU
7.4
-- 36%
Universal
3.9
-- 70%
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
84
J. G. Bartlett, MD
___________________________________
Slide 43
Both studies were well done, but:
Harbath et al
• Low adherence to precautions
• Incomplete screening
• Low yield population (ICU)
Robicsek et al
• Observational and sequential with
other interventions
• Adherence data unclear
• ICU data: Not significant
R. Wenzel: Harbath – B+
Robicsek – B (2008 ICAAC/IDSA)
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 44
VANCOMYCIN: THE WORKHORSE
FOR TREATING MRSA
___________________________________
Usage: 16 tons/yr
Resistance: 6 strains in 50 years (van A)
Issues: Suboptimal response
Renal toxicity
1.Heteroresistance (hVISA)
• Subpopulations <1/105 with MIC 8-16
ug/mL
• Account for 8-10%
• Clinical failures (CID 2004;38:21; JID
2009;199:619)
• Persistent bacteremia
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 45
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
85
J. G. Bartlett, MD
___________________________________
Slide 46
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 47
MRSA: VANCOMYCIN FAILURE WITH
MIC=4 mcg/mL + BACTEREMIA
Pt
1
2
3
4
5
6
Duration
Source
bacteremia
>10 wks
42 days
42 days
39 days
35 days
22 days
PC*
PC
PC
PC
PC
PC
Pt Duration
bacteremia
7
8
9
10
11
12
33 days
29 days
13 days
12 days
8 days
8 days
Source
___________________________________
___________________________________
___________________________________
___________________________________
Howden**
Howden
Howden
Howden
Howden
Howden
___________________________________
___________________________________
___________________________________
*PC=personal communication
**Howden BP. CID 2004;38:448
___________________________________
Slide 48
TREATMENT OF SERIOUS MRSA
INFECTIONS: VANCOMYCIN
___________________________________
Standard: 1 gm IV or 15-22 mg/kg Q
12 hr
___________________________________
Trough goal:
MRSA pneumonia
CNS infection
Endocarditis
Bacteremia
___________________________________
___________________________________
mcg/mL
15-20
20
10-20
10-15
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
86
J. G. Bartlett, MD
___________________________________
Slide 49
VANCOMYCIN FAILURES
___________________________________
___________________________________
Linezolid: 600 mg Q 12 h
Daptomycin: 6-10 mg/kg/d
Clindamycin: 600 mg Q 8 h
Trimethoprim – sulfa 10/50
mg/kg/d + rifampin 30 mg/kg/d
Tigecycline – 100 mg IV, then
50 mg IV q 12 h
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 50
LINEZOLID VS VANCOMYCIN
___________________________________
Wunderink RG et al. Chest 2003;124:1789)
___________________________________
Method: retrospective analysis of
two prospective, randomized,
double-blind studies of
nosocomial pneumonia
Results: MRSA – 28 day survival
___________________________________
___________________________________
___________________________________
• Linezolid – 60/75 (80%)
• Vancomycin – 54/85 (64%)
___________________________________
Survival OR 2.2
___________________________________
Slide 51
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
87
J. G. Bartlett, MD
___________________________________
Slide 52
ANTIBIOTICS FOR MRSA
___________________________________
Agent
ADR
Comment
___________________________________
Vancomycin
Renal
Levels
___________________________________
Linezolid
Lung static
___________________________________
Daptomycin
Marrow
optic
CPK
TMP-SMX
Rash
Dose
Not lung
Resistance
Clindamycin
C. difficile
Resistance
___________________________________
___________________________________
___________________________________
Slide 53
EPIDEMIOLOGY
___________________________________
___________________________________
Source: Nose, skin, objects, pus
• Nose: MSSA – 30%
MRSA – 2-5%
• St. Louis Rams – Objects
• MSM – Genital source
(CID 2007;44:410)
Intervention: Barrier precautions
• Nose: Mupirocin
• Body: Hebiclens, Phisohex
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 54
MRSA: WHAT WE KNOW
___________________________________
USA 300 (PVL +) is global epidemic
Abscesses need drainage
Vancomycin is active in vitro (but may not be
ideal)
Two separate epidemics (CA & HA)
are now merging
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
88
J. G. Bartlett, MD
___________________________________
Slide 55
MRSA: What we know
___________________________________
USA 300 (PVL +) is global epidemic
Abscesses need drainage
Vancomycin is active in vitro (but may not be
ideal)
Two separate epidemics (CA & HA)
are now merging
___________________________________
___________________________________
___________________________________
___________________________________
What we do not know
___________________________________
How to control epidemic
How to control recurrent skin infections
Optimal antibiotic treatment (when and what)
Pathogenic mechanism
___________________________________
Slide 56
WHAT WILL HAPPEN?
___________________________________
___________________________________
CMS: MRSA infection is
unreimbursed hospital mistake
Treatment: I & D +/- Abx: Telavancin
(?) and Ceftobiprole (?)
Infection control:
Effective strategies unclear but
policies established
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
89
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
90
STRATEGIES FOR ANTIRETROVIRAL THERAPY:
CASE-BASED PANEL DISCUSSION
Michael S. Saag, MD
___________________________________
___________________________________
Strategies for Antiretroviral
Therapy: Case-Based Panel
Discussion
___________________________________
Michael S. Saag, MD
___________________________________
Professor of Medicine
The University of Alabama at Birmingham
___________________________________
___________________________________
___________________________________
International AIDS Society–USA
___________________________________
Slide 2
8 Year Survival in HAART Era
___________________________________
t 1.00
u
b
i
r
t 0.75
s
i
D
___________________________________
___________________________________
___________________________________
l 0.50
a
v
i
v
r
u 0.25
S
___________________________________
___________________________________
0.00
0
2
STRATA:
4
6
8
Survival Time (Years)
CD4Grp=<50
CD4Grp=51-200
CD4Grp=201-350
CD4Grp=>350
10
Updated from Chen, et al, 8th CROI, 2001
CD4 Count at HAART Initiation
___________________________________
Slide 3
___________________________________
Median
CD4
% CD4 <
200
___________________________________
2005
278
39.6%
___________________________________
2006
300
35.4%
47.8%
2007
296
35.2%
212
49.3%
2008
310
29.4%
197
50.1%
2001
277
39.5%
2002
210
48.8%
2003
220
47.2%
2004
207
49.1%
Median
CD4
% CD4 <
200
115
62.8%
1997
180
53.8%
1998
221
1999
2000
1996
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
91
M. S. Saag, MD
___________________________________
Slide 4
When To Start Treatment? –
Summary of Current Guidelines
Guidelines
symptoms
symptoms
or
___________________________________
___________________________________
CD4 200- CD4 >350
350
___________________________________
CD4 <200
IAS-USA:
treat
Therapy should be
considered and
decision
individualized
treat
JAMA 2008
<www.iasusa.
org>
DHHS:
treat
treat
Special populations:
___________________________________
___________________________________
___________________________________
Preg
/ HBV/ HIVAN
<www.aidsinfo.
Others case by case
nih.gov>
___________________________________
Slide 5
___________________________________
When to Start Therapy: Balance Tipping in
Favor of Earlier Initiation
• Drug toxicity
• Preservation of limited Rx options
___________________________________
___________________________________
• Potency, durability, simplicity
and safety of current regimens
• Improved formulations and PK
• Enhanced adherence
• Diminished emergence of resistance
• More treatment options
• Recognition of deleterious effect
of uncontrolled viremia at all CD4 levels
___________________________________
___________________________________
___________________________________
___________________________________
Slide 6
Probability of death in ART-naïve AIDS-free
non-IDU patients starting cART after 1998
___________________________________
0.15
___________________________________
Probability of death
0-50
___________________________________
0.10
___________________________________
51-150
151-250
0.05
251-350
351-450
451-550
0.00
0
1
2
3
4
Years since start of HAART
5
Based on 24,444 patients from 15 cohort studies,
808 deaths in 81,071 person-years of follow up
___________________________________
___________________________________
6
ART
Cohort Collaboration
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
92
M. S. Saag, MD
___________________________________
Slide 7
___________________________________
___________________________________
___________________________________
AIDS/death
CD4 250
___________________________________
AIDS/death
CD4 350
___________________________________
___________________________________
Time
Time on cART
___________________________________
Slide 8
Unseen event
AIDS/death
CD4 350
Missing data
Lead time
___________________________________
___________________________________
AIDS/death
CD4 350
CD4 250
CD4 350
CD4 250
___________________________________
___________________________________
AIDS/death
___________________________________
___________________________________
Time
Time not on cART
Time on cART
___________________________________
Slide 9
Unmeasured confounding
___________________________________
___________________________________
___________________________________
Outcome
___________________________________
Confounding
factor
___________________________________
Factor of
interest
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
93
M. S. Saag, MD
Distribution of 8,374 Study Patients
500
350
Deaths (PY)
in cohort analysis
___________________________________
Slide 10
___________________________________
% Censored
in IPW analysis
___________________________________
1st
CD4+
between
351-500
measured
1996-2006
and no prior
AIDS or ARVs
(N=8,374)
Initiate HAART
(N = 2,473)
Defer HAART
(N = 5,901)
Transit to
CD4 < 350
221
(8,358)
0%
No Transit
(N = 2,452)
209
(5,295)
10%
No HAART
Initiation
(N = 2,229)
100
(5,815)
57%
HAART
Initiation
(N = 1,220)
137
(5,526)
0%
___________________________________
___________________________________
___________________________________
___________________________________
2006
1996
*Stratified by Cohort and Year
Deferral of HAART at 351-500
Relative
Hazard
(RH)*
1.7
95%
Confidence
Interval
1.4, 2.1
___________________________________
Slide 11
Inverse Probability Weighted Cox
Regression Multivariate Analysis
___________________________________
P-value
___________________________________
<0.001
___________________________________
Female Sex
1.1
0.9, 1.5
0.290
Older Age (per 10 years)
Baseline CD4 count (per 100
cells/mm3)
1.6
1.5, 1.8
<0.001
0.9
0.7, 1.0
0.083
___________________________________
___________________________________
• Results were similar when restricting the analysis to the 77% of
participants with baseline HIV RNA data
• Adjusted RH for deferral vs. immediate treatment was also 1.7
95% C.I. 1.4, 2.2; p <0.0001
• HIV RNA was not an independent predictor of mortality
___________________________________
___________________________________
Slide 12
___________________________________
___________________________________
___________________________________
CD4 > 500 &
Defer HAART
(N=6,539)
___________________________________
0.10
0.15
0.20
Cumulative Mortality Estimates
Calculated Using Extended Kaplan-Meier Survival Estimates
___________________________________
___________________________________
0.00
0.05
CD4 > 500 &
Initiate HAART
(N= 2,616)
0
2
4
6
8
10
Years after 1996
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
94
M. S. Saag, MD
Inverse Probability Weighted Cox
Regression Multivariate Analysis
*Stratified by Cohort and
Calendar Year
Relative
Hazard
(RH)*
___________________________________
95%
Confidence
Interval
P-value
___________________________________
___________________________________
Deferral of HAART at >500
1.6
1.3, 1.9
<0.001
Female Sex
1.2
0.9, 1.6
0.117
Older Age (per 10 years)
Baseline CD4 count (per 100
1.6
1.5, 1.7
<0.001
1.0
1.0, 1.1
0.696
cells/mm3)
___________________________________
Slide 13
___________________________________
___________________________________
Baseline HIV RNA (RH Deferral = 1.5, 95% C.I. 1.2,1.9; p <0.001)
• HIV RNA was not an independent predictor of mortality
Increased risk of mortality with deferral was similar throughout the
10 year study period
___________________________________
___________________________________
Slide 14
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 15
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
95
M. S. Saag, MD
___________________________________
Slide 16
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 17
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 18
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
96
M. S. Saag, MD
___________________________________
Slide 19
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide 20
___________________________________
Summary of Principles
♦ Avoid Sequential Monotherapy; Wait for new
agents if possible.
___________________________________
♦ Hypersusceptability can occur with 3TC / FTC
mutations
___________________________________
___________________________________
♦ Mutations can be harbored well after a drug has
been used
___________________________________
♦ Phenotypes are often helpful in determining
which drugs are active when complex
genotypes are likely
___________________________________
♦ Goal of Therapy is < 50 c/ml in any patient
regardless of stage of disease or prior exposure
Summary of Principles
___________________________________
Slide 21
___________________________________
• Key to achievement of < 50 c/ml is the availability
of at least 2 potent drugs; the more, the better
• If at least 2 potent drugs are not available, it is
usually best to hold the current regimen until they
are available
• No evidence for double-boosted PIs; Double
boosted PIs only ‘count’ as one active drug
• Likely some residual benefit of continued 3TC or
FTC
• No consensus / clarity on how to ‘count’ partially
active drugs in a new regimen
• Difficult to know when to use the new drugs in
earlier therapy
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
97
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
98
HIV AND HEPATITIS C VIRUS COINFECTION
Kenneth E. Sherman, MD, PhD
NOTES
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
99
FREQUENTLY ASKED QUESTIONS ABOUT IAS–USA CME COURSES
course⎯they make changes, in order to include
very new data. Unfortunately, these changes
cannot be made in our course syllabus, because it
has already been printed.
How do I sign up for the IAS–USA mailing list
and receive course announcements? How do I
have my name removed?
A mailing list sign-up sheet is located at the
educational materials table at each course (usually
next to the registration desk). The form is also
found on our Web site (www.iasusa.org) and in our
®
journal, Topics in HIV Medicine . Every individual
who is on our mailing list has requested that his or
her name be added; we will not add your name
unless you request us to do so. The IAS–USA
does not sell, rent, loan, or distribute mailing or
registration lists to sources outside of our
organization. You may remove your name from the
IAS–USA mailing list at any time by e-mailing us,
faxing us, contacting us via our Web site, or
sending a written request via postal service to our
office at 425 California Street, Suite 1450, San
Francisco, CA 94104-2120.
Where and when do I receive a CME
certificate?
To receive your CME certificate (or your certificate
documenting your attendance at this CME activity),
return the CME claim form, which you received at
registration, to the IAS–USA. When completing
your form, please note the actual number of hours
that you participated in this CME activity. As of
2009, a PDF of your CME certificate will be emailed to you within 14 days of receipt of your
CME claim form. It is yours to keep as a record of
attendance and credit hours for this course.
Can CME credits be awarded to
nonphysicians?
American Medical Association Physician’s
Recognition Award CME guidelines state that only
physicians are eligible to receive CME credits.
Nonphysician health care professionals are eligible
to receive certificates of attendance that document
their attendance at this CME activity. If you are a
nonphysician health care professional and you did
not receive a certificate of attendance at
registration, you may request one from an IAS–
USA staff member. The American Academy of HIV
Medicine will honor certificates of attendance as
proof of participation for the credentialing process.
Nursing Continuing Education contact hours are
also available at this course.
How are topics and speakers selected?
The overall education needs of the audience for
any particular CME activity are determined by the
participant evaluations from previous courses,
results of epidemiologic research, perceptions of
experts in the field, and recommendations of the
IAS–USA Board of Directors and faculty. The
Board of Directors and the course chairs are
responsible for identifying and monitoring the
needs of the target audience. The course chairs
then design an agenda—choosing topics and
inviting speakers—that meets the needs of the
local audience. Our participants often suggest that
particular topics be covered. The selection process
prioritizes topics that meet the educational
objectives of the majority of the participants.
Can I request a reduced registration fee?
Although registration fees are low, the IAS–USA is
flexible if a participant has an economic hardship. If
you believe you qualify for a reduced registration
fee, contact the IAS–USA prior to the course. Note
that commercial companies may not pay the
registration fees for health care providers to attend
this course. Direct payment of registration fees by
commercial companies is not permitted, as
described in (among other documents) the AMA
Why do the slides in the course syllabus not
match the presentation slides?
Faculty members are asked to submit their
presentations to the IAS–USA 4 to 6 weeks before
the course, to allow time for peer review, revision,
print production, and shipping of the syllabus.
Often, when faculty members review their slides at
the faculty meeting⎯held the evening before the
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
101
ethical position on gifts to physicians and the
ACCME guidelines.
What do I do if I have a special dietary
requirement?
The course venue requies advance notice to plan
and prepare special meals. If you noted your
special dietary requirement on the registration form
or notified our office, a special meal ticket will be
provided to you upon check-in at the registration
desk. When you are seated for lunch, please put
the special meal ticket next to your place setting.
The venue wait staff will be instructed to watch out
for the ticket to ensure prompt service of your
lunch. The venue may charge additional fees for
supplying special meals, in which case this fee
may be passed on to the registrant.
Where do I turn in my evaluation, audience
response touchpad, and CME claim form?
Turn in your evaluation, audience response
touchpad, and CME claim form at the registration
desk, which is staffed by several IAS–USA
representatives.
How can I get a recording of course lectures?
Presentations from this and other courses may be
available as Webcasts and Podcasts on the IAS–
USA Web site at www.iasusa.org.
How can I make a donation to the IAS–USA?
What about other IAS–USA programs or the
IAS–USA journal?
The IAS–USA is exempt from tax under section
501(c)(3) of the Internal Revenue Code. To make
a tax-deductible donation to the organization,
please see a staff member at the registration desk.
You can also make a donation by writing to the
organization. And finally, donation information is
available on our Web site (www.iasusa.org). If you
donate $100 or more, you will receive a
Resistance Mutations Figure T-shirt. Donations are
deposited in a specific fund for the distribution of
Topics in HIV Medicine to HIV practitioners in
developing countries.
How do I order more drug resistance
mutations cards or other resource cards (ie,
oral manifestation cards and dermatologic
manifestation cards)?
Order forms for all IAS–USA resource materials
are available on the educational materials table in
the registration area. Order forms are also
available on the Web site on the following Web
pages:
• Drug resistance mutation pocket card:
http://www.iasusa.org/resistance_mutation
s/muta_request_form.pdf.
• Oral manifestations card:
http://www.iasusa.org/oral_manifestations/
request_form.pdf
• Dermatologic manifestations card:
http://www.iasusa.org/dermatology/reques
t_form.pdf
How can I communicate my comments,
questions, or suggestions about other IAS–
USA programs or the IAS–USA journal?
We are very interested in what you have to say.
For suggestions about this CME program,
complete an evaluation form (located at the
registration desk) and give it to an IAS–USA staff
member. Or visit our Web site (www.iasusa.org),
where you can share your comments with us via email. Send your comments, questions, or
suggestions regarding other educational programs
or Topics in HIV Medicine to info2009 “at”
iasusa.org.
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
102
COMMON ABBREVIATIONS
ORGANIZATIONS, CONFERENCES, AND LEGISLATION
AAHIVM
ACIP
American Academy of HIV Medicine
Advisory Committee on Immunization
Practices
HPTN
HRSA
HIV Prevention Trials Network
Health Resources and Services
Administration
ACTG
AIDS Clinical Trials Group
IAS
International AIDS Society (an
international federation of AIDS
societies not affiliated with IAS–USA)
ACTU
AIDS Clinical Trials Unit, a single site of
the ACTG
IAS–USA
International AIDS Society–USA
AETC
AIDS Education and Training Center, a
Health Resources and Services
Administration (HRSA)-funded provider
training center
ICAAC
Interscience Conference on
Antimicrobial Agents and
Chemotherapy
ASM
CCTG
American Society for Microbiology
California Collaborative Treatment
Group
IDSA
IHI
Infectious Diseases Society of America
Institute for Healthcare Improvement
CROI
Conference on Retroviruses and
Opportunistic Infections
NIAID
National Institute of Allergy and
Infectious Diseases
EATG
European AIDS Treatment Group
NIH
National Institutes of Health
HIVMA
HIV Medicine Association of the
Infectious Diseases Society of America
RWCA
HOPS
HIV Outpatient Study
WIHS
Ryan White Comprehensive AIDS
Resources Emergency (CARE) Act
(now called Ryan White HIV/AIDS
Program)
Women’s Interagency HIV Study
General Medical Terms
AFB
ALT
ART
ASCUS
acid fast bacilli
alanine aminotransferase
antiretroviral therapy
atypical squamous cells of undetermined
significance
EIA
ELISA
gt
HAART
enzyme immunoassay
enzyme linked immunosorbent assay
genotype
highly active antiretroviral therapy
AST
bDNA
BAL
BLD
aspartate aminotransferase
branched DNA
bronchoalveolar lavage
below the limit of detection
HCC
HLA
HSR
IC50, IC90
hepatocellular carcinoma
human leukocyte antigen
hypersensitivity reaction
50%, or median, inhibitory
concentration, 90% inhibitory
concentration
BLQ
below the limit of quantification
IL-1 − 16
interleukins (eg, IL-2 indicates
interleukin-2)
INTERNATIONAL AIDS SOCIETY–USA
May 8, 2009
103
IFA
immunofluorescence assay
PGL
INH
ITT
LFT
MDR
MSM
isoniazid
intent-to-treat
liver function test
multidrug resistance/resistant
men who have sex with men
PLWHA
PR
RC
RT
SI
NAM
nucleoside analogue reverse
transcriptase inhibitor (nRTI)-associated
mutation
SIV
simian immunodeficiency virus
NASBA
nucleic acid sequence-based
amplification
nonsyncytium-inducing (also CCR5tropic, M-tropic)
TAM
THcell
thymidine analogue-associated
mutation
T-helper cell
optimized background regimen
polymerase chain reaction
postexposure prophylaxis
TMP/SMX
VL
trimethoprim/sulfamethoxazole
viral load
NSI
OBR
PCR
PEP
persistent generalized
lymphadenopathy
person(s) living with HIV/AIDS
protease
replication capacity
reverse transcriptase
syncytium-inducing (also CXCR4-tropic,
T-tropic)
Opportunistic Infections (OIs)
CMV
EBV
cytomegalovirus
Epstein-Barr Virus
MTB
PCP
Mycobacterium tuberculosis
Pneumocystis jiroveci (formerly carinii)
pneumonia
HBV
hepatitis B virus
PML
progressive multifocal
leukoencephalopathy
HCV
MAC
hepatitis C virus
Mycobacterium avium complex
VZV
Varicella-zoster virus
Drug Classes
Fusion
inhibitor
Entry
inhibitor
(fusion,
CCR5, or
CXCR4)
Integrase
inhibitor
nRTI
nucleoside (or nucleotide) analogue
reverse transcriptase inhibitor
ntRTI
nucleotide analogue reverse
transcriptase inhibitor
Maturing
inhibitor
(gag
processing,
assembly)
NNRTI
PI
INTERNATIONAL AIDS SOCIETY–USA
nonnucleoside analogue reverse
transcriptase inhibitor
protease inhibitor
May 8, 2009
104
ANTIRETROVIRALS
This list is not necessarily comprehensive and is intended as an aid in following course presentations.
Generic Names
abacavir
abacavir/lamivudine
(fixed dose)
abacavir/lamivudine/
zidovudine (fixed dose)
Common Abbreviation(s)
ABC
(ABC/3TC) or fd ABC/3TC
Class
nRTI
nRTI
(ABC/3TC/ZDV) or fd ABC/3TC/ZDV
nRTI
amdoxovir*
amprenavir**
aplaviroc***
apracitabine*
atazanavir
bevirimat*
brecanavir*
capravirine***
dexelvucitabine*
darunavir
delavirdine
†
didanosine
efavirenz
elvitegravir*
elvucitabine*
emtricitabine
emtricitabine/tenofovir (fixed dose)
emtricitabine/tenofovir/efavirenz (fixed
dose)
enfuvirtide
etravirine
fosamprenavir
indinavir
lamivudine
lamivudine/zidovudine (fixed dose)
AMD-070*
DAPD
APV
GW873140
-dOTC
ATZ, ATV
PA-457
GSK 640385
Ag1549
DFC, D-D4FC
DRV, TMC114
DLV
ddI
EFV, EFZ
GS-9137
ACH-1Zb, 443; Beta-L-Fd4C
FTC
(FTC/TDF) fd FTC/TDF
(FTC/TDF/EFV) or (FTC/TDF/EFZ) or
fd FTC/TDF/EFZ
T-20, ENF
TMC 125, ETR
FPV
IDV
3TC
(3TC/ZDV)
Entry inhibitor⎯CXCR4 inhibitor
nRTI
PI
Entry inhibitor⎯CCR5 inhibitor
nRTI
PI
Gag processing/assembly inhibitor
PI
NNRTI
nRTI
PI
NNRTI
nRTI
NNRTI
Integrase inhibitor
nRTI
nRTI
nRTI/ntRTI
nRTI and NNRTI
lopinavir/ritonavir
maraviroc
LPV/r
MVC
nelfinavir
nevirapine
(None)*
raltegravir
rilpivirine*
ritonavir
NFV
NVP
PSI-5004
RGV, MK-0518
TMC 278
RTV; low or boosting dose is often
indicated by “/r”
SQV
d4T
TAK-652*
TDF
TPV
*
SCH-417690, SCH-D
ddC
ZDV, AZT
saquinavir
stavudine
tenofovir
tipranavir
TNX-355*
vicriviroc*
zalcitabine**
†
zidovudine
Entry inhibitor⎯fusion inhibitor
NNRTI
PI
PI
nRTI
nRTI
PI
Entry inhibitor – CCR5 receptor
inhibitor
PI
NNRTI
nRTI
Integrase inhibitor
NNRTI
PI
PI
nRTI
Entry inhibitor⎯CCR5 inhibitor
ntRTI
PI
Entry Inhibitor⎯CXCR4 inhibitor
Entry inhibitor⎯CCR5 inhibitor
nRTI
nRTI
†
*investigational drug; **no longer on the market; ***investigational drug; research trials have been halted; generic formulations are FDAapproved for sale in the United States; ****available in expanded access program
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