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

2010
Improving the Management of HIV Disease ®
AN ADVANCED CME COURSE IN HIV
PATHOGENESIS, ANTIRETROVIRALS, AND
OTHER SELECTED ISSUES IN HIV DISEASE
MANAGEMENT
Monday, May 17, 2010
Grand Hyatt San Francisco
345 Stockton Street
San Francisco, CA 94108
COURSE CHAIR
Robert T. Schooley, MD
Member, Board of Directors (Volunteer)
International AIDS Society−USA
Professor and Vice Chair, Department of Medicine
Head, Division of Infectious Diseases
University of California San Diego
La Jolla, CA
COURSE VICE-CHAIR
Stephen E. Follansbee, MD
Associate Clinical Professor of Medicine
University of California San Francisco
Director of HIV Services
Kaiser Permanente Medical Center
San Francisco, CA
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.
©2010 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 Policies 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
Help Rebuild GHESKIO ..............................................................................................17
Topics in HIV Medicine® Subscription Form ...............................................................18
Presentation Summaries
♦ Vaginal Microbicides as a Method to Prevent HIV-1 Sexual
Transmission
John P. Moore, PhD ........................................................................................19
♦ When to Start Antiretroviral Therapy?
Mari M. Kitahata, MD, MPH............................................................................29
♦ Current Issues in the Diagnosis and Management of HIV/Tuberculosis
Coinfection
Annie Leutkemeyer, MD .................................................................................43
♦ Investigational Drugs for Hepatitis C Virus Infection
David L. Wyles, MD ........................................................................................57
♦ New Antiretroviral Drugs: Expanding Options for Initial Therapy
Steven C. Johnson, MD..................................................................................67
♦ Monitoring and Prevention for Non-HIV-Related Conditions
Stephen E. Follansbee, MD............................................................................81
♦ Influenza Now: An Update on the H1N1 Epidemic
Robert T. Schooley, MD ..................................................................................97
♦ Management of Treatment-Experienced Patients
Eric S. Daar, MD .......................................................................................... 121
Frequently Asked Questions About IAS–USA CME Courses ................................ 127
Common Abbreviations ............................................................................................ 129
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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, Division of Infectious Diseases
Weill Medical College of Cornell University
New York, New York
Constance A. Benson, MD
Professor of Medicine
Director, UCSD Antiviral Research Center
University of California San Diego
School of Medicine
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
Jim Straley Chair in AIDS Research
Director, Center for AIDS Research
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 and Vice Chair, Department of Medicine
Head, Division of Infectious Diseases
University of California San Diego
San Diego, California
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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
2010 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
on page 18 and on the IAS–USA Web site at
www.iasusa.org. Subscriptions are complimentary
and are available in either electronic form only
(paperless) or in both paper and electronic form.
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 17, 2010
3
COURSE FACULTY
CHAIRS
Robert T. Schooley, MD
Stephen E. Follansbee, MD
Course Chair
Member, Board of Directors (Volunteer)
International AIDS Society−USA
Professor and Vice Chair, Department of Medicine
Head, Division of Infectious Diseases
University of California San Diego
La Jolla, California
Course Vice-Chair
Associate Clinical Professor of Medicine
University of California San Francisco
Director of HIV Services
Kaiser Permanente Medical Center
San Francisco, California
SPEAKERS
Eric S. Daar, MD
Annie Luetkemeyer, MD
Professor of Medicine
David Geffen School of Medicine at UCLA
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Torrance, California
Assistant Clinical Professor of Medicine
University of California San Francisco
San Francisco, California
John P. Moore, PhD
Professor of Microbiology and Immunology
Weill Medical College of Cornell University
New York, New York
Steven C. Johnson, MD
Professor of Medicine
University of Colorado School of Medicine
Director, University of Colorado HIV/AIDS
Clinical Program
Aurora, Colorado
David L. Wyles, MD
Assistant Professor of Medicine
University of California San Diego
La Jolla, California
Mari M. Kitahata, MD, MPH
Professor of Medicine
Director, Clinical Epidemiology and
Health Services Research
Center for AIDS Research
University of Washington
Seattle, Washington
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
4
COURSE AGENDA
7:30 AM
Registration
1:30
8:15
Welcome and Introduction
Robert T. Schooley, MD
Stephen E. Follansbee, MD
Monitoring and Prevention of
Non-HIV-Related Conditions
Stephen E. Follansbee, MD
2:15
Question-and-Answer Period
2:25
Influenza Now: An Update on
the H1N1 Epidemic
Robert T. Schooley, MD
2:55
Management of TreatmentExperienced Patients. A CaseBased Panel Discussion
Eric S. Daar, MD
8:30
Vaginal Microbicides as a
Method to Prevent HIV-1
Sexual Transmission
John P. Moore, PhD
9:00
Question-and-Answer Period
9:10
When to Start Antiretroviral
Therapy?
Mari M. Kitahata, MD, MPH
3:40
Question-and-Answer Period
9:40
Question-and-Answer Period
3:55
9:50
Current Issues in the Diagnosis
and Management of
HIV/Tuberculosis Coinfection
Annie Luetkemeyer, MD
Summary of Afternoon
Presentations
Robert T. Schooley, MD
Stephen E. Follansbee, MD
4:00
Closing Remarks
10:20
Question-and-Answer Period
10:30
Morning Break
10:50
Investigational Drugs for
Hepatitis C Virus Infection
David L. Wyles, MD
11:20
Question-and-Answer Period
11:30
New Antiretroviral Drugs:
Expanding Options for Initial
Therapy. A Case-Based Panel
Discussion
Steven C. Johnson, MD
12:15 PM
Question-and-Answer Period
12:25
Summary of Morning
Presentations
Robert T. Schooley, MD
Stephen E. Follansbee, MD
12:30
Hosted Lunch
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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 activity has been reviewed and is acceptable
for up to 5.75 Prescribed credits by the American
Academy of Family Physicians.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
6
Calculate CME credits:
Maximum allowed
Morning Session
4.0 hours
___________
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, Susan A.
Richardson, MN, MPH, FNP-BC, 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 and staff:
Susan A. Richardson, MN, MPH, FNP-BC
Clinical Instructor
Southeast AIDS Training and Education Center
Atlanta, Georgia
Elizabeth Fullerton
Training Coordinator
Emory University School of Medicine
Family and Preventive Medicine Department
Southeast AIDS Training and Education Center
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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.
testing, and complications of HIV and its
therapies.
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
current data on:
− When to initiate therapy
− Managing treatment failure
− Newer approved drugs
Identify and differentiate current microbicides
as they impact HIV care
Formulate appropriate management strategies
for HIV and tuberculosis coinfection
Describe current data on investigational
hepatitis C virus drugs as they impact the
potential for treatment
Apply practical management strategies for
monitoring non-HIV-related diseases
Describe the current state of the H1N1 virus
epidemic
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.
EDUCATIONAL FORMAT
WEBCAST RECORDING
In this course, information is presented through
lectures and clinically relevant case studies
developed by a distinguished faculty of expert HIV
clinicians and researchers.
This course will be recorded 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.
Lectures provide state-of-the-art updates on
timely and clinically relevant issues, such as
new drugs and regimens, use of resistance
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
8
RELEVANT POLICIES ON DISCLOSURE, CONFLICTS OF INTEREST, AND
PROXIMATE ACTIVITIES
DISCLOSURE AND CONFLICTS OF INTEREST
cannot be resolved through these mechanisms,
the party will be removed from the activity.
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.
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
information will also be provided directly by the
IAS–USA office upon request.
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..
IAS–USA has policy on separation of commercial
promotion from its education and information
activities. Individuals who conduct marketing or
promotional activities for commercial firms may not
contribute to IAS–USA programs. A marketing or
promotional activity includes any activity in which
the commercial entity controls key elements, such
as speaker or topic selection, that could be used to
serve the entity’s commercial interests (eg,
speakers bureaus, advertorials, etc). Individuals
may not participate in IAS–USA programs for 12
months after functioning in a promotional or
marketing effort for a commercial firm.
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
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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. This course is
part of a national effort that includes this and other live CME courses, live course Webcasts, Cases on the
®
Web, and 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 program. 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
Merck & Co, Inc
Tibotec Therapeutics
Bristol-Myers Squibb
Gilead Sciences, Inc
GENEROUS GRANT SUPPORT
ViiV Healthcare
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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
05/11/10.
COURSE FACULTY
Dr Moore has no relevant financial affiliations to
disclose. (Updated 05/10/10)
Dr Daar has received grants and research support
from Abbott Laboratories, Merck & Co, Inc, and
Pfizer Inc. He has served as a consultant to
Bristol-Myers Squibb, Gilead Sciences, Inc, and
Merck & Co, Inc. (Updated 05/10/10)
Dr Schooley has served as a consultant to
Achillion Pharmaceuticals, Inc, Gilead Sciences,
Inc, GlaxoSmithKline, Inhibitex, Inc, Johnson and
Johnson, LabCorp, and Merck & Co, Inc. He has
stock options for Achillion Pharmaceuticals, Inc.
(Updated 05/10/10)
Dr Follansbee has no relevant financial affiliations
to disclose. (Updated 05/03/10)
Dr Johnson has served as a consultant to Gilead
Sciences, Inc, GlaxoSmithKline, and ViiV
Healthcare. (Updated 05/10/10)
Dr Wyles has received grants awarded to the
University of California San Diego from ScheringPlough and Vertex Pharmaceuticals. (Updated
05/11/10)
Dr Kitahata has served as a consultant to Gilead
Sciences, Inc. (Updated 05/05/10)
Dr Luetkemeyer has no relevant financial
affiliations to disclose. (Updated 05/10/10)
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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):
Dr Gulick has served as a consultant to BristolMyers Squibb, Gilead Sciences, Inc, and
Virostatics and as an investigator for research
study grants (to Weill Cornell) from Pfizer Inc,
Schering-Plough Corp, Tibotec Therapeutics, and
Wyeth. (Updated 03/13/10)
Dr Benson has received research grants awarded
to the University of California San Diego from
Gilead Sciences, Inc. She has served on scientific
advisory boards for GlaxoSmithKline, ViiV
Healthcare, and Merck & Co, Inc, and has chaired
a data and safety monitoring board for Achillion
Pharmaceuticals, Inc. (Updated 4/08/10)
Ms Jacobsen has no relevant financial affiliations
to disclose. (Updated 04/12/10)
Dr Currier has received research grants awarded
to the University of California Los Angeles from
Merck & Co, Inc, and Schering-Plough Corp.
(Updated 05/11/10)
Dr Richman has been a consultant to Biota,
Bristol-Myers Squibb, CHIMERx, Gen-Probe, Inc,
Gilead Sciences, Inc, Idenix Pharmaceuticals, Inc,
Merck & Co, Inc, Monogram Biosciences, Myriad
Genetics, and Theraclone Sciences. He has been
on an endpoint adjudication committee for
Schering-Plough Corp and has been the recipient
of research grants or contracts from Merck & Co,
Inc. Dr Richman has been a stock options holder
of CHIMERx and Idenix Pharmaceuticals, Inc, and
a stock shareholder of Monogram Biosciences,
Inc. (Updated 03/16/10)
Dr del Rio has received research grants awarded
to Emory University from Merck & Co, Inc,
Schering-Plough Corp, and Sanofi Pasteur. He
served as a consultant to, or received honoraria
from Bristol-Myers Squibb, Merck & Co, Inc, and
Janssen-Cilag. (Updated 05/07/10)
Dr Gallant has served as a paid lecturer for
Monogram Biosciences, Inc, and has been a
consultant to Abbott Laboratories and Japan
Tobacco. He has been a member of data and
safety monitoring boards and endpoint
adjudication committees for Gilead Sciences, Inc,
and Sangamo Biosciences, Inc, and has been a
member of scientific or clinical advisory boards for
Bristol-Myers Squibb, Gilead Sciences, Inc, Merck
Serono, and Tibotec Therapeutics. Johns Hopkins
University has been the recipient of research
grants or contracts from Roche Laboratories for
research conducted by Dr Gallant. (Updated
03/03/10)
Dr Saag has received grants and research support
from and has been a scientific advisor to Adrea
Biosciences, Inc, Avexa, Ltd, Boehringer Ingelheim
Pharmaceuticals, Inc, Gilead Sciences, Inc,
GlaxoSmithKline, Merck & Co, Inc, Pain
Therapeutics, Pfizer Inc, Roche Laboratories,
Tibotec Therapeutics, and Virco Lab, Inc.
(Updated 03/15/10)
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
12
Dr Schooley has served as a consultant to
Achillion Pharmaceuticals, Inc, Gilead Sciences,
Inc, GlaxoSmithKline, Inhibitex, Inc, Johnson and
Johnson, LabCorp, and Merck & Co, Inc. He has
stock options for Achillion Pharmaceuticals, Inc.
(Updated 05/10/10)
IAS–USA CME STAFF
Dr Volberding has served on data and safety
monitoring boards for Merck & Co, Inc, and
TaiMed Biologics, and on an endpoint adjudication
committee for Schering-Plough Corp. He has
provided paid legal consultation for Stanford
University and expert testimony for commercial
firms. He has served on scientific or clinical
advisory boards for Bristol-Myers Squibb, Gilead
Sciences, Inc, GlaxoSmithKline, Pfizer Inc, and
Tobira Therapeutics and he has been the recipient
of service grants for, or held contracts from,
GlaxoSmithKline Italy. (Updated 04/07/10)
Dr Carmichael has no relevant financial affiliations to
disclose. (Updated 05/07/10)
Ms Jacobsen has no relevant financial affiliations
to disclose (see above).
PROGRAM DEVELOPMENT COMMITTEE
Ms Fullerton has no relevant financial affiliations to
disclose. (Updated 05/07/10).
Ms Richardson has no relevant financial affiliations
to disclose. (Updated 05/06/10).
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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.
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–
Questions are multiple choice, and answers are
numbered 1 to 10. Use the number 1 for yes
and 2 for no.
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enter an answer choice. A timer on the screen
at the front of the room shows you how much
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If you think your touchpad is not working
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Please do not remove the touchpad from its plastic
cover. Responses will transmit through the plastic.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
14
INTERNATIONAL AIDS SOCIETY–USA CME PROGRAMS
The IAS–USA is sponsoring the following CME courses in 2010. For additional information, visit
www.iasusa.org or call (415) 544-9400.
®
THE EIGHTEENTH YEAR OF CME COURSES: Improving the Management of HIV Disease
Atlanta, Georgia
Hyatt Regency Atlanta
Tuesday, March 2, 2010
Chairs: Michael S. Saag, MD, and Jeffrey Lennox, MD
Los Angeles, California
Renaissance Hollywood
Wednesday, March 10, 2010
Chairs: Ronald T. Mitsuyasu, MD, and Constance A. Benson, MD, FACP
New York, New York
Grand Hyatt New York
Monday, March 22, 2010
Chairs: Gerald H. Friedland, MD, and Paul A. Volberding, MD
Chicago, Illinois
Marriott Chicago Downtown
Monday, April 19, 2010
Chairs: John P. Phair, MD, and Paul A. Volberding, MD
San Francisco, California
Grand Hyatt San Francisco
Monday, May 17, 2010
Chairs: Robert T. Schooley, MD, and Stephen E. Follansbee, MD
Washington, DC
Capital Hilton
Thursday, June 17, 2010
Chairs: Henry Masur, MD, and Michael S. Saag, 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, Marshall J.
Glesby, MD, PhD, Judith A. Aberg, MD, Roger Bedimo, MD, Meg Newman, MD, and Paul E. Sax, MD.
Current Cases on the Web include:
Human Papillomavirus-Related Anal
Squamous Cell Dysplasia and Carcinoma in
HIV Infection
John Koeppe, MD, and Steven C. Johnson, MD
Management of an HIV-Infected Patient After
Initial Antiretroviral Regimen Failure
Warangkana Sangchan, MD, and Lisa M.
Chirch, MD
Common Drug Interactions in Patients
Receiving Antiretroviral Therapy
John J. Faragon, PharmD, BCPS, David
Condoluci, DO, and Cindy M. Hou, DO, MBA
The Use of Chemokine Receptor Antagonists
in Antiretroviral Treatment Failure
David M. Margolis, MD, FACP, and Gretchen
Shaughnessy Arnoczy, MD
Non-AIDS-Defining Cancers in Patients with
HIV Infection
Roger J. Bedimo, MD, MS
End-Stage Renal Disease in the HIV-Infected
Patient
Christina M. Wyatt, MD
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
15
Pregnancy Planning and Preconception Health
Care for HIV-Infected Individuals and Couples
Erika Aaron, MSN, CRNP, and Shannon M. Criniti,
MPH
Special Cases in Antiretroviral Therapy
Initiation: Focus on Acute HIV and
HIV/Hepatitis B Virus Coinfection
Charles Hicks, MD, and Elizabeth Reddy, MD
Initiation and Maintenance of HIV Treatment in
Adolescents
Jaime Martinez, MD
Sexual Addiction in an HIV-Infected Patient
Edward R. Hammond, MD, MPH, and Glenn J.
Treisman, MD, PhD
HIV-Infection and International Travel:
Pretravel Patient Assessment and
Management
Carlos Franco-Paredes, MD, MPH
Initiation of Antiretroviral Therapy: A Patient
with Chronic Substance Use and Depression
Sara Vazquez, MD, and J. Kevin Carmichael, MD
Managing Oral Health Problems in People with
HIV Infection
David A. Reznik, DDS
Initial Evaluation of a Patient with a New HIV
Diagnosis
Michael Melia, MD, and Howard Libman, MD
Strategic Use of Antiretroviral Drugs in the
Patient with Numerous Treatment Failures and
Multidrug Resistance
Harry W. Lampiris, MD, and Elvin H. Geng, MD,
MPH
Management of Cryptococcal Meningitis in the
Antiretroviral Therapy Era: More than Just
Antifungals
Anuradha Ganesan, MD, and Henry Masur, MD
Syphilis in the HIV-Infected Patient
Jeanne M. Marrazzo, MD, MPH
Immune Reconstitution Inflammatory
Syndrome in HIV-Infected Patients
Jaime C. Robertson, MD, and Carl J.
Fichtenbaum, MD
The Use of Preexposure and Postexposure
Prophylaxis for HIV Prevention
Raphael J. Landovitz, MD
Issues in the Care of HIV and Hepatitis C VirusCoinfected Patients: Antiretroviral
Pharmacokinetics, Drug Interactions, and Liver
Transplantation
David L. Wyles, MD
Selected Endocrine Problems in HIV-infected
Patients
Todd T. Brown, MD, PhD
HIV-Associated Cognitive Impairment
Susan Swindells, MBBS, and Miguel G.
Madariaga, MD
HIV-Related Renal Disease
Christina M. Wyatt, MD, and Lynda Anne Szczech,
MD, MSCE, FASN
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-Associated Dyslipidemias: 2009 Edition
Roger J. Bedimo, MD, MS
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
16
HELP REBUILD GHESKIO
begun to set up emergency healthcare services for
those in need.
Every year the International AIDS Society-USA
partners with an HIV/AIDS charitable organization
in a developing nation that is severely impacted by
HIV disease.
Since the earthquake on January 12, 2010,
GHESKIO has been providing humanitarian
assistance and emergency care to those affected
by the disaster and continues to provide life-saving
medications to people with HIV/AIDS.
This year the IAS-USA is turning its attention to
assisting in rebuilding GHESKIO, Haiti’s largest
provider of HIV/AIDS care, treatment, education,
and research. For more than 20 years, GHESKIO
has served as the Haitian Government’s research
and training center for HIV/AIDS, and it is now an
internationally recognized center of excellence,
under the leadership of Dr Jean William Pape.
HOW YOU CAN MAKE A DIFFERENCE
GHESKIO will be rebuilt, one brick at a time. You
can help provide refugee relief and urgent medical
care by donating funds to support GHESKIO
medical clinic in Haiti. Weill Cornell Medical
College (WCMC) has been collaborating with
GHESKIO for 25 years in research, care, and
prevention of HIV/AIDS. Both WCMC and IASUSA are 501(c)(3) organizations, and your
donation is tax deductible. Both organizations are
donating their administrative costs to ensure that
100% of every dollar donated goes directly to
GHESKIO.
IN THE HEART OF PORT-AU-PRINCE:
GHESKIO IN HAITI
GHESKIO CENTER in Port-au-Prince, is a nongovernmental organization provided continuous
medical care in Haiti since 1982⎯never once
shutting its doors or charging fees. The buildings at
GHESKIO were severely damaged in the
earthquake, but despite this, the medical staff has
Donate by Cash, Credit Card, or Check
Donations in any amount are welcome: please make checks payable to IAS-USA GHESKIO or WCMCGHESKIO and send to:
IAS–USA-GHESKIO
425 California Street
Suite 1450
San Francisco, CA 94104
WCMC-GHESKIO
The Center for Global Health
440 East 69th Street
New York, NY 10021
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
17
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Fax or mail this form to:
May 17, 2010
VAGINAL MICROBICIDES AS A METHOD TO PREVENT HIV-1
SEXUAL TRANSMISSION
John P. Moore, PhD
___________________________________
___________________________________
Vaginal Microbicides as a
Method to Prevent HIV-1
Sexual Transmission
___________________________________
John P. Moore, PhD
___________________________________
Professor of Microbiology and Immunology
Weill Medical College of Cornell University
___________________________________
___________________________________
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
What is a microbicide?
___________________________________
A microbicide is a substance that can prevent
or reduce HIV-1 sexual transmission when
applied to the vagina or rectum. An ARV taken
orally is NOT a microbicide.
___________________________________
A microbicide could, potentially, take several
forms:
– gel or cream
– sponge
– film
– suppository
– ring or diaphragm
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #3
Any microbicide must be
“safe, effective, cheap, user-friendly”
•
___________________________________
___________________________________
Safe - must have no localized toxicity, including no
damage to the vaginal epithelium during sustained,
repetitive use, with no localized inflammatory
responses.
___________________________________
•
Effective - must have a significant degree of efficacy
in routine use.
•
Cheap - must be priced comparably to a condom, so
high-tech approaches will be a problem.
•
User-friendly - must be compatible with use during
sex (consistency, taste, smell etc, must be
satisfactory, from both female and male viewpoints).
INTERNATIONAL AIDS SOCIETY–USA
___________________________________
___________________________________
___________________________________
May 17, 2010
19
J. P. Moore, PhD
Slide #4
Understanding HIV-1 sexual transmission is important for the
rational design of microbicides
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #5
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
For any prevention technology, success will
depend on maintaining protective inhibitor
concentrations at the mucosal portals of entry.
State of the microbicide field
___________________________________
Slide #6
___________________________________
• First generation concepts (detergents and polyanions)
___________________________________
were successfully tested, but they lacked potency and
required application before each sex act.
___________________________________
• The effort now is now focused mostly (although still not
entirely!) on ARVs.
___________________________________
• Many early clinical (Phase I-II) studies are ongoing.
___________________________________
• Some concepts may merit efficacy testing.
• New formulations that maximize adherence are a priority.
___________________________________
• Developing combination products is important.
• It is now a critical time for the microbicide field!
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
20
J. P. Moore, PhD
ARVs, the next generation of
vaginal microbicides
___________________________________
Slide #7
• The recent failure of PRO 2000 in efficacy trials is (or
should be) the death knell of the sulfated polyanion
approach to vaginal microbicides.
• The next microbicide generation is the RT inhibitors, of
which several are being developed in parallel by various
funding agencies.
• Other than the lack of validation of some RT inhibitors in
animal models, the most obvious problem with this class
is the increasing emergence of resistant viruses in the
developing world, because the same drug class is also
used for therapy in the same regions.
• The CCR5 inhibitors are compelling alternative
candidates, because these drugs are NOT being used for
treatment in, e.g., Africa.
Proving microbicide efficacy is difficult...
Large Phase III trials (7-12,000 subjects) are needed to
measure efficacy, but are very complex and expensive.
•
Intervening against an infection with a relatively low
incidence after counseling about safe sex practices is
hard.
•
Microbicide trials require a high level of compliance by
women who are not, or only infrequently, using condoms.
•
Although some microbicide candidates merit
advancement into Phase III trials, not enough resources
are available to test all of them - hence a method for
prioritization is needed.
•
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #8
•
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
We should avoid simultaneous testing of too many
broadly similar concepts (the mistake made with the first
generations of microbicide compounds).
___________________________________
Slide #9
Targeting HIV-1 replication with ARVs
___________________________________
___________________________________
___________________________________
___________________________________
CCR5/
CXCR4
___________________________________
Inhibit
fusion
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
21
J. P. Moore, PhD
___________________________________
Slide #10
Some drugs now used in HIV-1 therapy
Nucleos(t)ide Reverse Transcriptase
Inhibitors (NRTIs)
Zalcitabine (ddC)
Abacavir (ABC)
Zidovudine (ZDV)
Didanosine (ddI)
3TC/ABC
Emtricitabine (FTC)*
3TC/ABC/ZDV
Lamivudine (3TC)* 3TC/ZDV
Stavudine (d4T)
FTC/TDF*
Tenofovir (TDF)*
Nonnucleoside RTIs (NNRTIs)
Delavirdine (DLV)
Efavirenz (EFV)
Nevirapine (NVP) (Dapivirine)*
___________________________________
Protease Inhibitors (PIs)
___________________________________
Amprenavir (APV)
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir (FPV)
Indinavir (IDV)
Lopinavir/ritonavir (LPV/r)
Nelfinavir (NFV)
Ritonavir (RTV)
Saquinavir (SQVhgc)*
Tipranavir (TPV)
___________________________________
___________________________________
___________________________________
Fusion Inhibitors (FIs)
___________________________________
Enfuvirtide (ENF)
Multiple Class Combinations
CCR5 Inhibitors
EFV/FTC/TDF
Integrase Inhibitors
Raltegravir*
Maraviroc (MVC)*
*current candidates for PrEP and/or microbicides
___________________________________
Slide #11
Any drug used for oral prophylaxis must be extremely safe
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Tolerability standards will have to be higher in
uninfected people than in HIV-positive individuals
___________________________________
Slide #12
The macaque model has its uses for microbicide research
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
• “Proof of concept” studies can be valuable.
• Protecting a macaque does not guarantee protecting a
woman, but failure to protect a macaque raises concerns
about an inhibitor’s potency.
• Similar compounds can be ranked for potential.
• PK/PD data can inform human studies.
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
22
J. P. Moore, PhD
___________________________________
Slide #13
Compounds protective in monkey models
___________________________________
R5 virus challenges
b12: MAb, SHIV-162P4, vaginal.
PSC-RANTES: Modified chemokine, SHIV-162P3, vaginal.
BMS-806: Small molecule to gp120, SHIV-162P3, vaginal.
C52L: Peptide to gp41, SHIV-162P3, vaginal.
T1249: Peptide to gp41, SHIV-162P3, SIVmac251, vaginal.
CMPD 167: Small molecule to CCR5, SHIV-162P3, vaginal.
Maraviroc: Small molecule to CCR5, SHIV-162P3, vaginal.
PMPA (tenofovir): NRTI, SIVmac251, vaginal + rectal
___________________________________
___________________________________
___________________________________
___________________________________
X4 virus challenges
CAP: Polyanion, SHIV-33A, vaginal.
Cyanovirin-N: Protein lectin, SHIV-89.6P, vaginal + rectal.
T1249: Peptide to gp41, SHIV-1KU1, vaginal.
PRO-2000: Polyanion, SHIV-89.6PD, vaginal.
AMD3465: Small molecule to CXCR4, SHIV-189.6P, vaginal.
___________________________________
___________________________________
Slide #14
Testing the small molecule CCR5 inhibitor,
Maraviroc, as a vaginal microbicide in macaques
___________________________________
___________________________________
Maraviroc (Pfizer) is the first CCR5 inhibitor
approved as a drug for treating HIV-1 infection.
___________________________________
The IPM has licensed Maraviroc for development
as a vaginal microbicide.
___________________________________
Neither Pfizer nor IPM has plans to test
maraviroc for efficacy in the rhesus macaque
vaginal transmission model.
___________________________________
___________________________________
Although other CCR5 inhibitors (e.g., PSC-RANTES, CMPD167) have been shown to be protective in macaques, we
believe it is important that all microbicides are proven
effective in macaques before testing in women on a large
scale.
___________________________________
Slide #15
How to obtain a solution of maraviroc
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Take one
friendly
physician
Scrounge a
maraviroc
tablet
Grind it up
Add sterile
saline
Voila!
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
23
J. P. Moore, PhD
___________________________________
Slide #16
Testing Maraviroc in macaques
Methods
___________________________________
___________________________________
• Progesterone-treatment to thin the vaginal epithelium and
facilitate virus transmission.
___________________________________
• Apply maraviroc vaginally as an HMC gel formulation at
known concentrations.
___________________________________
• Wait 30 min (or a variable time), challenge vaginally with a
single “high dose” of SHIV-162P3 (R5) or SHIV-KU1 (X4).
___________________________________
___________________________________
• Assess the outcome of challenge by measuring plasma
viremia.
A CCR5 inhibitor does not protect
against X4 viruses
___________________________________
Slide #17
___________________________________
Although it is “obvious” that MVC would not protect against X4
virus challenge, we confirmed this but also assessed whether
the CCR5 inhibitor might exacerbate X4 virus infection.
___________________________________
___________________________________
Experiment 1: Three macaques received 6 mM MVC before
challenge with SHIV-KU1 (500 TCID50). All three animals were
infected.
___________________________________
Experiment 2: Three macaques received 2 mM MVC, three
animals a placebo gel. All six animals were challenged with
SHIV-KU1 (10 TCID50). All six animals were infected, but there
was no significant difference in post-infection viral load between
the two groups.
___________________________________
___________________________________
In principle, a follow-up experiment could be performed to see
whether the presence of MVC increases acquisition risk when
macaques are exposed to sub-infectious doses of an X4 virus
(+/- an R5 virus).
___________________________________
Slide #18
Testing Maraviroc in Macaques - Conclusions
___________________________________
Dose- and time-dependent protection of macaques against
vaginal challenge with an R5 SHIV, but not an X4 SHIV.
___________________________________
Half-maximal protection at ~0.5 mM (0.25 mg/mL).
___________________________________
Fully protective MVC dose is ~12 mg (4 ml at 3 mg/mL).
___________________________________
Half-life of protection at ~6 mM (3 mg/mL) is 4 hours.
___________________________________
A single MVC tablet (300 mg, retailing for ~$15) contains
enough drug to fully protect ~25 macaques (and probably
a roughly similar number of women) if applied vaginally.
___________________________________
These studies validate the development of MVC for use in
women and should guide the clinical process.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
24
J. P. Moore, PhD
___________________________________
Slide #19
The need for improved microbicide
delivery methods
___________________________________
• Even a microbicide that contains truly active ingredients
is useless if it is not used consistently.
___________________________________
___________________________________
• Our studies with MVC, and earlier ones with other entry
inhibitors, show that protection decays over time (a few
hours) after bolus application of a gel.
___________________________________
___________________________________
• Develop microbicide formulations that can be applied
infrequently. For example, semi-solid gels for use once a
day, or vaginal rings that are left in place for a few weeks.
___________________________________
• We are now using the macaque model to test the in vivo
performance of vaginal rings.
___________________________________
Slide #20
Sustained delivery devices and vaginal rings offer a
path away from coitally-dependent microbicides
___________________________________
Sex acts, A, B, C
___________________________________
___________________________________
Semi-solid formulation,
coitally independent
Vaginal ring reservoir
___________________________________
___________________________________
___________________________________
Gel formulation,
coitally dependent
Karl Malcolm - Queen’s University Belfast
___________________________________
Slide #21
___________________________________
21
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
25
J. P. Moore, PhD
___________________________________
Slide #22
Reservoir vs. matrix types of vaginal rings
Cross-sectional
profiles
___________________________________
___________________________________
TMC120
Raman maps
___________________________________
Map view
___________________________________
13
mm
Core-type
___________________________________
13 mm
Map view
___________________________________
15
mm
Courtesy of Karl Malcolm, QUB
Matrix-type
15 mm
___________________________________
Slide #23
CMPD167 (Merck)
A small molecule CCR5 inhibitor
___________________________________
___________________________________
C35H47FN4O2
MW: 575 Da
Log P: 4.99 (i.e., hydrophobic compound)
In vitro IC50: 0.1 - 0.5 nM
___________________________________
___________________________________
___________________________________
___________________________________
CMPD167 was developed by Marty Springer and colleagues
___________________________________
Slide #24
CMPD167 ring development
___________________________________
• Queen’s University Belfast
–
–
–
–
___________________________________
pre-formulation drug solubility studies
matrix ring manufacture
in vitro release testing (sink condition model)
measure residual drug content post-use
___________________________________
___________________________________
• Tulane – macaque PK study
– 400 mg CMPD167 matrix rings
– depo vs. non-depo treatment of macaques
– vaginal fluid levels (Weck cell) on days 0, 1, 2, 3,
4, 7, 9, 11, 14, 28
– blood levels on days 0, 1, 2, 3, 4, 7, 9, 11 ,14
– biopsies
___________________________________
___________________________________
• Particle Sciences – all sample analyses
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
26
J. P. Moore, PhD
___________________________________
Slide #25
CMPD167 levels in macaque vaginal
fluid after in vivo release
25
___________________________________
(averaged across animal groups)
___________________________________
___________________________________
~20 μM = 100,000 x in vitro IC50
DMPA
___________________________________
___________________________________
No DMPA
___________________________________
Vaginal CMPD167 levels are significantly lower in
the DMPA-treated animals, because of reduced
vaginal fluid volumes and hence less release of
the compound from the rings.
___________________________________
Slide #26
CMPD167 levels in macaque plasma
___________________________________
(averaged across animal groups)
26
___________________________________
Plasma CMPD167 levels are low,
but are significantly higher in the
DMPA-treated animals, probably
because the compound
penetrates the thinner vaginal
epithelium more easily.
___________________________________
___________________________________
DMPA
___________________________________
No DMPA
~2 nM = 10 x in vitro IC50
CMPD167 vaginal ring studies
Conclusions
___________________________________
___________________________________
Slide #27
___________________________________
• CMPD167 release from vaginal rings in vitro is efficient.
___________________________________
• CMPD167 is released into the macaque vagina to steadystate levels of 20-200 µM, 105 to 106 times greater than the
in vitro IC50.
___________________________________
___________________________________
• DMPA treatment modestly reduces CMPD167 release,
probably by reducing the volume of vaginal fluid that
bathes the rings.
___________________________________
___________________________________
• CMPD167 levels in the plasma are almost undetectable
(<1nM, no DMPA) or low (2-10nM, + DMPA).
• Challenge studies with R5 (vs X4 control) SHIVs are now
planned, to validate the vaginal ring concept.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
27
J. P. Moore, PhD
___________________________________
Slide #28
Acknowledgements
___________________________________
___________________________________
• Ron Veazey - Tulane
• Tom Ketas - Cornell
• Leslie Geer - Particle Sciences
• Robin Shattock - St. George’s
• Karl Malcolm - Queen’s University Belfast
• Steve Wolinsky - Northwestern University
• PJ Klasse - Cornell
___________________________________
___________________________________
___________________________________
___________________________________
NIH awards R01 AI 41420 (MVC study)
U19 AI 76982 + IPM support (vaginal ring and SHIV transmission studies)
SUGGESTED READINGS
Klasse PJ, Shattock R, Moore JP. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission.
Annu Rev Med. 2008;59:455-471.
Klasse PJ, Shattock RJ, Moore JP. Which topical microbicides for blocking HIV-1 transmission will work in the
real world? PLoS Med. 2006;3:e351.
Malcolm RK, Woolfson AD, Toner CF, Morrow RJ, McCullagh SD. Long-term, controlled release of the HIV
microbicide TMC120 from silicone elastomer vaginal rings. J Antimicrob Chemother. 2005;56:954-956.
Promadej-Lanier N, Smith JM, Srinivasan P, et al. Development and evaluation of a vaginal ring device for
sustained delivery of HIV microbicides to non-human primates. J Med Primatol. 2009;38:263-271.
Shattock RJ, Moore JP. Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol. 2003;1:25-34.
Veazey RS, Ketas TA, Klasse PJ, et al. Tropism-independent protection of macaques against vaginal
transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249. Proc Natl Acad Sci USA. 2008;105:1053110536.
Veazey RS, Ketas TJ, Dufour J, Green LC, Klasse PJ, Moore JP. Protection of rhesus macaques from vaginal
infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis.
2010;In press.
Veazey RS, Klasse PJ, Schader SM, et al. Protection of macaques from vaginal SHIV challenge by vaginally
delivered inhibitors of virus-cell fusion. Nature. 2005;438:99-102.
Veazey RS, Springer MS, Marx PA, Dufour J, Klasse PJ, Moore JP. Protection of macaques from vaginal SHIV
challenge by an orally delivered CCR5 inhibitor. Nat Med. 2005;11:1293-1294.
Woolfson AD, Malcolm RK, Morrow RJ, Toner CF, McCullagh SD. Intravaginal ring delivery of the reverse
transcriptase inhibitor TMC 120 as an HIV microbicide. Int J Pharm. 2006;325:82-89.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
28
WHEN TO START ANTIRETROVIRAL THERAPY?
Mari M. Kitahata, MD, MPH
___________________________________
Slide #1
___________________________________
___________________________________
When to Start
Antiretroviral Therapy?
___________________________________
___________________________________
Mari M. Kitahata, MD, MPH
___________________________________
Professor of Medicine
University of Washington
___________________________________
The International AIDS Society–USA
Overview
___________________________________
Slide #2
‘When to Start ART?’ guidelines evolved over past decade
• ‘Asymptomatic’ HIV-infected individuals
• Limited RCT data
___________________________________
Why start ART earlier?
• HIV-associated aging: inflammation, immune activation
• Immunosenescence: non-AIDS morbidity
• Life expectancy
• Lower risk of toxicities
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
What observational data informing ‘When to Start ART?’
• Strengths and limitations
Current 2009 DHHS Guidelines
• Earlier initiation of ART and entry into care
___________________________________
Slide #3
HOPS: Effect of ART on Mortality Over Time
90
7
80
70
6
60
5
50
4
40
3
30
2
1
___________________________________
Deaths per 100 Person-Years
8
P <0.01 for trend
20
___________________________________
Patients on ART, %
Deaths per 100 Person-Years
% of Patients on ART
___________________________________
___________________________________
___________________________________
___________________________________
10
0
0
1996 1997 1998 1999 2000 2001 2002 2003 2004
Palella JAIDS 2006
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
29
M. M. Kitahata, MD, MPH
___________________________________
Slide #4
DHHS Guidelines Evolved
1998
AIDS
2001-3/2004 10/2004-2006 12/2007-2008
Treat
Treat
• <500
Treat
CD4
count
Treat
• <200 Treat
• <350 Offer
• >350 Indiv.
• VL >55K
• VL >20K
Consider
Other
• <200 Treat
• <350 Offer
• >350 Defer
• VL >100K
Consider
• >350
stopping
(4/01-3/04)
Consider
___________________________________
2009
Treat
Treat
• ≤350 Treat
• >350 Consider
___________________________________
• <350 Treat
• 350-500 Recomd.
• >500
Favor/optional
___________________________________
• Pregnant women • Pregnant women
• HBV
• HBV
• HIVAN
• HIVAN
___________________________________
• Older Age
• Co-morbidities
• CD4 decline
___________________________________
2001-06: concern for resistance / potential toxic effects
___________________________________
• Recommend delaying ART / No RCT to support
2007-09: consequences HIV replication Æ Immune dysfunction
• Recommend earlier ART start / Inform patients about data on
clinical benefit not conclusive
___________________________________
Slide #5
Only RCT of ‘When to Start ART?’: CIPRA HT 001
Survival Probability
1.00
6 deaths
.95
___________________________________
___________________________________
23 deaths
___________________________________
.90
Early
Standard
.85
___________________________________
.80
0
6
12
18
24
30
___________________________________
36
Months from Randomization
ART CD4 200-350 vs. defer CD4 <200 or AIDS (WHO)
___________________________________
• DSMB stopped trial early (N=816)
• Defer ART: Mortality HR=4.0; p=0.001; TB HR=2.0; p<0.01
No RCT CD4 >350
Fitzgerald ICAAC 2009
Cum. probability (X100)
Post-Hoc Subset Analysis SMART
___________________________________
Slide #6
___________________________________
25
___________________________________
20
Deferred ART
15
___________________________________
10
5
___________________________________
Immediate ART
0
0
4
8
12
16
20
Months
24
28
32
___________________________________
38
Subset: ART-naïve or off prior ART at time of randomization
___________________________________
• Immediate ART: n=249 (131 naïve) CD4 >350
• Deferred ART:n=228 (118 naïve) CD4 <250
Deferred ART: greater risk of OI/death, non-AIDS event/death
• HR 4.19 (95% CI, 1.69–10.39; P < 0.002)
Emery JID 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
30
M. M. Kitahata, MD, MPH
___________________________________
Slide #7
Estimated number of people living with AIDS
US HIV-Infected Population is Aging
___________________________________
100000
___________________________________
2001
2005
90000
80000
___________________________________
70000
60000
___________________________________
50000
___________________________________
40000
30000
___________________________________
20000
10000
0
<13
13-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64
>65
Age
Luther ClinGeriatr Med 2007
___________________________________
Slide #8
NA-ACCORD: Proportion of patients with virologic
failure of >2 ART regimens has declined (N=36,188)1
___________________________________
Incidence per 100 py
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
ACTG 51242: Greater risk of virologic failure when
ART started at older age
• HR 1.23 (per decade) 95% CI, 1.06 to 1.45
1Deeks
CID 2009; 2Riddler NEJM 2008
___________________________________
Slide #9
FHDH: Age ? 50 Slower Immunologic
Response and Greater Clinical Progression
___________________________________
___________________________________
Mean CD4 Count
Increase/Mo
Within First 6 Mos of ART*
___________________________________
After 6 Mos of ART*
Age < 50 Yrs
Age ≥ 50 yrs
Age < 50 Yrs
Age ≥ 50 Yrs
BL VL < 5 log
17.3
14.1
11.1
9.8
BL VL ≥ 5 log
42.9
36.9
17.9
15.6
___________________________________
___________________________________
*P< 0.0001
Outcome
Adjusted HR
P Value
Progression to ADE / Death
1.52
0.004
Progression to new ADE
1.50
0.009
VL < 500
1.23
< 0.05
___________________________________
Grabar AIDS 2004
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
31
M. M. Kitahata, MD, MPH
Slide #10
___________________________________
HIV infection confers a phenotype of “premature frailty”1
___________________________________
HIV-Associated Aging / Immunosenescence
• Immune system defects in HIV+ patients similar to
normal aging, occur prematurely2
___________________________________
• Accelerated aging / similar to advanced age >70 yrs
___________________________________
HIV-associated immune deficiency, inflammation and
immune activation
___________________________________
• Increased pro-inflammatory cytokines
___________________________________
• Decreased capacity to renew T cells
• Thymic / lymphoid fibrosis
___________________________________
• Immune defects persist after years of effective ART2
No ‘asymptomatic’ phase of HIV disease
• Detrimental effects at all stages of HIV infection
1
Desquilbet J Gerontol A BiolSci Med Sci 2007; 2Cao JAIDS 2009; TenorioClinImmunol 2009; AppayTrendsImmunol 2002; 2 Deeks BMJ
2009; KullerPloS Med 2008; Neal PLoS Med 2008; Moore CID 2007; Gras JAIDS 2007
Slide #11
Inflammatory Markers Associated with CVD/Mortality
Unadjusted
Adjusted for age, gender, race
Fully adjusted
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Higher levels in HIV+ vs. HIV- controls
SMART vs. MESA / CARDIA
Neuhaus CROI 2009
___________________________________
Slide #12
Immune Activation: HIV Infection and ART
%CD38+ HLA-DR+
CD8+ T-cells
75
___________________________________
___________________________________
P <0.001
___________________________________
P <0.001
50
___________________________________
25
0
___________________________________
HIV +
Untreated
N=13
HIV +
Treated
N=99
___________________________________
HIV N=6
Hunt JID 2003
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
32
M. M. Kitahata, MD, MPH
___________________________________
Slide #13
Initiating ART at Lower CD4 counts
Greater risk of virologic failure ACTG
___________________________________
51241
___________________________________
• HR 1.14; 95% CI, 1.01 to 1.27 (per 100 CD4 cells)
___________________________________
Greater risk of viral resistance2
___________________________________
Incomplete restoration of CD4 counts3
___________________________________
Higher residual inflammation and
immunodefficiency on ART4
___________________________________
1Kuller
PloS Med 2008; Neal PLoS Med 2008; Riddler NEJM 2008; 2Uy et al. JAIDS 2009; 3Moore CID 2007;
Gras JAIDS 2007, Kelly CID 2009; 4Deeks BMJ 2009
___________________________________
Slide #14
HOPS 1999-2006: Increasing Risk of Resistance
when Starting ART at Lower CD4 Counts
0-199 cells/mm3
P=0.06*
200-349 cells/mm3
P=0.005
___________________________________
___________________________________
>350 cells/mm3
P=0.04
___________________________________
P=0.06
___________________________________
___________________________________
Any mutation
(N=78)
NRTI mutation
(n=77)
NNRTI mutation
(n=37)
___________________________________
PI mutation
(n=48)
Frequency of mutations by CD4 count at ART initiation among persons
with virologic failure after successful suppression on ART
UyJAIDS 2009
Slide #15
CNICS (n=300): 40% pts CD4 <200 at Start of ART
Fail to Achieve CD4 >500 after 10 yrs of Viral Suppression
___________________________________
___________________________________
1500
CD4 count
___________________________________
___________________________________
1000
___________________________________
___________________________________
500
___________________________________
0
0
1
2
3
4
5
6
7
8
Year of suppressive HAART
9
10
1
1
Kelley CID 2009
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
33
M. M. Kitahata, MD, MPH
ATHENA: Less Likely to Achieve Higher CD4
with Older Age and Lower CD4 at Start of ART
___________________________________
Slide #16
___________________________________
Median CD4 Response ≥50yrs at Start of ART
1100
1000
___________________________________
? 500
Mean CD4 Count (cells/mm3)
900
800
350-500
700
200-350
600
___________________________________
___________________________________
50-200
500
___________________________________
<50
400
300
___________________________________
200
Solid: <50 yrs. at start of ART
Dashed: ? 50 yrs. at start of ART
100
0
0
1
2
3
4
5
6
7
Years from Starting ART
Gras JAIDS 2007
___________________________________
Slide #17
Non-AIDS Morbidity and ART
___________________________________
Longer duration of immune compromise:
• Exposure to HIV-associated inflamm / immune activation
___________________________________
Lower nadir CD4
___________________________________
• Higher risk non-AIDS morbidity
• Cardiovascular
___________________________________
• Renal
___________________________________
• Liver diseases
• Non-AIDS malignancies
___________________________________
ART reduces risk of non-AIDS morbidity
• Greater among patients with CD4 counts below normal
during long-term treatment
1El-Sadr
et al NEJM 2006; Marin AIDS 2009; Baker AIDS 2008; Phillips AIDS 2008; Baker JAIDS 2008;
Bruyand CID 2009
___________________________________
Slide #18
___________________________________
Current CD4 Count and Non-AIDS Morbidity
Study
Non-AIDS
Malignancies
Renal
Disease/
Death
CVD
Events/
Death
___________________________________
Liver
Disease/
Death
___________________________________
FIRST
Yes
Yes
Trend
No
___________________________________
D:A:D
Yes
Yes
Trend
Yes
___________________________________
CASCADE
Yes
NA
Yes
Yes
Trend
Trend
Trend
Yes
SMART
___________________________________
PhilipsAIDS 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
34
M. M. Kitahata, MD, MPH
___________________________________
Slide #19
HOPS: CD4 Count <350 Increases Risk CVD
___________________________________
Hazard Ratio
for CVD*
___________________________________
Age ≥42 yr
Male sex
2.5
2.0
___________________________________
Smoking
2.0
Baseline CD4 count <350
1.8
___________________________________
Risk Factor
*CVD:
___________________________________
MI, CAD, PVD, TIA, angina, aortic aneurysm, CABG, angioplasty
___________________________________
CD4 <350 independent risk factor for CVD: 80% (n=1,697)1
FIRST study: higher on-treatment CD4 count Ælower risk of
non-AIDS morbidity, including CVD2
1Lichtenstein
IAC 2008; 2Baker AIDS.2008
Slide #20
Non-AIDS Morbidity More Common Even After
Adjustment for Age, ART, Traditional Risk Factors
___________________________________
___________________________________
___________________________________
Normal
Aging
ART
___________________________________
Immune
Suppression
Inflammation
Immune
Activation
___________________________________
Premature
Aging
___________________________________
___________________________________
Lifestyle
DeeksBMJ 2009
Lower Risk of Toxicities
___________________________________
Slide #21
___________________________________
Starting ART at progressively higher CD4 counts lowers
risk of developing toxicity1
___________________________________
• Peripheral neuropathy
• Anemia
___________________________________
• Renal insufficiency
___________________________________
• Lypodystrophy
___________________________________
CIPRA HT001
___________________________________
• Increased toxicity in group deferring ART – anemia2
Side effects of ART are not as deleterious as untreated HIV
All potential long-term side effects not known
1Lichtenstein
JAIDS 2008; Lichtenstein JAIDS 2003; 2Fitzgerald ICAAC 2009
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
35
M. M. Kitahata, MD, MPH
___________________________________
Slide #22
ART and Life Expectancy
___________________________________
Life Expectancy
___________________________________
___________________________________
___________________________________
CD4 Nadir
___________________________________
___________________________________
1
Egger Int J Epi 2009;2Lohse Annals 2007 3Lewden JAIDS2007
Methodological Challenges
Studying ‘When to start ART?’
___________________________________
Slide #23
___________________________________
___________________________________
RCT or Observational Cohort study
• Require large numbers of HIV+ with high CD4 counts
• Followed over many years to clinical outcome
• RCT 2003: 6,500 pts followed for 10 yrs = 65,000 py1
___________________________________
___________________________________
• Feasibility: START Æ SMART
Observational Data
___________________________________
• Prognostic data does NOT address ‘When to start ART?’
• Numerous studies
___________________________________
• Cohort approach to answer ‘When to start ART?’
• NA-ACCORD2
• Imputation approach to answer ‘When to start ART?’
• ART-CC3
1Lane,
NeatonAnn Intern Med 2003; 2Kitahata NEJM 2009; 3Sterne Lancet 2009
___________________________________
Slide #24
Prognostic Data
___________________________________
500
___________________________________
Death or
Censoring
Initiate
HAART
___________________________________
350
Initiate
HAART
___________________________________
Death or
Censoring
___________________________________
200
Initiate
HAART
___________________________________
Death or
Censoring
1996
2006
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
36
M. M. Kitahata, MD, MPH
___________________________________
Slide #25
Prognostic Data
___________________________________
Only observe patients after starting ART1
• Missing patients who defer ART for comparison
___________________________________
___________________________________
DHHS 2008 Guidelines cited
• ART-CC: CD4 >350
___________________________________
• Observed 3-5 yrs: short-term risk for AIDS or death low2
• Pts at higher CD4 are not expected to progress in short term
___________________________________
• Long-term risk progression / disease-free survival
• Pts CD4 >350 had too few endpoints to provide stable estimate
of short-term risk of AIDS or death3
___________________________________
1Hogg
JAMA 2001; CozziLepriAIDS 2001; Kaplan CID 2003; Van SighemAIDS 2003; 2Egger Lancet 2002,
May AIDS 2007; 3Moore JAIDS 2009
___________________________________
Slide #26
Addressing ‘When to Start ART’ Question
___________________________________
Wide agreement that looking at post-ART survival variation
by initial CD4 does not address the question
___________________________________
• Requires observation of pts who start AND defer ART from
same CD4 count level
___________________________________
Early cohort studies1
• Lacked power: sample size and follow up Æ too few events
___________________________________
• Lacked methods: selection bias, time-varying confounding
___________________________________
Cohort approach
• Study design similar to a clinical trial protocol
• Follow a cohort of individuals over time for
___________________________________
• Immediate ART-initiation
• CD4 transit and subsequent ART initiation
• Development of outcome or censoring
Opravil AIDS 2002; Anastos Arch Intern Med 2002; Palella Ann Intern Med 2003; Sterling CID 2003
___________________________________
Slide #27
Ideal Trial Protocol
500
350
1st
CD4+
between
351-500
measured
1996-2006
and no prior
AIDS or ARVs
Initiate HAART
Death or
Censoring
Defer HAART
Death or
Censoring
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Transit to
CD4 < 350
Initiate
HAART
___________________________________
Death or
Censoring
1996
2006
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
37
M. M. Kitahata, MD, MPH
___________________________________
Slide #28
North American AIDS Cohort
Collaboration on Research and Design
___________________________________
United States
Atlanta, GA
Galveston, TX
___________________________________
Pittsburgh, PA
Baltimore, MD
Greensboro, NC
Portland, OR
Birmingham, AL
Honolulu, HI
Providence, RI
Boston, MA
Houston, TX
Rochester, NY
Bronx, NY
Indianapolis, IN
Sacramento, CA
Brooklyn, NY
Iowa City, IA
San Diego, CA
Buffalo, NY
Kansas City, MO
San Juan, PR
Chapel Hill, NC
Los Angeles, CA
San Francisco, CA
Chicago, IL
Miami, FL
San Leandro, CA
Cincinnati, OH
Minneapolis, MN
San Rafael, CA
Nashville, TN
Seattle, WA
Cleveland, OH
Columbus, OH
New Orleans, LA
St. Louis, MO
Dallas, TX
New York, NY
Stanford, CA
Denver, CO
Oakland, CA
Stony Brook, NY
Detroit, MI
Omaha, NE
Tampa, FL
Durham, NC
Philadelphia, PA
Torrance, CA
___________________________________
___________________________________
___________________________________
___________________________________
Washington, DC
Canada
Vancouver, BC
Ottawa, ON
Montreal, QC
Hamilton, ON
Sudbury, ON
Southern Alberta
Kingston, ON
Thunder Bay, ON
London, ON
Toronto, ON
___________________________________
Slide #29
Statistical Analysis
___________________________________
Modern statistical methods for comparing treatment
strategies in observational data
___________________________________
Multivariate Cox regression with time-dependent
inverse probability weights (IPW)
___________________________________
• Correct for informative censoring (protocol violations)
___________________________________
Complimentary role for observational cohort analysis
___________________________________
• Examine multiple treatment strategies to optimize pt
outcomes – multiple CD4 count thresholds
___________________________________
• Initiate ART CD4 351-500
• Initiate ART CD4 >500
Limitations of RCT study design – examine finite
number of treatment strategies at randomization
___________________________________
Slide #30
9,155 Pts with CD4 >500 F/U 26,439 PYs
Multivariate Regression Analysis: CD4 >500
*Stratified by Cohort
and Calendar Year
Deferral of ART at >500
Female Sex
Older Age (per 10 years)
CD4 count (per 100 cells)
•
•
•
•
•
•
•
Hazard Ratio
(HR)*
1.94
1.85
1.83
0.93
95% C.I.
P-value
1.37, 2.79
1.33, 2.59
1.62, 2.06
0.87, 0.99
<0.001
<0.001
<0.001
0.03
___________________________________
___________________________________
___________________________________
___________________________________
Baseline HIV RNA (HR Deferral=1.85, 95% C.I. 1.20, 2.86; p=0.006
HIV RNA was not an independent predictor of mortality
Increased risk of mortality with deferral similar 10 yr study
HCV and IDU independent predictors of mortality
Female not associated with death after adjusting for HCV or IDU
Race not associated with death
Sensitivity analyses show increased risk of death with deferral of ART
INTERNATIONAL AIDS SOCIETY–USA
___________________________________
___________________________________
May 17, 2010
38
M. M. Kitahata, MD, MPH
___________________________________
Slide #31
___________________________________
Current ART Regimens are more Potent,
Durable, Convenient, and Well-Tolerated
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
ART-CC/Sterne Lancet 2009: Prognostic
Data Impute Deferral Patient Group
500
CD4
between
351-500
___________________________________
Slide #32
___________________________________
Initiate HAART
Death or
Censoring
Observed
Defer HAART
Death or
Censoring
Imputed
___________________________________
___________________________________
___________________________________
350
___________________________________
Transit to
CD4 < 350
Initiate
HAART
Death or
Censoring
___________________________________
Observed
2006
1996
Imputed
Imputation Approach
___________________________________
Slide #33
___________________________________
‘Imputation approach’
• No observation from time of eligibility
• Use data from < 1996:
___________________________________
• Impute lead-time
• Impute ‘unseen events’
___________________________________
Validity of Imputed Data
___________________________________
• Accuracy of mortality rate from 1989-1995 to estimate
death rate prior to CD4 transition?
• Accuracy of rate of CD4 decline from 1989-1995 to
estimate lead-time?
• Assumes all individuals adhere to “Ideal Protocol”
• Further assumes missing at random given CD4
___________________________________
___________________________________
• Covariates for imputed events?
• Stratified imputation?
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
39
M. M. Kitahata, MD, MPH
___________________________________
Slide #34
Hazard ratio for AIDS or death with 95% CI
Adjusted HR for AIDS or death for ART initiation
4
___________________________________
___________________________________
___________________________________
• HR in the deferred
initiation groups in
steps of 25 cells
•Include CD4 <550
2
___________________________________
___________________________________
1
___________________________________
0.5
500
400
300
200
100
0
CD4 cell count threshold (cells per μL)
Sterne Lancet 2009
2009 DHHS Guidelines
Clinical Status
___________________________________
Slide #35
___________________________________
Recommendations
• AIDS
___________________________________
• CD4<350
• Other (regardless of CD4
count)
•Pregnant
•
•
___________________________________
• ART should be initiated
women
___________________________________
HIVAN
HBV
• CD4 350 - 500
• Patients with CD4 count
>500
___________________________________
• ART is recommended
•
Strength of recommendation:
55% (AII), 45% (BII)
___________________________________
• ART favored or optional
•
•
50% favor starting ART (BIII)
50% view treatment as
optional (CIII)
2009 DHHS Guidelines: early ART to
Prevent HIV/Aging-Associated Morbidity
___________________________________
Slide #36
___________________________________
Kidney disease: ART can prevent or reverse HIVAN1
___________________________________
• Potential TDF nephrotoxicity
Liver disease: ART may slow progression of viral hepatitis
___________________________________
• Allows optimal treatment of HBV2
___________________________________
CVD: HIV is independent risk factor (endothelial dysfx, inflam)
• Untreated HIV worse than ART (atherogenic lipid profile, “cardiotoxic”
ARV agents)
___________________________________
Malignancies: early ART reduces risk of AIDS-defining and
non-AIDS cancers (not all: Hodgkin’s)
___________________________________
Neurocognitive dysfunction: ART prevents/treats dementia
• Uncertain if can completely prevent cognitive dysfunction
1Post
Clin Infect Dis 2008; 2Weber Arch Intern Med 2006
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
40
M. M. Kitahata, MD, MPH
___________________________________
Slide #37
ART and Sexual Transmission/Pregnancy
___________________________________
Rakai study1
• 205 serodiscordant couples
• 20 HIV+ partners started on ART based on guidelines
• 34 transmissions among untreated couples
• 8.6/100 py vs. 0 among treated couples
___________________________________
___________________________________
___________________________________
Rwanda/Zambia study2
• 2,993 serodiscordant couples
• 171 of 175 transmissions occurred in untreated couples
• 3.4/100 py vs. 0.7/100 py: 5-fold reduction in risk
___________________________________
___________________________________
Pregnancy / breast feeding: reduce HIV transmission
Acute OI: ACTG51643 ART beneficial, no difference in IRIS
(excluded TB); TB4 early ART survival; Crypto/Myco wait
1Reynolds
CROI 2009; 2Sullivan CROI 2009; 3Zolopa PLoS One 2009; 4Veloasco JAID S2009
RCT ‘When to Start ART?’
___________________________________
Slide #38
___________________________________
• Well-powered study could provide definitive answer if
goes to completion
___________________________________
• START Initial design: 7 years, following 5,000 pts
___________________________________
Randomize to: start ART CD4 >500 or delay CD4 <200
• Current design: 4.5 years, following 4,000 pts
___________________________________
Randomize to: start ART CD4 >500 or delay CD4 <350
___________________________________
Previous attempts to enroll in such a trial have failed
___________________________________
Relevance in 2015?
Expensive
___________________________________
Slide #39
Start ART at CD4 500 vs. 350
Adds ~2.5 yrs ART over Lifetime (>40 yrs)
___________________________________
CD4 Count
___________________________________
___________________________________
500
___________________________________
350
200
___________________________________
25
•
•
•
•
•
65
Age
25 y.o. with CD4 550 and VL 40,000
Annual loss of ~80 cells without ART
If delay until CD4 350 would take ~2.5 years
Assume lifelong ART (at least 40 years)
Earlier ART at CD4 550 adds ~7% time on ART
___________________________________
Volberding, Gallant with permission
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
41
M. M. Kitahata, MD, MPH
Who NOT to Treat with ART?
___________________________________
Slide #40
___________________________________
2009 DHHS where deferral might be considered
• Significant barriers to adherence
___________________________________
• Comorbidities that prohibit ART e.g. surgery that
requires an extended interruption of ART
___________________________________
• Not expected to have survival / quality-of-life benefits
___________________________________
• Incurable malignancies
• End-stage liver disease not considered for transplant
___________________________________
• Elite controllers (~1%); long-term non-progressors
(~3-5%)
___________________________________
San Francisco Policy
• Treat as soon as HIV-infected
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
42
CURRENT ISSUES IN THE DIAGNOSIS AND MANAGEMENT OF
HIV/TUBERCULOSIS COINFECTION
Annie Luetkemeyer, MD
___________________________________
___________________________________
Current Issues in the
Diagnosis and Management
of HIV/Tuberculosis
___________________________________
___________________________________
Coinfection
___________________________________
Annie Luetkemeyer, MD
___________________________________
Assistant Clinical Professor of Medicine
University of California San Francisco
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
Overview
___________________________________
• The global view of the overlapping TB &
HIV epidemics
• US epidemiology
• Diagnosis of latent and active TB in HIV
infection
• Optimal treatment of HIV in TB coinfection
• Preview of new drug and diagnostics in
development
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #3
___________________________________
HIV/TB: Global Landscape
___________________________________
• 1.4 million new cases of TB in HIV+
population in 2008
• Highest concentration of cases in SubSaharan Africa
• TB one of highest causes of mortality in
HIV+ persons – 26% of AIDS related
deaths
• MDR/XDR TB: extraordinarily high
mortality rates in HIV co-infection
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
43
A. Luetkemeyer, MD
___________________________________
Slide #4
HIV Prevalence in TB cases
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #5
TB in the US: 2009
___________________________________
• 11.4% decrease from 2008
___________________________________
– Underreporting?
• 50% of cases in 4 states: California, New
York, Florida, Texas
• Drivers of Epidemic in San Francisco:
___________________________________
___________________________________
– Foreign born individuals with reactivation
disease (76%)
– Active infection in homeless populations (12%)
___________________________________
___________________________________
• HIV coinfection: 10%
TB in the US in high risk populations,
including HIV+, is here to stay
___________________________________
Slide #6
Contribution of Foreign-Born
Persons
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
44
A. Luetkemeyer, MD
___________________________________
Slide #7
Estimated HIV Coinfection in Persons Reported
with TB, United States, 1993–2006*
___________________________________
___________________________________
% Coinfection
30
___________________________________
20
___________________________________
10
___________________________________
0
1993
1995
1997
1999
All Ages
2001
2003
2005
2006
___________________________________
Aged 25–44
*Updated as of April 23, 2008.
Note: Minimum estimates based on reported HIV-positive status
among all TB cases in the age group.
___________________________________
Slide #8
Bidirectional Interaction:
HIV effect on TB
___________________________________
___________________________________
• Altered clinical presentation: more
paucibacillary and disseminated TB
• Diagnosis challenging
• Increased TB risk throughout history of
HIV disease: acquisition, reactivation,
reinfection, despite ART
• 20-37 fold higher risk of TB if HIV
coinfected
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
TB is a risk throughout courseSlide #9
of HIV infection
___________________________________
Increased TB
diagnosis in 1st
12 mos of ART
___________________________________
___________________________________
Decreased risk with
ART response
___________________________________
TB risk never
returns to baseline
despite ART
Gradual increase
with CD4 decline
___________________________________
___________________________________
2 fold increase at
HIV seroconversion
Modified from Havlir JAMA 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
45
A. Luetkemeyer, MD
___________________________________
Slide #10
Bidirectional Interaction:
TB effect on HIV
___________________________________
___________________________________
• May increase HIV viral load
• Further CD4+ suppression and increased risk
of OI’s
• Increased mortality
• In resource-limited settings, high early
mortality in TB-HIV co-infection, particularly in
low CD4+, despite ART (Lawn 2009)
• Overlapping toxicity complicates effective
therapy
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #11
Rationale for LTBI screening and
treatment in HIV infection
___________________________________
• PPD+ HIV negative: 5-10% lifetime risk
of developing TB (Horsburgh 2004)
• PPD+ HIV Infected: 3-10% risk per year
of developing active TB (Selwyn 1989,1992, Whalen
___________________________________
___________________________________
___________________________________
___________________________________
1997)
___________________________________
• Estimated lifetime risk of active TB in
HIV-infected 20% (Horsburgh 2004)
___________________________________
Slide #12
INH works to prevent TB in HIV
Exposure
category
PersonYears
TB cases
IR
(per 100 PYs)
IRR
Naïve
3,865
155
4.01
(3.40-4.69)
1.0
ART only
11,627
221
1.90
(1.66-2.17)
0.48
(0.39-0.59)
IPT only
395
5
1.27
(0.41-2.95)
0.32
(0.10-0.76)
Both
1,253
10
0.80
(0.38-1.47)
0.20
(0.09-0.91)
TOTAL
17,142
391
2.28
(2.06-2.52)
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
ART prevents TB as well
(CIPRA HT001)
Golub, AIDS, 2007
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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A. Luetkemeyer, MD
___________________________________
Slide #13
IPT in HIV coinfection
___________________________________
• Prevents TB- RR 0.68 (Akolo Cochrane Review 2010)
• Has not convincingly been associated with
INH resistance (Ballcells EID 2006)
• Appears to work even if INH-R TB present
___________________________________
___________________________________
___________________________________
(Halsey 1998)
• Generally safe, well tolerated
• May impact mortality, even in setting of ART,
which drives down mortality dramatically
___________________________________
___________________________________
– HR 0.47 for death in cohort of S.African HIV
starting ART and IPT, compared with those on
ART alone (Innes, CROI 2010)
___________________________________
Slide #14
LTBI Diagnosis: IGRAs
___________________________________
___________________________________
• Measure free IFN-γ or IFN-γ releasing
cells after incubation with MTB
mycobacterial antigens
___________________________________
___________________________________
– Antigens also found in M. kansasii
• Results: Positive, Negative, Indeterminate
• Unlike PPD, there are not different cut-offs
based on risk categories, including HIV
infection
___________________________________
___________________________________
___________________________________
Slide #15
___________________________________
IGRAs for LTBI detection
___________________________________
• Excellent estimated specificity in low TB
prevalence settings: both assays 98% or
greater
• No cross reactivity with BCG
___________________________________
___________________________________
___________________________________
___________________________________
Lalvani 2001, Chapman 2002, Pathan 2001, Mori 2004, Ravn 2005, Pai 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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A. Luetkemeyer, MD
___________________________________
Slide #16
IGRA in HIV+ for LTBI diagnosis
___________________________________
• Positive whole blood IGRA more strongly
associated with TB risk factors in HIV+ than
TST in NYC study (Jones 2007)
• Greater predictive value for subsequent
active TB with whole blood IGRA+ than
TST+ in contact study (Diel 2008)
• Similar predicative value of whole blood
IGRA+ and TST+ in HIV+ patients
undergoing routine TB screening (16.2% vs
18.5%) (Aichelburg IAS 2008)
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
– TST+ but whole blood IGRA neg/indeterminate
-> No active TB
IGRA performs as well as or better than TST
___________________________________
Slide #17
Indeterminate results in HIV
___________________________________
• More likely to have indeterminate result at
low T cell counts
___________________________________
___________________________________
– Whole blood IGRA 5% indeterminate overall,
up to 24-28% at CD4 <100 (Brock, Luetkemeyer)
– EliSPOT based IGRA 3-15% overall, also
increased at lower T cell counts (Dheda,
___________________________________
___________________________________
Mandalakas, Stephan, Talati)
___________________________________
• However, if test result is interpretable,
results can be useful, regardless of CD4+
cell count
___________________________________
Slide #18
Active Tuberculosis:
Clinical presentation of TB in HIV
___________________________________
___________________________________
• Presentation affected by degree of
immunosuppression
• CD4+ > 350:
___________________________________
___________________________________
– Most often disease limited to lungs
– Histopathology similar to HIV negative
(granuloma +/- central caseation)
– Extrapulmonary involvement usually nodal or
pleural
___________________________________
___________________________________
Burman WJ, Semin Resp Infect 2003; 18:263-271
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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A. Luetkemeyer, MD
___________________________________
Slide #19
___________________________________
TB in Advanced HIV
___________________________________
• Pulmonary involvement still most common
• Increasing extra-pulmonary involvement
___________________________________
– 70% of those with CD4+ <100
– 50% with positive MTB blood culture
___________________________________
• Histopathology: Poorly formed/absence of
granuloma
• Radiographic changes
___________________________________
___________________________________
– “Classic” TB findings such as cavities less common
with CD4 < 300
– 21% with normal CXR despite AFB smear positive
Burman WJ, Semin Resp Infect 2003; 18:263-271, Chamie G IAS 2009 TUPEB133
___________________________________
Slide #20
“Ruling out” Active TB
___________________________________
• PPD /IGRA testing cannot “rule out”
active tuberculosis
• Sputum smears do not “rule out” TB,
particularly in HIV infection
___________________________________
___________________________________
___________________________________
– 50-62% of HIV+ with culture positive
pulmonary TB are smear negative (Getahun
___________________________________
2007, Monkongdee 2009)
___________________________________
• Transmission from smear negative
patients is well documented
• Gold standard of culture is imperfect
Clinical suspicion for TB is essential
___________________________________
Slide #21
New Rapid TB Diagnostics- At Last!
___________________________________
___________________________________
• Nucleic acid based tests that rapidly
detect both TB and rifampin resistance
___________________________________
___________________________________
– Results available in less than a day
– Sensitivity 100% AFB+, 71% AFB- (Helb
___________________________________
2009)
• Not FDA-approved yet in the US
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
49
A. Luetkemeyer, MD
___________________________________
Slide #22
TB treatment recommendations
in TB/HIV
___________________________________
___________________________________
• Standard six-month regimen for drug
susceptible TB
• Extend to 9 months if delayed clinical or
microbiologic response (culture positive
or continued symptoms at 2 months)
• CD4+ <200: should receive daily
therapy
___________________________________
___________________________________
___________________________________
___________________________________
Burman WJ, Clin Chest Med 2005; 26:283-94.
___________________________________
Slide #23
When to start ART in Active TB
___________________________________
• SAPIT trial: waiting to start ART until TB
treatment completed is too long
___________________________________
– 56% lower mortality if ART started before TB
treatment completed
– Viral load response better if ART started
during TB therapy
___________________________________
___________________________________
• Unclear how soon to start- immediately or
wait until intensive phase of TB treatment
with 4 drugs is completed?
• Ongoing trials: CAMELIA, 5221, SAPIT
___________________________________
___________________________________
Until more data available, recommend
between 2 weeks and 2 months
Abdool Karim NEJM 2010
___________________________________
Slide #24
What to start:
Drug interactions in HIV-TB
___________________________________
___________________________________
• Rifamycins are key tral to effective TB
therapy
• HIV+ patients may be more prone to
RIF resistance, particularly
inadequately or intermittently doses
dosed
• Rifamycins associated with significant
drug interactions with ART
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
50
A. Luetkemeyer, MD
___________________________________
Slide #25
Effect of rifampin on NNRTIs
___________________________________
___________________________________
% of normal AUC
100
78
80
___________________________________
69
60
___________________________________
40
___________________________________
20
___________________________________
0
Efavirenz
Nevirapine
___________________________________
Slide #26
___________________________________
Choice of ART
___________________________________
• Rifampin and NNRTI preferred if possible
___________________________________
– Limited data on rifabutin + NNRTIs
• Efavirenz may be preferable to nevirapine
___________________________________
– Lower NVP levels with rifampin
– Concern for subtherapeutic NVP during NVP if
already on rifampin
___________________________________
___________________________________
• If NNRTIs cannot be used (drug resistance,
pregnancy, HIV-2, etc), protease inhibitors
are an option
% of normal concentrations
Rifamycin effect on protease
inhibitors
___________________________________
___________________________________
Rifabutin
Rifampin
120
___________________________________
Slide #27
___________________________________
AUC
trough
100
80
___________________________________
60
___________________________________
40
___________________________________
20
0
RT
V
TZ
/
A
RT
V
LP
V/
RT
V
TZ
/
A
LP
V/
RT
V
Higher doses of PIs to overcome rifampin effect is
associated with hepatitis (and may still be inadequate in
children)
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
51
A. Luetkemeyer, MD
___________________________________
Slide #28
___________________________________
Rifabutin and TB therapy
___________________________________
• Current recommendation: Decrease
rifabutin from 300 mg daily to 150 mg
thrice-weekly for boosted PIs
• CAUTION: rifabutin dose would then be
inadequate if patient stopped protease
inhibitor!
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #29
Another Caution: rifampin
resistance with PI/rifabutin
___________________________________
___________________________________
• 3 cases of relapse with acquired rifampin
resistant TB, while on boosted PI +
rifabutin 150 mg QOD TB regimen
• 7 of 10 patients on lopinavir/ritonavir and
rifabutin 150 QOD subtherapeutic rifabutin
AUC
___________________________________
___________________________________
___________________________________
___________________________________
– One acquired Rifamycin resistance
Higher dose of rifabutin may be
required with protease inhibitors
Jenny Avital CID, 2009, Boulanger CID 2010
___________________________________
Slide #30
New drugs in development for TB:
At last!
___________________________________
___________________________________
• ATP synthetase inhibitor (TMC-207):
___________________________________
– MDRTB 2 month culture conversion 48%
vs 9% with standard OBT (Diacon 2009)
___________________________________
• Cell wall inhibitors (PA824,OPC-67683,
SQ-109)
• Rifamycins
___________________________________
___________________________________
– given at higher doses (rifampin) or more
frequently (rifapentine)
• Fluoroquinolones
Burman CID 2010; 50(S3): S165
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
52
A. Luetkemeyer, MD
___________________________________
Slide #31
___________________________________
IRIS: 2 Distinct Syndromes
___________________________________
• Paradoxical IRIS: worsening of
tuberculosis despite effective TB
treatment, often seen in context of ART
initiation (10-40%)
• Unmasking IRIS: new presentation of
TB or OI after start of ART, often with
an atypical or exaggerated presentation
___________________________________
___________________________________
___________________________________
___________________________________
Meinjtes et al Lancet ID 2009
___________________________________
Slide #32
CD4+ cell count and
development of IRIS
___________________________________
___________________________________
% who developed IRIS
25
21
___________________________________
20
___________________________________
14
15
10
___________________________________
7
5
___________________________________
0
0
< 50
50-99
100-149
> 150
Baseline CD4 cell count
AIDS 2007;21:35-41
___________________________________
Slide #33
% who developed IRIS
Association between timing of
ART and risk of IRIS event
100
90
80
70
60
50
40
30
20
10
0
___________________________________
___________________________________
100
___________________________________
___________________________________
___________________________________
33
14
___________________________________
7
0
0-30
31-60
61-90
91-120
>120
Days from TB therapy to ART
AIDS 2007;21:35-41
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
53
A. Luetkemeyer, MD
___________________________________
Slide #34
Diagnosis & Management of TB IRIS
___________________________________
• Diagnosis of exclusion
• Usually not life threatening
• Treated symptomatically with NSAIDs and
pain medication
• Prednisone may be indicated for severe IRIS
___________________________________
– 1 mg/kg x 4-6 weeks, may require protracted
treatment
___________________________________
• Avoid ART interruption if at all possible
• IRIS should be discussed at time of ART
initiation as a possible complication of
therapy
___________________________________
___________________________________
___________________________________
___________________________________
Slide #35
Conclusions
___________________________________
• TB is an uncommon but serious
complication of HIV infection the US
• Vigilance is required to make the
diagnosis of TB in HIV- be wary of “ruled
out” TB
• Treatment of LTBI and use of ART are
excellent preventative measures
• Therapy of HIV-TB coinfection can be
complex, but ART should not be deferred
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #36
Acknowledgements
___________________________________
___________________________________
•
•
•
•
•
•
•
•
Diane Havlir
Padmini Srikantiah
Gabe Chamie
Jennifer Grinsdale
Masae Kawamura
Edwin Charlebois
Sharad Jain
Bill Burman
___________________________________
___________________________________
___________________________________
___________________________________
Thank you!
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
54
A. Luetkemeyer, MD
SUGGESTED READING
Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis
therapy. N Engl J Med. 2010;362:697-706.
Akolo C, Adetifa I, Shepperd S, Volmink J. Treatment of latent tuberculosis infection in HIV infected persons.
Cochrane Database Syst Rev. 2010;CD000171.
Boulanger C, Hollender E, Farrell K, et al. Pharmacokinetic evaluation of rifabutin in combination with lopinavirritonavir in patients with HIV infection and active tuberculosis. Clin Infect Dis. 2009;49:1305-1311.
Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J
Med. 2009;360:2397-2405.
Havlir DV, Getahun H, Sanne I, Nunn P. Opportunities and challenges for HIV care in overlapping HIV and TB
epidemics. JAMA. 2008;300:423-430.
Helb D, Jones M, Story E, et al. Rapid detection of Mycobacterium tuberculosis and rifampin resistance by use of
on-demand, near-patient technology. J Clin Microbiol. 2010;48:229-237.
Khan FA, Minion J, Pai M, et al. Treatment of active tuberculosis in HIV-coinfected patients: a systematic review
and meta-analysis. Clin Infect Dis. 2010;50:1288-1299.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
55
INVESTIGATIONAL DRUGS FOR HEPATITIS C VIRUS INFECTION
David L. Wyles, MD
___________________________________
___________________________________
___________________________________
Investigational Drugs for
Hepatitis C Virus Infection
___________________________________
___________________________________
David L. Wyles, MD
___________________________________
Assistant Professor of Medicine
University of California San Diego
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
4
3
1
1
___________________________________
2
2
Modified from Sarrazin and Zeuzem. Gastro 2010.
___________________________________
Slide #3
Outline
___________________________________
• Why do we need new therapies for HCV?
• The Hepatitis C virus
___________________________________
___________________________________
– Virology as it relates to novel therapies
• Major classes of novel inhibitors
___________________________________
– NS3 Protease Inhibitors (PIs)
– NS5B polymerase inhibitors
___________________________________
• Nucleoside/tide Inhibitors (NIs)
• Non-nucleoside Inhibitors (NNIs)
___________________________________
– Other inhibitor classes of interest
• Resistance
• The way forward
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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D. L Wyles, MD
___________________________________
Slide #4
Burden of HCV infection
___________________________________
___________________________________
AIm
ddpr
-oonv
erde
geim
ffice
ancsy
___________________________________
___________________________________
___________________________________
___________________________________
Improved
acceptance/tolerability
Interferon
free regimens
Davis GL. Gastro 2010.
___________________________________
Slide #5
___________________________________
Prospective follow-up of 23,441 HIV-infected patients
___________________________________
% mortality
Liver-related mortality: D.A.D. Study
Liver Death
RR by CD4
___________________________________
<50
16.1
___________________________________
50-99
11.5
100-199
7.1
200-349
4.0
350-499
1.7
>500
1.0
___________________________________
___________________________________
For each Ï1 log in HIV RNA there was a 27% increase in liver-related mortality
Arch Int Med 2006. Smith C for D:A:D Study Group. #145 16th CROI, 2009.
___________________________________
Slide #6
Limitations of Interferon Therapy
___________________________________
___________________________________
• Efficacy
– 40-45% SVR in HCV gt1
– Significantly lower in certain populations
___________________________________
• HIV-1 co-infection 20%
• African Americans 20-25%
___________________________________
• Tolerability
___________________________________
– Discontinuation rates of 10-15% for AEs alone
– Frequent growth factor use
___________________________________
• HIV/HCV
• Contraindications
• Acceptance
Modeled on Falck-Ytter Y. Annals 2002.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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D. L Wyles, MD
___________________________________
Slide #7
HCV life cycle
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
CyPA
Modified from Lindenbach and Rice. Nature 2005.
___________________________________
Slide #8
HCV genetic diversity
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Copyright Elsevier, 2005.
___________________________________
Slide #9
A tale of 3 viruses
HCV
HBV
10 virions/day
Error prone viral
polymerase
Viral quasi-species
Eradication possible (no
known latency)
10
virions/day
Error prone viral
polymerase
Viral quasi-species
Eradication not
possible?
(cccDNA)
Overlapping reading
frames
Slow infected cell
turnover
12
No overlapping reading
frames
Moderate infected cell
turnover
12-13
___________________________________
HIV
10
10 virions/day
Error prone viral
polymerase
Viral quasi-species
Eradication not possible?
(Integrated pro-viral
DNA)
Overlapping reading
frames
Rapid infected cell
turnover
INTERNATIONAL AIDS SOCIETY–USA
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
May 17, 2010
59
D. L Wyles, MD
___________________________________
Slide #10
NS3 Protease Inhibitors
___________________________________
• Necessary for replication
___________________________________
– Difficult target- geometry
• Cross-resistance
___________________________________
– Modeled on inhibitory
substrate cleavage products
– 2 chemotypes
___________________________________
___________________________________
• First class validated in the
clinic
___________________________________
– BILN-2061 (Lamarre D. Nature 2003.)
– Farthest in clinical trials
___________________________________
Slide #11
Phase 2b SVR data
Telaprevir
___________________________________
Boceprevir
___________________________________
6
___________________________________
SVR%
2
___________________________________
23
48
33
___________________________________
r4
8
BP
8
48
BP
R
48
PR
BP
R2
48
PR
4
T1
2/P
R4
8
T1
2/P
12
/P
R2
T1
2
T1
2
/P
R1
2
___________________________________
McHutchinson J. NEJM, 2009. Hezode C. NEJM, 2009. Kwo P. EASL 2009.
___________________________________
Slide #12
Resistance and tolerability
___________________________________
___________________________________
• Telaprevir
– Severe rash in 5-7% (0-1% PEG/RBV)
– additional ~0.5g/dL Hgb drop
– 7-10% viral breakthrough in TVR arms
___________________________________
___________________________________
• Nearly all with resistant virus (1a>>1b)
• 95% of relapsers with resistance mutations
___________________________________
• Boceprevir
___________________________________
– Anemia: 52-63% boceprevir arms (34% control)
– Dysgeusia: 21-44% boceprevir (9% control)
• Discontinuation rates higher in PI arms
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
60
D. L Wyles, MD
___________________________________
Slide #13
Overview of NS5B inhibitor sites
S282T
P495L5
S96T±N142T
NNI Site 1 (A)
(Thumb 1)
NI- Active Site
___________________________________
___________________________________
2’-C-methyl
4’-Azido
Benzimidazole
Indole
Tetracyclicindole
___________________________________
___________________________________
M414L/T1
NNI Site 3 (C)
(Palm 1)
M423T4
Thiophene
DihydropyroneP
yranoindole
VCH-759
VCH-222
M414I/V2
C316Y2,3
C445F2
NNI Site 4 (C)
(Palm 2)
Modified from Isabel Najera
Benzofuran
HCV-796
___________________________________
Benzothiadiazine
Acylpyrrolidine
Tetramic acids
Isothiazoles
GS 9190
ANA-598
ABT-333
NNI Site 2 (B)
(Thumb 2)
___________________________________
1)Lu, AAC 2007. 2)Howe, AAC 2008. 3) Villano, AASLD 2006
4) Le Pogam, J Virol 2006. 5)Tomei, J Virol2004.
___________________________________
Slide #14
Nucleoside Polymerase Inhibitors
2’-C-METHYL
___________________________________
4’-AZIDO
___________________________________
___________________________________
• R7128 (PSI-6130)
– -2.7log @ 1500mg BID
– -5.0log with PEG/RBV
• 85% RVR rate
– Phase2 trials (w/ PEG/R)
• 1000 and 1500mg BID
___________________________________
• R1626:
– -5.2log with PEG/RBV
– Hematologic toxicity
___________________________________
• 90% dose modifications
• 50% discontinued
___________________________________
– High relapse rate
– Halted in phase2
Lalezari J. EASL 2008. Pockros P. Hepatol 2008.
Uridine analogs
___________________________________
Slide #15
• PSI-7851: phosphoramidate prodrug of PSI-6206
___________________________________
– Uridine nucleotide analog (β-D-2'- deoxy-2'-fluoro-2'-C-methyluridine
___________________________________
5'-monophosphate)
• Improved activity and PK/PD compared to R7128/PSI-6130
___________________________________
– In phase2a (PSI-7977): 4 week combination with
PEG/RBV
___________________________________
___________________________________
___________________________________
Murakami E. 14thIntnlSymp HCV 2007.Furman P. AASLD 2008. Rodriguez-Torres M. AASLD 2009.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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___________________________________
Slide #16
Polymerase Inhibitors: NNIs
___________________________________
___________________________________
• HCV-796: palm 2
– EC50: 4.5-8.5 nM (1a and b)
– Rapid resistance emergence
– Halted in phase 2
• Hepatotoxicity
___________________________________
___________________________________
11/21(52%) C316Y
• ANA598: palm 1 (benzothiadiazine?)
___________________________________
– -2.9log at 800mg BID x 4d
– cross resistance to palm 2
___________________________________
• VCH-222: thumb 2
– -3.7log at 750mg BID
– Acquired by Vertex Pharmaceuticals
Villano S. AASLD 2006. Appleman JR. HepDart 2009. Vertex press release.
___________________________________
Slide #17
Other targets
___________________________________
Viral
• Entry inhibitors- preclinical for HCV
___________________________________
– ITX 5061 (Wong-Staal F. HCV Drug Discovery, San Diego 2009)
• NS4A antagonists- proof of concept
___________________________________
– ACH-806 halted after phase 1b (Pottage J. EASL 2007)
• NS4B antagonists- preclinical for HCV
___________________________________
– Clemizole (Einav S. Nat Biotech 2008.)
• NS5A-phase 1
___________________________________
Non-viral
___________________________________
• Thiazolides: Nitazoxanide
• Cyclophilin inhibitors
___________________________________
Slide #18
NS5A antagonists
___________________________________
• Phosphoprotein essential for HCV replication
___________________________________
– Dimerizes, binds RNA, Zn+2
___________________________________
• BMS-790052-Broad genotype coverage
• Likely QD dosing (C24hr> EC90 for 1mg dose)
___________________________________
___________________________________
1mg
10mg
100mg
___________________________________
Nettles R. AASLD 2008.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
62
D. L Wyles, MD
___________________________________
Slide #19
Protease Inhibitor Resistance
___________________________________
• In vivo
___________________________________
– rapid resistance during monotherapy
– preexisting mutants rare (<1%)
– cross-resistance: A156, R155
___________________________________
MK-7009
boceprevir
R155K
V36M/L
T54S
R155K
V170A
D168V/E
A156S/V
Q41R
S138T
R155K
___________________________________
___________________________________
D168V/T
R155K
___________________________________
– Subtype and resistance barrier
R
1a AGG
1b CGG
K
AAG
AAG
Sarrazin C, Hepatol 2007. Seiwert SD, EASL 2007. Schiff E, EASL 2008. Bartels DJ, JID 2008. Barnard RJO. HEPDart 2009.
___________________________________
Slide #20
Telaprevir Resistance
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Sarrazin C. Gastro 2007.
___________________________________
Slide #21
Nucleoside Resistance
___________________________________
• General Characteristics
___________________________________
– modest changes in EC50
– marked loss of replicative fitness
– consistent cross-genotype activity
– 2 distinct resistance patterns
___________________________________
___________________________________
___________________________________
___________________________________
McCown M. AAC 2008. Le Pogam S, AASLD 2007. Klumpp K. JBC, 2008.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
63
D. L Wyles, MD
___________________________________
Slide #22
Intrinsic Resistance to NNIs
___________________________________
• Analysis of 92 HCV-1 patient samples
___________________________________
– No baseline resistance to nucleosides
– 19/92 (21%) with resistance to NNIs
___________________________________
___________________________________
___________________________________
___________________________________
Le Pogam S. JAC 2008.
___________________________________
Slide #23
Getting rid of Interferon?
___________________________________
• INFORM1: IFN free combination therapy
___________________________________
– 14 d R7128 (NI) + R7227 (PI: ITMN-191)
– Highest dose 1000mg/900mg
___________________________________
• 63% undetectable at day 14
• 5.1log median decrease
– No resistance detected
500/100mg
___________________________________
___________________________________
R712
R722
8
7both
• Immunologic boost?
___________________________________
– ÏHCV specific CD4/CD8 responses with IFN
– Reversal of HCV induced immunosuppression
• Direct inhibitors may not
Gane EJ. 44th EASL 2009. Gane EJ. AASLD 2009. Liang Y. Gastro 2008
___________________________________
Slide #24
Modeling
___________________________________
• All single and 10% of double mutants are likely
to pre-exist in every patient
___________________________________
___________________________________
– Pre-existing triple mutants expected to be rare
___________________________________
(less than 1 in a million)
• Compensatory mutations will occur within
days of exposure (selection)
• For an all direct acting antiviral regimen a
barrier of 4 or more mutations is likely needed
___________________________________
___________________________________
Perelson A. CROI 2009.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
64
D. L Wyles, MD
___________________________________
Slide #25
Overview of NS3 Protease Inhibitors
___________________________________
___________________________________
• Potent inhibition (3-4log)
• Low resistance barrier
___________________________________
– Difficult target geometry
– Cross resistance
___________________________________
• Farthest along in clinical trials
___________________________________
– Phase 3 telaprevir and boceprevir
– Likely to be first new agent(s) approved
___________________________________
___________________________________
Slide #26
Overview of NS5B Inhibitors
___________________________________
• Nucleosides
___________________________________
– Cross genotype and subtype activity
– High resistance barrier
___________________________________
• 2 distinct resistance profiles
___________________________________
– Tolerability and side effect issues thus far
___________________________________
• Non-nucleosides
– Multiple target sites (at least 4)
– Variable activity across genotypes and subtypes
– Intrinsic resistance and low barrier
___________________________________
• cross resistance at palm sites
___________________________________
Slide #27
Studies in HIV+ subjects
___________________________________
___________________________________
• Phase 2 NS3 Protease Inhibitor trials
– Telaprevir
– Boceprevir
___________________________________
___________________________________
• A5269
– Pilot study of Nitazoxanide with PEG/RBV
___________________________________
___________________________________
All studies only in IFN naïve, gt1 subjects at this
point.
Clinicaltrials.gov
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
65
D. L Wyles, MD
___________________________________
Slide #28
Take home points
___________________________________
• HCV disease burden will increase over time
___________________________________
– Treatment impact requires efficacious and tolerable R x
– Current PEG/RBV therapy unlikely to have significant impact
___________________________________
• Initial regimens will be add-ons to PEG/RBV
– RBV appears essential when only a single novel agent is added
– Do not address contraindications/tolerability of IFN
___________________________________
• Rapid resistance development
___________________________________
– In particular for PI and NNIs
– Cross resistance major issue for PIs
___________________________________
• All direct acting antiviral (STAT-C) therapy?
– Modeling suggests a 4 resistance mutation barrier
– Are the immunomodulatory aspects of IFN needed for cure?
SUGGESTED READING
Hezode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV
infection. N Engl J Med. 2009;360:1839-1850.
Kuntzen T, Timm J, Berical A, et al. Naturally occurring dominant resistance mutations to hepatitis C virus
protease and polymerase inhibitors in treatment-naive patients. Hepatology. 2008;48:1769-1778.
Le Pogam S, Seshaadri A, Kosaka A, et al. Existence of hepatitis C virus NS5B variants naturally resistant to
non-nucleoside, but not to nucleoside, polymerase inhibitors among untreated patients. J Antimicrob Chemother.
2008;61:1205-1216.
McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV
genotype 1 infection. N Engl J Med. 2009;360:1827-1838.
Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients
treated with the protease inhibitor telaprevir. Gastroenterology. 2007;132:1767-1777.
Sarrazin C, Zeuzem S. Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection.
Gastroenterology. 2010;138:447-462.
Soriano V, Perelson AS, Zoulim F. Why are there different dynamics in the selection of drug resistance in HIV
and hepatitis B and C viruses? J Antimicrob Chemother. 2008;62:1-4.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
66
NEW ANTIRETROVIRAL DRUGS: EXPANDING OPTIONS FOR
INITIAL THERAPY
Steven C. Johnson, MD
___________________________________
___________________________________
New Antiretroviral Drugs:
Expanding Options for
Initial Therapy
___________________________________
Steven C. Johnson, MD
___________________________________
Professor of Medicine
University of Colorado School of Medicine
___________________________________
___________________________________
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
Case
___________________________________
32 yo male recently diagnosed with HIV infection.
___________________________________
• No significant past medical history apart from
___________________________________
depression, which is not active now.
___________________________________
• Initial lab testing:
–
–
–
–
CD4 744 cells/mm3,
HIV viral load 15,000 copies/mL,
Hep B surface antigen negative
Chemistry panel normal
___________________________________
___________________________________
• He is interested in ART and wants your opinion
on the best treatment regimen.
CDC Survey Update: Patterns of
Transmitted Drug Resistance (%)
20
18
16
14
12
10
8
6
4
2
0
___________________________________
Slide #3
___________________________________
___________________________________
1 5 .6
___________________________________
8. 1
6.1
4. 2
2 .2
Any
N N R TI
N R TI
PI
M DR
___________________________________
___________________________________
___________________________________
20 07 (N = 24 80 )
Common mutations: NNRTI: K103N, NRTI: M41L, PI: L90M
Kim D, et al. CROI 2010. Abstract 580.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
67
S. C. Johnson, MD
___________________________________
Slide #4
Targets for Antiretroviral Drugs
___________________________________
___________________________________
Integrase Inhibitors
Nucleus
Entry
Inhibitors:
Fusion, CCR5
___________________________________
Integrase
RNA
Protease
___________________________________
DNA
Reverse
Transcriptase
HIV
___________________________________
CD4+ T-Cell
Reverse Transcriptase Inhibitors:
NRTIs, NNRTIs
___________________________________
Protease
Inhibitors
___________________________________
Slide #5
Raltegravir
___________________________________
• Drug class: Integrase Strand-Transfer Inhibitor
___________________________________
• FDA approval in October 2007 for use in ARV-
___________________________________
• FDA approval in July 2009 for use in ARV-naïve
___________________________________
experienced patients
patients
___________________________________
• Usual dose: one 400 mg tablet twice daily
___________________________________
___________________________________
Slide #6
STARTMRK: Raltegravir vs. Efavirenz
(with TDF/FTC) at 96 Weeks
___________________________________
___________________________________
Randomized (1:1), double blind
___________________________________
RAL (400 mg BID)
+ TDF/FTC QD
+ EFV Placebo
N=245 (86.9%)
ART-naïve
subjects
(N=561)
___________________________________
96 wks
EFV (600 mg QHS)
+ TDF/FTC QD
+ RAL Placebo
N=232(81.7%)
___________________________________
___________________________________
• HIV RNA >5000 c/mL
• Susceptible to EFV, TDF and FTC
Lennox J, et al. 49th ICAAC; 2009. Abst. H-924b.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
68
S. C. Johnson, MD
STARTMRK Trial: Virologic
Results at 96 WEEKS
___________________________________
Slide #7
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Lennox J, et al. 49th ICAAC; 2009. Abst. H-924b.
___________________________________
Slide #8
Selected Side Effects Occurring in > 10%
of Subjects in Either Treatment Arm
___________________________________
___________________________________
Raltegravir Arm Efavirenz Arm
Diarrhea
17.8%
25.5%
Nausea
14.2%
12.8%
Fatigue
6.8%
11.7%
Dizziness
8.5%
37.2%
Headache
23.1%
25.2%
Abnormal Dreams
7.5%
13.1%
Skin rash
6.0%
12.1%
___________________________________
___________________________________
___________________________________
___________________________________
Lennox J, et al. 49th ICAAC; 2009. Abst. H-924b.
___________________________________
Slide #9
Mean Fasting Lipids (mg/dl) at Baseline
and at Week 96
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Change in lipids greater with efavirenz but total
cholesterol to HDL ratio similar in the two treatment arms
DeJesus E, et al. 17th CROI; 2010. Abst 150.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
69
S. C. Johnson, MD
___________________________________
Slide #10
Mutations in the Integrase Gene Associated
With Resistance to Raltegravir
___________________________________
___________________________________
___________________________________
___________________________________
• Raltegravir failure is associated with mutations at 3
___________________________________
distinct genetic pathways
• Raltegravir can also be assessed with a phenotypic
___________________________________
assay
Johnson et al, Topics in HIV Medicine, December 2009.
Updates available at www.iasusa.org
___________________________________
Slide #11
Drug Summary: Raltegravir
___________________________________
___________________________________
• Potency: comparable to efavirenz in large ARVnaïve trials
___________________________________
• Convenience: one pill twice daily with studies
___________________________________
looking at once daily dosing
• Side effects: favorable profile with fewer CNS
___________________________________
side effects than efavirenz
___________________________________
• Drug interactions: few dose modifications with
concomitant therapy
• Resistance: high level resistance can develop
with virologic failure
___________________________________
Slide #12
Case (Continued)
___________________________________
___________________________________
• The patient has heard about the dizziness with
efavirenz and wants to try an alternative regimen.
___________________________________
• He prefers once daily therapy.
___________________________________
• After discussion of different options, he expresses
interest in a protease inhibitor-based regimen.
___________________________________
• Initial lab testing:
–
–
–
–
___________________________________
CD4 744 cells/mm3,
HIV viral load 15,000 copies/mL,
Hep B surface antigen negative
Chemistry panel normal
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
70
S. C. Johnson, MD
___________________________________
Slide #13
Treatment-Naïve Patients:
Major Comparative Studies for Boosted PIs
___________________________________
• ARTEMIS: Darunavir/ritonavir versus
___________________________________
lopinavir/ritonavir
___________________________________
• CASTLE: Atazanavir/ritonavir versus
lopinavir/ritonavir
___________________________________
• GEMINI: Saquinavir/ritonavir versus
___________________________________
lopinavir/ritonavir
___________________________________
• KLEAN: Fosamprenavir/ritonavir versus
lopinavir/ritonavir
• ALERT: Fosamprenavir/ritonavir versus
atazanavir/ritonavir
___________________________________
Slide #14
Darunavir
___________________________________
• Drug class: Protease Inhibitor
___________________________________
• FDA approval in June 2006 for use in ARV-
___________________________________
• FDA approval in October 2008 for use in ARV-
___________________________________
experienced patients
naïve patients
___________________________________
• Usual dose in ARV-naïve patients: two 400 mg
___________________________________
tablets and one 100 mg ritonavir tablet once daily
___________________________________
Slide #15
ARTEMIS: Darunavir + Ritonavir Versus
Lopinavir/Ritonavir
___________________________________
___________________________________
• Prospective, randomized clinical trial
ART-naïve
Any CD4
BL VL > 5000
N = 689
___________________________________
DRV = RTV 600/100 mg BID
+ TDF/FTC QD
(N=343)
___________________________________
96 wks
LPV/r 400/100 mg BID
+ TDF/FTC QD
(N=346)
___________________________________
___________________________________
Mills A, et al. AIDS 2009;13:1679-1688
.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
71
S. C. Johnson, MD
___________________________________
Slide #16
ARTEMIS: Darunavir + Ritonavir Versus
Lopinavir/Ritonavir, HIV VL < 50 at 96 Wks
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Nelson M, et al. 16th CROI. Montreal, 2009. Abstract 575.
Mills A, et al. AIDS 2009;13:1679-1688.
___________________________________
Slide #17
ARTEMIS: Darunavir + Ritonavir Versus
Lopinavir/Ritonavir, HIV VL < 50 at 96 Wks
___________________________________
___________________________________
• Darunavir arm versus the Lopinavir arm
–
–
–
Lower rates of treatment discontinuation (4%
versus 9%)
Lower rates of grade 2-4 diarrhea (4% versus
11%)
Smaller median increases in triglycerides and
total cholesterol
___________________________________
___________________________________
___________________________________
___________________________________
• Protease inhibitor resistance not seen in either
treatment arm
Mills A, et al. AIDS 2009;13:1679-1688
___________________________________
Slide #18
Drug Summary: Darunavir
___________________________________
___________________________________
• Potency: superior to lopinavir-ritonavir in a large
ARV-naïve clinical trial
___________________________________
• Convenience: once daily dosing, two pills with
___________________________________
one ritonavir tablet
• Side effects: fewer GI side effects than some of
___________________________________
the older protease inhibitors
___________________________________
• Drug interactions: given with ritonavir, an inhibitor
of CYP 3A4 and 2D6; review concomitant agents
• Resistance: uncommon when used in ARV-naïve
patients
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
72
S. C. Johnson, MD
___________________________________
Slide #19
Case: Modification 1
___________________________________
32 yo male recently diagnosed with HIV infection.
___________________________________
• No significant past medical history apart from
___________________________________
depression which is not active now.
___________________________________
• Initial lab testing:
–
–
–
–
CD4 count 44 cells/mm3,
HIV viral load 715,000 copies/mL
Hep B surface antigen negative
Chemistry panel
___________________________________
___________________________________
• He is interested in ART and wants your opinion
on the best treatment regimen.
___________________________________
Slide #20
Antiretroviral Regimens Recommended
for Treatment-Naïve Patients
___________________________________
___________________________________
Preferred Regimens
NNRTI-based Efavirenz/tenofovir/emtricitabine (AI)
Regimen
PI-based
Atazanavir + ritonavir +
Regimens
tenofovir/emtricitabine (A1)
INSTI-based
Regimen
___________________________________
___________________________________
___________________________________
Darunavir + ritonavir +
tenofovir/emtricitabine (A1)
Raltegravir + tenofovir/emtricitabine
(A1)
___________________________________
DHHS Guidelines, 12/1/09, www.aidsinfo.nih.gov
___________________________________
Slide #21
ACTG 5257: A Study of Three NNRTI-Sparing
Antiretroviral Regimens for ARV-Naïve Subjects
___________________________________
___________________________________
• Eligibility:
–
–
–
Men and women age >18 years with HIV
Any CD4+ cell count
Plasma HIV-1 RNA >1000 copies/mL
___________________________________
___________________________________
• Randomized Treatment:
–
–
–
___________________________________
Arm A: Atazanavir + RTV + FTC/TDF
Arm B: Raltegravir + FTC/TDF
Arm C: Darunavir + RTV + FTC/TDF
___________________________________
• Duration:
–
Minimum 96 wks
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
73
S. C. Johnson, MD
___________________________________
Slide #22
Maraviroc
___________________________________
• Drug class: CCR5 antagonist, a type of entry
___________________________________
inhibitor
___________________________________
• FDA approval in August 2007 for use in ARV-
___________________________________
experienced patients
• FDA approval in November 2009 for use in ARV-
___________________________________
naïve patients
___________________________________
• Use limited to the subset of patients whose virus
only uses the CCR5 receptor
___________________________________
Slide #23
Tropism Assay
___________________________________
• Evaluates patient’s virus to determine if it is CCR5-
___________________________________
using, CXCR4-using, or both (dual or mixed)
___________________________________
• 44% of patients were screening failures for the
___________________________________
Motivate trials of treatment-experienced patients
because they had either dual or X4-using virus
___________________________________
• 80-90% of early, treatment-naïve patients will have
___________________________________
R5 virus only and be susceptible to CCR5
antagonists
• The tropism assay is necessary to determine if
individuals will respond to maraviroc
___________________________________
Slide #24
MERIT: Study Design
___________________________________
• Randomized double-blind 5-year study, unblinded after week 96
• ARV-naïve adults ? 16 years old with CCR5-tropic HIV-1 infection
• Maraviroc QD arm was included but discontinued at Week 16
___________________________________
Efavirenz (600 mg QD) + ZDV/3TC FDC
Randomization
1:1
Screening
(6 wks)
___________________________________
___________________________________
Maraviroc 300 mg BID + ZDV/3TC FDC
0
48 wk
First patient
visit
Nov 2004
Primary
analysis
___________________________________
96 wk
___________________________________
All patients received zidovudine/lamivudine but were
allowed to substitute an alternative NRTI for toxicity.
Heera J, et al. 5th IAS 2009;AbstractTUAB103.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
74
S. C. Johnson, MD
___________________________________
Slide #25
Merit: Percentage of Patients with
Undetectable HIV-1 RNA by Visit
100
100
< 400 copies/mL
___________________________________
___________________________________
< 50 copies/mL
90
90
80
70
72.6%
70.0%
60
80
70
69.0%
64.4%
60
50
50
40
40
30
30
20
EFV + AZT/3TC (N=361)
10
MVC BID + AZT/3TC (N=360)
20
10
___________________________________
___________________________________
___________________________________
___________________________________
0
0
24 8
16 24 32
Time (weeks)
40
48
24 8
16 24 32
Time (weeks)
48
40
Clumeck et al. 4th IAS 2007: Oral WESS104
___________________________________
MERIT Study Post-Hoc Analysis Using Slide #26
Enhanced Tropism Assay: Percent with HIV
RNA Level < 50 Copies/ml at Week 48
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Saag M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-1232a
.
___________________________________
Slide #27
MERIT Post-Hoc Analysis Using
Enhanced Phenotype Assay
___________________________________
___________________________________
Standard
Enhanced
Tropism Assay Tropism Assay
MVC
EFV
MVC
EFV
HIV VL < 50 copies/mL 65.3
69.3
68.5
68.3
HIV VL < 50 copies/mL 69.6
71.6
71.8
72.1
___________________________________
___________________________________
___________________________________
Baseline VL < 100K
HIV VL < 50 copies/mL
Baseline VL > 100k
59.6
66.0
64.2
62.5
CD4 Cell Gain
170
144
174
144
Saag M, et al. 48th ICAAC. Washington, DC, 2008. Abstract H-1232a
___________________________________
.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
75
S. C. Johnson, MD
___________________________________
Slide #28
MERIT: Most common virologic
correlate of failure through week 48
Any resistance
EFV resistance
MVC resistance
3TC resistance
MVC
(N = 29)
100
h
it
w
t
n
e
c
r
e
P
e80
c
n
a
t60
s
i
s
e40
R
77%
___________________________________
69%
___________________________________
60
45%
CCR5
n=4
38%
40
14%
20
N=
___________________________________
EFV
(N=13)
62%
62%
20
___________________________________
8%
CXCR4
n=9
0
___________________________________
ZDV resistance
100
80
___________________________________
0
18
13
18
4
10
9
5
1
Craig C, et al. 17th CROI 2010;Poster 536.
___________________________________
Slide #29
Drug Summary: Maraviroc
___________________________________
• Potency: comparable to efavirenz in a large RCT
___________________________________
• Convenience: usually one pill twice daily
___________________________________
• Side effects: postural hypotension in healthy
___________________________________
in ARV-naïve subjects
volunteer trials; dizziness, higher rate of URIs.
___________________________________
• Drug interactions: significant interactions with
multiple drugs which affect dosing
___________________________________
• Resistance: can include both emergence of
CXCR4 virus as well as maraviroc resistance
mutations. Need for tropism assay prior to use.
___________________________________
Slide #30
Case: Modification 2
___________________________________
32 year old male recently diagnosed with HIV
___________________________________
• No significant past medical history apart from
___________________________________
depression which is not active now.
• Initial lab testing:
–
–
–
–
___________________________________
CD4 744 cells/mm3,
HIV viral load 15,000 copies/mL,
Hep B surface antigen negative
Chemistry panel: serum creatinine 1.6 (creatinine
clearance is 55)
___________________________________
___________________________________
• He is interested in ART and wants your opinion
on the best treatment regimen.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
76
S. C. Johnson, MD
___________________________________
Slide #31
Some Recent Safety Concerns with
Antiretroviral Agents
___________________________________
___________________________________
Drug
Abacavir
Darunavir
Didanosine
Toxicity/Association
Myocardial infarction
Hepatitis
Non-cirrhotic portal hypertension
Myocardial infarction
Fosamprenavir
Myocardial infarction
Lopinavir/ritonavir Myocardial infarction
Saquinavir/ritonavir Prolonged QT interval
Tenofovir
Renal toxicity
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #32
Chronic Kidney Disease and Exposure to
ART in a Large Cohort: The EuroSIDA Study
___________________________________
• 6843 persons; 21,482 person-years of follow-up
___________________________________
• Chronic Kidney Disease defined as an estimated
___________________________________
GFR < 60 for persons > 60 at baseline or a
confirmed 25% decline in GFR for those starting
at < 60
___________________________________
___________________________________
• 225 (3.3%) progressed to CKD for an incidence of
1.1 per 100 person-years
___________________________________
• Incidence of CKD varied from 0.7 per 100 personyears in persons never on TDF to 2.4 per 100
person-years in persons on TDF for > 4 years
Kirk O, et al. 17th CROI 2010; Abstract 107LB.
___________________________________
Slide #33
Incidence Rate Ratio (IRR) per year of exposure
to ARVs on risk of Chronic Kidney Disease
Univariate
___________________________________
___________________________________
Multivariate
IRR/Yr
95% CI
P
IRR/Yr
95% CI
P
Tenofovir
1.32
1.21-1.41
<0.0001
1.16
1.06-1.25
<0.0001
Indinavir
1.18
1.13-1.24
<0.0001
1.12
1.06-1.18
<0.0001
Atazanavir
1.48
1.35-1.62
<0.0001
1.21
1.09-1.34
0.0003
___________________________________
Lopinavir
1.15
1.07-1.23
<0.0001
1.08
1.01-1.16
0.030
___________________________________
___________________________________
___________________________________
Other factors independently associated with CKD:
Older age, HTN, Hep C, lower baseline GFR, and CD4
Kirk O, et al. 17th CROI 2010; Abstract 107LB.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
77
S. C. Johnson, MD
___________________________________
17th Conference on Retroviruses and Slide #34
Opportunistic Infections, February 16-19, 2010,
San Francisco, California
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #35
TBR-652, a CCR5 Antagonist: Median Change
in HIV RNA Level in 10-day Monotherapy Trial
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Palleja S, et al. CROI 2010. Abstract 53.
___________________________________
Slide #36
Mean Change from Baseline in
HIV-1 RNA (log10 copies/mL)
S/GSK1349572: An Integrase Inhibitor
Dosing period
0.5
___________________________________
___________________________________
Follow-up period
0.0
___________________________________
-0.5
___________________________________
-1.0
___________________________________
-1.5
-2.0
___________________________________
2 mg
10 mg
50 mg
PBO
-2.5
1 2
(BL)
3
4
7
8
9 10 11
Once daily dose-ranging monotherapy
study. Maximal VL reduction of 2.46 log
Day
14
21
(FU)
Lalezari J, et al. Tuab105,
5th IAS, 2009
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
78
S. C. Johnson, MD
___________________________________
GS-9350–Boosted Elvitegravir + FTC/TDF Slide #37
Versus EFV/FTC/TDF in Naive Pts: % with HIV
RNA Level < 50 copies/ml (ITT M = F)
___________________________________
___________________________________
90% at 24 wks
83% at 24 wks
___________________________________
___________________________________
___________________________________
___________________________________
Cohen C, et al. CROI 2010. Abstract 58LB.
___________________________________
Slide #38
Status of Selected Investigational
Antiretroviral and Related Agents
Investigational Agent
Mechanism of
Action
TBR 652
CCR5 antagonist
Rilpivirine (TMC 278)
NNRTI
S/GSK1349572
Integrase inhibitor
Elvitegravir
Integrase inhibitor
Cobicistat (GS-9350)
pK booster
TDF/FTC/GSFixed-dose
9350/EVG (“Quad Pill”)
combination
___________________________________
___________________________________
Current
Status
Phase II
Phase III
Phase II
Phase III
Phase III
Phase III
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #39
Summary: Newer Uses for New
Antiretroviral Drugs
___________________________________
___________________________________
• The licensure of raltegravir, darunavir, and
maraviroc has added important new treatment
options for ARV-naïve patients.
___________________________________
• All 3 drugs appear to offer potency similar to
___________________________________
• Two of the drugs, raltegravir and darunavir, are
___________________________________
other first-line treatment regimens.
now part of the preferred initial regimens in the
DHHS treatment guidelines.
___________________________________
• Ongoing clinical trials will help to clarify the role of
these drugs in initial therapy.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
79
S. C. Johnson, MD
SUGGESTED READING
Heera J, Ive P, Botes M, et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96week results. [Abstract TUAB103.] 5th International AIDS Society Conference on HIV Pathogenesis, Treatment
and Prevention. July 19-22, 2009; Cape Town, South Africa.
Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus efavirenz-based
combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised
controlled trial. Lancet. 2009;374:796-806.
Lennox J, DeJesus E, Lazzarin A, et al. Raltegravir demonstrates durable efficacy through 96 weeks: Results
from STARTMRK, a Phase III study of raltegravir-based vs efavirenz-based therapy in treatment-naïve HIV+
patients. [Abstract H924b.] 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. September
12-15, 2009; San Francisco, CA.
Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive,
HIV-1-infected patients: 96-week analysis. AIDS. 2009;23:1679-1688.
Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily
lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive
HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646-655.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents
in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed January 29, 2010.
Saag M, Ive P, Heera J, et al. A multicenter, randomized, double-blind, comparative trial of a novel CCR5
antagonist, maraviroc versus efavirenz, both in combination with Combivir (zidovudine [ZDV]/lamivudine [3TC]),
for the treatment of antiretroviral naive subjects infected with R5 HIV-1: week 48 results of the MERIT study.
[Abstract WESS104.] 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and
Prevention. July 22-25, 2007; Sydney, Australia.
Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N
Engl J Med. 2009;361:2230-2240.
Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched, multicenter trial of
abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23:15471556.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
80
MONITORING AND PREVENTION OF NON-HIV-RELATED CONDITIONS
Stephen E. Follansbee, MD
___________________________________
___________________________________
___________________________________
Monitoring and Prevention of
Non-HIV-Related Conditions
___________________________________
___________________________________
___________________________________
Stephen E. Follansbee, MD
Associate Clinical Professor of Medicine
University of California San Francisco
Director of HIV Services
Kaiser Permanente Medical Center
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
Obvious statement: Patients with HIV are living longer.
Implication: We should be alert to risk and clinical
course of historically considered non-HIV-related
conditions.
•
•
•
•
___________________________________
___________________________________
___________________________________
Metabolic: Osteoporosis
Malignancy
Infections
Not going to address majority of
issues such as cardiovascular disease,
hepatic disease, renal disease
___________________________________
___________________________________
___________________________________
___________________________________
Slide #3
___________________________________
Case 1
___________________________________
• 58 yo man presents to ED having
fallen on wet landing down 4 stairs at
home while feeding his cat
• C/O right ankle pain
• Examination shows closed wound,
with foot at 45 degrees angulation
from ankle
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
81
S. E. Follansbee, MD
___________________________________
Slide #4
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #5
___________________________________
Case 1
___________________________________
• Current ART: TDV/3TC/ABV/LPV/R
for at least 6 years, having a variety of
regimens fail—mono-Rx, dual-Rx, and
NNRTIs based in past
• No family history of osteoporosis and
does not smoke nor use anabolic steroids
• Labs: HIV VL <75 copies/mL
CD4 520 cells/uL and 38%
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #6
___________________________________
Case 1, continued
___________________________________
•
•
•
•
•
SPINE BMD T-score =-2.5; Z-score =-2.9
TOTAL HIP BMD T-score =-2.0; Z= -1.5
NECK OF FEMUR T-score =-2.3; Z= -1.4
Vit D (25-OH) = 21 ng/mL (30-100)
Patient started on Vitamin D 2000 IU per
day, ALENDRONATE 70 MG PO Q week
• HIV regimen not changed
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
82
S. E. Follansbee, MD
___________________________________
Slide #7
___________________________________
Got Milk?
___________________________________
___________________________________
___________________________________
• Do we need to pay additional
attention to bones and vitamin D
for our adult patients with HIV?
Increased Fracture Rate
___________________________________
___________________________________
___________________________________
Slide #8
___________________________________
HIV Outpatient Study Patients (HOPS)
• Comparison:
– HOPS cohort (n=8456) vs National
Hospital Discharge Survey and National
Hospital Ambulatory Care Medical
Survey
– Adjusted for age and gender
Gender-adjusted rates of fracture
among adults aged 25-54 years
___________________________________
___________________________________
HOPS*
P = 0.01
• Fractures:
___________________________________
– 276 during median 4.8 yrs follow-up
• Risk factors for fractures
–
–
–
–
–
Age >47
Nadir CD4+ count <200
HCV co-infection
Diabetes
Substance use
___________________________________
NHAMCS-OPD
P = 0.32
___________________________________
• Conclusion: Fracture rates are higher
in HIV infected population and rate is
increasing with age
* Indirectly standarized using rates from NHAMCS-OPD data
17th CROI #128 Dao et al
Dao C, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 128.
Fracture Rates: HIV+ vs HIV-
___________________________________
Slide #9
___________________________________
• Women
– WIHS: no increase in fractures between HIV+ and HIV- women
(17th CROI #130 Yin et al.) with >5 years follow-up (1728 HIV+
and 663 HIV- women)
– Traditional risk factors associated with fractures:
___________________________________
___________________________________
• White, menopausal, renal failure, HCV infection
___________________________________
• Veterans
– Veterans Aging Cohort Study (VACS)
(17th
___________________________________
CROI #129 Womack et al.)
• 105,706 men (40,216 HIV+, 64,971 HIV-) with median follow-up
8 years
___________________________________
– HIV infection not independently associated with fragility
fracture overall
• Probably because of # traumatic wrist fractures in younger men
– If >50 years old HIV+, increase risk of fracture vs HIV• HR 1.37 after adjustment for traditional risk factors
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
83
S. E. Follansbee, MD
___________________________________
Slide #10
BMD changes with ART
___________________________________
• ART initiation associated with 2-6% loss in
BMD at 48-96 weeks
___________________________________
___________________________________
– regardless of regimen
• Osteoporosis 9.57/1000 PY
___________________________________
– incidence rate of 31.61/1000 PY in 2 years
___________________________________
• Initial loss tends to stabilize or improve after
48 weeks
• TDF often associated with larger changes
• Clinical significance is unknown
___________________________________
17th CROI 2010 #747 Cazanave et al.
___________________________________
Slide #11
A5224s: Mean Percent Change in Lumbar Spine BMD
(Week 192)
NRTI Component:
Primary Analysis
Lumbar Spine percent BMD
change from week 0 to 192
ABC/3TC
TDF/FTC
___________________________________
NNRTI/PI Component:
Secondary Analysis
EFV
___________________________________
ATV/r
___________________________________
___________________________________
___________________________________
P=0.004
___________________________________
P=0.035
• Hip BMD: Significantly greater percent decline with TDF/FTC
than ABC/3TC; not significant for NNRTI/PI
• No significant difference in fracture rate between arms
McComsey, G, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 106LB.
___________________________________
Slide #12
Vitamin D Deficiency
___________________________________
• Italian cohort: (17th CROI #751 Borderi et al.)
___________________________________
-- 852 pts contributing 1,498 vitD measures: 262 obtained before and 1,236
after the initiation cART
– ICONA cohort with pre and post-cART specimens, median 14 months
• Insufficient (<75 nmol/L) 54%
• Deficient (<30 nmol/L) 7%
– Associated with age, non-White and duration of ART
___________________________________
___________________________________
– Not dependent on NNRTI vs PI based regimen
___________________________________
• Swiss Cohort: (17th CROI #752 Mueller et al.)
___________________________________
-- 211 patients
– Deficient (<30nmol/l) more prevalent in spring (42%) vs fall (14%)
– Deficiency associated with NNRTI use and IDU
– TDV associated with increased 1,25(OH)D and higher alk phos level
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
84
S. E. Follansbee, MD
___________________________________
Slide #13
___________________________________
Vitamin D Deficiency, Continued
___________________________________
SUN cohort: (17th CROI #750 Dao et al.)
- 672 not on vitamin D evaluated
- 71.6% 25(OH)D deficient –
- Associated with efavirenz (aOR 1.98),
low UV exposure, Black/Latino
- Inversely associated with CKD,
RTN use
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #14
Vitamin D deficiency: Problems with our knowledge
___________________________________
___________________________________
• Different definitions for insufficiency and deficiency
(75 nM vs 30 nM)
• Uncontrolled for time of year and regional/seasonal
variation in HIV-ve 25(OH)-D levels
• Uncontrolled for anabolic steroid levels/replacement
• Often not controlled for supplementation, DEXA
scan, family history, activity, or diet
• Not clear of impact of vitamin D supplementation
and normalization of vitamin D levels on subsequent
risk for fracture
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #15
___________________________________
Case 2
___________________________________
• 45 yo man with “hemorrhoids”
• Diagnosed with AIDS based on PCP 9
months before as well as chronic persistent
Hepatitis B virus infection
• Responded well to TDV/FTC/EFV with
CD4 rise from 9 cells/2% to 170/14%
• Presented with 5 month history of perianal
discomfort, worsening in last 2 months
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
85
S. E. Follansbee, MD
___________________________________
Slide #16
___________________________________
Case 2
___________________________________
• Examination showed 3 cm perianal mass
from 6 o’clock to 9 o’clock with fissure,
ulceration, w/o regional lymphadenopathy
• Staging with biopsy and PET scan showed
Stage III SC CA of anus
• Has done well S/P 5FU/Mitomycin C and
XRT, with apparent complete remission at 4
years
Got cancer?
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #17
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Anal cancer and other “non-HIV”
related malignancies
___________________________________
Slide #18
Cancer Mortality in AIDS patients
___________________________________
#27 Simard et al. NCI
Population attributable risk among people with AIDS in the US
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
86
S. E. Follansbee, MD
___________________________________
Slide #19
Cancer Incidence in AIDS Patients
Cancer type
ƒ Study of cancer risk in
AIDS patients from 19802006 (n=372,364) in 15
cancer registries
ƒ Predominantly male
(79%),
non-hispanic black (42%),
MSM (42%)
ƒ Median age of 36 years at
the onset of AIDS
ƒ Cancer risk in years 3 - 5
after AIDS onset
increased for AIDS but
also Non-AIDS-defining
cancers
No cases
___________________________________
SIR
95% CI
___________________________________
___________________________________
AIDS-defining cancers
Kaposi sarcoma
3136
5321
5137 5511
Non-Hodgkin
lymphoma
3345
32
31 - 33
Cervical cancer
101
5.6
5.5 - 6.8
___________________________________
___________________________________
Non-AIDS-defining cancers
Anal cancer
219
27
24 - 31
Liver cancer
86
3.7
3.0 - 4.6
Lung cancer
531
3.0
2.8 - 3.3
Hodgkin
lymphoma
184
9.1
7.7 - 11
All non-AIDS
related cancers
2155
1.7
1.5 - 1.8
___________________________________
Simard E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 27.
N
___________________________________
Slide #20
Study Population
HIV+
HIV-
19,280
202,313
Mean age, years
40
40
Men, %
90
90
Men who have sex with men, %
75
--
Non-White, %
44
53
Smoking, %
39
23
Overweight/obese, %
39
41
Alcohol/drug abuse, %
19
8
Known hepatitis C, %
8
1
Known hepatitis B, %
5
1
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
17th CROI #28 Silverberg et al.
Infection-Related NADC Rates:
___________________________________
Slide #21
___________________________________
HIV+ vs. HIVHIV+
n rate†
HIVn rate†
___________________________________
Adjusted Hazard
Ratio (95% CI)‡
Any
215
267
284
28
Anal
140
174
21
2
74.9 (46.8-120.0)
___________________________________
5.9 (4.7-7.5)
Hodgkin’s
44
54
29
3
17.7 (10.6-29.7)
Oral cavity/pharynx
35
43
162
16
1.7 (1.1-2.5)
Liver
21
26
94
9
0.6 (0.4-1.0)
___________________________________
___________________________________
___________________________________
† Cases per 100,000 person-years;
‡ Adjusted for age, sex, tobacco use, overweight/obese, alcohol/drug abuse, hepatitis B/C
17th CROI #28 Silverberg et al.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
87
S. E. Follansbee, MD
___________________________________
Slide #22
___________________________________
Anal Cancer & HPV
___________________________________
• Summary of relative risk:
___________________________________
– VAMC: HR 31.9 (22.3-45.6; p <0.001)
___________________________________
• 31,315 HIV+ veterans (954 women) and
168,030 HIV- veterans (17th CROI #764 Chiao et al.)
___________________________________
– Kaiser: adjRR 74.9 (17th CROI #28 Silverberg et al)
– NCI: SIR 27 (17th CROI #27 Simard)
___________________________________
___________________________________
Slide #23
SAFETY & IMMUNOGENICITY OF THE QUADRIVALENT
HPV VACCINE IN HIV-INFECTED MEN
AIDS MALIGNANCY CONSORTIUM TRIAL 05
___________________________________
___________________________________
• 112 HIV+ men enrolled
___________________________________
– 236 screened;
• 123 excluded: 62+HGAIN histology;6+cytology
___________________________________
– CD4 >350/off cART or on cART with VL
<200 and CD4 >200
– No HGAIN by history or cytopathology
___________________________________
___________________________________
• Endpoint:
– Seroconversion of HPV type-specific
antibodies who were PCR –/Ab – at baseline
17th CROI #1015 Wilkin et al.
___________________________________
Slide #24
SAFETY & IMMUNOGENICITY OF THE QUADRIVALENT
HPV VACCINE IN HIV-INFECTED MEN
AIDS MALIGNANCY CONSORTIUM TRIAL 05
___________________________________
___________________________________
• Safe
• Titers 40-50% lower than historic HIVmales and females.
• Predictors of Geometric Mean Antibody
Titer rise
___________________________________
___________________________________
___________________________________
– Higher baseline GMT (appr. 15-40% +ve at
baseline
– + cART --- higher anti-HPV 16/18 titers
– Baseline HPV 11/16 (and marginally 6) anal
DNA detection --- lower GMT
___________________________________
17th CROI #1015 Wilkin et al.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
88
S. E. Follansbee, MD
___________________________________
Slide #25
SAFETY & IMMUNOGENICITY OF THE QUADRIVALENT
HPV VACCINE IN HIV-INFECTED MEN
AIDS MALIGNANCY CONSORTIUM TRIAL 05
___________________________________
___________________________________
• HPV DNA detected at week 28
– HPV 6: 9%
• Persistent Infection: 44%
• Incident Infection: 5%
___________________________________
– HPV 11: 9%
___________________________________
• Persistent Infection: 75%
• Incident Infections: 3%
– HPV 16: 13%
___________________________________
• Persistent Infection 58%
• Incident Infection 2%
– HPV 18: 3%
___________________________________
• Persistent Infection 29%
• Incident Infection 1/93 (1%)
• HGAIN or HSIL at week 28: 12%
• Progression from No AIN: 10%
• Progression from low-grade AIN: 22%
17th CROI #1015 Wilkin et al.
___________________________________
Slide #26
___________________________________
Another cancer case
___________________________________
• 66 yo man seroconverted to HIV 7/09
with 5 day history of low grade fever
and transient exanthem, all occurring
about 4 weeks after he was informed by
SF DPH that he was exposed to
chlamydia
• Initial CD4 467/uL and 25% and HIV
VL 31,000 copies/mL
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #27
___________________________________
Another cancer case, continued
___________________________________
• Noted to have a 6-7 wk hx of intermittent chest
pain and R hip and upper leg pain
• Enrolled in OPTIONS project and followed off
ART
• Hx: 60 PYH tobacco - so quit after HIV diagnosis
• Within 6 months, while still contemplating ART,
developed increased R upper leg pain, despite Dx
and Rx for L4/5 and L5/S1 mod-severe foraminal
stenosis with multi-level disc disease and
protrusions seen on MRI
• A bone scan was done
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
89
S. E. Follansbee, MD
___________________________________
Slide #28
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #29
Infection-Unrelated NADC Rates
HIV+
n rate†
Any
Melanoma
Kidney
Blood
Lung
Colorectal
Prostate
HIVn rate†
___________________________________
Adjusted Hazard
Ratio (95% CI)‡
___________________________________
373
465
3,418
341
1.3 (1.1-1.4)
___________________________________
48
59
359
35
1.8 (1.3-2.5)
16
20
126
12
1.4 (0.8-2.4)
___________________________________
16
20
141
14
1.3 (0.8-2.3)
51
63
342
34
1.2 (0.9-1.7)
41
51
410
40
1.1 (0.8-1.6)
74
101
1,195
131
0.8 (0.6-1.0)
___________________________________
___________________________________
† Cases per 100,000 person-years;
‡ Adjusted for age, sex, tobacco use, overweight/obese, alcohol/drug abuse, hepatitis B/C
17th CROI #28 Silverberg et al.
___________________________________
Slide #30
HIV Infection and Lung Cancer
ƒ VA-Cohort
(3,707 HIV-positive
patients)
___________________________________
___________________________________
___________________________________
26 cases per
10,000 pt-yrs
ƒ Predominantly
male (98%),
white (43%)
___________________________________
15 cases per
10,000 pt-yrs
___________________________________
ƒ Median age of 47 years
___________________________________
ƒ Lung cancer risk factors
- smoking and drug
abuse more often
among HIV+
- Similar rates of COPD
Sigel K, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 30.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
90
S. E. Follansbee, MD
___________________________________
Slide #31
___________________________________
Pneumonia
___________________________________
• 52 y.o. man admitted with 2 week history of
“sniffles” and URI symptoms, followed by
two days of fever, chills, cough, and
pleuritic chest pain with diarrhea
• Diagnosed with HIV in 2004; last CD4 375
(nadir 264) and HIV VL appr 7,000 copies
by history 4 mo PTA; to start ART in about
2 weeks
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #32
___________________________________
Pneumonia continued
___________________________________
• Hx remarkable for hyperlipidemia and
coronary artery disease, S/P stenting in
2008 on ASA, clopidogril, rosuvastatin, and
niacin
• Vaccinations up to date (pneumococcal
2008; seasonal influenza and H1N1
influenza 2009
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #33
___________________________________
Pneumonia continued (3)
___________________________________
• Admission white blood cell count 4,400
(70% PMN; 14% BANDS); lactic acid 2.3
mmol/L, LDH 692 (nl <680 U/L),
creatinine 1.79 mg/dL
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
91
S. E. Follansbee, MD
___________________________________
Slide #34
___________________________________
H1N1: Can we protect with vaccination?
___________________________________
• Response rates:
___________________________________
– titer >40 to single i.m. vaccination lower than in HIV(53-69% vs. 70-100%) (#805LB Bickel; #806LB Tebas et al.)
– compared to 70% response for seasonal flu vaccine
___________________________________
(#811 Sharif et al.)
• Response better if
___________________________________
– previous titer
• 53% if no titer vs 90% if titer >40 (Tebas only),
___________________________________
– younger
– higher CD4
– VL BLQ
___________________________________
Slide #35
Vaccination for Pneumococcus
Background
___________________________________
___________________________________
Pneumococcal polysaccharide vaccine (PPSV)
___________________________________
23-valent
Covers 90% of types found in bacteremia
B-cell dependent response
Not licensed for infants under 60 months
___________________________________
___________________________________
Pneumococcal vaccine conjugate (PCV)
7-valent
Covers 80% of strains found in infant pneumococcal
bacteremia
Links bacterial capsule sugars to protein of diphtheria toxin
Combining with protein leads to enhanced t-cell response
___________________________________
___________________________________
Slide #36
___________________________________
Pneumococcal Vaccination
___________________________________
• Background:
___________________________________
– HIV+ ass. with 6-8x risk of pneumonia and 40x
risk of invasive pneumococcal disease
compared to HIV-
___________________________________
___________________________________
• PPV-23 vaccine response variable &
dependent on cART
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
92
S. E. Follansbee, MD
___________________________________
Slide #37
Does 23-valent polysaccharide
pneumococcal vaccine work?
___________________________________
___________________________________
• CDC ASD project (Adult/Adolescent
Spectrum of HIV Disease)
• 23,255 persons analyzed 1998-2003 with
47.5% vaccination rate and 52,040 PY
follow-up
• Looked at all cause pneumonia (excluding
PCP, tuberculosis and candidiasis)
• 1148 cases with pathogen specified; 25.9%
S. pneumoniae
___________________________________
___________________________________
___________________________________
___________________________________
Teshale EH et al. Vaccine 2008;26:5830-34.
___________________________________
Slide #38
RR all-cause pneumonia and death,
controlled
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Teshale EH et al. Vaccine 2008;26:5830-34.
___________________________________
Slide #39
Effectiveness of 23-polyvalent
pneumococcal vaccine: another view
___________________________________
___________________________________
• Case control study in Brazil
• 79 cases of invasive S. pneumoniae disease
and 242 controls, matched for CD4 cell
count (87% bacteremic pneumonia)
• Duration between vaccination and infection
(cases) or enrolment (controls): 35-988 days
• 40/47 (85%) isolates were serotype included
in 23-valent vaccine
___________________________________
___________________________________
___________________________________
___________________________________
Veras M et al. BMC Inf Dis 2007;7:119-26
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
93
S. E. Follansbee, MD
___________________________________
Effectiveness of 23-polyvalent Slide #40
pneumococcal vaccine: another view
Characteristic
Crude OR
Adj OR
Pulmonary Tb ever
2.54 (1.43 –
4.50)
1.95 (0.95 –
4.03)
Close contact with child
2.81 (1.53 –
5.14)
3.22 (1.60 –
6.48)
Injection drug use
2.79 (1.48 –
5.28)
2.43 (1.13 –
5.23)
Previous hospitalization
with pneumonia
2.80 (1.58 –
4.98)
2.23 (1.16 –
4.30)
Antiretroviral therapy at the
last visit
0.26 (0.14 –
0.49)
0.27 (0.12 –
0.59)
Had received pneumococcal
polysaccharide vaccine
0.37 (0.19 –
0.72)
0.82 (0.38 –
1.77)
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Veras MA SM et al. BMC Inf Dis 2007;7:119-25.
___________________________________
Slide #41
___________________________________
PCV-7 for revaccination?
___________________________________
• PCV-7 conjugate vaccine (4,6B, 9V, 14,
18C, 19F, 23F)
• Military study, 5 centers
___________________________________
___________________________________
– Vaccinating HIV+ 3-8 yrs after initial PPV-23
vaccination
– Initial IGG responses better in PCV-7 (n=121)
compared to PPV23 (n=73)
___________________________________
___________________________________
• Response difference not durable at 180 days and
neither as robust as HIV- (n=25)
Crum-Cianflone et al 17th CROI, #810
___________________________________
Slide #42
___________________________________
African Study with PCV-7
___________________________________
• 23-PPV pneumococcal vaccine not
recommended in Africa
• Double-blind, placebo-controlled study for
secondary prophylaxis after surviving
invasive S. pneumoniae disease
• Baseline: CD4 median 212,214; ARV 14.6,
11.9%, HIV VL median 4.9, 4.5 cases (248)
and placebo controls (248)
• Median follow-up 1.2 years
___________________________________
___________________________________
___________________________________
___________________________________
French N et al. NEJM 2010;362:812-22
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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S. E. Follansbee, MD
___________________________________
Slide #43
African Study with PCV-7, Continued
___________________________________
• Results: 67 episodes of invasive
pneumococcal disease in 52 patients (98 per
1000 PY), with 40.6% of cases and 43.6%
of controls on ART + TMP-SMX “at any
time” during follow-up
• 24 episodes (35.8%) caused by vaccine
serotypes or 6A
• Adjusted HR 0.26 (.08-.78) for vaccine
serotype/6A; w/o difference in HR for any
invasive pneumococcal disease (.80); any
pneumonia (.71) or death (1.24)
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
French N et al. NEJM 2010;362:812-22
___________________________________
Slide #44
___________________________________
Conclusion
___________________________________
• We need a better vaccine against
invasive pneumococcal disease
worldwide!
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
95
INFLUENZA NOW: AN UPDATE ON THE H1N1 EPIDEMIC
Robert T. Schooley, MD
___________________________________
___________________________________
Influenza Now: An Update on
the H1N1 Epidemic
___________________________________
___________________________________
___________________________________
Robert T. Schooley, MD
___________________________________
Professor and Vice Chair
Department of Medicine
University of California San Diego
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
H1N1: 2009 and Beyond
___________________________________
___________________________________
• Where did it come from?
• What accounted for the differences in its
clinical manifestations?
• Is it worse in people with HIV?
• How should it be treated?
• How can it be prevented?
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #3
H1N1
___________________________________
• Patient 1
___________________________________
– March 30, 2009: 10 year old boy with asthma > onset of fever, cough and vomiting
– April 1: Urgent care visit; nasal swab taken as
part of an evaluation of a diagnostic device
sensitivity and specificity study
– Recovered uneventfully
– Reference laboratory: Influenza A but negative
by PCR for H1 or H3 hemagglutinin sequence
– April 15: CDC identifies the isolate of being of
swine origin
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
97
R. T. Schooley, MD
___________________________________
Slide #4
H1N1
___________________________________
• Patient 2
___________________________________
– March 28, 2009: healthy 9 year old girl in
Imperial County presents with cough and fever
– Nasopharyngeal swab obtained as part of a
respiratory surveillance project
– Treated with amoxicillin and recovered
– Naval Health Research Center made an
Influenza A call but could not identify the
subtype
– April 17: sent to CDC where it was found to be
nearly identical to the San Diego case
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #5
Epidemiologic Surveillance Launched
___________________________________
• Two new isolates not epidemiologically linked
• State and local health departments asked to
look for Influenza A virus that could not be
subtyped
• Case definition:
___________________________________
___________________________________
___________________________________
___________________________________
– Acute febrile respiratory illness
– Residence in or travel to place where S-OIV had
been identified
– Contact with an ill person from these areas within
7 days
___________________________________
___________________________________
Slide #6
Diagnostic Algorithm
___________________________________
___________________________________
• Rapid antigenic test or culture identified as
Influenza A
___________________________________
___________________________________
• PCR for seasonal A, B, H1, H3 and avian H5
___________________________________
___________________________________
• If negative -> send to CDC
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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___________________________________
Slide #7
Epidemiology of Initial 642 US Cases
___________________________________
___________________________________
• 18% had Mexican travel within 7 days of
illness
• Four clusters in returning American school
and University students
___________________________________
___________________________________
– South Carolina, Texas, Delaware, and New York
___________________________________
___________________________________
___________________________________
Slide #8
Rapid Rise in Cases
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Novel Influenza Team, NEJM, 2009
___________________________________
Slide #9
Molecular Organization of Influenza
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
99
R. T. Schooley, MD
Slide #10
Genes and Proteins of Influenza A
1
2
3
4
5
6
7
8
PB1
PB2
___________________________________
RNA transcriptase
Cap binding,
endonucleolytic cleavage
PA
Acidic polymerase
Unknown
HA
Hemagglutinin
Viral attachment, fusion
NA
Neuraminidase
Cleaves SA from membrane
NP Nucleoprotein
RNA encapsidation,
transcription regulation
M
Matrix
Surrounds core, nuclear
transport control
M2
Matrix 2
Ion channel
NS1
NEP
Basic polymerase 1
Basic polymerase 2
Nonstructural protein
Nuclear export
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Antagonizes Ifn α
Transport of RNP to
cytoplasm
Slide #11
Influenza: Life Cycle
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Hayden, NEJM, 2006
Slide #12
Drift and Shift
___________________________________
HA
HA
___________________________________
NA
NA
___________________________________
___________________________________
Drift
___________________________________
HA
HA
___________________________________
NA
NA
___________________________________
Shift
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May 17, 2010
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R. T. Schooley, MD
Slide #13
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #14
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #15
H1N1: 2009 and Beyond
___________________________________
___________________________________
___________________________________
• Where did it come from?
• What accounted for the differences in its
clinical manifestations?
• Is it worse in people with HIV?
• How should it be treated?
• How can it be prevented?
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
101
R. T. Schooley, MD
Slide #16
Rapid Rise in Cases
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Novel Influenza Team, NEJM, 2009
Slide #17
Demography
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Novel Influenza Team, NEJM, 2009
Slide #18
Presenting Symptoms
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Novel Influenza Team, NEJM, 2009
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May 17, 2010
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R. T. Schooley, MD
Slide #19
Severe Outcomes
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Novel Influenza Team, NEJM, 2009
Slide #20
CDC Nationwide Study of 272
Hospitalized Patients with H1N1 Sw
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Jain, NEJM, 2009
Slide #21
Percentage of Hospitalized Patients
with H1N1 Sw by Age Group
___________________________________
___________________________________
Percent of Patients in Age Range
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Age Range, Years
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
103
R. T. Schooley, MD
Slide #22
Influenza-Attributed Age Specific
Death Rates in the US (1990 – 1999)
___________________________________
___________________________________
Deaths per 100,000 Population
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Age Group
Thompson, JAMA 2003
Slide #23
Underlying Conditions in
Hospitalized Patients
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Jain, NEJM, 2009
Slide #24
Radiographic Abnormalities Upon
Admission
___________________________________
___________________________________
___________________________________
• 249 patients with chest X-ray: 100 (40%) had
evidence of pneumonia
___________________________________
– Of those with pneumonia:
___________________________________
• median age: 27 years
• Underlying condition: 66%
___________________________________
• Radiographic findings
___________________________________
– Bilateral infiltrates: 66 patients
– Unilobular infiltrate: 26 patients
– Multiple lobes in one lung: 6 patients
– Data not available: 2 patients
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
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R. T. Schooley, MD
Slide #25
Characteristics of Patients Who
Were Admitted to ICU
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Jain, NEJM, 2009
Slide #26
___________________________________
Treatment of Hospitalized Patients
___________________________________
• Antiviral therapy: 75%
___________________________________
– Most received oseltamivir
– Some received zanamivir
– Some received combination therapy with one of
the above plus amantidine or rimantidine
___________________________________
___________________________________
___________________________________
• When started
– Before admission: 9%
– On admission: 44%
– Within 48 hours of admission: 31%
– Later than 48 hours after admission: 15%
___________________________________
Jain, NEJM, 2009
Slide #27
___________________________________
Treatment of Hospitalized Patients
___________________________________
• Antibiotic therapy: 79%
___________________________________
–
–
–
–
–
Median of 2 antibiotics (range 1 – 7)
Ceftriaxone: 94 patients
Azithromycin: 84 patients
Vancomycin: 56 patients
Levofloxacin: 47 patients
___________________________________
___________________________________
___________________________________
• When started
–
–
–
–
Before admission: 15%
On admission: 59%
Within 48 hours of admission: 22%
Later than 48 hours after admission: 4%
___________________________________
Jain, NEJM, 2009
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
105
R. T. Schooley, MD
Slide #28
Outcomes of Hospitalized Patients
___________________________________
___________________________________
• 253 of 272 (93%) patients were discharged
• 19 (7%) died - all had been in the ICU on a
respirator.
___________________________________
___________________________________
– Median age 26.
– Median time from illness onset to death: 15 days
– 13 had underlying medical conditions
___________________________________
___________________________________
• Neurological diseases – 21%
• Asthma or COPD – 16%
• Pregnancy – 16%
___________________________________
– All received antiviral therapy but none in 48 hours
of illness. Median time to start: 8 days
Jain, NEJM, 2009
Slide #29
H1N1: 2009 and Beyond
___________________________________
___________________________________
___________________________________
• Where did it come from?
• What accounted for the differences in its
clinical manifestations?
• Is it worse in people with HIV?
• How should it be treated?
• How can it be prevented?
___________________________________
___________________________________
___________________________________
___________________________________
Slide #30
___________________________________
Why Was H1N1 So Lethal in 1918?
___________________________________
• New strain of influenza with which there was
little human experience
• Bacterial superinfection likely played a major
role
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Morens, J Infect Dis 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
106
R. T. Schooley, MD
Slide #31
Evidence for Bacterial Superinfection
___________________________________
___________________________________
___________________________________
___________________________________
Bronchopneumonia
___________________________________
Alveolar Infiltration
___________________________________
___________________________________
Intra-alveolar Hemmorhage
Repair and Scarring
Histology
Morens, J Infect Dis 2008
Slide #32
Evidence for Bacterial Superinfection
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Bacterial Cultures from Lung Tissue at Autopsy
Morens, J Infect Dis 2008
Slide #33
Evidence for Bacterial Superinfection
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Blood and Pleural Fluid Cultures
Morens, J Infect Dis 2008
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
107
R. T. Schooley, MD
Slide #34
Influenza Pathogenesis Sequence
With Superinfection
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #35
Why Have We Seen Less of a Contribution
of Bacterial Superinfection in More
Recent Pandemics?
___________________________________
___________________________________
___________________________________
• Antibiotics?
• Different living conditions?
• Vaccination?
___________________________________
___________________________________
___________________________________
– Influenza
– Bacterial infection
___________________________________
• Antiviral Drugs?
• Different viral tropism for pulmonary
receptors?
Slide #36
Pathogenesis of H5N1
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
108
R. T. Schooley, MD
Slide #37
Comparison of HA’s
___________________________________
___________________________________
Viet 04 H5
Duck H5
___________________________________
___________________________________
___________________________________
1918
___________________________________
___________________________________
Slide #38
Hemagglutinin Carbohydrate Binding
Preferences
___________________________________
___________________________________
___________________________________
___________________________________
• Avian: galactose to sialic acid α 2,3 linkage
• Human: galactose to sialic acid α 2,6
linkage
___________________________________
___________________________________
___________________________________
Slide #39
Distribution of α 2,3 and α 2,6 Linkage Sialic
Acids in Human Respiratory Tissue
___________________________________
___________________________________
___________________________________
___________________________________
Nasal Mucosa
Sinus
Bronchus
___________________________________
___________________________________
___________________________________
Bronchiole
Alveoli
Human: α 2,6 binding lectin
Avian: α 2,3 binding lectin Shinya, Nature, 2006
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
109
R. T. Schooley, MD
Slide #40
Differential Sialylation Preferences Likely Account for
the Differences in Clinical Manifestations
___________________________________
___________________________________
___________________________________
H3N2, Seasonal H1N1
___________________________________
HPAI H5N1
___________________________________
___________________________________
Pandemic H1N1
___________________________________
Slide #41
H1N1: 2009 and Beyond
___________________________________
___________________________________
• Where did it come from?
• What accounted for the differences in its
clinical manifestations?
• Is it worse in people with HIV?
• How should it be treated?
• How can it be prevented?
___________________________________
___________________________________
___________________________________
___________________________________
Slide #42
• Culture
___________________________________
Diagnosis
___________________________________
___________________________________
___________________________________
– Grows on MDCK or monkey kidney cells
– Sensitive but takes several days
___________________________________
• “Rapid” tests
___________________________________
– Several available that detect Influenza A antigen
– developed with seasonal H1N1 antigen so only
35 – 60% sensitive for H1N1 Sw
• PCR
___________________________________
___________________________________
– New gold standard. Rapid but must be done in
reference laboratory
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
110
R. T. Schooley, MD
Slide #43
Prevention
___________________________________
___________________________________
___________________________________
• Not possible to prevent infection in general
population by quarantine or other draconian
measures: it is already here
• Focus areas
___________________________________
___________________________________
– Healthcare settings
– Institutional settings
___________________________________
___________________________________
• Primarily schools
• Military populations
Slide #44
Treatment: Two Approved
Influenza Drug Classes
___________________________________
___________________________________
Neuraminidase
Inhibitors:
Zanamivir and
Oseltamivir
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Adamantanes:
Ion
channel
Blockers:
Amantidine
Amantidine
And
and rimantidine
Rimantidine
Slide #45
Anti-Influenza Drugs
Seasonal H1N1
Pandemic H1N1
H3N2
Influenza B
Adamantanes
S
R
R
R
___________________________________
___________________________________
___________________________________
Neuraminidase
Inhibitors
R
S
S
S
___________________________________
___________________________________
___________________________________
___________________________________
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
111
R. T. Schooley, MD
Slide #46
Benefits of Therapy are Relatively
Modest in Uncomplicated Influenza
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #47
Reduction in days of illness with treatment
with oseltamivir in comparison with delayed
treatment at 48 hr
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Aoki, F. Y. et al. J. Antimicrob. Chemother. 2003 51:123-9
Slide #48
Day of onset of antibiotic therapy for lower
respiratory tract complications in oseltamivir and
placebo recipients with influenza infection
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Kaiser, L. et al. Arch Intern Med 2003;163:1667-72.
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
112
R. T. Schooley, MD
Slide #49
Who is At Higher Risk for
Complications from H1N1 Sw?
___________________________________
___________________________________
• Children less than 5 years old
• Persons aged 65 years or older
• Children and adolescents (less than 18 years) who are receiving longterm aspirin therapy and who might be at risk for experiencing Reye
syndrome after influenza virus infection
• Pregnant women
• Adults and children who have chronic pulmonary, cardiovascular,
hepatic, hematological, neurologic, neuromuscular, or metabolic
disorders
• Morbidly obese
• Adults and children who have immunosuppression (including
immunosuppression caused by medications or by HIV)
• People with arthritis
• Residents of nursing homes and other chronic-care facilities
___________________________________
___________________________________
___________________________________
___________________________________
807LB: Elevated 2009 H1N1 Antibody Titers and Serologic Evidence of Infection in
Slide #50
HIV-infected and –uninfected Women: A Sero-study conducted March 1 – September 30, 2009
Keri N. Althoff, Stephen J. Gange, Gerald B. Sharp, Maryna Eichelberger, Jin Gao, Marshall Glesby,
Mary Young, Ruth Greenblatt, Audrey French and Howard Minkoff for the Women’s Interagency HIV Study (WIHS)
•
?4-fold increase: “infection”
Jan
Feb
Mar
Apr
May June
___________________________________
?1:40: “elevated titer”
N=96 (5%)
(n=67(5%) HIV+,
n=29 (5%) HIV-)
N=139 (8%)
(n=97 (7%) HIV+,
n=42 (8%) HIV-)
July
Aug
Sept
Oct
Nov
Dec
2008 specimens
(or 2007 if 2008 was unavailable)
Jan
Feb
Mar
Apr
May June
July
Aug
___________________________________
___________________________________
Women’s Interagency HIV study (WIHS) is an ongoing, prospective cohort study of
HIV-infected and similar uninfected women in 5 US cities; est. 1994.
Hemagglutination inhibition assays for 2009 H1N1 antibody titers on stored serum
•
___________________________________
___________________________________
___________________________________
Sept
2009 Sero-survey
N=1854 (n=1307 HIV+, n=542 HIV-)
___________________________________
___________________________________
807LB: Elevated 2009 H1N1 Antibody Titers and Serologic Evidence of Infection in
Slide #51
HIV-infected and –uninfected Women: A Sero-study conducted March 1 – September 30, 2009
Keri N. Althoff, Stephen J. Gange, Gerald B. Sharp, Maryna Eichelberger, Jin Gao, Marshall Glesby,
Mary Young, Ruth Greenblatt, Audrey French and Howard Minkoff for the Women’s Interagency HIV Study (WIHS)
___________________________________
• Infections found in March (HIV+: 7/48, HIV-: 2/24)
• Overall infection rate: 17.1 [14.0, 20.9] infections per 100 person years
• Infection rates did not differ by HIV status
HIV-uninfected
HIV-infected
IR
18.0 [12.5, 25.9]
16.8 [13.2, 21.3]
___________________________________
aIRR
REF
0.91 [0.58, 1.42]
___________________________________
• Infection rates differed by age, as seen in other studies of 2009 H1N1
<30 years
30-<50 years
50-<65 years
?65 years
IR
27.0 [14.5, 50.1]
14.5 [11.0, 18.9]
21.4 [15.0, 30.4]
17.4 [4.3, 39.5]
___________________________________
aIRR
REF
0.33 [0.20, 0.55]
0.41 [0.24, 0.70]
0.40 [0.09, 1.72]
___________________________________
___________________________________
• Infection rates differed by HIV-1 RNA in the year prior to the pandemic
?80 copies/mL
80-<10,000 copies/mL
?10,000 copies/mL
IR
23.6 [18.1, 30.8]
7.2 [3.5, 15.2]
8.4 [3.5, 20.1]
___________________________________
aIRR
REF
0.31 [0.13, 0.73]
0.37 [0.12, 1.16]
Ongoing, prospective cohort studies are an important resource!
INTERNATIONAL AIDS SOCIETY–USA
May 17, 2010
113
R. T. Schooley, MD
___________________________________
New Swine Origin Influenza A (H1N1)v in HIV-Infected
Patients During the 2009 Outbreak in Mexico City
___________________________________
Campos-Loza*, Soto Ramírez, Sierra-Madero, Crabtree-Ramirez, Lourdes-Guerrero, Arturo Galindo, Moreno-Espinoza, Ruiz-Palacios.
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Male
Median age
Years
(min-max)
HIV-VL <400
copies RNA/mL
Median CD4+
cells/mcl
(min-max)
CD4+ <200
cells/mcl
Active HIV infected patients at INCMNZ (n=1017)
896 (88%)
39 (18-79)
810 (80%)
408 (3-1957)
163 (16%)
Patients with nasopharyngeal swab sample (n=20)
p=NS
p=NS
p=NS
p=NS
p=NS
2009 Influenza A H1N1 cases (n=11)
10 (91%)
47 (20-59)
9 (82%)
432 (3-945)
___________________________________
2 (18%)
NS: non-significant
Case
Site of Acquisition
2009 H1N1
severity
Pneumonia
Mechanical ventilation
support
Respiratory Coinfectant
Agent
CD4+ T count
(cells/mcL)
Outcome
1
Community acquired
Mild
No
-
-
336
Survived
2
Community acquired
Mild
No
-
-
627
Survived
3
Community acquired
Mild
No
-
Rhinovirus
431
Survived
4
Community acquired
Mild
No
-
-
351
Survived
5
Community acquired
Mild
No
-
-
579
Survived
6
Community acquired
Mild
No
-
-
569
Survived
7
Community acquired
Mild
No
-
-
399
Survived
8
-
Community acquired
Mild
No
-
434
Survived
9
Community acquired
Moderate
Yes
No
-
88
Survived
10
Community acquired
Moderate
Yes
No
Diseminated C. immitis
945
Survived
11
Nosocomial acquired
Severe
Yes
Yes
PCP/CMV
3
___________________________________
___________________________________
___________________________________
___________________________________
Died
17th CROI P-154
___________________________________
New Swine Origin Influenza A (H1N1)v in HIV-Infected
Patients During the 2009 Outbreak in Mexico City
___________________________________
Campos-Loza*, Soto Ramírez, Sierra-Madero, Crabtree-Ramirez, Lourdes-Guerrero, Arturo Galindo, Moreno-Espinoza, Ruiz-Palacios.
Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
• 2009 H1N1: main cause of ARI in HIV-infected subjects (55%).
___________________________________
• 2009 H1N1 was the only Influenza virus identified.
• No major differences in clinical presentation, severity and survival between HIV-infected and
HIV-non-infected.
___________________________________
• Hospitalized 2009H1N1/HIV cases were in advanced HIV stages, mainly with other pulmonary
OI.
___________________________________
• The fatal case was a nosocomial acquired 2009 H1N1 in a late presenter with an active
PCP/CMV pneumonitis.
___________________________________
• All mild Influenza cases occurred in patients who had CD4 > 300 cells/mm3.
•
•
20% of a sample of HIV patients reported having an ARI in a telephonic survey but only a small fraction
look for medical care.
A low rate of anti-influenza vaccination was found, mainly related to failure to prescribe the vaccine by
HCW
___________________________________
A high rate of viral control and low rate of AIDS in our cohort could contribute to avoid additional
severe cases of 2009 H1N1
17th CROI P-154
___________________________________
802LB Epidemiologic curve and Demographics
___________________________________
Number of patients
___________________________________
___________________________________
___________________________________
___________________________________
Calendar week
DEMOGRAPHICS
Men (n, %)
Age (years) (mean, SD)
Active smoker (n, %)
Travel / contacts (n, %)
Co-morbidities (n, %)
HIV+ (n=56)
44 (79)
44 ± 8
30 (54)
4 (7%)
8 (14)
HIV- (n=168)
74 (44)
39 ± 15
21 (13)
40 (24)
103 (61)
___________________________________
P value
0.0001
0.0153
0.0001
0.0066
0.0001
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R. T. Schooley, MD
Slide #55
802LB
Clinical characteristics and Outcome
ALL PATIENTS
Days from onset (mean, SD)
Delayed influenza A (H1N1) diagnosis (n, %)
Pneumonia (X-ray lung infiltrate) (n, %)
Respiratory failure (PaO2 <60 mmHg) (n, %)
Days at hospital (mean, SD)
?1 day at hospital (n, %)
Complications after admission (n, %)
Anti-influenza therapy (oseltamivir) (n, %)
Antibiotic therapy (n, %)
Clinical recovery <1 week (n, %)
Evolution to death (n, %)
HIV+ (n=56)
2.8 ± 1.6
4 (7)
5 (9)
5 (9)
1.1 ± 2.3
15 (27)
7 (13)
53 (95)
29 (52)
43 (77)
0 (0)
HIV- (n=168)
3.2 ± 2.0
21 (13)
42 (25)
36 (21)
2.0 ± 3.4
70 (42)
18 (11)
119 (71)
82 (49)
94 (56)
3 (2)
P Value
NS
NS
0.0105
0.0362
NS
0.0469
NS
0.0003
NS
0.0056
NS
PATIENTS WITHOUT CO-MORBIDITIES
Delayed diagnosis (n, %)
Pneumonia (n, %)
Respiratory failure (n, %)
Days at hospital (mean, SD)
?1 day at hospital (n, %)
Complications after admission (n, %)
Anti-influenza therapy (oseltamivir) (n, %)
Antibiotic therapy (n, %)
Clinical recovery <1 week (n, %)
Evolution to death (n, %)
HIV+ (n=48)
4 (8)
5 (10)
3 (6)
1.0 ± 2.2
11 (23)
7 (15)
45 (94)
24 (50)
37 (77)
0 (0)
HIV- (n=65)
10 (15)
14 (22)
6 (9)
1.2 ± 3.4
16 (24)
7 (11)
26 (40)
21 (32)
46 (71)
3 (5)
P Value
NS
NS
NS
NS
NS
NS
0.0001
NS
NS
NS
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #56
___________________________________
Oseltamivir Resistance
___________________________________
– Oseltamivir resistant H1N1 Sw influenza viruses
have been detected here and there but so far no
evidence of transmitted drug resistance. All
resistant viruses had the characteristic mutation
at position 274/275 associated with resistance.
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #57
Prophylaxis and Therapy
___________________________________
___________________________________
___________________________________
• Amantidine and rimantidine are universally
ineffective
• Oseltamivir
___________________________________
___________________________________
– Less active vs: H1 neuraminidase
– Some recommend using twice the usual dose for
treatment or prophylaxis: 150 mg twice daily
___________________________________
• Zanamivir
___________________________________
– Inhaled; therefore no systemic levels
– 2-5 mg inhalations twice daily
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Slide #58
The Vaccine
___________________________________
___________________________________
• Hemagglutinin differs from previously
circulating H1N1 strain by 20%
• Neuraminidase varies by 70%
• Minimal de novo protection from current
vaccine
___________________________________
___________________________________
___________________________________
___________________________________
– Demonstrated clearly in Australian experience
___________________________________
• “Seasonal” influenza vaccinations ready since
early September
• Initial S-OIV vaccine available now with more
to come
Slide #59
Neutralizing Antibody Titers to
H1N1 S-OIV by Decade of Birth
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Hancock K et al. NEJM ,2009
Slide #60
Seroconversion after
H1N1 Sw Vaccine
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Greenberg, NEJM, 2009
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Slide #61
Serological Responses with
H1N1 Sw Vaccine
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Greenberg, NEJM, 2009
Study design
Slide #62
___________________________________
___________________________________
___________________________________
Table 1. Baseline characteristics (n=120)
Study design
Age median years (IQR)
46 (40-53)
Male, n(%)
85 (71%)
___________________________________
Race n(%)
Vaccine dosing (days):
HIV (+)
Individuals
with an
indication for
vaccination
D0
IM injection of Novartis
H1N1 vaccine(15µg)
(n=120)
Immunogenecity evaluations (days):
% with HIV RNA load <400
D21-28
___________________________________
2 (2%)
81 (68%)
7 (6%)
30 (25%)
Asian/pacific
Black
Hispanic/Latino
White
___________________________________
92%
84%
% with BLQ HIV RNA
502 (307-640)
Current CD4 median (IQR)
(cells/µL)
___________________________________
131 (37-253)
CD4 Nadir median (IQR)
(cells/µL)
Duration of undetectability
(months)
26 (12-65)
Slide #63
Figure 1. Reverse Cumulative Distribution Curves of HIA Antibody Titters
___________________________________
___________________________________
• All enrolled participants
completed both visits
• Thirty of the 120 (25%)
subjects had antibody HIA
titers greater than 1:40 at
baseline.
• 69% of subjects achieved
antibody levels above 1:40
(week 3)
• Among the 89 participants
without evidence of previous
exposure to H1N1, only 61%
(95% CI, 51-71%) develop
protective titers
___________________________________
Reverse Cumulative Distribution
Curves of HIA Antibody Titers
ge
ta
n
e
cr
e
P
100
90
80
70
60
50
40
30
20
10
0
___________________________________
Week 3
___________________________________
Week 0
___________________________________
___________________________________
Dilution
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R. T. Schooley, MD
Slide #64
High Priority Groups for H1N1
Vaccination
___________________________________
___________________________________
___________________________________
• pregnant women
• persons who live with or provide care for infants
aged <6 months (e.g., parents, siblings, and daycare
providers)
• health-care and emergency medical services
personnel
• persons aged 6 months--24 years
• persons aged 25--64 years who have medical
conditions that put them at higher risk for influenzarelated complications
___________________________________
___________________________________
___________________________________
___________________________________
Slide #65
Influenza H1N1 SOIV and HIV
Infection
___________________________________
___________________________________
• Currently no evidence that it is more severe in
HIV-1 infected persons in most cases
• Shedding of virus likely more prolonged –
especially in those with advanced disease
• Vaccine
___________________________________
– No evidence that it is harmful in terms of HIV
activation
– Less likely to be efficacious in those with low CD4
cell counts or high viral loads
– Killed virus vaccine (traditional egg based vaccine)
rather than inhaled vaccine should be used
___________________________________
___________________________________
___________________________________
___________________________________
Slide #66
WHO Global Influenza Update
March 2010
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
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R. T. Schooley, MD
Slide #67
Influenza Activity: March 28- April 3
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #68
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
The End
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MANAGEMENT OF TREATMENT-EXPERIENCED PATIENTS
Eric S. Daar, MD
___________________________________
___________________________________
___________________________________
Management of TreatmentExperienced Patients
___________________________________
___________________________________
Eric S. Daar, MD
___________________________________
Professor of Medicine
David Geffen School of Medicine
University of California Los Angeles
___________________________________
The International AIDS Society–USA
___________________________________
Slide #2
Current challenges facing treatmentexperienced patients
___________________________________
___________________________________
• Adherence
• Drug resistant virus
• On therapy
• Off therapy
• Persistent low-level viremia
• Poor immune reconstitution
• Drug toxicity
• Comorbid conditions
• Coinfection
• Metabolic, renal, hepatic dysfunction
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #3
Patient NL
___________________________________
• 43-year-old man to ED with 4 weeks fever, DOE,
cough and weight loss
• HIV-infected since 2000 with intermittent ARVs in
Texas prior to stopping all meds and moving to Los
Angeles approximately 12 months ago
• Lowest CD4 in past was 25 cells/uL
• Patient states last CD4 was 290 cells/uL but not
aware of previous viral loads
• ARVs changed several times in the past; having
received at least ZDV, 3TC, d4T, TDF, EFV, NFV,
LPV/r and most recently DRV/r
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___________________________________
___________________________________
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E. S. Daar, MD
___________________________________
Slide #4
Patient NL
___________________________________
• Physical exam:
___________________________________
• T-103.2o F, BP 110/60, HR 110 regular, RR 25,
RA pulse ox 88% (RA ABG 7.45/30/55)
___________________________________
• Dyspneic, thin, oral thrush, onychomycosis
___________________________________
• Labs:
___________________________________
• HCT 32%, normal liver enzymes, creatinine
0.9 mg/dL, LDH 722 Units/L
• CD4 12 cells/uL
___________________________________
• Started on TMP/SMX and prednisone
___________________________________
Slide #5
Immediate vs. Deferred ARVs
during Acute OI: ACTG 5164
___________________________________
___________________________________
___________________________________
HR = 0.53 Immediate versus Deferred
95% CI : 0.30, 0.92, p=0.023
___________________________________
___________________________________
___________________________________
Zolopa AR, et al. PLoS ONE; 2009;4:e5575.
___________________________________
Slide #6
BENCHMRK-1 and -2: VL <50 c/mL at
Week 24 by Specific Agents in OBR
___________________________________
___________________________________
% of pts with HIV RNA <50 c/mL at Week 24* by selected ARTs in OBT
Enfuvirtide
Darunavir
+
+
+
-
Mean Δ from BL
N
74%
23
45
-
+
-
+ First use in OBT
- Not used in OBT
___________________________________
82%
50%
24
-
___________________________________
80%
44
78
___________________________________
68%
48
48%
191
___________________________________
62%
22%
91
0
20
40
60
80
100
* Virological failures carried forward; ARTs = antiretroviral therapies
Cooper DA, et al. NEJM 2008; 359:355-365.
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E. S. Daar, MD
___________________________________
Slide #7
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
Slide #8
Patient NR
___________________________________
• 25-year-old AA man diagnosed with HIV and
Candida esophagitis
___________________________________
• CD4 count- 20 cells/uL
• HIV RNA- 476,000 c/mL
___________________________________
• History of HTN
• No drug or alcohol use
• Labs normal except CrCl- 61 mL/min, 1+
proteinuria, ALT- 80-100 U/L
• HCV-negative
• HBsAg+, HBeAg-neg, HBV DNA >1 million
copies/mL
• Baseline HIV drug resistance GT- wild type
___________________________________
___________________________________
___________________________________
___________________________________
Slide #9
IAS-USA Guidelines: When to Initiate
Therapy in Treatment-Naïve Patients
Measure
Symptomatic HIV disease
Recommendation
___________________________________
___________________________________
Comments
Therapy recommended
___________________________________
Asymptomatic HIV disease
CD4 <350/µL
Therapy recommended
CD4 >350/µL
Therapy should be
considered and decision
individualized
Correlates of faster HIV disease
progression:
• >100,000 RNA copies/mL
___________________________________
___________________________________
• >100/µL CD4 decline/year
Coexistent conditions
influenced by uncontrolled
viremia:
• Presence of, or high risk for,
cardiovascular disease
• Active HBV or HCV coinfection
• HIV-associated nephropathy
___________________________________
Hammer SM, et al. JAMA 2008; 300: 555-570
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E. S. Daar, MD
Slide #10
When to Start: 2009 DHHS Guidelines
CD4+ Cell Count
Recommendation
ƒ CD4+ cell count < 350 cells/mm³
ƒ CD4+ cell count 350-500 cells/mm³
ƒ Start ART
___________________________________
___________________________________
ƒ Start ART*
ƒ Panel
ƒ CD4+ cell count > 500 cells/mm³
___________________________________
___________________________________
divided†
Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell
Count
___________________________________
ƒ History of AIDS-defining illness
ƒ Certain acute opportunistic infections
ƒ Pregnancy
ƒ HIVAN
ƒ HBV coinfection when HBV treatment is indicated
ƒ CD4+ count decline > 100 cells/mm3 per yr
ƒ HIV-1 RNA > 100,000 copies/mL
___________________________________
___________________________________
*Panel divided: 55% strongly recommend and 45% moderately recommend. †50% favor
initiating therapy at this stage. 50% view initiating therapy at this stage as optional.
US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/Guidelines.
Slide #11
HBV Antiviral Therapy: Cross
Resistance
L
73
V1
L1
80
M
A1
81
V
A1
84
G
0
S2
2I
M2
04
I
V
04
M2
___________________________________
___________________________________
N2
36
T
___________________________________
V
50
M2
LAM
___________________________________
ETV
___________________________________
LdT
___________________________________
FTC
___________________________________
ADV
TDF
Slide #12
___________________________________
Patient NN
___________________________________
• Factors associated with poor immune
reconstitution
___________________________________
___________________________________
– Starting with lower CD4 cells
– Older age
– HIV-2 coinfection
– HTLV coinfection
– Other coinfections
– Suboptimal virologic response
– Select antiretrovirals (e.g. ZDV, EFV?)
___________________________________
___________________________________
___________________________________
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E. S. Daar, MD
Slide #13
IL-2 Therapy: SILCAAT and ESPRIT
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, et al. NEJM 2009; 361:1548-59.
Slide #14
IL-2 Therapy: SILCAAT and ESPRIT
___________________________________
___________________________________
___________________________________
SILCAAT, IL-2 + ARV
___________________________________
SILCAAT, ARV only
___________________________________
ESPRIT, ARV only
ESPRIT, IL-2 + ARV
___________________________________
___________________________________
INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee, et al. NEJM 2009; 361:1548-59.
Slide #15
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
___________________________________
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Slide #16
Patient RLB
___________________________________
___________________________________
• 48-year-old male diagnosed with HIV in 1984 (CD4220 cells/uL)
• Antiretroviral experience through 2006
___________________________________
___________________________________
• All NRTIs, EFV and all PIs except DRV and TPV
• Mostly viremic throughout
– 2006-2007 ZDV/3TC/ABC + TDF + LPV/r
• CD4+: 250 cells/uL, RNA 5-10,000 copies/mL
• Historical GTs have shown multiple TAMs, protease
mutations and NNRTI mutations- 98G, 108I, 181C
– 2007 resistance testing
• GT- resistant to all drugs
• PT- resistant to all except intermediate to DRV/r
___________________________________
___________________________________
___________________________________
SUGGESTED READING
Hammer SM, Eron JJ, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the
International AIDS Society-USA panel. JAMA. 2008;300:555-570.
Hirsch MS, Gunthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008
recommendations of an International AIDS Society-USA panel. Clin Infect Dis. 2008;47:266-285.
Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.
Kim HH, Daar ES. Newer antiretroviral agents and how to use them. Curr HIV/AIDS Rep. 2009;6:55-62.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents
in HIV-1-infected adults and adolescents. Department of Health and Human Services. December 1, 2009; 1-161.
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed January 29, 2010.
INTERNATIONAL AIDS SOCIETY–USA
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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 17, 2010
127
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
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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 1-16 (eg, IL-2 indicates
interleukin-2)
INTERNATIONAL AIDS SOCIETY–USA
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129
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
Entry inhibitor (fusion, CCR5, or CXCR4)
Fusion inhibitor
Integrase inhibitor
Maturing inhibitor (gag processing, assembly)
nRTI
nucleoside (or nucleotide) analogue
reverse transcriptase inhibitor
NNRTI
nonnucleoside analogue reverse
transcriptase inhibitor
ntRTI
nucleotide analogue reverse
transcriptase inhibitor
PI
protease inhibitor
INTERNATIONAL AIDS SOCIETY–USA
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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***
apricitabine*
atazanavir
bevirimat*
brecanavir*
capravirine***
darunavir
delavirdine
dexelvucitabine*
†
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
DRV, TMC114
DLV
DFC, D-D4FC
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
PI
NNRTI
nRTI
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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