SEARCH 011: Peripheral Reservoir of HIV DNA in Monocytes Pivotal to Cognition in HIV
Version 1.4, April 20,, 2011
PI: V. Valcour
CLINICAL STUDY PROTOCOL
SEARCH 011: Peripheral Reservoir of HIV DNA in Monocytes Pivotal to Cognition in HIV
PROTOCOL TEAM
Version 1.4Page 1 of 28
SEARCH 011: Peripheral Reservoir of HIV DNA in Monocytes Pivotal to Cognition in HIV
Version 1.4, April 20,, 2011
PI: V. Valcour
Principal Investigator:
Victor Valcour MD
Assistant Professor
Memory and Aging Center, UCSF
350 Parnassus Avenue, Suite 905
San Francisco, CA 94143-1207
email:
phone: 415-476-1895
fax: 415-476-4800
Co-Investigators
Jintanat Ananworanich MD,PhDProtocol Clinical Director
Chief, SEARCH
Thai Red Cross AIDS Research Center
104 Rajdamri Rd. Tower 2, 2nd floor
Pathumwan, Bangkok 10330
email:
phone: 011-66-2-254-2566-9
fax: 011-66-2-254-2567
Silvia Ratto-Kim PhD, Protocol Laboratory Director
Associate Researcher, HACRP and
United Sates Military HIV Research Program
Henry M. Jackson Foundation
13 Taft Court. Rockville MD 20850
email:
phone : +1301 251-8354
fax : +1301 762-4177
Victor DeGruttola PhD, Protocol Biostatistician
655 Huntington Avenue
Building II, Room 439A
Boston, Massachusetts, USA 02115
email:
phone: 617 432-2820
Mark deSouza PhD, MPH, Associate Laboratory Investigator
Department of Retrovirology, USAMC-AFRIMS
315/6 Rajvithi Rd, Bangkok, Thailand
email:
phone: 011-66-2-644-4888 ext 1515
fax: 011-66-2-644-4824
Yotin Chinvarun MD, Associate Clinical Investigator
Division of Neurology, Department of Medicine
Phramongkutklao Hospital
315/6 Rajvithi Rd.
Bangkok 10400, Thailand
email:
phone: 66 02-354-7660
Pasiri Sithinamsuwan MD
Neurologist, Co-investigator
Division of Neurology, Department of Medicine
315/6 Rajvithi Rd.
Bangkok 10400, Thailand
Email:
Phone: 01-847-6034
Nittaya Phanuphak MD, Associate Clinical Investigator
Thai Red Cross AIDS Research Centre
104 Rajdamri Road, Pathumwan
Bangkok 10330, Thailand
email:
phone: 66 2 253 0996
fax: 66 2 253 0998
Thep Chalermchai MD, Co-investigator
SEARCH
Thai Red Cross AIDS Research Center
104 Rajdamri Rd. Tower 2, 2nd floor
Pathumwan, Bangkok 10330
email:
phone: 011-66-2-254-2566-9
fax: 011-66-2-254-2567
Bruce Shiramizu MD, Associate Laboratory Investigator
Professor, HACRP, University of Hawaii
3675 Kilauea Avenue, Leahi Hospital
Honolulu, Hawaii USA 96816
email:
Alexandra Schuetz, Ph.D.
Research Scientist
Department of Retrovirology, USAMC-AFRIMS
315/6 Rajvithi Rd, Bangkok, Thailand
email:
phone: 011-66-696-2700 x 4912
fax: 011-66-2-644-4824
External Consultants
Bruce Brew MBBS MD FRAC
Department of Neurology
Level 4 Xavier Building, St. Vincent's Hospital
Victoria St, Darlinghurst
Sydney, Australia 2010
email:
David Clifford MD
Seay Professor of Clinical Neuropharmacology in Neurology
Washington University School of Medicine
Neurology, Box 8111
660 South Euclid
Saint Louis, Missouri, USA 63110
email:
Sukalaya Lerdlum MD
Department of Radiology, Chulalongkorn Hospital and SEARCH
Thai Red Cross AIDS Research Center
104 Rajdamri Rd. Tower 2, 2nd floor
Pathumwan, Bangkok, Thailand 10330
email:
Robert Paul PhD
Assistant Professor, University of Missouri
Behavioral Neuroscience/Neuropsychology
One University Blvd., 412 Stadler Hall
St. Louis, Missouri, USA 63121
email:
Pom Sailasuta PhD
Spectroscopy Unit, Huntington Medical Research Institute, 10 Pico Street
Pasadena, California, USA 91105
email:
Cecilia Shikuma MD
Professor, Hawaii AIDS Clinical Research Program
University of Hawaii
3675 Kilauea Avenue, Leahi Hospital
Honolulu, Hawaii USA 96816
email:
Clinical Monitor
Somchai Sriplienchan, MD, MPH
Chief of disease prevention
Department of Retrovirology, USAMC-AFRIMS
315/6 Rajvithi Rd, Bangkok, Thailand
E-Mail:
Phone Number: 011-66-2-644-4888 ext 1505
Fax number: 011-66-2-644-4824
Study Nurse
Ms.Somporn Tipsuk RNClinical nurse
South East Asia Research Collaboration with Hawaii
(SEARCH)
Thai Red Cross AIDS Research Center
104 Rajdamri Rd. Tower 2, 2nd floor
Pathumwan, Bangkok 10330
email:
phone: 011-66-2-254-2566-9
fax: 011-66-2-254-2567
Version 1.4Page 1 of 28
SEARCH 011: Peripheral Reservoir of HIV DNA in Monocytes Pivotal to Cognition in HIV
Version 1.4, April 20,,2011
PI: V. Valcour
SPONSOR AND FUNDING AGENCY
National Institute of Neurological Disorders and Stroke (NINDS)/NIH
Bethesda, Maryland, USA.
STUDY CLINICAL SITES
Phramongkutklao Medical Center
Chulalongkorn University including the Thai Red Cross AIDS Research Center
SCHEMA
Title
SEARCH 011: Peripheral Reservoir of HIV DNA in Monocytes Pivotal to Cognition in HIV
Participants
Sixty HIV+ individuals stratified by pre-HAART peripheral blood mononuclear cell (PBMC) HIV DNA level (30 above or equal to 5000 copies/106 cells and 30 below 5000 copies/106 cells). All HIV-subjects will be ARV-naïve and intend to start ARV in the month following enrollment.
Primary Objectives
(1)To determine the long-term relationship between cognition and HIV DNA in circulating PBMCs and monocytes (CD14+ PBMCs) among patients initiating HAART for the first time
(2)To define the longitudinal relationships between CD14+ HIV DNA and: (a) cerebrospinal fluid (CSF) biomarkers of immune activation (neopterin, MCP-1, and IL-6), (b) CD14+ supernatant markers of immune activation (MCP-1 and IL-6), and (c) increased myoinositol/creatine ratio by MRS
(3)To prospectively determine the performance characteristics of the International HIV Dementia Scale and the neuropsychological z-score composite summary score (NPZcomp) in Thailand
Study Design
This application focuses on the role of PBMC HIV DNA in HIV-associated neurocognitive disorders (HAND). Early evidence suggests it is a robust marker of HAND in ARV-naïve and ARV-treated individuals. This study is designed to prospectively determine the predictive value of HIV DNA in an HIV population from Bangkok, Thailand initiating HAART for the first time. Primary dependent variables include neuropsychological testing summary scores, consensus diagnostic categorization of HAND, and blood, CSF and MRS markers of inflammation. CSF HIV RNA is a principle covariate. We propose that HIV DNA will remain detectable in a subset of patients despite undetectable plasma and CSF HIV DNA and that HIV DNA levels in CD14+ PBMCs will correlate to markers of inflammation at all time points. We posit that baseline HIV DNA in CD14+ PBMCs will predict attenuated cognitive recovery. Finally, we intend to test the performance characteristics of both the NPZcomp and the International HIV Dementia Scale for the diagnostic categories of HAND in Thailand.
Study Procedure
HIV-infected Individuals intending to initiate ARV for the first time (n=60) will be identified in Bangkok, Thailand and screened for PBMC HIV DNA level. Individuals will be stratified by high (more than or equal to 5000 copies/106 cells, n=30) or low (less than 5000 copies/106 cells, n=30). All HIV individuals will undergo evaluations at baseline, 6 months, and annually for up to 4 years and will include: brain MRI/MRSneuropsychological testing, neurological examination, blood draw. Lumbar puncture will be optional at baseline and 12 months for person who agree to participate to this study procedure. Blood monocytes will be separated and cultured to obtain supernatants to assess inflammation and to determine HIV DNA levels in cellular subsets (CD14+, CD14-). Blinded to HIV DNA levels and international HIV Dementia Scale data, a consensus conference will determine HAND diagnoses using 2007 criteria.1 Neuropsychological data will be compared to previously enrolled, age- and education-stratified HIV-negative controls from Bangkok.
Study Duration
Six years with two years of enrollment and four years duration per enrolled participant.
Sponsor
National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA
Study Sites
Coordination site:
- SEARCH/The Thai Red Cross AIDS Research Centre (TRCARC), 104 Rajdamri Road, PathumwanBangkok 10330, Thailand
Clinical sites:
- Phramongkutklao Medical Center (PMK), 315 Rajvithi Rd Bangkok 10400, Thailand
- Chulalongkorn University Hospital and TRCARC, Rajdamri Road, Pathumwan, Bangkok 10330, Thailand
Data management and statistical support sites:
- SEARCH, Bangkok, Thailand
- Department of Biostatistics, Harvard School of Public Health
Laboratory sites:
- AFRIMS Department of Retrovirology (U.S. Component), 315/6 Rajvithi Rd., Bangkok 10400, Thailand
- Hawaii HIV and Immunobiology Lab/HACRP, University of Hawaii, Honolulu, Hawaii, USA
TABLE OF CONTENTS
Protocol title and personnel………………………………………………………………………....1
Schema .……………………………………………………………………………………………….2
Protocol:
1. Abbreviations used... …………………………..………………………………………………...6
2. Ethics……………………………………………………………………………………………….7
3. Location of study…………………………………………………………………………………...8
4. Duration of study …………………………………………………………………………………9
5. Objectives…………………………………………………………………………………………..9
6. Background and significance…………………………………………………………………..10
7. Study population…………………………………………………………………………………12
8. Study design and methodology ………………………………………………………………15
9. Laboratory procedures ………………………………………………………………………...17
10. Risks, benefits, research-related injury and confidentiality…………………………………19
11. Data collection, management, and analysis ………………………………………………..20
12. Medical monitor ………………………………………………………………………………...21
13. Participant compensation ……………………………………………………………………22
Appendices
Appendix I (Tables)………………………………………………………………………………26
Appendix II (Consent form)…………………………………………………………………………27
Appendix III (Capacity Assessment Record)……………………………………………………..33
Appendix IV (Assent Form)…………………………………………………………………………34
1. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
3TClamivudine
AANAmerican Academy of Neurology
AbAntibody
ADLActivity of Daily Living
AFRIMSArmed Forces Research Institute of Medical Sciences
AIDSAcquired immunodeficiency syndrome
APNACAsia Pacific NeuroAIDS Consortium
ARVantiretroviral therapy
BD Becton-Dickinson
CARcapacity assessment record
CBCComplete blood count
CDRClinical Dementia Rating Scale
CFRCode of Federal Regulations (USA)
Chocholine
CIDIComposite International Diagnostic Interview
Crcreatine
CRFCase Report Form
CRF01_AECirculating Recombinant Form AE
CRRcontinuing review report
CSFcerebrospinal fluid
d4Tstavudine
DoDDepartment of Defense
DMSOdimethyl sulfoxide
DSMDiagnostic and Statistical Manual of Mental Disorders
DTIDiffusion Tensor Imaging
FACSFluorescence Activated Cell Sorter
FDAFood and Drug Administration
FWAFederal wide assurance
GCPGood Clinical Practice
GDSGlobal Deficit Score
GNPIGlobal Neuropsychological Impairment
GPOGovernment Pharmaceutical Organization
GPO-vircombination ARV pill of stavudine, lamivudine, and nevirapine
GPO-virZ combination ARV pill of zidovudine, lamivudine, and nevirapine
HAARThighly active antiretroviral therapy
HACRP Hawaii AIDS Clinical Research Program
HADHIV-associated Dementia
HANDHIV-associated neurocognitive disorder
HIVhuman immunodeficiency virus
HSRRBHuman Subjects Research Review Board (WRAIR)
IADLInstrumental Activity of Daily Living
ICDInternational Classification of Diseases
ICHInternational Conference on Harmonization
IL-Interleukin
IRBInstitutional Review Board
LPLumbar Puncture
MCP-1monocyte chemotactic protein-1
MCMDMinor Cognitive Motor Disorder
MImyoinositol
M/MФmonocyte/macrophage
MOPHMinistry of Public Health
MRImagnetic resonance imaging
MRSmagnetic resonance spectroscopy
NAAN-acetyl-aspartate
NINDS/NIHNational Institutes of Neurological Disorders and Stroke/National Institutes of Health
NVPnevirapine
NPZcompneuropsychological z-score composite summary score
OHRPOffice for Human Research Protections
PAOFIPatients Assessment of Own Functioning Inventory
PBMCperipheral mononuclear cells
PCRPolymerase Chain Reaction
PIPrincipal Investigator
PINPersonal Identification Number
PMKPhramongkutklao Medical Center
POCPoint of contact
RNAribonucleic acid
RTARoyal Thai Army
SASStatistical Analysis System
SEARCH Southeast Asia Research Collaboration with Hawaii
SIV Simian Immunodeficiency Virus
TNF-Tumor Necrosis Factor
TRCARCThai Red Cross AIDS Research Center
UHUniversity of Hawaii
ULNupper limit of normal
USAMC-AFRIMSUnited States Army Medical Center – Armed Forces Research Institute of the Medical Sciences
USAMMDAU.S. Army Medical Materiel and Development Agency
USAMRMCU.S. Army Medical Research and Materiel Command
WHOWorld Health Organization
WRAIRWalter Reed Army Institute of Research
ZDVzidovudine
2. ETHICS
2.1 Institutional Review Boards (IRBs)
The Principal Investigator (PI) agrees to provide the Institutional Review Boards (IRBs) with all appropriate materials, including the protocol, proposed informed consent document, other written participant information, and any proposed advertising material and any changes made to these documents subsequent to submission. This study will not be initiated until appropriate IRB approvals of the protocol and informed consent document have been obtained in writing by the Principal Investigator. Appropriate reports on the progress of the study by the Principal Investigator will be made to the IRBs and the Sponsor in accordance with applicable Thai and U.S. governing regulations and in agreement with policy established by the Sponsor.
2.2Office for Human Research Protections (OHRP) or Department of Defense (DoD)
Assurance numbers of participating Institutions:
Chulalongkorn University Hospital (SEARCH, Thai Red Cross)FWA00000943
Harvard School of Public HealthFWA00002642
Royal Thai Army Medical Department (Phramongkutklao Medical Center)FWA00001813
University of HawaiiFWA00003526
University of California San FranciscoFWA00003470
WRAIRFWA00000015
2.3 Informed Consent
A properly executed, written, IRB-approved informed consent (in Thai), in compliance with the Declaration of Helsinki, guidelines of the International Conference on Harmonization (ICH) and U.S. law 45 CFR §46, shall be obtained from each participant prior to performing any of the screening assessments. The investigator shall provide a copy of the IRB-approved informed consent to the participant and the signed original shall be maintained in the participant’s record file. Attention is directed to the basic elements that need to be incorporated into the informed consent under U.S. Federal Regulations for Protection of Human Subjects (45 CFR §46.116[a] ). Templates for the informed consents are provided in Appendix II. It describes the aspects involved in study participation. It is the investigator’s (or designee’s) responsibility to obtain this written informed consent from the participant, after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific procedures are administered. When decisional capacity is not clear, a legally authorized surrogate signs consent with the participant. In such cases, capacity is re-assessed at future visits and if the participant regains capacity to consent, they will be consented at that time.
3. Location of Study
Coordination site:
- SEARCH/The Thai Red Cross AIDS Research Centre (TRCARC), 104 Rajdamri Road, Pathumwan, Bangkok 10330, Thailand
Clinical sites:
- Phramongkutklao Medical Center (PMK), 315 Rajvithi Rd Bangkok 10400, Thailand
- Chulalongkorn University Hospital and TRCARC, Rajdamri Road, Pathumwan, Bangkok 10330, Thailand
Data management and statistical support sites:
- SEARCH, Bangkok, Thailand
- Department of Biostatistics, Harvard School of Public Health
Laboratory sites:
- AFRIMS Department of Retrovirology (U.S. Component), 315/6 Rajvithi Rd., Bangkok 10400, Thailand
- Hawaii HIV and Immunobiology Lab/HACRP, University of Hawaii, Honolulu, Hawaii, USA
3.1 Study Responsibilities (by Institution)
SEARCH/The Thai Red Cross AIDS Research Centre (TRCARC): SEARCH will coordinate the clinical portion of this study, including recruitment of subjects, consenting, and clinical protocol management. Participants will be seen at SEARCH for neuropsychological testing and physical examinations. SEARCH will conduct screening PBMC HIV DNA assays and manage all study data. SEARCH operates in Thailand under TRCARC which utilizes the Chulalongkorn University IRB.
Phramongkutklao Medical Center (divisions of Neurology and Infectious Diseases, Department of Medicine): Participants will be screened and attend study visits at PMK Medical Center. Lumbar punctures will occur at PMK, Division of Neurology. The infectious diseases division will facilitate recruitment and assist with HIV care of the subjects. PMK laboratory will perform routine assays.
Chulalongkorn University:Participants will undergo MRI/MRS at Chulalongkorn University Hospital.
AFRIMS, Department of Retrovirology: Immunological assays including cell separation will occur at AFRIMS laboratory complex. Specimens will be stored and shipped to collaborators as indicated in the protocol.
HACRP (Hawaii HIV and Immunobiology Lab): HACRP will complete cells separation and assays of HIV DNA in subsets for enrollment and subsequent assays.
Harvard School of Public Health: Harvard will direct statistical analysis in coordination with the PI and the SEARCH data management team.
3.2 Personnel role and responsibility
Victor Valcour MD (Principal Investigator) will have final responsibility for all protocol issues and will primarily coordinate all administrative issues and over-see clinical issues with Dr. Ananworanich. He will work with Dr. DeGruttola for all data analyses and will direct all publications.
Jintanat Ananworanich MD (Protocol Clinical Director) will be responsible for all day-to-day clinical aspects of this protocol. She will directly manage protocol flow and report directly to the PI. She will be responsible for collection of clinical data and is listed as the point of contact (POC) in the consent forms. Nittaya Phanuphak MD (Associate Clinical Investigator) will assist Dr. Ananworanich with all activities as outlined above. Yotin Chinvarun MD (Associate Clinical Investigator) will be the primary protocol neurologist and work directly with Drs. Ananworanich, Sithinamsuwanand Chalermchai to evaluate participants.
Silvia Ratto-Kim PhD (Protocol Laboratory Director) will direct all laboratory aspects of the protocol, including processing, storage, shipping and completion of all immunological assays with the direct assistance of Mark deSouza PhD, MPH (Associate Laboratory Investigator) who will be primarily responsible for day-to-day management of immunological assays. Bruce Shiramizu MD (Associate Laboratory Investigator) will oversee all HIV DNA assays in Thailand and the US.
Alexandra Schuetz, Ph.D(Research Scientist) She has recently joined the Department of Retrovirology at AFRIMS. She will help with the day to day operation of the protocol. She will conduct part of the experiments proposed together with the laboratory technician. She will be under the direct supervision of Dr deSouza.
Victor DeGruttola PhD (Protocol Biostatistician) will direct statistical analyses.
Ms SompornTipsukRN will be the primary study nurseresponsible for the day-to-day management of the study. She will also perform the neuropsychological testing.
There are several external consultants on the protocol. Bruce Brew MBBS MD FRAC will provide external expertise on the interpretation of CSF assays. David Clifford MDand Robert Paul PhDwill provide external validation of consensus conference determinations. Sukalaya Lerdlum MDand Pom Sailasuta PhD will provide expertise in the interpretation of MRI and MRS data. Cecilia Shikuma MDwill provide logistical support for fiscal and administrative issues at the University of Hawaii, as needed
4. Duration of study
July 2008– July 2014 (6 years – 2 years of recruitment and 4 years of follow-up)
5. Objectives
Activated cells of the monocyte/macrophage (M/MФ) lineage play a pivotal role in the pathogenesis of HIV-associated Dementia (HAD)2. The accumulation of perivascular macrophages is observed in brain tissue of individuals with HAD and is a better marker of brain injury than is the presence of HIV virus. This pattern remains present in the era of HAART3. The expansion of peripheral M/MФ subsets displaying an activated phenotype is associated with HAD4 and with encephalopathy in SIV-infected macaques5.
Our recent data demonstrate that the level of HIV DNA within PBMCs is a better marker of cognitive dysfunction than is the degree to which expansion of M/MФ expressing an activated phenotype is observed. Our published data demonstrate a relationship between high PBMC HIV DNA and cognitive dysfunction in HAART-naïve patients with advanced HIV disease6 and among individuals heavily treated with HAARTeven when plasma HIV RNA is undetectable7. Based on preliminary data, PBMC HIV DNA likely represents the degree of HIV infection in circulating M/MФ rather than lymphocytes.