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Immunologic Responses to Infection
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6.6.7 Immunologic Responses to Infection: Assays for cellular immune response are improving rapidly and the specific assays to be employed with the specimens stored during the study will be determined based on the level of technology at the time. CD4, CD8 and NK cellular responses may be evaluated by a variety of assays including intracellular cytokine staining and ELISPOT assays. Levels of IL-1, IL-6, IL-10, TNF-α, MCS-F, MCP-1, MIP-1α, MIP-1β, and RANTES in the plasma will be measured by sandwich-ELISA method-based cytokine kits (BioSource). Further advances in immunologic assays will occur and may be utilized. Any use of the samples outside of this defined plan will be submitted as a protocol amendment or a new protocol. These assays will be performed at AFRIMS and/or the TRCARC. 6.6.8 Urine collection: Urine collection will be performed and samples stored at -80˚C for evaluation of HIV diagnostic serology assays on urine and HIV humoral immune response studies to include measurement of HIV binding antibodies and neutralizing antibodies. A urine pregnancy test will be done at baseline and subsequently every 12 weeks in females of child bearing age. Urinalysis will be done at baseline on all subjects, and at weeks 12, 24, and every subsequent 24 weeks. 6.6.9 Genital secretion collection: In volunteers who have consented for this procedure, the following genital secretions will be collected at the TRCAC by the study investigator or a study nurse: semen (in men), anal wash and swab (in MSM), cervicovaginal wash and vaginal swab (in women). Genital secretion samples will be assayed for HIV RNA PCR using the Roche Amplicor® 1.5 kit or other nucleic acid amplification method. Left over samples will be stored at –80˚C and will be used to isolate and sequence HIV, for cytokines assay and detection of human papilloma virus. 6.6.10 CSF: Lumbar puncture for CSF collection (10ml) will be done at the TRCAC by the study investigator in volunteers who give consent for this procedure regardless of neurological symptoms. CSF will be assayed for HIV RNA PCR using the Roche Amplicor® 1.5 kit or another nucleic acid amplification method. CSF cell count, glucose and protein quantification will be performed. Left over CSF will be spun and stored at –80˚C and will be used to isolate and sequence HIV, and for cytokine/chemokine assays (such as MCP-1, neopterin, IL6 and tau). In order to interpret the CSF data, blood glucose, protein and HIV RNA will be measured at time of lumbar puncture. 6.6.11 Colon biopsy: This will be done at the Chulalongkorn University Hospital which is 500 meters from the TRCARC by a gastroenterologist in volunteers who give consent for this procedure. Biopsy specimens will be cryo-preserved for transcriptional analysis and immunohistochemistry and collected in RPMI medium 1640 (Invitrogen) for flow cytometric analysis. Phenotyping of colon lymphocytes using fresh lymphocytes and multi-parameter flow cytometry may include the following panels: Activation: CD3/CD4/CD8/HLA-DR/CD38; Memory:CD3/CD4/CD8/CD27/CD45RO/CCR5; T reg: CD3/CD4/CD8/CD25/FoxP3/Ki67. HIV quantification in tissue will be determined by real time PCR at NIAID, NCI or VGTI laboratory. Other HIV-specific immune responses may be evaluated. 6.6.12 Imaging studies: EKGs will be performed at the TRCARC. CXR and brain MRI/MRS will be performed at Chulalongkorn University which is 100 meters from the TRCARC. Gadolinium will not be used for research purposes. 6.6.13 HLA testing: HLA testing will be performed on stored PBMCs at a collaborating or commercial laboratory. 6.6.14 Neuropsychological assessment: An abridged neuropsychological battery (appendix D) will include the Grooved pegboard test, non-dominant hand, color trails 1 and 2, and the trail making A test. Testing will be completed by certified nurse-psychometrists. The procedure will take 10 minutes and will be done at weeks 0, 12, 24, 96, 144 and 192. 6.6.15 Comprehensive neurological examination: This will be done by the study neurologist or a team physician who has been trained and undergoes regular QA/QC by a neurologist in the unexpected event that the neurologist is unavailable. These will occur at weeks 0, 4, 12, 24, 96, 144 and 192 and will add 10 minutes to the physical examination (appendix D). The team neurologist will provide over-sight for additional evaluation in the event that neurological signs/symptoms are identified. 6.6.16 Psychiatric assessment and assessment of function: This will take 20 minutes in total and will be done at weeks 0, 4, 12, 24, 96, 144 and 192. Volunteers will be asked to complete the following questionnaires: Hospital Anxiety and Depression Scales (HADS), depression score from Patient Health Questionnaire, the WHO QOL-BREF questionnaire, a visual analog scale (Distress Thermometer) and Clinical Dementia Rating (CDR) scale. The questionnaires are in appendix D.
Functional genomics is a powerful tool to investigate host responses to infection. We will determine host genetic factors which may include Fc gamma, APOBEC, cyclophilin, TRIM5a, and KIR APOBEC3s, TRIM5α and TLRs. We will apply a real-time PCR platform and the Illumina Infinium Whole Genome Human1M BeadChip within the Duke IGSP genotyping facility to accomplish these goals. The Human1M BeadChip combines both single nucleotide polymorphisms (SNP) and copy number variation (CNV) analysis, along with additional unique, high-value genomic regions of interest, such as the MHC region. Commercial reagents will be used when available. 6.7 Data Management 6.7.1 Overview of Case Report Forms: Case report or data collection forms (CRF or DCF) will be provided by AFRIMS for each subject and used in accordance with Good Clinical Practices. It is the policy of the sponsor that the study data must be verifiable to the source data, which necessitates access to any original recordings, laboratory reports, and subjects’ records. The following CRFs will be used: Enrollment and demographics, medical and social history, physical examination, acute retroviral syndrome checklist, medication use, adverse events and laboratory results. The self-administered questionnaires for demographic and HIV risk behavior will serve as both CRFs and source documents. Information on the number of samples tested by pooled NAT and sequential EIA and their results will also be collected. 6.7.2 Source Documents: Source documents will include demographic details, two questionnaires (demographic and risk behavior assessment), laboratory results, signs and symptoms, HIV-related illnesses, medication use and adverse events. Serious pre-existing conditions will be recorded at the baseline visit. 6.7.3 Data Compilation: Data from CRFs will be double-data entered and compiled in an electronic database at AFRIMS. The database is password protected and maintained in a locked, fingerprint-controlled access room. In addition, personal identifying information such as names and national or passport ID numbers will not be stored in the electronic database. 6.7.4 Disposition of Data: Data, both electronic and hard copy (CRFs) will be stored in locked facilities at AFRIMS. The electronic database will be backed up and maintained by the information technology section. Data from this protocol will be retained for at least 5 years after study completion. The AFRIMS data manager will be responsible for data storage. The contact information on the information sheet from subjects who sign the document but are found not to have acute HIV infection will be stored in locked facilities at AFRIMS for the duration of the study. They will be destroyed by shredding at study completion. 6.8 Unanticipated Events Associated with Study Participation No test article is being administered in this study, hence, only adverse events or injury related to study participation will be assessed at each study visit by open-ended questioning of the volunteer, and recorded on source documents. Potential events include injury due to phlebotomy, colon biopsy, lumbar puncture, collection of genital secretion, MRI/MRS and accidental disclosure of HLA testing results or HIV serostatus. Unanticipated problems involving risk to subjects or others, serious adverse events related to participation in the study and all subject deaths will be promptly reported to all participating IRB’s (Chulalongkorn, WRAIR IRB, UCSF IRB). For the WRAIR IRB, contact by phone (301-319-9940) or by facsimile (301-319-9961) should be followed by a complete written report sent to the Director, Division of Human Subjects Protection, Walter Reed Army Institute of Research, 503 Robert Grant Ave., Silver Spring, MD 20910-7500. Copies of the reports will be provided simultaneously to the Chulalongkorn University. 6.9 Withdrawal Criteria (1) A volunteer may withdraw his/her consent to participate in the study at any time, in whole or in part, without prejudice. (2) The investigator may withdraw a subject if, in her/his judgment, it is in the best interest of the volunteer, or if the volunteer cannot comply with the protocol. Any data generated from clinical or laboratory procedures prior to volunteer withdrawal may be used in analyses. 6.10 Criteria for Study Termination If there is inadequate study progress and it is felt that study objectives will not be achieved, or for other administrative or scientific reasons, the sponsor and investigative team may cancel the study after informing all ethical review committees and institutional review boards. 6.11 Biohazard Containment Transmission of HIV and other blood borne pathogens can occur through contact with contaminated needles, blood, and blood products. Therefore, all personnel involved in drawing blood and handling laboratory specimens for this study will employ standard universal precautions for blood and body fluids. 6.12 Quality Control and Quality Assurance For all laboratory tests, quality assurance will be performed according to Good Clinical Laboratory Practices (GCLP) and/or College of American Pathologists’ standards (the AFRIMS lab is CAP accredited). For quality management of the study, the principal investigator will ensure that clinical staff is appropriately trained on protocol procedures and GCP prior to the study start with updates during the study. Data recorded onto the CRFs will be verified against the source documents by study staff. All deficiencies will be corrected on site. 7 Statistical Methods 7.1 Sample Size Estimation Estimation of sample size is based on the expected number of infections established in a feasibility study [78]. We expect to identify 1 acute infection for approximately every 500-800 antibody negative persons screened. Hence, we expect to enroll up to 20 volunteers per one-year period. 7.2 Population for Analysis All enrolled volunteers will be evaluated. If a volunteer withdraws from the study, samples and data collected up to the day of withdrawal will be included in analyses. 7.3 Data Analysis Methods There will be limited power to conduct statistical inference testing in this protocol and analyses for this protocol will largely be descriptive and exploratory, with no pre-planned formal hypothesis testing. Preliminary results of immunophenotyping and cytokine profiles in the first 10 subjects revealed diverse results and the study remains to be exploratory. Outcomes will be described as a whole group without formally comparing the Thai and non-Thai volunteers. We do not expect a significant impact of ethnicity on lymphocyte polyfunctional studies, immunophenotyping or markers of effector T cell activity and cell turnover. We expect most subjects to have acquired HIV infection in Thailand whether they are Thais or non-Thais, and will monitor and describe the HIV subtypes in viremic subjects. The host genomic factors may be affected by ethnicity and will be described for Thais and non-Thais but as this is an exploratory study, we do not expect to have enough numbers to perform a formal comparison. data to be collected is expected to have a non-normal distribution and non-parametric tests of inference will be used where appropriate. For normally distributed continuous variables, T-tests will be used. For categorical variables, the Chi-square statistic or Fisher’s exact test will be used. Multivariable models of CD4 and log10 plasma viral RNA trajectories will be analyzed using generalized estimating equations or similar mixed-effects regression methods to compare the effect of immune responses or other factors on these biomarkers of HIV-disease progression. When feasible, the breadth of responses (e.g., responses to one or more regions of the HIV genome vs. none) and the magnitude of the response (e.g., percentage of cells staining for multiple cytokines on ICS) will be compared. 8. Ethical Considerations 8.1 Informed Consent Informed consent will be obtained from each volunteer before enrollment in the study. The Informed Consent Form (ICF) will be written in English and translated into Thai. Documentation of the accuracy of the Thai language translation of the English information sheet and consent form is provided. Volunteers may withdraw from the study at any time point. 8.2 Volunteer Identification and Confidentiality Subjects’ medical information obtained in this study will be maintained in a confidential manner, and disclosure to third parties other than those noted below is prohibited. Upon the subject’s permission, medical information may be given to his/her personal physician or other appropriate medical personnel responsible for his/her welfare. Personal health information will only be available to the volunteer’s physician with their permission, study staff, and investigators, monitors, and, other Thai and US regulatory authorities (including IRB’s with oversight of the study) if deemed appropriate. Data generated by this study must be available for inspection upon request by representatives of Thai regulatory authorities, the USAMRMC, the US Department of Defense and the approving IRBs, as appropriate. Clinical information generated by study procedures and specimens will be identified only by a coded identification number without any personal identifiers. The name of the volunteer will only appear on source documents for enrolment (e.g. consent form) and, potentially from clinical data obtained during the course of their clinical care separate from participation in the study (e.g. radiological exams). Study data will only be destroyed after completion or cancellation of the study, IRB approval, and written agreement between investigators and sponsor. 8.3 Risk to Volunteers and Precautions to Maximum Risk A minimal risk associated with phlebotomy from pain, bruising, infection, and in rare cases, syncope from a vaso-vagal response to the site of blood. To minimize these risks, phlebotomists with training in sterile technique will be employed, and will be observed for proficiency by the trained medical staff. In addition, all volunteers will be seated or recumbent when blood is drawn. Adverse reactions to leukopheresis procedure are rare and include vasovagal episodes related to needle insertions and transient volume loss, and cutaneous paresthesias, chills, nausea, and heartburn caused by the citrate anticoagulant used during the procedure. Vasovagal reactions are handled by postural manipulation and fluid administration. Volunteers will be observed closely by an experienced blood bank technician during the procedure. Citrate reactions are usually relieved by slowing the rate of the anticoagulant infusion and by administering oral calcium carbonate tablets. Leukopheresis has been shown to be safe in HIV-infected donors and does not affect CD4+ T-cell count or immune status of short-term donors [79]. The risk of primary concern in this study is related to ascertaining and providing HIV diagnostic information and, in particular, involuntary disclosure of HIV status to others. It is acknowledged that these disclosures may result in depression and rarely suicide among individuals learning that they are infected with the HIV virus. Furthermore, involuntary disclosure to others may result in extreme prejudice by the community, family, employers, and psychosocial factors including stigma and discrimination. This risk will be minimized by the fact that all counselors will be trained in pre- and post-test counseling for HIV and will aim at fully informing volunteers of all activities in the study and attendant risks and benefits. The study staff will not contact or attempt to contact any persons who may be subject’s sexual contacts without permission from the subject. In no circumstance will the study staff inform the sexual contacts about the subject’s test results and medical information. Study staff will not reveal to the sexual contacts how they receive their contact information without the subject’s permission. Risks associated with HIV diagnosis will be minimized by providing information regarding prognosis, transmissibility and potential steps which can be taken by the volunteer to extend life through opportunistic infection management, prevent transmission of HIV and obtain additional support and care. Further, should the volunteers HIV test results become known to others, the study staff will take appropriate action to assist volunteers with any discrimination they may experience by their participation in this study. Such measures will be accompanied with appropriate counseling. However, the study staff will take great care to minimize this risk occurring. To ensure this, personal identifying information like names, age, etc will be collected at the time of enrolment and stored in a secure, locked cabinet, to which only key study team members will have access. Volunteers will be allocated a unique identification number, which will be used on all subsequent visits. This measure will ensure confidentiality of personal information and minimize the chances of their HIV status, and other volunteer information becoming known to others. An additional risk includes stigmatization regarding volunteers’ practices. To minimize this risk, terms like “high risk individuals” will not be used. In this study a number of volunteers will test HIV-positive. The study team will take all possible measures to ensure that any social harm that may arise as a result of participation in this study is minimized. Because MRI/MRS is a medical device which uses a magnet, any metal object placed in the strong magnetic field of the MRI/MRS scanner will be pulled to it and may cause injury. In order to avoid this, the volunteers will be asked to leave as many metal objects as possible at home, and they will be asked to remove all metallic objects including jewelry, dentures, glasses, watches, and artificial limbs before the MRI/MRS. Gadolinium will not be used for research purposes. The volunteers may feel claustrophobic (fear of being in a small, closed space) or anxious. If this is likely to happen, the investigators can give the volunteers a sedative such as lorazepam to take by mouth. The risks of lumbar puncture include local soreness at the site of needle entry. There is a small risk of headache or decreased blood pressure from removing the small amount of fluid or leaking of cerebral spinal fluid after the procedure. There is a small risk of infection and a very small risk of damage to nerves in the lumbar spinal roots after the procedure which could cause pain, numbness, or loss of sensation to the legs. In order to reduce side effects of the lumbar puncture, the volunteers will be asked to remain lying flat for about an hour after the procedure and be given fluid to drink after the procedure. A band-aid will be placed on the skin where the needle went in and the volunteers will be asked to remove it the next day and tell the study doctor right away if any redness or tenderness is present. The investigators will ask the volunteers about history of any allergies to anesthetics and will not perform lumbar puncture in any volunteer with such history. Genital secretion collection will be done in a private room in order to decrease the uncomfortable feeling volunteers may have. Inserting an instrument (speculum), swab and injecting solution (without needle) into the anus or the vagina may cause slight irritation but it should not cause any pain. The sample collection will be done by trained study personnel in order to minimize the discomfort to the volunteers. During colon biopsy, the volunteers will receive sedative and analgesic medications which will normally provide relaxation and produce a drowsy feeling. Colon biopsies will be performed via colonoscopy. Brief cramping and gas pains may be felt as air is inserted or as the scope advances. The passing of gas is necessary and should be expected after the procedures are terminated. Because of sedation, the volunteers may not feel discomfort and have no memory of the test. There may be slight bleeding from the biopsy site but if it is necessary it can be stopped using an interventional endoscopic technique. A gastroenterologist will perform this procedure in order to minimize these risks. 8.4 Benefits to Volunteers The volunteer will receive education and counseling about HIV/AIDS and the behaviors that could reduce the risk of spreading this infection to others. Volunteers will receive counseling in a confidential manner and additional important clinical information may be provided to their physicians. In addition, there will be benefits to the Public Health of the Community as counseling and treatment of participants may decrease transmission of HIV in relevant networks and thus prevent potential infections. 8.5 Risks to Study Personnel and Precautions to Maximum Risk Study personnel may be at risk for needle stick injury. Universal precautions and phlebotomy procedures according to GCLP and SOP will be used to minimize the risk. 8.6 Financial Incentives to Volunteers Volunteers who agree to give their contact information will not be given any compensation. However, subjects with acute HIV infection who enroll in the cohort study will receive compensation at 1000 Thai baht (approximately $29) per regular visit for travel, meal expenses and loss of income. Subjects will receive additional compensation for loss of time at 1000 Thai baht per visit without hospitalization which includes leukopheresis. For days that the subject is hospitalized, a compensation of 2,000 Thai baht daily (approximately $59) will be given. For optional procedures, the following compensation will be given in addition to the above to cover for extra time and discomfort: genital secretion collection (500 Baht), CSF collection (1,000 Baht), MRI/MRS (500 Baht) and colon tissue biopsy (1,500 Baht). Therefore, the minimum compensation for a given visit will be 1,000 Baht and the maximum amount (if subject agrees to participate in all optional procedures) would be 4,500 Baht (about $132) without leukopheresis and 5,500 (about $162) with leukopheresis. Subjects who agree to be hospitalized will receive an additional 2,000 to 14,000 Baht ($67 to $467) for 1-7 days in the hospital. As not every subject will have the same amount of follow up, it is difficult to correctly estimate the total amount of compensation, however, for subjects who have a full 192 weeks of follow up and agree to all optional procedures, the total maximum amount will be around 58,000 Baht in four years (approximately $1,705). For subjects who do not agree to any additional procedures, the total maximum amount including 7 days of hospitalization will be 44,000 Baht (about $1,294) in 4 years. We will also reimburse the volunteers for the cost they incur for contacting their sexual subjects including travel and communication cost not to exceed 5000 Baht (approximately $147). 8.7 Medical Care for Injury or Illness The study sponsor will provide medical treatment to study volunteers for injuries or medical problems considered to result from study procedures. Treatment will include any necessary emergency and follow up care. 9. Administrative Procedures 9.1 Protocol Amendments Amendments to the protocol will be made only after consultation and agreement between sponsor and investigators. The only exception is where the investigators consider that a subject’s safety is compromised if action is not immediate. In such circumstances the investigators must inform the sponsor and all overseeing review boards within 5 working days after the emergency occurred. All amendments must be approved by all participating IRB’s prior to implementation. 9.2 Protocol Deviations Major deviations and unanticipated problems involving risks to volunteers or others and problems that affect the scientific integrity of the study will be promptly reported to the Chulalongkorn IRB and WRAIR IRB. Both major and minor deviations from the approved protocol must be reported to the IRB’s in the continuing review and final reports. 9.3 Continuing Review and Final Reports Continuing review reports will be submitted to each IRB for review and approval on no less than an annual basis. A final study report will be submitted to each IRB for review and approval upon completion of the study. 9.4 Publication Policy It is understood by the investigators that the information generated in this study will be used by the Sponsor in connection with the development of vaccine trials and therefore may be disclosed to government agencies in various countries. To allow for the use of information derived from the study, it is understood that the investigator is obliged to provide the Sponsor with complete test results, all study data, and access to all study records. The Sponsor and investigators recognize the importance of communicating medical study data and therefore encourage their publication in reputable scientific journals and presentation at seminars or conferences, while protecting the integrity of the study, if ongoing. Any results pursuant to the conduct of this protocol and/or publication, lecture, manuscripts based thereon, shall be exchanged and discussed by the investigators and the WRAIR/USAMRMC prior to submission for publication or presentation. Results from investigations shall not be made available to any third party by the investigating team outside this publication procedure. Within any presentation or publication, confidentiality of individual subjects will be maintained, with identification by ID number if applicable. Any publications with WRAIR/AFRIMS investigators must be submitted to the Office of Research, Technology, and Applications (ORTA) at WRAIR for review prior to submission. 9.5 Responsibilities of Study Personnel 9.5.1 WRAIR/AFRIMS: Dr. Jintanat Ananworanich is responsible for study design, study oversight and coordinating the study including recruitment and follow up of the volunteers according to the protocol. Dr. Mark de Souza is responsible for laboratory testing done at AFRIMS. Dr. Jerome Kim and Dr. Joseph Chiu are responsible for overseeing the study. Dr. Silvia Kim and Dr. Sodsai Tovanabutra will be responsible for laboratory testing done at WRAIR (for samples that are shipped to the US). Dr. Paris is also responsible for data analysis. Dr. Sriplienchan will be the medical monitor for this study. 9.5.2 TRCARC: Drs. Praphan Phanuphak, Kiat Ruxrungtham and Nittaya Phanuphak will provide supervision in VCT, recruiting and enrolling volunteers into the study as well as provide clinical expertise in the care of HIV-infected volunteers. They will also oversee the tracking/behavioral intervention of the volunteers and their sexual contacts. Study staff at the TRCARC will enroll volunteers and perform study procedures. Dr. Sunee Sirivichayakul will provide assistance in collection of blood specimens and performance of laboratory testing at the TRCARC.
9.6 Compliance with Laws and Regulations The undersigned Principal and Associated Investigators have reviewed this protocol and will conduct the study in full compliance with current Good Clinical Practice Guidelines, as well as Thai and US Government, and US Army regulations pertaining to human subjects research. The study team will not report any of the subject’s health information, including communicable diseases, to the Thai government authority 9.7 Responsibilities of the Principal Investigator 1. To promptly report changes or unanticipated problems in a research activity. Normally, changes may not be initiated without OTSG approval, except where necessary to eliminate apparent immediate hazards to the human subject or others. 2. To immediately report by telephone any serious or unexpected adverse experiences which occur to the human subject or others to the WRAIR Division of Human Subjects Protection at (301) 319-9940 during duty hours
9.8 Protocol addendum The following are reporting requirements and responsibilities of the Principal Investigator to the United States Army Medical Research and Materiel Command’s (USAMRMC) Office of Research Protections (ORP), Human Research Protection Office (HRPO). (1) The protocol will be conducted in accordance with the protocol submitted to and approved by the USAMRMC ORP HRPO and will not be initiated until written notification of approval of the research project is issued by the USAMRMC ORP HRPO. (2) Accurate and complete study records will be maintained and made available to representatives of the U.S. Army Medical Research and Materiel Command as a part of their responsibility to protect human subjects in research. Research records will be stored in a confidential manner so as to protect the confidentiality of subject information. (3) Any deviation to the protocol that may have an effect on the safety or rights of the subject or the integrity of the study must be reported to the USAMRMC ORP HRPO as soon as the deviation is identified. (4) Major modifications to the research protocol and any modifications that could potentially increase risk to subjects must be submitted to the USAMRMC ORP HRPO for approval prior to implementation. All other amendments will be submitted with the continuing review report to the USAMRMC ORP HRPO for acceptance. (5) A copy of the approved continuing review report and the local IRB approval notification will be submitted to the USAMRMC ORP HRPO as soon as these documents become available. A copy of the approved final study report and local IRB approval notification will be submitted to the USAMRMC ORP HRPO as soon as these documents become available. (6) The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or other government agency concerning clinical investigation or research, the issuance of Inspection Reports, FDA Form 483, warning letters or actions taken by any Regulatory Agencies including legal or medical actions and any instances of serious or continuing noncompliance with the regulations or requirements will be reported immediately to USAMRMC ORP HRPO. Guidance for the Requirement of a Medical Monitor Per DoD Directive 3216.02, all greater than minimal risk studies require a Medical Monitor. The USAMRMC ORP HRPO also reserves the authority to require assignment of a Medical Monitor for those protocols assessed as presenting no greater than minimal risk to the subjects participating in the study. Responsibilities of the Medical Monitor The medical monitor is required to review all unanticipated problems involving risk to subjects or others, serious adverse events and all subject deaths associated with the protocol and provide an unbiased written report of the event. At a minimum, the medical monitor must comment on the outcomes of the event or problem and in case of a serious adverse event or death, comment on the relationship to participation in the study. The medical monitor must also indicate whether he/she concurs with the details of the report provided by the principal investigator. Reports for events determined by either the investigator or medical monitor to be possibly or definitely related to participation and reports of events resulting in death must be promptly forwarded to the USAMRMC ORP HRPO. 
Please indicate the name of the medical monitor and the role they will have in this research study. This individual will be a qualified physician, other than the principal Investigator, not associated with this particular study, able to provide medical care to research subjects for conditions that may arise during the conduct of this study, and will monitor the subjects during the conduct of the study. Medical Monitor: Dr. Somchai Sriplienchan_____________________________ Describe the specific role of the Medical Monitor in this research study: The medical monitor will review all acute HIV-infected participants’ medical records. The medical monitor will provide an unbiased written report of unanticipated problems involving risk to subjects or others, serious adverse events and all subject deaths associated with the protocol. The medical monitor will comment on the outcomes of the event or problem and in case of a serious adverse event or death, comment on the relationship to participation in the study. The medical monitor will indicate whether he concurs with the details of the report provided by the principal investigator. I have read the foregoing protocol and agree to conduct the study as outlined herein.
Jintanat Ananworanich, MD, PhD Date _______________________________ Title
_______________________________ _______________________ Nittaya Phanuphak, MD Date _______________________________ Title
10. References:
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Mattapallil JJ, Smit-McBride Z, McChesney M, Dandekar S. Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1beta expression and display antiviral cytotoxic activity despite severe CD4(+) T-cell depletion in primary simian immunodeficiency virus infection. J Virol 1998,72:6421-6429. 7. Staprans SI, Barry AP, Silvestri G, Safrit JT, Kozyr N, Sumpter B, et al. Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein. Proc Natl Acad Sci U S A 2004,101:13026-13031. 8. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004,200:749-759. 9. Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol 2006,7:235-239. 10. Sankaran S, Guadalupe M, Reay E, George MD, Flamm J, Prindiville T, Dandekar S. 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J Acquir Immune Defic Syndr 2008,49:151-155. 79. van Lunzen J, Schmitz J, Dengler K, Schmidt L, Schmitz H, Dietrich M. Recovery of T-lymphocytes for adoptive immunotherapy by lymphapheresis of HIV-infected patients without alterations of virological, immunological or clinical parameters. Br J Haematol 1994,88:46-51. 11.1 Appendix A: HIV Testing Algorithm at Thai Red Cross HIV ½ Ag/Ab Combo assay (Abbott Laboratories or Roche Diagnostics)  
Negative Positive ** 
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