Thinking and Memory Problems in People With HIV

Tracking Information
First Submitted Date	June 11, 2013
First Posted Date	June 12, 2013
Last Update Posted Date	June 14, 2018
Study Start Date	June 11, 2013
Estimated Primary Completion Date	December 31, 2021 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures; (submitted: August 4, 2016)	To characterize in detail the natural course of HAND in subjects with low CD4 nadir (<200 cells/mm(3)) and prolonged plasma HIV virologic suppression (<50 copies/mL). [ Time Frame: 8 years ]
Original Primary Outcome Measures; (submitted: June 11, 2013)	To characterize in detail the natural course of HAND in subjects with low CD4 nadir (< 200 cells/mm(3)) and prolonged plasma HIV virologic suppression (< 50 copies/mL). [ Time Frame: 8 years ]
Change History	Complete list of historical versions of study NCT01875588 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures	Not Provided
Original Secondary Outcome Measures	Not Provided
Current Other Outcome Measures	Not Provided
Original Other Outcome Measures	Not Provided
Descriptive Information
Brief Title	Thinking and Memory Problems in People With HIV
Official Title	Screening and Recruitment for HIV-associated Neurocognitive Disorders (HAND) Studies and an Evaluation of HIV-associated Neurocognitive Disorders in Virologically Controlled Patients
Brief Summary	Background: - People with human immunodeficiency virus (HIV) can sometimes develop thinking and memory problems. These problems can vary widely, from few symptoms to severe problems with memory and concentration. It initially was thought that good HIV treatment could prevent almost all HIV-related memory problems. However, even people with low HIV viral loads can have these problems. It may be caused by HIV affecting the brain and spinal fluid. It is not yet clear why HIV causes these problems and why they may be worse in some people than others. Researchers want to study people with HIV and healthy volunteers to see how HIV may affect people with only small amounts of the virus in their blood. Objectives: - To study thinking and memory problems in individuals with HIV that is otherwise controlled with medications. Eligibility: Individuals between 18 of age or older whose HIV has been controlled with medications for at least 1 year.; Healthy volunteers between 18 of age or older. Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. A neurological test will also be given. Participants will have a baseline imaging study of the brain.; Within 12 weeks of the first visit, participants will have a second visit. Additional blood samples will be drawn. Another brain imaging study will be performed.; Within 8 weeks of the second visit, participants will have a third visit to collect more blood samples. They will also provide spinal fluid samples, either as a single visit or a longer procedure.; After this visit, participants will return every 6 months for up to 5 years. Blood samples will be collected as needed at these visits. Thinking and memory tests and imaging studies may also be given as needed. Spinal fluid may be collected at one visit a year.
Detailed Description	The natural history of neurocognitive impairment in human immunodeficiency virus (HIV)- infected individuals remains poorly understood. While the advent of highly active antiretroviral therapy (HAART) has led to a decreased incidence of the most severe form of HIV associated neurocognitive disorders (HAND), HIV-associated dementia, it does not appear to have impacted overall prevalence of HAND. Existing evidence suggests that the central nervous system (CNS) could be an important reservoir for HIV regardless of cumulative time on treatment. This 8 year multi-institute screening protocol will identify approximately 200 HIV-infected individuals and 100 healthy volunteers for enrollment in multiple HAND studies at the National Institutes of Health (NIH). Subjects will undergo a one-time screening and evaluation assessment, which will include history and physical, blood and urine collection, neuropsychological testing, Client Diagnostic Questionnaire (CDQ), and brain magnetic resonance imaging (MRI). Those who meet eligibility criteria will be offered enrollment and co-enrollment into active HIV-associated neurocognitive disorder protocols, including the natural history study presented here. This observational study will characterize the natural course of HAND in subjects with HIV viral loads <50 copies/mm3. Subjects will be followed yearly for 5 years. Visits will include updated exam, blood and urine collection, neuropsychological testing, brain MRI, optional lumbar puncture or drain, and optional ophthalmology exam. The option to have a lumbar drain is only on the first visit and extended to HIV positive individuals only. HIV- negative controls will have the option of doing a positron emission tomography/computed tomography (PET/CT) imaging during the first visit. Cerebrospinal fluid (CSF) markers of immune activation, chronic monocyte activation, cytomegalovirus/Epstein- Barr virus (CMV/EBV) infection/reactivation, and neuronal injury will be collected. In addition, HIV viral load and genotype, genetic susceptibility factors and CNS penetration- effectiveness score (CPE) and CSF levels of antiretroviral drugs may be assessed. A repository of cryopreserved biological samples will be developed and used for validation of candidate biomarkers in future studies. Collection and analysis of these data will not only enhance understanding of the CNS as a potential HIV reservoir in virally-controlled individuals but will further define the association among cortical thickness, biomarkers and neurocognitive function in an aging HIV-infected population.
Study Type	Observational
Study Design	Time Perspective: Retrospective
Target Follow-Up Duration	Not Provided
Biospecimen	Not Provided
Sampling Method	Not Provided
Study Population	Not Provided
Condition	Acquired Immunodeficiency; Neurocognitive Disorders
Intervention	Not Provided
Study Groups/Cohorts	Not Provided
Publications *	Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007 Oct 30;69(18):1789-99. Epub 2007 Oct 3.; McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol. 2004 Dec;157(1-2):3-10. Review.; Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol. 2002 Apr;8(2):136-42.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status	Recruiting
Estimated Enrollment; (submitted: January 20, 2016)	600
Original Estimated Enrollment; (submitted: June 11, 2013)	250
Estimated Study Completion Date	December 31, 2022
Estimated Primary Completion Date	December 31, 2021 (Final data collection date for primary outcome measure)
Eligibility Criteria	ELIGIBILITY CRITERIA FOR PART I SCREENING STUDY: INCLUSION CRITERIA: All Subjects (HIV-infected and HIV-negative Controls): While different individual HIV neurocognitive studies have specific selection criteria, especially related to HIV viral load and antiretroviral therapy, inclusion criteria for this overarching protocol will be flexible in order to identify the broadest base of potential enrollees possible. An upper age limit of 61 years old will be used because changes in neurocognitive function occur more commonly in the general population after this age.; Men and women, 18 years of age and older; Ability to sign informed consent by the subject; At least seventh grade educational level and ability to speak, read, and understand English. Education level will be assessed by subject self-report. Because many of the neuropsychological subtests were validated using United States norms, subjects must be native English speakers or if foreign-born, demonstrate ability to understand the English language at the time of screening protocol consent and neuropsychological testing. HIV-infected Only: HIV-1 infection, as documented by OraQuick rapid test using venipuncture whole blood, or fingerstick whole blood done at screening; or with HIV-1/HIV-2 Multispot rapid test and Western Blot as determined by NIH Clinical Pathology Laboratory or Leidos Biomedical Research. Monitoring Laboratory.; Outside primary medical doctor who provides care HIV-negative Controls Only: 1.HIV-antibody negative EXCLUSION CRITERIA: Screening Study (all participants): Illness or other condition that, in the opinion of the PI, may interfere with study participation at the time of enrollment, including, but not limited to those listed below: CNS infections: this includes but is not limited to Varicella zoster virus (VZV) encephalitis, CNS lymphoma and toxoplasmosis. Subjects who have recovered from effectively treated CNS infections may be considered once they resume baseline daily activities. Non-CNS opportunistic infections: subjects who recovered from or are completing treatment for non-CNS opportunistic infections (OIs) (e.g., Pneumocystis pneumonia, Candida esophagitis, or pulmonary TB) can be enrolled if they have returned to self-reported baseline activity and functional level.; Conditions other than HAND associated with cognitive impairment or dementia such as Alzheimer s, Parkinson s disease, head injury with loss of consciousness >30 minutes, untreated sleep apnea with day-time sleepiness, or seizure disorders. Subjects with a history of seizure disorder with no seizure activity that are on a stable, non-sedating anti-seizure regimen for >6 months may be enrolled.; Concurrent severe, unstable psychiatric illness that, in the opinion of the investigators, may interfere with study participation and/or data interpretation. Subjects on psychotropic anxiolytic, attention deficit-hyperactivity disorder (ADHD), and other psychiatric medications may be included if clinically stable for >6 months.; Concurrent substance abuse that, in the opinion of the investigators may interfere with study participation and/or data interpretation. Active substance abuse includes illegal drug use and/or excessive narcotic or alcohol use as determined by the investigator. Urine drug screen will be performed on all subjects at screening. Use of nicotine containing products will not be an exclusion criterion.; Contraindication to MRI/ MRS scanning, including pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), implanted delivery pump, or shrapnel fragments. Patients requiring a low dose oral benzodiazepine for mild to moderate claustrophobia will be allowed to participate. Pregnancy testing will be performed in enrolled female participants 48 hours prior to any MRI.; Medications: narcotics, psychiatric, and anti-seizure medications will not be allowed except under certain conditions as noted above. Corticosteroids may be permitted for subjects on stable short-term therapy without CNS disease (i.e., resolving Pneumocystis pneumonia). Participants must be willing not to take the following medications within 48 hours of neuropsychological testing : sedating antihistamines such as diphenhydramine, zolpidem and other drugs identified by the study team that are associated with altered alertness or impaired memory.; Pregnant or Lactating women: Women of childbearing potential must have a negative serum or urine pregnancy test at the time of screening. Pregnancy testing will also be performed in enrolled female participants prior to any radiation exposure. ELIGIBILITY CRITERIA FOR PART II NATURAL HISTORY STUDY: INCLUSION CRITERIA: Natural History Study (HIV-infected Only): In addition to the inclusion criteria for the screening study (see above); Plasma HIV-RNA <50 copies/mm(3) or BLD for greater than one year. Patients who experience transitory episodes of an HIV viral load > 50 copies/mm (3) preceded and followed by plasma viremia < 50 copies/mm(3) may be included.; At least one year of continuous ART; Consent to store blood and tissue; Willing to participate on this study for 5 years Natural History Study (Healthy Controls Only): Men and women, 18 years of age and older; Ability to sign informed consent by the subject; At least seventh grade educational level and ability to speak, read, and understand English. Education level will be assessed by subject self-report. Because many of the neuropsychological subtests were validated using United States norms, subjects must be native English speakers or if foreign-born, demonstrate ability to understand the English language at the time of screening protocol consent and neuropsychological testing.; HIV-antibody negative PARTICIPANT EXCLUSION CRITERIA: In addition to the exclusion criteria from the screening protocol (see section above): Inability to refrain from use of anticoagulant/antiplatelet medication, such as dipyridamole (Persantine), clopidogrel (Plavix), dabigatran (Pradaxa), or warfarin (Coumadin) for at least 72 hours prior to invasive procedures (lumbar puncture [LP], lumbar drain).; Prior or planned/anticipated exposure to radiation due to clinical care or participation in other research protocols, which would exceed the recommended acceptable annual limit of radiation exposure once accounting for the requirements of the current study.; Pregnant or Lactating females are excluded due to exposure to the radioactive compound for PET/CT scans, which may be excreted in the breast milk and could be potentially harmful to breast-fed infants. There is also exposure to radiation from the CT part of the PET/CT scan and the lumbar puncture if done under fluoroscopy. Women of childbearing potention must have a negative serum or urine pregnancy 48 hours prior to any radiation exposure. EXCLUSION OF PREGNANT OR LACTATING WOMEN: The study requires exposure to high magnetic fields and irradiation, which could pose a risk to the fetus. Futher, we will be studying growth factors and inflammatory mediators in blood and CSF all of which will be affected by the state of pregnancy and then post partum state. Women who are lactating are excluded because the study may result in transfer of radioactive tracer in breast milk. EXCLUSION OF CHILDREN:: Subjects younger than 18 years of age are excluded because the developing brain is not within the scope of this study. Department of Defense MRI-only Inclusion/Exclusion Criteria: Due to the nature of the military population, the ALLHANDS DOD protocol has some notable differences in the inclusion/exclusion criteria. Note that only HIV+ participants will come from the DOD.; No ART use or HIV viral load level requirement.; Outside primary medical doctor requirement not included as subjects are military beneficiaries who have primary medical care; Illicit drug testing will not be performed for this study to avoid risk of inadvertent identification and disclosure of a positive result. Prior studies have shown drug use to be very low in this population.; Head injury with loss of consciousness >30 minutes will be noted, but not an exclusion criterion.; Untreated sleep apnea with daytime sleepiness will be noted, but not an exclusion criterion Sleep disorders were found to be prevalent among this population.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	Yes
Contacts	Contact: Amanda M Wiebold (301) 594-5194 amanda.wiebold@nih.gov Contact: Avindra Nath, M.D. (301) 496-1561 natha@mail.nih.gov
Listed Location Countries	United States
Removed Location Countries
Administrative Information
NCT Number	NCT01875588
Other Study ID Numbers	130149; 13-N-0149
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Institute of Neurological Disorders and Stroke (NINDS) )
Study Sponsor	National Institute of Neurological Disorders and Stroke (NINDS)
Collaborators	Not Provided
Investigators	Principal Investigator: Avindra Nath, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	May 31, 2018