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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02989285




Registration number
NCT02989285
Ethics application status
Date submitted
6/07/2016
Date registered
12/12/2016
Date last updated
15/02/2019

Titles & IDs
Public title
Identification and Quantification of HIV CNS Latency Biomarkers
Scientific title
The Identification and Quantification of HIV CNS Latency Biomarkers
Secondary ID [1] 0 0
APP1105808
Secondary ID [2] 0 0
15/277
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV 0 0
HIV-associated Neurocognitive Disorder (HAND) 0 0
Condition category
Condition code
Neurological 0 0 0 0
Other neurological disorders
Mental Health 0 0 0 0
Other mental health disorders

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
HIV+ cognitively impaired (HAND) - Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.

HIV+ cognitively normal (no-HAND) - Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.

Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker) - BCL11b is a C2H5 zinc-finger DNA binding protein that is expressed in the brain and immune system and inhibits HIV gene transcription by recruiting chromatin modifiers and establishing a heterochromatic environment in HIV-infected microglia. It is a promising candidate biomarker for latent HIV infection in the brain. Change in CSF BCL11b levels from baseline at 24 months will be reported. BCL11b will also be tracked against HAND development/progression at each visit to determine its suitability as a marker of latent HIV reservoir size.
Timepoint [1] 0 0
Baseline and 24 months
Primary outcome [2] 0 0
Change in Mean Level of 1H-MRS Myo-Inositol in Frontal White Matter at 24 months (latency burden biomarker) - Myo-Inositol (mIo) is a brain metabolic marker measured by 1H-Magnetic Resonance Spectroscopy (MRS) that is thought to reflect astroglia and microglia activation in cognitively-impaired individuals. The finding that mIo in the frontal white matter is elevated in HIV+ individuals and remains elevated with HAND progression while other metabolite levels fluctuate, supports its possibility as a HIV latency biomarker. Change in 1H-MRS mIo levels in the FWM from baseline at 24 months will be reported. mIo will also be tracked against HAND development/progression to determine its suitability as a marker of latent HIV reservoir size.
Timepoint [2] 0 0
Baseline and 24 months
Primary outcome [3] 0 0
Change in Mean CSF HIV RNA by Single Copy Assay at 24 months (latency significance biomarker) - Single copy assay (SCA) of CSF HIV RNA will allow for precise detection of intermittent HIV brain infection productivity at low levels. This assay is highly sensitive and can measure levels of HIV RNA as low as 0.3 copies per ml. Change in CSF HIV RNA levels from baseline at 24 months will be reported. Detectability of CSF HIV RNA by SCA is related to increased risk of HAND development in asymptomatic patients suggesting that it may reflect a marker of latent HIV reservoir significance (i.e., the potential for latent HIV replication that is not defective). Such a marker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
Timepoint [3] 0 0
Baseline and 24 months
Primary outcome [4] 0 0
Change in Mean CSF HIV tat at 24 months (latency significance biomarker) - Tat is a post-transcriptional regulatory protein that promotes inflammation and enhances the effectiveness of HIV transcription to neighbouring cells. Therefore it may act as a latency significance biomarker. Change in CSF HIV tat levels from baseline at 24 months will be reported. HIV tat will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
Timepoint [4] 0 0
Baseline and 24 months
Primary outcome [5] 0 0
Change in Mean CSF neopterin at 24 months (latency significance biomarker) - Neopterin is an immune activation biomarker that is elevated in almost all persons with HAND on antiretroviral medication and in some without HAND, supporting its possible role as a latency significance marker. Change in CSF neopterin levels from baseline at 24 months will be reported. CSF neopterin will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
Timepoint [5] 0 0
Baseline and 24 months
Primary outcome [6] 0 0
Change in Mean CSF MCP-1 at 24 months (latency significance biomarker) - CSF MCP-1 is an immune activation biomarker that has been found to correlate with change in HAND status. Therefore it may be a latency significance marker. Change in CSF MCP-1 levels from baseline at 24 months will be reported. CSF MCP-1 will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
Timepoint [6] 0 0
Baseline and 24 months
Primary outcome [7] 0 0
Change in Mean CSF NFL at 24 months (latency significance biomarker) - CSF NFL is a marker of neuronal injury. It has been shown to correlate with HAND severity and predict its development, suggesting that it is likely to serve as a latency significance biomarker. Change in CSF NFL levels from baseline at 24 months will be reported. CSF NFL will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
Timepoint [7] 0 0
Baseline and 24 Months
Secondary outcome [1] 0 0
Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months - Cumulative levels of HIV tat in CSF will be quantified from baseline to 24 months as per primary outcome #4. They will then be correlated against HAND development/progression as quantified by neurocognitive global deficit score (GDS), and levels of inflammatory markers neopterin and MCP-1.
Timepoint [1] 0 0
Baseline and 24 months
Secondary outcome [2] 0 0
Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden - Cumulative HAART history will be recorded and scored as follows: drugs that target the pre-integration/integration phase of HIV replication will be given a score of 1; other drugs will be given a score of 0. Total scores will then be correlated with CSF BCL11b levels and any other CNS latency marker that is identified during primary outcome analyses.
Timepoint [2] 0 0
Baseline and 6 months, 12 months, 18 months, and 24 months

Eligibility
Key inclusion criteria
- HIV-infected

- Aged >18 years

- On HAART with viral load suppression (<50 copies / ml) in both plasma and CSF for at
least 6 months

- Able to provide informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Non-HIV related neurological disorder or active CNS opportunistic infection as
assessed by full blood count, electrolytes, creatinine, glucose, liver function tests,
venereal disease reaction level (VDRL), MRI brain scan and CSF analyses for cell
count, protein, glucose, culture, VDRL and cryptococcal antigen

- Psychiatric disorders on the psychotic axis, current major depression, current
substance use disorder and/or 12 month history of severe substance use disorder

- Active Hepatitis C co-infection

- History of severe traumatic brain injury (post-traumatic amnesia (PTA) duration>1 day)
or loss of consciousness > 30 minutes from other cause (e.g., hypoxic brain injury)

- Non-proficient in English

Study design
Purpose
Duration
Selection
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
Unknown status
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
St Vincent's Hospital, Sydney - Darlinghurst
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst

Funding & Sponsors
Primary sponsor type
Other
Name
St Vincent's Hospital, Sydney
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Human Immunodeficiency Virus (HIV) remains in infected patients receiving highly active
antiretroviral therapy (HAART) for many years. Stopping HAART usually leads to re-emergence
of small reservoirs of latent (inactive) HIV that reside inside certain types of infected
cells, that can replicate and cause a full HIV infection. Chronic HIV infection also leads to
long-term immune activation which is associated with higher incidence of serious non-AIDS
events including cardiovascular disease and cancers. Thus HIV+ patients must remain on HAART
indefinitely or replication-competent latent HIV reservoirs must be eradicated.

The central nervous system (CNS) is a sanctuary site for latent HIV. For example,
HIV-associated neurocognitive disorders (HAND) develop and persist in about 40% of HIV+
persons despite long-term HAART and viral suppression in blood and cerebrospinal fluid (CSF).
Continued CSF immune activation is also frequently observed despite viral suppression. Both
of these are likely to indicate ongoing low-level HIV replication in the CNS.

Several strategies to eradicate latent HIV are being explored. One of these, known as "shock
and kill" involves "awakening" latent HIV and inducing replication to make it more
susceptible to host immune responses and HAART. However, there are several major caveats to
its application in the CNS such as the risk of triggering a serious immunoinflammatory
response (e.g., meningoencephalitis) that cannot be easily controlled by HAART. Other
eradication strategies may also be problematic given that many latency-reversing agents have
limited penetration of the blood brain barrier and limited efficacy in astrocyte cells. To
improve the effectiveness of new eradication therapies it will be crucial to develop better
methods to identify and quantify latent HIV reservoir sites with greater precision.

To identify potential HIV latency biomarkers in the CNS, the investigators will study HIV+
patients stable on HAART and virally-suppressed in blood and CSF over 24 months. Because such
a marker should be associated with HAND or its development without changing significantly
with HAND progression, half of the sample will have HAND at study entry and half will not.
Patients will undergo neuropsychological testing and give blood and CSF samples every 6
months to identify candidate biomarkers and track them prospectively against HAND development
and progression. MRI brain scan will also occur at study entry and after 24 months.
Trial website
https://clinicaltrials.gov/show/NCT02989285
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bruce J Brew, MBBS, MD
Address 0 0
St Vincent's Hospital, Sydney
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Bruce J Brew, MBBS, MD
Address 0 0
Country 0 0
Phone 0 0
+61 2 8382 1111
Fax 0 0
Email 0 0
bruce.brew@svha.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02989285