HIVNCT02989285
Identification and Quantification of HIV CNS Latency Biomarkers
An observational study of HIV and HIV-associated Neurocognitive Disorder (HAND), run by St Vincent's Hospital, Sydney at 1 site in Australia.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV, HIV-associated Neurocognitive Disorder (HAND)
- How many people
- 70 participants
- Where
- 1 siteAustralia
- Study dates
- Jul 2016to Dec 2020
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: HIV+ patients who are stable on HAART and have achieved viral suppression in blood and CSF who attend outpatient hospital and primary care clinics.
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Australia1 site, 1 recruiting
- Recruiting
St Vincent's Hospital, Sydney
Darlinghurst, New South Wales, 2010
Sarah Barney, RN, +61 2 8382 4976, sarah.barney@svha.org.au
Bruce J Brew, MBBS, MD
About this study
Official title: The Identification and Quantification of HIV CNS Latency Biomarkers
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.
Read more
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.
- Conditions
- HIV, HIV-associated Neurocognitive Disorder (HAND)
- Keywords
- HIV, HIV-associated neurocognitive disorder (HAND), Neurology, Latent HIV, HIV Reservoirs
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and 24 months
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.
Measured: Baseline and 24 months
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).
Measured: Baseline and 24 months
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).
Measured: Baseline and 24 months
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).
Measured: Baseline and 24 months
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).
Measured: Baseline and 24 months
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).
Measured: Baseline and 24 Months
Secondary outcomes (2)
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.
Measured: Baseline and 24 months
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.
Measured: Baseline and 6 months, 12 months, 18 months, and 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2016 (estimated)
- Study startJul 2016
- Primary completionDec 2020 (estimated)
- Study completionDec 2020 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIVStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- St Vincent's Hospital, Sydney
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Bruce Brew, St Vincent's Hospital, Sydney
- Investigators
- Bruce J Brew, MBBS, MD, Principal investigator, St Vincent's Hospital, Sydney
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02989285
- Sponsor's protocol ID
- 15/277
- Other IDs
- APP1105808
- Status last verified
- Feb 2019
- First submitted
- 6 Jul 2016
- Last updated
- 15 Feb 2019
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Identification and Quantification of HIV CNS Latency Biomarkers
- ClinicalTrials.gov ID
- NCT02989285
- Acronym / sponsor ID
- 15/277
- Conditions
- HIV, HIV-associated Neurocognitive Disorder (HAND)
- Keywords
- HIV, HIV-associated neurocognitive disorder (HAND), Neurology, Latent HIV, HIV Reservoirs
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- St Vincent's Hospital, SydneyUniversity, hospital or other
- Study start
- Jul 2016
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Dec 2020 (estimated)
- First posted
- 12 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- HIV+ patients who are stable on HAART and have achieved viral suppression in blood and CSF who attend outpatient hospital and primary care clinics.
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker)
Time frame: Baseline and 24 months
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.
Change in Mean Level of 1H-MRS Myo-Inositol in Frontal White Matter at 24 months (latency burden biomarker)
Time frame: Baseline and 24 months
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.
Change in Mean CSF HIV RNA by Single Copy Assay at 24 months (latency significance biomarker)
Time frame: Baseline and 24 months
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).
Change in Mean CSF HIV tat at 24 months (latency significance biomarker)
Time frame: Baseline and 24 months
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).
Change in Mean CSF neopterin at 24 months (latency significance biomarker)
Time frame: Baseline and 24 months
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).
Change in Mean CSF MCP-1 at 24 months (latency significance biomarker)
Time frame: Baseline and 24 months
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).
Change in Mean CSF NFL at 24 months (latency significance biomarker)
Time frame: Baseline and 24 Months
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).
2 secondary outcomes
Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months
Time frame: Baseline and 24 months
Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden
Time frame: Baseline and 6 months, 12 months, 18 months, and 24 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Feb 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bruce J Brew, MBBS, MD principal investigator
St Vincent's Hospital, Sydney
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of HIV and HIV-associated Neurocognitive Disorder (HAND), run by St Vincent's Hospital, Sydney at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 15 Feb 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Bruce J Brew, MBBS, MD (+61 2 8382 1111 ext. 4100, bruce.brew@svha.org.au), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker) (time frame: Baseline and 24 months). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Feb 2019.