Identification and Quantification of HIV CNS Latency Biomarkers

• ClinicalTrials.gov Identifier: NCT02989285
• Recruitment Status: Unknown
• First Posted: December 12, 2016
• Last Update Posted: February 15, 2019
• Sponsor: St Vincent's Hospital, Sydney
• Information provided by (Responsible Party): Bruce Brew, St Vincent's Hospital, Sydney

Study Description

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.

Condition or disease
HIV; HIV-associated Neurocognitive Disorder (HAND)

Study Design

• Study Type: Observational
• Estimated Enrollment: 70 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: The Identification and Quantification of HIV CNS Latency Biomarkers
• Study Start Date: July 2016
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2020

Groups and Cohorts

Group/Cohort
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.

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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).
4. 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).
5. 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).
6. 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).
7. 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).

Secondary Outcome Measures :

1. Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months [ Time Frame: Baseline and 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.
2. Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden [ Time Frame: Baseline and 6 months, 12 months, 18 months, and 24 months ]
   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.

Biospecimen Retention:   Samples Without DNA

Cerebrospinal fluid and bloods

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

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.

Criteria

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

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

Contacts and Locations

Contacts

Contact: Bruce J Brew, MBBS, MD; +61 2 8382 1111 ext 4100; bruce.brew@svha.org.au

Contact: Thomas M Gates, MPsychol; +61 2 8382 1111 ext 2435; thomas.gates@svha.org.au

Locations

Australia, New South Wales

St Vincent's Hospital, Sydney; Recruiting

Darlinghurst, New South Wales, Australia, 2010

Contact: Sarah Barney, RN +61 2 8382 4976 sarah.barney@svha.org.au

Principal Investigator: Bruce J Brew, MBBS, MD

Sponsors and Collaborators

St Vincent's Hospital, Sydney

Investigators

• Principal Investigator: Bruce J Brew, MBBS, MD; St Vincent's Hospital, Sydney

More Information

• Responsible Party: Bruce Brew, Professor, St Vincent's Hospital, Sydney
• ClinicalTrials.gov Identifier: NCT02989285
• Other Study ID Numbers: 15/277; APP1105808 ( Other Grant/Funding Number: NHMRC )
• First Posted: December 12, 2016
• Last Update Posted: February 15, 2019
• Last Verified: February 2019

Keywords provided by Bruce Brew, St Vincent's Hospital, Sydney:

HIV; HIV-associated neurocognitive disorder (HAND); Neurology; Latent HIV; HIV Reservoirs

Additional relevant MeSH terms:

Neurocognitive Disorders; Mental Disorders