Clinical trial NCT02989285: Identification and Quantification of HIV CNS Latency Biomarkers
Official title: The Identification and Quantification of HIV CNS Latency Biomarkers
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: HIV
HIV-associated Neurocognitive Disorder (HAND)
Keywords: HIV
HIV-associated neurocognitive disorder (HAND)
Neurology
Latent HIV
HIV Reservoirs
Lead sponsor: St Vincent's Hospital, Sydney
Sponsor class: OTHER
First posted: 2016-12-12
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.


Eligibility 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

Primary outcomes:
measure: Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean Level of 1H-MRS Myo-Inositol in Frontal White Matter at 24 months (latency burden biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean CSF HIV RNA by Single Copy Assay at 24 months (latency significance biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean CSF HIV tat at 24 months (latency significance biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean CSF neopterin at 24 months (latency significance biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean CSF MCP-1 at 24 months (latency significance biomarker)
timeFrame: Baseline and 24 months
measure: Change in Mean CSF NFL at 24 months (latency significance biomarker)
timeFrame: Baseline and 24 Months
Secondary outcomes:
measure: Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months
timeFrame: Baseline and 24 months
measure: Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden
timeFrame: Baseline and 6 months, 12 months, 18 months, and 24 months
Other outcomes:
Locations:
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital, Sydney
state: New South Wales
Study officials:
affiliation: St Vincent's Hospital, Sydney
name: Bruce J Brew, MBBS, MD
role: PRINCIPAL_INVESTIGATOR
References: