Identification and Quantification of HIV CNS Latency Biomarkers

NCT ID: NCT02989285

Last Updated: 2019-02-15

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 70 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-07-31
• Study Completion Date: 2020-12-31

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.

Conditions

HIV; HIV-associated Neurocognitive Disorder (HAND)

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

No interventions assigned to this group

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.

No interventions assigned to this group

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

St Vincent's Hospital, Sydney

OTHER

Sponsor Role: lead

Responsible Party

Bruce Brew

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bruce J Brew, MBBS, MD

Role: PRINCIPAL_INVESTIGATOR

St Vincent's Hospital, Sydney

Locations

St Vincent's Hospital, Sydney

Darlinghurst, New South Wales, Australia

Site Status: RECRUITING

Countries

Australia

Central Contacts

Bruce J Brew, MBBS, MD

Role: CONTACT

bruce.brew@svha.org.au

+61 2 8382 1111 ext. 4100

Thomas M Gates, MPsychol

Role: CONTACT

thomas.gates@svha.org.au

+61 2 8382 1111 ext. 2435

Facility Contacts

Sarah Barney, RN

Role: primary

sarah.barney@svha.org.au

+61 2 8382 4976

Other Identifiers

APP1105808

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

15/277

Identifier Type: -

Identifier Source: org_study_id