HIV Cerebrospinal Fluid Escape: Interventions for the Management, Current Evidence and Future Perspectives

Overview

Journal Trop Med Infect Dis

Specialty Infectious Diseases

Date 2025 Feb 25

PMID 39998049

Authors

Sophie H Kelly

Sam Nightingale

Ravindra K Gupta

Dami A Collier

Affiliations

Soon will be listed here.

Abstract

Neurocognitive impairment is an important cause of HIV-associated morbidity. The advent of antiretroviral therapy (ART) has shifted the spectrum of HIV-associated cognitive impairment from HIV-associated dementia to milder forms of cognitive impairment. Independent replication of HIV within the central nervous system in those on effective ART with peripheral suppression is a recognised phenomenon known as cerebrospinal fluid (CSF) HIV RNA escape. CSF HIV RNA escape is independently associated with neurocognitive impairment but has also been detected in asymptomatic persons with HIV. The current consensus for management of CSF HIV RNA escape is based on expert opinion rather than empirical evidence. The current evidence suggests having a low threshold to investigate for CSF HIV RNA escape and optimising ART based on resistance profiles. The use of central nervous system (CNS) penetration effectiveness scores is no longer recommended. The evidence for statins, SSRIs, minocycline, lithium and valproate is limited to small-scale studies. There are potential new developments in the form of nanoparticles, Janus Kinase inhibitors and latency reversal agents.

References

Varatharajan L, Thomas S . The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res. 2009; 82(2):A99-109. PMC: 2678986. DOI: 10.1016/j.antiviral.2008.12.013. View

Joseph S, Kincer L, Bowman N, Evans C, Vinikoor M, Lippincott C . Human Immunodeficiency Virus Type 1 RNA Detected in the Central Nervous System (CNS) After Years of Suppressive Antiretroviral Therapy Can Originate from a Replicating CNS Reservoir or Clonally Expanded Cells. Clin Infect Dis. 2018; 69(8):1345-1352. PMC: 6938202. DOI: 10.1093/cid/ciy1066. View

Hu Z, Cinque P, Dravid A, Hagberg L, Yilmaz A, Zetterberg H . Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection. PLoS Pathog. 2024; 20(9):e1012470. PMC: 11469498. DOI: 10.1371/journal.ppat.1012470. View

Winston A, Antinori A, Cinque P, Fox H, Gisslen M, Henrich T . Defining cerebrospinal fluid HIV RNA escape: editorial review AIDS. AIDS. 2019; 33 Suppl 2:S107-S111. DOI: 10.1097/QAD.0000000000002252. View

Marra C, Maxwell C, Collier A, Robertson K, Imrie A . Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy. BMC Infect Dis. 2007; 7:37. PMC: 1871592. DOI: 10.1186/1471-2334-7-37. View

Gavegnano C, Haile W, Hurwitz S, Tao S, Jiang Y, Schinazi R . Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro. J Neuroinflammation. 2019; 16(1):182. PMC: 6764124. DOI: 10.1186/s12974-019-1565-6. View

Chan T, Marta M, Rackstraw S . Relapse of neurosymptomatic cerebrospinal fluid HIV RNA escape. HIV Med. 2023; 24(11):1158-1163. DOI: 10.1111/hiv.13527. View

Antinori A, Giancola M, Grisetti S, Soldani F, Alba L, Liuzzi G . Factors influencing virological response to antiretroviral drugs in cerebrospinal fluid of advanced HIV-1-infected patients. AIDS. 2002; 16(14):1867-76. DOI: 10.1097/00002030-200209270-00003. View

Collier D, Haddow L, Brijkumar J, Moosa M, Benjamin L, Gupta R . HIV Cerebrospinal Fluid Escape and Neurocognitive Pathology in the Era of Combined Antiretroviral Therapy: What Lies Beneath the Tip of the Iceberg in Sub-Saharan Africa?. Brain Sci. 2018; 8(10). PMC: 6211092. DOI: 10.3390/brainsci8100190. View

10.

Popovic M, Sarngadharan M, Read E, Gallo R . Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984; 224(4648):497-500. DOI: 10.1126/science.6200935. View

11.

Spudich S, Nilsson A, Lollo N, Liegler T, Petropoulos C, Deeks S . Cerebrospinal fluid HIV infection and pleocytosis: relation to systemic infection and antiretroviral treatment. BMC Infect Dis. 2005; 5:98. PMC: 1299327. DOI: 10.1186/1471-2334-5-98. View

12.

Routy J, Tremblay C, Angel J, Trottier B, Rouleau D, Baril J . Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012; 13(5):291-6. DOI: 10.1111/j.1468-1293.2011.00975.x. View

13.

Castellano P, Prevedel L, Eugenin E . HIV-infected macrophages and microglia that survive acute infection become viral reservoirs by a mechanism involving Bim. Sci Rep. 2017; 7(1):12866. PMC: 5634422. DOI: 10.1038/s41598-017-12758-w. View

14.

Nair M, Jayant R, Kaushik A, Sagar V . Getting into the brain: Potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev. 2016; 103:202-217. PMC: 4935582. DOI: 10.1016/j.addr.2016.02.008. View

15.

Pillai S, Kosakovsky Pond S, Liu Y, Good B, Strain M, Ellis R . Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain. 2006; 129(Pt 7):1872-83. DOI: 10.1093/brain/awl136. View

16.

van Zoest R, Underwood J, De Francesco D, Sabin C, Cole J, Wit F . Structural Brain Abnormalities in Successfully Treated HIV Infection: Associations With Disease and Cerebrospinal Fluid Biomarkers. J Infect Dis. 2017; 217(1):69-81. DOI: 10.1093/infdis/jix553. View

17.

Del Real G, Jimenez-Baranda S, Mira E, Lacalle R, Lucas P, Gomez-Mouton C . Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med. 2004; 200(4):541-7. PMC: 2211926. DOI: 10.1084/jem.20040061. View

18.

Spudich S, Robertson K, Bosch R, Gandhi R, Cyktor J, Mar H . Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance. J Clin Invest. 2019; 129(8):3339-3346. PMC: 6668666. DOI: 10.1172/JCI127413. View

19.

Heaton R, Franklin D, Ellis R, McCutchan J, Letendre S, LeBlanc S . HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2010; 17(1):3-16. PMC: 3032197. DOI: 10.1007/s13365-010-0006-1. View

20.

Gong Y, Chowdhury P, Nagesh P, Rahman M, Zhi K, Yallapu M . Novel elvitegravir nanoformulation for drug delivery across the blood-brain barrier to achieve HIV-1 suppression in the CNS macrophages. Sci Rep. 2020; 10(1):3835. PMC: 7052245. DOI: 10.1038/s41598-020-60684-1. View