Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load

Abstract

Objective: To characterize HIV-infected patients with neurosymptomatic cerebrospinal fluid (CSF) 'escape', defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA more than 1-log higher than plasma RNA.

Design: Retrospective case series.

Setting: Four urban medical centers in the United States and Europe.

Participants: Virologically controlled HIV-infected patients on antiretroviral therapy (ART) with progressive neurologic abnormalities who were determined to have CSF 'escape'. INTERVENTION Optimization of ART based upon drug susceptibility and presumed central nervous system exposure.

Main outcome measures: Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and MRI findings.

Results: Ten patients presented with new neurologic abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/ml (range 134-9056), whereas median plasma HIV RNA was 62 copies/ml (range <50 to 380). Median CD4 T-cell count was 482 cells/μl (range 290-660). All patients had been controlled to less than 500 copies/ml for median 27.5 months (range 2-96) and five of 10 had been suppressed to less than 50 copies/ml for median 19.5 months (range 2-96). Patients had documentation of a stable ART regimen for median 21 months (range 9-60). All had CSF pleocytosis or elevated CSF protein; seven of eight had abnormalities on MRI; and six of seven harbored CSF resistance mutations. Following optimization of ART, eight of nine patients improved clinically.

Conclusion: The development of neurologic symptoms in patients on ART with low or undetectable plasma HIV levels may be an indication of CSF 'escape'. This study adds to a growing body of literature regarding this rare condition in well controlled HIV infection.

Figure 1a-j. Selected MRI images for Patients 2000 and 7000

Panels a-d show imaging at the time of neurologic workup when CSF ‘escape’ was detected for patients 2000 (a,b) and 7000 (c,d), demonstrating diffuse T2-prolongation (a,b) and suggesting focal lesions (d) at the time of CSF ‘escape.’ Panels e-h show follow-up imaging for patient 2000 at 111 days and patient 7000 at 60 days. Even though neurologic symptoms had resolved in both cases, imaging still shows diffuse leukoencephalopathy (e,f) and hyperintense, diffuse signal alteration of bilateral white matter (h), despite improvement of previous focal lesions (h). Panels i and j show imaging for patient 2000 at 567 days follow-up, demonstrating significant interval decrease in T2-prolongation.

Figure 2. Longitudinal plasma HIV RNA levels for patients with CSF ‘escape’

HIV RNA is calculated in days prior to time CSF/plasma discordance was detected (time “0”). Reference dotted horizontal line indicates log₁₀ 500 copies/mL. Corresponding CSF HIV RNA levels are indicated on the right axis of the graph at the time when CSF escape was identified (“CSF Escape”) and at a standardized follow-up timepoint, where repeat CSF was available (“Follow-up”).