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 neuro-symptomatic CSF ‘escape,’ defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA >1 log higher than plasma RNA. Design Retrospective case series. Setting 4 urban medical centers in the United States and Europe. Subjects 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 CNS exposure. Main outcome measures Levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, magnetic resonance imaging findings. Results 10 patients presented with new neurological abnormalities, which included sensory, motor, and cognitive manifestations. Median CSF HIV RNA was 3900 copies/mL (range 134-9056), while median plasma HIV RNA was 62 copies/mL (range <50-380). Median CD4+ T cell count was 482 cells/mm3 (range, 290-660). All patients had been controlled <500 copies/mL for median 27.5 months (range, 2-96) and 5/10 had been suppressed <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; 7/8 had abnormalities on MRI; and 6/7 harbored CSF resistance mutations. Following optimization of ART, 8/9 patients improved clinically. Conclusions 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.

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[22,23,[139][140][141][142] In most of the subjects differential viral evolution (with resistance-associated mutation selected in the CSF compartment) was shown and it was explained by asymmetrical penetration of ARVs (with some cerebrospinal fluid concentrations below the limit of detection) but not confirmed by other reports. [143] In a large longitudinal study the factors associated with CSF escape were the presence of CSF pleocytosis, the use of a PI-containing HAART and ultrasensitive plasma HIV RNA level: [144] the poor CSF to plasma ratios observed with protease inhibitors (0 to 1.4% with currently used PIs) may possibly explain these results as well as persistent intrathecal immune activation and plasma residual viremia.…”

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy

“…The patient was a 46-year-old man, who was admitted with behavioral and cognitive changes while on treatment with lamivudine, abacavir, and saquinavir. Blood and CSF examinations at admission showed plasma HIV RNA <40 c/mL, CSF HIV RNA 274 c/mL, CSF HIV genotyping M184V reverse transcriptase mutation, CSF white blood cells 68/μL, and CD4+ 545/μL Values refer to refs [57,58] a Ref [57] only; ref. [58]: median 31, range achieved in the CNS is inadequate to suppress the local, compartmentalized infection.…”

“…Blood and CSF examinations at admission showed plasma HIV RNA <40 c/mL, CSF HIV RNA 274 c/mL, CSF HIV genotyping M184V reverse transcriptase mutation, CSF white blood cells 68/μL, and CD4+ 545/μL Values refer to refs [57,58] a Ref [57] only; ref. [58]: median 31, range achieved in the CNS is inadequate to suppress the local, compartmentalized infection. Biologically, the relative preservation of the systemic immune system with restored CD4 and high CD8 T cells characteristic of treated patients may be important in determining the phenotype of the disease with its CSF pleocytosis and frequent CD8 encephalitis.…”

Clinical Trials in Neurovirology: Successes, Challenges, and Pitfalls

“…Ongoing cognitive impairment, occasional episodes of viral replication developing in the brain (termed CSF viral escape), and evidence of ongoing inflammatory responses in the brain compartment reflected in CSF continue to support trials targeting CNS HIV complications [24][25][26]. The target of curing HIV must include the brain reservoir of virus, which is likely to be one of the most challenging targets for this agenda, because of the unique environment of the brain.…”