Temporal Patterns and Drug Resistance in CSF Viral Escape Among ART-Experienced HIV-1 Infected Adults

Abstract

Background: Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels.

Methods: Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016.

Results: Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm and CD4 nadir 21 cells/mm. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51-999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA <200 or ≥200 copies/mL). High-level viremia cases reported more substance abuse, whereas LLV or plasma suppression cases were more neurosymptomatic (81% vs. 53%); 75% of repeat CSF escape cases were classified LLV. M184V/I mutations were identified in 74% of CSF samples when plasma levels were ≤50 copies per milliliter.

Conclusions: Characteristics frequently observed in CSF escape include HIV-1 infection >15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

FIGURE 1.

Representative plasma (blue) and CSF (red) HIV-1 RNA levels in patients with persistent high-level or low-level viremia (top panels), CSF blips, or CSF escape (bottom panels). Patients with low-level viremia for at least 6 months, and those with durable plasma suppression for up to 24 months prior to CSF blips (<200 copies/mL) or CSF HIV-1 RNA escape (≥200 copies/mL) were more likely to report neurological symptoms at the time of CSF analysis than patients with high-level viremia. ART, antiretroviral therapy; ANI, asymptomatic neurocognitive impairment; HAD, HIV-associated dementia; MND, mild neurocognitive disorder; PML, progressive multifocal leukoencephalopathy.