Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India

Abstract

Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0– 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.

Differences in human immunodeficiency virus-1C viral load and drug resistance mutation between plasma and cerebrospinal fluid in patients with human immunodeficiency virus-associated cryptococcal meningitis in Botswana

“…[ 26 – 28 ] If these participants were previously exposed to PIs then occurrence of these mutations solely in the CSF compartment would be attributable to low CNS penetration effectiveness of PIs via the BBB. [ 6 , 29 , 30 ] In all these participants with HIV-1 DRM discordance, there was no evidence of viral escape as a result of present DRMs. One patient harboured HIV-1 strain with extensive DRMs and high HIV-1 VL in both CSF and plasma (patient ID:1736, Table 3 ).…”

“…After HIV-1 seeds to the CNS, compartmentalisation and replication in the CNS may yield elevated cerebrospinal fluid (CSF) HIV-1 ribonucleic acid (RNA) despite undetectable or low viral loads (VL) in the plasma, a phenomena commonly known as CSF viral escape or discordance. [ 5 , 6 ] The global prevalence of CSF viral escape is reported to be between 0.7% and 27.4%. [ 7 ] Factors such as low nadir CD4 count, ART treatment interruptions, persistent low level viremia and poor penetration of some antiretroviral drugs (ARV) through the blood brain barrier (BBB) into the CNS contribute to CSF viral escape.…”

Cerebrospinal fluid HIV-1 escape according to different thresholds and underlying comorbidities

“…This phenomenon, called CSF viral escape (CSF-E), has in fact been associated erratically with central nervous system (CNS) complications [1][2][3][4] and represents a rare opportunity to understand the establishment and persistence of the virus in compartmentalised reservoirs [3]. CSF-E prevalence varies widely from 0,7% to 42,3%, as recently reviewed [3,5]; this difference may be explained by variability in methods and clinical features of patients' samples and by the surprisingly large range of adopted CSF-E definitions [3][4][5]. An International Consortium has been recently founded: [3] one of its aims is to find consensus on CSF-E through the identification of clinically meaningful CSF HIV-RNA thresholds and level of discordance with plasma HIV-RNA [3].…”

Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

“…The standards of LLV vary greatly with different guidelines. In resource-limited countries or regions [2,7,8], LLV is defined as a viral load (VL) between 50 and 1000 copies/ ml, according to the World Health Organization (WHO) guidelines [9]. In United States and some other resource-rich countries [10][11][12], LLV is defined as a VL between 50 and 200 copies/ml according to the Department of Health and Human Services (DHHS) guidelines (USA, 2016) [13].…”