Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape

Abstract

The aims of this study were to investigate the frequency of HIV-1 RNA level discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients with HIV-1 subtype C on antiretroviral therapy, and evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p < 0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of > 5 cells/mm³ than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15 cells/mm³) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance was 83% and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher than those for an HIV(-) person. Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

Keywords: Central nervous system (CNS); Cerebrospinal fluid (CSF); Discordance; HIV-1; Scape; White blood cell.

Figure 1.

A. Cerebrospinal fluid (CSF) and plasma HIV RNA levels (Log₁₀) in the groups with cerebrospinal fluid (CSF) white blood cell (WBC) count increased (>5 cell/mm³) and on normal range (≤5 cell/mm³). The line in the center of the box represents median; the superior and inferior borders of the box represent interquartiles (IQRs); the whiskers represent the least and greatest values; the number of cases in each group are indicated by the dots. B. Receiver operating characteristic (ROC) curve to evaluate predictive characteristics of CSF WBC in characterizing subjects with CSF HIV RNA discordance. CSF HIV RNA discordance was defined as CSF HIV RNA greater than 1log₁₀ of the plasma HIV RNA (Canestri et al. 2010); optimal cut-off point 15 cells/mm³; area under the curve (AUC) = 0.981; 95% CI = 0.951−1. The AUC acts as a single measure, independent of prevalence, which summarizes the discriminative ability of a test across the full range of cut-offs, where the higher the AUC is, the better the test will be. The higher the AUC, the better the test. A perfect test would have an AUC of 1.0, while a completely ineffective test (where the curve falls on diagonal line) has an AUC of 0.5. Youden’s index (J) is the difference between the true positive rate and the false positive rate. According to its definition, “J” is the vertical distance between the ROC curve and the first bisector (or chance line), dashed line. Maximizing this index allows to find, from the ROC curve, an optimal cut-off point independently from the prevalence.

Figure 2.. Frequency of global neuropsychological impairment based on global deficit score (GDS) ≥ 0.5 in the escape, discordance, HIV viral load higher in plasma than cerebrospinal fluid (CSF), aviremic in CSF and plasma, and HIV seronegative control groups.

All HIV seropositive groups were significantly worse than the seronegative group, but not different from one another. Comparison of all four groups p=0.0004, pairwise comparisons of the groups escape, discordance, HIV RNA in plasma higher than in CSF and aviremic in CSF and plasma with the HIV− control group were p= 0.005, 0.014, 0.003, 0.003 respectively. The other comparisons were not significant (p>0.05). The odds of cognitive impairment for a participant with escape, discordance, HIV RNA in plasma higher than in CSF, and CSF and plasma aviremic were 19.0 (95 % CI: 2.0 to 181.6), 15.2 (95 % CI:1.6 to 151.5), 6.0 (95 % CI: 1.8 to 19.4) and 4.7 (95 % CI: 1.7 to 12.8) times higher, respectively, than those for a person without HIV infection (p = 0.011, 0.020, 0.003 and 0.003, respectively).