HIV‐1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment

Abstract

Background Occasional cases of viral escape in cerebrospinal fluid (CSF) despite suppression of plasma HIV-1 RNA have been reported. We investigated CSF viral escape in subjects treated with commonly used ART regimens in relation to intrathecal immune activation and CNS penetration effectiveness (CPE) rank. Methods Sixty-nine neurologically asymptomatic subjects treated with ART >6 months and plasma HIV-1 RNA <50 copies/ml were cross-sectionally included in the analysis. ART regimens included efavirenz, lopinavir/ritonavir or atazanavir/ritonavir combined with tenofovir, abacavir or zidovudine and emtricitabine or lamivudine. HIV-1 RNA was analysed with real-time PCR assays. Neopterin was analysed by ELISA. Results Seven (10%) of the 69 subjects had detectable CSF HIV-1 RNA, in median (IQR) 121 (54–213) copies/ml. Subjects with detectable CSF virus had significantly higher CSF neopterin and longer duration of treatment. Previous treatment interruptions were more common in subjects with CSF escape. CPE-rank was not a significant predictor of detectable CSF virus or CSF neopterin levels. Conclusions Viral escape in CSF is more common than previously reported, suggesting that low-grade CNS infection may continue in treated patients. Although these findings need extension in longitudinal studies, they suggest the utility of monitoring CSF responses, as new treatment combinations and strategies modify clinical practice.

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[137] In some patients despite plasma viral control escape is currently unknown since it may occur in approximately 10% of patients on HAART and no neurological impairment was observed in a longitudinal study after 5 years of follow up: this event may therefore be similar to the emergence of plasma "blips". [21,138] However two case series and several case reports have clearly documented the concrete, though uncommon, possibility of symptomatic CSF escape:…”

“…[160][161][162][163][164][165][166][167][168][169][170][171][172] Furthermore while several retrospective studies found an association between higher CPE scores and lower CSF viral loads [153,154,[173][174][175] only one study (out of three) found a correlation with CSF escape. [21,143,176] Some reports tried to define a CPE cut off: respectively a value of 6 or 7 were found to be associated with heterogeneous CSF outcomes. [143,144,173,177] Some limitations of the CPE score must be highlighted: the limited amount of evidence regarding PD data and regarding drugs standard dosages, the absence of a clear cut off, the validation in patients receiving triple therapies and with fully sensitive viruses.…”

Antiretroviral Therapy and HIV-Associated Neurocognitive Disorders

“…Further, markers of oxidative stress, such as 4-hydroxynonenal (4-HNE), are well documented in HAND patients (Haughey, Cutler et al 2004;Sacktor, Haughey et al 2004). In addition, several studies have reported that neopterin and 2-microglobulin, regarded as indirect markers of macrophage activation, are elevated in the CSF of HIV infected patients (Yilmaz, Fuchs et al 2006;Edén, Fuchs et al 2010;Hagberg, Cinque et al 2010). Finally, the neuropathological correlates of inflammation, including astrocytosis and increased perivascular macrophage infiltration are commonly observed in the brains of HIV-infected patients (Kolson 2002;Kusdra, McGuire et al 2002;Lindl, Marks et al 2010).…”

Update and New Directions in Therapeutics for Neurological Complications of HIV Infections

“…This may be a detectable CSF viral load with undetectable plasma in a patient on stable cART, or a CSF viral load that is 5 to 10-fold higher than plasma. Patients with CSF viral escape can be symptomatic [8] or asymptomatic [17]. Reported symptoms are nonspecific and include headache, neck stiffness, confusion, and incoordination.…”