Lopinavir/r Monotherapy: Evidence of Ongoing CNS Damage, Regardless of Viral Replication
Levels of S100B and neopterin were elevated in the cerebrospinal fluid of HIV-infected patients on lopinavir/ritonavir monotherapy, with S100B elevation seen even in the absence of detectable viral loads.
Despite prolonged survival and decreased incidence of overt dementia in HIV-infected patients on suppressive antiretroviral therapy (ART), the central nervous system (CNS) can suffer ongoing damage due to immune activation, viral escape, or toxicity of the therapeutic agents. With advances in ART options and the aging of people with long-term HIV infection, potential adverse CNS effects need to be considered when choosing regimens.
To explore this, researchers evaluated cerebrospinal fluid (CSF) samples collected as part of the randomized, open-label Monotherapy Switzerland/Thailand trial of boosted lopinavir, which was terminated prematurely because of virologic failure in plasma and CSF of six patients in the lopinavir/ritonavir-monotherapy arm who had low CD4 nadirs (JW AIDS Clin Care Sep 20 2010). Thirty-four CSF samples obtained from participants on combination ART, 31 from those on lopinavir/r monotherapy, and 29 from HIV-uninfected controls with Alzheimer disease were evaluated for markers of astrocytosis (S100B), macrophage/microglial cell activation (neopterin), and neuronal damage (total tau, phosphorylated tau, amyloid-β 1-42).
S100B levels were significantly higher in patients on monotherapy than in those on combination ART or in controls, regardless of whether HIV RNA was detectable in the plasma or CSF. Neopterin levels were significantly higher for the monotherapy group than for the other groups only when patients with a detectable viral load in plasma or CSF were included in the analysis. For the 16 participants with paired samples — one while on combination ART and a later one while on lopinavir/r monotherapy — levels of both neopterin and S100B were significantly higher in the samples taken while on monotherapy.
Comment: Elevated S100B reflects astrocyte reactivity, and elevated neopterin is a sign of ongoing immune activation. These occurrences can result in parenchymal damage and loss of blood–brain barrier integrity, which can manifest as sustained neurocognitive dysfunction. The results of this small study are particularly discouraging for monotherapy — at least with lopinavir/r — because in addition to virologic failure with this regimen, there is now evidence of ongoing CNS insult. Notably, lopinavir/r is believed to be one of the better antiretroviral agents in terms of CNS penetration, yet these study findings argue against its ability to effectively manage CNS damage when used alone.
— Jennifer L. Lyons, MD, and Paul Sax, MD
Dr. Lyons is a postdoctoral fellow in the Division of Neuroimmunology and Neurological Infections at Johns Hopkins University in Baltimore. She reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care January 14, 2013
Du Pasquier RA et al. Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy. AIDS 2013 Jan 14; 27:203.
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