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HIV CSF/Plasma Ratio and Genetic Distance in People With Neurologic Disorders
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International HIV and Hepatitis Drug Resistance Workshop, June 8-12, 2010, Dubrovnik, Croatia
Mark Mascolini
A high cerebrospinal fluid (CSF)/plasma viral load ratio correlated with HIV encephalitis in a 71-person French study [1]. The investigators believe their findings mean CSF/plasma ratio predicts encephalitis better than CSF load alone. They also found a lower genetic distance between CSF and plasma virus in people with a plasma load above 40 copies than in those with a lower load.
Neurologic disorders remain doggedly prevalent in people treated with current antiretroviral regimens, and progress in demonstrating the value of central nervous system (CNS)-penetrating regimens has been slow. To complicate things, the relation between HIV in the peripheral circulation and in CSF remains imperfectly understood despite much research.
To address these issues, Cathia Soulie (Pierre and Marie Curie University) and colleagues at other centers in Paris analyzed blood and CSF samples collected from 71 HIV-infected people with neurologic disorders. They diagnosed HIV-associated encephalitis (1) clinically by evaluating behavioral problems and psychomotor slowing and by eliminating other possible diagnoses, (2) by CSF analysis of pleocytosis, elevated protein, and detectable HIV, and (3) by computed tomography and/or magnetic resonance imaging.
Soulie and collaborators analyzed paired CSF and plasma or cellular DNA samples for HIV load and genotypic resistance. When the plasma load lay below 40 copies, genotyping for resistance focused on proviral DNA. The investigators used the French (ANRS) resistance tool to interpret genotypic findings. They figured genetic distance between CSF and plasma virus by the Kimura model [2,3], and they calculated antiretroviral penetration of CSF by the CNS Penetration Effectiveness (CPE) score [4].
Of the 71 patients with neurologic disorders, 39 had HIV encephalitis, 5 meningitis, 5 neurosyphilis, 5 cerebral toxoplasmosis, 4 progressive multifocal leukoencephalopathy, 2 cryptococcosis, 2 cytomegalovirus encephalitis, 2 lymphocytic meningitis, 2 varicella zoster encephalitis, 1 lymphoma, 1 psychiatric disorder, 1 peripheral neuropathy, 1 hydrocephalus, and 1 Guillaine-Barre syndrome.
Forty-three study participants (61%) were men, age ranged from 24 to 72 years (median 43), CD4 count ranged from 3 to 2369 (median 268), and lowest-ever CD4 count ranged from 1 to 656 (median 92). Median plasma load stood at 3.2 log (about 1600 copies) and median CSF load at 3.8 log (about 6300 copies). CPE scores of antiretrovirals being taken ranged from 3 to 14 (median 7). When the investigators took into account the genotypic sensitivity scores of antiretrovirals in CSF, CPE scores ranged from 0 to 10 (median 3).
Median CSF HIV load measured 3.3 log (about 2000 copies) in people with encephalitis and 4.2 log (about 16,000 copies) in people without encephalitis, a negative correlation verging on statistical significance (P = 0.054). However, the CSF/plasma viral load ratio was significantly higher for people with HIV encephalitis than for those without encephalitis (11.1 versus 0.7, P = 0.0006). Because of the strong positive correlation between CSF/plasma ratio and encephalitis, Soulie and colleagues proposed that the ratio predicts encephalitis better than CSF load alone. The researchers also suggested that the higher CSF/plasma ratio in people with encephalitis points to ongoing replication of virus in the CSF compartment.
Genetic distance between virus in CSF and virus in plasma was significantly lower in people with a plasma load above 40 copies than in those with a sub-40 plasma load (median 0.006 versus 0.011, P = 0.038). CSF genetic sensitivity score and CPE score of the current regimen were not associated with genetic distance between CSF and plasma virus. But CPE score corrected for genotypic sensitivity score of the current regimen did correlate with genetic distance: This score was higher when the genetic distance was lower (P = 0.007).
The link between lower HIV diversity in plasma and CSF virus among people with a plasma load above 40 copies suggested to Soulie and colleagues "that plasma and CSF viruses were similar" in people with a detectable plasma load, so in these people CSF virus probably comes from plasma by diffusion across the blood-brain barrier. The investigators proposed that the higher plasma-versus-CSF viral diversity in people with a plasma load under 40 copies suggested ongoing replication of virus sequestered in the CSF compartment.
Finally, Soulie and colleagues suggested that the correlation between genetic distance and CPE score corrected for genotypic sensitivity score--but not between genetic distance and CPE score or genotypic sensitivity score alone--argue that the CPE score's value can be improved by factoring in the impact of resistance on antiviral potency in the CNS.
References
1. Soulie C, Fourati S, Lambert-Niclot S, et al. HIV genetic distance between plasma and CSF in patients with neurological disorders. International HIV and Hepatitis Drug Resistance Workshop. June 8-12, 2010. Dubrovnik, Croatia. Abstract 127.
2. Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980;16:111-120.
3. Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Mol Biol Evol. 2007;24:1596-1599.
4. Letendre S, FitzSimons C, Ellis R, et al, and the CHARTER Group. Correlates of CSF viral loads in 1221 volunteers of the CHARTER cohort. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 172.
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