Ask the Experts - Necessity of Suppressing CSF Viral Load?
Ask the Experts - Necessity of Suppressing CSF Viral Load?
My patient's plasma HIV-1 RNA level is undetectable, but after a seizure I checked his cerebrospinal fluid (CSF) viral load and found it to be greater than 200,000 copies/mL. He is receiving efavirenz and 3 protease inhibitors because he has the 69S insertion associated with resistance to nucleoside analogue reverse transcriptase inhibitors. The CSF genotype did not reveal the K103N mutation. How necessary is it to get the CSF viral load under control?
Delia Bullock, MD
The first step should be to determine the cause of the seizure. A comprehensive neurologic examination should be performed to determine the presence of generalized or focal neurologic abnormalities. Appropriate diagnostic tests in this setting include blood studies and neuroradiologic tests, particularly brain MRI, and lumbar puncture. Assuming that these studies do not reveal a specific etiology to explain the seizure, such as a focal brain lesion or neurosyphilis, the seizure may be assumed to result from the effects of HIV on the brain. While there have been several series reporting "idiopathic" seizures in HIV-infected patients, possibly due to HIV encephalopathy, their frequency and mechanism have not been determined.
There is increasing evidence linking CSF HIV-1 RNA levels with neurocognitive dysfunction. Increased CSF HIV-1 RNA is correlated with neuropsychologic abnormalities in cross-sectional studies, and with the risk of development of future neurocognitive dysfunction. Several studies have examined the correlation between plasma and CSF viral load. CSF HIV-1 RNA levels are generally 1-2 log10 copies/mL below the plasma level. Ellis and colleagues have reported that plasma and CSF HIV-1 RNA levels are correlated in patients with CD4+ cell counts above 200 cells/mm, irrespective of the presence of neurocognitive dysfunction. When CD4+ cell counts fall below 200 cells/mm, CSF HIV-1 RNA levels are significantly elevated in patients with neurocognitive dysfunction.
More recently, Stingele and coworkers reported serial plasma and CSF HIV-1 RNA samples in a cohort of HIV-infected subjects. They found no correlation between viral load in the 2 compartments. Of note, genotypic analysis revealed that in approximately 20% of subjects, there were mutations exclusive to either the plasma or CSF, and not present in the other compartment. While antiretroviral agents have differing capacities to penetrate the blood-brain barrier, CSF HIV-1 RNA levels did not appear to be related to either the number or type of antiretrovirals taken.
In summary, these data suggest that the CNS may be an independently replicating reservoir of HIV, distinct from the plasma. Current data indicate the importance of maintaining virologic control in both compartments. Since knowledge of the HIV viral load and genotype in the plasma may not be sufficient, physicians might consider monitoring the CSF as well, especially in advanced patients with neurologic deficits.
In this particular patient, it is important to control CSF viral load to the extent that this is possible. Among the NNRTIs, nevirapine has the best CNS penetration of the blood-brain barrier. Although efavirenz is highly protein-bound, with less than 1% of plasma levels present in the CSF, nevertheless the CSF concentration of efavirenz exceeds the IC95, and is effective in suppressing CSF HIV viral replication in preliminary studies. Among the PI agents, indinavir is the least protein-bound, and has the best CSF penetration. Further studies are needed to demonstrate the optimal antiretroviral and adjuvant therapies to optimize CNS virologic control.
My patient's plasma HIV-1 RNA level is undetectable, but after a seizure I checked his cerebrospinal fluid (CSF) viral load and found it to be greater than 200,000 copies/mL. He is receiving efavirenz and 3 protease inhibitors because he has the 69S insertion associated with resistance to nucleoside analogue reverse transcriptase inhibitors. The CSF genotype did not reveal the K103N mutation. How necessary is it to get the CSF viral load under control?
Delia Bullock, MD
The first step should be to determine the cause of the seizure. A comprehensive neurologic examination should be performed to determine the presence of generalized or focal neurologic abnormalities. Appropriate diagnostic tests in this setting include blood studies and neuroradiologic tests, particularly brain MRI, and lumbar puncture. Assuming that these studies do not reveal a specific etiology to explain the seizure, such as a focal brain lesion or neurosyphilis, the seizure may be assumed to result from the effects of HIV on the brain. While there have been several series reporting "idiopathic" seizures in HIV-infected patients, possibly due to HIV encephalopathy, their frequency and mechanism have not been determined.
There is increasing evidence linking CSF HIV-1 RNA levels with neurocognitive dysfunction. Increased CSF HIV-1 RNA is correlated with neuropsychologic abnormalities in cross-sectional studies, and with the risk of development of future neurocognitive dysfunction. Several studies have examined the correlation between plasma and CSF viral load. CSF HIV-1 RNA levels are generally 1-2 log10 copies/mL below the plasma level. Ellis and colleagues have reported that plasma and CSF HIV-1 RNA levels are correlated in patients with CD4+ cell counts above 200 cells/mm, irrespective of the presence of neurocognitive dysfunction. When CD4+ cell counts fall below 200 cells/mm, CSF HIV-1 RNA levels are significantly elevated in patients with neurocognitive dysfunction.
More recently, Stingele and coworkers reported serial plasma and CSF HIV-1 RNA samples in a cohort of HIV-infected subjects. They found no correlation between viral load in the 2 compartments. Of note, genotypic analysis revealed that in approximately 20% of subjects, there were mutations exclusive to either the plasma or CSF, and not present in the other compartment. While antiretroviral agents have differing capacities to penetrate the blood-brain barrier, CSF HIV-1 RNA levels did not appear to be related to either the number or type of antiretrovirals taken.
In summary, these data suggest that the CNS may be an independently replicating reservoir of HIV, distinct from the plasma. Current data indicate the importance of maintaining virologic control in both compartments. Since knowledge of the HIV viral load and genotype in the plasma may not be sufficient, physicians might consider monitoring the CSF as well, especially in advanced patients with neurologic deficits.
In this particular patient, it is important to control CSF viral load to the extent that this is possible. Among the NNRTIs, nevirapine has the best CNS penetration of the blood-brain barrier. Although efavirenz is highly protein-bound, with less than 1% of plasma levels present in the CSF, nevertheless the CSF concentration of efavirenz exceeds the IC95, and is effective in suppressing CSF HIV viral replication in preliminary studies. Among the PI agents, indinavir is the least protein-bound, and has the best CSF penetration. Further studies are needed to demonstrate the optimal antiretroviral and adjuvant therapies to optimize CNS virologic control.
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