June 29 and July 2, 1998
Among antiretroviral agents zidovudine (ZDV) is often touted as the most active nucleoside reverse transcriptase inhibitor for use in treating HIV related dementia and other manifestations of neurocognitive dysfunction because the ratio of drug concentrations in cerebrospinal fluid (CSF) to serum is higher for ZDV than for stavudine (d4T) and lamivudine (3TC). A group from the Netherlands recently completed a study confirming that the CSF to serum ratio of ZDV is higher than that for d4T and 3TC, but the absolute concentrations of d4T and 3TC were higher in CSF than ZDV. It is the absolute concentration of drug that is delivered to a body compartment and determines the activity of the drug, rather than a ratio of drug concentrations in one compartment compared to another. Therefore, investigators have been testing the ability of d4T to reverse the neurological complications of HIV infection observed at more advanced stages of disease, and also are trying to more accurately determine the concentrations of drug in CSF.
Session 564/32207: Stavudine stops neuro-AIDS in AZT-non-responders
One study in Geneva reported on the change in fine motor skills, a marker for early signs of HIV dementia, that occurred when a patient's antiretroviral therapy was switched from a ZDV to a d4T containing combination compared to a switch from a ZDV to a non-d4T containing regimen. 1286 patients were included in the study, and these patients had over 4,000 neurological examinations during the trial. Patients had at least six months of ZDV experience prior to a change in therapy. The fine motor skills that were measured included postural tremor of outstretched hands, rapid alternating finger motion, rapid contraction of the index finger, and reaction time. Changes in examination were monitored at three month intervals.
Over the first six months of study there were improvements in rapid contraction of the index finger and reaction time tests in the group that had the non-d4T inclusive combination. However, at month 9 and 12 following drug modification the benefit for the non-d4T recipients was lost, and the patients that were receiving d4T had measurable improvements in index finger contraction time and reaction times. CD4+ count increases were seen in the patients receiving d4T at months 6, 9, and 12; no improvement in CD4+ counts was observed in the patients who did not receive d4T.
This study suggests that d4T can reverse some of the abnormalities in fine motor skills that can occur in individuals with more advanced HIV infection, even if these abnormalities occur in patients receiving ZDV. The study would have been more insightful if patients were followed with neuropsychological testing that could detect changes in cognitive function as well, since it is the memory loss and personality changes that are often the most distressing component of the neurological complications of HIV infection.
Poster Session 12355: Stavudine entry into cerebrospinal fluid of HIV-infected subjects after single and multiple doses
A second study presented in Geneva sought to more clearly define the pharmacokinetics of d4T in spinal fluid compared to serum. Thirty-six patients received blood drawn one hour after a dose of d4T, and then a lumbar puncture to measure CSF concentrations of the drug 2, 4, or 6 hours after the dose. Twenty-one patients were on d4T therapy prior to their participation in this study, while 15 others were on no or other medications and had a single dose of d4T given prior to the pharmacokinetic analysis. The number of participants makes this one of the largest studies of the CSF pharmacokinetics of any antiretroviral agent, and the largest including d4T.
In the patients taking d4T, the mean peak concentration of drug in plasma was 2.59 mmol/L, with a range of 0.14 to 4.82 mmol/L. The true peak concentration in serum may have been higher, but the investigators only studied a single time point after the dose. The mean CSF peak concentration was 0.28 mmol/L, and this occurred 4.7 hours after the dose was taken. In those patients who only received single dose of d4T the peak concentrations in plasma and CSF were lower. In this group, the mean plasma peak concentration was 2.11 mmol/L (range 0.54 - 3.29 mmol/L) and that in CSF was 0.18 mmol/L. The IC50 for d4T against HIV (the concentration of drug able to inhibit 50% of viral replication in a tissue culture assay) is 0.05 mmol/L. Therefore, the concentrations of drug exceeded that required to inhibit viral replication in CSF. In the patients who received only one dose of d4T, the time to peak CSF concentration was 5.0 hours. There was no relationship between CSF concentrations of drug and the white blood cell count or protein level in CSF. There was an inverse correlation between CSF d4T concentrations and weight -- the higher the weight, the lower the drug concentration.
This study is insightful for a number of reasons. There is no clear consensus on how important it is for antiretroviral agents to cross the blood brain barrier in order to control viral replication that may be ongoing in the central nervous system. Some studies suggest that virus in spinal fluid and brain are in unique body compartments with respect to HIV replication. Evidence for his comes from studies that have sequenced isolates of virus and demonstrated distinct HIV genotypes in brain and spinal fluid compared to those seen in blood. We have relatively little information on how well drugs penetrate into the brain and spinal fluid. This study shows that drugs may be delayed in reaching the spinal fluid after a dose is taken and, therefore, specimens need to be obtained at multiple time points after a dose is taken in order to ensure that an accurate measurement of drug into spinal fluid can be obtained.