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Low Enfuvirtide and Maraviroc Penetration of CSF--and CSF Resistance to Enfuvirtide
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Targeting HIV Entry: 4th International Workshop, December 8-9, 2008, Rio Grande, Puerto Rico
Mark Mascolini
A case report from the University Medical Center Utrecht documented low levels of the entry inhibitors enfuvirtide and maraviroc in cerebrospinal fluid (CSF) despite adequate levels in plasma and undetectable plasma viremia. Virus resistant to enfuvirtide, but not to maraviroc, could be detected in CSF of this salvage therapy patient.
A 50-year-old man with multidrug-resistant virus began a rescue regimen including the fusion inhibitor enfuvirtide (90 mg twice daily), the CCR5 antagonist maraviroc (300 mg twice daily), and reverse transcriptase inhibitors tenofovir plus zidovudine and lamivudine coformulated as Combivir. Presalvage genotyping disclosed no enfuvirtide-related mutations in gp41, and the Trofile assay determined that the virus used the CCR5 coreceptor. After a months-long drop in plasma viremia, the viral load eventually did fall below 50 copies and remained undetectable for 8 months. At that point clinicians performed a spinal tap in an attempt to diagnose neurologic symptoms.
Although viral load remained undetectable in plasma, two CSF samples had detectable loads of 2780 and 1490 copies. Adding darunavir/ritonavir to the regimen pushed CSF loads below the limit of detection.
Plasma concentrations of enfuvirtide and maraviroc were adequate at 3.74 and 0.146 micrograms/mL, but CSF levels of both drugs were low: 0.055 micrograms/mL for enfuvirtide and only traces of maraviroc below the limit of detection. CSF levels of darunavir were low but detectable.
Population sequencing disclosed no maraviroc-related mutations in CSF, but sequencing of the HR1 and HR2 regions of HIV-1 gp41 revealed the enfuvirtide-related V38A mutation in CSF. Viral protease and reverse transcriptase in CSF remained the same as plasma sequences genotyped before the salvage regimen began. Analysis of HIV-1 gp120 V3 loop sequences in CSF showed no changes from baseline plasma sequences, a result suggesting no change in coreceptor use by the virus.
The Utrecht team outlined two mechanisms that may explain detection of an enfuvirtide-related resistance mutation in CSF but not in plasma. First, enfuvirtide-resistant virus may have emerged at low levels in plasma during the slow decline in plasma viremia after the salvage regimen began. This mutant virus could have leaked across the blood-brain barrier into CSF. "In this scenario," they explained, "replication of enfuvirtide-resistant virus was effectively inhibited by the other components of the antiviral regimen in the plasma and not in the CSF." Second, meager enfuvirtide concentrations in CSF could have permitted low-level viral replication and resulting emergence of resistant virus.
Large-volume ultrasensitive gp41 genotyping uncovered no enfuvirtide-related mutations in plasma when the salvage regimen began or 2 years later, a result favoring the hypothesis that enfuvirtide-resistant virus first evolved in CSF. In addition, the investigators proposed that resuppression of HIV in CSF after addition of darunavir/ritonavir suggests ongoing viral replication in CSF before darunavir/ritonavir began. Eventually the salvage regimen failed and enfuvirtide-resistant virus also emerged in plasma.
Little is known about how well the newest antiretrovirals penetrate CSF and other sanctuary sites. This case report indicates that antiretroviral penetration of these sites--and its possible consequences--deserve closer study.
Reference
1. van Lelyveld SFL, Nijhuis M, Wilting I, et al. Development of resistance to enfuvirtide in cerebrospinal fluid in a patient with suppressed plasma HIV-1 RNA. 4th International Workshop. December 8-9, 2008. Rio Grande, Puerto Rico. Abstract 13.
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