Relationship of postmortem brain tissue viral load to antiretroviral treatment during life

Ronald J. Ellis, Dianne Langford, Jennifer Marquie-Beck, Meredith Childers, Allen McCutchan, Igor Grant, Scott Letendre, Eliezer Masliah. UCSD HIV Neurobehavioral Research Center, University of California, San Diego (USA)

Background: Pharmacological studies suggest that the penetration of certain antiretroviral (ARV) agents into central nervous system (CNS) tissues may be insufficient to suppress HIV replication.  We performed this study to evaluate whether the introduction of highly active ARV therapy (HAART) in clinical practice was associated with a reduction in brain viral load at autopsy. Material and Methods: Brain tissue from individuals dying with HIV infection was provided by the California NeuroAIDS Tissue Network (CNTN) and the autopsy service at the University of California, San Diego. Brain viral load measurements in at least one tissue region were available for 118 subjects who died between December 1994, and April 2002. Viral loads in all specimens were measured by RT-PCR.  Information on ARV treatments was collected through chart review.  Regimens comprising at least three different agents were classified as HAART. Results: Compared to the pre-HAART era (1995 and earlier), median brain tissue viral load for patients dying in the post-HAART era was lower for midfrontal cortex (3.3 vs. 5.2); basal ganglia (3.0 vs. 7.4); and hippocampus (3.0 vs. 6.5) (all ps < .04).  Information on ARV treatments within the three months prior to death was available for 54 patients, 27 of whom (50%) took HAART within 3 months of death. Compared to subjects who did not take HAART, those receiving HAART had significantly lower viral loads in all brain tissue regions assessed: midfrontal cortex (median 2.5 vs. 4.1 log10 copies/g, Wilcoxon p < .003); basal ganglia (2.2 vs. 3.9 , p < .006); hippocampus (2.3 vs. 3.6 , p < .007); white matter (2.1 vs. 3.8, p < .02).  Antemortem (A-M) plasma and CSF viral loads were also lower in HAART-treated subjects for whom these values were available.  Postmortem brain tissue viral loads were better predicted by A-M CSF than by A-M plasma. Conclusions: Despite concerns about the CNS penetration of ARVs, HAART treatment prior to death is associated with a reduction in viral burden in CNS tissues.  These data must be interpreted in the light of knowledge that individuals dying in the HAART era usually do so after ARV therapy fails or is withdrawn, suggesting that the observed magnitude of reduction in viral load is an underestimate of the true magnitude of the treatment effect.