Primary Scientific Aims

PRIMARY SCIENTIFIC AIMS

• SCIENTIFIC AIM 1: To determine if patients taking HAART have reduced risk of CNS and PNS complications of HIV infection compared to those who are naïve to or have stopped prior ARV treatment. Epidemiologic studies suggest that HAART has reduced CNS complications of HIV, including opportunistic infections and cognitive impairment. This aim was designed to address this observation.
• SCIENTIFIC AIM 2: To determine if the CNS penetration profile of HAART is related to antiviral effects within the CNS (as measured by CSF HIV Ribonucleic Acid (RNA) levels) and to risk of HIV associated neurocognitive dysfunction (HAND) as measured by neurocognitive assessments.CNS complications of HIV appear to result from a combination of viral replication and secondary inflammatory damage. HIV replication in the CNS may be reflected better by its concentration in CSF than in plasma. Thus, viral suppression and prevention or reversal of CNS disease may depend on how well the ARV penetrates the blood-brain barrier (as reflected in CSF concentration) and how sensitive HIV in the CSF is to the drug regimen. Treatment of CNS HIV may require therapies directed at this compartment.
• SCIENTIFIC AIM 3: To determine if the mechanism of neurocognitive damage in late stage HIV disease differs from that in earlier stages of HIV disease.In later stages of HIV disease, the CNS becomes a compartment with "autonomous" HIV replication and evolution independent of the systemic (plasma/lymphoid) compartment. Evidence for this compartmentalization comes from a number of observations. Patients have discordant responses to ARVs in plasma and CSF. Reductions in CSF and plasma viral load are not parallel, with decline occurring more slowly in CSF than in plasma. This difference may reflect HIV originating from long-lived cells in the CNS (microglia and macrophages) in contrast to the short-lived lymphocytes that produce most of the plasma HIV. Phylogenetic analysis of the envelope, protease, and reverse transcriptase regions of multiple clones of HIV from plasma, lymph nodes, CSF, and brain show that the brain and CSF samples cluster separately from the systemic virions. Thus, these advanced patients, more so than those in earlier stages of HIV infection, may require penetration of ART for suppression of HIV in the CNS.
• SCIENTIFIC AIM 4: To measure the relationship of HIV replication within the CNS (as measured by CSF HIV RNA) and of immune competence (as measured by CD4 levels) to the prevalence and incidence of syndromic HIV associated neurocognitive dysfunction. Beneficial effects of ARVs in the CNS may result both from suppression of HIV replication and from immune reconstitution. In the pre-HAART era, higher CD4 counts correlated with lesser risk for neurocognitive complications. HAART-induced immune reconstitution as reflected by higher CD4 counts may reduce risk independent of its effect on HIV replication in the CNS.
• SCIENTIFIC AIM 5: To determine the prevalence of discordant ARV resistance in HIV plasma and CSF. Poor penetration with residual replication in the CNS has been postulated to promote evolution and selection of drug resistant HIV. Alternatively, because the resident viral population may be smaller and drug selection pressure may be less in the CNS, resistant strains may evolve there more slowly than in the plasma. A number of observations have shown that discordance in phenotypic or genotypic resistance can be demonstrated in HIV originating in the CNS and plasma. In addition, we have shown that ARV treatment may continue to suppress HIV in the CNS after loss of plasma suppression (see Virology Core).
• SCIENTIFIC AIM 6: To determine if the predictors and risk factors for peripheral neuropathy from HIV differ from that of d-drug (dideoxynucleoside HIV reverse transcriptase inhibitors; ddC, ddI, d4T) ARV neurotoxicity.

SUPPLEMENTARY AIMS
While the above aims were seen as central in guiding CHARTER, the original protocol also envisioned a number of additional questions which might be addressed through examinations of selected subsets of participants.

• How frequently are psychotropic drugs prescribed to patients at different stages of disease? What are the effects of such psychotropics on plasma concentrations of various ARVs and vice versa?
• Do dideoxynucleoside analog reverse transcriptase inhibitors (e.g., Videx or didanosine (ddI) and Zerit or stavudine (d4T)) induce peripheral neuropathy by mitochondrial toxicity for which serum lactic acidosis is a marker?
• Do protease inhibitors (PI) increase risk of white matter disease in the brain?
• What patient characteristics place a person at risk for adverse neurocognitive effects of ART? For example, what are the predictors of behavioral toxicity from Efavirenz? What are the predictors of nucleotide/nucleoside reverse transcriptase inhibitors induced (NRTI-induced) peripheral neuropathy? Does treatment with Cytochrome P450-3A, CYP2D6 utilizing ARV (e.g., Ritonavir (RTV)) result in enhanced behavioral toxicity in those receiving certain benzodiazepines and certain antidepressants? If so, what patient characteristics are associated with such adverse events?
• Can functional and physiological characteristics of peripheral neuropathy due to HIV and d-drugs be prospectively identified using a novel clinical and quantitative battery?
• What are the risk factors for progression of peripheral neuropathy, with emphasis on transitions from neuropathy-free to neuropathy, and asymptomatic to symptomatic neuropathy. Variables of interest include exposure to d-drug ARV, CD4 (current and nadir), HIV viral load (plasma and CSF), body weight, and anthropomorphic measurements?
• What are the determinants of severe painful sensory neuropathies?

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