Study 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?

In September 2007, the Option Period of CHARTER began. The Option Period was an opportunity to take findings from the initial study period and refine the study to focus on current areas of interest in neuroAIDS. To this end the Option Period will focus on these four major areas: host genetics, viral genetics, peripheral neuropathy, and white matter disease . In addition, we will take advantage of the CHARTER infrastructure and population to begin characterizing the effects of newly emerging ARV treatments on HAND, and to characterize the neurologic profiles of the subset of early/acute infection cases that have become available to us.

Host Genetics

• Specific Aim 1: Validation of the genetic signature associated with HAND derived during the initial period
• Specific Aim 2: To determine the association of genetic variability with longer term neurocognitive and peripheral neurological outcomes
• Specific Aim 3: To determine the pharmacogenetic associations for newer antiretrovirals

Viral Genetics

• Specific Aim 1: To determine the prevalence of HIV env mutations in CSF and plasma among participants with and without HAND at enrollment
• Specific Aim 2: To determine the impact of viral genetics on the evolution of HAND in treated and untreated HIV infected participants over 7 years of follow-up
• Service Aim: To provide an initial database of HIV env sequences that can be used as a reference for future studies aimed at defining the evolution of drug resistance in CSF virus to antiretroviral drugs that target viral binding and fusion

Peripheral Neuropathy

• Specific Aim 1: To evaluate genetic susceptibility factors that may influence the expression of DSPN and d-drug neurotoxicity in patients with HIV infection
• Specific Aim 2: To determine the potential impact on peripheral neuropathy of long term exposure to HAART and its component antiretroviral agents

Supplementary Aims

• To detect potential increases in epidermal nerve fiber densities during a lengthy period of virological control in HAART-treated subjects

• To evaluate whether lower epidermal nerve fiber densities predict the appearance of symptomatic neuropathy (SN) in those previously neuropathy-free, and worsening of SN in those with extant SN

• To determine the potential neurotoxicity of protease inhibitor (PI)-containing HAART regimens[1]

• To better define the relationship between DSPN in HIV and the metabolic syndrome, a recognized complication of HAART and perhaps of HIV infection itself

Neuroimaging

• Specific Aim 1: To assess the longitudinal relationship between volume of white matter abnormality and markers of neuroinflammation
• Specific Aim 2: To investigate the relationship over time between volumes of AbWM and WM metabolites and executive functioning performance
• Specific Aim 3: To characterize the association between cortical damage and cumulative effects of neuroinflammation in the presence of high viral load
• Specific Aim 4: To investigate the performance impact of cortical tissue loss on learning and speed of information processing

Scientific Exploratory Aims

Acute and Early Infection

• Specific Aim: To further our understanding of acute and early HIV infection, particularly the risk factors associated with the development of neurocognitive impairment

New Antiretroviral Agents

• Specific Aim 1: To determine the distribution of selected new antiretrovirals in cerebrospinal fluid (CSF)
• Specific Aim 2: To determine the effectiveness of new antiretrovirals and regimen types in reducing HIV ribonucleic acid (RNA) levels (viral load) in CSF
• Specific Aim 3: To determine the relationships between new antiretrovirals and regimen types on the neurological and neurocognitive complications of HIV

In September 2010, The CHARTER Extension began.  In the Extension, the CHARTER aims were further refined to focus on how extended follow-up of a select number of CHARTER participants could provide further insight into the effects of low-level viral replication in the CNS, predictors of neurocognitive and neuroimaging worsening, and the reversibility of nerve injury in the context of ART.

Specific Aim 1: To explore the longitudinal neurological consequences of disproportionate HIV replication in the nervous system.

Hypothesis: Participants with evidence of disproportionate HIV replication in the nervous system (defined as viral loads in CSF that are at least as high as those in plasma) will be more likely to have progressive neurological disease (as determined by neuropsychological testing and neuroimaging) than participants who do not have disproportionate HIV replication in the nervous system.

Specific Aim 2: To examine cases that are receiving ART and undergoing cognitive decline or increasing white matter abnormalities based on neuroimaging in order to determine predictors of neurological injury.

Hypothesis:  In participants on ART, those having more evidence of white matter injury will have greater decline in neuropsychological functioning than those without any evidence of white matter injury. For our purposes, indicators of white matter injury include:  increased volume of abnormal white matter signal and white matter volume loss on structural MRI; altered diffusion along fibre tracts, such as reduced fractional anisotropy, measured with diffusion tensor imaging (DTI); and changes in metabolite concentrations that may reflect injury in white matter, such as reduced N-acetylaspartate (NAA) or increased choline (Cho), determined by MR spectroscopy.