Participant Groups

The likelihood of new neurocognitive complications, remission of such complications, or fluctuating patterns of complications were hypothesized to be related to several key variables. These variables include whether or not virus is suppressed in the CSF compartment, whether or not the individual is currently on treatment, the history of past treatment, and whether or not a particular neurological complication has already occurred. To determine the importance of these influences on changes in neurocognitive and neurological complications, we followed longitudinally a series of cases termed "Group A".

Group A consists of individuals characterized by the following variables:

History of HAART; Whether or not virus is detectable in the CSF; Presence or absence of neurocognitive complications at the beginning of the study.

It was anticipated that careful six monthly observation of these groups would reveal the degree to which HAART history and viral suppression predict near future onset of neurological complications; and secondly, would shed light on some of the intermediate steps in this link, for example, evolution of resistant virus in the CSF compartment.

Exposure to HAART regimens containing d-drugs (ddI, Hivid or zalcitabine (ddC), or d4T) is known to cause or contribute to peripheral neuropathy in some cases; however it is unclear how specific drugs, duration of exposure, and recency of exposure interact with individual characteristics as risk factors for developing distal sensory-predominant polyneuropathy (DSPN). To investigate these questions, Group B enrolled participants into three subgroups: (1) no clinical DSPN (no signs or symptoms of DSPN); (2) asymptomatic DSPN (1 or more signs of DSPN, but no symptoms); (3) symptomatic DSPN (both signs and symptoms present). Severity of neuropathy was characterized according to the Total Neuropathy Score, including nerve conduction studies and quantitative sensory testing.  Serum lactate levels were measured as a marker of mitochondrial dysfunction to investigate whether changes in lactate levels correlate with stabilization or improvement in neuropathy as measured by the Total Neuropathy Score.

The original CHARTER peripheral neuropathy aims focused on ascertaining the short-term neurotoxic impact of so-called “d-drugs” (dideoxynucleoside HIV reverse transcriptase inhibitors; ddC, ddI, d4T) on distal sensory polyneuropathy (DSPN). Our CHARTER experience to date has motivated a revision of this focus to emphasize the influence on neuropathy of long term antiretroviral drug exposure and genetic risk factors. To improve earlier ascertainment and longitudinal monitoring of nerve injury we propose to add intraepidermal nerve fiber (IENF) layer assessments (skin biopsies). The IENF technique, developed and validated over the past 5 to 10 years, provides a more direct measure of cutaneous innervation than clinical examinations or electrophysiological testing. Simple, superficial skin biopsies will be repeated over time to assess factors associated with both deterioration and improvement in peripheral nerve function.

Metabolic disorders such as lipoatrophy and centripetal fat re-distribution, elevated blood cholesterol and triglyceride levels (dyslipidemias), and insulin resistance (diabetes and impaired glucose tolerance) are commonly induced by HAART, but their impact on the CNS not been assessed systematically. Patients in the HAART era appear to have reduced rates of more severe cognitive deterioration. However, epidemiologic data showing the continuing incidence and prevalence of cognitive problems in HAART-treated patients raises concern about the possibility that HAART has protective effects through its antiviral effects, but is also toxic for the CNS in some patients. The primary aim was to relate lipoatrophy indicators to manifestations of HIV-associated neurocognitive dysfuntion HAND and peripheral neuropathy (PN).

Although highly active antiretroviral therapy (HAART) has made a major impact on the course of HIV-related illnesses, neurological complications continue to occur and several syndromes of mild to moderate neurocognitive impairment, as well as occasional frank dementia, continue to be described in HAART-treated individuals. Imaging studies have shown that these symptoms are often accompanied by various forms of brain tissue damage; however, the mechanisms by which this damage occurs are still not understood, the links between tissue damage and functional impairment have not been clearly delineated, and the basis for the neuropathological heterogeneity within the treated population is not known. The proposed studies would address these questions by charting the development of tissue damage over time in individuals with evolving central nervous system (CNS) disease and attempting to link specific human immunodeficiency virus (HIV) disease factors and comorbidities to the tissue alterations. In addition, tissue alterations would be linked to changes in specific cognitive functions, and the role of genetic and disease interaction effects in mediating neurocognitive heterogeneity would be examined.

100 participants with evidence of significant white matter damage and 50 participants with apparently unaffected white matter.

100 participants with evidence of significant white matter damage. In order to control for the relationship between age and white matter, an white matter-age residual will be used to determine eligibility. The affected group will be those 20 participants at each site with the highest white matter-age residuals. 50 subjects who have apparently unaffected white matter (those 10 participants at each site with the lowest white-matter-age residuals)

In the years since the inception of CHARTER, antiretroviral drugs that target the HIV entry process have been introduced that are expected to elicit changes in the HIV env sequence when drug resistance develops. Data from several groups also indicate that env sequence features are correlated with neurocognitive impairment in vivo and biological phenotypes in vitro that may be relevant to infection in the CNS. During the Option Period, the Virology Core will focus on testing viral genetics as predictors of neurocognitive dysfunction and the reversibility of neurocognitive dysfunction to antiretroviral treatment and to establishing a database of baseline env sequences that will be of value for comparative studies as use of antivirals targeting viral entry increases.

Participants will be chosen having both Plasma and CSF viral load with > 400 copies/mL, or only a plasma viral load > 400 copies/mL. We expect approximately one third of the participants to be co-enrolled in Group N and another one third to be co-enrolled in Group V.

It has long been known that HIV enters the central nervous system (CNS) shortly after infection, resulting in neurocognitive impairment in one third of individuals who are otherwise in a physically “asymptomatic” phase of illness. The timing, characteristics, features, and factors affecting risk of neurocognitive impairment, and their relationship to antiretroviral therapy, remain unclear. In hopes of understanding the earliest phases of development of neurocognitive impairment, all participants identified as either Acute or Early (infected (duration of infection <= 1 year) will be enrolled into the Option Period and will undergo the standard Option Period Protocol. Though we will have a relatively small cohort, data collected on these well characterized individuals will be unique and may provide valuable preliminary insights for planning future studies into the pathogenesis and possibly prevention of HIV-associated peripheral neuropathy and neurocognitive impairment.