Clinical Trial of CNS-targeted HAART (CIT2)

"HIV Neurocognitive Disorders: A Randomized Clinical Trial of CNS-targeted HAART" is a
randomized, controlled clinical trial to assess the efficacy of a strategy for targeting
highly active antiretroviral therapy (HAART) to the CNS in patients with HIV associated
neurocognitive impairment (HNCI). Contemporary cohort studies have consistently demonstrated
that HNCI remains a prevalent disorder in patients receiving HAART. HNCI is a significant
burden to persons living with HIV infection, caregivers, and the healthcare system. Thus the
development of effective treatment strategies is of critical public health importance.

This study is based on findings from a previous study. Briefly, among individuals with HNCI
who initiated a new antiretroviral (ARV) therapy regimen, those receiving more highly
CNS-penetrating ARV regimens were more likely to successfully suppress cerebrospinal fluid
(CSF) viral load (VL), and those who achieved CSF suppression (VL < 50 c/mL) had better
neurocognitive (NC) outcomes. These findings suggest that NC outcomes of ART may be enhanced
by the planned application of an ARV selection and clinical monitoring strategy designed to
optimize the treatment of CNS infection. In the future it will become increasingly important
to consider CNS penetration issues in selecting ART regimens. The randomized clinical trial
proposed here would provide the level of evidence needed to formulate ART guidelines
specific to HNCI.

Subjects eligible for this trial will be individuals with HNCI who anticipate initiation of
a new ARV regimen or substitution of their existing regimen following contemporary treatment
guidelines. A total of 120 patients at 3 study sites will be randomized 1:1 to receive a
CNS-targeted (CNS-T) ARV strategy versus a non-CNS-targeted (Comparison) strategy. The
primary outcome, change in global neuropsychological (NP) performance, will be assessed at
16 weeks. CNS-T will comprise two components: 1) initial selection of agents to optimize CNS
penetration of the overall regimen; and 2) modification of the regimen if an interim
pharmacokinetic (PK) assessment determines that plasma ARV exposure is not appropriate
(overdosing, underdosing).

Inclusion Criteria:

- HIV infected- confirmed by ELISA or 2 prior viral loads >2000

- 18 years or older

- Under consideration to initiate or change their HAART regimens (based on current
consensus treatment guidelines) as directed by their primary care physicians.

- Measurable HIV Neurocognitive Impairment (HNCI)

- Willing and able to undergo at least 3 lumbar punctures safely during the course of
the study.

- Potential subjects must have a Karnofsky score of > or = to 60 within 60 days prior
to study entry.

- Potential subjects must have a CD4 cell count obtained within 60 days prior to study
entry.

Exclusion Criteria:

- Presence of serious illness, including HIV-related opportunistic infections,
requiring systemic treatment and/or hospitalization until candidate either completes
therapy or is clinically stable on therapy, in the opinion of the investigator, for
at least 14 days prior to study entry.

- Presence of neurologic disorders other than HIV judged to be the principal cause of
neurocognitive impairment.

- Presence of active, severe psychiatric disorders (e.g., major depression,
schizophrenia) that would interfere with interpretation of the study evaluations or
adherence to the study protocol or that might make their participation in the study
problematic or unsafe.

- Presence of active drug or alcohol use or dependence that, in the opinion of the
investigator, would interfere with adherence to study requirements.

- Use of any immunomodulator (interferons, interleukins, cyclosporine), vaccine, or
investigational therapy including dexamethasone within 30 days prior to study entry.

- Inability to provide informed consent.

- Enrollment in other ARV treatment studies, unless the study is: 1) observational; 2)
a compassionate use study that predated the current study; 3) one that does not
require specific interventions (or one that does not dictate the regimen); or 4) one
that does not include NP testing.

- A positive serum or urine pregnancy test, if female and of reproductive potential.