HIV-Associated Dementia and Cognitive Impairment - Neuroprotective Effects of Antiretroviral Therapy
in: Neurological Disorders, Justin McArthur, MBBS, MPH
[Medscape HIV/AIDS 5(Supplement):1999 Annual Update. © 1999 Medscape, Inc.]
There have been only three placebo-controlled studies of the effect of antiretroviral
therapy on dementia. The only placebo-controlled trial of AZT in HIV dementia
(ACTG-005) suggested that the greatest neurocognitive improvement is seen with
very high doses of AZT, around 2000mg daily.[3] The effect was modest, however,
and no change in clinical severity of dementia was demonstrated. Experience with
open-label use of zidovudine suggests that cognitive function can be improved with
doses of 800 to 1000mg, particularly in an AZT-naive patient.
In 1998, the newly licensed reverse transcriptase inhibitor, abacavir, was tested in a
placebo-controlled, double-blinded study in 99 patients with HIV dementia.[4]
Ninety-nine individuals with HIV dementia were randomized to add abacavir,
600mg BID, or placebo, onto stable background ART. The patients were heavily
pretreated with ART, and 90% of subjects had nucleoside resistance mutations at
study entry. Very few subjects showed neurological deterioration during the 12
weeks of the study: 2 in the placebo group, and none on abacavir. Overall, both
groups showed improvements in neuropsychological (NP) performance on
standardized tests, with a trend favoring abacavir. The more severely impaired
group on abacavir showed a greater improvement than placebo recipients. The
CSF virological response favored abacavir with a 0.64 log10 drop during the study,
while the placebo group showed a rise of 0.25 log10.
This was an important study partly because of the inherent difficulty of performing
clinical trials in demented subjects, and partly because of the relatively limited
treatment options available. The lack of any dramatic treatment effect emphasizes
that a switch of one ART is unlikely to be an effective treatment for dementia,
especially in heavily pretreated patients with multiple resistance mutations. The
improvement in the background treatment group suggests that triple combination
ART may produce neurological improvement which continues over several months.
Thus, despite entering the study on "stable" ART therapy, in fact, the placebo group
overall were still improving. Abacavir did reduce CSF levels to a greater extent than
background ART.
There are multiple implications from this study including:
single agent changes in ART are not likely to be very effective
the progression of dementia may be different in an era when combination therapies are used
other types of outcome measures, in addition to neuropsychological testing, may be needed to detect changes in CNS function.
Summary: Implications for Clinical Practice
The incidence of HIV dementia and CNS opportunistic infections is declining, but the incidence of sensory neuropathy is potentially rising as a result of double dideoxynucleoside analog use.
Effective and sustained treatment of established dementia will require both antiretrovirals and agents targeting the pathophysiological mechanisms which underlie neuronal damage.
A variety of pain modifying regimens including the tricyclic antidepressants and anticonvulsants are available. Nerve growth factor, insulin-like growth factor type-1 (IGF-1), and the neuroimmunophilins might be useful agents in patients with severe or treatment refractory HIV-associated neuropathies -- as well as in cases of toxic neuropathies. However, pharmaceutical companies need to be encouraged to participate in clinical trials for this important and increasingly frequent complication. |
