The Bay Area Reporter - May 20, 1996
Matthew Chappell, ACT UP/Golden Gate Writers Pool

ADC, marked by cognitive (thought) and motor (movement) dysfunction, is one of the conditions that can lead to an AIDS diagnosis. Symptoms include impaired or slowed thought, speech problems, impaired concentration, forgetfulness, poor judgment and psychomotor problems. Psychomotor motor problems involve your mind telling your body to move. This may include difficulty walking, slowed general movements, and incontinence. Behavioral changes may include apathy, social withdrawal, inattentiveness, agitation, contusion, depression, and manic behaviors.

Not everyone develops all these symptoms. And since similar symptoms can be caused by other problems, such as toxoplasmosis or lymphoma, an evaluation by an experienced neurologist is recommended.

ADC most often occurs in advanced disease and is rare in early HIV infection. Incidence of ADC has decreased with the introduction of AZT and other antiretroviral treatments, and ADC is less likely to be a person's first major AIDS-related complication than it was a decade ago.

How does HIV cause dementia?

It is clear that HIV can cause serious damage to the central nervous system (CNS; the brain and spinal cord), but exactly how it causes the damage is not completely understood. HIV is known to infect immune cells called macrophages, which communicate with a similar functioning cell in the CNS called microglial cells, and may enter the CNS by this route. The virus replicates in these microglial cells and releases certain proteins and parts of its DNA into the CNS.

GP120 is one of the proteins that, in combination with an overproduction of chemicals naturally produced by microglial cells, bind to receptors on the cells that make thinking possible. When this occurs the cells die. When cells die, lesions form. When enough lesions form, the brain goes into a wasted state.

Treatments

The most common treatment used against ADC is AZT. AZT crosses the blood-brain barrier much more easily than any other approved anti-HIV drug. AZT penetrates this barrier at a 40 percent rate, so higher than normal doses are needed. The standard dose of AZT is 600 mg per day. ACTG (AIDS Clinical Trials Groups) study #005 compared 1000 mg of AZT per day to 2000 mg per day. The higher dose was significantly more effective at improving symptoms of dementia.

Unfortunately, the benefits of high dose AZT begin to decrease after 12 weeks. Also, that much AZT may produce significant side effects, including anemia and bone marrow depletion. Many late-stage patients have trouble tolerating AZT at all.

The other nucleoside analogs (ddI, ddC, 3TC, d4T) penetrate the blood brain barrier at lower levels. Unfortunately, no trials of combination nucleoside therapy, or of the new protease inhibitors, have been completed.

Other types of drugs have been studied against ADC, but most results have been less than exciting. In 1993, Australian scientists looked at U87, a non-nucleoside reverse transcriptase inhibitor (NNRTI) made by Upjohn, which had activity against HIV-infected macrophages, but it did not improve ADC symptoms. Results of its sister drug, Delaverdine, are still pending.

Calcium channel blocking agents have been shown to block the binding of GP120 to receptors on brain cells in the test tube. The study required highly toxic doses to achieve this. One study, ACTG 162, looked at non-toxic doses of the calcium channel blocker Nimodipine (approved for cerebral hemorrhage) with nucleoside analog treatments (AZT, ddI, ddC). The drug was proved safe - but produced only weak improvements.

Peptide T is another compound that raised some hopes, being non-toxic and potentially useful against peripheral neuropathy. Unfortunately, it did no better than placebo in clinical trials and is no longer available.

The Dana Foundation, a private neurological research foundation on the East Coast, conducted a small study of ADC. The only data available is from a 30-patient study of a nutritional supplement called OPC14,117. Again, the drug was safe, but produced extreme diarrhea and rashes, causing six subjects to drop out of the study. The study was too small to find any significant difference in effectiveness between the drug and placebo.

Drugs like pentoxyphilline that inhibit tumor necrosis factor, one of the chemicals that may be involved in a variety of AIDS-related symptoms, have been studied with no substantial improvement,

One study set to begin this summer will look at memantine (ACTG 301), a treatment approved in Europe for Parkinson's disease, in combination with any combination of nucleoside analog, NNRTI (if approved), or protease inhibitor. This trial aims to evaluate the drugs' safety while improving diagnostic techniques, and hopes to evaluate the effect of viral load decreases on improvement of ADC symptoms.

Glaxo Wellcome's new nucleoside analog, BW 1259U87, may be a promising new treatment. This drug has the great ability to enter the CNS and may be as potent against HIV as the combination of AZT and 3TC combined. Planned phase two studies will include people with ADC.

Better treatment clearly requires more basic science research to understand the mechanisms that cause ADC. Such research has historically been severely underfunded; studies of ADC are complicated because patients tend to be very sick and the research very expensive to conduct.

The need is critical. Activists from ACT UP/Golden Gate have been invited to attend a Neurological Research Agenda planning meeting in Baltimore this summer, sponsored by the National Institutes of Neurological Disorders and Stroke of the NIH. We will press for a strong agenda of ADC research and energetic support for this agenda by the NIH.
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Always watch for outdated information. This article first appeared in 1996. This material is designed to support, not replace, the relationship that exists between you and your doctor.

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