The Bay Area Reporter - March 2, 2001
Bob Roehr

Justin McArthur, a leading figure in the study of neurological aspects of HIV infection and its treatment, presented work being done at Johns Hopkins University and elsewhere to attendees of the eighth annual Conference on Retroviruses and Opportunistic Infections held last month in Chicago.

McArthur said that HIV disease itself can produce neuropathy. "The most important single predictive risk factor for developing HIV sensory neuropathy is viral load," he said. About a quarter of those with a high viral load set point will develop sensory neuropathy over a 10-year period. Older age, wasting, lower CD4 count, and the presence of other neuropathy producing conditions such as diabetes also increase the likelihood of developing this problem.

McArthur has developed a skin punch biopsy that is less invasive than older techniques of measuring nerve dysfunction. It can "offer an important window into the structure and damage" of neuropathy. Through a series of slides, he showed macrophage activation around swollen nerve fibers. Over a short period of time the fibers degenerate, then disappear.

He drew upon studies that have associated increased levels of tumor necrosis factor-alpha (TNF-a) in the brain with dementia, and he speculated that increased production of TNF-a and other inflammatory cytokines by macrophages is responsible for nerve death.

Mitochondrial toxicity

McArthur separated out toxicity associated with the "d" drugs (didanosine [ddI], stavudine [d4T], and zalcitabine [ddC]) that have similar overlapping neuropathic characteristics. Drug induced neuropathy may reverse when the regimen is changed, though nerve regeneration is a slow process.

"Dideoxynucleoside [the 'd' drugs] toxicity is much more common in patients who have distal [distant] neuropathy from diabetes or cancer chemotherapy. It seems to be cumulative or possibly even multiple with double dideoxynucleoside regimens," he said (see chart below). Acute sensory neuropathy also has been linked to lactic acidosis and should be seen as a warning sign to that life-threatening condition.

Most researchers and clinicians believe that the "d" drugs inhibit mitochondrial DNA replication, said McArthur. There is a general correlation that the more potent the drug, the more likely it is to produce greater neuropathy in a greater percentage of patients.

Researchers at Johns Hopkins have tried to find an animal model of neuropathy. But rats dosed with high levels of "d" drugs did not show any sign of nerve damage as is seen in humans. So they developed a laboratory nerve tissue culture to test toxicity.

"Within three hours of exposure to ddC there is extensive pruning" of the nerve tissue culture, mimicking what McArthur has seen in patient skin biopsies. He tried different concentrations of different antiretroviral drugs. Far away the most toxic was ddC, while ddI and d4T showed toxicity only at higher concentrations. "With AZT there is minimal effect on neuron outgrowth."

In tissue cultures, "one can apparently rescue the neurons by using pyruvate and uridine," he said. That opens the possibility of at least stabilizing further decline in nerve cells and perhaps even stimulating their re-growth.

Treatments and research

Amitriptyline and topical lidocaine have shown "no significant effect on neuropathic pain" in clinical trials. Lamotrigine, a new anticonvulsive agent, "showed a very significant effect on neuropathic pain" in data published last year. Nerve growth factor showed similar impressive results "but industry support is not there" for additional trials.

Nerve regeneration is measured in months or years rather than weeks, said McArthur, which increases the difficulty and cost of clinical trials.

Furthermore, existing pain outcome measures "are relatively crude and require a large sample size." They are geared more toward the larger central nervous system rather than the smaller peripheral nerves where HIV-related neuropathy tends to occur.

He presented a model "to rapidly test regenerative agents" for sensory neuropathy. Capsaicin, an extract of red pepper, is applied to a small portion of skin for two days to destroy nerve fibers there. The fibers begin to re-grow within two weeks and normal density is restored within about 60 days. Diabetic patients show a much slower re-growth of nerve fibers. Study has begun in patients with HIV-related and drug-related neuropathy.

McArthur believes the model can be used to measure if particular trial interventions speed up the re-growth of peripheral nerve fibers and if so, by how much. This will allow chemical agents to be tested for effect more quickly and at reduced cost.

He pushed for fast track trials of regenerative agents such as timcodar, a neutrophilin "which acts downstream of nerve growth factor to stimulate nerve fiber repair."

McArthur also encouraged physicians to "improve their screening techniques" for neuropathy by using both symptom questionnaires and techniques such as skin biopsy, particularly with patients on the "d" drugs. Presently the best way to deal with neuropathy is to remove those drugs that may be causing or worsening the problem.

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