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New advances promising in treating neuropathy
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Neuropathies among HIV patients have continued to increase in recent years, particularly in the case of antiretroviral toxic neuropathy (ATN).
Research data suggest about one-third of HIV patients experience some form of neuropathy symptoms, ranging from mild cases of peripheral neuropathy, in which there is some numbness and tingling in the feet, to severe pain, where a person would have difficulty walking a few blocks without resting, explains Justin McArthur, MBBS, MPH, professor of neurology and epidemiology at Johns Hopkins University in Baltimore.
"I see a huge number of patients with this problem," he says. "Many of them have said to me that this is the worst aspect of their HIV disease; this is what ruins their lives."
Investigators have focused on developing three different types of treatments for HIV-associated neuropathies:
One approach would prevent the onset of neuropathy; another would treat the symptoms of neuropathy; and a third would reverse neuropathy and repair damage, says David M. Simpson, MD, professor of neurology, director of the Neuro-AIDS Research Program, and director of clinical neurophysiology laboratories at Mount Sinai School of Medicine in New York City. Simpson’s research includes a study scheduled for presentation at the 11th Conference on Retroviruses and Opportunistic Infections, held in February in San Francisco. "Probably most studies to date have been in the second category of symptomatic therapy, the treatment of pain," he explains.
Generally, the disorders are called HIV-associated sensory neuropathies of which the two most common types are distal sensory peripheral (DSP) and antiretroviral toxic neuropathy (ATN), McArthur explains.
ATN is caused by the "d-drugs," Simpson adds. Those include didanosine (ddI), stavudine (d4T), and zalcitabine (ddC). Researchers do not fully understand how HIV causes neuropathy, he says. "Neuropathy does not appear to be directly a result of infection by HIV, so it’s probably a secondary, related mechanism. It is known, and we and others have shown, that the more advanced HIV disease is the higher the risk of developing neuropathy, particularly as CD4 cell counts drop lower; and the higher the plasma viral load, the more severe the neuropathy is." Despite the fact that one solution for patients who experience neuropathy because of a d-drug is to switch antiretroviral regimens, the incidence of HIV-associated neuropathies remains as high as it has ever been, Simpson notes.
"What’s happened in the last five to 10 years, especially since the introduction of highly active antiretroviral therapy (HAART), is that the incidence of ATN has gone up dramatically," says McArthur. "We see some form of neuropathy in 35% of all individuals with HIV; and so it’s quite common, and there is another 25% to 30% of those with HIV who have a silent form and have no symptoms." The silent form of neuropathy is detected through testing as abnormalities in peripheral nerves, he explains.
Compounding the problem is the fact that HIV-infected people who are coinfected with hepatitis C also may experience neuropathic damage, as will the 12% to 15% of people on HAART who develop diabetes mellitus, McArthur continues. "Then there are a host of other conditions, including B12 deficiencies, alcohol abuse, and nutritional deficiencies, that can result in neurological damage," he adds.
Here are a few of the treatments being studied:
Among the newer treatment possibilities is the capsaicin dermal patch (Capreve). Capsaicin, a crystalline alkaloid, is the active ingredient that causes the burning sensation when a person eats chili peppers, Simpson says. Capsaicin has been developed into a topical pharmaceutical compound that, in a low concentration formulation (Zostrix), has been used to treat diabetic neuropathy, he says.
Researchers have been studying a high concentration compound (Capreve — manufactured by NeurogesX of San Carlos, CA) in the treatment of pain from neuropathy experienced by HIV and AIDS patients, says Simpson, who is the principal investigator of a 30-site, placebo-controlled study of the patch. "It’s painful when the patch is applied to the surface of the skin, and the patient is treated with pain medication for a couple of hours," notes Simpson.
"Within a day or so, the pain of the treatment administration abates." Investigators are studying whether the patch will provide relief from pain for up to three months, he says.
The mechanism seems to be that the application of the patch causes degeneration of nerve fibers, which in turn causes pain relief. "After a period of time, those fibers regenerate, which is why we think the pain may return and further applications will be necessary, but it has not been studied over the long term," Simpson adds. Investigators are recruiting patients for the study.
Investigators hope this experimental drug will improve pain and stimulate growth of damaged nerve fibers, McArthur says. "We think it acts as an analgesic and as a repair stimulant for damaged nerve fibers," he explains.
"Prosaptide has an exciting potential," adds Simpson. While early studies are looking at prosaptide’s ability to provide pain relief, the long-term goal is to develop a drug that will regenerate nerves and function, he says.
"We’re hoping that once the drug company has long-term [animal study] safety data for the drug, that we can test it for longer periods of time in patients. We’re hoping that patients enrolled in the shorter duration trial will be able to receive the drug over a longer term when it’s available." There have been some exciting data from preliminary studies of prosaptide in the treatment of diabetic neuropathy, and now there is a large placebo-controlled study of its use in the treatment of HIV-associated neuropathy, Simpson says.
The study is sponsored by Savient Pharmaceuticals Inc. of East Brunswick, NJ, the AIDS Clinical Trials Group, and the Neurologic AIDS Research Consortium.
Other experimental drugs.
Possibilities also exist for the use of neuroimmunophilins, a class of drugs that initially was developed as immunosuppressants for transplant patients, McArthur says. "These drugs are able to stimulate repair of damaged nerve fibers and are in clinical trials for a number of neurological disorders, including peripheral neuropathy."
Another drug with preliminary data is a supplement called acetyl-L-carnitine or L-acetyl-carnitine, which is a natural substance in the body that assists in mitochondrial metabolism, Simpson continues. "There are investigators in London who have some evidence suggesting that acetyl carnitine might be beneficial in treatment of neuropathies related to d-drugs. And there are many patients taking the supplement over the counter in health food stores." So far, the information on the supplement is preliminary and needs to be confirmed, and investigators in the United States also are developing a study to look at the use of this supplement for treatment, provided the supplement can be obtained from its Italian manufacturer, he says. Regulatory issues are proving a barrier, however, Simpson notes.
Investigators also have studied recombinant nerve growth factor (NGF) for potential regeneration of damaged nerve fibers in patients suffering from diabetic neuropathy; but while the agent significantly reduced pain, it didn’t show evidence of nerve fiber regeneration, Simpson says. Based on those mixed results, the company halted development of NGF, he adds.
Treatments that currently are available include anticonvulsant drugs to treat neuropathic pain, McArthur says. "Especially when a patient has tried several different drugs, we’ll switch to one of these other drugs.
"What happens during a seizure is the nerve fibers in the brain fire by themselves, so the anticonvulsants suppress the firing of irritated or damaged nerve fibers," he explains. "In peripheral neuropathy, we have the firing of damaged nerves in the peripheral areas."
Studies have shown that anticonvulsants, such as topiramate and trileptal, are well-tolerated, do not interact with the antiretrovirals, and have no serious side effects, McArthur adds.
From a clinician’s perspective, the most important thing to keep in mind is that it’s easy to mistake another condition for a peripheral neuropathy, so a diagnosis should be made with great care, Simpson says. For instance, myelopathy may be mistaken for a peripheral neuropathy, because it causes spasticity and sensory abnormalities, gait problems, and weakness in the lower limbs.
By contrast, peripheral neuropathy generally starts in the feet with numbness or tingling, and it will start symmetrically. A patient’s symptoms may include a sensation of pins and needles, spontaneous pain, burning, aching, and stabbing pain, all occurring first in the feet and progressing to the hands, McArthur says.
"Also, there are several types of HIV-related neuropathy, so be sure to diagnose the correct kind," Simpson advises. "A second point is this is another reason to maintain maximum control of the HIV virus, because besides all the other reasons, it may prevent peripheral neuropathy as well." And lastly, he suggests that HIV clinicians should aggressively treat neuropathic pain, as well as watch for results from the current clinical trials involving new treatments for the condition.
[Editor’s note: Clinical trial enrollment is open to new participants for NGX-4010, the capsaicin dermal patch, for treatment of HIV-associated neuropathy (Study C107). For information, contact Catherine Vilahu, clinical project manager, at (650) 508-2116, ext. 108. E-mail: email@example.com. The study is recruiting for subjects at 31 sites in the United States, and there is a study listing on ClinicalTrials.gov. At the web site, use the search form with the words HIV and NeurogesX or capsaicin.]