People with HIV infection can develop damaged nerves in the hands, feet and legs. This condition is called peripheral neuropathy (PN). As a result of PN, people can develop very painful sensations in their limbs, such as burning or stabbing pains. They can also lose their ability to feel hot or cold in the affected limb. Sometimes, depending on the severity of nerve damage, they may even feel numbness. Neurologic testing can reveal reflexes that have degraded. Having symptoms of PN can impair quality of life.

PN can occur in people with HIV infection because the mitochondria (energy-producing parts) of cells become damaged. When mitochondria do not produce enough energy, nerve cells can malfunction or even die. Some studies have found factors that may increase the risk for developing peripheral neuropathy, such as the following:

• having a low CD4+ cell count
  
  
• being older
  
  
• being taller
  
  
• excessive production of harmful substances by HIV-infected cells
  
  
• exposure to so-called “d” drugs – older anti-HIV drugs that are no longer routinely recommended for first-line therapy in Canada or other high-income countries, such as ddI (didanosine, Videx), d4T (stavudine, Zerit) and ddC (zalcitabine, Hivid)
  
  
• co-infection with CMV (cytomegalovirus)
  
  
• excessive intake of vitamin B6 (pyridoxine)
  
  
• deficiency of B-complex vitamins
  
  
• excessive intake of alcohol
  
  
• having diabetes
  
  
• excessive exposure to drugs with the potential to cause nerve damage, including the antibiotics isoniazid and metronidazole (Flagyl); the anticancer drugs vincristine, etoposide, paclitaxel, docetaxel and cisplatinum
  
  

A research team in the U.S. recently reviewed health-related information collected from 1,592 HIV-positive people (80% men, 20% women) in an attempt to find associations between various factors and the future risk for developing symptoms of PN in people who had symptom-free PN. Participants were monitored for about five years and underwent neurologic and other assessments.

The researchers found that exposure to what they called “neurotoxic ART” (combinations that included “d” drugs) was associated with a twofold increased risk for developing symptoms of peripheral neuropathy.

However, what surprised the researchers was that participants who used medicines other than insulin (such as metformin (Glucophage)) to help control their blood sugar were less likely to develop symptoms of PN.

Due to the observational nature of the present study’s design, its conclusions are not definitive. However, they are suggestive of a protective effect of diabetes medicines on nerves. The researchers are not certain how or why this occurred.

Muscle and fat cells are dependent on insulin to help pull sugar from the blood into them so that that their mitochondria can use sugar as a source of energy. Canadian researchers have found that while nerve cells are not dependent on insulin for helping to transport sugar from the blood into nerve cells, these cells are sensitive to its effects. That is, insulin might have other effects on nerves, perhaps helping them grow and survive. If nerve cells in the periphery (outside of the brain and spinal cord) lose their sensitivity to insulin, they can malfunction and degenerate. Many diabetes medicines work by making cells more sensitive to the effects of insulin and that may be one possible way that these drugs could help prevent the worsening of peripheral neuropathy.

The findings from the U.S. study about the potentially beneficial effects of insulin-sensitizing agents such as metformin in HIV-positive people at risk for symptoms of PN need to be confirmed in a study of a more robust design. If they are confirmed, clinical trials of insulin-sensitizing agents commonly used in the management of type 2 diabetes may be the next step. Such research may, in part, explain the beneficial effect of the antioxidant alpha-lipoic acid, which has been tested in clinical trials of HIV-negative people with peripheral neuropathy and to help improve insulin sensitivity.

By Sean R. Hosein

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