31 March 2015 

Predictors of HIV-related peripheral neuropathy in the modern era

HIV infection can cause many problems, including some that affect the nerves. The nervous system that permeates the vast majority of the body outside of the brain is called the peripheral nervous system. As early as 1983, doctors in Manhattan noted the strange appearance of injury to the nerves in the feet and legs of people with HIV. This type of injury is called peripheral neuropathy (PN). Neurologists have found that PN generally first appears in the toes and feet and can result in numbness, intermittent sensations and pain. In one study, doctors have documented the severe nature of the pain associated with PN and found that affected patients used strong words such as the following to describe it: “stabbing,” “burning” and “aching.”

Possible causes of peripheral neuropathy

The causes of PN among HIV-positive people can vary. For instance, in the early 1980s when no effective treatment was available, PN was likely a consequence of untreated HIV disease. In the 1990s, a group of anti-HIV drugs commonly called “d-drugs” was often used:

  • d4T (stavudine, Zerit)
  • ddI (didanosine, Videx)
  • ddC (zalcitabine, Hivid)

Although the use of ddC quickly fell out of favour because of its toxicity and weak antiviral effect, ddI and d4T continued to be used into the early 21st century as part of potent combination anti-HIV therapy (commonly called ART or HAART). These d-drugs could be toxic for nerve cells, and even in the early 1990s doctors found that they could cause PN.

However, today the use of d-drugs is strongly discouraged by treatment guidelines in high-income countries, so their use is unlikely to be the cause of new cases of PN.

Peripheral neuropathy today

Researchers at major clinical centres in the U.S. have collaborated to study potential causes of PN among HIV-positive people in the modern era. They recruited about 500 people who were free from PN and monitored them for an average of two years, performing extensive assessments. Taking into account many issues, statistical analysis found that there were several factors associated with an increased risk for PN. In this CATIE News bulletin we explore some of those findings and what they mean.

Study details

Researchers recruited 1,583 HIV-positive people between 2003 and 2010 for a large study about HIV and neurological issues. A subset of this group—493 people—who did not have PN when they entered the study comprised participants for the current analysis. 

Doctors and nurses were trained by neurologists to interview, examine and assess participants for any signs and symptoms of PN. Participants were also screened for depressive illness. Blood samples were collected and additional information was obtained from medical records.

The average profile of the 493 participants when they entered the study was as follows:

  • 81% men, 19% women
  • age – 42 years
  • 68% (335 people) were taking ART, of whom 201 (61%) had an undetectable viral load
  • Nearly one-third of participants were previously exposed to d4T or ddI
  • 14% of participants were taking d4T or ddI when they entered the study
  • doctors diagnosed 73% of participants with a "substance use disorder;" commonly used substances were alcohol (55%), cocaine (40%), crystal meth (18%) and opioids (17%)


After an average of two years of monitoring, 131 participants (27%), all of whom were free from PN at the start of the study, subsequently developed PN.

Possible risk factors

Taking many factors into account, researchers found statistical links between a number of factors and the subsequent development of PN. Here are some of those factors:

  • age (50 years or more) – This finding is important because as HIV-positive people age, they may need screening for PN.
  • detectable HIV viral load – Untreated or poorly managed HIV results in a greater degree of inflammation. HIV-infected cells also produce viral proteins that injure nerve cells. Therefore, it is not surprising that the researchers found that participants with detectable HIV viral load were more likely to develop PN than people whose viral loads were undetectable.

Treatment and its relationship to PN

Researchers found that “HIV disease and treatment status significantly affected [rates of new cases of PN] in this study.” For instance, they discovered that the “highest rate of PN occurred in a relatively small group of individuals (50 people) who had [previously used ART but discontinued it].” The reasons for discontinuation were not revealed. These participants had very low CD4+ cell counts because they were not on treatment. In part, new cases of PN in this group of people could have been due to untreated HIV infection. Thus the research team issued the following warning:

“Because 30% to 40% of HIV-infected persons on ART in the U.S. do not maintain durable virologic suppression because of transfer of care, poor adherence and other factors, our findings suggest that [PN] will be a persistent or increasing problem.”

Researchers noticed that participants who had never taken ART and who had relatively high CD4+ counts were least likely to develop PN. This is probably because their immune systems had experienced minimal degradation.

The researchers also found that the following factors put participants at a higher risk of developing PN:

  • substance use – People with a history of opioid use were more likely to subsequently develop PN.
  • depressive illness – Participants whose depressive illness became more severe over the course of the study were more likely to develop PN.
  • gender – Women were more likely to develop PN than men. This finding needs to be explored in another analysis but could be related to biological factors—genetics, hormones—or social and psychological factors such as substance use and possibly depression.

Pain and depression

The researchers were struck by the intersection of opioid use, worsening depression and the development of PN. They suspect that the pathways used by brain cells to communicate with each other are affected by addiction and overlap with the pathways that deal with pain. They noted that previous research has found that “regardless of the cause of the underlying pain…pain and depression reinforce each other.” They also pointed out that depression alters the brain, and stimulation that is not normally painful may be experienced as pain by depressed people. It is possible that in people with a history of addiction or substance use, pathways in the brain change and such people become more vulnerable to experiencing pain, particularly when the brain receives and tries to process signals from nerves that are dysfunctional because of PN.

The modern era

The findings from the current era are important and underscore PN-related risk factors that are different from previous eras. For instance, in the past, height and the presence of type 2 diabetes among HIV-positive people were co-factors in the development of PN. However, in the present study, no link was found with these factors. Part of the reason for this is that only a small proportion of participants had type 2 diabetes (8%).

Also, in previous eras the use of d-drugs was a major factor in the development of PN. However, today d-drugs are seldom used, and even in the cases where they were taken by participants in the present study, their use was not linked to the development of PN.

In general, alcohol addiction is a major co-factor for the development of PN. This occurs in part because alcohol can be toxic to nerves and also because it depletes the body of nutrients (such as B-complex vitamins) that are needed by nerve cells. However, researchers did not find alcohol use linked to PN in the present study.

Future research

PN can cause distress, disability and a reduction in quality of life. The researchers stated that “neuropathic pain can wax and wane in severity”; also, sometimes PN can resolve or go into remission “either spontaneously or as a result of treatment and might even recur at a later time.” This underscores the importance of studying PN.

The researchers suggest that future studies are needed to address strategies to help prevent PN, particularly among people at high risk for this complication, such as people who use opioids or who have depression.


Nerve pain and numbnessPractical Guide to HIV Drug Side Effects

Ask the Experts: Peripheral NeuropathyThe Positive Side

—Sean R. Hosein


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