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CATIE News - Alberta-neurologic disease linked to survival

September 22, 2010 - The brain is surrounded by a layer called the blood-brain barrier. To bypass this protective barrier, HIV can infect cells of the immune system and hide inside these cells. As these infected cells get inside the brain, they spew new copies of HIV, viral proteins and chemical signals that cause brain cells to become dysfunctional and in some cases die. So, while HIV infection is commonly explained as a disease that affects the immune system, the complexity and reach of the immune system is such that ultimately this infection affects many other organ-systems, including the nervous system.

Even in the earliest days of the AIDS pandemic, doctors quickly recognized that HIV could cause a range of neurologic problems, perhaps the most disturbing of which is HIV-related dementia.

Today, given the widespread availability of potent anti-HIV therapy (commonly called ART or HAART) in high-income countries, HIV-associated dementia is much less common that it was in the time before HAART. But dementia is just one of several neurologic complications that could arise from HIV infection, and researchers in Alberta were interested in studying these complications in the present era. The findings from their large study suggest that while HIV-related dementia is much less common because of HAART, other neurologic issues can affect a substantial proportion of HIV-positive people. Furthermore, some neurologic disorders seen in HIV-positive people today appear to affect their survival.

Study details

Researchers at Calgary's Southern Alberta Clinic conducted a study that monitored the health of participants between 1998 and 2009. They were particularly interested in neurologic disorders among HIV-positive people. They compared features of 404 HIV-positive people who had also been diagnosed with a neurologic disorder to features from 1,247 other HIV-positive people who did not have neurologic disorders. In total, 1,651 HIV-positive people were enrolled in this study. Their average profile was as follows:

  • 20% females, 80% males
  • age - 33 years
  • the main ethno-racial distribution was as follows: 70% White, 10% Aboriginal, 10% Black
  • 50% were gay or bisexual
  • 23% were injection drug users
  • 24% had hepatitis C virus co-infection

Results

Over the course of the study, 25% of participants were diagnosed with a neurologic disorder. People who received this diagnosis were more likely to have:

  • sought care relatively late in the course of HIV disease, as their CD4+ counts were generally lower (111 cells) than people without neurologic disease who sought care (208 cells). And, not surprisingly, people with low CD4+ counts who were diagnosed with neurologic disorders also were more likely to have a greater rate of AIDS-related illnesses.
  • relatively higher viral loads (25,000 copies/ml) than people who did not have neurologic disorders (15,000 copies/ml)

The following factors did not have any relationship to the development of a neurologic disorder:

  • age
  • gender
  • substance use
  • hepatitis C virus co-infection

Focus on neurologic diagnoses

At the time neurologic disease was diagnosed, participants had been living with HIV for an average of six years. During the study period, 53 neurologic disorders were found, the most common being the following:

  • peripheral neuropathy
  • HIV-associated neurocognitive disorders (HAND; this term encompasses dementia as well as minor neurocognitive impairment)
  • seizures
  • very severe headaches
  • brain infections
  • problems controlling and coordinating muscles and movement
  • muscle weakness

Key findings were as follows:

  • People who had AIDS were between two and three times more likely to be diagnosed with a neurologic disorder compared to people who were HIV positive but did not have AIDS.
  • About 50% of people with a diagnosis of one neurologic disorder were also diagnosed with at least one other neurologic disorder.

Trends in time

Over time, the number of neurologic diagnoses decreased. For instance, between 1998 and 1999, 86 diagnoses were made. In 2006 to 2007, only 65 new cases of neurologic disorders were diagnosed. However, because of the sizeable, though decreasing, number of neurologic diagnoses made each year, over time the number of HIV-positive people coping with these problems rose, reaching a steady level in 2004.

Who is at greatest risk?

The people who were at greatest risk for neurologic disease were called "late presenters" by the researchers. These are HIV-positive people who, for whatever reason(s), seek care relatively late in the course of their illness. In the present study, late presenters often sought care when their CD4+ counts had plunged below the 200-cell mark. On average, late presenters developed neurologic disorders an average of three years after a diagnosis of HIV infection.

Neurocognitive issues

The researchers also found that people whose viral loads were more than 10,000 copies/ml were at significantly increased risk for developing HIV-associated neurocognitive disorders.

According to the researchers, to put their overall findings in perspective, neurocognitive problems occurred at a rate that would be seen in HIV-negative people about 20 years older than people in the current study; that is, in people who were about 55 to 60 years old. This finding supports a concept that seems to be increasingly common-that HIV infection is associated with an apparent accelerated aging of organ-systems, particularly the cardiovascular system and brain.

The good news is that rates of HIV-related neurocognitive disorders fell during the latter five years of the study. This suggests that the increased effectiveness of HAART was able to help reduce the appearance of this troublesome complication.

Causes of death

Over the course of the study, 171 people died. People diagnosed with a neurologic disorder were at significantly increased risk for death. Causes of death in this study were divided into three common groups as follows:

  • AIDS-related deaths - 79 people
  • non-AIDS-related deaths - 81 people
  • unknown causes - 11 people

Having a diagnosis of HIV-associated neurocognitive disorder increased the risk of subsequent death by 300%.

Having a diagnosis of a life-threatening infection of the brain/spinal cord increased the risk of death by 500%.

Having a diagnosis of peripheral neuropathy did not increase the risk of death.

Comparing death rates

In the present study, the annual rate of death in those with and without neurologic disorders was expressed this way by researchers:

  • 18 deaths per 1,000 HIV-positive people with a neurologic disorder
  • 8 deaths per 1,000 HIV-positive people without a neurologic disorder

In comparison, the annual rate of death of HIV-negative people of similar age and gender in Canada was as follows:

  • 2 deaths per 1,000 people

These estimates are sobering and suggest that HIV-positive people who have a neurologic disorder may need more frequent monitoring and/or other interventions to help prolong their survival.

An important study

The rates of HIV-associated neurocognitive problems and life-threatening infections of the brain reported in the Alberta study were similar to those seen in large studies in the United States and the European Union. So it is likely that the Alberta findings and their implications are robust. Other studies are now needed to assess the impact of the burden of neurocognitive disorders in other countries to confirm and extend the results reported from this large Canadian clinic.

Implications

The results from the Alberta study underscore the need to begin monitoring and treating HIV disease long before the CD4+ count falls to dangerous levels. This is because the damage to a weakened immune system wrought by HIV may have unexpected and far-reaching consequences for the brain and overall health, long after HAART is initiated.

-Sean R. Hosein

REFERENCES:

  1. Kraft-Terry SD, Buch SJ, Fox HS, et al. A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron . 2009 Oct 15;64(1):133-45.
  2. Smith EM. Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis. Brain, Behavior, and Immunity . 2008 Jan;22(1):3-14
  3. Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Annals of Neurology. 1983 Oct;14(4):403-18.
  4. Levy JA, Shimabukuro J, Hollander H, et al. Isolation of AIDS-associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet. 1985 Sep 14;2(8455):586-8.
  5. Carne CA, Tedder RS, Smith A, et al. Acute encephalopathy coincident with seroconversion for anti-HTLV-III. Lancet. 1985 Nov 30;2(8466):1206-8.
  6. Ances BM, Liang CL, Leontiev O, et al. Effects of aging on cerebral blood flow, oxygen metabolism, and blood oxygenation level dependent responses to visual stimulation. Human Brain Mapping . 2009 Apr;30(4):1120-32.
  7. Ances BM, Vaida F, Yeh MJ, et al. HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging. Journal of Infectious Diseases . 2010 Feb 1;201(3):336-40.
  8. Crowe SM, Westhorpe CL, Mukhamedova N, et al. The macrophage: the intersection between HIV infection and atherosclerosis. Journal of Leukocyte Biology . 2010; Apr;87(4):589-98.
  9. Guaraldi G, Zona S, Alexopoulos N, et al. Coronary aging in HIV-infected patients. Clinical Infectious Diseases . 2009 Dec 1;49(11):1756-62.
  10. Vivithanaporn P, Heo G, Gamble J, et al. Neurologic disease burden in treated HIV/AIDS predicts survival. A population-based study. Neurology . 2010; in press .

 

CATIE-News is written by Sean Hosein, with the collaboration of other members of the Canadian AIDS Treatment Information Exchange, in Toronto.

From Canadian AIDS Treatment Information Exchange (CATIE). For more information visit CATIE's Information Network at http://www.catie.ca

Source: CATIE: CANADIAN AIDS TREATMENT INFORMATION EXCHANGE


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