Shortly after HIV enters the body, it infects cells of the immune system. These infected cells are transported by the lymphatic system and distributed to lymph nodes and tissues, where the virus can infect more cells. Within a week of initial infection, HIV has been spread in infected cells via the blood throughout the body, including the brain. HIV does not infect brain cells but it does infect cells of the immune system that travel to or are resident within the central nervous system (CNS) - the brain and spinal cord.
HIV-infected cells release chemicals that impair the functioning of brain cells. Infected cells also trigger inflammation within the CNS. Together, these cause dysfunction within the brain. In cases of untreated HIV infection this can lead to problems affecting neurocognitive abilities such as thinking clearly, memory and concentration. In extreme cases, changes in personality could occur and loss of control of key muscles and reflexes could become issues.
Fortunately, the widespread availability of potent combination anti-HIV therapy (commonly called ART or HAART) in Canada and other high-income countries has tremendously improved the health and well-being of HIV-positive people who are engaged in their care and treatment. Researchers increasingly expect that HIV-positive people with minimal pre-existing health conditions and who can adhere to therapy will have near-normal life spans.
Today, cases of moderate or severe neurocognitive impairment are no longer common. Neurocognitive dysfunction, if present, is generally mild and symptom free, thanks to ART. Such dysfunction is usually detectable only with complex testing. Mild neurocognitive dysfunction usually does not affect a person’s ability to carry out everyday activities.
Researchers in Alberta have been monitoring about 1,300 HIV-positive participants in a long-term study where they sought factors linked to the development of HIV-related neurocognitive problems.
Over a period of 10 years, they found that 7% of participants developed such symptoms and had the following profile compared to participants who did not have symptoms:
- they were older
- they were living with HIV longer
- their lowest-ever CD4+ count (called the nadir) was about 100 cells
- they had a high pre-treatment HIV viral load (greater than one million copies/ml)
It is important to note that not everyone with these factors developed symptoms of HIV-related neurocognitive dysfunction. However, having factors from the list above was associated with an increased relative risk for developing such problems.
The Alberta team says that doctors and nurses in clinics can use these findings when making decisions about which HIV-positive patients should be prioritized for screening for neurocognitive dysfunction.
Researchers in Calgary and Edmonton reviewed health-related data collected from January 1998 to September 2008 from 1,320 HIV-positive participants. Study participants visited the Southern Alberta Clinic every three or four months to undergo laboratory testing and be interviewed. At each visit the participant and/or his or her caregiver or family member was questioned about new symptoms of neurocognitive problems, including the following:
- poor concentration
- problems with walking, balance and control of muscles
If such symptoms were present, participants underwent brief neurocognitive assessment. If this initial assessment confirmed the presence of neurocognitive dysfunction, participants were referred to a neurologist experienced with HIV-positive people for a comprehensive screening.
Comprehensive neurological screening
This involved the following:
- a complete medical history
- a physical examination
If deemed necessary, further assessments were done, such as the following:
- CT or MRI scans of the brain
- a spinal tap to analyse the fluid that bathes the brain and spinal cord (the cerebrospinal fluid)
Furthermore, blood tests were done to exclude problems that could affect the functioning of the brain, including the following:
- dysfunction of the thyroid gland
- higher-than-normal levels of medication in the blood
Additionally, the neurologist screened participants for the following issues that can cause neurocognitive impairment:
- substance use
- inherited neurological problems
Participants also underwent extensive neurocognitive testing.
Finally, a team consisting of a nurse, physician and social worker reviewed each participant’s results, and the diagnosis of neurocognitive disorder was made by consensus.
The average profile of participants upon entering the study was as follows:
- 1,068 men and 252 women
- age – 44 years
- length of time HIV-positive – 10 years
- lowest-ever CD4+ count – 174 cells
- HIV viral load – 161,000 copies/ml
- HCV co-infection – 277 participants
Overall, 90 participants developed symptoms of neurocognitive dysfunction, graded as follows:
- minor neurocognitive dysfunction – 19 participants
- HIV-associated dementia – 71 participants
Different risk factors
Taking many factors into account, the following were significantly linked to an increased relative risk for developing symptoms of HIV-neurocognitive impairment:
Length of survival
Researchers found that for every year of being HIV positive, there was a 7% increased relative risk for developing symptoms of neurocognitive dysfunction. This does not mean that every year 7% of people developed these problems. Rather, it means that the risk increased by 7% for every year that participants survived. Note that the relative risk for an event can eventually exceed 100%. Again, this does not mean that 100% of people will develop a certain problem, just that the relative risk for it exceeds 100%.
For each year of increase in age, there was a 3% increased relative risk for developing symptoms of neurocognitive problems.
CD4+ cell count
Previous studies have found that the lowest-ever CD4+ cell count (the nadir CD4+ count) has been linked to an increased risk for developing neurocognitive problems. In the present study, for every one-cell decrease below the average nadir (174 cells) there was a 0.4% increase in the relative risk of developing symptoms of neurocognitive dysfunction.
Pre-treatment HIV viral load
Participants whose HIV viral load at the start of the study was greater than one million copies/ml had a relative risk of developing neurocognitive problems that was five-fold greater than those participants whose pre-treatment viral load was less than 1,000 copies/ml.
Bear in mind
1. A European study called Cascade also studied possible risk factors for HIV-related dementia in the present era. The Cascade dataset included 15,308 HIV-positive participants, 222 of whom developed dementia. Similar to the Alberta team, researchers working with Cascade also found that factors such as older age and longer duration of being HIV positive were linked to an increased relative risk for developing neurocognitive dysfunction.
2. Two other studies have found that increased years of education appears to reduce the risk for developing neurocognitive dysfunction.
In the Alberta study, researchers found a statistical trend toward an increased risk for developing symptoms of neurocognitive dysfunction among participants who were less educated. However, this trend did not become statistically significant, perhaps because the numbers of participants in the study was insufficient.
This issue of the size of the study may have affected the Alberta researchers’ ability to detect associations between factors such as a history of substance use and hepatitis C virus infection and the subsequent risk for developing symptoms of neurocognitive dysfunction.
Overall, the Alberta researchers stated that their findings can be used to help care teams in other HIV clinics decide which HIV-positive patients require screening for neurocognitive problems.
Now the Alberta researchers as well as other teams working in the field of neurocognitive research need to study ways to prevent and treat HIV-related neurocognitive dysfunction.
We thank infectious disease specialist John Gill MD, PhD, for his research assistance, helpful discussion and expert review.
- Sean R. Hosein
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