Neil McKellar-Stewart considers some of the more specific benefits that treatment can offer ... starting here with the central nervous system (CNS) and your brain.
How HIV affects the CNS
We know that HIV has a profound effect on our immune system and on the T-helper cells which defend us against infections. But HIV also infects the CNS, and although it doesn’t infect nerves cells (neurons), they can be injured by HIV viral proteins and by neurotoxins that are produced over the long term.
Up to 50% of people with HIV who are on treatment may be living with CNS abnormalities. Most of these are mild and include things like peripheral neuropathy, myopathy (limb muscle weakness, myalgia and muscle cramps) and changes in brain structure and functioning (1,2,3,4,5).
For most of us, HIV gets into the CNS quite early on — often within a week of being infected. Over time, it can cause an immune response, inflammation and the production of chemicals (cytokines and chemokines). All this may result in damage to a range of cells, particularly in the brain.
For people who are on treatment, HIV seems to affect those parts of the brain related to cognitive ability — including memory, learning, attention and how fast we process things — losses similar to those we experience in older age. So, this intersection between ageing, HIV in the CNS, inflammation and activation of the immune system, can make it difficult to untangle the relative contribution of each.
HIV treatment reduces some of these damaging processes, but it does not stop them altogether. The CNS is a reservoir in which HIV-infected cells can become active and contribute to the HIV that is circulating in the bloodstream. The extent to which antiretroviral (ARV) drugs penetrate the blood-brain barrier (BBB) depends on individual factors, the integrity of the barrier itself and also the characteristics of different HIV drugs and drug-classes (something we will discuss later).
Measuring HIV-associated neuro disorders
Neurocognitive impairment (NCI) is caused by many things, including the ageing process and a range of other health conditions such as HIV, CNS trauma, diabetes, viral infections, cardiovascular disease and psychiatric illness. Lifestyle factors such as a bad diet, drug use, smoking and lack of exercise also play a part, as do environmental contaminants (6).
In 2007, an internationally agreed classification scheme was devised to describe the range of HIV-associated neurocognitive disorders (HAND) that were increasingly being seen in people with HIV even on treatment. This scheme is based on someone’s performance against a range of age and education standardised neuropsychological (NP) measures. There are three categories:
- HIV-associated Asymptomatic Neurocognitive Impairment (ANI), while picked up by NP measures, does not interfere with everyday functioning. The person and their immediate significant others cannot identify any symptoms of impairment.
- HIV-associated Mild Neurocognitive Disorder (MND) does affect performance and the person reports that they have lost some mental sharpness. They may be less effective at work, at home or socially and significant others may also have noticed these changes.
- HIV-Associated Dementia (HAD) is the severest form of HAND and usually affects a number of areas including learning new information, processing ideas, and being able to concentrate. HAD interferes with day-to-day functioning, including work, home life and social activities.
Fortunately, the vast majority of PLHIV will never experience any symptoms of neurocognitive impairment. However, if measured by a battery of exhaustive tests, a significant proportion may well be diagnosed with ANI and not even know they had it. Much fewer PLHIV will have MND.
Whether or not you develop an asymptomatic or a mild NCI is strongly associated with your lowest-ever CD4 count (nadir) and with older age. It is also about the level of viral load in your cerebrospinal fluid (CSF), how much inflammation there is and how much your immune system has been activated; plus the health of your cardiovascular (blood) circulation.
Does treatment reduce the risk of HAND?
Those of you who’ve been around will know the toll that HIV can exact on people’s neurological health. Early on in the epidemic, about one in seven people with AIDS-developed AIDS dementia; a diagnosis that usually progressed to severe disability and death within a year (7,8). Fortunately, with the introduction of highly active antiretroviral therapy (HAART), the incidence has reduced to almost zero.
In 2002, just six years after the introduction of HAART ,they estimated that cases of AIDS dementia had gone down by 60% and toxoplasmosis by 72%. Combination treatment certainly had a profound impact on these CNS manifestations (9).
A recent review (10) of 15 studies of neurocognitive change in people after starting treatment found that in 11 of them, neurocognitive performance improved after an average of six months on HAART .
This is heartening news despite the fact that most of these studies had only a small number of participants.
A ‘then and now’ comparison published in December 2010  compared 857 PLHIV from the pre-HAART era (1988-95) with 937 from 2000-2007. They found mild impairment occurred in both groups at all stages of HIV disease, even in those on effective treatment. Importantly, the single predictor appears to be low nadir CD4. Sixty percent of those receiving HAART and with neurocognitive impairment had a nadir CD4 count of less than 200. Clearly, allowing the immune system to be severely compromised increases the risk.
Neurocognitive response to HAART varies across individuals, as was shown in a recent analysis of 1,160 PLHIV involved in 14 different clinical trials (11). Investigators found that 39% of participants had some (commonly mild) impairment at the start of treatment, and that nearly half of these showed improvements after 48 weeks on treatment. However, they found that by this endpoint, 21% had also developed a new NCI. So, overall, the rate was only slightly reduced by starting treatment. Again, any history of immunosuppression was associated with higher rates of NCI. Those with a CD4 nadir of less than 200 were 1.73 times more likely to have sustained impairment compared to those with nadirs above 350. In fact, every 50 cell decrease in someone’s lowest ever CD4 count was associated with an 8% increased likelihood of ongoing NCI.
Of 94 PLHIV with NCI in a recent Italian study (12), impairment persisted for nearly two-thirds of them, even after five years of treatment.
A recent analysis of the CHARTER Group data (13) concluded that the risk of NCI was lowest in PLHIV who never allowed their CD4 count to fall to low levels.
Data from a Swiss cohort of 100 PLHIV on effective treatment found that 28% of them had mild neurocognitive disorders while a further 42% had asymptomatic neurocognitive impairment and experienced no problems with everyday functioning (14).
All these studies point to a strong association between low nadir CD4 count and an increased risk of ongoing neurocognitive impairment even when on treatment. So, does HIV treatment reduce the risk of neurocognitive impairment? Yes, but treatment is not absolutely protective. There are many other factors which come together to increase the risk.
Shopping around for the most effective drugs
Treating HIV effectively stops replication in the bloodstream (i.e. undetectable viral load), and reduces inflammation and immune activation. But to prevent HIV replication in the brain, HIV drugs must cross the blood-brain barrier and be present in the cerebrospinal fluid (CSF) at levels sufficient to effectively inhibit HIV.
Viral levels are not routinely measured in the CSF. A lumbar puncture is not the most pleasant procedure to undergo or without risk; and so it is only done when there is a good clinical reason.
Studies suggest that not all antiretrovirals function in the brain at sufficient levels . In 2008, a score to measure the CNS penetration-effectiveness (CPE) of HIV treatments was published. The text box (below) shows the scores for those treatments commonly used in Australia (older drugs are not included and newer drugs have yet to be scored).
The total score for a HAART combination can be calculated by adding the scores of the individual drugs. . A score greater than seven or the use of protease inhibitors are about equal in predicting whether someone may have an undetectable viral load in their cerebrospinal fluid (CSF). Put simply, the more effective the drug combination is in penetrating into the CSF, the more chance of HIV being suppressed in the brain.
The evidence demonstrating the benefit of having a treatment regime with a higher CPE score is mixed. A recent longitudinal study of PLHIV with some cognitive impairment showed that by starting them on a treatment regime with higher CPE score for 48 weeks, their cognition gradually improved and peaked at approximately 24–36 weeks (15). The two factors which predicted cognitive improvements were undetectable VL in blood and a higher CPE score.
Another study of PLHIV switching or initiating treatment reported that CPE scores correlated with greater improvement in concentration, speed of mental processing and mental flexibility after 20 and 39 months. Higher CPE scores were also associated with an improvement in global NP scores after 39 months . Other studies have failed to confirm these findings.
Recent UK data suggests that for those on long-term HAART with no symptoms, the rates of impairment are low ( less than 20%). Where impairment was found it was associated with lower nadir and older age but not CPE score or ARV drug class (16).
So, CPE score may have some validity as a tool to guide treatment but more convincing evidence is needed, especially for those who commence treatment early.
Over time, there are many variables associated with having a detectable CSF viral load (17).
In the CHARTER Study, 413 PLHIV had their blood and CSF samples tested for detectable HIV and of those whose plasma viral load was consistently undetectable, only 6% had any measureable viral load in their cerebrospinal fluid. This is good news, especially as many people in this cohort had very low nadir CD4 counts and a high prevalence of NCI .
It would seem that having an undetectable blood plasma VL is by far the most influential factor for indicating suppression of HIV in the CSF. This suggests that having undetectable HIV in your bloodstream usually protects you from having detectable HIV in your CSF.
What does it all mean for me?
HIV treatment is beneficial. It drives down viral load both in the blood and in the CSF.
Having HIV does put you at risk of declining cognitive function. But that risk is greatest when HIV has gone unsuppressed for many years and CD4 counts have fallen below 200. Plus there are other compounding factors including recreational drug use, co-infection with other viruses and, perhaps most significantly, just getting older.
There are things you can do to maintain your brain health:
- Start treatment when your CD4 counts are relatively high — possibly over 500 and certainly when they fall below 500.
- Adhere to your HIV treatment regimen exactly.
- Ensure that you maintain an undetectable viral load .If it does becomes detectable across more than one visit, you and your doctor should talk about switching to a more potent combo.
- Maintain the best possible cardiovascular health by ensuring that your blood pressure, lipids (cholesterol and triglycerides) and blood sugar are monitored and maintained in healthy ranges and that you follow any treatments your doctor recommends.
- The basics: quit smoking; limit your alcohol and other drug use; have a diet high in poly-unsaturated fatty acids (omega-3s); reduce your risk of diabetes and cardiovascular disease; get adequate rest, physical and mental exercise; and promptly address issues of depression.
- If you, or those with whom you share your life, have concerns that your cognitive sharpness has dulled (e.g. a lot of the time: not remembering familiar things, forgetting why you started an action, losing your train of thought in a conversation, making mistakes in everyday tasks) then talk to your doctor. Study data suggests that if a problem is suspected by the person with HIV or their close acquaintances then there may well be some underlying issue. It may be that some further investigation is suggested.
- If you have been diagnosed with asymptomatic or mild impairment through neuropsychological testing, your doctor will suggest regularly monitoring. To reduce the likelihood of having further declines it is important that you stick to an optimum treatment regimen and maintain an undetectable viral load .Recent research suggests that declines only occur in a small percentage of people (less than 25%) and this is usually associated with severe comorbidities (such as hepatitis C or major depression), lifelong methamphetamine use and ceasing treatment (18).
Finally, take a deep breath and relax: you aren’t going to go ‘mad’. If you follow the suggestions above and ensure that you and your doctor are regularly monitoring your health, the risk of serious descent into significant neurocognitive decline is very low.
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