When antiretroviral therapy (ART) first became available, many neurologists had expected HIV would continue to cause damage to the brain, a sheltered compartment of the body where the virus would replicate hidden from the full force of treatment, but clinical experience has shown that ART has had a profound impact upon the incidence of HIV-associated dementia (HAD) in the industrialised world — leaving some neurologists at a recent meeting in Venice debating whether dementia really remains a significant problem wherever effective systemic ART is available.
“I think if you treat people adequately, systemically, they do not get progressive neurologic disease,” asserted Dr Colin Hall of the University of North Carolina.
“Certainly they won’t go back to normal - there’s no disease I know of that damages the brain badly and then you can see [the patient] go completely back to normal," he said. "But people who are adequately treated do not get progressive neurological disease in any way that’s a public health problem. Certainly you see deficits, but I have seen no evidence from anyone that there is a progressive continuous deficit in people who adequately treated [with ART]."
While some experts disagreed and said that they do have small numbers of patients who are getting worse despite suppressive ART, most of the experts at the meeting agreed that the character of HIV-associated neurological disturbances (HAND as opposed to HAD) has changed substantially since ART has become available.
“There is certainly less of the severest form of dementia; certainly less of the apathetic withdrawn type of case that can’t look after him or herself with severe motor [problems],” said Dr Igor Grant of the University of California, San Diego (UCSD).
Instead, “there is more of the milder type of disturbance: disturbances in learning new information, abstraction or executive functioning and then a mix of sensory and motor problems. These are people who are up and about in the community but they have problems with things like shopping, financial management, transportation, communication and so forth.”
“If we want to argue with regards to clinical evolution or how that has changed or not, there might be diverse opinions,” said Dr Elieser Masliah, also of UCSD, “but if you go to a patient with HIV and ask if their neurological problems are still a problem, I’m sure that you’re going to get a different response.”
Dr. Masliah nevertheless believes that since ART, HAND has gone from a sub-acute illness (with overt and permanent neuronal damage) to more of a chronic pathology — with synapto-dendritic problems that may be more easily reversible. But he is also concerned by the growing importance of confounding morbidities, including serious depression, drug use, hepatitis C virus coinfection and aging that are increasingly complicating the lives of people with HIV.
“There are so many other factors involved, he said, “Sure, there are patients that are getting worse if they are co-infected with HCV. There are patients that are getting worse if they are methamphetamine users. I think from a public health point of view, it’s definitely a problem.”
Finally, other researchers who have been monitoring the changes in brains of people with HIV are worried that with increased survival, other aging-related neurological disorders could become much more common.
“Just to say that they won’t get worse, without waiting for five to ten years to see how they are going to do, I think is premature,” said Dr Cristian Achim of the University of Pittsburgh.
Dr Achim and other researchers reported seeing changes in brain tissue consistent with premature aging, with abnormal protein deposition in the brains of people with HIV (including beta-amyloid and alpha-synuclein) that could be portents that Alzheimer’s or Parkinson’s-like diseases might develop decades earlier than usual in susceptible people with HIV. At present, though, clinical evidence that aging people with HIV may be at greater risk of these other forms of dementia is anecdotal.
The discussion took place in April in Venice, at the Evolving Mechanisms of HIV Neuropathogenesis in the HAART Era meeting, which was sponsored by the US National Institute of Mental Health and National Institute of Neurological Disorders and Stroke and which had the goal of setting priorities for future NIH-funded research in HIV neurology. It was held directly after the Second HIV Infection and the Central Nervous System: Developed and Resource Limited Settings meeting, organised by Dr Paola Cinque of the San Raffaele Scientific Institute in Milan and other Italian colleagues.
The debate really began towards the end of this earlier meeting, when Dr Richard Price of the University of California, San Francisco (UCSF) told the audience that ART can continue to exert a profound effect on CSF viral load and prevent neurological deterioration — even when patients have become resistant to it.
Go to part two - Brain-penetrating ARVs not always necessary for control of HIV in the brain?