October 17, 2013
A virus called CMV (cytomegalovirus) is commonly found in adults. This virus generally does not cause serious disease except in cases when the immune system is greatly weakened, such as in cases of organ transplantation, cancer and AIDS.
In the time before potent combination anti-HIV therapy (commonly called ART or HAART) was available, CMV could cause damage to the intestinal tract and other organ-systems. Another feared CMV-associated complication was inflammation of the light-sensitive portion of the eye called the retina. This complication, called CMV-retinitis, was most common in HIV-positive people with severe immune dysfunction (those whose CD4+ count had fallen below the 50-cell mark) and could lead to blindness.
Today, ART is widely available in Canada and other high-income countries, and thanks to its profoundly beneficial effects on the immune system, new cases of AIDS-related CMV-retinitis are rare.
In the past decade in the U.S. there have been increasing reports of unexpected and subtle visual problems in some HIV-positive people who had either previously developed AIDS-related infections or whose CD4+ counts had fallen below the 200-cell level. In extensive and complex testing by different teams of research ophthalmologists, findings have included the following:
These changes have been linked to a thinning of the retina in some HIV-positive people and are called HIV-associated neuroretinal disorder (HIV-NRD).
HIV-NRD is not linked to any loss of sharpness of vision.
Potential causes of HIV-NRD are explored later in this CATIE News bulletin.
The consequences of HIV-NRD are not yet clear. One possibility, based on studies with HIV-negative people, is that the subtle changes associated with HIV-NRD could make reading more difficult and slow the pace of this activity. However, this requires confirmation in a large, robustly designed study.
One small study claimed that HIV-positive people who had driver's licenses were more likely to have accidents when using driving simulators. However, that study had a number of important limitations -- it was small and participants were not screened for pre-existing HIV-related neurocognitive dysfunction. In the real world, there have not been reports of increased accidents among HIV-positive drivers, particularly in the present era now that ART is widely available.
The retina is made up of layers of nerves. This part of the eye is treated by neurologists as "an extension of the central nervous system [CNS]" (the CNS consists of the brain and spinal cord). The retina reacts to the presence of light and transmits data about images via a bundle of nerves (the optic nerve) to the brain.
The cells of the retina and associated nerve fibres are very busy and require a lot of energy. These cells are rich in cellular power generators called mitochondria.
As the discovery confirming the thinning of the retinas in some HIV-positive people is relatively recent, research ophthalmologists are not certain as to its precise cause(s). So far they have been able to rule out retinal injury due to exposure to the following drugs:
This is important because these drugs (nick-named "d" drugs) became notorious for causing damage to mitochondria in nerves outside the brain and spinal cord. However, they are old and because of their many toxicities are seldom used in high-income countries today.
Indirect evidence suggests the possibility that long-term HIV infection may play a role in HIV-NRD by inciting low-grade inflammation in the eye and perhaps the retina itself. Over a period of many years it is possible that low-grade inflammation could very slowly cause subtle retinal injury.
Researchers in New York City and Baltimore recently began to study HIV-NRD. They note that there are reports of subtle HIV-related neurocognitive injury to the brains of some ART users. Also, they point out that HCV infection can affect the brain -- it has been linked to increased inflammation and diminished memory either on its own (HCV mono-infection) or together with HIV (HIV-HCV co-infection). Therefore, they sought to find a link between HIV-NRD and HIV-HCV co-infection. To do this, the researchers analysed health-related data collected from an ongoing study of 1,576 HIV-positive people. This study was specifically designed to assess changes in visual health.
All participants had previously been diagnosed with AIDS (either because of the presence of a life-threatening infection or because their CD4+ count had at some point fallen below the 200-cell threshold). None of these participants had any AIDS-related infections that affected their eyes when they entered the study. Among the 1,576 participants, 290 had chronic hepatitis C infection and 74 had recovered from a previous HCV infection. Note that for the present analysis, researchers excluded participants who had serious eye infections in the past (such as CMV-retinitis) or severe visual difficulties, as these could have affected their results. Participants were monitored for almost nine years in some cases. The study began recruitment in August 1999 and the data analysis we now report extended to December 31, 2011.
The researchers found that 244 cases of HIV-NRD were diagnosed when participants entered the study. The following factors were associated with a diagnosis of HIV-NRD when participants first entered the study:
Over the course of the study, a further 263 cases of HIV-NRD were detected. Factors associated with this subsequent development of HIV-NRD were as follows:
The study team did an analysis on a subset of 342 participants to check whether liver injury played any role with HIV-NRD. They assessed many factors and zeroed in on platelets -- small cells found in the blood that play many roles in the body. Initially the only role of platelets was considered to help blood clot. However, emerging research suggests that platelets can play a role in immunity to infections as well as a role in inflammation. Platelets, like all red and white blood cells, originate in the bone marrow.
The researchers found that there is likely "some factor associated with advanced liver disease such as inflammation, or some factor associated with HIV/AIDS such as [severe bone marrow injury] increased the risk of HIV-NRD."
Cells produce chemical signals, called cytokines. Examples of cytokines include interferon-alpha, interleukin-2 (IL-2) and so on. In order for cytokines to work they must attach themselves to a particular receptor on a cell. In the case of IL-2, there is an IL-2 receptor. Without this specialized receptor, cells would not be able to respond to IL-2.
One cytokine that plays a role in reducing inflammation is IL-10 (interleukin-10). Researchers checked the blood of a subset of about 870 participants for a gene that is associated with abnormalities in the receptor for IL-10. Such abnormalities in that receptor would likely result in cells with either weakened or with no ability to sense and respond to IL-10. The researchers found that HIV-HCV co-infected participants were more likely to have a gene associated with abnormalities of the IL-10 receptor. However, HIV-NRD was not linked to the presence of the gene in the present study.
The findings from the present study are interesting -- some people who have survived long after a diagnosis of AIDS may be at increased risk for gradually thinning retinas (a condition called HIV-associated neuroretinal disorder). None of these participants have had decreased sharpness of vision so it is not clear if HIV-NRD has very serious consequences.
Researchers are not certain as to the causes of retinal thinning among some HIV-positive people and years of intensive research lies ahead to uncover possible causes. What is certain is that relatively early initiation of ART and high adherence can prevent AIDS-related diseases from ever occurring. Scientists need to assess ART users who have never had AIDS to determine if thinning retinas is also an emerging health issue for them.