Strange changes deep in the eye linked to HIV and possibly hepatitis C virus

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.

Eye problems in the modern era

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:

• decreased sensitivity in colour vision
• reduced sensitivity to contrast
• subtle visual defects

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.

Consequences of HIV-NRD

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.

Focus on the retina

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:

• ddC (zalcitabine, Hivid)
• ddI (didanosine, Videx)
• d4T (stavudine, Zerit)

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.

The role of other germs—hepatitis C virus (HCV)

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.

Initial cases of HIV-NRD

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:

• chronic HIV infection
• being female
• being a person of colour

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:

• chronic HCV infection
• being 43 years of age or older
• being female
• having an HIV viral load greater than 10,000 copies/ml

Bone marrow and liver

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] increases the risk of HIV-NRD.”

Chemical signals

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.

Dampening inflammation

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.

Putting the findings in context

1. It is important to note that all of the people in the present study had previously been diagnosed with AIDS—due to the presence of a life-threatening infection or having a CD4+ count below the 200-cell threshold. It is not clear if the study’s findings are sufficiently robust that they are relevant to other people who have had AIDS but are enjoying prolonged survival thanks to ART. Also, another area of uncertainty is whether or not the findings are relevant to the average HIV-positive person taking ART who has never had AIDS.

2. More research is necessary to determine the long-term consequences of HIV-NRD.

3. The present study was observational in design. This means that its findings are not definitive; in other words, it cannot prove that having HIV-HCV co-infection increases the risk for HIV-NRD. What it does is raise a signal about the presence of HIV-HCV co-infection possibly being a factor for HIV-NRD. Another potential flaw is that the study was not randomized; from the start it was designed to explore trends in visual health. It may therefore have biased its recruitment by inadvertently favouring volunteers with visual problems or who were predisposed to develop such problems.

4. HIV-NRD seems unusually common in the present study. Other studies in other parts of the world need to be done to assess the health of the retinas of HIV-positive people. As scientists strive to better understand the potential cause(s) of HIV-NRD, there are at least several additional research issues that need to be explored, including the following:

• Assessments of inflammation – If inflammation does play a role in gradually degrading the retina, can anti-inflammatory agents counter this?
• The potential role of cardiovascular disease on the retina – This is important because at least one study has found that the tiny vessels that supply the retina with blood are not always in the best health in some people with AIDS.
• Other health conditions – Studies in HIV-negative people suggest that in conditions such as type 2 diabetes, kidney injury and higher-than-normal blood pressure are associated with abnormal health of blood vessels in the retina. Therefore, the impact of these other co-morbidities needs to be explored in people with HIV who might also have HIV-NRD.
• The potential impact of other co-infections, such as syphilis, on the retina – Rates of syphilis are high among some MSM, particularly those who are HIV positive. In part, syphilis can cause injury by triggering the onset of inflammation in affected organs and tissues. There are reports of visual damage caused by syphilis in HIV-positive people. Furthermore, there are reports of the rapid development of neurosyphilis in this population.
• The role of gender in the development of HIV-NRD – In the present study, it could be that women were more likely to inject street drugs than men and so gender itself may not be a risk factor but merely be a statistical mask for behaviour such as injecting drugs (IDU). Such behaviour could expose people to more germs, including HCV. However, it is also possible that gender could play an important role because generally women are more likely than men to develop certain inflammatory disorders linked to a dysfunctional immune system.

Bear in mind

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.

—Sean R. Hosein

REFERENCES:

1. Friedman AH, Orellana J, Freeman WR, et al. Cytomegalovirus retinitis: a manifestation of the acquired immune deficiency syndrome (AIDS). British Journal of Ophthalmology.1983 Jun;67(6):372-80.
2. Holland GN. AIDS and ophthalmology: the first quarter century. American Journal of Ophthalmology. 2008 Mar;145(3):397-408.
3. Iragui VJ, Kalmijn J, Plummer DJ, et al. Pattern electroretinograms and visual evoked potentials in HIV infection: evidence of asymptomatic retinal and postretinal impairment in the absence of infectious retinopathy. Neurology. 1996 Dec;47(6):1452-6.
4. Shah KH, Holland GN, Yu F, et al. Contrast sensitivity and color vision in HIV-infected individuals without infectious retinopathy. American Journal of Ophthalmology. 2006 Aug;142(2):284-92.
5. Gabrielian A, MacCumber MM, Kukuyev A, et al. Didanosine-associated retinal toxicity in adults infected with human immunodeficiency virus. JAMA Ophthalmology. 2013 Feb;131(2):255-9.
6. Kalyani PS, Holland GN, Fawzi AA, et al. Association between retinal nerve fiber layer thickness and abnormalities of vision in people with human immunodeficiency virus infection. American Journal of Ophthalmology. 2012 Apr;153(4):734-42, 742.e1.
7. Goldbaum MH, Kozak I, Hao J, et al. Pattern recognition can detect subtle field defects in eyes of HIV individuals without retinitis under HAART. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2011 Apr;249(4):491-8.
8. Kozak I, Sasik R, Freeman WR, et al. A degenerative retinal process in HIV-associated non-infectious retinopathy. PLoS One. 2013 Sep 17;8(9):e74712.
9. Branch AD, Drye LT, Van Natta ML, et al. Evaluation of hepatitis C virus as a risk factor for HIV-associated neuroretinal disorder. Clinical Infectious Diseases. 2013; in press.
10. Sullivan PS, Hamouda O, Delpech V, et al. Reemergence of the HIV epidemic among men who have sex with men in North America, Western Europe, and Australia, 1996-2005. Annals of Epidemiology. 2009 Jun;19(6):423-31.
11. Leber A, MacPherson P, Lee BC. Epidemiology of infectious syphilis in Ottawa. Recurring themes revisited. Canadian Journal of Public Health. 2008 Sep-Oct;99(5):401-5.
12. Sánchez C, Plaza Z, Vispo E, et al. Scaling up epidemics of acute hepatitis C and syphilis in HIV-infected men who have sex with men in Spain. Liver International. 2013 Oct;33(9):1357-62.
13. Hughes EH, Guzowski M, Simunovic MP, et al. Syphilitic retinitis and uveitis in HIV-positive adults. Clinical & Experimental Ophthalmology. 2010 Dec;38(9):851-6.
14. Dumaresq J, Langevin S, Gagnon S, et al. Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early syphilis. Journal of Clinical Microbiology. 2013; in press.
15. Centers for Disease Control and Prevention (CDC). Notes from the Field: Repeat syphilis infection and HIV coinfection among men who have sex with men - Baltimore, Maryland, 2010-2011. Morbidity and Mortality Weekly Report. 2013 Aug 16;62(32):649-50.
16. Ho EL, Lukehart SA. Syphilis: using modern approaches to understand an old disease. Journal of Clinical Investigation. 2011 Dec;121(12):4584-92.
17. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circulation Research. 2013 May 24;112(11):1506-19.
18. Boilard E, Blanco P, Nigrovic PA. Platelets: active players in the pathogenesis of arthritis and SLE. Nature Reviews Rheumatology. 2012 Sep;8(9):534-42.
19. Zamora C, Cantó E, Nieto JC, et al. Functional consequences of platelet binding to T lymphocytes in inflammation. Journal of Leukocyte Biology. 2013 Sep;94(3):521-9.