Retinal thinning in well-controlled HIV and decline in information processing

The eyes have been called the windows to the soul, but practically speaking, for doctors, they’re a window to systemic diseases, including diabetes and multiple sclerosis. A study published in the Oct. 1 online issue of JAIDS looked at retinal measurements in people living with HIV (PLWH) and found that people on antiretroviral therapy (ART) have thinning of two important layers of the retina, which are proxies for potential neurodegenerative issues.

In a sense, the retina, a paper-thin tissue lining the inside of the eye, is an extension of the brain, and it can tell a lot about how well the brain is functioning—or not functioning. Using a variety of measurements, the research team led by Bryan Smith, M.D., head of the Clinical Neuro-HIV research program at the National Institutes of Health (NIH), investigated retinal layer thicknesses obtained from spectral domain optical coherence tomography (SD-OCT), a noninvasive technique for high-resolution imaging of retinal layers, to determine whether retinal thickness could be a biomarker for central nervous system (CNS) disease in PLWH with long- and well-controlled HIV (a mean time of 10 or 11 years on treatment). SD-OCT, which has a predictive value in neurodegenerative conditions such as multiple sclerosis, glaucoma, and Alzheimer disease, might be useful for PLWH as well, specifically in predicting how fast their brains process information, researchers hypothesized.

PLWH and HIV-negative controls with similar comorbidities were recruited from the same communities. In addition to SD-OCT, the participants underwent brain MRI and neuropsychological testing. Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GC-IPL) thicknesses were compared between groups using analysis of covariance. The team used linear regression to explore HIV history variables, cognitive domain scores, and MRI volume measurements within the HIV group.

Study Findings: Retinal Thinning in PLWH and Sex Differences

The investigators found that the PLWH group had thinner retinal layers—both GC-IPL and RNFL—than the HIV-negative control group, and that GC-IPL thickness was associated with information processing speed in the PLWH group. The researchers used seven cognitive tests, six MRI volume variables, and one visual acuity test to explore whether this retinal thinning might have any correlation with brain function. They measured cognition using domain scores of attention/working memory, executive functioning, information processing, verbal fluency, learning, psychomotor functioning, and memory, and found that information processing had a positive correlation with GC-IPL thickness. The good news is, there was no association between retinal thinning and other measures of cognition, including executive function, motor skills, and attention.

“[Retinal thinning] is really a biomarker of what’s happening in the brain,” says one researcher, Emily Chew, M.D., director of the Division of Epidemiology and Clinical Applications and deputy clinical director at the National Eye Institute of the NIH.

Chew adds that, with a cross-sectional study like this, there was no way to tell how quickly the retina thins for PLWH, nor over what length of time. But she tells TheBodyPro that the team plans to do a follow-up study using additional data from the same participants, plus a few others, in a prospective study.

The researchers did not account for differences based on various antiviral regimens, because of the small sample size and wide variation in regimens. But the team did make a finding that could not be easily explained: Women in the study were more likely to have retinal thinning than men. The researchers did not speculate on why that is the case. But in speaking with TheBodyPro, one researcher, Avindra Nath, M.D., a senior investigator and clinical director of the National Institute of Neurological Disorders and Stroke at the NIH, emphasizes that the sex differences in retinal thickness were due to biological factors, not social factors, because the team endeavored to match both the PLWH group and HIV-negative control group socio-economically. They also recruited a significant number of women for the study, something that can’t be said for all HIV-related research.

Implications for Treating PLWH

Do these results mean that PLWH have more vision issues to expect, and cognitive decline? Possibly, although both Chew and Nath emphasize that surveillance is key, and that any changes in a patient’s vision or brain function should be investigated.

As for what causes retinal thinning in PLWH on ART, Nath explains that although ART is effective in keeping the HIV in check, people whose HIV is well-controlled may still have neurocognitive issues due to higher levels of the viral protein HIV-1 Tat. “[ART] can prevent the virus from replicating but doesn’t prevent the RNA from being formed. You don’t prevent the proteins from being formed once the virus is integrated in the genome,” Nath says. “The only thing that prevents the complete replicating viral particle from being formed is one class of drugs, protease inhibitors, that prevents the assembly of the virus. And we’ve shown that these [Tat] proteins are very toxic.” Unfortunately, there’s nothing to prevent these proteins from being formed, Nath says.

Clinicians have some therapeutic and investigational options, at least for PLWH who come to them concerned about cognition or vision problems. First, Nath says, is to determine whether a patient has another underlying disease, such as undiagnosed glaucoma or undiagnosed vascular disease, that could be contributing to vision or cognition issues.

Second, optimize the antiretroviral regimen. “It is possible that they’re not on the right combination with good penetration into the brain and into the eye, because sometimes you can get what’s called viral escape. That means that there are small amounts of virus still being produced because the drugs that they’ve chosen are really good at controlling it in the blood, but not necessarily in the brain,” Nath says. If a patient still has cognitive deficits, he says, they need cognitive rehabilitation.

If neurological problems are caught early, reversal might be possible, and that’s especially important for a patient who has not yet been treated for HIV. Nath emphasizes that every PLWH should get on ART ASAP. “If someone [who is] not on HIV [medications] has neurocognitive problems with a very high CD4 cell count, if you start them on antiretroviral drugs, they may not return 100%, but they will get better.”

For early detection, CT scans will catch changes to the brain or eyes, Chew says, adding that most of the participants in the study had 20/20 vision and no noticeable problems. Anyone with HIV must have regular checkups and a complete workup, both Chew and Nath say. And Nath recommends that clinicians ask some basic questions about neurological function. For example, Has your memory changed in any way? Are you slowing down? Have you had any trouble with vision, or with driving?

As for pre-symptomatic testing, Nath says, that would be unrealistic in most cases. “The health care system cannot handle that.”

By Larry Buhl