Ocular complications of infection with the human immunodeficiency virus were first described in 1982. A lot has changed since then. The introduction of highly active antiretroviral therapy (HAART) in 1996 dramatically improved the health of immunocompromised patients, thus reducing the incidence of cytomegalovirus (CMV) retinitis—the most prevalent of the blinding diseases associated with acquired immunodeficiency syndrome.
As the incidence and severity of vision-threatening manifestations of HIV have decreased in the HAART era, ophthalmologists have turned their attention to eye disorders that may not be as urgent as CMV retinitis but which still affect patients’ quality of life, and which may have important implications for their systemic health.1
HIV-related eye disease remains an important problem in the United States. CMV retinitis has not been eliminated altogether, and, ironically, the overall decreased incidence of HIV-associated eye disease has in some ways made it more difficult to study, given the smaller potential subject pool.
The Sequelae of CMV
“In the HAART era, increased patient survival has made CMV retinitis a chronic problem, rather than a pre-terminal disease of short duration, as it was before HAART became available,” said Gary N. Holland, MD, a professor of ophthalmology at the University of California, Los Angeles.
Today, most patients presenting with active CMV retinitis have already been treated with HAART but either have stopped the medications or have become resistant to them, leading to a recurrence of immunodeficiency. HAART-naive patients constitute the minority of cases, at least in the urban United States.
Ophthalmologists are also likely to encounter long-term survivors who have inactive CMV retinitis but who may still have visual problems caused by the previously active infection. Challenges in this group include immune recovery uveitis (IRU), cataracts, silicone oil in the eye, a risk of reactivation and a risk of retinal detachment.
“Patients who had CMV retinitis when HAART became available and are still alive with inactive retinal infection may have suffered vision loss and are candidates for visual rehabilitation,” said Dr. Holland. “Many patients who are healthier because of HAART are now becoming more active, perhaps getting back into the workforce. For some, cataract surgery or removal of silicone oil from the eye can provide needed visual rehabilitation.”2
The debris of repairs. HIV-infected patients whose CMV retinitis was complicated by retinal detachment have usually undergone repair by the placement of silicone oil, but the oil itself affects vision.
Even with inactive, well-healed lesions, removal of the oil is not an easy decision, as doing so could put the patient at risk for redetachment of the retina. Also, patients who still have their vision but have inactive scars in their eyes are at some risk for reactivation, even with good immune function. “These are all issues to which ophthalmologists need to be attuned,” said Dr. Holland.
IRU post-CMV. Immune recovery has brought new difficulties in the process of diagnosing and managing ocular disease. Conditions such as IRU result from heightened immunological reactions against intraocular pathogens—usually CMV—that become possible with immune reconstitution. Inflammation is most prominent in the vitreous cavity but can also involve the anterior segment. In some cases, it can be sufficiently severe to cause hypopyon.
“Whereas CMV retinitis occurred primarily in HIV-infected patients with CD4 counts below 100, we are now seeing ocular inflammations occur in patients with higher counts,” said Richard A. Wolitz, MD, a comprehensive ophthalmologist at Kaiser Permanente Medical Center in San Francisco. “The challenge in all patients with ocular inflammation is determining the etiology. We’ve seen an increase in noninfectious causes, including lymphoma. Also, we are seeing cases of visually significant ptosis, which may be a result of mitochondrial toxicity associated with nucleoside analogs such as ddI and d4T used to manage HIV disease.”
Implications of Microvasculopathy
Subtle visual problems that can have functional consequences, like abnormalities in contrast sensitivity and color vision, have also been observed in HIV-infected patients.
While the prevalence of these disorders is relatively low, they are still three or four times more common than in the general population. A number of observers have hypothesized that these disorders are caused by abnormalities of the retinal vasculature at the microscopic level, which is known to occur with HIV disease, said Dr. Holland. “It is similar to diabetic retinopathy, and we can assume that similar microvascular changes are occurring elsewhere in the body. There is a renewed focus on the retinal microvasculopathy of HIV disease, the long-term damage to the retina and the optic nerve that it appears to cause, and whether that damage will progress in the long term. With many years of survival, is the damage going to be like diabetic retinopathy, where people get more and more problems? And if so, are there implications for understanding HIV disease in other organs?”
A new marker for disease status? Indeed, ophthalmologists may find that changes in vision caused by microvasculopathy can serve as a marker to help establish the severity of disease elsewhere in the body or to understand the mechanism of vessel-associated diseases. “Patients, of course, have their kidney function and blood pressure monitored regularly,” said Dr. Holland, “but if they also have changes in vision, clinicians might be alerted early to the fact that a patient’s disease is particularly severe or progressing. I think ophthalmologists can continue to work in conjunction with the whole medical team, just as we did with infectious disease specialists in the pre-HAART era, to alert them to the presence of CMV in the eye, so that they can watch for it in other organs as well.”
It’s not enough to have a HAART. “We know that some of the contributors to HIV-associated microvascular disease, like activation of white blood cells and abnormal blood flow, are ongoing despite HAART, and we anticipate that patients may develop more eye problems in the future,” Dr. Holland said. “We know, for example, that the retina thins in HIV-infected individuals. In long-term survivors, it’s possible that visual functions will progressively deteriorate.”
Anterior Segment and External Ocular Disorders
Though posterior segment pathology can be vision-threatening, a variety of anterior segment manifestations of HIV also lead to morbidity and affect quality of life. “With improved prophylaxis and treatment of opportunistic infections of the retina, we have seen an increase in attention to anterior segment and adnexal disorders,” said Dr. Holland.
Common lesions range from relatively benign conditions such as blepharitis and dry eye, which can affect even those with immune recovery, to infections such as herpes zoster ophthalmicus and molluscum contagiosum, and to malignancies such as squamous cell carcinoma and Kaposi’s sarcoma.
Advice for Comprehensive Ophthalmologists
A common question, noted Dr. Holland, is whether the community-based ophthalmologist who doesn’t have a research interest in HIV disease and doesn’t participate in trials can still appropriately evaluate and manage people who have HIV disease. “Comprehensive ophthalmologists are certainly able to follow people who are HIV infected and have eye disease,” Dr. Holland said. However, because the management of CMV retinitis and other inflammatory conditions in HIV-positive patients has become increasingly complicated, he said, many comprehensive ophthalmologists will end up referring patients to specialists for management.
Don’t forget non-CMV infections. The incidence of opportunistic infections of the eye may have decreased in the HAART era, but the increasing longevity of HIV-infected individuals means that the cumulative numbers of patients with a variety of infectious retinopathies will increase.
Fortunately, many of these infections are now treatable with therapeutic agents, but it is important to recognize these diseases early so that appropriate therapy can be administered, said Dr. Wolitz. “HIV and other sexually transmitted diseases often accompany one another, and it is therefore appropriate to have a high level of suspicion for syphilis, for example, as an underlying cause of many types of ocular disease. Conversely, if a patient presents with syphilis, testing for HIV status is strongly encouraged.”
A History of Ophthalmic Benefits
The aggressive management of CMV retinitis in the pre-HAART era generated some positive developments in the field of ophthalmology, Dr. Wolitz noted. “Tolerance of repeated injections into the vitreous and the development of the ganciclovir implant to control CMV retinitis for extended periods led to some of today’s treatment strategies for chronic posterior inflammations as well as age-related macular degeneration.” Hopefully, ophthalmology can return the favor with further contributions to the momentous progress in treating HIV disease.
1 Holland, G. N. Am J Ophthalmol
2 Jeng, B. H. et al. Surv Ophthalmol
___________________________ Drs. Holland and Wolitz report no related financial interests.