HIV infection causes various lesions in and around the eye. Ocular symptoms are closely related to the CD4-positive T lymphocyte count (normal range 700–1,500/μL), and the diseases that appear change as immunodeficiency progresses.
HIV infects CD4-positive T lymphocytes and reduces cell-mediated immunity. After rapid viral proliferation in the acute phase, followed by an asymptomatic phase, the CD4 count decreases over several years to 10 years, and when it falls below 200/μL, the patient develops AIDS with opportunistic infections and malignancies.
In a large observational study in 2007, 9.2% of HIV-infected patients had visual impairment in the better eye, and 41.4% had other major ocular complications. Since 1996, the introduction of combination antiretroviral therapy (ART) has significantly changed the pattern of ocular symptoms. Even in the ART era, HIV infection remains an important clinical challenge for ophthalmologists.
The number of HIV-infected individuals in Japan is about 20,000, which is small globally, but the number of new infections is still increasing. It is quite possible that infected individuals living normal lives may visit an ophthalmologist without disclosing their HIV-positive status.
HIV is a physically very weak virus and is easily inactivated by common disinfectants. The amount of virus in tears is extremely small, so there is no possibility of infection through ophthalmic examination instruments. However, in situations involving blood exposure such as injections or surgery, sufficient caution is needed for needlestick accidents.
Ocular symptoms in HIV/AIDS are diverse. Subjective symptoms depend on the location and type of lesion.
Ocular complications of HIV/AIDS are broadly classified into three categories.
HIV Retinopathy
Cotton-wool spots: The most common ocular complication. White spots less than 500 μm with feathery borders. They resolve spontaneously within 6 to 8 weeks.
Dot hemorrhages: Caused by microvascular damage.
Activity indicator: Their appearance correlates with serum HIV viral load and is important as an indicator of HIV activity.
Opportunistic Infections
Cytomegalovirus retinitis: Occurs when CD4 count is 50–100/μL or less. Characterized by yellowish-white opacification with hemorrhage and atrophy.
Toxoplasmosis: Occurs when CD4 count is 100/μL or less. Characterized by large, bilateral lesions.
Progressive outer retinal necrosis: Rapidly progressive necrotizing retinitis caused by varicella-zoster virus.
Malignancies
Kaposi sarcoma: A vascular tumor caused by human herpesvirus 8. Forms deep red to purple nodules on the eyelids and conjunctiva.
Malignant lymphoma: Intraocular infiltration occurs, presenting findings similar to uveitis. Incidence is 200 times higher than in healthy individuals.
Conjunctival squamous cell carcinoma: Commonly occurs at the limbus.
The relationship between CD4-positive T lymphocyte count and ocular complications is shown below.
| CD4 Count (/μL) | Commonly Associated Diseases | Characteristics |
|---|---|---|
| 500 or less | Herpes zoster, Kaposi sarcoma | Appears relatively early |
| 100 or less | Toxoplasmosis, tuberculosis | Progression of immunodeficiency |
| 50 or less | Cytomegalovirus retinitis, progressive outer retinal necrosis | Severe immunodeficiency |
HIV is an RNA virus belonging to the Retroviridae family, genus Lentivirus. The main routes of transmission are sexual contact, mother-to-child transmission (transplacental, during delivery, through breastfeeding), and blood-borne transmission (blood transfusion, medical accidents, sharing of needles).
The main factors associated with the risk of developing ocular complications are as follows.
Syphilis is very often co-infected with HIV. In recent years, the number of syphilis patients in Japan has increased dramatically, and many cases of HIV positivity are discovered after syphilis infection. In HIV-positive patients, the frequency of bilateral ocular syphilis is 62%, significantly higher than the 38% in HIV-negative patients 1).
Herpes zoster is not included as an AIDS-indicator disease, but its incidence in HIV-infected individuals is 15 times higher than in healthy individuals. The onset of herpes zoster ophthalmicus before age 50 is a finding suggestive of HIV infection.
In HIV-positive patients, ocular syphilis tends to progress early, and the frequency of bilateral lesions is high. Additionally, non-treponemal tests may be falsely negative, making diagnosis difficult 1). High-dose penicillin is required for syphilis treatment in HIV-positive patients.
Diagnosis of ocular complications associated with HIV/AIDS is made by combining ocular findings with assessment of systemic immune status.
Fundus examination under mydriasis is most important. Diagnosis of major retinal diseases such as cytomegalovirus retinitis, HIV retinopathy, toxoplasmosis, and PORN is based on characteristic fundus findings.
Severe ocular herpes zoster in patients under 50 years of age may suggest HIV infection. Herpes zoster can be the first overt symptom of HIV infection, and HIV testing should be considered.
Treatment of ocular complications in HIV/AIDS is based on a combination of immune recovery through antiretroviral therapy and specific treatment for each opportunistic infection.
This is a potent anti-HIV therapy combining reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors. Antiretroviral therapy can improve the immunodeficiency state, and the incidence of cytomegalovirus retinitis has decreased by 80%. Currently, there are over 30 types of anti-HIV drugs, but none can eliminate the virus itself, and discontinuation of medication inevitably leads to progression to AIDS.
Intravenous ganciclovir is the first-line treatment. The treatment method is selected based on the location, size, and side effects of the lesion.
Prescription examples in Japan are as follows:
In patients on ART with stable retinitis and CD4 count ≥100/μL, discontinuation of anti-cytomegalovirus therapy may be considered. Success rate is high if viral load is below the detection limit. After discontinuation, there is a risk of recurrence of cytomegalovirus retinitis, so follow-up every 3 months is necessary.
No effective treatment has been established. Acyclovir alone is ineffective; combination therapy with ganciclovir and foscarnet is used. Either both drugs are given systemically, or one is given systemically and the other intravitreally. Concurrent antiretroviral therapy aims to restore immune function.
Treatment should follow the regimen for neurosyphilis.
HIV-positive patients often have early symptomatic neurosyphilis and require higher doses of penicillin 1).
The mainstay is continuation of anti-cytomegalovirus therapy against residual pathogens. The course varies depending on severity and timing, ranging from spontaneous remission to cases requiring surgical treatment. For severe inflammation, systemic administration of moderate-dose steroids may be combined. For macular edema, orbital, sub-Tenon, or intravitreal steroid injections are considered effective, but careful attention must be paid to side effects including endophthalmitis.
When retinal detachment complicates cytomegalovirus retinitis, surgical treatment is indicated. Depending on the size of the lesion and the extent of detachment, vitrectomy, endophotocoagulation, encircling band, and silicone oil tamponade are combined. With antiretroviral therapy improving control of retinitis, the risk of retinal detachment is reduced by 60%.
Antigen-antibody reactions against HIV cause microcirculatory disturbances in the retina, leading to cotton-wool spots and punctate hemorrhages. Although these lesions may resolve on ophthalmoscopy, recent studies using optical coherence tomography and scanning laser ophthalmoscopy have shown that permanent structural damage remains in the inner retinal layers.
Cytomegalovirus has endothelial tropism, so lesions are distributed along the course of blood vessels. Depending on the size of the infected vessels, the following three clinical forms are seen:
Because viral replication is slow, the typical pattern is that the center of the lesion heals while the border remains yellow-white and progresses with satellite lesions. In healed cytomegalovirus retinitis, the full thickness of the retina becomes necrotic and thins in a lace-like pattern, and vitreous traction can lead to multiple breaks and retinal detachment.
The exact mechanism is not fully understood, but the leading hypothesis is as follows: When antiretroviral therapy restores cytomegalovirus-specific T-cell responses, an immune reaction becomes apparent against residual cytomegalovirus antigens that are slightly replicated within cells at the edge of already quiescent cytomegalovirus retinitis lesions, leading to uveitis.
Risk factors for immune recovery uveitis include the following:
Ocular findings in immune recovery uveitis are diverse and include iridocyclitis, vitritis, posterior synechiae, posterior subcapsular cataract, optic disc edema, macular edema, epiretinal membrane, retinal neovascularization, proliferative vitreoretinopathy, and retinal detachment.
Varicella-zoster virus directly damages the outer retina in severely immunocompromised hosts. Because the host cannot mount an inflammatory response, the outer retina rapidly progresses to necrosis with minimal anterior chamber and vitreous inflammation. It often occurs secondary to cutaneous herpes zoster.
It usually develops within 3 months after starting antiretroviral therapy, but can occur up to 12 months later. It is more common in eyes with a history of cytomegalovirus retinitis when the CD4-positive T-cell count increases to 100/μL or more.
HIV-related neuroretinal disorder, defined as loss of the nerve fiber layer, has been reported in some HIV/AIDS patients. It presents as decreased contrast sensitivity, color vision abnormalities, and visual field defects. Risk factors include hepatitis C infection, detectable viral load, and low CD4 T-cell count. Quantitative assessment of retinal layer structure using optical coherence tomography is considered useful for early detection of this disorder.
Even after the widespread use of antiretroviral therapy, cytomegalovirus retinitis has not completely disappeared. It still occurs in patients with delayed initiation of antiretroviral therapy or in those who do not respond to treatment. Recently developed multiplex PCR is a groundbreaking test that can comprehensively detect viruses from a small sample of aqueous humor, contributing to improved diagnostic accuracy, including the differentiation of necrotizing retinitis.
