You are in: eMedicine Specialties > Ophthalmology > INFECTIOUS DISEASE HIVArticle Last Updated: Jan 4, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Lisa J Faia, MD, Staff Physician, Department of Ophthalmology, Mayo Clinic Lisa J Faia is a member of the following medical societies: American Academy of Ophthalmology, American Medical Association, California Medical Association, and Minnesota Medical Association Coauthor(s): Sophie Bakri, MD, Assistant Professor of Ophthalmology, Vitreoretinal Diseases and Surgery, Mayo Clinic; DooHo Brian Kim, BA, Albany Medical College; Nader Moinfar, MD, Consulting Staff, Vitreoretinal Department, Magruder Eye Institute Editors: Russell P Jayne, MD, Consulting Vitreoretinal Surgeon, The Retina Center at Las Vegas; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; R Christopher Walton, MD, Professor, Director of Uveitis and Ocular Inflammatory Diseases Service, Assistant Department of Ophthalmology, Assistant Dean for Graduate Medical Education and Continuing Education, University of Tennessee College of Medicine; Consulting Staff, Regional Medical Center, Memphis Veterans Affairs Medical Center, St Jude Children's Research Hospital; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences Author and Editor Disclosure Synonyms and related keywords: human immunodeficiency virus, AIDS, acquired immunodeficiency syndrome INTRODUCTIONSection 2 of 11
  BackgroundHIV (human immunodeficiency virus) is a retrovirus that causes the disease AIDS (acquired immunodeficiency syndrome). AIDS was first recognized in 1981 in Los Angeles when 5 cases of Pneumocystis carinii pneumonia in homosexual men were reported to the Centers for Disease Control and Prevention (CDC). HIV is believed to have originated in Central Africa in the 1950s and subsequently spread via the Caribbean to the United States, Europe, and the rest of the world. PathophysiologyHIV is a retrovirus member of the Lentivirinae family. Retroviruses are enveloped RNA viruses characteristically possessing an RNA-dependent DNA polymerase termed reverse transcriptase. Two types of virus are known to affect humans; HIV-1 causes AIDS and is found worldwide, and HIV-2 has been isolated from some African cases of AIDS. In its extracellular form, the virus exists as a lipid-encoated cylindrical nucleocapsid of approximately 100 nm in diameter. Inserted within its lipid envelope are glycoproteins, a portion of which (glycoprotein [gp] 120) forms the binding region that attaches to the CD4 receptor on host cells (T-lymphocyte helper cells, activated monocytes and macrophages, and glial cells). After fusing with the cell membrane and entering the cytoplasm, the virus loses its envelope, and reverse transcription of RNA to DNA occurs. Viral DNA integrates into host cell DNA as a latent provirus by a viral endonuclease. If the host cell is latently infected, no infection develops. If the host is actively infected, the proviral DNA is transcribed and translated, producing viral proteins and RNA. The viral proteins assemble and bud (by reverse endocytosis) through the host cell plasma membrane as new virions. The virus disseminates by budding or by cell-to-cell transfer. Abnormalities in all components of the immune system can be seen as the severity of HIV disease progresses. The most profound consequence of HIV infection is impairment of cell-mediated (T cell) immunity. HIV binds directly to the CD4 receptor of the T helper cell, resulting in progressive depletion of this T-cell population. As a result, the immune system is less able to (1) mount cytotoxic T-cell responses to virally infected cells or cancers, (2) to form delayed-type hypersensitivity reactions, and (3) to process new foreign substances presenting to the immune system. Significant impairment of the humoral immune system occurs in most persons infected with HIV. HIV also can infect monocytes and macrophages. The HIV virus is spread primarily by exposure to contaminated fluids. It has been isolated from blood, semen, vaginal secretions, saliva, cerebrospinal fluid, breast milk, amniotic fluid, cervical cells, and bronchioalveolar lavage fluid. In a 1997 study, 70% of HIV cases were acquired from sexual intercourse, 27% from intravenous drug use, 3% from blood transfusions, and only 1% from perinatal transmission. FrequencyUnited StatesBy June 1993, 302,000 cases of AIDS were reported in the United States. InternationalCurrently, it is estimated that 40 million people are infected worldwide with the HIV virus. The incidence of HIV is increasing, especially in poverty-stricken countries and countries with high rates of sexually transmitted diseases (STDs). The number of new cases in persons who use intravenous drugs, women, and children is rising, whereas the proportion of cases in homosexual and bisexual men is decreasing. Mortality/MorbidityThe mortality in patients with AIDS is discussed elsewhere in this journal and is beyond the scope of this article. Most patients die from opportunistic infections or malignancies associated with the progressive decline in T-cell function. The morbidity of some HIV-related ocular disease is severe and, if untreated, can lead to blindness. CLINICALSection 3 of 11
HistorySee Physical. PhysicalHIV retinopathyHIV retinopathy is the most common ocular manifestation, occurring in 40-60% of HIV-positive patients and recognized in 89% of autopsies. Histopathological findings resemble those of diabetic retinopathy, with pericyte necrosis, endothelial cell swelling, and thickening basement membrane. Hypotheses for vascular injury include immunoglobin deposition, endothelial cell infection by HIV, and hyperviscosity secondary to increased red cell aggregation, fibrinogen, and increased polymorphonuclear leukocyte rigidity. In the anterior segment, these changes are seen as dilated and tortuous segments of vessels. Occurring in up to 50% of individuals with HIV, cotton wool spots are the most common findings in patients with AIDS. These occur primarily in the posterior pole in the peripapillary region. Cotton wool spots seen in individuals with HIV are identical to those seen in other conditions. Cystoid bodies represent swollen axons caused by interruption of axoplasmic flow. Although ischemia is the most common cause of cotton wool spots, any interruption of axoplasmic flow leads to the formation of cotton wool spots. Accumulation of axoplasmic debris in the nerve fiber layer leads to the appearance of cotton wool spots. Retinal hemorrhages develop in up to 30% of patients with AIDS. A variety of hemorrhages are seen, including flame shaped, dot-blot, or peripheral punctate hemorrhages. Clinically, HIV retinopathy is a sign of a low CD4+ count (usually <50 cells/µL) and requires close screening (every 3 mo) to look for other manifestations that can occur with such a low CD4+ count, such as cytomegalovirus (CMV) retinitis. See Image 3. Infectious causes of ocular complicationsCytomegalovirus CMV retinitis is the most common ocular infection in patients with AIDS, occurring in the pre-HAART (highly active antiretroviral therapy) era in 20-40% of patients. The median onset from AIDS diagnosis is 9 months, although it has been reported as late as 5 years. The median time to progression was 47-104 days, with a mean survival after diagnosis of 6-10 months. The risk for CMV retinitis increases with lower CD4+ counts, particularly when this count is less than 50 cells/µL. The average count at diagnosis is 17 cells/µL. Occasionally, CMV retinitis can be the initial manifestation of AIDS. Intimate exposure to infectious sources of virus (ie, blood, urine, saliva, other secretions) sometimes leads to hematogenous seeding of CMV-infected monocytes to the retina. HIV-damaged capillary endothelial cells in the retina also may facilitate the entry of infected monocytes to the retina. Infrequently, contiguous spread from the optic nerve may occur. CMV retinitis is a full-thickness retinal infection that originates peripherally as perivascular, opaque white granular areas of necrosis associated with hemorrhages. Infiltrates are composed of retinal edema, infected retinal cells, and cellular necrosis affecting all layers of the retina. Vitritis is typically minimal, although reconstitution of the immune system with HAART can lead to more vigorous vitritis. Intranuclear and intracytoplasmic DNA-positive viral inclusions are found within necrotic cytomegalic cells. Untreated, CMV retinitis progresses at a median rate of 24 µm/d. Of those patients with CMV retinitis, 35% may present with bilateral disease, and up to 52% will eventually develop bilateral disease. Contiguous spread is more common than skip lesions. Active virus is present in the advancing edge, with a necrotic retina remaining in its wake. In clinical studies, progression has been defined as the movement of disease by 750 µm along a 750 µm-wide front or as the development of new CMV lesions. Retinal damage leads to a corresponding absolute scotoma. The thin atrophic retina is susceptible to breaks and rhegmatogenous retinal detachments can occur within 3-6 months of diagnosis. The median time to retinal detachment is 18.2 months. Before HAART, retinal detachments occurred in one third of affected eyes. The larger the area of involvement, the greater the risk of retinal detachment. Retinitis involving 25-50% of the retina conferred a risk 5-6 times greater of retinal detachment than that observed with only 10% involvement. Visual loss is primarily due to retinal necrosis and retinal detachment. Macular edema, CMV papillitis, and neuroretinitis also contribute to visual loss. Several clinical forms exist. In the fulminant form, diffuse retinal hemorrhage with a whitened necrotic retina similar to a retinal vein occlusion is seen. Patients are often aware of vision loss. The indolent form presents with granular lesions in the peripheral retina often with little or no associated hemorrhage. Patients may notice floaters, or they may be asymptomatic. A third uncommon presentation is frosted branch angiitis. Routine screening with dilated eye examinations has been recommended at 3-month intervals in patients with CD4+ counts of less than 50 cells/µL because 15% of those patients with active CMV retinitis are asymptomatic. See Image 2. Differential diagnoses include HIV retinopathy, toxoplasmosis, Candida, syphilis, herpes simplex retinitis, herpes zoster retinitis, and progressive outer retinal necrosis (PORN). Diagnosis is based on the history and the clinical appearance of a white, necrotic, enlarging retinitis, with or without hemorrhage, in a patient who is immunocompromised. In predicting the development of CMV disease, the characteristics in the Table below apply. Characteristics Predicting the Development of CMV Disease
Viremia does not necessarily lead to retinitis, and vitreous cultures are usually negative, even during the active phase. Equivocal lesions may be observed for progression without treatment. In the HAART era, CMV retinitis has declined by 80% and survival after diagnosis has increased to over 1 year. The number of new cases of CMV retinitis has declined 55-99%, and the odds of progression are reduced by 50%. Immune recovery on HAART has allowed safe discontinuation of maintenance therapy with regressed CMV retinitis. While on HAART, up to 63% of patients with AIDS may experience immune recovery uveitis (IRU). This occurs in those patients with regressed CMV retinitis and elevated CD4+ counts. IRU is discussed further in the section on noninfectious ocular manifestations. Toxoplasmosis Ocular toxoplasmosis is the third most common infectious retinopathy and accounts for 1-3% of ocular infections in patients with AIDS. Ocular toxoplasmosis is often bilateral, multifocal, and not associated with chorioretinal scars, suggesting that in most cases it is a primary infection. Since 56% of AIDS patients with ocular toxoplasmosis have simultaneous toxoplasmic central nervous system disease, performing a neurologic examination and obtaining CNS imaging studies are recommended for all patients with ocular involvement. Histopathologically, toxoplasmal cysts and free forms of the organism are present in the retina. Yellow-white areas of necrosis with indistinct borders involving the posterior pole are seen. A significant inflammatory reaction may be present despite the immunosuppression, resulting in the typical "headlight in the fog" funduscopic image. Blindness results from fulminant retinal necrosis, retinal detachment, and optic neuritis. See Image 1. Differential diagnoses include CMV retinitis and PORN. However, a circumferential pattern of progression with sparing of the perivascular retina is not seen as in PORN. In toxoplasmosis, a significant amount of overlying inflammation with no significant retinal hemorrhage is seen, helping to distinguish toxoplasmosis from CMV. Diagnosis is based on clinical findings; however, serologic tests may be helpful in some cases. Patients with AIDS respond to combination therapy consisting of pyrimethamine, sulfadiazine, and folinic acid. Clindamycin, tetracycline, and spiramycin also are effective. High doses of systemic corticosteroids are avoided in patients with AIDS to avoid opportunistic infections. Among patients who respond to HAART, the number of cases of ocular toxoplasmosis has declined. Herpes Herpes zoster ophthalmicus Herpes zoster ophthalmicus (HZO) may be the presenting sign in HIV and may predict an increased risk for developing AIDS in those already infected with HIV. The causative agent is varicella-zoster virus (VZV). A vesicular rash develops in the trigeminal nerve distribution with predilection for the ophthalmic division. Blepharitis, conjunctivitis, keratitis, and uveitis may occur. The course of disease is more severe and prolonged in an individual with HIV. Active virus may be cultured from corneal scrapings weeks after the onset of HZO. Any young individual presenting with HZO should be tested for HIV. Treatment includes systemic acyclovir (10 mg/kg q8h IV or 600-800 mg PO 5 times/d), and close observation for evidence of dissemination. Topical corticosteroids may be warranted for uveitis, but systemic corticosteroids should be avoided to prevent further suppression of the immune system. Acute retinal necrosis Acute retinal necrosis (ARN) has been reported in patients with AIDS and is most often secondary to VZV reactivation, though it has also been associated with herpes simplex virus (HSV). Its incidence is second only to CMV retinitis in patients with AIDS. The clinical triad consists of full-thickness peripheral retinal necrosis, occlusive vasculitis, and prominent vitritis. Peripheral patches of necrotic retina coalesce over several weeks. A sharp boundary exists between involved areas and uninvolved areas. Dense vitritis with inflammatory cells and necrotic debris is often present and may produce fibrotic bands that exert traction on necrotic retina. This leads to retinal detachments in 75% of patients and blindness in 64% of patients within 2-3 months. Papillitis can also be seen with ARN. As a result, patients complain of severe ocular pain, photophobia, floaters, and decreased vision. A history of previous herpetic infection is not a prerequisite. Bilateral involvement occurs in 90% of patients who are immunocompromised, usually appearing within the first 6 weeks but sometimes months to years later. To prevent infection in the fellow eye, intravenous acyclovir is followed by oral acyclovir for 14 weeks. Differential diagnoses include retinitis caused by CMV, toxoplasmosis, syphilis, HIV, large cell lymphoma, and Behçet syndrome. However, with ARN, more pain occurs than with large cell lymphoma and more vitritis occurs than with CMV. If a clinical diagnosis is not possible, confirmation is possible through tissue culture identification of VZV or HSV, seroconversion, or a 4-fold increase between acute and convalescent antibody titers. Diagnostic vitrectomy and/or retinal biopsy are performed for unequivocal cases. Demonstration of characteristic viral particles through PCR may be useful in some cases. Traditional treatment starts with intravenous acyclovir administered at 10 mg/kg every 8 hours for 2 weeks. Complete resolution of inflammation may occur in 6-12 weeks. Occlusive vasculopathy and optic neuropathy are treated additionally with corticosteroids and aspirin. Severe visual loss occurs rapidly. The primary cause of visual loss is rhegmatogenous retinal detachment but also may result from optic neuropathy, retinal and choroidal vasculopathies, and vitreous opacities. Multiple posterior holes in a necrotic retina complicate repair. Laser treatment is often performed to barricade areas of retinitis posteriorly. In cases of retinal detachment, pars plana vitrectomy, endolaser, or long-acting gas or silicone oil tamponade is performed. Treatment with intravenous acyclovir reduces the risk of developing bilateral disease. Patients who are immunocompromised may develop life-threatening encephalitis. Progressive outer retinal necrosis PORN, considered by some to be a variant of ARN, is another common retinopathy, occurring in 2% of patients with AIDS with CD4+ counts of usually less than 50 cells/µL. Peripheral outer retinal necrosis sparing the perivascular retina occurs in a circumferential pattern. These lesions coalesce in weeks and progress to full-thickness retinal necrosis. Posterior progression occurs with minimal inflammation. Visual deterioration to no light perception occurs within weeks. The fellow eye can be involved in weeks to months. Differential diagnoses include CMV and toxoplasmosis retinitis. Neither spreads so quickly in a circumferential pattern nor spares the perivascular retina. A clinical diagnosis is made with the appropriate history and the characteristic fundus findings. Diagnosis can be confirmed via PCR on aqueous humor samples or histopathologic and/or immunohistochemical stains on retinal biopsy specimens obtained from the patient. No effective therapy is available. Intravenous ganciclovir and/or foscarnet given simultaneously with acyclovir may stabilize the infection and delay progression. Intravitreal ganciclovir and foscarnet also have been used with limited success. Syphilis Syphilis is an STD caused by the spirochete Treponema palladium. Syphilis may be spread by transfusion or accidental contact with an active lesion. The incidence of syphilis has increased in association with HIV. In patients with AIDS, the symptoms are more prolonged, more difficult to treat, and are associated with a higher rate of recurrence. Syphilis may develop when CD4+ counts are greater than 200 cells/µL. Since ocular syphilis may be associated with CNS involvement in 85-100% of AIDS patients, a lumbar puncture is generally recommended. Coexistence of HIV and syphilis should be considered. The advent of AIDS also has revived the concept of quaternary syphilis to describe an aggressive form of neurosyphilis associated with immune deficiency. The concentration of spirochetes is believed to maximize around the second stage during which nonspecific iritis and iridocyclitis are the predominant findings. The most common ocular findings in patients with concurrent HIV infection are uveitis, chorioretinitis, and retrobulbar neuritis. A large spectrum of ocular inflammation, including scleritis, uveitis, optic neuritis, retinitis, chorioretinitis, pseudoretinitis pigmentosa, uveal effusion, vasculitis with or without occlusion, and subretinal neovascular membrane formation, has been reported. In patients with AIDS, acute syphilitic posterior placoid chorioretinitis has been described. These large yellow-to-gray lesions are at the level of the retinal pigment epithelium (RPE) in a macular or juxtapapillary location with baited centers. Fluorescein angiography shows a leopard spot pattern with early hypofluorescence and late staining. Diagnosis requires positive syphilis antibody test (fluorescent treponemal antibody absorption [FTA-ABS] or microhemagglutination-Treponema pallidum [MHA-TP]) and a positive reagin test (Venereal Disease Research Laboratory [VDRL] test or rapid plasma reagin [RPR]). Although serologically negative syphilis has been documented in patients with AIDS, it is believed to be uncommon. A skin rash typical of secondary syphilis may occur simultaneously with the retinitis, but no other systemic signs may be present. Treatment of syphilis in patients with AIDS requires the regimen used for neurosyphilis regardless of the CNS examination. Treatment consists of aqueous penicillin 2 million units intravenously every 4 hours for 1 week, or doxycycline 100 mg orally twice a day for 21 days may be used in patients who are allergic to penicillin. A decline in the VDRL titer to 1:4 occurs within 6 months. Partners should be examined and treated, if necessary. Recurrence is more common in patients with AIDS and may occur without reinfection. Long-term therapy may be required in some patients. Differential diagnoses include toxoplasmosis, lymphoma, acute retinal necrosis, tuberculosis, cryptococcosis, and IRU. Infectious multifocal choroiditis Of patients with AIDS, 8-10% develop multifocal choroidal lesions that result from various infectious agents, including Pneumocystis carinii and Cryptococcus neoformans. Particularly, P carinii pneumonia is a ubiquitous protozoan parasite accounting for 60% of all opportunistic infections in patients with AIDS, with choroiditis occurring in 1% of AIDS patients. Patients may be completely asymptomatic, or they may present only with blurred vision. This may be the first clinical sign of a systemic infection and, therefore, requires a full systemic evaluation. Multifocal, round-oval, yellow plaquelike lesions, ranging from 300-3000 µm, appear deep in the midperiphery or posterior choroid. The lesions enlarge slowly and occur bilaterally in 76% of patients. Survival after diagnosis ranges from 2-44 weeks. C neoformans choroiditis is uncommon and is characterized by focal, yellow-white choroidal granulomas. The lesions may be solitary, multifocal, or confluent. Vision loss often results from papillitis, which occurs as a result of direct invasion. Differential diagnoses include ocular toxoplasmosis and ocular histoplasmosis, which are associated with significant intraocular inflammation and retinal involvement. The causative organisms are identified with special stains. However, systemic evaluation, including imaging studies, blood/sputum cultures, biopsy, and histologic examination of the affected visceral organs, may be required. Treatment of infectious multifocal choroiditis depends on the causative agent. Since systemic involvement is common, intravenous therapy often is required. Over a period of 1-3 months, these lesions may fade gradually, with minimal overlying RPE changes. Fungus Although fungal keratitis is not a common occurrence, impairment of the host immune system makes treatment more difficult and infection should be identified early and treated aggressively. Such predisposing conditions as exposure, sicca, or trichiasis should be identified and corrected. In the general population, 12% of fungemia leads to fungal chorioretinitis. This rate is higher among patients with AIDS. Candida is the most common organism involved. Histoplasmosis and Aspergillus infection involve the choroid. Typical candidal lesions begin as fluffy yellow retinal infiltrates resembling cotton wool spots, which may enlarge to involve the overlying vitreous. Vitreous abscess may result, leading to retinal detachment. Treatment is with systemic or intravitreal antifungal medications. Molluscum contagiosum Molluscum contagiosum is a DNA virus that is characterized by a pearly white, centrally umbilicated skin papule. The characteristic lack of vasculature and lack of necrosis differentiates molluscum lesions from neoplastic lesions, such as squamous cell carcinoma, Kaposi sarcoma (KS), and lymphoma. If the lid margin is involved, a follicular conjunctivitis or keratitis may be seen from direct spread of the virus particles. These lesions contain eosinophilic and basophilic bodies in the cytoplasmic inclusions, which contain the viral particles. In hosts who are immunocompetent, the infection is self-limited with fewer than 10 lesions being present on the face and eyelids. Resolution occurs spontaneously within 3-12 months, although excision or curettage is curative. In patients with AIDS, lesions are larger, bilateral, more rapid in onset, and more numerous. Resistance to standard therapies is higher. If symptomatic, the lesions may need to be removed using surgical excision, cautery, or cryotherapy to the base. Microsporidia Microsporidia are intracellular obligate parasitic protozoa that can cause punctate epithelial keratopathy in individuals infected by HIV. The patient may develop mild conjunctivitis. CD4+ lymphocyte count in such patients usually is less than 50 cells/µL. A Gram stain of the conjunctival and corneal epithelial cells reveals organisms. Some patients respond well to topical fumagillin. Noninfectious ocular manifestationsKaposi sarcoma KS is a multifocal, malignant sarcoma affecting 10% of patients with AIDS of which 20% show ophthalmic involvement. Adnexal involvement typically occurs late but also may be the initial manifestation of AIDS. Orbital involvement can cause proptosis, ptosis, eyelid edema, and ocular nerve palsies. Eyelid involvement causes trichiasis, irritation, and cosmetic changes. The inferior conjunctiva more frequently is involved, although all parts of the conjunctiva can be involved. The differential diagnosis consists of subconjunctival hemorrhage, hemangioma, foreign body, pyogenic granuloma, sebaceous carcinoma, basal cell carcinoma, conjunctival granuloma, and amelanotic melanoma. Diagnosis is based on the clinical findings and an associated diagnosis of HIV/AIDS. Tortuous and dilated vessels around the mass and subconjunctival hemorrhages are seen. Subconjunctival hemorrhage caused by KS should be differentiated from the thrombocytopenia-related hemorrhage by serial examinations. Tissue diagnosis may be obtained by local excision of the tumor. Systemic treatment often causes resolution of ocular symptoms. Local ocular treatment is considered for symptomatic relief and consists of surgical excision or radiation therapy. Recurrences are frequent despite treatment. Other tumors In addition to KS, non-Hodgkin lymphoma and Hodgkin disease are significantly more common among persons infected with HIV. Clinical observations not yet proven epidemiologically have suggested that cervical/anal dysplasia, prostate cancer, germ cell cancers, and lung cancer are more common in individuals infected with HIV. Non-Hodgkin lymphoma is second only to toxoplasmosis as a cause of cortical vision loss. Intraocular lymphoma is uncommon. Posterior segment manifestations include necrotizing retinitis, multifocal choroiditis, retinal vasculitis, vitritis, subretinal mass, and pseudohypopyon uveitis. A retinal biopsy may help in establishing a diagnosis in eyes without vitreous cellular infiltrate. IRU is a noninfectious intraocular inflammation that develops in patients with inactive CMV retinitis who have had a substantial elevation in CD4+ counts with HAART (>50 cells/µL). IRU is the leading cause of new vision loss in patients with AIDS. The severity of inflammation is believed to be due to the degree of immune reconstitution, the extent of CMV retinitis, the amount of intraocular CMV antigen, and any previous treatment. Patients complain of floaters and decreased vision. IRU has been diagnosed in 16-63% of patients who respond to HAART. Patients who have greater than 30% involvement of the retina are at a higher risk of developing IRU. Clinical findings include anterior chamber or vitreous reaction, panuveitis with hypopyon, optic disc and macular edema, epiretinal membrane, cataract, vitreomacular traction syndrome (VMT), neovascularization of the optic disc (NVD), and proliferative vitreoretinopathy. Treatment of patients with cidofovir increases the risk of occurrence 3.3 times compared to those patients not previously treated with cidofovir. Treatment with corticosteroids may be effective in controlling the inflammation and may or may not cause reactivation of CMV. Surgical options may be viable for patients with VMT, epiretinal membrane, cataract, and proliferative vitreoretinopathy. Other findings Additional ocular manifestations have been described, including noninfectious peripheral corneal ulceration, keratoconjunctivitis sicca, subconjunctival hemorrhages, cranial nerve palsies, visual field defects, and papillitis. CausesThe ocular complications of AIDS are directly related to the immune suppression associated with AIDS. DIFFERENTIALSSection 4 of 11
Acute Retinal Necrosis Cancer Associated and Related Autoimmune Retinopathies Ocular Manifestations of HIV Retinitis, CMV WORKUPSection 5 of 11
Lab Studies
Imaging Studies
Procedures
Histologic FindingsDiscussed under specific diagnoses TREATMENTSection 6 of 11
Medical CareThe treatment of CMV retinitis is discussed in this section. Specific treatment options for other conditions are discussed previously under each topic. Ganciclovir Introduced in 1989, ganciclovir is an acyclic nucleoside analog of acyclovir with structural similarity to guanosine but with 10-100 times increased potency against CMV. The drug is activated through monophosphorylation by the CMV enzyme and subsequently inhibits CMV DNA polymerase. Induction therapy consists of 5 mg/kg q12h IV for 2-3 weeks, followed by indefinite maintenance therapy of 5 mg/kg IV daily. Clinical regression of CMV retinitis occurs in 90-100% of newly diagnosed CMV retinitis. The effect is seen within 2-4 weeks after initiation of therapy. Reactivation of CMV retinitis is inevitable because of CMV resistance, decline in immune function, and low ocular concentration of the drug. If the drug is stopped, reactivation occurs in all patients within 3 weeks. Adverse effects include reversible bone marrow toxicity leading to neutropenia and thrombocytopenia. Neutropenia can be reversed by administration of granulocyte colony-stimulating factor. Concomitant use of other marrow-suppressive drugs, such as AZT (azidothymidine, zidovudine, Retrovir) and pyrimethamine, may complicate the decision to use ganciclovir in the patient with AIDS. Other complications include elevated liver enzymes, confusion, dizziness, headache, or seizures. The intravitreal sustained-release ganciclovir implant (Vitrasert) contains 5 mg of ganciclovir that is released at a rate of 1 mcg/h for 8 months. The device is surgically implanted in the pars plana region. Intravitreal injections of ganciclovir are another therapeutic option. Each injection includes 2000 mcg of ganciclovir in 0.1 mL sterile water and is given through the pars plana with a 27- or 30-gauge needle 1-3 times per week. Potential complications include endophthalmitis, retinal detachment, and vitreous hemorrhage. Approved in 1995, oral ganciclovir is administered for maintenance therapy. However, intravenous ganciclovir has been shown to be more effective than oral ganciclovir when comparing progression to retinitis. With the advent of HAART, if CD4+ counts remain above 100 cells/µL for 3-4 months on HAART, antiviral therapy may be discontinued with close observation for recurrences. Valganciclovir The Food and Drug Administration (FDA) approved valganciclovir (Valcyte) in 2001 for induction and maintenance therapy of CMV retinitis. It is an L-valyl ester (prodrug) of ganciclovir that is converted rapidly to ganciclovir following oral administration. The bioavailability of valganciclovir is significantly higher than from ganciclovir capsules. Induction therapy consists of 900 mg PO twice daily for 2-3 weeks. Maintenance therapy is 900 mg PO daily. Dosage adjustments may be required for patients with abnormal renal function. Oral valganciclovir was shown to be equivalent to intravenous ganciclovir in the initial therapy for CMV retinitis. The progression rates of new CMV retinitis in patients treated with intravenous ganciclovir and oral valganciclovir were similar. Fomivirsen Fomivirsen is a 21 base synthetic phosphorothioate oligonucleotide antisense RNA drug. It inhibits gene expression by base pairing with its complementary single stranded mRNA, which codes for the major immediate early region essential proteins of CMV. A second-line therapy, fomivirsen is approved for the treatment of CMV retinitis refractory to other therapies or for patients who are intolerant of other therapies. Administered intravitreally, 165 mcg is effective for the treatment of new CMV retinitis and also delays progression. Others have stated that induction therapy requires 330 mcg weekly for 2 weeks followed by maintenance therapy every 4 weeks. Dose-dependent toxicities specially associated with fomivirsen injection include electrophysiological abnormalities, visual field loss, retinal pigment epitheliopathy, iritis, and increased intraocular pressure. Foscarnet (trisodium phosphonoformate hexahydrate) Introduced in 1991, foscarnet is a pyrophosphate analog that is also a virustatic agent. Unlike ganciclovir, it does not have to be phosphorylated to become active. DNA polymerase and reverse transcriptase are affected. Induction therapy consists of 90 mg/kg bid for 2-3 weeks, followed by maintenance therapy of 90-120 mg/kg/day until reactivation occurs. Each infusion requires hydration with saline. Similar to ganciclovir, disease relapse is inevitable. Resistance also occurs by similar methods to ganciclovir. Complications include elevated creatinine, electrolyte imbalance, anemia, and nausea. The dosage must be adjusted based on serum creatinine levels because of its reversible nephrotoxicity. Intravitreal injection of foscarnet is given as 2400 mcg in 0.1 mL sterile water through the pars plana with a 27- or 30-gauge needle at least once a week. No intraocular toxicity has been documented at this dosage. Given the virustatic nature of ganciclovir and foscarnet, relapse is inevitable. Studies of Ocular Complications of AIDS (SOCA) demonstrated that combination therapy of foscarnet and ganciclovir had improved efficacy in controlling relapse. However, because of the poor quality of life measures that the combined adverse effects yield, monotherapy reinduction is the preferred approach for relapse. Combined therapy reinduction is reserved for severely clinically resistant retinitis. Cidofovir (1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl] cytosine dihydrate [HPMPC]) Cidofovir is an acyclic nucleotide analogue active against ganciclovir-resistant CMV. Induction therapy is 5 mg/kg IV once a week for 2 weeks, followed by 5 mg/kg every 2 weeks for maintenance. For newly diagnosed retinitis, the median time to progression is 120 days, as opposed to 115 days for those with relapsing retinitis. Major dose-limiting adverse events include elevated serum creatinine and proteinuria. Hydration and probenecid decrease the incidence of nephrotoxicity. Other adverse effects included neutropenia, and Fanconi syndrome. Ocular adverse effects of cidofovir include uveitis and hypotony. Surgical CareTreatment of retinal detachment may require any combination of pars plana vitrectomy, endolaser, scleral buckle, or heavy liquids. Intravitreal ganciclovir implants may be required for CMV retinitis. Surgical excision of adnexal lesions may be required in KS. These subjects are discussed under each diagnosis. ConsultationsAppropriate medical consultations are required for systemic treatment. MEDICATIONSection 7 of 11
The first drugs approved for the treatment of CMV retinitis were intravenous ganciclovir and foscarnet. Both drugs required daily intravenous infusions. Additional treatment options were developed subsequently and included oral ganciclovir, intravenous cidofovir, and the ganciclovir implant. The latest drug approved for the treatment of CMV retinitis is valganciclovir. This oral prodrug has been approved for both induction and maintenance therapy of CMV retinitis.
Drug Category: AntiviralsTreatment of CMV retinitis.
FOLLOW-UPSection 8 of 11
Further Outpatient Care
In/Out Patient Meds
Complications
Prognosis
Patient Education
MISCELLANEOUSSection 9 of 11
Medical/Legal Pitfalls
MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Article Last Updated: Jan 4, 2007 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
