PERSPECTIVES Acquired Immunodeficiency Syndrome and Ophthalmology: The First Decade Gary N. H o l l a n d , M.D. developing countries. It is feared that the epi­ demic will be particularly severe in areas of Southeast Asia and India.

Ten years ago, THE AMERICAN JOURNAL OF OPH­ published the first patient series describing the ophthalmic manifestations of the acquired immunodeficiency syndrome (AIDS).1 At that time, AIDS was a newly de­ scribed, and still unnamed, disorder. 25 There were fewer than 300 cases nationwide and its cause remained a mystery. Few could have imagined the magnitude of the AIDS epidemic to come, or the enormous changes in society and health care that it would engender. The current statistics on AIDS are staggering. The rate at which new cases were reported began to slow in the late 1980s, but the number of new cases has increased every year since the syndrome was initially described. By late 1991, there had been approximately 200,000 patients with AIDS in the United States, 65% of whom had died. 6 The acquired immunodeficiency syndrome is now the second leading cause of death among men 25 to 44 years of age. 7 It is estimated that one in 75 men and one in 700 women in the United States between the ages of 15 and 49 years are infected with human immu­ nodeficiency virus (HIV), the agent responsible for AIDS.8 Over 1 million people in this country are believed to be infected with HIV. It is estimated that 58,000 to 85,000 of them will develop the full AIDS illness in 1992.9·10 Homo­ sexual/bisexual men still account for most cases, but the groups whose numbers are in­ creasing most rapidly include patients exposed through intravenous drug use or heterosexual contact and children infected by perinatal transmission. 11 THALMOLOGY

Ophthalmic Manifestations It became apparent early in the epidemic that ocular disease was a common manifestation of AIDS. 11315 Most ophthalmic disorders of pa­ tients with AIDS over the past decade belong to the following four major categories: lesions associated with disease of the microvasculature; opportunistic infections; neoplasms; and neuro-ophthalmic disorders associated with intracranial infections and neoplasms. Few new ophthalmic diseases have been described as a result of the epidemic; an example is choroidal pneumocystosis. 1618 In most cases, the ophthal­ mic diseases associated with HIV infection have been previously uncommon disorders or un­ usual manifestations of diseases known to develop in other patient groups. Toxoplasmic retinochoroiditis 19 and varicella-zoster virus retinitis, 20 · 21 for example, are disorders seen in otherwise healthy individuals and can have a different clinical appearance and course when they develop in patients with AIDS. The altered clinical signs and symptoms of various intraoc­ ular diseases in patients with AIDS continue to challenge the diagnostic skills of ophthalmolo­ gists. The most common lesions are cotton-wool spots. These focal areas of nerve fiber layer swelling develop in response to retinal ische­ mia associated with a diffuse retinal microvasculopathy. The cause of this vascular dis­ ease, which is ultrastructurally similar to diabetic retinopathy, has intrigued investiga­ tors throughout the decade, yet its pathogenesis has yet to be fully elucidated. Cotton-wool spots are not the sites of secondary opportunis­ tic infections. A variety of causes have been hypothesized, including damage caused by HIV infection of endothelial cells,22 deposition of immune complexes, 23 and alterations in blood flow.24 The cause is probably multifactorial. Retinal hemorrhages and microaneurysms are

The AIDS situation is even more serious in other parts of the world. Current estimates place the number of individuals infected with HIV in sub-Sahara Africa at 6.5 million, with one in every 40 persons between the ages of 15 and 49 years infected. 8 It is feared that 15% to 20% of the work force on that continent will die of AIDS. The World Health Organization has estimated 30 million adults and 10 million children throughout the world will be infected with HIV by the year 2000.12 Ten million people will have AIDS, 90% of whom will be from 86

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other, less frequent retinal disorders probably associated with microvascular damage. Cotton-wool spots do not usually cause gross visual disturbances and therefore are of little clinical significance to the individual patient. These lesions are, however, more common in patients with AIDS than in those with asympto­ matic HIV infections,26,26 and thus may repre­ sent a nonspecific clinical sign of severe immunosuppression. Although cotton-wool spots are generally considered to be asymptomatic lesions, some investigators suspect that the underlying reti­ nal microvascular disease may lead to diffuse retinal dysfunction with subtle visual changes. It may be a contributing factor to the recent finding of axonal loss in optic nerves of patients with AIDS and associated defects in color vi­ sion and contrast sensitivity among individuals infected with HIV.27·28 Some investigators also suspect retinal microvascular damage may fa­ cilitate the development of opportunistic infec­ tions of the retina. The study of these vascular changes will therefore continue to be intense in the next decade. The most devastating of the ophthalmic man­ ifestations of AIDS are opportunistic infec­ tions. More than a dozen different infectious agents have been found in ocular tissue, but only cytomegalovirus retinopathy develops commonly. Numerous clinical and autopsy re­ ports have convinced investigators that cyto­ megalovirus retinopathy develops in 20% to 25% of patients with AIDS. Before the AIDS epidemic, cytomegalovirus retinopathy was an uncommon disorder, seen primarily in patients who had received an organ transplant and who had been treated with immunosuppressive drugs. The infection was so uncommon that most ophthalmologists would probably never see a case of cytomegalovirus retinopathy dur­ ing their careers. Now, by contrast, it is the most common infection of the retina in many communities. Cytomegalovirus retinopathy usually develops in the later stages of the syn­ drome when patients have the most severe immunosuppression. It does, however, fulfill one of the current Centers for Disease Control criteria for diagnosis of AIDS,29 and does some­ times develop as the first manifestation of the syndrome. 30 It does not usually develop in pa­ tients without such symptoms of HIV infection as weight loss, fever, or lymphadenopathy. The diagnostic features of cytomegalovi­ rus retinopathy have been previously de­ scribed.1315·25·31'32 The most important features

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include a dry-appearing granular lesion border, slow enlargement of lesions, and lack of a prominent intraocular inflammatory reaction. These features help to differentiate cytomegalo­ virus retinopathy from other, less common, but equally important retinal infections that can be found in patients with AIDS. The disorders with which cytomegalovirus retinopathy is most easily confused include toxoplasmic retinochoroiditis, 19 varicella-zoster virus retini­ tis,20·21 and syphilitic retinitis. 33 A marked vitre­ ous inflammatory reaction, severe iridocyclitis, and a red, photophobic eye are important clini­ cal signs that suggest infection with Toxoplasma gondii or syphilis instead of cytomegalovirus retinopathy. In contrast to cytomegalovirus ret­ inopathy, varicella-zoster virus retinitis is rap­ idly progressive. Another disorder, recently de­ scribed in a patient with AIDS, that can mimic cytomegalovirus retinopathy is intraocular large cell lymphoma with retinal involve­ ment. 34 These various disorders must be differ­ entiated accurately. Not only will a correct diagnosis allow the initiation of proper treat­ ment before additional loss in visual acuity occurs, but retinal lesions may be the first manifestations of disseminated, life-threaten­ ing disease. Although HIV can infect the retina, 22 · 35 there has been no evidence that it directly causes inflammatory or necrotizing retinal lesions. On the basis of in vitro studies that demonstrate enhancement of cytomegalovirus replication by HIV, however, it has been suggested that coinfection of retinal cells by both viruses may be a factor that contributes to the frequency and severity of cytomegalovirus retinopathy in pa­ tients with AIDS.36 Diseases of the ocular surface and adnexa are less common than retinal disorders, but can be equally troublesome. 36 The most common of these disorders is herpes zoster ophthalmicu s 37,38 j t c a n v a r y i n severity, but in the worst cases, blindness can result from the associated keratitis and uveitis. Disseminated varicellazoster virus infections can also develop in pa­ tients with herpes zoster ophthalmicus. Ag­ gressive treatment with high-dose orally or intravenously administered acyclovir is there­ fore indicated in all patients with HIV infection and herpes zoster ophthalmicus. Chronic, ac­ tive infection of the corneal epithelium by vari­ cella-zoster virus after herpes zoster ophthal­ micus has been described. 39 This disorder, which can be mistaken for herpes simplex virus epithelial keratitis, is not seen in otherwise

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healthy individuals. In contrast to some other infectious disorders, herpes zoster ophthalmicus can develop relatively early in the course of a patient's illness, and is believed to be a poor prognostic sign for the eventual development of the full AIDS illness. The natural defenses of normal eyelid func­ tion, adequate tear production, and an intact corneal epithelium are critical for reducing the risk of corneal infections in patients with HIV infection. Therefore, treatment of ophthalmic Kaposi's sarcoma is most important when it involves the eyelid margins; advanced cases can result in entropion formation and trichiasis.40 Radiotherapy, cryotherapy, and excision have all been successful in the local treatment of this neoplasm. 40 · 41 Corneal microsporidiosis is an uncommon disorder that has recently been described in patients with AIDS.42·43 It is a particularly debil­ itating disease because it causes a chronic bilat­ eral diffuse corneal epitheliopathy that is pain­ ful and affects vision. Corneal microsporidiosis is one of the AIDS-related ophthalmic disor­ ders for which there is still no effective treat­ ment. The search for new drugs to treat this and other unusual ocular infections associated with AIDS will become increasingly important. Treatment of Cytomegalovirus Retinopathy The ability to treat cytomegalovirus infec­ tions has been the most important development related to the ophthalmic manifestations of AIDS in the past decade. When AIDS was first described, there was essentially no way to alter the relentless progression of cytomegalovirus retinopathy, and all patients with this infection became blind if they lived long enough. In 1984, ganciclovir was made available on a com­ passionate-use basis for the treatment of cyto­ megalovirus infections; it was eventually ap­ proved by the Food and Drug Administration for marketing in June 1989. In September 1991, foscarnet, a second antiviral drug with activity against cytomegalovirus, was also approved. (Currently, cytomegalovirus retinopathy in immunosuppressed patients is the only indication for which these drugs have been approved.) These drugs are difficult to use. Both are avail­ able commercially only as an intravenous prep­ aration. Neither eliminates virus from the eye; therefore, once treatment is initiated, intrave­ nous administration of these drugs must be continued for the rest of the patients' lives in an attempt to maintain disease quiescence. On the basis of early experience with ganciclovir, a treatment regimen was developed in which

July, 1992

patients were treated with a short (generally two-week) induction course of high-dose treat­ ment, followed by continuous lower-dose main­ tenance treatment. Foscarnet is administered similarly. These treatment regimens have been described in detail.32 · 4448 Both are associated with potentially life-threatening complica­ tions. Ganciclovir causes bone marrow sup­ pression with neutropenia and thrombocytopenia. Foscarnet can cause renal failure and electrolyte abnormalities. Because of these problems, patients are treated by a team of physicians; drugs are administered by an inter­ nist familiar with their side effects, while the response of the patient's retinal disease to treatment is monitored by an ophthalmol­ ogist. Recently, investigation of an oral prep­ aration of ganciclovir has begun, but its effi­ cacy may be limited by low bioavailability. Initially, the general medical and ophthalmic communities were unprepared to deal with problems such as cytomegalovirus retinopathy because of the magnitude and swiftness of the AIDS epidemic. As a result of many factors, including the urgent need to care for visually impaired patients, an incomplete understand­ ing of the natural course of cytomegalovirus retinopathy, and the need to involve clinicians from many subspecialties, ganciclovir was not studied in any large, prospective, and con­ trolled trials during its first few years of use. Most of our early concepts regarding the treat­ ment of cytomegalovirus retinopathy were therefore derived from small retrospective studies, anecdotal reports, and the clinical im­ pressions of numerous investigators involved in compassionate-use programs 4953 ; only re­ cently have well-designed treatment trials, us­ ing standardized nomenclature and techniques for assessing disease response, 54 · 55 been initiat­ ed. As a consequence, treatment strategies are still evolving. In 1988, the National Eye Institute allocated approximately 8.5 million dollars for additional clinical studies of the ocular complications of AIDS for a period of several years. The first of these studies, 56 performed by the Studies of the Ocular Complications of AIDS Research Group at 12 clinical centers, compared the efficacies and toxicities of ganciclovir and foscarnet. Al­ though all data have yet to be analyzed com­ pletely, there is no apparent difference between treatment groups for such major ophthalmic outcome variables as final visual acuity. 56 Be­ cause patient survival differed, however, the study's Policy and Data Monitoring Board rec­ ommended suspending randomization of treat-

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ment assignments. The survival of patients with cytomegalovirus retinopathy is particular­ ly important because the infection is usually a late manifestation of AIDS. The study found that patients initially treated with foscarnet lived for a median of approximately 12.6 months with treatment, whereas patients ini­ tially treated with ganciclovir lived for a medi­ an of approximately 8.5 months. 56 The cause for this differential survival was not identified. Although it may be related to the drugs them­ selves, it may also be related to factors not controlled in the study, such as the differential use of antiretroviral drugs. The choice between ganciclovir and foscarnet for initiation of treat­ ment for cytomegalovirus retinopathy is proba­ bly best left to the patient and his or her primary care provider, who can make a decision based on nonophthalmic factors, such as survi­ val or the risk of complications. Several other studies, sponsored by pharmaceutical compa­ nies or supported by the National Institutes of Health through their AIDS Clinical Trials Group, promise to provide additional insight into the use of these drugs. When ganciclovir was the only anticytomegalovirus drug widely available, intravitreal injec­ tions of the drug were explored as a possible alternative to systemic treatment in those pa­ tients who developed neutropenia. Studies showed that intravitreal injection of the drug can prevent or delay the enlargement of cyto­ megalovirus retinopathy lesions, 57,58 but several problems are associated with intravitreous treatment not the least of which are the logistic difficulties of performing intravitreal injections on a once- or twice-weekly basis for an indefi­ nite period of time. Systemic antiviral treat­ ment has the potential advantage of preventing progression of cytomegalovirus infections in all parts of the body. Autopsy studies have shown that probably all patients with cytomegalovirus retinopathy have tissue-invasive infections of other organs as well, even if they are not clini­ cally apparent, 23 and disseminated cytomegalo­ virus infection can be a cause of death in pa­ tients with AIDS. Intravitreal injection also poses the potential risks of endophthalmitis and retinal detachment. For these reasons, in­ travitreal injections should be reserved only for patients who cannot tolerate systemic antiviral treatment. With the introduction of foscarnet, and more recently, the use of leukocyte growth factors (sargramostim [granulocyte-monocyte colony-stimulating factor]; filgrastim [granulocyte colony-stimulating factor]) to treat ganciclovir-associated neutropenia, 59 additional

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treatment options are now available. As a re­ sult, the initial enthusiasm for intravitreous injection of ganciclovir has waned recently, and its ultimate role in the treatment of cyto­ megalovirus retinopathy has yet to be defined. Many problems still need to be solved in the treatment of cytomegalovirus retinopathy. Even with continuous ganciclovir or foscarnet administration, reactivation and progression of disease eventually develop in nearly all pa­ tients. A major problem to be addressed in future studies will be the best treatment of these late progressions. Currently, most pa­ tients are retreated with two weeks of induc­ tion-level treatment when reactivation occurs. Alternatives to be investigated include alternat­ ing ganciclovir and foscarnet administration, the concurrent use of both drugs, or the contin­ uous use of induction-level doses of ganciclovir with leukocyte growth factors to prevent neu­ tropenia. The emergence of ganciclovir-resistant strains of cytomegalovirus is also important. Viral isolates from patients with progressive disease have shown in vitro drug resistance in selected cases, 60 but other studies have not shown an association between in vitro resist­ ance and clinical response to the drug. 61 In most cases, reactivation of disease can be controlled with reinduction treatment. Rhegmatogenous retinal detachments are a well-recognized complication of cytomegalovi­ rus retinopathy. 62 65 The prevalence of this com­ plication has been approximately 20% in most series, but the risk has increased with the dura­ tion of infection. 63 Other factors that probably increase the risk of retinal detachment include the extent and location of disease 63 ; patients with infections involving more than 50% of the retina and anterior infections near the vitreous base have the highest risk. The effect of antivi­ ral treatment on the incidence of retinal detach­ ment has been debated, but remains undeter­ mined. Screening programs to identify patients with early cytomegalovirus retinopathy or other ophthalmic problems are needed. There is no consensus on the value of such programs, and the increasing number of patients with HIV infection makes frequent screening examina­ tions of all patients impossible. A more practi­ cal approach involves patient education. People with HIV infection and their primary care pro­ viders should be made familiar with the clinical signs and symptoms of cytomegalovirus reti­ nopathy; they include blurring of vision, blind spots, and floaters. Pain and redness do not

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develop. Even patients with small peripheral retinal lesions will usually have at least some subtle visual symptoms, even if central visual acuity remains normal. Patients should be en­ couraged to seek ophthalmic examination at the onset of such symptoms. Treatment of ocular toxoplasmosis in patients with AIDS has also been studied during the past decade. Lesions will respond to conven­ tional antiparasitic treatments, but patients re­ quire prolonged treatment with these drugs to prevent disease reactivation. 19 Currently an investigational drug, 566C80, is being studied as a treatment for T. gondii-induced infections in patients with AIDS.66,67 There is great interest in this drug, not only because it is a potent inhibitor of the parasite in vitro, but also be­ cause it has activity against T. gondii cysts. Patient Survival and Quality-of-Life Issues Because AIDS is still a fatal disease, aggres­ sive treatment of secondary infections such as cytomegalovirus retinopathy or toxoplasmic retinochoroiditis has been viewed by some as a futile effort. To the contrary, ophthalmic care is among the most important services provided to patients with AIDS because it increases their well-being. Furthermore, the length of patient survival has been increasing recently, and as a result, quality-of-life issues have become in­ creasingly important. Key among them is the preservation of sight. Blindness or fear of loss in vision is considered the leading cause of suicide among patients with AIDS.68 Before the availability of antiretroviral drugs that do not have bone marrow toxicity, such as didanosine, patients were sometimes forced to choose be­ tween ganciclovir (for treatment of cytomegalo­ virus retinopathy) and zidovudine (which may prolong life); because of similar toxicities, the two drugs cannot always be used simultaneous­ ly. In such cases, most ophthalmologists found that patients chose treatment with ganciclovir. Increasing survival can be attributed not only to the use of antiretroviral drugs, but also to prophylaxis against such opportunistic infec­ tions as pneumocystosis, toxoplasmosis, and cryptococcal meningitis. The use of inhaled pentamidine as prophylaxis against pneumo­ cystosis has been suggested as the cause of the emergence of choroidal pneumocystosis as a new ophthalmic disease by somehow facilitat­ ing the spread of organisms to sites other than the lungs. 17 (The current trend toward use of orally administered trimethoprim-sulfamethoxazole instead of inhaled pentamidine as a prophylactic agent may eliminate this possibili­ ty.) However, choroidal pneumocystosis can

July, 1992

develop without inhaled pentamidine use. The increasing survival and the increasing number of patients with AIDS may have allowed the development of unusual infections late in the course of the disease. If that is the case, other new or extremely unusual ophthalmic diseases will emerge as the AIDS epidemic expands further. Prophylaxis against ophthalmic disease will become an important topic in ophthalmology in the next decade, especially in terms of prevent­ ing cytomegalovirus retinopathy. Because of the toxicity and expense of currently available anticytomegalovirus drugs, it will be necessary to identify those patients at greatest risk for development of cytomegalovirus retinopathy, before effective and practical programs of pre­ vention can be initiated. Cytomegalovirus reti­ nopathy does not usually develop unless CD4 lymphocyte counts are less than 50 cells/ mm3,69 and the search for other important risk factors is under way. Another prerequisite for practical prevention programs is an orally ad­ ministered antiviral drug; interest in current trials of orally administered ganciclovir stems in part from its potential as a prophylactic agent. Health Care Delivery and the Risk of Disease Transmission Probably the greatest and most far-reaching impact of the AIDS epidemic on ophthalmology has been a heightened awareness of the poten­ tial for disease transmission in the workplace. After HIV was identified as the cause of AIDS in 1983 and was subsequently found in most body fluids, including tears, concern was raised about the possibility of disease transmission to health care workers or between patients. Be­ cause HIV infection may exist in asymptomatic people who do not know they have been ex­ posed to the virus, the problem of preventing HIV transmission should concern all ophthal­ mologists, whether they evaluate and treat pa­ tients with the overt manifestations of AIDS. Many studies have investigated the risk of HIV infection through occupational exposure. There have been approximately three dozen health care workers known or suspected to have been infected with HIV through patient con­ tact. On the basis of these cases, the risk of HIV transmission after percutaneous exposure to HIV-infected blood is estimated to be approxi­ mately 0.3%. (In contrast, the risk of hepatitis B virus transmission to health care workers is considerably higher: approximately 30%.) Many epidemiologie studies have shown that casual contact and routine patient care do not

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increase one's risk of HIV infection. In most cases, HIV infection has developed after deep intramuscular needle-stick injuries. There have been isolated cases of HIV infection among health care workers who had blood exposure to their mucous membranes or nonintact skin. Such cases have not been seen in large prospec­ tive studies of exposed health care workers, however, and the incidence of infection by this route must be extremely low. In response to the AIDS epidemic, the Cen­ ters for Disease Control have developed guide­ lines to protect health care workers from the risk of infection with blood or body fluid-borne agents.70·71 The guidelines are meant to be uni­ versal precautions, and should be used by all health care workers during all patient contacts. Handwashing is one of the most important precautions and should be performed before and after all patient examinations. Barrier pre­ cautions should be used to protect against di­ rect contact with blood or body fluids. Gloves, for example, should be worn whenever touch­ ing mucous membranes, nonintact skin, or ob­ jects contaminated by blood or body fluids, especially if there are cuts, scratches, or other dermatologie conditions resulting in open le­ sions on the health care worker's hands. Gloves should be used for venipuncture and similar procedures; many ophthalmologists now rou­ tinely wear gloves during the administration of retrobulbar anesthesia. Gloves, of course, will not prevent needle-stick injuries, but will pre­ vent contact with any blood that oozes from the injection site. Some ophthalmologists also wear gloves during such procedures as indirect ophthalmoscopy, when contact with tears can be expected. Other forms of barrier protection, such as gowns, masks, and protective eye wear, need only be used if splash or aerosolization of fluids is expected. Disinfection of contaminated instruments is another area of concern. Human immunodefi­ ciency virus is inactivated by heat and by a variety of hospital germicides, including 3% hydrogen peroxide, 70% ethanol, glutaraldehyde, and paraformaldehyde. A 1:10 solution of household bleach is also highly effective for inactivation of HIV. Before disinfection, instru­ ments should be mechanically cleaned to re­ move blood, mucus, or other particulate, organ­ ic materials. Because HIV has been found in tears, there has also been considerable concern over the proper methods to disinfect applanation to­ nometer tips. Like other instruments, they can be wiped clean after contact with the ocular surface, then soaked in one of several germici-

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dal solutions. 71 Swabbing the tips with a 70% isopropyl alcohol-soaked pledget, followed by air drying, will also effectively disinfect the tips. 72 Contact-lens fitting sets pose a potential problem for disease transmission. Human im­ munodeficiency virus is inactivated by both heat and hydrogen peroxide sterilization sys­ tems, and all current contact lenses can with­ stand one technique or the other. The adequacy of various commercially available chemical sterilization methods for inactivation of HIV has not been established for most clinical situa­ tions, and they are not currently recommended. Human immunodeficiency virus can be found in corneal tissue and tears, which raises the possibility that corneal transplant recipients might become infected. Although other viral diseases can be transmitted by corneal trans­ plantation, there have never been any docu­ mented cases of HIV transmission via this route, even in those few cases in which the donor was found in retrospect to be infected with the virus. 73 Nevertheless, to reduce the theoretical risk of such transmission, the Eye Bank Association of America established poli­ cies in 1984 requiring its members to screen potential donors for HIV risk factors and to test all donors routinely for evidence of antibodies against HIV. Attention has been generated in the past year by a cluster of HIV infections among patients of a dentist with AIDS.74 Five of approximately 850 patients from that practice were examined and were infected with HIV, with strong evi­ dence that the virus was transmitted to them during dental care, although the precise mecha­ nism of transmission was not determined. Oth­ er small series, however, have failed to find evidence of HIV transmission from infected health care workers to patients. The small size of these studies has limited the ability to define accurately the risk of HIV transmission from health care workers to patients, but estimates have varied from one in 40,000 contacts to one in 1 million contacts. This subject has become an emotional and politically explosive issue. As a result, the Centers for Disease Control have issued a set of guidelines to prevent transmis­ sion of HIV and hepatitis B virus from health care workers to patients. 74 The Centers for Disease Control do not rec­ ommend mandatory testing of health care workers for antibodies against HIV or hepatitis B antigen; their current assessment of the risk does not support the diversion of resources that would be required to implement mandatory testing programs. Also, they do not recommend

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restrictions in the practice of health care work­ ers infected with HIV or hepatitis B virus, as long as they do not perform invasive exposureprone procedures and they comply with rec­ ommended surgical techniques and universal precautions. They do recommend that expo­ sure-prone procedures not be performed by health care workers infected with HIV or hepa­ titis B virus. An exposure-prone procedure is one in which there is digital palpation of a needle tip in a body cavity or the simultaneous presence of the health care worker's fingers and a sharp object in a poorly visualized anatomic site. In an exposure-prone procedure, percuta­ neous injury to the health care worker may result in the worker's blood coming in contact with the patient. In general, ophthalmic surgi­ cal procedures would not be considered expo­ sure-prone by those criteria. The need for mandatory HIV testing for all physicians has recently been debated before Congress. Advocates of mandatory testing cite the ethical principle that patient welfare must be the primary concern of physicians and that therefore, testing is warranted even though the risk of transmission is extremely low. Oppo­ nents of mandatory testing cite the staggering cost of such a program, its lack of clear benefits, the possibility of false-positive tests, and the invasion of physicians' privacy. They believe the spread of HIV infection from physician to patient can best be controlled by rigorous en­ forcement of infection control measures. Con­ gress has approved legislation requiring states to comply with the Centers for Disease Control guidelines, but has not passed mandatory test­ ing laws. The issue of HIV transmission in the health care setting was discussed in detail by Ortiz and Aaberg. 75 Health Care Expenses The costs of the AIDS epidemic are enor­ mous. 10 It is estimated that the average yearly cost for treating one patient with AIDS is $32,000; the lifetime cost is believed to be more than $85,000. In 1992, 7.2 billion dollars will be spent on medical care for patients with AIDS in the United States. It is difficult to predict future costs because of potential changes in survival times and development of new treat­ ments, but a 2 1 % average increase in annual medical costs is expected through 1994. Treat­ ment costs are highest when expensive, new drug treatments are used. In Los Angeles, a year of treatment with ganciclovir alone can cost more than $30,000 when both the cost of the drug and the equipment and medical ser­ vices associated with its intravenous adminis­

July, 1992

tration are considered; a year of treatment with foscarnet can cost more than $100,000. In the coming decade, difficult decisions will have to be made regarding the allocation of limited health care resources. With this issue in mind, many investigators have begun to consid­ er the appropriate indications for treatment of various ophthalmic disorders. It may be, for example, that antiviral treatment for small foci of cytomegalovirus infection in the peripheral retina can be deferred until there is documenta­ tion of extension toward visually important structures in the posterior pole without ad­ versely affecting the patient's final visual out­ come. Future studies must continue to address the question of who will benefit from treatment of cytomegalovirus retinopathy. In one small retrospective study, stabilization of vision could be demonstrated only in patients whose visual acuity was 20/40 or better at the start of treatment 54 ; perhaps long-term retention of useful vision will not be possible for eyes that have already had extensive damage from cyto­ megalovirus retinopathy at the time of diagno­ sis, even with aggressive treatment. We may find that the expense and risks of treatment for such eyes cannot be justified. Likewise, surgical repair of every retinal detachment associated with cytomegalovirus retinopathy may not be warranted. Although surgical reattachment is usually successful, visual results are often poor after the procedure. A consideration of surgical indications has therefore been emphasized in recent publications regarding this disorder.62·64 Ophthalmologists will become increasingly in­ volved in these and other related health care delivery issues in the coming years. Acquired immunodeficiency syndrome is no longer solely in the domain of large, urban, and university-based practitioners. A dispropor­ tionately high number of new cases are from rural America. Therefore, all ophthalmologists, regardless of their practice situations, will probably encounter patients with HIV infec­ tion. With no cure for AIDS and no reasonable hope of an effective vaccine against HIV in the immediate future, prevention and treatment of secondary disorders will be a major focus of attention. Ophthalmologists will continue to have an important role in addressing these problems.

From the UCLA Ocular Inflammatory Disease Center, the Jules Stein Eye Institute, and Department of Oph­ thalmology, UCLA School of Medicine, Los Angeles, California. This study was supported in part by the Skirball Foundation, Los Angeles, California; and Re-

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search to Prevent Blindness, Inc., New York, New York. Reprint requests to Gary N. Holland, M.D., Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90024-7003.

References 1. Holland, G. N., Gottlieb, M. S., Yee, R. D„ Schanker, H. M., and Pettit, T. H.: Ocular disorders associated with a new severe acquired cellular immu­ nodeficiency syndrome. Am. J. Ophthalmol. 93:393, 1982. 2. Centers for Disease Control: Pneumocystis pneumonia—Los Angeles. M.M.W.R. 30:250, 1981. 3. Gottlieb, M., Schroff, R., Schanker, H., Weissman, J., Fan, P., Wolf, R., and Saxon, A.: Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. Evidence of a new severe acquired cellular immunodeficiency. N. Engl. J. Med. 305:1425, 1981. 4. Masur, H., Michelis, M. A., Greene, J. B., Onorato, I., Vande Stouwe, R. A., Holzman, R. S., Wormser, G., Brettman, L., Lange, M., Murray, H. W., and Cunningham-Rundles, S.: An outbreak of community-acquired Pneumocystis carinii pneumo­ nia. Initial manifestation of cellular immune dys­ function. N. Engl. J. Med. 305:1431, 1981. 5. Siegal, F. P., Lopez, C , Hammer, G. S., Brown, A. E., Kornfeld, S. J., Gold, J., Hassett, J., Hirschman, S. Z., Cunningham-Rundles, C , Adelsberg, B. R., Parham, D. M., Siegal, M., Cunningham-Rundles, S., and Armstrong, D.: Severe acquired immunodeficien­ cy in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions. N. Engl. J. Med. 305:1439, 1981. 6. Centers for Disease Control: Human immuno­ deficiency virus/AIDS Surveillance Report. Novem­ ber 1991:1-18. 7. Centers for Disease Control: Mortality attribut­ able to HIV infection/AIDS—United States, 19811990. M.M.W.R. 40:41, 199,1. 8. Palca, J.: The sobering geography of AIDS. Sci­ ence 252:372, 1991. 9. Centers for Disease Control: HIV prevalence estimates and AIDS case projections for the United States. Report based upon a workshop. M.M.W.R. 39:1, 1990. 10. Hellinger, F. J.: Forecasting the medical care costs of the human immunodeficiency virus epidem­ ic. 1991-1994. Inquiry 28:213, 1991. 11. Centers for Disease Control: Update. Acquired immunodeficiency syndrome—United States, 1 9 8 1 1990. M.M.W.R. 40:358, 1991. 12. World Health Organization: In Point of Fact. Geneva: World Health Organization, May 1991. No. 74. 13. Holland, G. N., Pepose, J. S., Pettit, T. H„ Gottlieb, M. S., Yee, R. D., and Foos, R. Y.: Acquired immune deficiency syndrome. Ocular manifesta­ tions. Ophthalmology 90:859, 1983. 14. Freeman, W. R., Lerner, C. W., Mines, J. A.,

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27. Quiceno, J. I., Caparelli, E., Sadun, A. A., Munguia, D., Grant, I., Listhaus, A., Caprotta, J., Lambert, B., and Freeman, W. R.: Visual dysfunction without retinitis in patients with acquired immuno­ deficiency syndrome. Am. J. Ophthalmol. 113:8, 1992. 28. Tenhula, W. N., Xu, S., Madigan, M. C , Hel­ ler, K., Freeman, W. R., and Sadun, A. A.: Morphometric comparisons of optic nerve axon loss in acquired immunodeficiency syndrome. Am. J. Ophthalmol. 113:14, 1992. 29. Centers for Disease Control: Revision of the Centers for Disease Control surveillance case defini­ tion for acquired immunodeficiency syndrome. M.M.W.R. 36:3S, 1987. 30. Sison, R. F., Holland, G. N., MacArthur, L. J., Wheeler, N. C , and Gottlieb, M. S.: Cytomegalovi­ rus retinopathy as the initial manifestation of the acquired immunodeficiency syndrome. Am. J. Oph­ thalmol. 112:243, 1991. 31. Bloom, J. N., and Palestine, A. G.: The diagno­ sis of cytomegalovirus retinitis. Ann. Intern. Med. 109:963, 1988. 32. Holland, G. N.: An update on AIDS-related cytomegalovirus retinitis. In Focal Points 1991. Clin­ ical Modules for Ophthalmologists, vol. 4, module 5. San Francisco, American Academy of Ophthalmolo­ gy, 1991, pp. 1-8. 33. Passo, M. S., and Rosenbaum, J. T.: Ocular syphilis in patients with human immunodeficiency virus infection. Am. J. Ophthalmol. 106:1, 1988. 34. Schanzer, M. C , Font, R. L., and O'Malley, R. E.: Primary ocular malignant lymphoma associat­ ed with the acquired immune deficiency syndrome. Ophthalmology 98:88, 1991. 35. Skolnik, P. R., Pomerantz, R. J., de la Monte, S. M., Lee, S. F., Hsiung, G. D., Foos, R. Y., Cowan, G. M., Kosloff, B. R., Hirsch, M. S., and Pepose, J. S.: Dual infection of retina with human immunodefi­ ciency virus type 1 and cytomegalovirus. Am. J. Ophthalmol. 107:361, 1989. 36. Shuler, J. D., Engstrom, R. E., and Holland, G. N.: External ocular disease and anterior segment disorders associated with AIDS. Int. Ophthalmol. Clin. 29:98, 1989. 37. Cole, E. L., Meisler, D. M., Calbrese, L. H. H., Holland, G. N., Mondino, B. J., and Conant, M. A.: Herpes zoster ophthalmicus and acquired immune deficiency syndrome. Arch. Ophthalmol. 102:1027, 1984. 38. Sandor, E. V., Millman, A., Croxson, T. S., and Mildvan, D.: Herpes zoster ophthalmicus in patients at risk for the acquired immune deficiency syndrome (AIDS). Am. J. Ophthalmol. 101:153, 1986. 39. Engstrom, R. E., and Holland, G. N.: Chronic herpes zoster virus keratitis associated with the ac­ quired immunodeficiency syndrome. Am. J. Ophthal­ mol. 105:556, 1988. 40. Shuler, J. D., Holland, G. N„ Miles, S. A., Miller, B. J., and Grossman, I.: Kaposi sarcoma of the conjunctiva and eyelids associated with the acquired immunodeficiency syndrome. Arch. Ophthalmol. 107:858, 1989.

July, 1992

41. Dugel, P. U„ Gill, P. S., Frangieh, G. T., and Rao, N. A.: Treatment of ocular adnexal Kaposi's sarcoma in the acquired immune deficiency syn­ drome. Ophthalmology, in press. 42. Lowder, C. Y., Meisler, D. M., McMahon, J. T., Longworth, D. L., and Rutherford, I.: Microsporidia infection of the cornea in a man seropositive for human immunodeficiency virus. Am. J. Ophthalmol. 109:242, 1990. 43. Friedberg, D. N., Stenson, S. M., Orenstein, J. M., Tierno, P. M., and Charles, N. C : Microsporidial keratoconjunctivitis in acquired immunodeficien­ cy syndrome. Arch. Ophthalmol. 108:504, 1990. 44. Jacobson, M. A., O'Donnell, J. J., Brodie, H. R., Wofsy, C , and Mills, J.: Randomized prospec­ tive trial of ganciclovir maintenance therapy for cytomegalovirus retinitis. J. Med. Virol. 25:339, 1988. 45. Jabs, D. A., Enger, C , and Bartlett, J. G.: Cyto­ megalovirus retinitis and acquired immunodeficien­ cy syndrome. Arch. Ophthalmol. 107:75, 1989. 46. Gross, J. G., Bozzette, S. A., Mathews, W. C , Spector, S. A., Abramson, I. S., McCutchan, J. A., Memdez, T., Munguia, D., and Freeman, W. R.; Lon­ gitudinal study of cytomegalovirus retinitis in ac­ quired immune deficiency syndrome. Ophthalmolo­ gy 97:681, 1990. 47. Jacobson, M. A., O'Donnell, J. J., and Mills, J.: Foscarnet treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syn­ drome. Antimicrob. Agents Chemother. 33:736, 1989. 48. Palestine, A. G., Polis, M. A., de Smet, M. D., Baird, B. F., Falloon, J., Kovacs, J. A., Davey, R. T., Zurlo, J. J., Zunich, K. M., Davis, M., Hubbard, L., Brothers, R., Ferris, F. L. Ill, Chew, E., Davis, J. L., Rubin, B. I., Mellow, S. D., Metcalf, J. A., Manischewitz, J., Minor, J. R., Nussenblatt, R. B., Masur, H., and Lane, H. C : A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann. Intern. Med. 115:665, 1991. 49. Felsenstein, D., D'Amico, D. J., Hirsch, M. S., Neumeyer, D. A., Cederberg, D. M., de Miranda, P., and Schooley, R. T.: Treatment of cytomegalovi­ rus retinitis with 9-[2-hydroxy-l-(hydroxymethyl) ethoxymethyljguanine. Ann. Intern. Med. 103:377, 1985. 50. Palestine, A. G., Stevens, G., Lane, H. C , Masur, H., Fujikawa, L. S., Nussenblatt, R. B., Rook, A. H., Manischewitz, A. S., Baird, B., Megill, M., Quinnan, G., Gelmann, E., and Fauci, A. S.: Treat­ ment of cytomegalovirus retinitis with dihydroxy propoxymethyl guanine. Am. J. Ophthalmol. 101:95, 1986. 51. Holland, G. N., Sidikaro, Y., Kreiger, A. E., Hardy, D., Sakamoto, M. J., Frenkel, L. M., Winston, D. J., Gottlieb, M. S., Bryson, Y. J., Champlin, R. E., Ho, W. G., Winters, R. E., Wolfe, P. R., and Cherry, J. D.: Treatment of cytomegalovirus retinopathy with ganciclovir. Ophthalmology 94:815, 1987. 52. Jabs, D. A., Newman, C , De Bustros, S., and

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Polk, B. F.: Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 94:824, 1987. 53. Orellana, J., Teich, S. A., Friedman, A. H., Lerebours, F., Winterkorn, J., and Mildvan, D.: Com­ bined short- and long-term therapy for the treatment of cytomegalovirus retinitis using ganciclovir (BW B759U). Ophthalmology 94:831, 1987. 54. Holland, G. N., Buhles, W. C , Mastre, B., Kap­ lan, H. J., and the UCLA Cytomegalovirus Retinopathy Study Group: A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. Arch. Ophthalmol. 107:1759, 1989. 55. Studies of Ocular Complications of AIDS (SOCA) Research Group in collaboration with the AIDS Clinical Trials Group (ACTG): Studies of ocular complications of AIDS foscarnet-ganciclovir cyto­ megalovirus retinitis trial. 1. Rationale, design, and methods. Controlled Clin. Trials 13:22,1992. 56. Studies of Ocular Complications of AIDS (SOCA) Research Group in collaboration with the AIDS Clinical Trials Group (ACTG): Mortality in patients with the acquired immunodeficiency syn­ drome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. N. Engl. J. Med. 326:213, 1992. 57. Heinemann, M.-H.: Long-term intravitreal ganciclovir therapy for cytomegalovirus retinopathy. Arch. Ophthalmol. 107:1767, 1989. 58. Cochereau-Massin, I., LeHoang, P., LautierFrau, M., Zazoun, L., Marcel, P., Robinet, M., Mat­ heron, S., Katlama, C , Gharakhanian, S., Rozenbaum, W., Ingrand, D., and Gentilini, M.: Efficacy and tolerance of intravitreal ganciclovir in cytomega­ lovirus retinitis in acquired immune deficiency syn­ drome. Ophthalmology 98:1348, 1991. 59. Hardy, W. D.: Combined ganciclovir and granulocyte-macrophage colony-stimulating factor in the treatment of cytomegalovirus retinitis in AIDS pa­ tients. Rationale for and preliminary results from a phase II randomized trial (ACTG 073). In Spector, S. A. (ed.): Ganciclovir Therapy for Cytomegalovirus Infection. New York, Marcel Dekker, Inc., 1991, pp. 197-213. 60. Erice, A., Chou, S., and Biron, K. K.: Progres­ sive disease due to ganciclovir-resistant cytomegalo­ virus in immunocompromised patients. N. Engl. J. Med. 320:289, 1989. 61. Jordan, M. C , and Biron, K. K.: Cytomegalovi­ rus resistance to ganciclovir. In Spector, S. A. (ed.): Ganciclovir Therapy for Cytomegalovirus Infection. New York, Marcel Dekker, Inc., 1991, pp. 185-196. 62. Sidikaro, Y., Silver, L., Holland, G. N., and Kreiger, A. E.: Rhegmatogenous retinal detachments in patients with AIDS and necrotizing retinal infec­ tions. Ophthalmology 98:129, 1991.

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Acquired immunodeficiency syndrome and ophthalmology: the first decade.

PERSPECTIVES Acquired Immunodeficiency Syndrome and Ophthalmology: The First Decade Gary N. H o l l a n d , M.D. developing countries. It is feared th...
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