Epidemiology
As of December 2004, the Joint United Nations Programme on HIV/AIDS (UNAIDS; Geneva, Switzerland) and the World Health Organization (WHO; Geneva, Switzerland) estimated that 39.4 million people are living with HIV worldwide, with a prevalence of approximately 1% among people aged 15 to 49 years (Table 1). This statistic includes 4.9 million who acquired the virus in 2004, with 3.1 million deaths due to AIDS in the past year.1 Since the first case was identified in 1981, more than 20 million individuals have succumbed to AIDS, which is now the fourth leading cause of death worldwide. The number of HIV-infected people has been rising in every region of the world, with the most pronounced increases seen in East Asia, Eastern Europe, and Central Asia. Sub-Saharan Africa remains the most severely affected region, where 65% of all people living with HIV/AIDS worldwide suffer, including 76% of all women with this disease.2 The mirage of currently stable HIV prevalence rates in sub-Saharan Africa disguises the reality of very high infection rates and more or less equivalent mortality rates. Finally, AIDS orphaned an estimated 12 million children in this region by the end of 2003.1
HAART
The introduction of highly active antiretroviral therapy (HAART) in 1996 has significantly changed the face of the AIDS epidemic in the industrialized world, with dramatic reductions in the incidence of HIV-related morbidity and mortality and thus an increased prevalence of patients alive with HIV/AIDS.3 HAART consists of a combination of antiretroviral therapy, typically with three or more drugs, and includes either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or a triple-nucleoside reverse transcriptase inhibitor combination. The WHO currently recommends first-line therapy with two-nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor. By suppressing HIV replication for sustained periods of time, HAART promotes the restoration of immune function (immune recovery) and immunity to specific pathogens, resulting in a reduction in the incidence and prevalence of both systemic and ocular opportunistic infections, including cytomegalovirus (CMV) retinitis (Figure 1) and other ocular complications of HIV/AIDS.4 Moreover, HAART has provided a beacon of hope for patients and caregivers alike, transforming an otherwise uniformly fatal disease into a potentially treatable chronic condition.
On the other hand, the situation in the developing world has, until very recently, been bleak. The vast majority of patients go untreated, with those surviving long enough to develop ocular complications of HIV/AIDS living their brief remaining time on earth in utter darkness. In September 2003, the WHO declared the lack of access to HAART a global-health emergency and announced the so-called “3 by 5” initiative, an unprecedented call to action to ensure that by the end of 2005, at least 3 million people in need of HAART in the developing would have access to it.5 Despite the recent availability of additional funding to help resource-constrained countries scale up their HIV treatment and prevention activities—including initiatives sponsored by the Global Fund to Fight AIDS, Tuberculosis and Malaria; the US President's Emergency Plan for AIDS Relief; the World Bank's Multi-Country AIDS Programme; the Department of International Development in the United Kingdom; and private sources such as the William J. Clinton Foundation and the Bill and Melinda Gates Foundation—globally, only 15% of the estimated 6.5 million people who need treatment were receiving it in June 2005.6
Ocular Complications
Most of the ocular complications of HIV/AIDS mentioned in the medical literature focuses on those observed among patients in the industrialized world, despite the fact that the vast majority (95%) of the world's afflicted population lives in poor countries. The few prevalence studies available from developing nations suggest that HIV/AIDS and associated ocular complications manifest differently compared with the industrialized world, including higher mortality rates earlier in the course of the disease and a different spectrum and prevalence of both systemic and ocular opportunistic infections.7 The reasons for these differences are multifactorial and relate partially to variations in the prevalence of various opportunistic infections in different areas of the world. In sub-Saharan Africa, for example, the burden of HIV infection occurs early in the course of the disease, with many patients dying of systemic infections due to tuberculosis, Salmonella sepsis, and cerebral toxoplasmosis before clinical AIDS develops. In industrialized countries, however, patients with HIV remain relatively healthy until the onset of clinical AIDS, when systemic opportunistic infections such as Pneumocystis carinii, Mycobacterium avium complex, and CMV are the leading causes of death.8
Although a broad range of ocular complications due to HIV infection may occur, with the majority of patients being affected at some time during the course of the disease, CMV retinitis is by far the most important, because it has the potential to produce bilateral blindness. In the pre-HAART era, an estimated 30% of patients with AIDS developed CMV retinitis sometime during their lifetime.9 The availability of HAART in the industrialized world has resulted in a 75% annual decline in new cases of CMV retinitis,3,10 although this decrease appears to have stabilized and new cases of CMV retinitis continue to occur.11 In the developing world, where HAART is just now becoming available, the risk of CMV retinitis is similar, although its prevalence is less than that reported in the pre-HAART era in the US.12 Sub-Saharan Africa is a notable outlier, with significantly lower prevalence rates that vary from 0 to 8.5%.13 It is likely that African patients die from other opportunistic infections before reaching levels of immunosuppression sufficient to place them at risk for the development of CMV retinitis. It has been suggested that the incidence and prevalence of CMV retinitis in Africa might actually rise with the introduction of antiretroviral therapy, particularly with the improper administration of less expensive one- or two-drug regimens, which would prolong survival but fail to reconstitute the immune system.7 Indeed, the incidence of CMV retinitis may rise in less-developed countries as HIV care improves with respect to opportunistic infection prophylaxis. However, HAART, if used properly, would be expected to decrease the incidence of all ocular complications, including CMV retinitis. Even with a reduced lifetime risk of the disease with HAART, the number of cases is likely to increase as the prevalence of AIDS climbs worldwide. If the incidence of CMV retinitis rises substantially, so will the burden of blindness. Based on conservative estimates of CMV prevalence worldwide, between 1 million and 2 million people are currently living with bilateral vision loss due to CMV retinitis.14 If other potentially blinding HIV-associated ocular complications are considered (such as the acute retinal necrosis syndrome and its variant, progressive outer retinal necrosis; ocular syphilis, ocular tuberculosis, cryptococcal meningitis, and ocular toxic or allergic drug reactions), for which little data are available from the developing world, this figure could be significantly higher.
Other important ocular complications observed among HIV/AIDS patients in the developing world include herpes zoster ophthalmicus (Figure 2), itself a marker for early HIV infection in young Africans;8,15 ocular toxoplasmosis, affecting up to 8.5% of HIV/AIDS patients in Brazil, where this organism is endemic;16 Kaposi's sarcoma of the ocular adnexae; and conjunctival neoplasias.17 Although Kaposi's sarcoma is less common in Africa, Brazil, and Asia compared with North America, due most likely to a lower prevalence of the etiological agent human herpes virus, 8,18 papilloma virus-associated conjunctival squamous cell tumors are more common and more aggressive in HIV-infected Africans.15 The aforementioned complications typically affect only one eye and so are not, by definition, “blinding,” but the potential for both patient suffering and substantial visual impairment are great.
Treatment, Prevention, and Surveillance
Generic and fixed drug combinations of first-line antiretroviral medications prequalified by the WHO are becoming available at a low cost and appear to be effective.19 However, the cost of second-line combinations with protease inhibitors is still prohibitive. The successful management of CMV retinitis requires not only HAART, but also appropriate anti-CMV medications and the expertise needed to use them. Given that CMV retinitis is independently associated with increased mortality irrespective of immunologic status, HIV viral load, or HAART,20 as well as the clear mortality benefit associated with systemic anti-CMV therapy,21 the administration of such medication is important and would ideally be systemic (in order to reduce the risk of fellow-eye and visceral CMV disease), inexpensive, logistically practical to deliver, and associated with low complication rates. Gancyclovir, foscarnet, and cidofovir (administered intraveneously) and/or the gancyclovir implant (Bausch & Lomb, Rochester, NY) (inserted surgically), although effective in treating CMV retinitis, are likely not to meet these criteria, given the prohibitive costs of treatment and infrastructural limitations inherent in the delivery of such care throughout most of the developing world at present. Valgancyclovir, an orally bioavailable prodrug of gancyclovir, may prove to be a viable alternative for systemic coverage if the cost of the medication can be reduced, especially in the light of the fact that systemic anti-CMV medications may be discontinued in certain patients on HAART who enjoy immune recovery.4 Finally, intravitreal therapy with anti-CMV agents may prove to be a relatively inexpensive treatment for CMV retinitis in a resource-poor setting, with cidofovir being an attractive choice given its prolonged duration of action and long-term stability in cold storage. Because intravitreal administration of this agent carries a high risk of uveitis and hypotony,21 further study may be warranted to evaluate whether patients would benefit from this approach if alternative anti-CMV therapies or HAART are not available. Likewise, a retrospective analysis of patients with CMV retinitis treated with HAART alone due to resource constraints may reveal situations in which anti-CMV therapy can be safely omitted.12
Again, the management of the ocular complications of HIV/AIDS in a cost-effective manner in a resource-poor environment is extraordinarily challenging and is by necessity linked to initiatives that successfully integrate treatment and prevention programs. Such an undertaking will require sustained funding for both sets of activities as well as rigorous monitoring and the surveillance of the impact of treatment, both with respect to clinical results, including the prospective study of the incidence and prevalence of ocular complications, and broader epidemiological consequences.22 Ultimately, the treatment of HIV/AIDS and its ocular complications will only be affordable and sustainable with effective HIV prevention and a sustained global response with the willingness and ability of individuals and nations to acknowledge their moral obligation to take ownership of this uniquely challenging crisis, one which is both a global emergency and a long-term development problem.
Albert T. Vitale, MD, is Associate Professor, Chief of the Uveitis Service, and a member of the Vitreoretinal Division at the Department of Ophthalmology and Visual Sciences of the John A. Moran Eye Center, University of Utah Health Sciences Center, in Salt Lake City. He is a consultant with Bausch & Lomb, but states that he holds no financial interest in any product or technology mentioned herein. Dr. Vitale may be reached at (801) 581-2352; albert.vitale@hsc.utah.edu.
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