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Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroviral therapy (HAART)
PUBLIC HEALTH
Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroiiral therapy (HAART) Philip Roels, O.D.
VA Medical Center. Kansas City. Missouri
Background:Highly active anti-retroviral therapy (HAART)effectively restores the immune system and lowers the viral load in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Since widespread use of HAART drugs began in 1996, many AlDS patients are living longer and enjoying a higher quality of life. The incidence of AIDS-related ophthalmic infections, such as cytomegalovirus (CMV) retinitis, have declined sharply. AlDS patients with CMV are less likely to experience necrotizing retinitis and retinal detachment, once the major causes of vision loss. HAART and immune recovery is now considered the preferred treatment for CMV retinitis. The role of immune recovery vitritis (IRV), a new manifestation of CMV retinitis, is now understood. In patients with pre-existing CMV retinitis who begin HAART the manifestations of an active immune system are seen, as the body is now able to fight the CMV infection. Incidence of Kaposi's sarcoma has declined by an estimated 87% and molluscum contagiosum is seen less frequently in those using HAART. With the clinical picture of ocular AlDS changing, the role of optometry in the management of AlDS patients is also changing. Key Words: AIDS, CMV retinitis, cytomegalovirus, HAART, highly active anti-retroviral therapy
Roels P. Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroviral therapy (HAART). Optometry 2004:75:624-8. 624 OPTOMETRY
The influence of HAART on systemic AlDS Our understanding of acquired immunodeficiency syndrome (AIDS)and the associated ocular manifestations has been dynamic. Since the emergence of AIDS and accompanying opportunistic infections as threats to vision and life in the 19801s,the ongoing development and improvement of available treatments has continuously changed our per~pective.~ The advent of highly active anti-retroviral therapy (HAART) is changing the world of ophthalmic AIDS again. HAART has clearly been effective at reducing morbidity and mortality of the systemic manifestations of AIDS? HAART has also caused a significant decline in the incidence of ocular manife~tations.~ However, related to these new treatments, some new threats have emerged.4Understanding the effects of HAART on the systemic and ocular manifestations of AIDS may lead to revision of our examination strategies. HAART (previously referred to as the AIDS cocktail) was introduced in 1995 with FDA approval of the first protease i n h i b i t ~ rHAART .~ effectively lowers the copies of the HIV virus and allows the body to repopulate CD4+ T-lympho~ y t e sTreatment .~ is individualized and patients use many combinations of the therapy (see Box);the most commonly used combination consists of two reverse transcriptase inhibitors and one protease i n h i b i t ~ r . ~ Treatment is typically initiated when plasma HIV ribonucleic acid (RNA)levels reach 55,000 copieslml, or when the CD4 + count (cells/microL)drops below 350.'f8The decision to use HAART preventatively must be weighed against drug toxicity and the risk of side effects. Approximately 24% of patients who initiate HAART will need to change a medication because of adverse effects, the most common of V O L U M E 7 5 f N U M B E R 1 O/OCTOBER 2 0 0 4
P U B L I C HEALTH
which are nausea, vomiting, and diarrhea.gJO
AlDS Deaths By Year (United States)
It is important to understand the effect of these new treatments on AIDS as a systemic disease. When successful, HAART leads to repopulation of the immune system, which has led to marked reductions in the incidence of the three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) .2 Palella et a1.2 analyzed 1,255 1980 1985 1990 1995 2000 AIDS vatients with at least one C D +&count ~ below 100 (cellslpL) AlDS deaths by year (United States) from 1994 to 1997 and found that the three major opportunistically better visual outcomes for many patients tic infections declined from 21.9 per 100 personwith CMV retinitis.16 Unfortunately, for many years in 1994, to 3.7 per 100 person-years by others, CMV was still associated with significant mid-1997. Furthermore, among this population of visual morbidity.l4 AIDS patients, the mortality rate declined from 29.4 per 100 person-years in 1995, to 8.8 per 100 person-years in 1997.2 In the United States, the Successful HAART has been a major step forward total number of AIDS deaths peaked in 1995 (see in the treatment of CMV retinitis. With HAART, Figure) before declining rapidly. The United States the incidence of CMV has been markedly Centers for Disease Control (CDC)estimates that reduced because fewer patients have CD4 counts the total number of deaths for those with AIDS below 100, the level of significant risk for active declined from 50,876 in 1995, to 16,371 deaths CMV.17 Reporting on a large CDC-sponsored in 2002.11 As these numbers indicate, HAART's study of AIDS patients, Jones et a1.18 noted a introduction in 1995 has had a dramatic effect on decline in new CMV cases, from 66.2 per 1,000 mortality rates for those with AIDS. patient years in 1992, to 17.4 per 1,000 patient years in 1997. This large decline is due to repopThe influence of HAART on ophthalmic maniistaiions of AlDS ulation of the immune system (higher numbers of CD4 lymphocytes) that comes with HAART.19 Cytomegalovirus (CMV) is the most common This increased immunity has also improved the opportunistic ocular infection seen in AIDS. CMV outlook for those with pre-existing CMV retiniis a common virus, but does not lead to symptoms tis. Holbrook et al.14 examined the results of three in those with healthy immune systems. In the clinical trials conducted by the Studies of Ocular HIV-positive population, exposure to CMV has Complications of AIDS (SOCA)Research Group been estimated at 90%;12this immune-comproto evaluate the nature of CMV and visual loss. mised population is at risk for active CMV infecThey found anti-retroviral therapy to be assocition. Until 1996, CMV was thought to cause end ated with a 30% reduction in the risk of visual organ disease in 21% to 44% of patients with acuity loss. AIDS.12,13Before effective treatment, CMV was associated with devastating visual loss from retiPatients treated with HAART often experience nal necrosis and retinal detachment, as well as sigsuccessful immune recovery. For those with CMV, nificant m ~ r t a l i t y . ' ~ , ~ ~ immune recovery has been so successful that many specialists have suggested that anti-CMV Specific anti-CMV treatments are ganciclovir, valtherapy may be discontinued in most situation^.^^ ganciclovir, foscarnet, cidofovir, and fomivirsen. In general, ganciclovir and foscarnet maintenance Some of these drugs were available before therapy may be safely discontinued in patients HAART and their antiviral activity led to statis-
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who have responded to HAART with CD4 cell counts rising above 100 (cells1pL)for more than 3 to 6 m ~ n t h s .In ~ fact, ~ , ~ the ~ development of CMV retinitis in a patient taking HAART for more than 3 months should be considered a treatment failure, and further optimization of anti-retroviral treatment should be attempted.20~21 Despite fewer patients experiencing CMV necrotizing retinitis, the immune recovery associated with HAART has caused CMV-related vitritis to emerge as a new threat to vision. Karavellas et aLZ2 provide insight into this new clinical entity known as immune recovery vitritis (IRV),or immune recovery uveitis (IRU). Significant vitritis is not usually a manifestation of CMV retinitis because the inept immune system cannot produce enough white blood cells. With successful HAART and immune recovery, white blood cells are now responding to pre-existing CMV infection with a vitritis. This phenomenon is now frequent in patients with CMV retinitis who initiate HAART. Karavellas et reported on 30 patients with CMV retinitis and successful HAART, and found that an immune recovery vitritis developed in 26 of 44 eyes (59%).All affected patients reported floaters, and almost all had decreased visual acuity. Some have speculated that vitritis may be a consequence of cidofovir therapy, an anti-retroviral drug known to cause inflammation; however, the investigators found IRV to be unrelated to previous cidofovir therapy.22 IRV is only present when the immune system reacts to infection; it is not present in HAART patients who have never had CMV retinitis. IRV may dramatically change the clinical situation in some patients. Instead of CMV necrotizing retinitis, Goldberg et al.4 report that inflammatory involvement is leading to more patients experiencing epiretinal membrane, vitreal haze, cystoid macular edema, and optic nerve head edema. Henderson et al.23reviewed charts of 80 patients with inactive CMV retinitis who initiated HAART treatment. In most of these patients, a mild transient vitritis developed that did not require treatment. IRV developed in only seven patients significantly enough to require treatment (based on declining visual acuity). The nine total eyes involved with significant IRV had a mean visual acuity loss of 2.8 Snellen lines. Orbital floor injections of 40-mg methylprednisolone acetate or 20-mg triamcinolone successfully returned 8 of the 9 eyes to within one
Non-nucleoside reverse transcriptase inhibitors Delavirdine (Rescriptor@) Efavirenz (SustivaB) Nevirapine (ViramuneB)
Nucleoside reverse transcriptase inhibitors Abacavir (ZiagenTM) Abacavir + Lamivudine + Zidovudine (Trizivid) Didanosine (Videxa) Emtricitabine (EmtrivaB) Lamivudine (Epivir@) Lamivudine + Zidovudine (Combivir@) Stavudine (Zerit@) Tenofovir (VireadB) Zalcitabine (Hivid@) Zidovudine (RetroviB)
Protease inhibitors Amprenavir (AgeneraseB) A tazanavir (Reyataz@) Fosamprenavir (Lexiva@) lndinavir (CrixivanB) Lopinavir + Ritonavir (Kaletra@) Nelfinavir (ViraceptB) Ritonavir (Norvir@) Saguinavir (Fortovase@, lnvirase@)
Fusion inhibitors Enfuvirtide (FuzeonTM)
Box line of their pre-inflammation Snellen acuity. Interestingly, 6 of the 7 patients were initially treated with topical dexamethasone q.i.d. for at least three weeks, which provided no benefit.23 Besides CMV, HAART has also lowered the incidence of AIDS-related cancers, especially Kaposi's sarcoma (KS) and non-Hodgkinfs lymphoma. Portsmouth et al.24reported on 1,204patients with KS in England. The incidence of KS decreased from 3011,000 patient-years in 1995 to 0.03/1,000 patient-years in 2001.24The study determined that both protease inhibitor- and reverse transcriptase inhibitor-based regimens were equally effective as protection against KS. Additionally, Clarkez5 reported declining incidence of Kaposi's sarcoma and non-Hodgkinfslymphoma among young men in San Francisco. Incidence declined by 87% in 1995 and 77% in 1998.25 Another manifestation of ophthalmic AIDS, molluscum contagiosum, is occurring at a decreased fre-
62 6 OPTOMETRY
V O L U M E 7 5 l N U M B E R 1 OIOCTOBER 2 0 0 4
PUBLIC HEALTH
quency in patients using HAART. Molluscum contagiosum, a cutaneous infection caused by a DNA virus belonging to the poxvirus group, was estimated to affect 5% to 10% of patients with HIV disease prior to HAART.26 In AIDS, the skin lesions are often extensive and severe, and are frequently unresponsive to therapy. No studies of incidence have been done in the HAART era, but Calista et al.27report on three patients with molluscum contagiosum who had cutaneous lesions that cleared 5 to 6 months after initiation of HAART.
quently-i.e., every 3 to 6 months. It is important to realize that HAART failures exist in which some patients do not experience immune recovery despite treatment. When treatment is successful, fewer of these individuals are likely to experience necrotizing retinitis and retinal detachment. However, even when HAART is successful, vitritis, epiretinal membrane, cystoid macular edema, and optic nerve head edema are now common because the viable immune system is able to react to CMV.
Interestingly, herpes zoster ophthalmicus might occur at a higher incidence in patients using HAART. Martinez et a1.28followed patients who began using a protease inhibitor as initial treatment, and those who added a protease inhibitor to existing retroviral treatment. During the median followup of 64 weeks, a first or recurrent episode of herpes zoster developed in 7%, suggesting herpes zoster may be a more frequent manifestation of AIDS for those using HAART,28 though an explanation is not postulated.
Effective new medical treatments have improved the length and quality of life for AIDS patients in the United States. Hopefully, these treatment advances will reach other parts of the world, including sub-Saharan Africa, where infection rates are highest.29Many of these countries do not yet benefit from HAART. Given the relatively recent advent of HAART, time and future studies will continue to shape our understanding and long-term examination strategy.
Optometry's management of patients with AIDS
References
For 20 years our knowledge of AIDS, its complications, and its treatments have continued to change. Recently, HAART has caused a substantial reduction in the incidence of AIDS-defining i l l n e s ~ e s . For ~ ~ 'the ~ ophthalmic community, this means decreased incidence of CMV retinitis and Kaposi's sarcoma. Effective treatment has also been shown to decrease the incidence of nonHodgkin's lymphoma and molluscum contagzosum, though it might increase the incidence of herpes zoster ophthalmicus. HAART has reduced the risk of cytomegalovirus, the primary ophthalmic threat from AIDS, to less than 5% of patients with AIDS.ls Most AIDS patients now have an improved visual outlook. It is time to reconsider the recommendation for frequent eye examinations for patients with AIDS who have healthy immune systems on HAART. After review of the literature, one could argue that AIDS patients using HAART, who do not have a pre-existing diagnosis of CMV retinitis, probably do not need eye examinations any more often than healthy patients without AIDS. Conversely, published evidence of IRV may lead us to follow the AIDS patient with pre-existing CMV retinitis who initiates HAART more freVOLUME 75lNUMBER lO/OCTOBER 2004
1. Dybul M, Fauci AS, Bartlett JG, et al. Panel on Clinical Practices for Treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002;137(5, Pt 2):381-433. 2. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient Study Investigators. N Engl J Med 1998; 338:853-60. 3. Jacobson MA, Stanley H, Holtzer C, et al. Natural history and outcome of new AIDS-related cytomegalovirus retinitis diagnosed in the era of highly active anti-retroviral therapy. Clin Infect Dis 2000;30:231-3. 4. Goldberg DE, Wang H, Azen SP, et al. Long-term visual outcome of patients with cytomegalovirus retinitis treated with highly active anti-retroviral therapy. Br J Ophthalmol2003;87:853-5. 5. Saquinavir (Invirase). Treatment Review, published by AIDS Treatment Data Network. 1996;Apr;(no.21):5. 6. Williams AB. New horizons: anti-retroviral therapy in 1997.JAssoc Nurses AIDS Care 1997;8:26-38. 7. Sandstrom E, Uhnoo I, Ahlqvist-Rastad J, et al. Swedish Consensus Group. Anti-retroviral treatment of human immunodeficiency virus infection: Swedish recommendations. Scand J Infect Dis 2003;35:155-67. 8. Ahdieh-Grant L, Yamashita TE, Phair JP, et al. When to initiate highly active anti-retroviral therapy: a cohort approach. Am J Epidemiol2003;157:738-46. 9. dlArminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active anti-retroviral therapy (HAART] regimen in a cohort of anti-retroviral naive patients. 1.CO.N.A. Study Group. Italian Cohort of Anti-retroviral-Naive Patients. AIDS 2000; 14:499-507. 627 OPTOMETRY
PUBLIC HEALTH 10. O'Brien ME, Clark RA, Besch CL, et al. Patterns and cor-
22. Karavellas MP, Plummer DJ, Macdonald JC, et al. Inci-
relates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003;34:407-14. 11. HIVIAIDS Surveillance Report. U.S. HIV and AIDS cases reported through December 2002. End of Year Edition, Vol. 14. Available from Centers for Disease Control and Prevention. 12. Bowen EF, Griffiths PD, Davey CC, et al. Lessons from the natural history of cytomegalovirus. AIDS 1996; lO(S~pp11):S37-41. 13. Jacobson MA. Treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. N Engl J Med 1997; 337:105-14. 14. Holbrook JT, Jabs DA, Weinberg DV, et al. Visual loss in patients with cytornegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active anti-retroviral therapy. Studies of Ocular Complications of AIDS (SOCA)Research Group. Arch Ophthalmol 2003;121:99-107. 15. Ballinger R. CMV retinitis. Optom Vis Sci 1995;72:305-9. 16. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Rial. 4. Visual outcomes. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Ophthalmology 1994; 101: 1250-61. 17. Cunningham ET Jr, Margolis TP. Ocular manifestations of HIV infection. N Engl J Med 1998;339:236-44. 18. Jones JL, Hanson DL, Dworkin MS, et al. Surveillance for AIDS-defining opportunistic illnesses, 1992-1997. MMWR CDC Surveil1Summ 1999:48(2):1-22. 19. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000;342:1416-29. 20. Vrabec TR, Baldassano VF,Whitcup SM. Discontinuation of maintenance therapy in patients with quiescent cytomegalovirusretinitis and elevated CD4+ counts. Ophthalmology 1998; 105: 1259-64. 21. Whitcup SM, Fortin E, Lindblad AS, et al. Discontinuation of anticytomegalovirustherapy in patients with HIV infection and cytomegalovirus retinitis. JAMA 1999;
dence of immune recovery vitritis in cytornegalovirus retinitis patients following institution of successful highly active anti-retroviral therapy. J Infect Dis 1999; 179:697700. 23. Henderson HW, Mitchell SM. Treatment of immune recovery vitritis with local steroids. Br J Ophthalmol 1999: 83:540-5. 24. Portsmouth S, Stebbing J, Gill J, et al. A comparison of
regimens based on non-nucleoside reverse transcriptase inhibitors or protease inhibitors in preventing Kaposi's sarcoma. AIDS 2003; 17(11):F17-22. 25. Clarke CA. Changing incidence of Kaposi's sarcoma and non-Hodgkin's lymphoma among young men in San Francisco. AIDS 2001;15:1913-5. 26. Gottlieb SL, Mycowski PL. Molluscum contagiosum. Int J Dermatol 1994;33:453-61. 27. Calista D, Boschini A, Landi G. Resolution of disseminated molluscum contagiosum with Highly Active AntiRetroviral Therapy (HAART)in patients with AIDS. Eur J Dermatol 1999;9(3):211-3. 28. Martinez E, Gatell J, Moran Y, et al. High incidence of herpes zoster in patients with AIDS soon after therapy with protease inhibitors. Clin Infect Dis 1998;27:1510-3. 29. UNFPA, the United Nations Population Fund. Preventing HIV Infection, Promoting Reproductive Health. Published as UNFPA Response 2002.
Corresponding author: Philip Roels, O.D. EyeNlCTORS Clinic (PC 1126) Kansas City VAMC 4801 Linwood Boulevard Kansas City, Missouri 64128
282: 1633-7.
OPTOMETRY
VOLUME 75lNUMBER 1OIOCTOBER 2004
Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroiiral therapy (HAART) Philip Roels, O.D.
VA Medical Center. Kansas City. Missouri
Background:Highly active anti-retroviral therapy (HAART)effectively restores the immune system and lowers the viral load in patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Since widespread use of HAART drugs began in 1996, many AlDS patients are living longer and enjoying a higher quality of life. The incidence of AIDS-related ophthalmic infections, such as cytomegalovirus (CMV) retinitis, have declined sharply. AlDS patients with CMV are less likely to experience necrotizing retinitis and retinal detachment, once the major causes of vision loss. HAART and immune recovery is now considered the preferred treatment for CMV retinitis. The role of immune recovery vitritis (IRV), a new manifestation of CMV retinitis, is now understood. In patients with pre-existing CMV retinitis who begin HAART the manifestations of an active immune system are seen, as the body is now able to fight the CMV infection. Incidence of Kaposi's sarcoma has declined by an estimated 87% and molluscum contagiosum is seen less frequently in those using HAART. With the clinical picture of ocular AlDS changing, the role of optometry in the management of AlDS patients is also changing. Key Words: AIDS, CMV retinitis, cytomegalovirus, HAART, highly active anti-retroviral therapy
Roels P. Ocular manifestations of AIDS: new considerations for patients using highly active anti-retroviral therapy (HAART). Optometry 2004:75:624-8. 624 OPTOMETRY
The influence of HAART on systemic AlDS Our understanding of acquired immunodeficiency syndrome (AIDS)and the associated ocular manifestations has been dynamic. Since the emergence of AIDS and accompanying opportunistic infections as threats to vision and life in the 19801s,the ongoing development and improvement of available treatments has continuously changed our per~pective.~ The advent of highly active anti-retroviral therapy (HAART) is changing the world of ophthalmic AIDS again. HAART has clearly been effective at reducing morbidity and mortality of the systemic manifestations of AIDS? HAART has also caused a significant decline in the incidence of ocular manife~tations.~ However, related to these new treatments, some new threats have emerged.4Understanding the effects of HAART on the systemic and ocular manifestations of AIDS may lead to revision of our examination strategies. HAART (previously referred to as the AIDS cocktail) was introduced in 1995 with FDA approval of the first protease i n h i b i t ~ rHAART .~ effectively lowers the copies of the HIV virus and allows the body to repopulate CD4+ T-lympho~ y t e sTreatment .~ is individualized and patients use many combinations of the therapy (see Box);the most commonly used combination consists of two reverse transcriptase inhibitors and one protease i n h i b i t ~ r . ~ Treatment is typically initiated when plasma HIV ribonucleic acid (RNA)levels reach 55,000 copieslml, or when the CD4 + count (cells/microL)drops below 350.'f8The decision to use HAART preventatively must be weighed against drug toxicity and the risk of side effects. Approximately 24% of patients who initiate HAART will need to change a medication because of adverse effects, the most common of V O L U M E 7 5 f N U M B E R 1 O/OCTOBER 2 0 0 4
P U B L I C HEALTH
which are nausea, vomiting, and diarrhea.gJO
AlDS Deaths By Year (United States)
It is important to understand the effect of these new treatments on AIDS as a systemic disease. When successful, HAART leads to repopulation of the immune system, which has led to marked reductions in the incidence of the three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) .2 Palella et a1.2 analyzed 1,255 1980 1985 1990 1995 2000 AIDS vatients with at least one C D +&count ~ below 100 (cellslpL) AlDS deaths by year (United States) from 1994 to 1997 and found that the three major opportunistically better visual outcomes for many patients tic infections declined from 21.9 per 100 personwith CMV retinitis.16 Unfortunately, for many years in 1994, to 3.7 per 100 person-years by others, CMV was still associated with significant mid-1997. Furthermore, among this population of visual morbidity.l4 AIDS patients, the mortality rate declined from 29.4 per 100 person-years in 1995, to 8.8 per 100 person-years in 1997.2 In the United States, the Successful HAART has been a major step forward total number of AIDS deaths peaked in 1995 (see in the treatment of CMV retinitis. With HAART, Figure) before declining rapidly. The United States the incidence of CMV has been markedly Centers for Disease Control (CDC)estimates that reduced because fewer patients have CD4 counts the total number of deaths for those with AIDS below 100, the level of significant risk for active declined from 50,876 in 1995, to 16,371 deaths CMV.17 Reporting on a large CDC-sponsored in 2002.11 As these numbers indicate, HAART's study of AIDS patients, Jones et a1.18 noted a introduction in 1995 has had a dramatic effect on decline in new CMV cases, from 66.2 per 1,000 mortality rates for those with AIDS. patient years in 1992, to 17.4 per 1,000 patient years in 1997. This large decline is due to repopThe influence of HAART on ophthalmic maniistaiions of AlDS ulation of the immune system (higher numbers of CD4 lymphocytes) that comes with HAART.19 Cytomegalovirus (CMV) is the most common This increased immunity has also improved the opportunistic ocular infection seen in AIDS. CMV outlook for those with pre-existing CMV retiniis a common virus, but does not lead to symptoms tis. Holbrook et al.14 examined the results of three in those with healthy immune systems. In the clinical trials conducted by the Studies of Ocular HIV-positive population, exposure to CMV has Complications of AIDS (SOCA)Research Group been estimated at 90%;12this immune-comproto evaluate the nature of CMV and visual loss. mised population is at risk for active CMV infecThey found anti-retroviral therapy to be assocition. Until 1996, CMV was thought to cause end ated with a 30% reduction in the risk of visual organ disease in 21% to 44% of patients with acuity loss. AIDS.12,13Before effective treatment, CMV was associated with devastating visual loss from retiPatients treated with HAART often experience nal necrosis and retinal detachment, as well as sigsuccessful immune recovery. For those with CMV, nificant m ~ r t a l i t y . ' ~ , ~ ~ immune recovery has been so successful that many specialists have suggested that anti-CMV Specific anti-CMV treatments are ganciclovir, valtherapy may be discontinued in most situation^.^^ ganciclovir, foscarnet, cidofovir, and fomivirsen. In general, ganciclovir and foscarnet maintenance Some of these drugs were available before therapy may be safely discontinued in patients HAART and their antiviral activity led to statis-
Fiuure
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VOLUME 7 5 l N U M B E R 10lOCTOBER 2004
OPTOMETRY
PUBLIC HEALTH
who have responded to HAART with CD4 cell counts rising above 100 (cells1pL)for more than 3 to 6 m ~ n t h s .In ~ fact, ~ , ~ the ~ development of CMV retinitis in a patient taking HAART for more than 3 months should be considered a treatment failure, and further optimization of anti-retroviral treatment should be attempted.20~21 Despite fewer patients experiencing CMV necrotizing retinitis, the immune recovery associated with HAART has caused CMV-related vitritis to emerge as a new threat to vision. Karavellas et aLZ2 provide insight into this new clinical entity known as immune recovery vitritis (IRV),or immune recovery uveitis (IRU). Significant vitritis is not usually a manifestation of CMV retinitis because the inept immune system cannot produce enough white blood cells. With successful HAART and immune recovery, white blood cells are now responding to pre-existing CMV infection with a vitritis. This phenomenon is now frequent in patients with CMV retinitis who initiate HAART. Karavellas et reported on 30 patients with CMV retinitis and successful HAART, and found that an immune recovery vitritis developed in 26 of 44 eyes (59%).All affected patients reported floaters, and almost all had decreased visual acuity. Some have speculated that vitritis may be a consequence of cidofovir therapy, an anti-retroviral drug known to cause inflammation; however, the investigators found IRV to be unrelated to previous cidofovir therapy.22 IRV is only present when the immune system reacts to infection; it is not present in HAART patients who have never had CMV retinitis. IRV may dramatically change the clinical situation in some patients. Instead of CMV necrotizing retinitis, Goldberg et al.4 report that inflammatory involvement is leading to more patients experiencing epiretinal membrane, vitreal haze, cystoid macular edema, and optic nerve head edema. Henderson et al.23reviewed charts of 80 patients with inactive CMV retinitis who initiated HAART treatment. In most of these patients, a mild transient vitritis developed that did not require treatment. IRV developed in only seven patients significantly enough to require treatment (based on declining visual acuity). The nine total eyes involved with significant IRV had a mean visual acuity loss of 2.8 Snellen lines. Orbital floor injections of 40-mg methylprednisolone acetate or 20-mg triamcinolone successfully returned 8 of the 9 eyes to within one
Non-nucleoside reverse transcriptase inhibitors Delavirdine (Rescriptor@) Efavirenz (SustivaB) Nevirapine (ViramuneB)
Nucleoside reverse transcriptase inhibitors Abacavir (ZiagenTM) Abacavir + Lamivudine + Zidovudine (Trizivid) Didanosine (Videxa) Emtricitabine (EmtrivaB) Lamivudine (Epivir@) Lamivudine + Zidovudine (Combivir@) Stavudine (Zerit@) Tenofovir (VireadB) Zalcitabine (Hivid@) Zidovudine (RetroviB)
Protease inhibitors Amprenavir (AgeneraseB) A tazanavir (Reyataz@) Fosamprenavir (Lexiva@) lndinavir (CrixivanB) Lopinavir + Ritonavir (Kaletra@) Nelfinavir (ViraceptB) Ritonavir (Norvir@) Saguinavir (Fortovase@, lnvirase@)
Fusion inhibitors Enfuvirtide (FuzeonTM)
Box line of their pre-inflammation Snellen acuity. Interestingly, 6 of the 7 patients were initially treated with topical dexamethasone q.i.d. for at least three weeks, which provided no benefit.23 Besides CMV, HAART has also lowered the incidence of AIDS-related cancers, especially Kaposi's sarcoma (KS) and non-Hodgkinfs lymphoma. Portsmouth et al.24reported on 1,204patients with KS in England. The incidence of KS decreased from 3011,000 patient-years in 1995 to 0.03/1,000 patient-years in 2001.24The study determined that both protease inhibitor- and reverse transcriptase inhibitor-based regimens were equally effective as protection against KS. Additionally, Clarkez5 reported declining incidence of Kaposi's sarcoma and non-Hodgkinfslymphoma among young men in San Francisco. Incidence declined by 87% in 1995 and 77% in 1998.25 Another manifestation of ophthalmic AIDS, molluscum contagiosum, is occurring at a decreased fre-
62 6 OPTOMETRY
V O L U M E 7 5 l N U M B E R 1 OIOCTOBER 2 0 0 4
PUBLIC HEALTH
quency in patients using HAART. Molluscum contagiosum, a cutaneous infection caused by a DNA virus belonging to the poxvirus group, was estimated to affect 5% to 10% of patients with HIV disease prior to HAART.26 In AIDS, the skin lesions are often extensive and severe, and are frequently unresponsive to therapy. No studies of incidence have been done in the HAART era, but Calista et al.27report on three patients with molluscum contagiosum who had cutaneous lesions that cleared 5 to 6 months after initiation of HAART.
quently-i.e., every 3 to 6 months. It is important to realize that HAART failures exist in which some patients do not experience immune recovery despite treatment. When treatment is successful, fewer of these individuals are likely to experience necrotizing retinitis and retinal detachment. However, even when HAART is successful, vitritis, epiretinal membrane, cystoid macular edema, and optic nerve head edema are now common because the viable immune system is able to react to CMV.
Interestingly, herpes zoster ophthalmicus might occur at a higher incidence in patients using HAART. Martinez et a1.28followed patients who began using a protease inhibitor as initial treatment, and those who added a protease inhibitor to existing retroviral treatment. During the median followup of 64 weeks, a first or recurrent episode of herpes zoster developed in 7%, suggesting herpes zoster may be a more frequent manifestation of AIDS for those using HAART,28 though an explanation is not postulated.
Effective new medical treatments have improved the length and quality of life for AIDS patients in the United States. Hopefully, these treatment advances will reach other parts of the world, including sub-Saharan Africa, where infection rates are highest.29Many of these countries do not yet benefit from HAART. Given the relatively recent advent of HAART, time and future studies will continue to shape our understanding and long-term examination strategy.
Optometry's management of patients with AIDS
References
For 20 years our knowledge of AIDS, its complications, and its treatments have continued to change. Recently, HAART has caused a substantial reduction in the incidence of AIDS-defining i l l n e s ~ e s . For ~ ~ 'the ~ ophthalmic community, this means decreased incidence of CMV retinitis and Kaposi's sarcoma. Effective treatment has also been shown to decrease the incidence of nonHodgkin's lymphoma and molluscum contagzosum, though it might increase the incidence of herpes zoster ophthalmicus. HAART has reduced the risk of cytomegalovirus, the primary ophthalmic threat from AIDS, to less than 5% of patients with AIDS.ls Most AIDS patients now have an improved visual outlook. It is time to reconsider the recommendation for frequent eye examinations for patients with AIDS who have healthy immune systems on HAART. After review of the literature, one could argue that AIDS patients using HAART, who do not have a pre-existing diagnosis of CMV retinitis, probably do not need eye examinations any more often than healthy patients without AIDS. Conversely, published evidence of IRV may lead us to follow the AIDS patient with pre-existing CMV retinitis who initiates HAART more freVOLUME 75lNUMBER lO/OCTOBER 2004
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Corresponding author: Philip Roels, O.D. EyeNlCTORS Clinic (PC 1126) Kansas City VAMC 4801 Linwood Boulevard Kansas City, Missouri 64128
282: 1633-7.
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