Retinal Physician

JAN-FEB 2017

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56 R E T I N A L P H Y S I C I A N . C O M | M A Y 2 0 1 3 56 R E T I N A L P H Y S I C I A N | J A N U A R Y / F E B R U A R Y 2 0 1 7 e development of the sustained-release implant (approved in 1996) that releases intraocular ganciclovir at 1 μg/hour for up to eight months obviated the need for weekly injections during the maintenance phase. In a randomized study, the implant extended the mean time to retinitis pro- gression to 221 days vs 76 days with intravenous ganciclo- vir therapy. 49 Although coupling the ganciclovir implant with oral ganciclovir therapy has shown great efficacy against progression of retinitis (Data from the Ganciclovir Cidofovir CMV Retinitis Trial (GCCRT), SOCA com- pleted in 2000), 26 it is no longer commercially available, due to the declining incidence of CMV retinitis and perhaps the favorable ease of use of oral valganciclovir. In develop- ing countries, intravitreal injections alone are still employed to evade the cost of sustained-release implants and systemic therapy 9 (Figures 1, 2 and 3). We should indicate, however, that local therapy alone is associated with a higher risk of retinitis to the fellow eye, extraocular CMV-related disease, and increased mortality. 49,50 THE ADVENT OF NEWER FORMULATIONS While currently approved medications have shown efficacy against CMV, systemic treatment has inherent side effects (usually dose-limiting neutropenia and nephrotoxicity). 9, 23 Drug-resistant mutants have also evolved against AIDS, complicated further with cross-resistance as viral DNA poly- merase is the target of all currently used systemic drugs. 10 Despite the need for safer more convenient therapy, rela- tively fewer research programs have focused on anti-CMV drug development post-HAART, with additional progress expected from studies on pre-emptive treatment for other susceptible groups like organ recipients. 9 Most of these com- pounds are in various stages of clinical development. Of these, cidofovir esters have shown improved oral bioavailability and better safety profiles with enhanced effi- cacy against CMV infections. 51,52 Others — maribavir, BAY 38-4766, and AIC246 — mostly inhibit viral activity through interference with pathways other than viral DNA poly- merase decreasing chances of cross-resistance with available agents. 53-55 ere are also reports regarding oral leflunomide's success with ganciclovir- and foscarnet resistant- CMV reti- nitis in a series of organ transplant recipient patients. 56, 57 TREATMENT CONSIDERATIONS In view of the role of immune recovery for control of AIDS- associated CMV retinitis, treatment entails combining HAART-induced immune system reconstitution with effec- tive anti-CMV therapy. Treatment should be individualized considering the size and location of the retinitis, potential for immune recovery, and treatment-related side effects. 10 In general, anti-CMV therapy should be maintained for at least six months until the retinitis is inactive, with CD4+ T cell counts greater than 100 cells/ μ L. 58, 59 Long-term monitoring for CMV reactivation is needed, although clear data on optimum follow-up schedules are lacking. e US DHHS recommends that patients with immune recovery to >100 cells/ μ L for at least three to six months have anti-CMV therapy discontinued, but many authors await more robust evidence before treatment cessation. 59, 60 Small peripheral lesions in HAART-naïve patients are often treated with systemic therapy alone, while combining both systemic with local therapy is perhaps the preferred treatment option for sight-threatening zone 1 disease, as intravitreal injections can quickly establish high intraocu- lar antiviral concentrations and prevent progression. A brief period of observation for retinitis progression before initia- tion of anti-CMV treatment would probably not cause long- term adverse outcomes in patients with small far peripheral lesions which occupy less than 25% of the retinal area. 24, 61 To suppress viral replication rapidly and minimize sys- temic complications, physicians induce therapy at high frequent doses for two to three weeks until the retinitis stabilizes (induction phase with one of these four systemic drugs: ganciclovir, foscavir, cidofovir, or oral valganciclovir) followed by a continuous lower-dose therapy (maintenance phase) to suppress viral replication. Comparative studies have shown varied side effect profiles but no significant differences between drug choices in terms of efficacy. 24, 26, 30, 35 While these drugs suppress CMV replication, they do not eliminate the virus from the eye. So, unless the patient has adequate reconstitution of the immune system functions, retinitis treatment may need to be continued indefinitely. REFERENCES 1. Gallant JE, Moore RD, Richman DD, Keruly J, Chaisson RE. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunode- ficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis. 1992;166:1223-1227. 2. Heiden D, Ford N, Wilson D, et al. Cytomegalovirus Retinitis: The Neglected Disease of the AIDS Pandemic. PLoS Med. 2007;4:e334. 3. Biron KK. Antiviral drugs for cytomegalovirus diseases. Antiviral Res. 2006;71:154- 163. 4. Rubin RH, Kemmerly SA, Conti D, et al. Prevention of primary cytomegalovirus disease in organ transplant recipients with oral ganciclovir or oral acyclovir prophy- laxis. Transpl Infect Dis. 2000;2:112-117. 5. Britt WJ, Mach M. Human cytomegalovirus glycoproteins. Intervirology. 1996;39:401-412. 6. Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalovirus retinitis after fluocinolone acetonide (Retisert) implant. Am J Ophthalmol. 2007;143:334-335. 7. Park YS, Byeon SH. Cytomegalovirus retinitis after intravitreous triamcinolone injection in a patient with central retinal vein occlusion. Korean J Ophthalmol. 2008;22:143-144. 8. Tugal-Tutkun I, Araz B, Cagatay A. CMV retinitis after intravitreal triamcinolone acetonide injection in a patient with Behçet's uveitis. Int Ophthalmol. 2010;30:591- 593. 9. Stewart MW. Optimal management of cytomegalovirus retinitis in patients with AIDS. Clin Ophthalmol. 2010;4:285-299. 10. Jabs DA. Cytomegalovirus retinitis and the acquired immunodeficiency syndrome—bench to bedside: LXVII Edward Jackson Memorial Lecture. Am J Ophthalmol. 2011;151:198-216. 11. Radwan A, Metzinger JL, Hinkle DM, Foster CS. Cytomegalovirus retinitis in immu- nocompetent patients: case reports and literature review. Ocul Immunol Inflamm. 2013;21:324-328. 12. Rafailidis PI, Mourtzoukou EG, Varbobitis IC, Falagas ME. Severe cytomegalovirus infection in apparently immunocompetent patients: a systematic review. Virol J. 2008;5:47. CMV RETINITIS: EVIDENCE-BASED TREATMENT

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