Retinal Physician

JAN-FEB 2017

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R E T I N A L P H Y S I C I A N | J U N E 2 0 1 3 55 with the conclusion of the Ganciclovir Cidofovir CMV Retinitis trial (GCCRT) using the ganciclovir implant for the newly diagnosed or relapsed CMV retinitis patient. 23-26 Since 1998, LSOCA, a prospective observational sub study, has been ongoing to monitor changes in trends in those with ocular complications with AIDS and the effects of long-term treatment on visual function, survival, and quality of life. 19,27 ANTIVIRAL THERAPIES IN AIDS-ASSOCIATED CMV RETINITIS Although CMV retinitis appears as an isolated infection, the disease is part of a systemic infection with implications for the fellow eye and other organs. 28, 29 So, patients usually receive systemic, with or without concurrent local, therapy. As of September 1996, the FDA had approved three drugs for the treatment of CMV retinitis: ganciclovir, fos- carnet, and cidofovir; all are selective viral DNA polymerase inhibitors, generally commenced at higher induction doses for two to three weeks, followed by lower maintenance doses to prevent relapse of the retinitis. In 1989, ganciclovir was the only drug approved for treat- ment of CMV retinitis in immunocompromised patients. 3 It was administered twice daily at 5mg/kg IV infusions. A few years later, as foscarnet became available for investigational use, a large randomized trial, the Foscarnet-Ganciclovir CMV Retinitis Trial, designed to compare both drugs in terms of relative efficacy and safety in patients with AIDS, 22 revealed no difference in terms of the rate of retinitis progres- sion. However, it was stopped early as foscarnet showed a survival advantage for patients in the pre-HAART era. 30, 31 With completion of the HPMPC trial in 1996, the effi- cacy of cidofovir, a nucleotide analogue with broad antiviral activity, was demonstrated in 64 newly diagnosed CMV reti- nitis patients randomized to treatment and deferral arms. 24 In 51 patients on HAART, the Spanish Cidofovir Study Group further highlighted the efficacy of compassionate use of cidofovir in patients with previously treated retinitis who had relapsed or were unresponsive to induction with other anti-CMV agents. 32 Although the numbers in those non-comparative trials were relatively small, cumulative data suggest its efficiency in delaying progression of CMV reti- nitis with a less intrusive administration regimen because of its prolonged intracellular half-life. 24, 32-34 Induction dosing consists of once weekly infusions for two weeks, followed by infusions every other week during maintenance; no need for daily dosage administration and indwelling catheters. Another useful addition came in 2000 with the intro- duction of valganciclovir, the L-valyl ester prodrug of gan- ciclovir, with high oral bioavailability (60%) and convenient once-daily dosing (900 mg once daily for 2 to 3 weeks result in serum ganciclovir levels comparable with those achieved with daily intravenous induction). 10, 35 Oral valganciclovir has shown to be equally efficacious in comparative studies with intravenous ganciclovir for induction and maintenance for CMV retinitis in patients with AIDS. A satisfactory response to induction therapy was achieved in 77% of patients assigned to intravenous ganciclovir and 72% assigned to oral valganciclovir in one study randomizing 80 patients to each treatment group. 35 e median time to progression of retinitis was 125 and 160 days, respectively. Compared with intravenous therapy, oral valganciclovir also equally prevents and treats non-ocular CMV disease 36, and has hence become a preferred treatment option for most experts who had previously had a rather limited arse- nal of drugs approved for CMV. A retrospective analysis of anti-CMV retinitis treatment in managed-care plans in the United States from 1997 to 2002 has shown that the use of oral valganciclovir has largely surpassed the use of intrave- nous formulations. 37 DO COMBINATIONS WORK BETTER? In vitro data suggest that combining anti-viral therapies is synergistic in inhibiting viral replication. 38, 39 In the SOCA- CMV Retinitis Retreatment Trial, the combination of intra- venous ganciclovir and foscarnet was more effective but more toxic than either drug alone for the treatment of persistently active or relapsed retinitis. 23 Continuation of previous main- tenance therapy plus induction with the other for 2 weeks followed by maintenance with both drugs was most effective in controlling CMV retinitis, but quality of life suffers greatly with the time required for the infusions. With the advent of new oral formulations or implants the armamentarium only grows wider but we should note, how- ever, that evidence in support of particular combinations and their dosing over others has been lacking. Albeit a convenient treatment option, not necessitating an indwelling venous catheter or an ocular surgical procedure, results of a phase I trial on the combination of intermittent intravenous cidofo- vir and daily oral ganciclovir for relapsed CMV retinitis in patients with AIDS have shown dose-limiting side effects and poor tolerance, which had heralded further consideration for less frequent dosing. 40 INTRAVITREAL THERAPY Over the past decades, intravitreal drug injections of the available anti-CMV drugs were given to patients intoler- ant to systemic therapy. 41-43 Now, patients commonly receive intravitreal injections to control sight-threatening retini- tis (zone 1 disease) or to help bridge to an alternative regi- men. 9,10 Retinitis stabilizes to induction with two to three injections a week, while once weekly injections usually suf- fice for maintenance. Like ganciclovir, several non-controlled series of patients experienced successful induction therapy with injections of foscarnet solution. 44-46 Cidofovir, because of concerns regarding ocular toxicities via intravitreal admin- istration, is no longer recommended. 47 A double-masked, randomized trial of three intravitreal doses was prematurely terminated due to high incidences of post-injection uveitis and hypotony (87% and 16%), sometimes with irreversible severe visual loss. 48 55 R E T I N A L P H Y S I C I A N . C O M | J A N U A R Y / F E B R U A R Y 2 0 1 7

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