Continuous High-Dose (6 mg) vs. Low-Dose (3 mg) Intravitreal Ganciclovir for Cytomegalovirus Retinitis After Haploidentical Hematopoietic Stem Cell Transplantation: A Randomized Controlled Study.

Wei-Bin Chen,Ming-wei Zhao,Ze Long,Heng Miao,Jing Hou

doi:10.3389/fmed.2021.750760

Wei-Bin Chen, Ming-wei Zhao + Show 3 more

Open Access

https://doi.org/10.3389/fmed.2021.750760

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Abstract

Purpose: To evaluate the safety and efficacy of continuous high-dose (6 mg) intravitreal ganciclovir injections (IVG) for cytomegalovirus (CMV) retinitis (CMVR) after haploidentical hematopoietic stem cell transplantation (Haplo-HSCT), and to explore factors that may influence the treatment procedure.Design: Prospective, randomized, single-blinded, positive-controlled, interventional, comparative study.Methods: A total of 22 patients with CMVR (32 eyes) were randomized to either high-dose group (IVG 6 mg weekly) or low-dose group (IVG 3 mg given twice weekly for 2 weeks as induction phase and weekly thereafter as maintenance phase). Patients who were recorded any positive CMV DNAemia or other active CMV diseases and needed systemic anti-CMV treatment during the study period were excluded. The vision outcome, variables of the treatment procedure, and incidence of complication and CMVR recurrence were analyzed and compared. Logistic regression was applied to determine the factors that may have an impact on the treatment process at baseline.Results: Compared to the low-dose group, the high-dose group resulted in a median of two less intravitreal injections (4 vs. 6 times, respectively, P = 0.016), while the rate of vision stability or improvement (81.2 vs. 87.5%), the incidence of complication (6.2 vs. 18.8%), and CMVR recurrence (12.5% vs. 6.2%) were similar (all P > 0.05). No drug-related toxicity was observed. Initial aqueous CMV-DNA load (OR: 6.872, 95% CI: 1.335–35.377, P = 0.021) and extension of lesion (OR: 0.942, 95% CI: 0.897 to .991, P = 0.020), but not dosing regimen (P = 0.162), were predictors of the treatment duration.Conclusions: Continuous high-dose regimen was well tolerated and resulted in less intravitreal injections, with similar vision outcomes and safety profiles. The clinical course of CMVR after Haplo-HSCT was determined by its own nature at baseline and could not be modified by treatment protocols under consistent immune background.

Highlights

Haploidentical hematopoietic stem cell transplantation (HaploHSCT) expanded the selection range of donors but T-cell repletion and depletion approach around the procedure and subsequent immunomodulatory therapy altogether increased the risk of cytomegalovirus (CMV) disease after Haplo-HSCT [1]
Compared to the low-dose group, the high-dose group resulted in a median of two less intravitreal injections (4 vs. 6 times, respectively, P = 0.016), while the rate of vision stability or improvement (81.2 vs. 87.5%), the incidence of complication (6.2 vs. 18.8%), and cytomegalovirus retinitis (CMVR) recurrence (12.5% vs. 6.2%) were similar
Initial aqueous CMV-DNA load (OR: 6.872, 95% CI: 1.335–35.377, P = 0.021) and extension of lesion (OR: 0.942, 95% CI: 0.897 to .991, P = 0.020), but not dosing regimen (P = 0.162), were predictors of the treatment duration

Summary

Introduction

Haploidentical hematopoietic stem cell transplantation (HaploHSCT) expanded the selection range of donors but T-cell repletion and depletion approach around the procedure and subsequent immunomodulatory therapy altogether increased the risk of cytomegalovirus (CMV) disease after Haplo-HSCT [1]. We had preliminarily established a treatment protocol for patients with CMVR after Haplo-HSCT [3,4,5]. By continuously monitoring aqueous CMV-DNA load and interleukin-8 (IL-8) as biomarkers, the median number of the intravitreal injections of ganciclovir (IVG) was lowered by 2 times, and was proved to be safe and efficient [4]. In these studies, 3 mg ganciclovir was used for each injection and the protocol requires an induction phase with an IVG twice a week, followed by a maintenance phase during which injections were given weekly (low-dose protocol). Considering the fact that increasing the total drug exposure (measured as average concentration area under the curve [AUC0−24]) improved the efficacy of ganciclovir for the maintenance treatment of CMVR, it is rational to extrapolate that continuous higher dose of IVG would be associated with increased efficacy and reduced the number of injections

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