Low- and Very Low-Dose Bevacizumab for Retinopathy of Prematurity: Reactivations, Additional Treatments, and 12-Month Outcomes

Abstract

Purpose: Low-dose and very low-dose intravitreal bevacizumab (IVB) have been reported to be successful in short-term treatment of type 1 retinopathy of prematurity (ROP), down to an initial dose of 0.004 mg. We now report 12-month outcomes for these infants.

Design: Masked, multicenter, dose de-escalation study.

Participants: One hundred twenty prematurely born infants with type 1 ROP.

Methods: A cohort of 120 infants with type 1 ROP in at least 1 eye from 2 sequential dose de-escalation studies of low-dose IVB (0.25 mg, 0.125 mg, 0.063 mg, and 0.031 mg) or very low-dose IVB (0.016 mg, 0.008 mg, 0.004 mg, and 0.002 mg) to the study eye; the fellow eye (if also type 1) received 1 dose level higher of IVB. After primary success or failure at 4 weeks, clinical management was at investigator discretion, including all additional treatment.

Main outcome measures: Reactivation of severe ROP by 6 months corrected age, additional treatments, retinal and other ocular structural outcomes, and refractive error at 12 months corrected age.

Results: Sixty-two of 113 study eyes (55%) and 55 of 98 fellow eyes (56%) received additional treatment. Of the study eyes, 31 (27%) received additional ROP treatment, and 31 (27%) received prophylactic laser therapy for persistent avascular retina. No trend toward a higher risk of additional ROP treatment related to initial IVB doses was found. However, time to reactivation among study eyes was shorter in eyes that received very low-dose IVB (mean, 76.4 days) than in those that received low-dose IVB (mean, 85.7 days). At 12 months, poor retinal outcomes and anterior segment abnormalities both were uncommon (3% and 5%, respectively), optic atrophy was noted in 10%, median refraction was mildly myopic (-0.31 diopter), and strabismus was present in 29% of infants.

Conclusions: Retinal structural outcomes were very good after low- and very low-dose IVB as initial treatment for type 1 ROP, although many eyes received additional treatment. The rate of reactivation of severe ROP was not associated with dose; however, a post hoc data-driven analysis suggested that reactivation was sooner with very low doses.

Keywords: Bevacizumab; Pediatric ophthalmology; Retinopathy of prematurity.

Figure 1:. Dose vs Days Until Additional Treatment for Treatment Failure or Reactivation.

Figure includes both study and fellow eyes requiring additional treatment, and shows the first additional treatment for each eye. Initial treatment failure = never improved. Initial improvement then reactivation = improved but reactivated by or after 4 weeks; this includes both early and late reactivation.

Figure 2:. Probability of No Reactivation Over Time Following Initial Injection.

The restricted mean time to reactivation among study eyes with reactivation within 91 days was compared between the very-low dose (0.002, 0.004, 0.008, and 0.016 mg) and low dose (0.031, 0.063, 0.125, and 0.250 mg) groups using a time-to-event analysis, where reactivation was considered the event. Data of eyes treated for persistent avascular retina or treatment failure were censored at the time of treatment. Average time to reactivation was 76.4 days in the very-low dose group and 85.7 days in the low dose group based on this analysis.

Figure 3:. Spherical Equivalent (SE) at 12 Months vs Post-menstrual Age (PMA) by Primary Indication for Laser.

Figure shows first laser treatment for each eye (study and fellow), excluding two phakic eyes. The relationship between eye-level SE cycloplegic refractive error at 12 months and post-menstrual age (PMA) at the time of the first laser treatment in the eye (if applicable) was evaluated using a linear mixed model adjusted for the correlation between eyes as well as the zone (i.e., specific location in the eye) at the time of laser treatment. P-value for the association between refractive error and PMA was p=0.38. Additionally, a logistic regression model adjusted for the correlation between eyes and the zone at the time of laser treatment, was used to test for the association between high myopia (refractive error ≤ -5.0D) and PMA at the time of the first laser treatment in the eye, if applicable. P-value for the association between high myopia (Refractive error ≤ -5.0D) and PMA was p=0.09.