Background To evaluate the safety and efficacy of intravitreal conbercept (IVC) injection in the treatment of retinopathy of prematurity (ROP).
Methods Patients with ROP who underwent IVC injection in Zhujiang Hospital from June 2015 to July 2016 were studied retrospectively. The primary outcome was defined as the regression of plus disease. The secondary outcomes were defined as the presence of recurrence, number of injections and the final regression of disease.
Results A total of 48 eyes of 24 patients with ROP were included. Among them, 9 eyes of 5 patients had zone I ROP, 35 eyes of 18 patients had zone II ROP and 4 eyes of 2 patients had aggressive posterior ROP. The mean gestational age was 28.5±1.6 weeks, the mean birth weight was 1209.6±228.6 g, the mean postmenstrual age of first injection was 34.2±1.9 weeks and the mean follow-up period was 31.0±4.7 weeks. Forty of 48 eyes (83.3%) received IVC only once, and the regression of plus disease occurred at an average of 3.5±1.5 weeks after the first injection of conbercept. For eight recurrent eyes (16.7%), four eyes received a second IVC and the remaining four eyes received laser photocoagulation, and the regression of plus disease occurred in 3 weeks. No lens opacity, vitreous haemorrhage, entophthalmia or retinal detachment was observed during follow-up.
Conclusion IVC injection is an effective treatment for ROP.
- retinopathy of prematurity (ROP)
- anti-VEGF agents
- intravitreal conbercept injection
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Retinopathy of prematurity (ROP) is a vasoproliferative retinal disease that occurs in premature infants with low birth weight (BW) and young gestational age (GA); ROP remains a main cause of worldwide childhood blindness due to the higher survival rate of low BW preterm infants.1–3 The major pathological change of ROP is neovascularisation of the retina, which leads to retinal detachment and severe visual defects in late stages.4 ROP is mainly initiated by hyperoxia-induced withdrawal of vascular endothelial growth factor (VEGF).5 According to the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity and Early Treatment for Retinopathy of Prematurity, cryotherapy and laser photocoagulation are recommended for the treatment of type 1 ROP.6 7 However, these treatments will cause permanent destruction of the peripheral retina and have unignorable deficiencies, such as visual field loss, subsequent high myopia and amblyopia, especially in cases of zone I ROP.8–10 Therefore, new approaches for ROP therapy to decrease the use of laser or cryotherapy are urgently needed.
Within recent years, intravitreal injection of anti-VEGF agents has proved to be an emerging and effective way for ROP treatment.11–13 Mintz-Hittner et al have reported that compared with conventional laser treatment, intravitreal injection of bevacizumab (IVB) showed a significant benefit for zone I but not patients with zone II ROP.10 Wu et al have shown that IVB was an effective method with few side effects for prethreshold ROP therapy.2
Conbercept, a novel anti-VEGF agent, has 50-fold higher binding affinity for VEGF than does bevacizumab and a long half-life in the vitreous; it blocks the VEGF-A and VEGF-B isoforms, thus exerting strong antiangiogenic effects.14–16 Moreover, conbercept was approved for treatment of neovascular age-related macular degeneration (AMD) by China Food and Drug Administration in December 2013.17 Previous reports have demonstrated that conbercept was effective and safe in neovascularisation diseases, such as diabetic retinopathy18 and AMD.15 However, the use of conbercept for ROP treatment has been rarely reported. Thus, this study aims to evaluate the effectiveness and safety of intravitreal conbercept (IVC) for patients with ROP.
This retrospective study was approved by the Ethics Committee of Zhujiang Hospital, Southern Medical University, and conducted by ophthalmology department and neonatal intensive care units. A consecutive series of patients with ROP who accepted IVC injection as primary treatment from June 2015 to July 2016 were collected. All cases were hospitalised for 2 weeks after every treatment and followed up for at least 6 months. Written informed consent was signed before examination and treatment by the parents or guardians of each infant.
The International Classification of Retinopathy of Prematurity 2005 was applied to determine the disorder zone and stage of each case.19 Type 1 ROP was defined as zone I, any stage ROP with plus disease; zone I, stage 3 without plus disease; zone II, stage 2 or 3 with plus disease. Type 2 ROP was defined as zone I, stage 1 or 2 without plus disease; or zone II, stage 3 without plus disease.1 7 20 Aggressive posterior ROP (AP-ROP) was designated rapidly progressing ROP, which is located in the posterior retina with prominent plus disease.19 All screening during the examination and follow-up period was conducted by two expert ophthalmologists (XK and SF) using binocular indirect ophthalmoscopy. Cases with any other ocular or systemic diseases that may result in retinopathy or retinal detachment were excluded.
Each patient received a dose of 0.25 mg/0.025 mL conbercept (Chengdu Kanghong Biotech) monotherapy bilaterally (half an adult dose). Then, conbercept was injected at 1.5 mm posterior to the limbus with a 30-gauge needle under topical anaesthesia. Topical tobramycin dexamethasone was applied for 3 days after the operation. All operations were done by the same doctor (SF). Corneal and lens clarity, the retinal artery and the optic nerve were assessed by indirect ophthalmoscopy and slit lamp after the operation.
The gender, GA, BW and primary injection age, anatomical outcomes, time of recurrence, secondary injection or laser photocoagulation and the final outcomes of each case were analysed. The follow-up time was once a week or 2 weeks until at least 6 months after the operation. The primary outcome was defined as the regression of plus disease. The secondary outcomes were defined as the presence of recurrence, number of injections and the final regression of disease. Positive anatomic outcomes were defined as the regression of ridge and plus disease, retinopathy zone degradation and normal retinal vascularisation.19 21 The reactivation of ROP was defined as the recurrence of ridge or plus disease.12 21 Second rejection or laser photocoagulation was applied for reactivation cases.
In total, 48 eyes of 24 patients (15 men and 9 women) with type 1 ROP or AP-ROP were enrolled in this study. The mean GA of these patients was 28.5±1.6 weeks (median, 28.4; range, 25.7–31.7 weeks), and the mean BW was 1209.6±228.6 g (median, 1200; range, 540–1610 g). There were 44 eyes of type 1 ROP (91.7%) and 4 eyes of AP-ROP (8.3%) in total, and all eyes had plus disease. The detailed zone and stage of ROP, sex, mean GA, mean BW and postmenstrual age (PMA) of the first IVC treatment and follow-up time are listed in table 1. The proportions of ROP type, mean GA and BW are listed in table 2.
All 24 patients accepted IVC as their primary treatment and were followed-up for at least 6 months (mean, 31.0±4.7 weeks; range, 26–42 weeks), as listed in table 3. The mean PMA of the first injection was 34.2±1.9 weeks (median, 34.1; range, 30–37.3 weeks) and the mean time from birth to the first injection was 5.8±1.4 weeks (median, 5.7; range, 3–7.9 weeks). Among these 48 eyes of 24 patients, 40 eyes (83.3%) showed a regression of ROP without reactivation during the whole follow-up period while 8 eyes (16.7%) showed recurrence of plus disease or ridge. For the eight eyes with reactivation, four eyes were treated with a second injection of conbercept, whereas laser photocoagulation was applied for the other four eyes, and the regression of the ridge appeared in 3 weeks for all eight eyes. All recurrences occurred in patients with zone II ROP. Recurrence time from initial injection to reactivation was 5 weeks for four eyes, 6 weeks for two eyes and 7 weeks for the other two eyes, respectively. The basic information, time of treatments and regression of plus disease of all 48 eyes are listed in table 3.
At the end of follow-up, all 48 eyes achieved regression of ROP. Twelve eyes (25%) exhibited full retinal vascularisation, while 32 eyes (66.7%) retain an avascular area in zone III, and four eyes (8.3%) had scarring in the retina in zone II (shown in table 3). No corneal and lens opacity, vitreous haemorrhage, entophthalmia, retinal detachment or other systematic side effects were observed during treatment and follow-up.
ROP remains a main cause of childhood blindness.2 3 At the end of the 20th century, cryotherapy was the recommended therapy for threshold ROP.6 In regard to the 21st century, conventional laser treatment has become the primary method for type 1 ROP and has attained better outcomes.7 In recent years, with the extensive study of anti-VEGF inhibitors, intravitreal injection of bevacizumab and ranibizumab has become an emerging and effective treatment for ROP.13 21 Conbercept has been clinically permitted in the treatment of neovascular ocular diseases, such as AMD and diabetic retinopathy,14 15 18 while reports and case studies regarding ROP treatment remain insufficient.
In this study, 24 patients with mean GA and BW of 28.5±1.6 weeks and 1209.6±228.6 g, respectively, were enrolled. Our inclusion criteria are broader than the screening guideline recommendations in the USA (GA <30 weeks, BW <1500 g) and UK (GA <32 weeks, BW <1500 g)1 22 because severe ROP occurs in more mature and larger infants in China.23 24 The mean PMA for the time of first IVC is 34.2±1.9 weeks and 5.8±1.4 weeks, which is in accordance with 36.6±3.2 PMA by Wu et al and 36.0±2.34 PMA by Huang et al in the study of bevacizumab and ranibizumab treatment for infants with ROP, respectively,25 but slightly earlier than the 38.47±2.72 weeks reported by Jin et al.26 We found that using an IVC injection once, as monotherapy, resulted in the regression of plus disease without recurrence in 83.7% (40/48) of eyes with type 1 ROP and AP-ROP. This result bore a resemblance to the recently reported regression rate of 85% by Jin et al.26 Similarly, the regression rates are 83.3% by the bevacizumab treatment and 79.5% by ranibizumab treatment, respectively.2 10 21
There were eight eyes (16.7%) with recurred plus disease or ridge at mean 5.6±0.5 weeks (range, 5–7 weeks) after the first rejection. Four of these eyes received a second injection of conbercept and the other four eyes received laser photocoagulation after considering family economic status. Plus disease all regressed within 1 week in eyes that received the second conbercept injection. Plus disease also regressed in eyes with applied laser treatment but was scarred in the peripheral retina. All the recurrent eyes had achieved complete regression of ROP at the end of the follow-up. We found that reactivation all occurred in zone Ⅱ with stage 3+ ROP but not zone I, or AP-ROP. This result was in accordance with the favourable outcome in the treatment of zone Ⅰ ROP, but not zone Ⅱ ROP by bevacizumab injection.10 Hence, conbercept injection monotherapy has better outcome for zone Ⅰ ROP and AP-ROP.
The recurrence rate is 16.7% (8/28) in our study. For IVB monotherapy, the data are approximately 4%–14%,2 10 21 27–29 and approximately 4.3%–52% for intravitreal ranibizumab (IVR), as reported in previous studies.11 12 25 26 29 30 31 In Salman et al.’s study, the recurrence was 7.7% after aflibercept injection.32 Compared with IVB and laser therapy, IVR seems to have a higher recurrence rate, which may be related to the shorter half-life time (2 hours in serum) of ranibizumab when compared with bevacizumab (20 days in serum).33 34 Our recurrence rate is similar to that of IVB and may be due to the higher binding affinity and longer half-time in the vitreous compared with those of bevacizumab.14
At the end of the follow-up, 32 eyes (66.7%) retained an avascular area in zone III, but no ROP regression or other vascular disorders were observed in these eyes. Some studies also reported incomplete vascularisation in the peripheral retina after anti-VEGF treatment for infants with ROP, including ranibizumab and bevacizumab, and the avascular rate was approximately 3%–80% in different studies.26 35–39 The incomplete periphery retinal vascularisation may be related to the dosage of anti-VEGF agents. In the Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP), a lower dosage of ranibizumab showed better retinal vascularisation than did a higher dosage, while there was no difference in efficacy between the two doses.40 Long-term effects should definitely be considered, and the minimum conbercept dosage should be studied in the future.
VEGF is a crucial cytokine for the development of young infant organs, and the decrease of plasma VEGF may result in severe side effects.41 42 However, the optimal dose of conbercept for infants remains undefined. In the present study, we chose 0.25 mg conbercept (half an adult dose), which has been frequently used in off-label ROP therapy and is considered safe and effective.10 26 No topical or systemic adverse effects were observed during the whole treatment and follow-up period, demonstrating the safety of IVC injection with this dose. No apparent differences have been reported in the local and systemic side effects between different anti-VEGF agents. Some of the local side effects, including endophthalmitis, iatrogenic cataract and rhegmatogenous retinal detachment, are associated with the injection procedure and can be reduced by strict sterile operation and technique improvement.34 Several reports demonstrated the decrease of serum VEGF levels after IVB, intravitreal ranibizumab and intravitreal aflibercept,33 43 44 and a study regarding plasma VEGF concentration changes after IVB showed that VEGF concentrations were significantly lower at 7 weeks after treatment of IVB than at preinjection.45 However, no specific adverse events have been reported on organ development or neurodevelopment related to serum VEGF level. Unfortunately, we did not detect serum VEGF levels after IVC because of parental concerns about multiple blood sampling of the infants after treatment. A more rational and precise therapeutic dose should be identified in the future.
In conclusion, IVC injection is an effective method for type 1 ROP and AP-ROP. Although some cases of reactivation occurred, ROP was well controlled after the reinjection of conbercept. Due to the retrospective nature, our study has several limitations. The sample size was relatively small. Moreover, the long-term outcome of IVC treatment was not examined. Thus, well-designed, randomised, prospective trials are needed in the future.
YB and HN contributed equally.
Contributors SF designed this study and did the injection and scanning work with XK. YB and HN contributed equally to the data collection and the draft of this article. SW analysed the data of this study under the direct supervision of XL. XO gave the pediatric diagnosis for the included patients with ROP.
Funding This study was supported by the National Nature Science Foundation of China (81500722).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics Committee of Zhujiang Hospital, Southern Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.