Intravitreal Bevacizumab as anti-vascular endothelial growth factor in the management of complications of diabetic retinopathy

Arevalo, J. Fernando (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Bevacizumab is a complete full-length humanized antibody that binds to all subtypes of vascular endothelial growth factor (VEGF) and is used successfully in tumor therapy as a systemic drug. Recent studies have demonstrated the usefulness of an intravitreal injection of bevacizumab (IVB) in the reduction of macular edema secondary to central retinal vein occlusion, and choroidal neovascularization secondary to age-related macular degeneration (AMD). The drug is extremely cost-effective compared to similar anti-VEGF drugs on the market, hence the need to examine its effect in diabetic eye disease (the ever-growing global health epidemic challenge) for application in middle to low income countries. The purpose of the current research is to determine if intravitreal bevacizumab (IVB) as anti-VEGF is helpful in the management of complications of diabetic retinopathy. We conducted several multicenter retrospective studies of eyes with complications from diabetic retinopathy treated with off-label IVB. Ten previously published studies (one prospective), and one unpublished prospective study are included here on the management of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). We progressively reported over the years our experienced as we followed patients with DME treated with IVB at 6 months, 12 months, and 24 months of follow up. In addition, 5 year follow up data was added later on. We found that primary IVB at doses of 1.25 to 2.5 mg seem to provide stability or improvement in best correct visual acuity (BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) in diffuse DME at 24 months. The results show no evident difference between IVB at doses of 1.25 or 2.5 mg. However, the early visual gains due to IVB were not maintained 5 years after treatment. Later, we provide evidence to support the use of primary IVB with or without grid laser photocoagulation (GLP) as treatment of diffuse DME. Primary IVB without GLP seems to be superior to GLP alone to provide stability or improvement in best-corrected visual acuity in patients with diffuse diabetic macular edema at 24 months. We showed first that IVB resulted in marked regression of retinal neovascularization (RN) in patients with PDR and previous pan retinal photocoagulation (PRP), and rapid resolution of vitreous hemorrhage in three naive eyes. Six-months results of intravitreal bevacizumab at doses of 1.25 or 2.5 mg in patients with PDR did not reveal any safety concerns. Later, we published that IVB resulted in marked regression of RN in patients with PDR and previous pan-retinal photocoagulation at 2 years. Intravitreal bevacizumab in naive eyes resulted in control or regression of 42.1% of eyes without adjunctive laser or vitrectomy during 24 months of follow-up. Meaning that a large number of patients (almost 58%) needed PRP or vitrectomy. Another one of our studies demonstrated the usefulness of using preoperative IVB during small-gauge vitreoretinal surgery in eyes with tractional retinal detachment (TRD) in PDR. This was a prospective non-comparative study and patients had significant anatomic and functional success. In addition, we reported for the first time ever that TRD may occur or progress shortly following administration of IVB in patients with severe PDR (5.2% and 3.2% in two studies). Based on our data, we now believe that extreme care must be taken in using a dose of 2.5 mg or more of bevacizumab in patients with PDR. In addition, to have more than 15 years with a diagnosis of diabetes can increase the risk of TRD. Physicians must be prepared to perform the vitrectomy preferably before 13 days after the application of IVB and to perform a vitrectomy immediately on those patients in whom a TRD occurs. We recommend less than 5 days after injection as more than 80% of the retinal detachments developed after that period of time. Finally, in our prospective randomized clinical trial, pre-operative intravitreal bevacizumab therapy as adjuvant to PPV may be helpful and beneficial for patients with TRD secondary to severe PDR. Pre-operative IVB seems to reduce intraoperative bleeding, improving surgical visual field visualization, and reducing intraoperative and postoperative complications including iatrogenic retinal breaks and postoperative hemorrhage. In summary, IVB as anti-VEGF agent is helpful in the management of complications of diabetic retinopathy to prevent blindness with a more accessible drug worldwide.

AFRIKAANSE OPSOMMING: Bevacizumab is ‘n vaskulêre endoteel groei faktor inhibitor. Dit is primêr geregistreer vir die binneaarse gebruik as chemoterapeutiese middel vir verskeie kankers. Onlangs het die ongeregistreerde gebruik van die middel vir ouderdomsverwante makulêre degenerasie populêr geword. Die middel is baie koste-effektief vergeleke met soortgelyke anti-vaskulêre endoteel groei faktor inhibitore (anti-VEGF) op die mark. Dit het dus nodig geword om die effek van die middel op diabetiese oogsiekte, wat ‘n immers toenemende globale gesondheids uitdaging word, te bepaal. Veral middel tot lae inkomste lande sal hierby baat. Die doel van die huidige navorsing is om te bepaal of intravitreale bevacizumab (IVB) as anti-VEGF behulpsaam is in die hantering van komplikasies van diabetiese retinopatie. Ons het verskeie multisenter retrospektiewe studies uitgevoer op oë met komplikasies van diabetiese retinopatie wat behandel was met IVB. Tien voorheen publiseerde studies (een prospektief) en een ongepubliseerde studie oor die hantering van diabetiese makulêre edeem (DME) en proliferatiewe diabetiese retinopatie (PDR) word hier ingesluit. Soos ons die IVB behandelde pasiente met DME opgevolg het oor 6, 12, 24 maande en later 5 jaar het ons progressief ons ervaring publiseer. Ons het gevind dat IVB in dosisse van 1.25 tot 2.5mg stabiliteit of verbetering gebring het in die bes gekorrigeerde visie, optiese koherensie tomografie en fluoresien angiografie teen die 24 maande merk. Die resultate het geen merkbare verskil getoon tussen die 1.25 en 2.5mg dosisse nie, maar die vroeë verbetering in visie kon nie volgehou word oor die 5 jaar periode nie. Latere studie verskaf bewys dat die gesamentlike gebruik van ‘rooster’ laser fototerapie (GLP) met die eerste IVB merkbaar beter is in diffuse DME. Primêre IVB sonder GLP blyk beter te vaar as GLP alleen ten einde stabiliteit of verbetering van die bes-gekorrigeerde visie teen 24 maande in pasiente met DME te verseker. In drie pasiente met PDR en vorige pan retinale fotokoagulasie (PRP) was ons die eerste om te toon dat IVB betekenisvolle regressive van retinale neovaskularisasie induseer sowel as om glasvogbloeding op te klaar. Geen veiligheidskwessies was ondervind ses maande na die toediening van IVB in dosisse van 1.25 of 2.5mg in pasiente met PDR nie. Later het ons publiseer dat in pasiente met PDR en vorige PRP die toediening van IVB lei tot betekenisvolle regressive van retinale neovaskularisasie na 2 jaar. Die toediening van IVB sonder adjuvante laser of vetrektomie het in onbehandelde oë gelei tot die beheer van regressive in 42.1% van oë na 24 maande se opvolg. Dit beteken dat byna 58% van pasiente wel PRP of vitrektomie benodig het. In ‘n ander studie het ons gewys hoe waardevol pre-operatiewe IVB is tydens klein insisie vitreoretinale chirurgie in oë met traksie retinale loslatings in PDR. Hierdie was ‘n prospektiewe nie-vergelykende studie. Pasiente het betekenisvolle anatomiese en funksionele suksesvolle uitkomste. In twee studies het ons voorts vir die eerste keer rapporteer dat traksie retinale loslatings (TRD) mag plaasvind of vererger na die toediening van IVB in pasiente met erge PDR (5.2% en 3.2% respektiewelik). Gebasseer op ons data, glo ons nou dat ‘n dosis van 2.5mg of meer nadelig kan wees in pasiente met PDR. Voorts wys ons dat as pasiente diabetes het vir meer as 15 jaar is die risiko vir traksie loslatings van die retina verhoog. Dokters moet bereid wees om vitrektomie chirurgie te doen verkieslik voor dag 13 nadat IVB toegedien is. As ‘n TRD vorm, moet onmiddellike chirurgie gedoen word. Omdat meer as 80% van die retinale loslatings ontwikkel het na 5 dae post IVB, beveel ons nou aan dat vitrektomie chirurgie binne 5 dae na die inspuit van bevacizumab uitgevoer word. Laastens, in ons prospektiewe gerandomiseerde kliniese studie, het ons gewys dat IVB as adjuvant tot PPV behulpsaam en voordelig is in pasiente met traksie loslatings wat die gevolg is van erge PDR. In die studie het pre-operatiewe IVB intraoperatiewe bloeding verminder, chirurgiese gesigsveld en visualisasie verbeter en intra- en postoperatiewe kompliksasies soos iatrogene retinale gate en post-operatiewe bloedings, verminder. Opsommend is ons gevolgtrekking dat met ‘n middel wat geredelik wêreldwyd beskikbaar is in die vorm van IVB voordeel inhou in die hantering van die komplikasies van diabetiese retinopatie en so blindheid kan voorkom.

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