Neovascular AMD treated with anti-VEGF agents usually shows visual improvement over an intermediate period (about one to two years); however, over extended periods (≥4 years) visual acuity can decline, even despite treatment. Researchers recently shared new data on genetic influences on visual outcomes that may explain some patient-to-patient variability.

“Identifying factors associated with long-term visual outcome in nAMD is an important step toward developing new treatment strategies,” said the researchers, who undertook a study of associated risk factors and long-term outcomes in nAMD patients treated with anti-VEGF. “The relative importance and contribution of factors such as undertreatment, overtreatment, a decline in medication efficacy or development of macular scarring and/or atrophy, are unclear, and additional factors such as genetics may exist.”

The researchers used clinical and OCT findings from patients with nAMD who were treated with anti-VEGF, according to the treat-and-extend protocol. Additionally, they genotyped major risk alleles for AMD in the CFH (rs1061170), HTRA1 (rs1200638) and C3 (rs2230199) genes. “We previously reported that specific genetic variants are associated with short-term outcome in nAMD,” they said. “After four years of treatment, patients carrying the rs1061170 single-nucleotide polymorphism (SNP) in the CFH (encoding complement factor H) had a larger increase in central point thickness (CPT) and central subfield thickness (CST) compared with patients without this SNP.”

The researchers identified 80 eligible eyes of 66 patients with ≥8 years of follow-up data. Over a 10-year period, 73.3 anti-VEGF injections were administered to the patients. They reported that BCVA (logMAR) deteriorated significantly from 0.55 at baseline to 1.00 at 10 years. Additionally, CST decreased significantly from an average of 415µm at baseline to 323µm after three monthly injections. Throughout the rest of the follow-up period, CST remained lower than at baseline.

“We found several factors associated with visual outcome after eight and/or 10 years of treatment,” the researchers said. “These included baseline BCVA, baseline intraretinal fluid and macular atrophy and/or macular thinning. For example, eyes with a baseline BCVA ≥20/50 maintained their BCVA for approximately five years before experiencing a decline in visual acuity in subsequent years; in contrast, eyes with a baseline BCVA <20/50 experienced an early improvement that was maintained for five years before developing visual impairment.”

Additionally, and consistent with previous studies’ findings, they reported an inverse correlation between the number of risk alleles in CFH and/or C3 carried by a patient and change in macular thinness measured at eight or 10 years. 

“These results suggest that variants in complement-encoding genes may be associated with reduced macular thinning, representing a reduced anatomical response to anti-VEGF treatment and/or reduced development of atrophy,” they explained. “However, the prevalence of intraretinal fluid, subretinal fluid, atrophy or scar formation at baseline or at the end of follow-up and the number of anti-VEGF injections provided was similar among carriers of risk- or wild-type CFH and C3 alleles.”

Higher macular thickness at the end of follow-up was associated with better visual outcome, the researchers reported. “Taken together with the genotyping results, this finding may reflect higher retinal cell loss among wild-type allele carriers. Thus, long-term neuroprotective effect of complement activation in eyes under anti-VEGF therapy can’t be excluded.” They noted that if complement inhibition can be applied to slow the course of atrophic AMD in nAMD eyes, further research should consider the possibility of a neuroprotective role for complement activation in specific neurological pathologies.

Ultimately, the study concluded that patients receiving anti-VEGF for nAMD developed substantial vision loss in the long term, which was associated with baseline characteristics such as BCVA, intraretinal fluid and macular atrophy. Those carrying risk alleles for AMD in CFH and/or C3 genes were also more likely to have reduced long-term reduction in macular thickness.

Vofo BN, Beykin G, Levy J, et al. Long-term outcome of neovascular age-related macular degeneration: association between treatment outcome and major risk alleles. Br J Ophthalmol. June 2, 2021. [Epub ahead of print].