The burgeoning field of pharmacogenetics brings clinicians the ability to tailor pharmacotherapy to patients' individual genetic variations. In order to suggest a change in clinical practice recommendations, studies must first prove that therapeutic differences correlate with genotypes.[15
] In this retrospective study of patients with exudative AMD treated with ranibizumab monotherapy, we found that patients homozygous for the variant genotype for CFH
(CC) were more likely to require reinjection than the TT genotype. We also found that over a period of nine months, there was a trend toward requiring more total injections with the variant genotypes than with the TT genotype. In addition, we found that there was no difference in follow-up appointments by genotype, indicating that patients in each cohort were followed without bias and that the difference in injection timing was not due to differences in follow-up. Finally, we found a stepwise increase in risk of additional injections, as patients with the TC genotype had a 25% increased risk (p = 0.12), and patients with the CC genotype had a 37% statistically significant higher risk (p = 0.04), suggesting a possible genotype-dose dependent pharamacogenetic effect.
We found no difference in visual acuity outcomes after ranibizumab treatment at 6 and 9 months among the different genotypes, in contrast to our previous study with bevacizumab.[13
] Several factors may account for this difference. First, the current study had more stringent inclusion criteria, a longer follow up period, and controlled for variability in the length of follow-up. Second, the patient cohort in the current study had substantially better baseline VA (0.85 logMAR) compared to the baseline VA of 1.02 logMAR in the bevacizumab study, potentially affecting the post-treatment outcome. This difference in VA at baseline most likely reflects the current wide usage of ranibizumab for all exudative AMD patients, compared to more selective off-label use of bevacizumab at the time of the previous study. Finally, while the two drugs are similar in their mode of action and structure, treatment response could possibly be affected differently by CFH
One plausible pathophysiological explanation for our primary findings is that patients with the variant Y402H genotype in CFH have higher background levels of inflammation since CFH is the primary regulator of the alternative complement system. While it has been hypothesized that this variation may be a molecular mechanism for the onset of neovascular AMD, variations in the CFH gene may continue to affect the disease progression and lead to more rapid recurrence of neovascularization. Thus patients with the variant genotypes may respond differently to treatment, and require additional injections of ranibizumab.
While our study did find a potential pharmacogenetic association between CFH Y402H genotypes and efficacy of ranibizumab therapy, there are limitations to the study method. Since the study was retrospective in design, the predictive value of CFH genotypes could not be tested. The follow-up of patients was not consistent, and thus the cohorts at 6 and 9 months were not identical. While this could influence the results of the visual acuity outcomes, the recurrent event analysis is a type of survival analysis and thus is robust to variable follow-up and censored data. Finally, since there was not a placebo control group, the observed effects could potentially be based on the pathophysiology of natural disease rather than true pharmacogenetic effect.
In conclusion, we describe here the first association of a pharmacogenetic effect of the CFH Y402H variations with ranibizumab in exudative AMD. We found that response to treatment of AMD with ranibizumab differed according to CFH genotype, suggesting that further investigations are warranted to see if patients with the CC and TC genotype may need to be monitored more closely for disease recurrence than the TT genotype. Prospective studies are needed to confirm this association before any recommendation for genetic screening or change current standard of care with ranibizumab can be made.