Medicina · 5 authors, 4 centres
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This randomized controlled trial found that patients with age-related macular degeneration (AMD) treated with hydroxychloroquine (HCQ) for 12 months had less visual acuity deterioration and fewer drusen at two-year follow-up compared to placebo. The study suggests HCQ may slow AMD progression, with no observed retinal toxicity or adverse effects. These findings support further investigation into HCQ as a potential prophylactic treatment for AMD.
**Background:** Age-related macular degeneration (AMD) is a leading cause of blindness worldwide, with an estimated 288 million cases by 2040. Drusen are hallmark signs of early AMD, and their growth is associated with progression to advanced stages (geographic atrophy or neovascular AMD). Previous observational studies suggested that patients with rheumatoid arthritis treated with hydroxychloroquine (HCQ) had lower AMD incidence, possibly due to anti-inflammatory and antioxidative effects. However, no prospective trial had evaluated HCQ's effect on AMD. The HIT study aimed to assess the impact of HCQ on visual acuity, drusen characteristics, and safety in AMD patients.
**Methods:** This double-blind, randomized controlled trial enrolled 110 patients with AMD (ARDS categories 2 and 3) from a single center in Israel. Exclusion criteria included diabetes, hypertensive retinopathy, geographic atrophy, prior ocular surgery, or intravitreal injections. Patients were randomized 1:1 to receive HCQ 400 mg daily or placebo (calcium) for 12 months. Complete ophthalmic examinations, including visual acuity (decimal score), macular OCT, red-free fundus imaging, and visual field testing (red/white), were performed at baseline and at 3, 6, 9, 12, and 24 months. Drusen number and size were assessed using red-free images and OCT, with drusen volume calculated from area and height. Two independent examiners evaluated drusen; a third resolved discrepancies >5%. The primary outcomes were visual acuity change and drusen characteristics at two-year follow-up. Sample size calculation (25 per group) assumed 80% power and 5% significance, with 50% expected loss to follow-up, leading to recruitment of 55 per group. Statistical analysis used Mann-Whitney, chi-square, and Fisher's exact tests.
**Key Results:** Of 110 randomized patients, 46 in the HCQ group (29 females, mean age 76.0 ± 5.4 years) and 50 in the placebo group (29 females, mean age 77.5 ± 4.5 years) completed the study. Baseline characteristics were similar between groups. At two-year follow-up, visual acuity deterioration was significantly less in the HCQ group (−0.03 ± 0.07) versus placebo (−0.07 ± 0.07, p = 0.027). The mean number of drusen per eye for ARDS2 was lower in the HCQ group (8.1 vs. 12.3, p = 0.045), but similar for ARDS3 (7.4 vs. 9.2, p = 0.87). The proportion of eyes with increased drusen size was lower in the HCQ group for both ARDS2 (52% vs. 58%, p = 0.034) and ARDS3 (24% vs. 32%, p = 0.045). Total drusen growth was also lower in the HCQ group (70% vs. 80%, p = 0.051). Drusen volume growth was reduced in the HCQ group (0.20 ± 0.15 vs. 0.23 ± 0.16 mm^4, p = 0.058). Central macular thickness increase was not significantly different (8.9 ± 21.6 vs. 13.2 ± 9.5, p = 0.21). No participants in the HCQ group developed HCQ toxicity, corneal verticillata, visual field changes, geographic atrophy, or choroidal neovascularization. One placebo patient developed geographic atrophy in both eyes. No systemic adverse effects occurred.
**Clinical Implications:** This first randomized trial of HCQ in AMD suggests that 12 months of HCQ treatment may slow visual acuity decline and reduce drusen growth and formation over two years, without detectable retinal toxicity. The findings support a potential prophylactic role for HCQ in preventing AMD progression, possibly through anti-inflammatory and immunomodulatory mechanisms (e.g., inhibition of TLR signaling, MHC-II antigen presentation). However, the study's limitations include a small sample size, single-center design, and relatively short follow-up. The lack of HCQ toxicity is consistent with current safety guidelines (cumulative dose <1000 g). Further larger, longer-term studies are needed to confirm efficacy, optimal dosing, and safety before clinical adoption. The results highlight HCQ as a promising candidate to modify the natural history of AMD, potentially reducing blindness in the elderly.