Highlight
– Oral lamivudine, an inexpensive inflammasome inhibitor, significantly improves visual acuity in patients with center-involved diabetic macular edema (CI-DME).
– Lamivudine demonstrated superior visual improvement compared to intravitreous bevacizumab and ranibizumab, and comparable efficacy to aflibercept.
– The treatment was well tolerated with no significant differences in adverse events or retinal thickness compared to placebo.
Study Background and Disease Burden
Diabetic macular edema (DME) is a major cause of vision loss worldwide among individuals with diabetic retinopathy, affecting millions and posing a significant public health challenge. Standard care predominantly involves repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab, ranibizumab, and aflibercept. While effective, these treatments are expensive, invasive, and associated with injection-related complications including infection, hemorrhage, and patient discomfort. Furthermore, access to these treatments is limited in many low-resource settings.
Mounting evidence implicates inflammasome activation in the pathogenesis of DME, contributing to retinal inflammation and vascular permeability. Lamivudine, an oral nucleoside reverse transcriptase inhibitor widely used for HIV and hepatitis B, exerts inhibitory effects on inflammasomes. Repurposing lamivudine offers an intriguing, low-cost, oral therapeutic strategy to potentially modulate underlying inflammation in DME and improve clinical outcomes.
Study Design
This randomized, double-blind, placebo-controlled clinical trial (Brazilian Registry of Clinical Trials RBR-87b6r5s) enrolled 24 adult patients with one or two eyes affected by center-involved diabetic macular edema and best-corrected visual acuity (BCVA) below 69 letters. Participants were randomized into two groups: 10 individuals (16 eyes) received oral lamivudine 150 mg twice daily, and 14 individuals (21 eyes) received placebo, both for a duration of 8 weeks.
At week 4, all participants received an intravitreous injection of bevacizumab (1.25 mg) as adjunct therapy. Co-primary outcome measures were the mean change in BCVA from baseline to weeks 4 and 8. Secondary endpoints included changes in retinal thickness measured by optical coherence tomography (OCT) and safety profiles. The trial also incorporated synthetic control comparisons derived from the DRCR.net Protocol T dataset to benchmark lamivudine efficacy against established anti-VEGF treatments.
Key Findings
At the 4-week mark, prior to bevacizumab injection, patients treated with lamivudine exhibited a remarkable mean BCVA improvement of 9.8 letters, whereas the placebo group experienced a mean decline of 1.8 letters (p < 0.001). This early visual gain suggests a direct therapeutic effect of oral lamivudine on DME independent of anti-VEGF intervention.
Following bevacizumab administration at week 4, the 8-week outcomes revealed further visual improvement. The lamivudine plus bevacizumab group showed a mean BCVA increase of 16.9 letters compared to a 5.3-letter improvement in the placebo plus bevacizumab group (p < 0.001). These results underscore lamivudine's potential to enhance or possibly synergize with intravitreal anti-VEGF therapy.
Comparative analysis using synthetic controls indicated that lamivudine was associated with significantly greater BCVA improvements than bevacizumab or ranibizumab monotherapy (p < 0.05). Notably, lamivudine's efficacy was statistically comparable to aflibercept (p = 0.5), a more potent and expensive anti-VEGF agent commonly used for DME.
Importantly, there were no significant differences in retinal thickness reduction between lamivudine and placebo groups at any time point, suggesting that functional visual gains may occur through mechanisms beyond edema resolution alone. Safety assessments found no significant differences in adverse events, supporting the tolerability of oral lamivudine in this patient population.
Expert Commentary
This trial presents compelling evidence supporting oral lamivudine as a novel adjunct or alternative to current invasive anti-VEGF therapies for center-involved DME. The rapid improvement in BCVA observed with lamivudine prior to intravitreal injections supports its inflammasome-inhibitory mechanism in mitigating inflammatory components of DME pathogenesis.
The comparable efficacy to aflibercept is particularly notable given the lower cost and ease of administration of oral lamivudine, which could substantially improve accessibility worldwide, especially in resource-limited settings. However, the lack of significant retinal thickness changes raises questions about the precise structural versus functional effects, warranting further mechanistic studies.
While the study’s sample size was modest and follow-up relatively short at 8 weeks, these preliminary data open important avenues for larger, longer-term investigations to establish optimal dosing, durability, and potential combination regimens. Future trials should also explore lamivudine’s role in diverse diabetic populations and assess comparative cost-effectiveness in real-world settings.
Conclusion
The randomized, double-blind, placebo-controlled trial by Pereira et al. demonstrates that oral lamivudine significantly improves visual acuity in patients with center-involved diabetic macular edema, surpassing some conventional anti-VEGF agents in efficacy and comparable to aflibercept. Given its oral formulation, favorable safety profile, and affordability, lamivudine represents a promising therapeutic innovation for DME management.
These findings validate inflammasome inhibition as a viable therapeutic target and may shift clinical paradigms toward integrating oral anti-inflammatory agents into DME treatment algorithms. Nevertheless, further research is essential to confirm long-term benefits and optimize clinical implementation.
References
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