A longstanding oral HIV medication has emerged as a promising treatment for diabetic macular edema (DME), potentially offering millions of patients a more convenient and affordable alternative to expensive monthly eye injections. A recent randomized clinical trial led by Jayakrishna Ambati, MD, founding director of the Center for Advanced Vision Science at UVA Health, demonstrates that lamivudine can significantly improve visual acuity in patients with this sight-threatening diabetic complication.
Clinical Trial Results Show Significant Vision Improvement
The study, conducted in collaboration with researchers at Brazil's Universidade Federal de São Paulo, enrolled 24 adults with confirmed DME in a randomized clinical trial. Participants were assigned to receive either lamivudine or placebo for four weeks, followed by intravitreal bevacizumab injections.
The results were striking. Patients who received lamivudine experienced a mean improvement of 9.8 letters on standardized eye charts even before any injection therapy commenced, while the placebo group saw a decline of 1.8 letters. Following subsequent bevacizumab injections, the lamivudine cohort demonstrated an extraordinary 16.9-letter improvement, surpassing the 5.3-letter gain in the placebo group.
"An oral drug that improves vision in DME would be a game changer because it would be more convenient for patients than frequent, often monthly, injections into the eye," said Ambati. "The mechanism of action of lamivudine is also different from that of existing treatments, so we could also develop combination therapies."
Addressing a Major Health Burden
DME arises from fluid accumulation in the macula, the central region of the retina responsible for sharp, detailed vision. Approximately 1 in every 14 adults diagnosed with diabetes will experience some degree of DME, highlighting the significant need for accessible therapies. With over 37 million adults living with diabetes in the United States alone, many are vulnerable to vision loss due to progressive retinal damage.
Current treatment modalities primarily involve intravitreal injections of anti-VEGF agents like bevacizumab. While effective, these treatments pose substantial barriers due to cost, risk of complications, and frequent administration requirements.
Novel Mechanism of Action
At the mechanistic level, lamivudine's benefits in DME are attributed to its inhibitory action on inflammasomes, particularly multiprotein complexes such as the NLRP3 inflammasome. These complexes mediate innate immune responses and drive pathological retinal inflammation in diabetic retinopathy. While lamivudine is classically known to target HIV reverse transcriptase, its immunomodulatory role in eyes affected by hyperglycemia-induced stress attenuates inflammatory cascades central to vascular permeability and macular edema.
Cost-Effective Treatment Option
A key advantage of lamivudine is its affordability and well-established safety profile from decades of use in HIV patients worldwide. Cost analyses reveal the drug's monthly price ranges near $20, contrasting sharply with the $2,000 monthly fees associated with intravitreal injection regimens.
"A $20-a-month or even cheaper oral pill that improves vision as much as or more than therapy with injections into the eye that cost up to $2,000 per month could be transformative both for patients and the health care system," Ambati noted.
Future Development and Research
The research team has developed an improved derivative named K9, which retains inflammasome inhibitory properties while reducing potential side effects. Clinical trials evaluating K9's safety and efficacy in DME treatment are underway, representing advances in immune-targeted approaches for retinal disease therapeutics.
Despite the promising results, researchers emphasize that larger studies with longer follow-up periods will be needed to confirm lamivudine's efficacy and establish optimal dosing regimens. The current trial's limited sample size and eight-week duration, while encouraging, require validation through extensive Phase III trials.
Big Data Archeology Approach
This study exemplifies what Ambati calls "Big Data Archeology," leveraging large healthcare databases to uncover novel therapeutic indications for existing drugs. Prior analyses from Ambati's group revealed associations between nucleoside reverse transcriptase inhibitors like lamivudine and decreased risks of Alzheimer's disease, diabetes, and age-related macular degeneration.
The findings have been published in Med, the flagship clinical journal of Cell Press, marking a significant step toward potentially transforming DME treatment through drug repurposing strategies.
