Management of Adenoviral Keratoconjunctivitis: Challenges and Solutions

Labib, Bisant A; Minhas, Bhawanjot K; Chigbu, DeGaulle I

76% cure rate in a 6-week treatment period, with low risk of side effects limited to transient corneal epithelial defects and elevated intraocular pressure. While EKC is often considered to be self-limiting, this study concluded that the proposed treatment plan, specifically during the early phase of the disease, could markedly reduce the patient's symptoms, shorten the course of the disease, and lessen the risk of corneal complications. 27 Valganciclovir is a pro-drug of GCV that inhibits replication of adenoviral genomic DNA via blockade of HAdV DNA polymerase. However, because HAdV lacks thymidine kinase, a known target for valganciclovir, it would likely become a challenge in the treatment of adenoviral keratoconjunctivitis. 47 Ribavirin and cidofovir have also been shown to exhibit antiviral activity against HAdV in vitro. However, many of these systemic antiviral therapies lead to the risk of significant side effects. Cidofovir (CDV) is an acyclic nucleoside phosphonate and nucleotide analog of cytosine. It is converted by cells to its diphosphate form and binds to the HAdV DNA polymerase, causing viral DNA chain termination and viral inhibition. 13, 44 Intravenous cidofovir is often used in transplant clinics with only mild efficacy. This is due to poor cellular uptake because of its phosphate group, leading to accumulation of the drug in the renal tubules and, when used systemically, leads to nephrotoxicity. 44, 46 Locally, CDV may also cause ocular toxicity around the skin of eyelids and conjunctiva. 46 Similarly, ribavirin also results in poor systemic side effects and safety profile, associated with extravascular hemolysis, anemia, and bone marrow suppression. Due to these discoveries, it is necessary to determine an effective antiviral with a high therapeutic index for the treatment of HAdV associated infections. 46 In animal models, CDV was administered utilizing topical and intrastromal inoculation three times per day for 20 consecutive days; the results displayed significant effectivity against HAdV type 5 when compared to the placebo group, reducing both viral shedding and the severity of subepithelial infiltrates. This study showed great promise in the future of cidofovir for the treatment of ocular HAdV infections in the future. 48 Additionally, early systemic administration of CDV in immunocompetent patients with HAdV pneumonia was an effective treatment strategy. 42 Due to the positive results in the aforementioned studies, CDV was tested as a prophylactic measure due to the epidemic nature of HAdV. Romanowski et al determined that antiviral prophylaxis with 1% and 0.5% concentrations of CDV significantly reduced viral replication of HAdV type 5 in animal models, giving promise to the use of CDV in prophylaxis. 49 Despite favorable outcomes of cidofovir's antiviral activity in rabbit models, several studies discussed the significant side effects to the ocular surface, which is a potential limitation for therapeutic use. Gordon et al described the effects of topical cidofovir in uninfected animals, determining that there was consistent clinically significant ocular toxicity at a total dose exceeding 15mg over 10 days. 50 Significant eyelid redness and conjunctival hyperemia were also described in additional studies as well as nasolacrimal blockage and lacrimation. 50, 51 Even at lower and presumably ineffective dosages, 3.5 mg of cidofovir continued exhibit significant ocular surface toxicity in vivo. 52 Resistance to