Ranibizumab for exudative age-related macular degeneration: A five year study of adherence to follow-up in a real-life setting.

PURPOSE: To analyze adherence to follow-up over 5 years in patients treated with intravitreal ranibizumab for exudative age-related macular degeneration (AMD) in a tertiary health care center. To investigate factors associated with failure to continue follow-up. METHODS: Retrospective chart review of all consecutive patients with exudative AMD, who received their first intravitreal ranibizumab injection at the Créteil Intercommunal University Hospital Eye Clinic between October 1, 2006 and March 31, 2007. Patient clinical characteristics at baseline and at the last follow-up visit were recorded. Distance from home to hospital was measured for each patient. A multiple-choice telephone survey was conducted for patients lost to follow-up to determine the main reasons for failure to continue follow-up. RESULTS: Two hundred and one patients were included. The rate of loss to follow-up over the 5-year period was 57% (115/201). Fifty-eight patients lost to follow-up completed the questionnaire. The main reasons reported by patients for follow-up discontinuation were long distance from home to hospital (51.7%, 30/58), subjective dissatisfaction with the benefits of intravitreal injections (34.5%, 20/58), and the excessive burden of periodic follow-up visits (24.1%, 14/58). Three factors were significantly associated with follow-up discontinuation: high age at baseline (82.2 vs. 76.5 years, P<0.001), poor best-corrected visual acuity (BCVA) at baseline (42.5 vs. 51.0 letters, P=0.020), and long distance from home to hospital (132 vs. 17.1km, P<0.001). CONCLUSION: In this study, adherence to follow-up over 5 years was poor. Age and BCVA at baseline and distance from home to hospital were independently associated with long-term adherence.

Antigen-specific tolerance of human alpha1-antitrypsin induced by helper-dependent adenovirus.

As efficient and less toxic virus-derived gene therapy vectors are developed, a pressing problem is to avoid immune response to the therapeutic gene product. Secreted therapeutic proteins potentially represent a special problem, as they are readily available to professional antigen-presenting cells throughout the body. Some studies suggest that immunity to serum proteins can be avoided in some mouse strains by using tissue-specific promoters. Here we show that expression of human alpha1-antitrypsin (AAT) was nonimmunogenic in the immune-responsive strain C3H/HeJ, when expressed from helper-dependent (HD) vectors using ubiquitous as well as tissue-specific promoters. Coadministration of less immunogenic HD vectors with an immunogenic first-generation vector failed to immunize, suggesting immune suppression rather than immune stealth. Indeed, mice primed with HD vectors were tolerant to immune challenge with hAAT emulsified in complete Freund's adjuvant. Such animals developed high-titer antibodies to coemulsified human serum albumin, showing that tolerance was antigen specific. AAT-specific T cell responses were depressed in tolerized animals, suggesting that tolerance affects both T and B cells. These results are consistent with models of high-dose tolerance of B cells and certain other suppressive mechanisms, and suggest that a high level of expression from HD vectors can be sufficient to induce specific immune tolerance to serum proteins.

Modulation of TNFalpha, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors.

Understanding the determinants of the host innate immune response to systemic administration of adenoviral (Ad) vectors is critical for clinical gene therapy. Acute toxicity occurs within minutes to hours after vector administration and is characterized by activation of innate immune responses. Our data indicate that in mice, indicators of vector toxicity include elevations of cytokine levels, liver transaminase levels and thrombocytopenia. To discern potential targets for blunting this host response, we evaluated genetic factors in the host response to systemically administered first-generation Ad vectors (FGV) and helper-dependent Ad vectors (HDV) containing beta-galactosidase expression cassettes. A preliminary screen for modulation of vector-induced thrombocytopenia revealed no role for interferon-gamma, mast cells or perforin. However, vector-induced thrombocytopenia and interleukin 6 (IL-6) expression are less evident in tumor necrosis factor alpha (TNFalpha)-deficient mice. Moreover, we also demonstrated that TNFalpha blockade via antibody or huTNFR:Fc pretreatment attenuates both thrombocytopenia (>40% increase in platelet count) and IL-6 expression (>80% reduction) without affecting interleukin 12 , liver enzymes, hematological indices or vector transduction in a murine model. Our data indicate that the use of HDV, in combination with clinically approved TNFalpha immunomodulation, may represent an approach for improving the therapeutic index of Ad gene therapy for human clinical trials.