Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136

Corneal Endothelial Rejection After Penetrating Keratoplasty Treated With Intravenous And Topic Corticosteroid. One Year Follow Up

Objective: To analyze the recovery of visual acuity (VA) and graft survival after first episode of endothelial rejection in penetrating keratoplasty (PKP) treated with intravenous (IV) and topic corticosteroid. Methods: Interventional, prospective, non-comparative case series study evolving 32 PKP patients in one year follow up, who presented first episode of corneal endothelial rejection. The patients were submitted to 500 mg IV injection of methylprednisolone in association with topical prednisolone. Main outcome measures included VA recovery and corneal edema regression. Second outcome included new rejections and graft failure. Multivariate analysis techniques were used to estimate rates of graft outcome events and the impact of risk factors. Results: A total of 32 eyes from 32 patients (13 male and 19 female) were included in the study. The mean VA (in number of letters) before rejection was 48 (22 to 88 letters). Patients treated within 7 days or less of initial symptoms had better VA recovery, corneal edema regression and less graft failure (p<0.001). Patients with previous ocular surgery had worse VA recovery and more graft failure (p<0.047). Conclusion: The association between the other risk factors and the outcomes did not reach statistical significance in the multivariate model because of the small numbers of patients. Methylprednisolone in association with topical prednisolone is an alternative treatment for graft rejection. Our study showed that patients treated within 7 days of symptoms and no previous anterior segment surgery had better visual outcome and graft survival after treatment.7214245Patel, S.V., Graft survival after penetrating keratoplasty (2011) Am J Ophthalmol., 151 (3), pp. 397-398Williams, K.A., Lowe, M.T., Barlett, C.M., Kelly, L., Coster, D.J., (2007) Australian corneal graft registry, , report Adelaide: Flinders University Press2007Tan, D.T., Janardhanan, P., Zhou, H., Chan, Y.H., Htoon, H.M., Ang, L.P., Penetrating keratoplasty in Asian eyes: the Singapore Corneal Transplant Study (2008) Ophthalmology., 115 (6), pp. 975-982Patel, S.V., Diehl, N.N., Hodge, D.O., Bourne, W.M., Donor risk factors for graft failure in a 20-year study of penetrating keratoplasty (2010) Arch Ophthalmol., 128 (4), pp. 418-425Hill, J.C., Ivey, A., Corticosteroids in corneal graft rejection: double versus single pulse therapy (1994) Cornea., 13 (5), pp. 383-388Tandon, R., Verma, K., Chawla, B., Sharma, N., Titiyal, J.S., Kalaivani, M., Intravenous dexamethasone vs methylprednisolone pulse therapy in the treatment of acute endothelial graft rejection (2009) Eye (Lond)., 23 (3), pp. 635-639Costa, D.C., Castro, R.S., Camargo, M.S., Kara-Jose, N., Rejeição de transplantes de córnea: tratamento tópico vs (2008) pulsoterapia - resultados de 10 anos. Arq Bras Oftalmol., 71 (1), pp. 57-61Krueger, R.R., Ramos-Esteban, J.C., Kanellopoulos, A.J., Staged intrastromal delivery of riboflavin with UVA cross-linking in advanced bullous keratopathy: laboratory investigation and first clinical case (2008) J Refract Surg., 24 (7), pp. S730-S736. , Comment in J Refract Surg. 2009;25(8):687author reply 687-8Panda, A., Vanathi, M., Kumar, A., Dash, Y., Priya, S., Corneal graft rejection (2007) Surv Ophthalmol., 52 (4), pp. 375-396. , ReviewMeyer, P.A., Watson, P.G., Franks, W., Dubord, P., 'Pulsed' immunosuppressive therapy in the treatment of immunologically induced corneal and scleral disease (1987) Eye (Lond)., 1 (PART 4), pp. 487-49