Objective-The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CIS), and to evaluate their potential value in predicting conversion to MS.Methods-Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls.Results-Compared to controls, CIS patients showed increased humoral (p<0.0001) and cellular (p=0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins. IgG responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen towards which immune responses correlated with number of T2 lesions (p=0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p=0.012 both at 1 and 5 years), presence of new T2 lesions (p=0.003 and p=0.028 at 1 and 5 years), and EDSS (p=0.015 and p=0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria [hazard ratio (95% confidence interval), 2.2 (1.2-4.3); p=0.003].Interpretation-Our results indicate that elevated immune responses towards EBNA1 are selectively increased in CIS patients and suggest that EBNA1-specific IgG titers could be used as a prognostic marker for disease conversion and disability progression.

A significant proportion of recent HIV-1 seroconverters harbour X4 viruses (17.2%), without any evidence of association between co-receptor usage, transmission of drug-resistant viruses and HIV subtype.

.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2. T he introduction of highly active antiretroviral therapy (HAART) has transformed the prognosis of HIV-positive patients, with dramatic improvements in survival. However, selection for drug resistance still represents a major challenge and promotes switches in therapeutic regimens for a substantial proportion of patients (3). Virologic failure with some antiretroviral drugs is associated with cross-resistance to agents within the same family, limiting rescue therapeutic options (16). Nevirapine and efavirenz are good examples of crossresistance between members of the same drug family, almost completely sharing resistance patterns. To a lesser extent, this also occurs with failures of some protease inhibitors (12) and nucleoside analogues.Integrase inhibitors (INIs) are a new and promising drug family for the treatment of HIV infection. Raltegravir (RAL) is the first-in-class approved drug for clinical use in both treatmentnaïve (11) and treatment-experienced (19) individuals. Elvitegravir (EVG) will most likely be the second INI compound to be marketed (4). Resistance to INIs has been shown to be driven by changes located mainly in the central domain of the viral integrase. The results of clinical trials and clinical experience have highlighted that failure on RAL-containing regimens is generally driven by the selection of the mutations Y143RHC, Q148HRK, and/or N155H, often accompanied by secondary changes (G140SA, E138K, and L74M, etc.) (2). However, a relatively high proportion of patients does not show such changes upon virologic failure on RAL-containing regimens. Although unidentified resistance mutations might exist, a recent report highlighted that the absence of INI resistance mutations in these individuals is explained mainly by poor drug compliance, given that RAL plasma levels were undetectable in most of them (6).Information about resistance to EVG in vivo is scarce. In the phase II GS-US-183-105 study (13), 28 individuals failed EVG after 24 weeks of treatment. Overall, 39% of them selected the E92Q mutation, 32% selected the Q148HRK mutation, and 25% selected the N155H mutation. Accordingly, broad cross-resistance between RAL and EVG should be expected. The aim of our study was to characterize RAL phenotypic susceptibilities in samples from a group of patients experiencing RAL failure, exploring whether mutations not previously involved in RAL resistance might be recognized and the extent of phenotypic cross-resistance to EVG. MATERIALS AND METHODSStudy population. HIV-1-infected individuals treated at several clinics in Spain who experienced virological failure on a RAL-containing antiretroviral regimen were identified during 2009. Virological failure was defined...

RPV resistance is overall recognized in nearly 20% of patients failing other NNRTIs. It is more common following ETR (27.6%) or NVP (25%) failures than EFV (14.5%). E138 mutants are rarely seen in this context.

The combination of raltegravir, ETR, and DRV/r was a highly effective and well-tolerated antiretroviral salvage regimen in patients infected with multidrug-resistant HIV-1.