Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

UNLABELLED: Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751595.

Diagnostic and therapeutic approach in a rare case of primary bilateral adrenal tuberculosis.

Here, we report a case of a febrile patient with primary bilateral adrenalitis who was successfully treated with an antituberculous regimen. Primary isolated tubercular adrenalitis is a very rare clinical entity but it should be considered in cases of fever and enlargement of the adrenal glands. Integration of radiological pattern data with epidemiological, clinical and immunological data has high accuracy and specificity, even without histological examination.

Molecular epidemiology of a hepatitis C virus epidemic in a haemodialysis unit: outbreak investigation and infection outcome.

BACKGROUND: HCV is a leading cause of liver chronic diseases all over the world. In developed countries the highest prevalence of infection is reported among intravenous drug users and haemodialysis (HD) patients. The present report is to identify the pathway of HCV transmission during an outbreak of HCV infection in a privately run haemodialysis (HD) unit in Italy in 2005. METHODS: Dynamics of the outbreak and infection clinical outcomes were defined through an ambi-directional cohort study. Molecular epidemiology techniques were used to define the relationships between the viral variants infecting the patients and confirm the outbreak. Risk analysis and auditing procedures were carried out to define the transmission pathway(s). RESULTS: Of the 50 patients treated in the HD unit 5 were already anti-HCV positive and 13 became positive during the study period (AR = 28.9%). Phylogenic analysis identified that, all the molecularly characterized incident cases (10 out of 13), were infected with the same viral variant of one of the prevalent cases. The multivariate analysis and the auditing procedure disclosed a single event of multi-dose vials heparin contamination as the cause of transmission of the infection in 11 out of the 13 incident cases; 2 additional incident cases occurred possibly as a result of inappropriate risk management. DISCUSSION: More than 30% of all HCV infections in developed countries results from poor application of standard precautions during percutaneous procedures. Comprehensive strategy which included: educational programmes, periodical auditing on standard precaution, use of single-dose vials whenever possible, prospective surveillance for blood-borne infections (including a system of prompt notification) and risk assessment/management dedicated staff are the cornerstone to contain and prevent outbreaks in HD CONCLUSIONS: The outbreak described should serve as a reminder to HD providers that patients undergoing dialysis are at risk for HCV infection and that HCV may be easily transmitted whenever standard precautions are not strictly applied.

Rate of CD4+ cell count increase over periods of viral load suppression: relationship with the number of previous virological failures.

BACKGROUND: Although the kinetics of CD4(+) cell counts have been extensively studied in antiretroviral-naive HIV-infected patients, data on individuals who have failed combination antiretroviral therapy (cART) are lacking. METHODS: This analysis was based on the ICONA Foundation Study. Subjects with > or = 1 episode of viral suppression after starting first-line cART were included (n = 3537). Following a viral rebound, patients who achieved another episode of viral suppression could reenter the analysis. The percentage of patients with an increase in CD4(+) cell count >300 cells/mm(3) was estimated using Kaplan-Meier techniques; the rate of CD4(+) cell count increase per year was estimated using a multivariable, multilevel linear model with fixed effects of intercept and slope. Multivariable models were also fitted to include several covariates. RESULTS: The median time to reach a CD4(+) cell count increase >300 cells/mm(3) from baseline was significantly associated with the number of failed regimens: 34 months, 41 months, 51 months, and 45 months in subjects without evidence of previous virological failure, or 1, 2, or > or = 3 previous virologically failed regimens, respectively (P < .001, by log-rank test). The annual estimated increases in CD4(+) cell count were 36 cells/mm(3) (95% confidence interval [CI], 34-38 cells/mm(3)), 28 cells/mm(3) (95% CI, 11-21 cells/mm(3)), 31 cells/mm(3) (95% CI, 26-36 cells/mm(3)), and 26 cells/mm(3) (95% CI, 18-33 cells/mm(3)), respectively. Differences in the annual CD4(+) cell count increase were observed between specific antiretrovirals. CONCLUSIONS: Subjects with > or = 1 virological failure took a longer time to reach a CD4(+) cell count >300 cell/mm(3) and had a slower annual increase than those without virological failure. Efforts should be made to optimize first-line cART, because this represents the best chance of achieving an effective CD4(+) response.

Pulmonary embolism and acute cytomegalovirus infection in an immunocompetent patient.

A case of an immunocompetent man with acute CMV infection associated with a pulmonary embolism is described. Acute CMV infection could be a risk factor for developing thromboembolism. Pulmonary embolism should be included in differential diagnosis in patients with acute CMV infections and pulmonary opacities.

In vivo and in vitro effects of antituberculosis treatment on mycobacterial interferon-gamma T cell response.

BACKGROUND: In recent years, the impact of antituberculous treatment on interferon (IFN)-gamma response to Mycobacterium tuberculosis antigens has been widely investigated, but the results have been controversial. The objective of the present study was: i) to evaluate longitudinal changes of IFN-gamma response to M. tuberculosis-specific antigens in TB patients during antituberculous treatment by using the QuantiFERON-TB Gold (QFT-G) assay; ii) to compare the differences in T-cell response after a short or prolonged period of stimulation with mycobacterial antigens; iii) to assess the CD4+ and CD8+ T cells with effector/memory and central/memory phenotype; iv) to investigate the direct in vitro effects of antituberculous drugs on the secretion of IFN-gamma. PRINCIPAL FINDINGS: 38 TB patients was evaluated at baseline and at month 2 and 4 of treatment and at month 6 (treatment completion). 27 (71%) patients had a QFT-G reversion (positive to negative) at the end of therapy, while 11 (29%) TB patients remained QFT-G positive at the end of therapy. Among the 11 patients with persistent positive QFT-G results, six had a complete response to the treatment, while the remaining 5 patients did not have a resolution of the disease. All 27 patients who became QFT-G negative had a complete clinical and microbiological recovery of the TB disease. In these patients the release of IFN-gamma is absent even after a prolonged 6-day incubation with both ESAT-6 and CFP-10 antigens and the percentage of effector/memory T-cells phenotype was markedly lower than subjects with persistent positive QFT-G results. The in vitro study showed that antituberculous drugs did not exert any inhibitory effect on IFN-gamma production within the range of therapeutically achievable concentrations. CONCLUSIONS: The present study suggests that the decrease in the M. tuberculosis-specific T cells responses following successful anti-TB therapy may have a clinical value as a supplemental tool for the monitoring of the efficacy of pharmacologic intervention for active TB. In addition, the antituberculous drugs do not have any direct down-regulatory effect on the specific IFN-gamma response.

Patient-reported and physician-estimated adherence to HAART: social and clinic center-related factors are associated with discordance.

OBJECTIVES: To evaluate the rate of discordance between patients and physicians on adherence to highly active antiretroviral therapy (HAART) and identify factors related to discordance in these two assessments. DESIGN: Prospective, multicenter, cohort study (AdICONA) nested within the Italian Cohort Naive Antiretrovirals (ICONA) study. SETTING: Tertiary clinical centers. PARTICIPANTS: The patients filled out a 16-item self-administered questionnaire on adherence to HAART. At the same time, physicians estimated the current HAART adherence of their patient. MAIN OUTCOME MEASURE: Discordance between patient and physician on adherence to antiretroviral therapy. RESULTS: From May 1999 to March 2000, 320 paired patient-physician assessments were obtained. Patients had a mean plasma HIV RNA of 315 copies/ml (64% had undetectable HIV RNA) and a mean CD4+ cell count of 577 cells x 10(6)/L. Nonadherence was reported by 30.9% of patients and estimated by physicians in 45.0% cases. In 111 cases (34.7%), patients and physicians were discordant on adherence to HAART. Kappa statistics was 0.27. Using patient-assessed adherence as reference, sensitivity, specificity, positive predictive value, and negative predictive value of physician-estimated adherence were 64.7%, 66.6%, 81.2%, and 45.8%, respectively. On multivariable analysis, low education level, unemployment, absence of a social worker in the clinical center, and unavailability of afternoon visits were significantly correlated with patient-physician discordance on adherence to antiretrovirals. CONCLUSIONS: Physicians did not correctly estimate patient-reported adherence to HAART in more than one third of patients. Both social variables and factors related to the clinical center were important predictors of discordance between patients and physicians. Interventions to enhance adherence should include strategies addressed to improve patient-physician relationship.