Association of tuberculosis risk with the degree of tuberculin reaction in HIV-infected patients

Background: The risk of developing active tuberculosis associated with a different size of induration to purified protein derivative (PPD) has not been prospectively assessed among individuals infected with human immunodeficiency virus (HIV). The quantification of this risk is important to more appropriately identify candidates for preventive therapy for tuberculosis. Methods: A prospective, multicenter, cohort study on tuberculosis in HIV-infected patients was conducted in 23 infectious disease units in public hospitals in Italy. Two thousand six hundred ninety-five HIV-infected patients were enrolled in the study. Of these, 1054 patients who were nonanergic at the time of entry were included in the present analysis. The median duration of follow-up was 102 weeks. The main outcome measure was a diagnosis of active tuberculosis confirmed by the isolation of Mycobacterium tuberculosis in culture. Results: Among the 252 patients with PPD reactivity, patients with an induration to PPD of 2 to 4 mm had a median CD4(+) lymphocyte count of 0.34x10(9)/L (interquartile [IQ] range, 0.14x10(9)-0.56x10(9)), those with a response of 5 to 9 mm had a median count of 0.38x10(9)/L (IQ range, 0.24x10(9)-0.56x10(9)), and those with a response of 10 mm or higher had a median count of 0.37x10(9)/L (IQ range, 0.23x10(9)-0.52x10(9)) (P=.38). Compared with the 802 nonanergic PPD-negative patients, hazard ratios of tuberculosis were 2.1 (95% confidence interval [CI], 0.2-18.3) among the 55 patients with a response to PPD of 2 to 4 mm, 5.7 (95% CI, 1.6-19.8) among the 128 patients with a response to PPD of 5 to 9 mm, and 23.1 (95% CI, 7.8-68.6) among the 69 patients with a response to PPD of 10 mm or higher. Conclusions: Among nonanergic HIV-infected patients, the degree of response to tuberculin does not appear to reflect the degree of immunosuppression and is strongly correlated with the subsequent incidence of tuberculosis. To identify HIV-infected patients who are at an increased risk of tuberculosis and may benefit from preventive therapy, a response to PPD of 5 mm appears to be an appropriate cutoff point

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.

BACKGROUND: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS: In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION: Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences

Homogeneity of Antibody Responses in Tuberculosis Patients

The goals of the present study were twofold: (i) to compare the repertoires of antigens in culture filtrates of in vitro-grown Mycobacterium tuberculosis that are recognized by antibodies from noncavitary and cavitary tuberculosis (TB) patients and (ii) to determine the extent of variation that exists between the antigen profiles recognized by individual TB patients. Lipoarabinomannan-free culture filtrate proteins of M. tuberculosis were fractionated by one-dimensional (1-D) and 2-D polyacrylamide gel electrophoresis, and the Western blots were probed with sera from non-human immunodeficiency virus (non-HIV)-infected cavitary and noncavitary TB patients and from HIV-infected, noncavitary TB patients. In contrast to earlier studies based on recombinant antigens of M. tuberculosis which suggested that antibody responses in TB patients were heterogeneous (K. Lyashchenko et al., 1998, Infect. Immun. 66:3936–3940, 1998), our studies with native culture filtrate proteins show that the antibody responses in TB patients show significant homogeneity in being directed against a well-defined subset of antigens. Thus, there is a well-defined subset of culture filtrate antigens that elicits antibodies during noncavitary and cavitary disease. In addition, another set of antigens is recognized primarily by cavitary TB patients. The mapping with individual patient sera presented here suggests that serodiagnostic tests based on the subset of antigens recognized during both noncavitary and cavitary TB will enhance the sensitivity of antibody detection in TB patients, especially in difficult-to-diagnose, smear-negative, noncavitary TB patients