Safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in adults with tuberculosis: A phase II randomised study.

Previous studies have shown that the M72/AS01E candidate tuberculosis vaccine is immunogenic with a clinically acceptable safety profile in healthy and Mycobacterium tuberculosis-infected adults. This phase II, observer-blind, randomised study compared the safety, reactogenicity, and immunogenicity of M72/AS01E in 3 cohorts: tuberculosis-naïve adults (n = 80), adults previously treated for tuberculosis (n = 49), and adults who have completed the intensive phase of tuberculosis treatment (n = 13). In each cohort, 18-59-year-old adults were randomised (1:1) to receive two doses of M72/AS01E (n = 71) or placebo (n = 71) and followed-up until six months post-dose 2. Safety and reactogenicity were assessed as primary objective. Recruitment in the study ended prematurely because of a high incidence of large injection site redness/swelling reactions in M72/AS01E-vaccinated adults undergoing tuberculosis treatment. No additional clinically relevant adverse events were observed, except one possibly vaccine-related serious adverse event (hypersensitivity in a tuberculosis-treated-M72/AS01E participant). Robust and persistent M72-specific humoral and polyfunctional CD4(+) T-cell-mediated immune responses were observed post-M72/AS01E vaccination in each cohort. In conclusion, the M72/AS01E vaccine was immunogenic in adults previously or currently treated for tuberculosis, but further analyses are needed to explain the high local reactogenicity in adults undergoing tuberculosis treatment. ClinicalTrials.gov: NCT01424501.

Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis.

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB.

Factors related to patient delay in pulmonary tuberculosis in Estonia.

The resurgence of tuberculosis (TB) in Estonia, a post-socialist Eastern European country, has coincided with delayed case detection suggested by increase in advanced forms of pulmonary tuberculosis among newly detected cases. We estimated the determinants of patient delay in conditions of negligible HIV infection, insignificant immigration and free access to medical care with TB. All newly-detected symptomatic culture-positive patients aged > or =16 y with pulmonary TB from southern Estonia during 2002-2003 (n=185) were interviewed. Intervals greater than the median (79 d) and the 75th percentile (140 d) between onset of the first symptom and the first medical visit were defined as prolonged and extreme patient delay, respectively. Male gender was associated with both prolonged and extreme patient delay (OR 2.12; 95% CI 1.06-4.23 and OR 3.28; 95% CI 1.30-8.26, respectively), whereas rural residence was associated with prolonged patient delay (OR 2.08; 95% CI 1.06-4.08). Median patient delay was shortest when the first symptom was fever (22 d) and greatest when it was cough with haemoptysis (196 d). The study shows that even in absence of barriers in accessing health care, the median patient delay can be longer than in most former studies, whereas males and rural residents are at greater risk.

Tuberculosis during fundamental societal changes in Estonia with special reference to extrapulmonary manifestations.

STUDY OBJECTIVES: To characterize the incidence of extrapulmonary tuberculosis (EPTB) in Estonia, by site and age, in conditions of marked pulmonary tuberculosis (TB) increase, ie, during the period of fundamental societal changes, but where TB incidence has not been influenced by HIV infection. DESIGN AND SETTING: A retrospective study. PATIENTS: All new cases of EPTB (n = 622) detected in Estonia from 1991 to 2000. RESULTS: The incidence of pulmonary TB in Estonia increased from 21.5 in 1991 to 44.6/100,000 in 2000. In contrast, the incidence of EPTB did not increase at the same pace, changing only from 3.6 in 1991 to 4.7/100,000 in 2000. The increase in the incidence of EPTB was significantly lower than that of pulmonary TB (p < 0.05), and the relative frequency of EPTB among overall TB steadily decreased from 17.0% in 1991 to 10.1% in 2000. The incidence of EPTB forms with a long latency period (eg, osteoarticular and urogenital TB) remained unchanged, while that of EPTB forms with a short latency period (eg, intrathoracic lymph node TB) increased (p < 0.05). The number of cases of urogenital, pleural, and osteoarticular TB increased with age; the number of cases of intrathoracic lymph node TB decreased with age. The bacteriologic confirmation rate was lower in EPTB than in pulmonary TB and varied according to site. CONCLUSION: There was no increase in the incidence of EPTB during 10 years despite the dramatic increase in overall TB. The proportion of EPTB among all TB tended to decrease with increasing age, and different EPTB sites prevailed in different age groups.

Use of molecular techniques to distinguish between treatment failure and exogenous reinfection with Mycobacterium tuberculosis.

We investigated the means by which drug resistance emerges among drug-susceptible Mycobacterium tuberculosis strains during antituberculosis therapy. Patients who experienced failure of treatment for active pulmonary tuberculosis, who initially received diagnoses of infection with drug-susceptible M. tuberculosis, and who had had at least 3 isolates tested for drug susceptibility were selected from a 6-year period in the Estonian National Reference Laboratory archive. Eleven patients from whom 35 sequential isolates of M. tuberculosis had been obtained were recruited into the study. Their clinical data and treatment charts were analyzed and correlated with drug-susceptibility patterns and IS6110 restriction fragment-length polymorphism (RFLP) profiles. Six patients excreted isogenic drug-susceptible M. tuberculosis strains, whereas, in the other 5 patients, the isolated strain shifted from a susceptible to a resistant phenotype. In all cases, this shift correlated to a shift in RFLP pattern, which showed reinfection with a new strain. Exogenous reinfection with drug-resistant M. tuberculosis may be misinterpreted as the emergence of drug resistance if molecular testing techniques are not used.