Globally, an estimated 10.0 million cases and 1.4 million deaths of tuberculosis diseases
(TB) were reported in 2019. Despite a rate of latent tuberculosis estimated at 23% of the
world population, there are very large disparities in incidence between continents and
countries with an incidence of less than 10 cases per 100,000 inhabitants in Western Europe
to more than 500/100,000 for countries like South Africa, the Philippines or Mozambique.
Alt-hough the European Region accounted only for 2.5% of all cases, TB remains a common
in-fection in immigration and poor areas. The overall objective of the WHO by 2035 (The End
TB strategy) is to reduce the number of deaths from TB by 95% (compared to 2015) and to
reduce the incidence rate of TB by 90% to less than 10/100,000 people. In France, there is a
national notification rate of 7.6/100,000 but the North of Paris is the area of France with
the highest incidence of tuberculosis (25.9/100,000 for 2016-2018). The decreasing
notification rates observed in most countries are reassuring, but annual rates of decline are
still insufficient to achieve the WHO target of TB elimination by 2050 in European
low-incidence countries. TB control requires the early detection and treatment of patients,
and investigation of potentially exposed contacts. These measures can prevent ongoing
transmission of the infection and the development of drug resistance. Therefore, surveillance
of TB treatment outcomes is also of great importance when evaluating TB programs. Since 2014,
the target set by WHO is 90% of treatment success among new sputum smear-positive TB cases.
In 2017, 30 of 31 EU/EEA countries notified TB 55,337 TB cases. Only two-thirds (67.6%) were
treated successfully, and 7% died during TB treatment. Indeed, treatment outcome monitoring
(TOM) is part of mandatory notification in France since 2007, with treatment outcome forms
completed by clinician at 1 year. Unfortunately, in France, the available information on
treatment outcome is limited by frequent missing data with only 64.8% of treatment outcomes
files completed in 2018. Furthermore, thorough knowledge of a specific country's TB disease
epidemiology is essential to map out a comprehensive national strategic plan for TB and could
help identify determinants for unfavorable treatment outcome or loss to follow-up. The
healthcare pathway of patients with tuberculosis presents glaring shortcomings with a large
proportion of treatment outcomes unknown, including a large number of loss of follow-up
resulting in secondary transmissions, recurrences of tuberculosis and emergence of
resistance. Unknown treatment outcomes correspond to unspecified treatment outcomes 12 months
from the start of treatment (lost to follow-up, transfer, absence of information). Health
actors must mobilize to better understand the characteristics of patients with incomplete
treatment outcomes and provide solutions to achieve better control of tuberculosis in our
region. We also want to assess the relationship between plasma concentrations of major
anti-TB drugs (rifampicin and isoniazid) and treatment outcomes.
We propose to constitute for the first time in France a cohort of patients with tuberculosis
disease in order to meet these objectives.
The princeps study would recruit 75 patients per year for 4 years associated with 1 year of
follow-up for a total duration of the study estimated at 5 years.By setting up a prospective
cohort study of patients with tuberculosis disease in northern Paris, we aim to assess
tuberculosis treatment outcomes and their determinants in the area with the metropolitan
French highest TB incidence. At the same time, we want to evaluate the socio-demographic and
clinical characteristics of our patients as well as the relationship between plasma
concentrations of major anti-tuberculosis drugs (rifampicin and isoniazid) and treatment
outcomes.
Methods Study population and data collection An observational, prospective, monocentric
cohort study of adult patients treated for TB disease will be carried out in 1 centre in the
north of Paris: the department of infectious diseases and respiratory medicine of Avicenne
hospital (Bobigny).
Sociodemographic, physical, biological, and radiological data will be collected for patients
meeting the inclusion criteria according to the study schedule: day 0 (D0), D15, month 1
(M1), M2, M6 and M12. The primary endpoint will be an unfavorable treatment outcome at 12
months. The categories of treatment outcomes were defined by adapting European and WHO
recommendations to the French context. A patient who completed treatment within 12 months was
considered to have favorable treatment outcome even if he did not attend the visit at M12.
The secondary endpoints will include socioeconomic and clinical characteristics of TB cases,
and rifampicin and isoniazid pharmacokinetic.
The inclusion criteria are TB out- or in-patient newly treated in one of the inclusion center
for pulmonary or extra-pulmonary TB confirmed bacteriologically (direct examination,
Gen-eXpert MTB/RIF and/or positive culture), suggestive histology (epithelioid
gigantocellular granuloma with or without caseous necrosis), or strong clinical suspicion of
tuberculosis not yet biologically confirmed but with a decision to introduce treatment. The
non-inclusion criteria are: opposition to participate in the study, anti-tuberculosis
treatment for more than 7 days at the inclusion visit and participation in another research
protocol.
Data collected on inclusion will be: demographic, social and professional data (sex, age,
country of birth, date of arrival in France, stay in a foreign country in the last 2 years,
family situ-ation, profession, domiciliation, health insurance coverage, languages spoken,
co-infections, clinical history, addictions (tobacco, alcohol, drugs), WHO performance
status, clinical data (co-infections, WHO performance status, history of tuberculosis,
tuberculosis location, presence of cough, fever, sweating nocturnal, diagnostic context),
biological, microbiological and radiological data for monitoring the treatment and its
tolerance. Pharmacokinetic data will be also collected on Day 15 from the start of treatment
with peak dosing of rifampicin and isoniazid 3 hours after taking the treatment. The
follow-up for each patient will last 12 months. Data will be entered into an electronic data
capture system.
Statistical analysis Qualitative variables will be described as frequency (%) and
quantitative variables as median and interquartile range (IQR). Treatment outcome at 1 year
and associated socioeconomic and clinical factors will be studied by multivariate analysis.
Univariate and multivariate analyses will be performed using logistic regression. All
statistical tests will be based on two-tailed p values, with p<0.05 considered to indicate
statistical significance. Associations will be expressed using crude and adjusted Odds ratios
with 95% Confidence Intervals. In our final model, we will include all statistically
significant after a backward selection using a threshold of 0.20 for the p-value. All
analyses will be performed using RStudio statistical software (Version 1.4.869 © 2009-2020
RStudio, Inc).