Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease

Abstract

Background We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. Conclusions The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial

“…Two are evaluating levofloxacin versus placebo: TB-CHAMP (ISRCTN92634082) and VQUIN MDR (ACTRN12616000215426), and the PHOENIx trial comparing the efficacy and safety of delamanid versus isoniazid (NCT03568383). We conducted a feasibility study in preparation for the PHOENIx trial The feasibility study evaluated index cases with reported MDR-TB and their HHCs at 16 sites, in eight high TB burden countries [ 3 ]. The objectives of the feasibility study were to (1) identify, recruit, and characterize adult MDR-TB index cases and their adult and child HHCs; (2) describe the prevalence of TB disease, TBI, and HIV among HHC; and (3) estimate the proportion of HHCs at high risk of TB and, therefore, potentially eligible for the interventional trial.…”

Sample size estimation for stratified individual and cluster randomized trials with binary outcomes

“…A feasibility study was conducted to inform the design of the trial. 29 The results of the feasibility study suggest estimated parameters for the unstratified trial of 0 = 0.0645, m = 3.01, CV m = 0.75, and 0 = 0.0675. We use the conservative design effect F = F B = 1 + [ (CV 2 m + 1)m − 1 ] 0 and size the trial to have significance level = .05 and 90% power ( = 0.1) to detect a treatment effect of b = log(0.5) on the log-odds ratio scale.…”

“…Clusters are the contacts in the same household as the index patient who are considered at higher risk of themselves developing TB disease, potentially because of the exposure to the index patient. A feasibility study was conducted to inform the design of the trial …”

“…While many CRTs are not large enough to be analyzed by stratified GEEs, there have recently been many examples of CRTs with reasonably large numbers of clusters, studying out‐of‐hospital medical interventions, health policies, and especially infectious disease interventions . This work was originally motivated by the design of a tuberculosis (TB) prevention trial, described in the example in Section 4, which plans to enroll about 1600 households as clusters …”

“…[24][25][26][27][28] This work was originally motivated by the design of a tuberculosis (TB) prevention trial, described in the example in Section 4, which plans to enroll about 1600 households as clusters. 29 Stratification in both individual randomized trials (IRTs) and CRTs can lead to reductions in the required sample size when the stratification variable is predictive of the outcome. 1,10,30,31 In order to properly plan these trials, however, investigators need to be able to determine the sample size for the stratified trial.…”