Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Feasibility and acceptability of asynchronous VOT among patients with MDR-TB.

BACKGROUND: We conducted a feasibility and acceptability study of video-observed therapy (VOT) among patients with multidrug-resistant TB (MDR-TB) and other types of drug-resistant TB (DR-TB) in the Philippines.METHODS: Patients aged ≥13 years were approached to use VOT. A smartphone with VOT mobile application to video-record medication intake was provided. Healthcare workers (HCWs) monitored adherence by watching videos via a web-based dashboard. Good adherence was defined as intake of >90% of expected doses. Feasibility and acceptability were assessed using a semi-structured questionnaire on a Likert scale.RESULTS: Of 308 patients, 110 (36%) patients chose VOT; 67 completed treatment using VOT and 43 stopped VOT prior to treatment outcome; 74/110 (67%) had good adherence. The treatment success rate was 88% and the loss to follow-up rate was 8.1%. Among HCWs, 90% (9/10) had a positive perception of VOT. All HCWs agreed that VOT data accurately reflect medication intake of the patients; 88/89 (99%) mentioned benefits of VOT, notably convenience, sense of comfort, privacy and security.CONCLUSIONS: VOT is feasible and acceptable for both patients and HCWs. This study could provide guidance to the country programme to launch VOT for treatment of patients with MDR-TB and other DR-TB.

Predicting differential rifamycin resistance in clinical Mycobacterium tuberculosis isolates by specific rpoB mutations.

SETTING: Rifampin (RMP) resistant Mycobacterium tuberculosis is usually assumed to be resistant to all rifamycins. Increasing evidence indicates, however, that some rpoB mutations, detectable by rapid molecular diagnostics, confer resistance to RMP but not to rifabutin (RBT), suggesting that RBT may be effective for the treatment of M. tuberculosis with these mutations. OBJECTIVE: To determine if specific rpoB mutations reliably predict differential phenotypic resistance to RMP and RBT. DESIGN: We selected 60 clinical M. tuberculosis isolates from a repository of multinational multidrug-resistant tuberculosis isolates and stratified them into two groups: 1) those with rpoB mutations suspected to confer differential resistance to RMP and RBT, and 2) those expected to be cross-resistant to RMP and RBT. These assumptions were tested by comparing the phenotypic susceptibilities of RMP/RBT with those predicted by mutations in the rpoB gene. RESULTS: Of 20 suspected RMP-resistant/RBT-susceptible isolates, 15 were RMP-resistant but RBT-susceptible, 3 were RMP- and RBT-susceptible, and 2 were cross-resistant to both RMP and RBT. In comparison, 40 of 40 suspected cross-resistant isolates were both RMP- and RBT-resistant. CONCLUSION: Our data support the association between specific rpoB mutations and differential resistance of M. tuberculosis to RMP and RBT. Clinical studies are required to investigate the efficacy of RBT in the treatment of M. tuberculosis harboring these mutations.

Prognostic significance of novel katG mutations in Mycobacterium tuberculosis.

BACKGROUND: By using whole genome sequencing (WGS), researchers are beginning to understand the genetic diversity of Mycobacterium tuberculosis (MTB) and its consequences for the diagnosis of multidrug-resistant tuberculosis (MDR-TB) on a genomic scale. The Global Consortium for Drug-resistant TB Diagnostics (GCDD) conducted a genome scale variant analyses of 366 clinical MTB genomes (mostly MDR/XDR [extensively drug resistant]) from four countries in order to inform the development of rapid molecular diagnostics. This project has been extended by performing an evolutionary analysis of isoniazid (INH)-resistant isolates for prognostic purposes. METHODS: 151 (130 INHR, 21 INHS) clinical MTB isolates from India (19: 17 INHR, 2 INHS), Moldova (48: 42 INHR, 6 INHS), the Philippines (26: 20 INHR, 6 INHS), and South Africa (58: 51 INHR, 7 INHS) were included in this study. INH drug susceptibility was determined by using MGIT 960 and WHO (World Health Organization)-recommended critical concentration of 0.1 mg/L. Isolates were sequenced using PacBio RS WGS platform. A genome-wide variant analysis was conducted using a proprietary pipeline (PacDAP) developed at San Diego State University. To infer the amino acid changes in katG that confer resistance, PAML was utilized to detect sites in silico that are under positive selection. The dN/dS method was used in combination with Bayes empirical Bayes to determine sites under positive selection and Chi-Squared analysis to determine the significance of the selected sites. RESULTS: PacDAP variant analysis revealed 22 novel catalase-peroxidase (katG product) mutations. Of these, 14 were single nucleotide polymorphisms, while 8 novel mutations appeared in combination with katG S315T and/or with inhA promoter C-15T. These SNPs have not been previously reported. Additionally, 11 previously observed, but uncommon, katG mutations were also observed in these clinical isolates. These results suggest that 17 amino acids in the enzyme are under positive selective pressure; most significantly in South Africa and the Philippines. No selective pressure on codons other than 315 was observed in isolates from Moldova. Due to the low number of isolates from India, the significance of the sites under positive selection was low and no prediction for India could be made based on this study. CONCLUSIONS: Eleven of the 14 SNPs are resistance conferring, and it is believed that the remaining 8 combinatorial mutations are either compensatory in nature or, in combination with known SNPs, could increase resistance levels. Positive selection results indicate a diversifying evolutionary path to resistance more in line with long tail statistics and therefore indicate a departure from the traditional point mutation (or "hotspot") model that current molecular diagnostics are based on. Positive selection pressures indicate a future with elevated diagnostic and prognostic significance of the "long tail" (i.e., alternative mechanisms of resistance) and potentially diminishing significance of the canonical mutations (especially in South Africa and the Philippines), which could have significant future implications on narrowly targeting molecular diagnostics.

Screening outcomes from patients with suspected multidrug-resistant tuberculosis: lessons learned in the Philippines.

SETTING: The high prevalence of multidrug-resistant tuberculosis (MDR-TB) in the Philippines is a challenge for the National TB Programme. OBJECTIVE: To assess patterns of drug resistance and screening outcomes among MDR-TB suspects evaluated from 2003 to 2008 at DOTS-Plus clinics in the Philippines. METHODS: Descriptive study of 4897 consecutive patients with suspected MDR-TB. RESULTS: The median time from the first visit until a diagnosis of drug-resistant TB was 132 days (IQR 110-166 days). Among patients screened for MDR-TB, the most frequent resistance pattern among those previously treated in DOTS facilities was resistance to isoniazid (INH) and rifampicin (RMP). Resistance to INH+RMP plus fluoroquinolones was the most common pattern among those who had failed Category II treatment and patients treated by non-DOTS facilities. Among patients with MDR-TB, 57% ultimately received appropriate treatment with second-line drugs. The remaining 43% were lost to follow-up (25%), died (14%) or refused treatment (4%). CONCLUSION: Resistance to INH+RMP is the most frequent resistance pattern among patients referred from DOTS clinics in the Philippines for suspected MDR-TB. Initial use of standard regimens based on national survey data and quick uptake of new rapid molecular resistance tests may be useful to reduce diagnostic delays and expedite treatment for drug-resistant TB.

Impact of patient and program factors on default during treatment of multidrug-resistant tuberculosis.

SETTING: In the Philippines, programmatic treatment of drug-resistant tuberculosis (TB) was initiated by the Tropical Disease Foundation in 1999 and transitioned to the National TB Program in 2006. OBJECTIVE: To determine patient and socio-demographic characteristics associated with default, and the impact of patient support measures on default. DESIGN: Retrospective cohort analysis of 583 MDR-TB patients treated from 1999 to 2006. RESULTS: A total of 88 (15%) patients defaulted from treatment. The median follow-up time for patients who defaulted was 289 days (range 1-846). In multivariate analysis adjusted for age, sex and previous TB treatment, receiving a greater number of treatment drugs (≥ 5 vs. 2-3 drugs, HR 7.2, 95%CI 3.3-16.0, P < 0.001) was significantly associated with an increased risk of default, while decentralization reduced the risk of default (HR 0.3, 95%CI 0.2-0.7, P < 0.001). CONCLUSION: Improving access to treatment for MDR-TB through decentralization of care to centers near the patient's residence reduced the risk of default. Further research is needed to evaluate the feasibility, impact and cost-effectiveness of decentralized care models for MDR-TB treatment.

Multidrug-resistant tuberculosis among previously treated patients in the Philippines.

SETTING: Prior treatment has been associated with multidrug-resistant tuberculosis (MDR-TB) in many settings. The Philippines ranks fifth among 27 priority countries for MDR-TB. OBJECTIVE: To determine the rate of MDR-TB among previously treated patients referred for MDR screening and management. DESIGN: Descriptive study of the rate of MDR-TB among 4705 previously treated patients screened from 2003 to 2008. RESULTS: MDR-TB was present in 76% of 2438 screened patients who had positive cultures. The proportion of patients with MDR-TB was the same among patients referred from public or DOTS facilities and private or non-DOTS facilities. MDR-TB occurred most frequently among patients who failed treatment with the Category 2 regimen (97%), those who did not demonstrate culture conversion after 3 months of Category 2 treatment (91%), and Category 1 failures (83%). MDR-TB rates were respectively 78% and 57% for Category 2 relapse and return after default (RAD), and respectively 33% and 22% for Category 1 relapse and RAD. CONCLUSION: MDR-TB is frequent among previously treated patients in the Philippines. Screening with culture and drug susceptibility testing should be considered for these patients.