High variance in quantification of Mycobacterium tuberculosis at low bacterial loads and with differentially detectable mycobacteria.

We examined the correlation between three different methods of Mycobacterium tuberculosis quantification: time to positivity (TTP), log10 CFU, and an assay to detect differentially detectable M. tuberculosis (DD Mtb) from three different prospective studies. Participants with DD Mtb have significantly more variation in the CFU/TTP correlation than participants with no DD Mtb (P < 0.001). This may impact the design of early bactericidal activity studies that use TTP as the primary outcome.

Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis.

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion.

Effectiveness of a bedaquiline, linezolid, clofazimine "core" for multidrug-resistant tuberculosis.

Rationale: Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients. Objectives: We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline. Methods: We emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment. Measurements and Main Results: Adjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41). Conclusions: High treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.

Commensal antimicrobial resistance mediates microbiome resilience to antibiotic disruption.

Despite their therapeutic benefits, antibiotics exert collateral damage on the microbiome and promote antimicrobial resistance. However, the mechanisms governing microbiome recovery from antibiotics are poorly understood. Treatment of Mycobacterium tuberculosis, the world's most common infection, represents the longest antimicrobial exposure in humans. Here, we investigate gut microbiome dynamics over 20 months of multidrug-resistant tuberculosis (TB) and 6 months of drug-sensitive TB treatment in humans. We find that gut microbiome dynamics and TB clearance are shared predictive cofactors of the resolution of TB-driven inflammation. The initial severe taxonomic and functional microbiome disruption, pathobiont domination, and enhancement of antibiotic resistance that initially accompanied long-term antibiotics were countered by later recovery of commensals. This resilience was driven by the competing evolution of antimicrobial resistance mutations in pathobionts and commensals, with commensal strains with resistance mutations reestablishing dominance. Fecal-microbiota transplantation of the antibiotic-resistant commensal microbiome in mice recapitulated resistance to further antibiotic disruption. These findings demonstrate that antimicrobial resistance mutations in commensals can have paradoxically beneficial effects by promoting microbiome resilience to antimicrobials and identify microbiome dynamics as a predictor of disease resolution in antibiotic therapy of a chronic infection.

Estimating Post-treatment Recurrence After Multidrug-Resistant Tuberculosis Treatment Among Patients With and Without Human Immunodeficiency Virus: The Impact of Assumptions About Death and Missing Follow-up.

BACKGROUND: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment follow-up. METHODS: We analyzed data on 1991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using 5 approaches for handling post-treatment deaths, we estimated 6-month post-treatment TB recurrence risk overall and by HIV status. We used inverse-probability weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. RESULTS: The estimated TB recurrence risk was 7.4/1000 (95% credible interval: 3.3-12.8) when deaths were handled as non-recurrences and 7.6/1000 (3.3-13.0) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risks of composite recurrence outcomes were 25.5 (15.3-38.1), 11.7 (6.4-18.2), and 8.6 (4.1-14.4) per 1000 for recurrence or (1) any death, (2) death with unknown or TB-related cause, or (3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability weighting had a small impact on estimates. CONCLUSIONS: The estimated 6-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

A bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine second line regimen for tuberculosis displays similar early bactericidal activity as the standard rifampin based first line regimen.

BACKGROUND: In 2018 the World Health Organization (WHO) recommended a switch to an all oral bedaquiline based second line regimen for treatment of drug resistant (DR) tuberculosis (TB). How these new second line regimens fare in comparison to first line regimens for treatment of drug sensitive (DS) tuberculosis is not well known. METHODS: In this study, we contemporaneously enrolled subjects with DS (n = 31) and DR (n = 23) TB and assessed their response to therapy with first-line (rifampin, isoniazid, ethambutol, pyrazinamide) or second-line (bedaquiline, pyrazinamide, levofloxacin, linezolid, clofazimine) regimens, respectively. RESULTS: We found that the early bactericidal activity of first and second line regimens was similar during the first two weeks of therapy as determined by BACTEC MGIT, colony forming units (CFU), and a liquid limiting dilution (LD) assays capable of detecting differentially detectable/culturable Mtb (DD Mtb). Further, an identical percentage (77.8%) of subjects from the DS and DR cohorts converted to culture negative after two months of therapy. CONCLUSIONS: Despite presenting with more advanced disease at time of treatment, subjects with DR TB receiving an all oral bedaquiline based second line treatment regimen displayed a similar microbiological response to therapy as subjects with DS TB receiving a first-line treatment regimen.

Successful outcomes for patients with drug-resistant tuberculosis despite civil unrest and COVID-19 in Haiti.

Globally, treatment outcomes for people with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) are sub-optimal, with MDR/RR-TB programs further weakened due to the COVID-19 pandemic, and in Haiti, by severe civil unrest. We assessed the impact of these disruptions on treatment outcomes at GHESKIO, in Port-au-Prince, Haiti. We conducted a retrospective analysis including all adults (age ≥18 years) who initiated MDR/RR-TB treatment at GHESKIO from 2010 to 2020. We assessed predictors of poor treatment outcome using multivariable logistic regression, adjusting for baseline characteristics and year of treatment. 453 patients initiated treatment for MDR/RR-TB at GHESKIO. Median age was 31 (IQR: 25, 40), 233 (51.4%) were male, and 100 (22.1%) were living with HIV. Three hundred sixty-nine patients (81.5%) achieved cure, 42 (9.3%) died, 40 (8.8%) were lost to follow-up and 2 (<1%) failed treatment. HIV status was associated with poor treatment outcome (aRR: 1.65 (95% CI: 1.09, 2.48)) but there was no difference by year of treatment initiation. Outcomes for patients with MDR/RR-TB remained outstanding, even during the COVID-19 pandemic and severe civil unrest in Haiti. We attribute this resilience in care to the adaptability of program staff and provision of economic and psychosocial support.

Estimating post-treatment recurrence after multidrug-resistant tuberculosis treatment among patients with and without HIV: the impact of assumptions about death and missing follow-up.

Background: Quantification of recurrence risk following successful treatment is crucial to evaluating regimens for multidrug- or rifampicin-resistant (MDR/RR) tuberculosis (TB). However, such analyses are complicated when some patients die or become lost during post-treatment-follow-up. Methods: We analyzed data on 1,991 patients who successfully completed a longer MDR/RR-TB regimen containing bedaquiline and/or delamanid between 2015 and 2018 in 16 countries. Using five approaches for handling post-treatment deaths, we estimated the six-month post-treatment TB recurrence risk overall, and by HIV status. We used inverse-probability-weighting to account for patients with missing follow-up and investigated the impact of potential bias from excluding these patients without applying inverse-probability weights. Results: The estimated TB recurrence risk was 6.6 per 1000 (95% confidence interval (CI):3.2,11.2) when deaths were handled as non-recurrences, and 6.7 per 1000 (95% CI:2.8,12.2) when deaths were censored and inverse-probability weights were applied to account for the excluded deaths. The estimated risk of composite recurrence outcomes were 24.2 (95% CI:14.1,37.0), 10.5 (95% CI:5.6,16.6), and 7.8 (95% CI:3.9,13.2) per 1000 for recurrence or 1) any death, 2) death with unknown or TB-related cause, 3) TB-related death, respectively. Corresponding relative risks for HIV status varied in direction and magnitude. Exclusion of patients with missing follow-up without inverse-probability-weighting had a small but apparent impact on estimates. Conclusion: The estimated six-month TB recurrence risk was low, and the association with HIV status was inconclusive due to few recurrence events. Estimation of post-treatment recurrence will be enhanced by explicit assumptions about deaths and appropriate adjustment for missing follow-up data.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

A Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase Tuberculosis Clinical Trials.

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum.

Certain populations of Mycobacterium tuberculosis go undetected by standard diagnostics but can be enumerated using limiting dilution assays. These differentially detectable M. tuberculosis (DD M. tuberculosis) populations may have relevance for persistence due to their drug tolerance. It is unclear how well DD M. tuberculosis from patients is modeled by a recently developed in vitro model in which M. tuberculosis starved in phosphate-buffered saline is incubated with rifampin to produce DD M. tuberculosis (the PBS-RIF model). This study attempted to answer this question. We selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in patient sputa containing various proportions of DD M. tuberculosis. The expression of 12/14 genes correlated with the relative abundance of DD M. tuberculosis in patient sputa. Culture filtrate (CF), which promotes recovery of DD M. tuberculosis from certain patient sputa, improved these correlations in most cases. The gene whose reduced expression relative to M. tuberculosis 16S rRNA showed the greatest association with the presence and relative abundance of DD M. tuberculosis in patient sputa, icl1, was recently shown to play a functional role in restraining DD M. tuberculosis formation in the PBS-RIF model. Expression of icl1, combined with two additional DD M. tuberculosis-related genes, showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa (receiver operating characteristic [ROC] area under the curve [AUC] = 0.88). Thus, the in vitro DD M. tuberculosis model developed by Saito et al. (K. Saito, T. Warrier, S. Somersan-Karakaya, L. Kaminski, et al., Proc Natl Acad Sci U S A 114:E4832-E4840, 2017, https://doi.org/10.1073/pnas.1705385114) bears a resemblance to DD M. tuberculosis found in tuberculosis (TB) patients, and DD M. tuberculosis transcriptional profiles may be useful for monitoring DD M. tuberculosis populations in patient sputum. IMPORTANCE Differentially detectable M. tuberculosis (DD M. tuberculosis), which is detectable by limiting dilution assays but not by CFU, is present and enriched for in TB patient sputum after initiation of first-line therapy. These cryptic cells may play a role in disease persistence due to their phenotypic tolerance to anti-TB drugs. A recently developed in vitro model of DD M. tuberculosis (the PBS-RIF model) has expanded our understanding of these cells, though how well it translates to DD M. tuberculosis in patients is currently unknown. To answer this question, we selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in TB patient sputa. We found that 12/14 of these genes showed a similar expression profile in patient sputa that correlated with the relative abundance of DD M. tuberculosis. Further, the expression of three of these genes showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa. The use of DD M. tuberculosis transcriptional profiles may allow for easier monitoring of DD M. tuberculosis populations in patient sputum in comparison to limiting dilution assays.

An optimized method for purifying, detecting and quantifying Mycobacterium tuberculosis RNA from sputum for monitoring treatment response in TB patients.

Diagnostics that more accurately detect and quantify viable Mycobacterium tuberculosis (Mtb) in the sputum of patients undergoing therapy are needed. Current culture- and molecular-based tests have shown limited efficacy for monitoring treatment response in TB patients, either due to the presence of viable sub-populations of Mtb which fail to grow under standard culture conditions (termed differentially detectable/culturable Mtb, DD Mtb) or the prolonged half-life of Mtb DNA in sputum. Here, we report an optimized RNA-based method for detecting and quantifying viable Mtb from patient sputum during the course of therapy. We first empirically derived a novel RNA extraction protocol from sputum that improves recovery of Mtb RNA while almost completely eliminating contamination from Mtb DNA and host nucleic acids. Next, we identified five Mtb 16S rRNA primer sets with varying limits of detection that were capable of distinguishing between live versus dead H37Rv Mtb. This combined protocol was then tested on sputa from a longitudinal cohort of patients receiving therapy for drug sensitive (DS) or drug resistant (DR) TB with first-line or second-line regimens, respectively. Results were compared with that of culture, including CFU, BACTEC MGIT, and a limiting dilution assay capable of detecting DD Mtb. The five 16S rRNA primer sets positively identified nearly all (range 94-100%) culture positive sputa, and a portion (19-37%) of culture negative sputa. In comparison, ten highly expressed Mtb mRNAs showed positivity in 72-86% of culture positive sputa, and in 0-13% of culture negative sputa. Two of the five 16S rRNA primer sets were able to positively identify 100% of culture positive sputa, and when tested on culture negative sputa from the DS cohort at 2 months post-initiation of therapy, identified 40% of samples as positive; a percentage that is in line with expected treatment failure rates when first-line therapy is discontinued early. These two primer sets also detected 16S rRNA in 13-20% of sputa at 6 months post-initiation of therapy in the DR cohort. Cycle threshold values for 16S rRNA showed a strong correlation with Mtb numbers as determined by culture (R > 0.87), including as Mtb numbers declined during the course of treatment with first-line and second-line regimens. The optimized molecular assay outlined here may have utility for monitoring treatment response in TB patients.

Time to Culture Conversion of Bedaquiline and High-Dose Isoniazid for Drug-Resistant Tuberculosis.

Patients with multidrug-resistant tuberculosis who received regimens containing high-dose isoniazid (INHHD) had similar time to culture conversion and treatment outcomes as patients who received regimens with bedaquiline. INHHD is an inexpensive and safe medication that may contribute additive efficacy in combination regimens.

All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

BACKGROUND: Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. METHODS: Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. RESULTS: Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. CONCLUSIONS: Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

Characterization of Differentially Detectable Mycobacterium tuberculosis in the Sputum of Subjects with Drug-Sensitive or Drug-Resistant Tuberculosis before and after Two Months of Therapy.

Standard methods for enumerating Mycobacterium tuberculosis in patient sputum can miss large populations of viable M. tuberculosis cells that are unable to grow either on solid medium or in liquid medium unless the medium has been extensively diluted. Because these bacteria can be detected in liquid medium after limiting dilution, they have been termed differentially culturable or differentially detectable M. tuberculosis (DD-Mtb). Treatment with isoniazid (H), rifampin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) for 1 to 2 weeks has been shown to increase the representation of DD-Mtb in the sputum of drug-sensitive (DS) tuberculosis (TB) patients. However, little is known about DD-Mtb after longer periods of treatment with HRZE or in patients with drug-resistant (DR) TB who receive second-line therapies. Here, we measured the proportion of DD-Mtb cells in the sputum of 47 subjects, 29 with DS TB and 18 with DR TB, before initiation of treatment and at 2 weeks and 2 months thereafter. Prior to treatment, DD-Mtb cells represented the majority of M. tuberculosis cells in the sputum of 21% of subjects with DS TB, and this proportion rose to 65% after 2 weeks of treatment with first-line drugs. In subjects with DR TB, DD-Mtb cells were found in the sputum of 29% of subjects prior to treatment initiation, and this proportion remained steady at 31% after 2 weeks of treatment with second-line drugs. By 2 months, DD-Mtb cells were detected in the sputum of only 2/15 (13.3%) subjects with DS TB and in 0/15 of subjects with DR TB. One of the DS subjects whose sputum was positive for DD-Mtb at month 2 later experienced treatment failure.

Gastrointestinal microbiota composition predicts peripheral inflammatory state during treatment of human tuberculosis.

The composition of the gastrointestinal microbiota influences systemic immune responses, but how this affects infectious disease pathogenesis and antibiotic therapy outcome is poorly understood. This question is rarely examined in humans due to the difficulty in dissociating the immunologic effects of antibiotic-induced pathogen clearance and microbiome alteration. Here, we analyze data from two longitudinal studies of tuberculosis (TB) therapy (35 and 20 individuals) and a cross sectional study from 55 healthy controls, in which we collected fecal samples (for microbiome analysis), sputum (for determination of Mycobacterium tuberculosis (Mtb) bacterial load), and peripheral blood (for transcriptomic analysis). We decouple microbiome effects from pathogen sterilization by comparing standard TB therapy with an experimental TB treatment that did not reduce Mtb bacterial load. Random forest regression to the microbiome-transcriptome-sputum data from the two longitudinal datasets reveals that renormalization of the TB inflammatory state is associated with Mtb pathogen clearance, increased abundance of Clusters IV and XIVa Clostridia, and decreased abundance of Bacilli and Proteobacteria. We find similar associations when applying machine learning to peripheral gene expression and microbiota profiling in the independent cohort of healthy individuals. Our findings indicate that antibiotic-induced reduction in pathogen burden and changes in the microbiome are independently associated with treatment-induced changes of the inflammatory response of active TB, and the response to antibiotic therapy may be a combined effect of pathogen killing and microbiome driven immunomodulation.

Case Report: Multidrug-Resistant Tuberculosis and COVID-19 Coinfection in Port-au-Prince, Haiti.

The COVID-19 pandemic poses a unique threat to patients with multidrug-resistant tuberculosis (MDR-TB). We describe a case of a patient with pulmonary MDR-TB and COVID-19 in Port-au-Prince, Haiti, and highlight the challenges and approach to managing a patient with both diseases.

Mortality in adults with multidrug-resistant tuberculosis and HIV by antiretroviral therapy and tuberculosis drug use: an individual patient data meta-analysis.

BACKGROUND: HIV-infection is associated with increased mortality during multidrug-resistant tuberculosis treatment, but the extent to which the use of antiretroviral therapy (ART) and anti-tuberculosis medications modify this risk are unclear. Our objective was to evaluate how use of these treatments altered mortality risk in HIV-positive adults with multidrug-resistant tuberculosis. METHODS: We did an individual patient data meta-analysis of adults 18 years or older with confirmed or presumed multidrug-resistant tuberculosis initiating tuberculosis treatment between 1993 and 2016. Data included ART use and anti-tuberculosis medications grouped according to WHO effectiveness categories. The primary analysis compared HIV-positive with HIV-negative patients in terms of death during multidrug-resistant tuberculosis treatment, excluding those lost to follow up, and was stratified by ART use. Analyses used logistic regression after exact matching on country World Bank income classification and drug resistance and propensity-score matching on age, sex, geographic site, year of multidrug-resistant tuberculosis treatment initiation, previous tuberculosis treatment, directly observed therapy, and acid-fast-bacilli smear-positivity to obtain adjusted odds ratios (aORs) and 95% CIs. Secondary analyses were conducted among those with HIV-infection. FINDINGS: We included 11 920 multidrug-resistant tuberculosis patients. 2997 (25%) were HIV-positive and on ART, 886 (7%) were HIV-positive and not on ART, and 1749 (15%) had extensively drug-resistant tuberculosis. By use of HIV-negative patients as reference, the aOR of death was 2·4 (95% CI 2·0-2·9) for all patients with HIV-infection, 1·8 (1·5-2·2) for HIV-positive patients on ART, and 4·2 (3·0-5·9) for HIV-positive patients with no or unknown ART. Among patients with HIV, use of at least one WHO Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death. INTERPRETATION: Use of ART and more effective anti-tuberculosis drugs is associated with lower odds of death among HIV-positive patients with multidrug-resistant tuberculosis. Access to these therapies should be urgently pursued. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Improved Outcomes With High-dose Isoniazid in Multidrug-resistant Tuberculosis Treatment in Haiti.

We report outcomes for a cohort of patients with multidrug-resistant tuberculosis who received high-dose isoniazid in Haiti. Patients who received high-dose isoniazid had a faster time to culture conversion and higher odds of successful outcome, despite high-level isoniazid resistance. This suggests high-dose isoniazid may have effectiveness even with phenotypic resistance.

Potentially High Number of Ineffective Drugs with the Standard Shorter Course Regimen for Multidrug-Resistant Tuberculosis Treatment in Haiti.

Multidrug-resistant tuberculosis (MDR-TB) outcomes are poor partly because of the long treatment duration; the World Health Organization conditionally recommends a shorter course regimen to potentially improve treatment outcomes. Here, we describe the drug susceptibility patterns of a cohort of MDR-TB patients in Haiti and determine the number of likely effective drugs if they were treated with the recommended shorter course regimen. We retrospectively examined drug susceptibility patterns of adults initiating MDR-TB treatment between 2008 and 2015 at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections in Port-au-Prince, Haiti. First- and second-line drug susceptibility testing (DST) was analyzed and used to determine the number of presumed effective drugs. Of the 239 patients analyzed, 226 (95%), 183 (77%), 135 (57%), and 38 (16%) isolates were resistant to high-dose isoniazid, ethambutol, pyrazinamide, and ethionamide, respectively. Eight patients (3%) had resistance to either a fluoroquinolone or a second-line injectable and none had extensively resistant TB. Of the 239 patients, 132 (55%) would have fewer than five likely effective drugs in the intensive phase of the recommended shorter course regimen and 121 (51%) would have two or fewer likely effective drugs in the continuation phase. Because of the high rates of resistance to first-line TB medications, about 50% of MDR-TB patients would be left with only two effective drugs in the continuation phase of the recommended shorter course regimen, raising concerns about the effectiveness of this regimen in Haiti and the importance of using DST to guide treatment.