Browsing by Author "Diacon, Andreas H."
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- ItemBedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial(Elsevier, 2019) Tweed, Conor D.; Dawson, Rodney; Burger, Divan A.; Conradie, Almari; Crook, Angela M.; Mendel, Carl M.; Conradie, Francesca; Diacon, Andreas H.; Ntinginya, Nyanda E.; Everitt, Daniel E.; Haraka, Frederick; Li, Mengchun; Van Niekerk, Christo H.; Okwera, Alphonse; Rassool, Mohammed S.; Reither, Klaus; Sebe, Modulakgotla A.; Staples, Suzanne; Variava, Ebrahim; Spigelman, MelvinBackground: New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis. Methods: In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDR plus ) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1–14 then 200 mg three times per week (B load PaZ) or oral bedaquiline 200 mg daily (B 200 PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B 200 PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0–56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log 10 (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov , NCT02193776 , and all patients have completed follow-up. Findings: Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to B load PaZ, 60 to B 200 PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the B load PaZ group, 56 in the B 200 PaZ group, and 59 in the HRZE group were included in the primary analysis. B 200 PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61–5·77]), followed by B load PaZ (4·87% [4·31–5·47]) and HRZE group (4·04% [3·67–4·42]). The bactericidal activity in B 200 PaZ and B load PaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the B load PaZ (six [10%] of 59) and B 200 PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the B load PaZ group, three [5%] in the B 200 PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the B load PaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment. Interpretation: B 200 PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B 200 PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes. Funding: TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.
- ItemComparing rates of mycobacterial clearance in sputum smear-negative and smear-positive adults living with HIV(BMC (part of Springer Nature), 2021-05-22) Machowski, Edith E.; Letutu, Matebogo; Lebina, Limakatso; Waja, Ziyaad; Msandiwa, Reginah; Milovanovic, Minja; Gordhan, Bhavna G.; Otwombe, Kennedy; Friedrich, Sven O.; Chaisson, Richard; Diacon, Andreas H.; Kana, Bavesh; Martinson, NeilBackground: Pulmonary tuberculosis (TB) in people living with HIV (PLH) frequently presents as sputum smearnegative. However, clinical trials of TB in adults often use smear-positive individuals to ensure measurable bacterial responses following initiation of treatment, thereby excluding HIV-infected patients from trials. Methods: In this prospective case cohort study, 118 HIV-seropositive TB patients were assessed prior to initiation of standard four-drug TB therapy and at several time points through 35 days. Sputum bacillary load, as a marker of treatment response, was determined serially by: smear microscopy, Xpert MTB/RIF, liquid culture, and colony counts on agar medium. Results: By all four measures, patients who were baseline smear-positive had higher bacterial loads than those presenting as smear-negative, until day 35. However, most smear-negative PLH had significant bacillary load at enrolment and their mycobacteria were cleared more rapidly than smear-positive patients. Smear-negative patients’ decline in bacillary load, determined by colony counts, was linear to day 7 suggesting measurable bactericidal activity. Moreover, the decrease in bacterial counts was comparable to smear-positive individuals. Increasing cycle threshold values (Ct) on the Xpert assay in smear-positive patients to day 14 implied decreasing bacterial load. Conclusion: Our data suggest that smear-negative PLH can be included in clinical trials of novel treatment regimens as they contain sufficient viable bacteria, but allowances for late exclusions would have to be made in sample size estimations. We also show that increases in Ct in smear-positive patients to day 14 reflect treatment responses and the Xpert MTB/RIF assay could be used as biomarker for early treatment response.
- ItemDirect susceptibility testing of Mycobacterium tuberculosis for Pyrazinamide by Use of the Bactec MGIT 960 system(American Society for Microbiology, 2016-05) Demers, Anne-Marie; Venter, Amour; Friedrich, Sven O.; Rojas-Ponce, Gabriel; Mapamba, Daniel; Jugheli, Levan; Sasamalo, Mohammed; Almeida, Deepak; Dorasamy, Afton; Jentsch, Ute; Gibson, Mara; Everitt, Daniel; Eisenach, Kathleen D.; Diacon, Andreas H.Pyrazinamide (PZA) is a key antituberculosis drug, yet no rapid susceptibility test is commercially available. PZA drug susceptibility testing (DST) was performed directly on sputum samples from 327 patients and compared with the indirect method by using the Bactec MGIT 960 system in the context of patient screening for participation in a drug trial. Compared to standard indirect PZA DST, direct DST was successful in only 59% of cases, but results obtained were highly accurate and available faster. Agreement between the direct and indirect methods varied from 90 to 100% in each laboratory. The median times for obtaining PZA results from the time when the specimen was collected ranged from 11 to 16 days for the direct test and 18 to 95 days for the indirect test across laboratories. The direct method is accurate and reproducible across laboratories. It can be expected to accelerate results in >50% of cases, but it cannot replace indirect DST for PZA. Phenotypic methods remain the gold standard for DST in drug trials. If future studies can optimize the method to decrease the number of uninterpretable results, direct MGIT DST could be the new phenotypic DST standard for clinical trials, providing more rapid detection of resistance to new drugs in experimental regimens.
- ItemLimited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials(BioMed Central, 2016-02-04) Phillips, Patrick P. J.; Mendel, Carl M.; Burger, Divan A.; Crook, Angela M.; Nunn, Andrew J.; Dawson, Rodney; Diacon, Andreas H.; Gillespie, Stephen H.Background: Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decisionmaking for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Methods: Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Results: Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Conclusions: Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.
- ItemLiver toxicity associated with tuberculosis chemotherapy in the REMoxTB study(BioMed Central, 2018-03-28) Tweed, Conor Duncan; Wills, Genevieve Helen; Crook, Angela M.; Dawson, Rodney; Diacon, Andreas H.; Louw, Cheryl E.; McHugh, Timothy D.; Mendel, Carl; Meredith, Sarah; Mohapi, Lerato; Murphy, Michael E.; Murray, Stephen; Murthy, Sara; Nunn, Andrew J.; Phillips, Patrick P. J.; Singh, Kasha; Spigelman, M.; Gillespie, S. H.Background: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. Methods: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. Results: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14–56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). Conclusions: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
- ItemMycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis(PLoS, 2014-04-14) Wallis, Robert S.; Dawson, Rodney; Friedrich, Sven O.; Venter, Amour; Paige, Darcy; Zhu, Tong; Silvia, Annette; Gobey, Jason; Ellery, Craig; Zhang, Yao; Eisenach, Kathleen; Miller, Paul; Diacon, Andreas H.Rationale: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. Methods: Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. Results: All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. Conclusions: The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted.
- ItemA new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP)(BioMed Central, 2016-03-23) Phillips, Patrick P. J.; Dooley, Kelly E.; Gillespie, Stephen H.; Heinrich, Norbert; Stout, Jason E.; Nahid, Payam; Diacon, Andreas H.; Aarnoutse, Rob E.; Kibiki, Gibson S.; Boeree, Martin J.; Hoelscher, MichaelBackground: The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world’s greatest infectious disease killer. Methods: We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. Results: With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Conclusions: Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.
- ItemAn optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens : study protocol for a randomized controlled trial(BioMed Central, 2017-11-25) Bouton, Tara C.; Phillips, Patrick P. J.; Mitnick, Carole D.; Peloquin, Charles A.; Eisenach, Kathleen; Patientia, Ramonde F.; Lecca, Leonid; Gotuzzo, Eduardo; Gandhi, Neel R.; Butler, Donna; Diacon, Andreas H.; Martel, Bruno; Santillan, Juan; Hunt, Kathleen R.; Vargas, Dante; Von Groote-Bidlingmaier, Florian; Seas, Carlos; Dianis, Nancy; Moreno-Martinez, Antonio; Horsburgh, C. R.Background: Current guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined. Methods/design: We designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient’s Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen. Discussion: Fluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens.
- ItemThe population pharmacokinetics of meropenem in adult patients with rifampicin-sensitive pulmonary tuberculosis(Frontiers Media S.A., 2021-06) Abulfathi, Ahmed A.; De Jager, Veronique; Van Brakel, Elana; Reuter, Helmuth; Gupte, Nikhil; Vanker, Naadira; Barnes, Grace L.; Nuermberger, Eric; Dorman, Susan E.; Diacon, Andreas H.; Dooley, Kelly E.; Svensson, Elin M.Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
- ItemSputum volume predicts sputum mycobacterial load during the first 2 weeks of antituberculosis treatment(American Society for Microbiology, 2015-12) Karinja, Miriam N.; Esterhuizen, Tonya M.; Friedrich, Sven O.; Diacon, Andreas H.Disease severity in patients with pulmonary tuberculosis is associated with mycobacterial sputum load. To ascertain whether reduced sputum production during treatment is a useful clinical sign of improvement, we analyzed the mycobacterial loads of 5,552 sputum samples collected from 439 newly diagnosed sputum smear-positive tuberculosis patients who participated in six 14-day studies of antituberculosis treatment. Sputum volumes were categorized as low (<6 ml), medium (6 to 10 ml), or large (>10 ml), and mycobacterial load was measured by the time to positivity in liquid culture and the CFU counts on solid culture. The association of sputum volume with mycobacterial load was estimated with multiple linear regression models adjusted for repeated measures. The predictor variables were sputum volume category, treatment day, specific study , and the interaction of sputum volume category and treatment day. Mycobacterial load was significantly associated only with the day on treatment and sputum volume, which tended to decrease with ongoing treatment. With the volume held constant, each day on treatment decreased the log CFU by 0.082 (P < 0.001) and increased the time to positivity (TTP) by 1.04 h (P < 0.001). From low to medium and from medium to large sputum volumes, the log CFU/ml increased by 0.265 (P < 0.003) and 0.490 (P < 0.001), respectively, and the TTP decreased by 1.17 h (P < 0.001) and 1.30 h (P < 0.001), respectively, for a given day of treatment. The variability of the sputum load measurements increased with the day of treatment and lower sputum volumes. The significant association of sputum volume and mycobacterial load validates decreasing sputum production as a clinical sign of improvement during early antituberculosis treatment.
- ItemToxicity associated with tuberculosis chemotherapy in the REMoxTB study(BioMed Central, 2018-07-11) Tweed, Conor D.; Crook, Angela M.; Amukoye, Evans I.; Dawson, Rodney; Diacon, Andreas H.; Hanekom, Madeline; McHugh, Timothy D.; Mendel, Carl M.; Meredith, Sarah K.; Murphy, Michael E.; Murthy, Saraswathi E.; Nunn, Andrew J.; Phillips, Patrick P. J.; Singh, Kasha P.; Spigelman, Melvin; Wills, Genevieve H.; Gillespie, Stephen H.Background: The incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin. Methods: All grade 3 & 4 adverse events (AEs) and their relationship to treatment for patients who had taken at least one dose of therapy in the REMoxTB clinical trial were recorded. Univariable logistic regression was used to test the relationship of baseline characteristics to the incidence of grade 3 & 4 AEs and significant characteristics (p < 0.10) were incorporated into a multivariable model. The timing of AEs during therapy was analysed in standard therapy and the experimental arms. Logistic regression was used to investigate the relationship between AEs (total and related-only) and microbiological cure on treatment. Results: In the standard therapy arm 57 (8.9%) of 639 patients experienced ≥1 related AEs with 80 of the total 113 related events (70.8%) occurring in the intensive phase of treatment. Both four-month experimental arms (“isoniazid arm” with moxifloxacin substituted for ethambutol & “ethambutol arm” with moxifloxacin substituted for isoniazid) had a lower total of related grade 3 & 4 AEs than standard therapy (63 & 65 vs 113 AEs). Female gender (adjOR 1.97, 95% CI 0.91–1.83) and HIV-positive status (adjOR 3.33, 95% CI 1.55–7.14) were significantly associated with experiencing ≥1 related AE (p < 0.05) on standard therapy. The most common adverse events on standard therapy related to hepatobiliary, musculoskeletal and metabolic disorders. Patients who experienced ≥1 related AE were more likely to fail treatment or relapse (adjOR 3.11, 95% CI 1.59–6.10, p < 0.001). Conclusions: Most AEs considered related to standard therapy occurred in the intensive phase of treatment with female patients and HIV-positive patients demonstrating a significantly higher risk of AEs during treatment. Almost a tenth of standard therapy patients had a significant side effect, whereas both experimental arms recorded a lower incidence of toxicity. That patients with one or more AE are more likely to fail treatment suggests that treatment outcomes could be improved by identifying such patients through targeted monitoring.
- ItemToxicity related to standard TB therapy for pulmonary tuberculosis and treatment outcomes in the REMoxTB study according to HIV status(BMC (part of Springer Nature), 2019-08-14) Tweed, Conor D.; Crook, Angela M.; Dawson, Rodney; Diacon, Andreas H.; McHugh, Timothy D.; Mendel, Carl M.; Meredith, Sarah K.; Mohapi, Lerato; Murphy, Michael E.; Nunn, Andrew J.; Phillips, Patrick P. J.; Singh, Kasha P.; Spigelman, Melvin; Gillespie, Stephen H.Background: The phase III REMoxTB study prospectively enrolled HIV-positive (with CD4+ count > 250 cells, not on anti-retroviral therapy) and HIV-negative patients. We investigated the incidence of adverse events and cure rates according to HIV status for patients receiving standard TB therapy in the trial. Methods: Forty-two HIV-positive cases were matched to 220 HIV-negative controls by age, gender, ethnicity, and trial site using coarsened exact matching. Grade 3 and 4 adverse events (AEs) were summarised by MedDRA System Organ Class. Kaplan-Meier curves for time to first grade 3 or 4 AE were constructed according to HIV status with hazard ratios calculated. Patients were considered cured if they were culture negative 18 months after commencing therapy with ≥2 consecutive negative culture results. Results: Twenty of 42 (47.6%) HIV-positive and 34 of 220 (15.5%) HIV-negative patients experienced ≥1 grade 3 or 4 AE, respectively. The majority of these were hepatobiliary disorders that accounted for 12 of 40 (30.0%) events occurring in 6 of 42 (14.3%) HIV-positive patients and for 15 of 60 (25.0%) events occurring in 9 of 220 (4.1%) HIVnegative patients. The median time to first grade 3 or 4 AE was 54 days (IQR 15.5–59.0) for HIV-positive and 29.5 days (IQR 9.0–119.0) for HIV-negative patients, respectively. The hazard ratio for experiencing a grade 3 or 4 AE among HIV-positive patients was 3.25 (95% CI 1.87–5.66, p < 0.01). Cure rates were similar, with 38 of 42 (90.5%) HIV-positive and 195 of 220 (88.6%) HIV-negative patients (p = 0.73) cured at 18 months. Conclusions: HIV-positive patients receiving standard TB therapy in the REMoxTB study were at greater risk of adverse events during treatment but cure rates were similar when compared to a matched sample of HIV-negative patients.
- ItemUltrathin bronchoscopy for solitary pulmonary lesions in a region endemic for tuberculosis : a randomised pilot trial(BioMed Central, 2016) Franzen, Daniel; Diacon, Andreas H.; Freitag, Lutz; Schubert, Pawel T.; Wright, Colleen A.; Schuurman, Mace M.Background: The evaluation of solitary pulmonary lesions (SPL) requires a balance between procedure-related morbidity and diagnostic yield, particularly in areas where tuberculosis (TB) is endemic. Data on ultrathin bronchoscopy (UB) for this purpose is limited. To evaluate feasibility and safety of UB compared to SB for diagnosis of SPL in a TB endemic region. Methods: In this prospective randomised trial we compared diagnostic yield and adverse events of UB with standard- size bronchoscopy (SB), both combined with fluoroscopy, in a cohort of patients with SPL located beyond the visible range of SB. Results: We included 40 patients (mean age 55.2 years, 45 % male) with malignant SPL ( n = 16; 40 %), tuberculous SPL ( n = 11; 27.5 %) and other benign SPL ( n = 13; 32.5 %). Mean procedure time in UB and SB was 30.6 and 26.0 min, respectively ( p = 0.15). By trend, adverse events were recorded more often with UB than with SB (30.0 vs. 5.0 %, p = 0.091), including extensive coughing ( n = 2), blocked working channel ( n = 2), and arterial hypertension requiring therapeutic intervention ( n = 1), all with UB. The overall diagnostic yield of UB compared to SB was 55.0 % vs. 80.0 %, respectively ( p = 0.18). Sensitivity for the diagnosis of malignancy of UB and SB was 50.0 % and 62.5 %, respectively ( p =0.95). Conclusion: UB is not superior to SB for the evaluation of SPL in a region endemic with tuberculosis, when combined with fluoroscopic guidance only. Trial registration: ClinicalTrials.gov (Identifier: NCT02490059).
- ItemXpert mycobacterium tuberculosis/rifampicin-detected rifampicin resistance is a suboptimal surrogate for multidrug-resistant tuberculosis in Eastern Democratic Republic of the Congo : diagnostic and clinical implications(Oxford University Press, 2020-06) Bisimwa, Bertin C.; Nachega, Jean B.; Warren, Robin M.; Theron, Grant; Metcalfe, John Z.; Shah, Maunank; Diacon, Andreas H.; Sam-Agudu, Nadia A.; Yotebieng, Marcel; Bulabula, André N. H.; Katoto, Patrick D. M. C.; Chirambiza, Jean-Paul; Nyota, Rosette; Birembano, Freddy M.; Musafiri, Eric M.; Byadunia, Sifa; Bahizire, Esto; Kaswa, Michel K.; Callens, Steven; Kashongwe, Zacharie M.Background Rifampicin (RIF) resistance is highly correlated with isoniazid (INH) resistance and used as proxy for multidrug-resistant tuberculosis (MDR-TB). Using MTBDRplus as a comparator, we evaluated the predictive value of Xpert MTB/RIF (Xpert)–detected RIF resistance for MDR-TB in eastern Democratic Republic of the Congo (DRC). Methods We conducted a cross-sectional study involving data from new or retreatment pulmonary adult TB cases evaluated between July 2013 and December 2016. Separate, paired sputa for smear microscopy and MTBDRplus were collected. Xpert testing was performed subject to the availability of Xpert cartridges on sample remnants after microscopy. Results Among 353 patients, 193 (54.7%) were previously treated and 224 (63.5%) were MTBDRplus TB positive. Of the 224, 43 (19.2%) were RIF monoresistant, 11 (4.9%) were INH monoresistant, 53 (23.7%) had MDR-TB, and 117 (52.2%) were RIF and INH susceptible. Overall, among the 96 samples detected by MTBDRplus as RIF resistant, 53 (55.2%) had MDR-TB. Xpert testing was performed in 179 (50.7%) specimens; among these, 163 (91.1%) were TB positive and 73 (44.8%) RIF resistant. Only 45/73 (61.6%) Xpert-identified RIF-resistant isolates had concomitant MTBDRplus-detected INH resistance. Xpert had a sensitivity of 100.0% (95% CI, 92.1–100.0) for detecting RIF resistance but a positive-predictive value of only 61.6% (95% CI, 49.5–72.8) for MDR-TB. The most frequent mutations associated with RIF and INH resistance were S531L and S315T1, respectively. Conclusions In this high-risk MDR-TB study population, Xpert had low positive-predictive value for the presence of MDR-TB. Comprehensive resistance testing for both INH and RIF should be performed in this setting.