16 research outputs found
The impact of pyrazinamide resistance on the treatment outcome of patients with multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan
Pyrazinamide (PZA), is regarded as an important agent in the management of multi-drug resistant tuberculosis (MDR-TB) (defined as resistance to at least rifampicin and isoniazid) and has been shown to reduce treatment duration for drug-sensitive TB (1). Since the inclusion of PZA in a MDR-TB regimen adds significantly to both the pill burden and the side effects, (mainly arthralgia and hepatitis), it is logical to limit usage to patients where PZA has a proven effect. The current World Health Organisation (WHO) recommendation is to include PZA in MDR-TB regimens unless there is demonstrated evidence of resistance (2). However, large-scale data supporting this recommendation are lacking. No evidence was shown of an association between a successful outcome and PZA susceptibility for MDR-TB patients treated with a full intensive phase PZA standard WHO regimen in a high MDR-TB burden setting. Furthermore, there was no evidence of a dose-response association between a successful outcome and different PZA treatment regimens in the intensive phase. The major limitations was the low power for the main analysis and the retrospective and observational nature of the study contributing to an increased risk of bias. A possible explanation for the results might be that PZA treatment mainly has its effect in shortening a regimen (7) instead of improving outcomes or that patients had sufficient likely effective drugs in their regimen. The generalisability would be limited to settings with low HIV prevalence and where there is a high background prevalence of SLD resistance. This study provides provocative but insufficient evidence to warrant changing PZA treatment protocols, although the evidence relating to PZA for the WHO 2016 guideline is weak. Until further evidence emerges supporting these findings, it seems prudent to continue including PZA in standard MDR-TB regimens unless resistance is certain. We recommend research into alternative add-on agents in settings with high PZA resistance
Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial
BACKGROUND: Around 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis. METHODS: This open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36-80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete. FINDINGS: Between Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference -29·2 percentage points [96·6% CI -39·8 to -18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference -25·2 percentage points [96·6% CI -36·4 to -13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related. INTERPRETATION: The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis. FUNDING: Médecins Sans Frontières
Multidrug-Resistant Tuberculosis Treatment Outcomes in Karakalpakstan, Uzbekistan: Treatment Complexity and XDR-TB among Treatment Failures
BACKGROUND: A pilot programme to treat multidrug-resistant TB (MDR-TB) was implemented in Karakalpakstan, Uzbekistan in 2003. This region has particularly high levels of MDR-TB, with 13% and 40% among new and previously treated cases, respectively. METHODOLOGY: This study describes the treatment process and outcomes for the first cohort of patients enrolled in the programme, between October 2003 and January 2005. Confirmed MDR-TB cases were treated with an individualised, second-line drug regimen based on drug susceptibility test results, while suspected MDR-TB cases were treated with a standardised regimen pending susceptibility results. PRINCIPAL FINDINGS: Of 108 MDR-TB patients, 87 were started on treatment during the study period. Of these, 33 (38%) were infected with strains resistant to at least one second-line drug at baseline, but none had initial ofloxacin resistance. Treatment was successful for 54 (62%) patients, with 13 (15%) dying during treatment, 12 (14%) defaulting and 8 (8%) failing treatment. Poor clinical condition and baseline second-line resistance contributed to treatment failure or death. Treatment regimens were changed in 71 (82%) patients due to severe adverse events or drug resistance. Adverse events were most commonly attributed to cycloserine, ethionamide and p-aminosalicylic acid. Extensively drug resistant TB (XDR-TB) was found among 4 of the 6 patients who failed treatment and were still alive in November 2006. CONCLUSIONS: While acceptable treatment success was achieved, the complexity of treatment and the development of XDR-TB among treatment failures are important issues to be addressed when considering scaling up MDR-TB treatment
Risk factors associated with default from multi- and extensively drug-resistant tuberculosis treatment, uzbekistan: a retrospective cohort analysis.
The Médecins Sans Frontières project of Uzbekistan has provided multidrug-resistant tuberculosis treatment in the Karakalpakstan region since 2003. Rates of default from treatment have been high, despite psychosocial support, increasing particularly since programme scale-up in 2007. We aimed to determine factors associated with default in multi- and extensively drug-resistant tuberculosis patients who started treatment between 2003 and 2008 and thus had finished approximately 2 years of treatment by the end of 2010
Outcomes with a shorter multidrug-resistant tuberculosis regimen from Karakalpakstan, Uzbekistan
Background In 2016, WHO guidelines conditionally recommended standardised shorter 9–12 month regimens for multidrug-resistant tuberculosis (MDR-TB) treatment. We conducted a prospective study of a shorter standardised MDR-TB regimen in Karakalpakstan, Uzbekistan.
Methods Consecutive adults and children with confirmed rifampicin-resistant pulmonary TB were enrolled between 1st September 2013 and 31st March 2015; exclusions included prior treatment with second-line anti-TB drugs, and documented resistance to ofloxacin or to two second-line injectable agents. The primary outcome was recurrence-free cure at 1 year following treatment completion.
Results Of 146 enrolled, 128 patients were included: 67 female (52.3%), median age 30.1 (IQR 23.8–44.4) years. At the end of treatment, 71.9% (92/128) patients achieved treatment success, with 68% (87/128) achieving recurrence-free cure at 1 year following completion. Unsuccessful outcomes during treatment included 22 (17.2%) treatment failure with fluoroquinolone resistance amplification in 8 patients (8/22, 36.4%); 12 (9.4%) loss to follow-up; 2 (1.5%) deaths. Recurrence occurred in one patient. 14 patients (10.9%) experienced serious adverse events. Baseline resistance to both pyrazinamide and ethambutol (aOR 6.13, 95% CI 2.01;18.63) and adherence<95% (aOR 5.33, 95% CI 1.73;16.36) were associated with unsuccessful outcome in multivariable logistic regression.
Conclusions Overall success with a standardised shorter MDR-TB regimen was moderate with considerable treatment failure and amplification of fluoroquinolone resistance. When introducing standardised shorter regimens, baseline drug susceptibility testing and minimising missed doses are critical. High rates globally of pyrazinamide, ethambutol and ethionamide resistance raise questions of continued inclusion of these drugs in shorter regimens in the absence of DST-confirmed susceptibility
Where there is hope: a qualitative study examining patients’ adherence to multi-drug resistant tuberculosis treatment in Karakalpakstan, Uzbekistan
Patient and health-care worker perspectives on the short-course regimen for treatment of drug-resistant tuberculosis in Karakalpakstan, Uzbekistan.
IntroductionStandard multidrug-resistant tuberculosis (MDR-TB) treatment is lengthy, toxic, and insufficiently effective. New drugs and a shorter treatment regimen (SCR) are now recommended. However, patient and health-care worker (HCW) perspectives regarding the SCR are unknown. We aimed to determine the views and experiences of patients with MDR-TB and HCW regarding the SCR in Karakalpakstan, Uzbekistan.MethodsIn a qualitative study, we conducted 48 in-depth interviews with 24 people with MDR-TB and 20 HCW, purposively recruited to include those with a range of treatment-taking experiences and employment positions. Data were analysed thematically using Nvivo 12, to identify emergent patterns, concepts, and categories. Principles of grounded theory were drawn upon to generate findings inductively from participants' accounts.ResultsAll patients viewed the SCR favourably. The SCR was seen as enabling an expedited return to work, studies, and "normality". This reduced the burden of treatment and difficulties with treatment fatigue. The SCR appeared to improve mental health, ease difficulties with TB-related stigma, and foster improved adherence. While patients wanted shorter treatment, it was also important that treatment be tolerable and effective. However, HCW doubted the appropriateness and effectiveness of the SCR, which influenced their confidence in prescribing the regimen.ConclusionThe SCR was said to benefit treatment completion and patients' lives. HCW concerns about SCR appropriateness and effectiveness may influence who receives the regimen. These are important considerations for SCR implementation and MDR-TB treatment developments, and dissonance between patient and HCW perspectives must be addressed for successful implementation of shorter regimens in the future
Factors associated with default identified by multivariate analysis.
<p>OR = odds ratio. XDR = extensively drug-resistant. Cat II = category II treatment.</p
Baseline proportions and association of factors with default by univariate analysis.
<p>BMI = body-mass index. MDR = multidrug-resistant. Cat I = category I treatment. Cat II = category II treatment. XDR = extensively drug-resistant.</p