Drug-resistant tuberculosis (TB) has become one of the main obstacles to controlling (and eventually eliminating) this disease 1–4. The World Health Organization (WHO) reports that the number of ...patients suffering from TB with resistance to rifampicin (RR-TB) or multidrug-resistant TB (MDR-TB, resistance to at least isoniazid and rifampicin) is increasing alarmingly each year. Furthermore, the treatment success rates achieved globally are suboptimal, barely exceeding 50% 1, 2, 5. The proportion decreases to 25% in patients with extensively drug-resistant tuberculosis (XDR-TB) (MDR-TB plus resistance to at least one fluoroquinolone (FQ) and a second-line injectable (SLI) drug) and to <20% when the drug resistance profile is beyond XDR 1, 2, 5.
Bedaquiline: how better to use it Caminero, Jose A; Piubello, Alberto; Scardigli, Anna ...
The European respiratory journal,
11/2017, Letnik:
50, Številka:
5
Journal Article
Recenzirano
Odprti dostop
We read with interest the correspondence by J. Furin and co-workers and we wish to thank them for their useful comments on our editorial proposing a rationale for a standardised regimen to manage ...difficult-to-treat cases affected by extensively drug-resistant tuberculosis (XDR-TB) or by so-called pre-extensively drug-resistant tuberculosis (pre-XDR; multidrug-resistant tuberculosis (MDR-TB) cases with additional resistance to fluoroquinolones or second-line injectable drugs) 1. We agree with the comments by Furin and co-workers and the arguments discussing the possible use of the new drugs (bedaquiline and/or delamanid) for more than 6 months. Clinicians know very well how difficult it is to manage the treatment of these cases in view of their clinical complexity (with frequent adverse events), long duration and high cost 2–4. Considering the new perspectives for treating MDR-TB and XDR-TB we fully agree that we are presently facing exciting times. We finally have a couple of new and repurposed drugs and we are slowly discovering how best to use them, as well as how effective and safe they are 4–7. The necessary body of knowledge to support evidence-based recommendations will need time to be raised and this is reflected by the increase in new proposals and recommendations being issued 8, 9. Among the different ingredients for a potential, future standardised regimen for MDR/XDR-TB cases, the biological plausibility of the core drugs to be used (bactericidal and sterilising) is particularly important (table 1) 1. As both bedaquiline and delamanid have excellent characteristics, both their prolonged and/or combined use will be challenges that will need to be faced in the future. Slowly but surely new evidence is becoming available 2, 3 and we are confident that, given the high morbidity and mortality caused by MDR/XDR-TB, as well as the collaborative spirit animating clinicians, public health officers, policy makers, donors and members of the affected communities, better evidence will be raised to always ensure that the patient is adequately protected. Finally, the “off-label” use of drugs is sometimes necessary to manage patients for whom no other alternatives exist. Their use requires adequate capacity in terms of clinical expertise, laboratory support and infection control measures. We therefore hope that our proposal will soon be supported by the necessary evidence so as to be useful, safe and effective.
•Triple-dose rifampicin is known to be safe for tuberculosis treatment.•Triple-dose isoniazid is known to be safe for tuberculosis treatment.•A triple dose of both rifampicin and isoniazid causes ...excess drug-related adverse events.•Treatment for six months throughout with four first-line drugs, all at a normal dose, is safe.
High-dose rifampicin (R) and isoniazid (H) are known to be safe but were not yet combined in a single regimen. The primary objective of the TRIple-DOse RE-treatment (TRIDORE) study is to determine whether a 6-month firstline regimen with triple dose of both R and H (intervention arm; 6R3H3ZE) is non-inferior in terms of safety compared to a normal-dose regimen (6RHZE) in previously treated patients with R-susceptible (Rs) recurrent tuberculosis (TB).
TRIDORE is an ongoing pragmatic open-label multi-stage randomized clinical trial.
Between March 2021 and February 2022, 127 consenting patients were randomly assigned to either the intervention or control arm: 62 and 65 were treated with 6R3H3ZE and 6RHZE, respectively. Of 127, 111 (87.4%) were male and the median age (interquartile range) was 37 (30-48) years. The median body mass index at enrollment was 18.1 (16.3-19.7) kg/m2. Drugrelated severe adverse events (AEs) (grade III-V) were significantly more frequent when 6R3H3ZE was used (5/62 vs 0/65, P = 0.03, difference weighted for site 8% 95% confidence interval: 1.0,14.3). The Data and Safety Monitoring Board recommended publishing our interim safety data analysis.
We show that the combination of triple-dose R with triple-dose H in a re-treatment regimen for patients with Rs-TB causes excess drug-related AEs.
•Multidrug-resistant/rifampicin-resistant tuberculosis remains a major threat to global health, mainly in low-income settings.•We found a successful treatment outcome of 74.6% in Central and West ...Africa.•The World Health Organization reported an average global success rate of 59% in 2018.•Shorter and standardized regimens may have contributed to better success rates.•Treatment outcome data of multidrug-resistant/rifampicin-resistant tuberculosis is sparse in this region and further investigation is warranted.
We aimed to investigate published data on treatment outcomes of multidrug-resistant (MDR)/rifampicin-resistant tuberculosis (TB) in Central and West Africa because these, to the best of our knowledge, are sparsely available.
Systematic review and meta-analysis.
A total of 14 studies were included, representing 4268 individuals in 14 of the 26 countries. Using a random-effects model meta-analysis, we observed a pooled success rate of 80.8% (95% confidence interval CI 56.0-93.3) for the Central African subgroup and 69.2% (95% CI 56.3-79.7) for the West African subgroup (P = 0.0522). The overall treatment success for all studies was 74.6% (95% CI 65.0-82.2). We found high heterogeneity among included studies (I2 = 96.1%). The estimated proportion of successfully treated individuals with MDR/rifampicin-resistant TB was considerably higher than the global estimate provided by the World Health Organization (59%), reaching the 2015 World Health Organization target of at least 75% treatment success for MDR-TB.
The use of shorter treatment regimens and the standardized treatment conditions, including directly observed therapy in these studies, could have contributed to a high treatment success. Yet, the available literature was not fully representative of the regions, possibly highlighting the sparse resources in many of these countries.
The review was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/) (CRD42022353163).
We read with great interest the paper by Falzon et al. 1, which reported that gatifloxacin and moxifloxacin have been recommended by the World Health Organization (WHO) for both longer and shortened ...regimens in the treatment of rifampicin-resistant (RR) and multidrug-resistant (MDR) tuberculosis (TB). Gatifloxacin and moxifloxacin belong to the latest generation of fluoroquinolones that have comparable early bactericidal and sterilising activity in the treatment of TB. Gatifloxacin has been used in the treatment of bacterial infections and MDR-TB 2. Gatifloxacin was also used in a clinical trial (OFLOTUB) comparing a 4-month gatifloxacin-based regimen with the standard 6-month regimen for the treatment of rifampicin-susceptible pulmonary TB 3. The gatifloxacin-based shortened treatment was highly effective, achieving >84% treatment success among MDR-TB patients in Bangladesh, Cameroon and Niger 2.
Rifampicin-resistant tuberculosis (RR-TB) treatment requires combination treatment, which frequently causes serious adverse events and globally results in not much more than 60% treatment success. In ...Niger, a high cure rate was obtained with a RR-TB treatment strategy based on a second-line injectable drug (SLID)-containing Short Treatment Regimen (STR), with linezolid replacing the SLID in patients with ototoxicity. Given the availability of novel anti-tuberculosis drugs, WHO recommends all-oral RR-TB treatment. Considering the high level of success with the Niger treatment strategy, it would only be justified to replace it in case robust evidence shows that the WHO all-oral bedaquiline/linezolid (BDQ/LZD)-containing STR (experimental arm) performs better than the Niger RR-TB treatment strategy, (control arm) in terms of safety, effectiveness and adherence.
A pragmatic randomised clinical trial (RCT) using stratified block randomisation, conducted between April 2021 and March 2024, prospectively enrols participants diagnosed with RR-TB in one of the four RR-TB units of the nation. Depending of the month in which patients are diagnosed with RR-TB, patients with FQ-susceptible RR-TB are enrolled in either the experimental arm or control arm.
To increase the feasibility of conducting a RCT, embedded in routine activities of all Niger's RR-TB Units, we used a creative trial design. We randomised by monthly blocks, whereby the regimen used changes every month, using the month of RR-TB diagnosis as stratifying variable. This approach was deemed feasible for Niger's national tuberculosis programme, as it simplifies the work of the clinicians running the RR-TB units. Our creative design may serve as an example for other national programs. Findings will inform national and international RR-TB treatment guidelines, and will also strengthen the evidence-base on how to develop robust RR-TB treatment regimens.
Pan African Clinical Trial Register PACTR202203645724919 . Registered on 15 March 2022.
Leprosy is an ancient infectious disease with an annual global incidence of around 200,000 over the past decade. Since 2018, the World Health Organization (WHO) recommends single-dose rifampicin as ...post-exposure prophylaxis (SDR-PEP) for contacts of leprosy patients. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial evaluated PEP with a double dose of rifampicin in Comoros and Madagascar. Preliminary results of this trial show some reduction in leprosy incidence in intervention villages but a stronger regimen may be beneficial. The objective of the current Bedaquiline Enhanced ExpOsure Prophylaxis for LEprosy trial (BE-PEOPLE) is to explore effectiveness of a combination of bedaquiline and rifampicin as PEP.
BE-PEOPLE is a cluster-randomized trial in which 44 clusters in Comoros will be randomized to two study arms. Door-to-door screening will be conducted annually during four years, leprosy patients identified will be offered standard of care treatment. Based on study arm, contacts aged five years and above and living within a 100-meter radius of an index case will either receive bedaquiline (400-800 mg) and rifampicin (150-600 mg) or only rifampicin (150-600 mg). Contacts aged two to four years will receive rifampicin only. Household contacts randomized to the bedaquiline plus rifampicin arm will receive a second dose four weeks later. Incidence rate ratios of leprosy comparing contacts who received either of the PEP regimens will be the primary outcome. We will monitor resistance to rifampicin and/or bedaquiline through molecular surveillance in all incident tuberculosis and leprosy patients nationwide. At the end of the study, we will assess anti-M. leprae PGL-I IgM seropositivity as a proxy for the population burden of M. leprae infection in 8 villages (17,000 individuals) that were surveyed earlier as part of the PEOPLE trial.
The COLEP trial on PEP in Bangladesh documented a reduction of 57% in incidence of leprosy among contacts treated with SDR-PEP after two years, which led to the WHO recommendation of SDR-PEP. Preliminary results of the PEOPLE trial show a lesser reduction in incidence. The BE-PEOPLE trial will explore whether reinforcing SDR-PEP with bedaquiline increases effectiveness and more rapidly reduces the incidence of leprosy, compared to SDR-PEP alone.
NCT05597280. Protocol version 5.0 on 28 October 2022.
To describe treatment outcomes for rifampicin-resistant tuberculosis (Rr-TB) started on standard regimen and the frequency of acquired drug resistance in patients treated using the standard treatment ...regimen (STR) in Cameroon between 2015-2019.
This is a retrospective cohort study. Rr-TB patients were initiated on the STR, including a fluoroquinolone (FQ), a second-line injectable drug (SLI), and companion drugs. In case of resistance to fluoroquinolones (FQr) at baseline, FQ, SLI and ethionamide were replaced by bedaquiline, delamanid, and linezolid in a modified treatment regimen (mTR), FQr-mTR. In case of resistance to SLI (SLIr) at baseline, SLI was replaced by linezolid (LZD), SLIr-mTR. Logistic regression and competing risk regression were used to estimate predictors of early (first eight weeks) mortality and overall mortality, respectively.
Of 709 patients started on a standard regimen, treatment success occurred in 84.7% (587/693), 72.7% (8/11) and 100% (10/10) of patients treated with STR, FQr-mTR and SLIr-mTR as final regimens, respectively. Three (0.6%) patients acquired FQr during treatment. Early mortality occurred in 4.1% (29/709) and was associated with being HIV positive, male sex and being underweight. Overall mortality was associated with missing drug-susceptibility testing results at baseline, being HIV positive, age>40 and male sex.
Programmatic management of Rr-TB, with additional second-line drug resistance treated with mTR, resulted in excellent treatment outcomes.
About ten years ago, the first results of the so-called "Bangladesh regimen", a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) ...treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine.
Dr Georges Bakaswa Ntambwe, 1950-2016 Piubello, Alberto
The international journal of tuberculosis and lung disease,
10/2017, Letnik:
21, Številka:
10
Journal Article
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