The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, ...including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013–2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.
Treatment outcomes of the shorter regimen for rifampicin-resistant tuberculosis are not completely established. We report on these outcomes two years after treatment completion among patients ...enrolled in an observational cohort study in nine African countries.
1,006 patients treated with the nine-month regimen were followed every six months with sputum cultures up to 24 months after treatment completion. The risk of any unfavourable outcome, of failure and relapse, and of death during and after treatment was analysed according to patient's characteristics and initial drug susceptibility by Cox proportional hazard models.
Respectively 67.8% and 57.2% patients had >=1 culture result six months and 12 months after treatment completion. Fourteen relapses were diagnosed. The probability of relapse-free success was 79.3% (95% confidence interval CI 76.6–82.0%) overall, 80.9% (95% CI 78.0–84.0%) among HIV-negative and 72.5% (95% CI 66.5–78.9%) among HIV-infected patients. Initial fluoroquinolone (adjusted hazard ratio aHR 6.7 95% CI 3.4–13.1) and isoniazid resistance (aHR 9.4 95% CI 1.3–68.0) were significantly associated with increased risk of failure/relapse and of any unfavourable outcome.
The close to 80% relapse-free success indicates the good outcome of the regimen in low-and middle-income settings. Results confirm the lesser effectiveness of the regimen in patients with initial resistance to fluoroquinolones and support the use of high-dose isoniazid, but do not support exclusion of patients for resistance to drugs other than fluoroquinolones.
Expertise-France and Agence Française de Développement.
In this study, we retrospectively analysed a total of 605 clinical isolates from six West or Central African countries (Benin, Cameroon, Central African Republic, Guinea-Conakry, Niger and Senegal). ...Besides spoligotyping to assign isolates to ancient and modern mycobacterial lineages, we conducted phenotypic drug-susceptibility-testing for each isolate for the four first-line drugs. We showed that phylogenetically modern Mycobacterium tuberculosis strains are more likely associated with drug resistance than ancient strains and predict that the currently ongoing replacement of the endemic ancient by a modern mycobacterial population in West/Central Africa might result in increased drug resistance in the sub-region.
Decroo, de Jong et al express their opinions about an article by Dooley and colleagues which showed that high-dose isoniazid had early bacterial activity for Mycobacterium tuberculosis (MTB) strains ...with inhA mutations similar to that observed with normal-dose isoniazid for susceptible strains. The authors concluded that high-dose isoniazid represents a useful addition to second-line tuberculosis (TB) treatment regimens for patients with rifampicin-resistant TB and isolated inhA mutations. They believe that high dosage may also play a major role in first-line TB treatment. Also emphasized that the World Health Organization (WHO) has recommended adding a second-line TB drug (levofloxacin) to three firstline drugs such as rifampicin, ethambutol and pyrazinamide. Furthermore, no additional susceptibility testing beyond rifampicin testing would be needed and there would be no delay between a diagnosis of rifampicin-susceptible recurrent TB and initiation of treatment.
We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised ...regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0%
75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.
In Niger, the Shorter Treatment Regimen (STR) has been implemented nationwide for rifampicin resistant tuberculosis (RR-TB), since 2008. No previous publication has shown the results from countrywide ...programmatic implementation using few exclusion criteria, nor exhaustively assessed the effect of initial resistance to companion drugs on outcomes.
The National Tuberculosis Programme and the Damien Foundation conducted a retrospective observational study to evaluate the management of RR-TB from 2008 to 2016. Baseline resistance to drugs was assessed phenotypically, complemented by screening the inhA, katG and pncA genes. Cured patients were followed-up for a period of one year after cure.
Among 1044 patients tested for rifampicin resistance, mainly previously treated patients, 332 were diagnosed with pulmonary RR/TB, 288 were enrolled on treatment and 255 started on STR. Six patients received a modified STR.
Among 249 patients on standardised STR, 207 (83·1%) were cured relapse-free, eight (3·2%) had failure, 23 (9·2%) died, seven (2·8%) were lost to follow-up and four (1·6%) relapsed.
The risk of unfavourable outcome was higher in patients with initial resistance to fluoroquinolones (aOR 20·4, 95%CI:5·6–74·6) and very severely underweight (aOR 3·9, 95%CI:1·5–10·1). Successful outcome was not affected by initial resistance to companion drugs. Serious ototoxicity was reported in eight patients (3·2%).
A comprehensive nationwide approach to multidrug-resistant tuberculosis management using the STR was feasible and successful. Outcomes were not affected by initial resistance to companion drugs. Our study confirms the effectiveness and safety of the STR.
Damien Foundation and Institute of Tropical Medicine-Antwerp.
•Countrywide programmatic roll-out shows successful MDR-TB management in Niger.•The short treatment regimen resulted in 83·1% % relapse-free success.•Successful outcome was not affected by initial resistance to companion drugs.•Few patients with relapse or failure cured with bedaquiline-based regimens.•Audiometry to switch from injectable to linezolid prevented severe hearing loss.
The short treatment regimen (STR) achieves a >80% cure in rifampicin-resistant tuberculosis (RR-TB) patients. However, ototoxicity induced by the injectable is a concern. This is the first study to ...evaluate the replacement of injectables by linezolid in patients with audiometry abnormalities at baseline or during the treatment.We conducted a retrospective cohort study of all RR-TB patients started on the STR between 2016 and June, 2019, in Niger. Patients underwent audiometry every 2 months in 2016 and every month since 2017.Of 195 patients, 16.9% (33 out of 195) received linezolid from the start (n=17), or switched from injectables to linezolid during treatment (n=16), based on audiometry abnormalities. In 2016, two patients developed severe ototoxicity despite switching to linezolid. Since 2017, no patient developed severe hearing loss or complete deafness. Severe haematological toxicity was observed in 18.1% (six out of 33) of patients on linezolid, none of which was life threatening. The use of linezolid was associated with severe but manageable adverse events (hazard ratio 8.9, 95% CI 2.5-31.5; p=0.001). A total of 90.9% (30 out of 33) of patients on a linezolid-containing STR were cured, and none experienced treatment failure. Three died, but not due to adverse events.Baseline and monthly audiometry monitoring and using linezolid after detection of hearing abnormalities appears effective to prevent severe ototoxicity, while keeping high treatment success and manageable adverse events.
PDF
