BACKGROUND
Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid, and linezolid (BPaL)–based regimens have demonstrated higher rates of treatment success and have been recommended by the World Health Organization. Operational research is urgently required to evaluate these regimens in non-trial settings.
METHODS
This was a prospective cohort study of patients with microbiologically confirmed MDR/RR-TB and pre–extensively drug-resistant TB (pre-XDR-TB) initiated on BPaL-based regimens in Belarus and Uzbekistan (February 2022–June 2023). All clinical care and research procedures were delivered by treating physicians. After treatment completion, patients were followed up at 6 and 12 months, including collecting sputum to ascertain recurrence. The primary objective was to estimate the effectiveness (cured or treatment completed) and safety (the occurrence of serious adverse events) of BPaL-based regimens.
RESULTS
A total of 677 patients initiated treatment with BPaL-based regimens during the study. We documented successful treatment outcomes in 95.3% (427/448) of patients with MDR/RR-TB treated with BPaL plus moxifloxacin and 90.4% (207/229) of patients with pre–XDR-TB treated with BPaL plus clofazimine. 10.2% (69/677) experienced serious adverse events including 24 deaths (3.5%), 11 of which occurred during treatment. 83.3% (20/24) of deaths were not related to TB or TB treatment. Of patients who were successfully treated and completed 12-month follow-up, 0.5% (2/383) had recurrence.
CONCLUSIONS
BPaL-based regimens for MDR/RR-TB and pre–XDR-TB are safe and highly effective in non-trial settings. These regimens should be considered for widespread implementation globally, and further research is needed to evaluate their performance in other key populations.
BACKGROUND
TB is concentrated in populations with complex health and social issues, including alcohol use disorders (AUD). We describe treatment adherence and outcomes in a person-centred, multidisciplinary, psychosocial support and harm reduction intervention for people with multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) with harmful alcohol use.
METHODS
An observational cohort study, including multilevel mixed-effects logistic regression and survival analysis with people living in Minsk admitted with MDR/RR-TB and AUD during January 2019–November 2021 who received this person-centred, multidisciplinary, psychosocial support and harm reduction intervention, was conducted.
RESULTS
There were 89 participants enrolled in the intervention, with a median follow-up of 12.2 (IQR: 8.1–20.5) mo. The majority (n=80; 89.9%) of participants had AUD, 11 (12.4%) also had a dependence on other substances, six (6.7%) a dependence on opioids and three (3.4%) a personality disorder. Fifty-eight had a history of past incarceration (65.2%), homelessness (n=9; 10.1%) or unemployment (n=55; 61.8%). Median adherence was 95.4% (IQR: 90.4–99.6%) and outpatient adherence was 91.2% (IQR: 65.1–97.0%). Lower adherence was associated with hepatitis C, alcohol plus other substance use and outpatient facility-based treatment, rather than video-observed treatment, home-based or inpatient treatment support.
CONCLUSIONS
This intervention led to good adherence to MDR/RR-TB treatment in people with harmful use of alcohol, a group usually at risk of poor outcomes. Poor outcomes were associated with hepatitis C, other substance misuse and outpatient facility-based treatment support.
BACKGROUND
Drug-resistant TB (DR-TB) remains a major public health threat. In 2022, Uzbekistan reported 2,117 cases of DR-TB, with 69% tested for fluoroquinolone resistance. Limited information is available on the prevalence of resistance to bedaquiline, linezolid, and fluoroquinolone, which are key components of the all-oral treatment regimen for rifampicin-resistant TB in Uzbekistan.
METHODS
A retrospective study was conducted using extensive programmatic data from 2019 to 2023 in Uzbekistan. We assessed second-line drug-resistant TB (SLDR-TB) rates using phenotypic drug susceptibility testing (pDST). Demographic and clinical characteristics associated with SLDR-TB were analysed using multivariable logistic regression models based on the Allen-Cady approach.
RESULTS
In total, 2,405 patients with TB who had undergone pDST were included (median age 40 years, 47% female). The overall SLDR-TB resistance rate was 24% (95% CI 22-26). Prevalence of resistance to bedaquiline, linezolid, moxifloxacin, levofloxacin, and amikacin were respectively 3.1%, 0.8%, 15%, 13%, and 12%. Risk factors for SLDR-TB were resistance to rifampicin and/or isoniazid, exposure to clofazimine, retreatment status, contact with drug-susceptible TB case or DR-TB case, and diabetes.
CONCLUSIONS
The high prevalence of SLDR-TB is of major concern, emphasising the need for baseline pDST in RR-TB treatment. Identified risk factors can aid early detection of at-risk individuals and inform clinical practice.
BACKGROUND
The rate of TB in prison institutions is estimated to be 23 times higher than in the general population. Limited documentation exists regarding TB screening in Tajikistan's prisons. This study aims to report findings from a TB screening conducted in prison facilities in Tajikistan.
METHODS
A systematic TB screening was conducted between July 2022 and September 2023, following a locally adapted algorithm based on WHO recommendations. The screening yield was calculated as the proportion of confirmed TB cases, with categorical variables compared using a χ2 test.
RESULTS
A total of 7,223 screenings were conducted, identifying 31 TB cases, including 17 drug-susceptible TB cases, eight drug-resistant TB cases, and six clinically diagnosed cases. The overall screening yield was 0.43%. Notably, the screening yield was 3.4% among individuals with at least one TB symptom and 0.03% among those without TB symptoms (P < 0.001).
CONCLUSION
The identified rate of TB in these prisons is five times higher than in the general population. Symptomatic individuals had a higher likelihood of TB diagnosis, and using chest X-rays significantly improved screening yield. We recommend increasing the capacity for chest X-ray testing to enhance TB prevention and control within prison settings.
Background
Isoniazid (INH, H) resistance is the most common drug-resistant TB pattern, with treatment success rates lower than those in drug-susceptible TB. The WHO recommends a 6-month regimen of rifampicin (RIF, R), ethambutol (EMB, E), pyrazinamide (PZA, Z), and levofloxacin (Lfx) (6REZLfx) for INH-resistant, RIF-susceptible TB (HRRS-TB). Uzbekistan has a high burden of TB (62/100,000 population) and multidrug-resistant TB (12/100,000 population).
Methods
We conducted a retrospective, descriptive study of microbiologically confirmed HRRS-TB using routinely collected programmatic data from 2009 to 2020.
Results
We included 854 HRRS-TB cases. Treatment success was 80.2% overall. For REZLfx, the treatment success rate was 92.0% over a short treatment duration, with no amplifications to RIF or second-line anti-TB drug resistance. We documented 46 regimens with REZLfx plus linezolid (success 87.0%) and 539 regimens using kanamycin or capreomycin (success 76.6%). We identified 37 treatment failures (4.3%), 30 deaths (3.5%), 25 resistance amplifications (2.9%), including eight to RIF (0.9%), and 99 lost to follow-up (LTFU) cases (11.6%). Unsuccessful outcomes were more common with older age, diabetes, chest X-ray cavities, smear positivity, smear-positive persistence, and male sex. LTFU was more common with injection-containing regimens.
Conclusions
REZLfx is a safe and effective first-line treatment for INH-resistant, RIF-susceptible TB. Treatment success was lower and LTFU was higher for injection-containing regimens.
The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and products. We aimed to describe the TB drugs and prices available from the GDF over time and to assess trends.
METHODS
We searched the internet, including an internet archive, for past and recent GDF Product Catalogs and extracted the listed TB drugs and prices. We calculated the lowest price for the most common drug formulations assuming drugs with similar active pharmaceutical ingredients (APIs) are substitutes for each other. We assessed time trends in the TB drugs and prices offered by the GDF in univariable regressions over the longest possible period.
RESULTS
We identified 43 different GDF Product Catalogs published between November 2001 and May 2024. These product catalogs included 122 single medicines (31 APIs), 28 fixed-dose combinations (9 API combinations), and 8 patient kits (8 API regimens and other materials). The number of TB drugs listed in the GDF Product Catalog increased from 9 (8 APIs) to 55 (32 APIs). The price decreased for 17, increased for 19, and showed no trend for 12 APIs. The price of 15 (53.6%) of 28 APIs used against drug-resistant TB decreased, including the price of drugs used in new treatment regimens. The decreasing price trend was strongest for linezolid (-16.60 [95% CI: -26.35 to -6.85] percentage points [pp] per year), bedaquiline (-12.61 [95% CI: -18.00 to -7.22] pp per year), cycloserine (-11.20 [95% CI: -17.40 to -4.99] pp per year), pretomanid (-10.47 [95% CI: -15.06 to -5.89] pp per year), and rifapentine (-10.46 [95% CI: -12.86 to -8.06] pp per year). The prices of 16 (61.5%) of 23 APIs for standard drug-susceptible TB treatment increased, including rifampicin (23.70 [95% CI: 18.48 to 28.92] pp per year), isoniazid (20.95 [95% CI: 18.96 to 22.95] pp per year), ethambutol (9.85 [95% CI: 8.83 to 10.88] pp per year), and fixed-dose combinations thereof.
CONCLUSIONS
The number of TB drugs available from the GDF has substantially increased during its first 23 years of operation. The prices of most APIs for new TB treatments decreased or remained stable. The prices of most APIs for standard drug-sensitive TB treatment increased.
Tajikistan has a high burden of rifampicin-resistant TB (RR-TB), with 2,700 new cases estimated for 2021 (28/100,000 population). TB is spread among household members through close interaction and children exposed through household contact progress to disease rapidly and frequently.
METHODS
We retrospectively analysed programmatic data from household contact tracing in Dushanbe over 50 months. We calculated person-years of follow-up, contact tracing yield, number needed to screen (NNS) and number needed to test (NNT) to find one new case, and time to diagnosis.
RESULTS
We screened 6,654 household contacts of 830 RR-TB index cases; 47 new RR-TB cases were detected, 43 in Year 1 and 4 in Years 2 or 3. Ten were aged <5 years; 46/47 had TB symptoms, 34/45 had chest radiographs consistent with TB, 11/35 were Xpert Ultra-positive, 29/32 were tuberculin skin test-positive and 28/47 had positive TB culture and phenotypic drug susceptibility results. The NNS to find one RR-TB case was 141.57 and the NNT was 34.49. The yields for different types of contacts were as follows: 0.7% for screened contacts, 2.9% for tested contacts, 17.0% for symptomatic contacts and 12.1% for symptomatic contacts aged below 5 years.
CONCLUSION
RR-TB household contact tracing was feasible and productive in Tajikistan, a low middle-income country with an inefficient healthcare delivery system.
The total duration of treatment for rifampicin-resistant tuberculosis (RR-TB) in Belarus prior to December 2022 was 18-20 months. The efficacy of treatment with such regimens is low, with the WHO’s Global TB Report suggesting that efficacy was around 73% in Belarus in 2018. The development of effective short regimens for RR-TB treatment is urgent. In Belarus, six-month long treatment with all-oral regimens is used in patients with RR-TB, under operational research conditions, following WHO recommendations.
METHODS
A preliminary assessment of the effectiveness of six-month all-oral regimens containing bedaquiline, pretomanid, linezolid, and moxifloxacin or clofazimine (BPaLM/BPaLC), was performed in a cohort of RR-TB patients. Treatment outcomes, time to culture conversion, and time to adverse event (AE) occurrence, AE types, frequency, and outcomes are described.
ETHICS
This study was approved by the MSF Ethics Review Board (ERB) and by the Belarus Ministry of Health ERB.
RESULTS
Of 177 patients who were enrolled from February 2022 to July 2022, one patient was excluded due to linezolid resistance; this patient continued treatment under an individualised regimen. Of the rest of the cohort (133 (76%) male, 43 female (24%); median age, 44 years (interquartile range, IQR, 25-29 years), 93.2% (164/176) had a favourable treatment outcome, 11 patients were lost to follow-up, and one died. 52 (30%) patients had a sputum smear positive result at treatment start, 59 (34%) a cavitary lesion on chest X-ray, and 42 (24%) patients had been previously treated. 12 patients (7%) were HIV-positive; 23 (13%) had had hepatitis C infection; 45 (26%) abused alcohol, and 6 (3%) of patients had diabetes mellitus. Median time to culture conversion was 27 days (IQR, 25-29). In 96.0% of patients, culture conversion was achieved within 2 months of treatment. 9% of patients had serious AE’s (SAE). Out of total 19 SAE’s, 12 resolved, two resolved with sequelae, three were resolving at the time of assessment, one did not resolve, and one was fatal. Median time from treatment start to the first SAE was 92.5 days (IQR, 12.5-143). The most frequent SAE’s were elevated liver function (6 (32%) cases), acute kidney injury (4 (21%) cases), and amylase increased/pancreatitis (3 (16%) cases). Two cases also revealed cancer or progression of cancer; one showed QTcF prolongation; one, anemia, one, thrombotic cerebral infarction, and one, Clostridium difficile infection. Two cases of cancer and thrombotic cerebral infarction (a patient with a long-standing history of multiple strokes) were assessed as unrelated to study drugs. The one death from cancer was assessed as not related to treatment. Permanent withdrawal of one study drug (linezolid or clofazimine) was done only in three instances (15.8%).
CONCLUSION
The effectiveness of six-month all-oral regimens in this cohort was very high (93.2%). BPaLM/BPaLC regimens were observed to be characterised by a good safety profile. Further data are necessary to evaluate longer-term treatment outcomes.
CONFLICTS OF INTEREST
None declared
Bedaquiline (BDQ) is widely used in the treatment of rifampicin-resistant TB (RR-TB). However, resistance to BDQ is now emerging. There are no standardised regimens for BDQ-resistant TB. This study aims to share experience in managing primary BDQ-resistant TB.
METHODS:
We performed a retrospective study of patients treated for RR-TB in Karakalpakstan, Uzbekistan, from January 2017 to March 2022. We identified patients with resistance to BDQ with no history of BDQ exposure. We describe baseline characteristics, treatment and follow-up of these patients.
RESULTS:
Twelve of the 1,930 patients (0.6%) had baseline samples resistant to BDQ with no history of BDQ exposure, 75% (9/12) of whom had been previously treated for TB. Ten (83.3%) were resistant to fluoroquinolones; respectively 66% and 50% had culture conversion by Month 3 and Month 6. The interim
treatment outcomes were as follows: unfavourable treatment outcomes (3/12, 25%), favourable outcomes (2/12, 17%); the remaining seven (58%) were continuing treatment.
CONCLUSIONS:
A large proportion of the cases had previously been treated for TB and had TB resistant to quinolone.
Both patients who had not experienced culture conversion by Month 3 had an unfavourable treatment outcome. Therefore, we recommend monthly monitoring of culture status for patients on treatment regimens for BDQ resistance.