All-oral longer regimens are effective for the management of multidrug-resistant tuberculosis in high-burden settings.

BACKGROUND: Recent World Health Organization guidance on drug-resistant tuberculosis treatment de-prioritised injectable agents, in use for decades, and endorsed all-oral longer regimens. However, questions remain about the role of the injectable agent, particularly in the context of regimens using new and repurposed drugs. We compared the effectiveness of an injectable-containing regimen to that of an all-oral regimen among patients with drug-resistant tuberculosis who received bedaquiline and/or delamanid as part of their multidrug regimen. METHODS: Patients with a positive baseline culture were included. 6-month culture conversion was defined as two consecutive negative cultures collected >15 days apart. We derived predicted probabilities of culture conversion and relative risk using marginal standardisation methods. RESULTS: Culture conversion was observed in 83.8% (526 out of 628) of patients receiving an all-oral regimen and 85.5% (425 out of 497) of those receiving an injectable-containing regimen. The adjusted relative risk comparing injectable-containing regimens to all-oral regimens was 0.96 (95% CI 0.88-1.04). We found very weak evidence of effect modification by HIV status: among patients living with HIV, there was a small increase in the frequency of conversion among those receiving an injectable-containing regimen, relative to an all-oral regimen, which was not apparent in HIV-negative patients. CONCLUSIONS: Among individuals receiving bedaquiline and/or delamanid as part of a multidrug regimen for drug-resistant tuberculosis, there was no significant difference between those who received an injectable and those who did not regarding culture conversion within 6 months. The potential contribution of injectable agents in the treatment of drug-resistant tuberculosis among those who were HIV positive requires further study.

Phenotypically Adapted Mycobacterium tuberculosis Populations from Sputum Are Tolerant to First-Line Drugs.

Tuberculous sputum contains multipleMycobacterium tuberculosispopulations with different requirements for isolationin vitro These include cells that form colonies on solid media (plateableM. tuberculosis), cells requiring standard liquid medium for growth (nonplateableM. tuberculosis), and cells requiring supplementation of liquid medium with culture supernatant (SN) for growth (SN-dependentM. tuberculosis). Here, we describe protocols for the cryopreservation and direct assessment of antimicrobial tolerance of theseM. tuberculosispopulations within sputum. Our results show that first-line drugs achieved only modest bactericidal effects on all three populations over 7 days (1 to 2.5 log10reductions), and SN-dependentM. tuberculosiswas more tolerant to streptomycin and isoniazid than the plateable and nonplateableM. tuberculosisstrains. Susceptibility of plateableM. tuberculosisto bactericidal drugs was significantly increased after passagein vitro; thus, tolerance observed in the sputum samples from the population groups was likely associated with mycobacterial adaptation to the host environment at some time prior to expectoration. Our findings support the use of a simpleex vivosystem for testing drug efficacies against mycobacteria that have phenotypically adapted during tuberculosis infection.

Triple Priority: TB/HIV Co-Infection and Treatment Outcomes among Key Populations in The Kyrgyz Republic: A National Cohort Study (2018-2022).

Background: Improving tuberculosis (TB) care in key populations is an operational research priority in the Kyrgyz Republic. Here, we describe the characteristics of TB/HIV co-infected individuals, their affiliations with key country-wide population groups, and their TB treatment outcomes. Methods: This was a cohort study using national programmatic data (2018-2022). The key population groups included people with increased exposure to TB, limited access to TB services, and increased risk of acquiring TB. Results: Among 693 individuals with TB/HIV co-infection, the majority (58%) of individuals were from two regions of the Kyrgyz Republic (Chui and Bishkek). Eighty-four percent (84%) individuals had one or more affiliations to eight key population groups, with 49% of the individuals affiliated to ≥2 groups and 92% of the individuals were on both antiretroviral treatment and cotrimoxazole preventive therapy. Overall, 406 (59%) of the individuals had successful outcomes and 287 (41%) of the individuals had unsuccessful outcomes. Unsuccessful outcomes increased from 36% (n-39) with TB/HIV alone to 47% (n-86) with affiliations to ≥3 key population groups (P-0.03). Unsuccessful outcomes were associated with co-morbidities (diabetes mellitus and hepatitis B/C), migration, alcohol use, and extrapulmonary TB. Conclusions: For a long time, people with TB/HIV co-infection have been recognized as a "double priority". Affiliation to key populations accentuates their status to "triple priority". We advocate for increased attention and equity towards these populations.

"Together against Tuberculosis": Cascade of Care of Patients Referred by the Private Health Care Providers in the Kyrgyz Republic.

Until 2021, in the Kyrgyz Republic, tuberculosis (TB) was diagnosed and treated only in the public sector. With funding support of the STOP-TB partnership, the private providers in four regions of the country and Bishkek city were mapped, trained and incentivized to screen for and identify presumptive TB patients and refer them to the public facilities for diagnosis and treatment. In this study, we describe the cascade of care of such patients. This was a cohort study involving secondary analysis of routine data. Of 79,352 patients screened during February 2021-March 2022, 2511 (3%) had presumptive TB, of whom 903 (36%) were not tested for TB [pre-diagnostic loss to follow-up]. A total of 323 (13%) patients were diagnosed with TB, of whom, 42 (13%) were not started on treatment [pre-treatment loss to follow-up]. Among 257 patients eligible for outcome assessment, 197 (77%) had treatment success, 29 (11%) were lost-to-follow-up, 13 (5%) died, 4 (2%) had treatment failure and 14 (5%) were not evaluated. While this donor-funded, pioneering initiative was successful in engaging the private sector, we recommend that the national TB programme scales up the initiative nationally with dedicated budgets, activities and plans to monitor progress. Qualitative research is urgently needed to understand the reasons for the gaps in the care cascade.

Time to Treatment and Risk Factors for Unsuccessful Treatment Outcomes among People Who Started Second-Line Treatment for Rifampicin-Resistant or Multi-Drug-Resistant Tuberculosis in the Kyrgyz Republic, 2021.

The Kyrgyz Republic is a high-burden country for rifampicin resistant/multi-drug resistant tuberculosis (RR/MDR-TB). TB control efforts rely on early diagnosis and initiation of people on effective regimens. We studied the interval from diagnosis of RR-TB to starting treatment and risk factors for unsuccessful outcomes among people who started RR/MDR-TB treatment in 2021. We conducted a cohort study using country-wide programme data and used binomial regression to determine associations between unsuccessful outcomes and predictor variables. Of the 535 people included in the study, three-quarters were in the age category 18-59 years, and 68% had past history of TB. The median (IQR) time from onset of TB symptoms to diagnosis was 30 (11-62) days, 1 (0-4) days from diagnosis to starting treatment, and 35 (24-65) days from starting treatment to receipt of second-line drug susceptibility test (SL-DST) results. Overall, 136 (25%) had unsuccessful outcomes. Risk factors for unsuccessful outcomes were being homeless, fluroquinolone resistance, having unknown HIV status, past TB treatment, male gender and being unemployed. Treatment outcomes and the interval from diagnosis to starting treatment were commendable. Further reductions in unsuccessful outcomes by be achieved through ensuring timely diagnosis and access to SL-DSTs and by reducing the proportion of people who are lost to follow-up.

Contact Tracing and Tuberculosis Preventive Therapy for Household Child Contacts of Pulmonary Tuberculosis Patients in the Kyrgyz Republic: How Well Are We Doing?

Early identification, screening and investigation for tuberculosis (TB), and provision of TB preventive therapy (TPT), reduces risk of TB among child household contacts of pulmonary TB patients (index patients). A cohort study was conducted to describe the care cascade and timeliness of contact tracing and TPT initiation among child household contacts (aged < 15 years) of index patients initiated on TB treatment in Bishkek, the Kyrgyz Republic during October 2021-September 2022. In the register, information on the number of child household contacts was available for 153 (18%) of 873 index patients. Of 297 child household contacts identified, data were available for 285, of whom 261 (92%) were screened for TB. More than 50% were screened after 1 month of the index patient initiating TB treatment. TB was diagnosed in 23/285 (9%, 95% CI: 6-13%) children. Of 238 TB-free children, 130 (55%) were eligible for TPT. Of the latter, 64 (49%) were initiated on TPT, of whom 52 (81%) completed TPT. While TPT completion was excellent, there was deficiency in contact identification, timely screening and TPT initiation. Thus, healthcare providers should diligently request and record details of child household contacts, adhere to contact tracing timelines and counsel caregivers regarding TPT.

Strengthening the Operational Research Capacity of National Tuberculosis Control Programs: Necessity or Luxury?

'How to get research into practice: first get practice into research [...].

Budgetary impact of using BPaL for treating extensively drug-resistant tuberculosis.

INTRODUCTION: Bedaquiline, pretomanid and linezolid (BPaL) is a new all oral, 6-month regimen comprised of bedaquiline, the new drug pretomanid and linezolid, endorsed by the WHO for use under operational research conditions in patients with extensively drug-resistant tuberculosis (XDR-TB). We quantified per-patient treatment costs and the 5-year budgetary impact of introducing BPaL in Indonesia, Kyrgyzstan and Nigeria. METHODS: Per-patient treatment cost of BPaL regimen was compared head-to-head with the conventional XDR-TB treatment regimen for respective countries based on cost estimates primarily assessed using microcosting method and expected frequency of each TB service. The 5-year budget impact of gradual introduction of BPaL against the status quo was assessed using a Markov model that represented patient's treatment management and outcome pathways. RESULTS: The cost per patient completing treatment with BPaL was US$7142 in Indonesia, US$4782 in Kyrgyzstan and US$7152 in Nigeria - 57%, 78% and 68% lower than the conventional regimens in the respective countries. A gradual adoption of the BPaL regimen over 5 years would result in an 5-year average national TB service budget reduction of 17% (US$128 780) in XDR-TB treatment-related expenditure in Indonesia, 15% (US$700 247) in Kyrgyzstan and 32% (US$1 543 047) in Nigeria. CONCLUSION: Our study demonstrates that the BPaL regimen can be highly cost-saving compared with the conventional regimens to treat patients with XDR-TB in high drug-resistant TB burden settings. This supports the rapid adoption of the BPaL regimen to address the significant programmatic and clinical challenges in managing patients with XDR-TB in high DR-TB burden countries.

Who is doing worse? Retrospective cross-sectional study of TB key population treatment outcomes in Kyrgyzstan (2015-2017).

INTRODUCTION: Tuberculosis (TB) is a global public health problem. The incidence of TB is especially high among TB key populations, such as the homeless, people who use drugs, prisoners, and migrants. The study aimed to assess the associations between affiliation to TB key populations and treatment outcome. METHODOLOGY: This retrospective cross-sectional study used data extracted from the National TB Registry of Kyrgyzstan for the region of Chuy (including the city of Bishkek) for 2015-2017. Descriptive statistics was used to summarize the data. Logistic regression was used to assess the associations. RESULTS: The study included 1,526 patients among whom more than half (52.5%) fell into the youngest group (18-35 years old). Migrants were the most highly represented group comprising 67.8% of all TB key populations. Men (63.0%) and patients with pulmonary TB (83.0%) prevailed in the cohort. The proportions of patients who had completed the treatment were high among all the key populations. Logistic regression was used to assess the association between affiliation to a certain TB key population and the TB treatment outcome. Patients who belonged to more than one TB key population were found to have the highest risk of unsuccessful TB treatment outcomes, both in the region of Chuy (OR = 9.9, 95% CI 2.0-48.1, p = 0.04) and the city of Bishkek (OR = 24.9, 95% CI 7.2-86.4, p < 0.001). CONCLUSION: The homeless, people who use drugs, ex-prisoners, and TB patients who belonged to more than one TB key population were found to have higher risks of unsuccessful TB treatment outcome in comparison to migrants.