National Multidrug-resistant Tuberculosis Research Articles

Risk factors for mortality among patients diagnosed with multi-drug resistant tuberculosis in Uganda- a case-control study

BackgroundThe World Health Organization (WHO) End TB strategy aims to reduce mortality due to tuberculosis (TB) to less than 5% by 2035. However, mortality due to multidrug-resistant tuberculosis (MDR-TB) remains particularly high. Globally, almost 20% of patients started on MDR-TB treatment die during the course of treatment every year. We set out to examine the risk factors for mortality among a cohort of patients diagnosed with MDR-TB in Uganda.MethodsWe conducted a case-control study nested within the national MDR-TB cohort. We defined cases as patients who died from any cause during the course of MDR-TB treatment. We selected two controls for each case from patients alive and on MDR-TB treatment at the time that the death occurred (incidence-density sampling). We matched the cases and controls on health facility at which they were receiving care. We performed conditional logistic regression to identify the risk factors for mortality.ResultsData from 198 patients (66 cases and 132 controls) started on MDR-TB treatment from January 1 to December 31, 2016, was analyzed for this study. Cases were similar to controls in age/sex distribution, occupation and history of TB treatment. However, cases were more likely to be HIV infected while controls were more likely to have attained secondary level education. On multivariate regression analysis, co-infection with HIV (aOR 1.9, 95% CI [1.1–4.92] p = 0.05); non-adherence to MDR-TB treatment (aOR 1.92, 95% CI [1.02–4.83] p = 0.04); age over 50 years (aOR 3.04, 95% CI [1.13–8.20] p = 0.03); and having no education (aOR 3.61, 95% CI [1.1–10.4] p = 0.03) were associated with MDR-TB mortality.ConclusionTo mitigate MDR-TB mortality, attention must be paid to provision of social support particularly for older persons on MDR-TB treatment. In addition, interventions that support treatment adherence and promote early detection and management of TB among HIV infected persons should also be emphasized.

Survival status and its predictors among multi-drug resistance tuberculosis treated patients in Ethiopia: Multicenter observational study.

Although substantial progress has been made in combating the crisis of multi-drug resistance tuberculosis (MDR-TB), it remained the major public health threat globally. To assess patients' survival and its predictors among patients receiving multi-drug resistance tuberculosis treatment at MDR-TB treatment centers of southern and southwestern Ethiopia. A multicenter retrospective observational study was conducted from April 14 to May 14, 2019, among patients receiving MDR-TB treatment at three MDR-TB treatment centers, Butajira, Arbaminch and Shenengibe Hospitals, located in south and southwestern Ethiopia. A total of 200 records were reviewed using a check list adopted from the national MDR-TB treatment charts and other relevant documents. Data were entered into Epi-Data version 4.2.0 for cleaning and exported to STATA-13 for analysis. Descriptive analysis was carried out and results were presented by text, tables, and charts. Kaplan-Meier (log-rank test) and Cox regression were used to compare baseline survival experience and to determine predictors of patients' survival (death), respectively. The adjusted hazard ratio (AHR) was used to measure the strength of association and a p-value of <0.05 was considered to declare statistical significance. Of 200 patients, 108 (54%) of them were males. The mean (+ standard deviation) age of the study population was 32.9±9.5years. During follow-up, 22 (11%) deaths were reported. The overall incidence density of death was 11.99, 95% CI [7.89-18.21] per 100,000person-years. The median (interquartile range (IQR)) survival time was 375(249-457) days. Comorbidity (AHR = 23.68, 95% CI [4.85-115.46]), alcohol consumption (AHR = 4.53, 95% CI [1.21-16.97]), and history of poor adherence (AHR = 12.27, 95% CI [2.83-53.21]) were independently associated with patients' survival (death). In this study, the incidence density of mortality was very high. Alcohol consumption, poor adherence, and the presence of comorbidity were independently associated with death. Hence, alcohol users, patients with comorbidity and poor adherence should be given due attention during therapy.

Introduction and scaling up of new drugs for drug-resistant TB: experiences from the Americas.

The number of multidrug-resistant tuberculosis (MDR-TB) cases reported in the Americas has increased by 21.2%, from 3737 in 2016 to 4791 in 2018. The WHO has been recommending changes on the treatment of DR-TB, moving from long-duration treatment with injectables to a short oral regimen with new drugs such as bedaquiline (BDQ) and delamanid (DLM), in selected cases and only under programmatic conditions. Injectables are no longer recommended by the WHO due to lower efficacy and the increasing seriousness of adverse events. The introduction of new oral drugs for DR-TB received a boost with a global donation of BDQ to some eligible countries, which continues with the countries purchasing drugs through the Pan American Health Organization Strategic Fund. The main challenges in the scaling up of new drugs for DR-TB include low DR-TB detection rate, the slow pace in transitioning to molecular testing and delays in the introduction of new oral short regimens for MDR-TB. The Americas need to accelerate the scale up of new oral treatments, improve detection rates, increase molecular diagnosis of resistance, and ensure the registration and introduction of the shorter treatment regimen in national MDR-TB guidelines.

Multidrug-resistant tuberculosis surveillance and cascade of care in Madagascar: a five-year (2012\u20132017) retrospective study

BackgroundIn Madagascar, the multidrug-resistant tuberculosis (MDR-TB) surveillance programme was launched in late 2012 wherein previously treated TB cases and symptomatic MDR-TB contacts (hereafter called presumptive MDR-TB cases) undergo drug susceptibility testing. This retrospective review had per aim to provide an update on the national MDR-TB epidemiology, assess and enhance programmatic performance and assess Madagascar’s MDR-TB cascade of care.MethodsFor 2012–2017, national TB control programme notification, clinical management data and reference laboratory data were gathered. The development and coverage of the surveillance programme, the MDR-TB epidemiology and programmatic performance indicators were assessed using descriptive, logistic and spatial statistical analyses. Data for 2017 was further used to map Madagascar’s TB and MDR-TB cascade of care.ResultsThe geographical coverage and diagnostic and referral capacities of the MDR-TB surveillance programme were gradually expanded whereas regional variations persist with regard to coverage, referral rates and sample referral delays. Overall, the rate of MDR-TB among presumptive MDR-TB cases remained relatively stable, ranging between 3.9% in 2013 and 4.4% in 2017. Most MDR-TB patients were lost in the second gap of the cascade pertaining to MDR-TB cases reaching diagnostic centres but failing to be accurately diagnosed (59.0%). This poor success in diagnosis of MDR-TB is due to both the current use of low-sensitivity smear microscopy as a first-line diagnostic assay for TB and the limited access to any form of drug susceptibility testing. Presumptive MDR-TB patients’ sample referral took a mean delay of 28 days before testing. Seventy-five percent of diagnosed MDR-TB patients were appropriately initiated on treatment, and 33% reached long-term recurrence-free survival.ConclusionsAn expansion of the coverage and strengthening of MDR-TB diagnostic and management capacities are indicated across all regions of Madagascar. With current limitations, the surveillance programme data is likely to underestimate the true MDR-TB burden in the country and an updated national MDR-TB prevalence survey is warranted. In absence of multiple drivers of an MDR-TB epidemic, including high MDR-TB rates, high HIV infection rates and inter-country migration, Madagascar is in a favourable starting position for MDR-TB control and elimination.

What steps can researchers take to increase research uptake by policymakers? A case study in China.

Empirical analysis of the connections between research and health policymaking is scarce in middle-income countries. In this study, we focused on a national multidrug-resistant tuberculosis (TB) healthcare provider training programme in China as a case study to examine the role that research plays in influencing health policy. We specifically focused on the factors that influence research uptake within the complex Chinese policymaking process. Qualitative data were collected from 34 participants working at multilateral organizations, funding agencies, academia, government agencies and hospitals through 14 in-depth interviews and 2 focus group discussions with 10 participants each. Themes were derived inductively from data and grouped based on the 'Research and Policy in Developing countries' framework developed by the Overseas Development Institute. We further classified how actors derive their power to influence policy decisions following the six sources of power identified by Sriram et al. We found that research uptake by policymakers in China is influenced by perceived importance of the health issues addressed in the research, relevance of the research to policymakers' information needs and government's priorities, the research quality and the composition of the research team. Our analysis identified that international donors are influential in the TB policy process through their financial power. Furthermore, the dual roles of two government agencies as both evidence providers and actors who have the power to influence policy decisions through their technical expertise make them natural intermediaries in the TB policy process. We concluded that resolving the conflict of interests between researchers and policymakers, as suggested in the 'two-communities theory', is not enough to improve evidence use by policymakers. Strategies such as framing research to accommodate the fast-changing policy environment and making alliances with key policy actors can be effective to improve the communication of research findings into the policy process, particularly in countries undergoing rapid economic and political development.

Management of adverse reactions to high-dose moxifloxacin used in multidrug-resistant tuberculosis treatment programmes.

The ‘Bangladesh regimen’, which is a 9-month multidrug-resistant tuberculosis (MDR-TB) treatment regimen that contains high-dose (maximum 800 mg once daily) gatifloxacin, clofazimine, ethambutol and pyrazinamide given throughout supplemented by high-dose isoniazid, prothionamide and kanamycin in the initial 4–6 months, has demonstrated safety and efficacy among second-line treatment-naïve patients.1 Gatifloxacin has been withdrawn from the market owing to reports of associated dysglycaemia. A prospective observational study of a modified Bangladesh regimen comprising standard-dose (400 mg once daily) moxifloxacin instead of high-dose gatifloxacin has demonstrated high treatment success rates among second-line treatment-naïve MDR-TB patients.2 STREAM Stage 1, a randomized controlled trial, has evaluated a modified Bangladesh regimen that contains high-dose (maximum 800 mg once daily) moxifloxacin instead of high-dose gatifloxacin in comparison with the longer 20-month fluoroquinolone-based MDR-TB treatment regimen recommended by the World Health Organization. Preliminary findings of the STREAM Stage 1 trial suggested that both regimens were similar by efficacy and the rates of severe adverse events, but with a non-significantly higher frequency of new-onset QT prolongation on electrocardiography.3 With publication of the final results, some national MDR-TB programmes may consider using shorter MDR-TB treatment regimens that contain high-dose rather than standard-dose moxifloxacin. We submit here some views that might help optimize management of the adverse reactions to high-dose moxifloxacin under programmatic settings. Standard-dose moxifloxacin can incur a wide range of adverse reactions (see Table 1, based on https://www.drugs.com/sfx/moxifloxacin-side-effects.html). Other important toxicities pertain to fungal superinfections and drug–drug interactions. Intuitively, as an extensive spectrum of adverse reactions to standard-dose moxifloxacin has been reported among non-TB patients treated for 1–2 weeks, one can reasonably predict similar, if not more frequent or severe, reactions to high-dose moxifloxacin among TB patients treated for 9 months. The current focus of many clinical trials on serious adverse drug reactions may not adequately address treatment tolerance, which substantially affects treatment adherence and outcomes in programmatic settings. Thus, many adverse drug reactions, which are frequently dose-dependent and aggravated by co-morbidities (especially those with organ dysfunction and ageing4, 5), are often insufficiently evaluated in clinical trial settings but highly pertinent at both patient care and programme implementation levels when a very large patient population is involved. The need of clinical vigilance and diligent monitoring for all potential toxicities associated with high-dose moxifloxacin is imperative, especially for cardiotoxicity, which necessitates periodic electrocardiographic assessment throughout the treatment for all patients, with possibly 24-h Holter monitoring for selected cases to comprehensively detect potentially dangerous arrhythmia. More research is apparently required to further inform clinical decision for the optimal management of moxifloxacin-induced cardiotoxicity, and to unravel a possible association between cardiac arrhythmia and disturbance of cardiac metabolism in the context of drug-induced cardiotoxicity.6 The use of a shorter MDR-TB treatment regimen containing high-dose moxifloxacin has potential programmatic advantages, especially pertaining to anticipated adherence and curtailment of drug resistance, but intensified clinical and related monitoring possibly has resource implication that might offset cost-effectiveness in programmatic settings. W.W.Y. was consultant to Otsuka Pharmaceutical Company until July 2016, and member of the Independent Data and Safety Monitoring Committee of the STREAM trial until September 2018.

Multidrug-resistant tuberculosis treatment programmes insufficiently consider comorbid mental disorders.

The successful treatment of multidrug-resistant tuberculosis (MDR-TB) is a global health priority and a key pillar of the World Health Organization's (WHO's) End TB strategy. There has been significant global investment in diagnostic capabilities in recent years. However, we argue that the mental distress of those with MDR-TB and their families continues to be overlooked by TB programmes. Priorities in the End TB Strategy of 'patient-centred care' and 'patient support' are still to be delivered in practice in many low-income settings, and in particular consideration of mental distress. Our experience of undertaking MDR-TB operational research in China, Pakistan, Bangladesh, Nepal and Swaziland has given us detailed insight into the challenges facing patients, their families, health professionals and wider health systems. We are increasingly concerned that psychosocial support, and particularly support focused on mental health, is being insufficiently addressed in national MDR-TB programmes. We suggest that the presence of comorbid mental disorders reduces treatment adherence. We recommend the trialling within TB programmes of brief screening tools for common mental disorders and the incorporation of principles from the WHO Mental Health Gap Action Programme programme into TB programme treatment guidance. Our work in Nepal also suggests that brief psychological counselling delivered by non-specialist counsellors may be feasible.

Impact of Infection Control Measures to Control an Outbreak of Multidrug-Resistant Tuberculosis in a Human Immunodeficiency Virus Ward, Peru.

Multidrug-resistant tuberculosis (MDRTB) rates in a human immunodeficiency virus (HIV) care facility increased by the year 2000—56% of TB cases, eight times the national MDRTB rate. We reported the effect of tuberculosis infection control measures that were introduced in 2001 and that consisted of 1) building a respiratory isolation ward with mechanical ventilation, 2) triage segregation of patients, 3) relocation of waiting room to outdoors, 4) rapid sputum smear microscopy, and 5) culture/drug–susceptibility testing with the microscopic-observation drug-susceptibility assay. Records pertaining to patients attending the study site between 1997 and 2004 were reviewed. Six hundred and fifty five HIV/TB–coinfected patients (mean age 33 years, 79% male) who attended the service during the study period were included. After the intervention, MDRTB rates declined to 20% of TB cases by the year 2004 (P = 0.01). Extremely limited access to antiretroviral therapy and specific MDRTB therapy did not change during this period, and concurrently, national MDRTB prevalence increased, implying that the infection control measures caused the fall in MDRTB rates. The infection control measures were estimated to have cost US$91,031 while preventing 97 MDRTB cases, potentially saving US$1,430,026. Thus, this intervention significantly reduced MDRTB within an HIV care facility in this resource-constrained setting and should be cost-effective.

Multidrug‐resistant TB in Zambia: review of national data from 2000 to 2011

Multidrug-resistant tuberculosis (MDR-TB) is posing a great threat to global TB control. The burden in Zambia is not well defined because routine surveillance data are scarce. We reviewed national MDR-TB data for the last decade to inform future public health policy with respect to MDR-TB in Zambia. Retrospective review of national surveillance of MDR-TB data, TB programme and laboratory reports between 2000 and 2011. The total number of DSTs performed during this 11-year period was 2,038 and accounted for 2.6% (2,038/78,639) of all the retreatment cases notified. The total number of diagnosed MDR-TB cases for this period was 446, of which 56.3% (251/446) were male and 41.7% (186/446) female. Only one child was found to have MDR-TB. Poly-drug resistance accounted for 18.9% (172/911) of the DR-TB cases and 8.4% of the total DSTs. 8.8% (80/911) of the DR-TB cases showed either rifampicin mono- or poly-resistance other than MDR-TB. No XDR-TB was reported. There were no data available on DR-TB and HIV co-infection. Only 65 MDR-TB patients were notified and put on second-line treatment according to WHO guidelines. Multidrug-resistant tuberculosis may be an emerging challenge in Zambia. There is a need to invest in improving the capacity of the TB programme to detect and manage MDR-TB.

Role of Technical Assistance in the Establishment and Scale Up of Programmatic Management of Drug Resistant Tuberculosis (PMDT) in Ethiopia

Implementation and scale up of programmatic management of drug resistant tuberculosis (PMDT) has proven to be a challenge in many resource-constrained settings like in Ethiopia, despite the political commitment. A critical programmatic gap analysis was conducted by technical experts to develop feasible recommendations for incorporating multi drug resistant tuberculosis (MDR-TB) management in the national TB program following international guidelines and receiving continuous technical and financial support. The major achievement was building of technical capacity in the country at the level of a national MDR-TB technical working group (TWG) as well as at the level of the MDR-TB treatment hospitals among the MDR management teams. In addition, guideline development, improved access to second line drugs and renovation of health facilities in accordance with TB infection control standards contributed to optimize implementation. Between February 2009 and September 2012, 575 MDR-TB patients accessed treatment under the program. Building programmatic and clinical capacity at different levels of the health system in combination with strong political commitment and partner's engagement were key elements of the PMDT approach. Structured technical assistance combined with financial support during key steps was critical in the initiation and subsequent scale up of the program.

Early Outcomes of MDR-TB Treatment in a High HIV-Prevalence Setting in Southern Africa

BackgroundLittle is known about treatment of multidrug-resistant tuberculosis (MDR-TB) in high HIV-prevalence settings such as sub-Saharan Africa.Methodology/Principal FindingsWe did a retrospective analysis of early outcomes of the first cohort of patients registered in the Lesotho national MDR-TB program between July 21, 2007 and April 21, 2008. Seventy-six patients were included for analysis. Patient follow-up ended when an outcome was recorded, or on October 21, 2008 for those still on treatment. Fifty-six patients (74%) were infected with HIV; the median CD4 cell count was 184 cells/μl (range 5–824 cells/μl). By the end of the follow-up period, study patients had been followed for a median of 252 days (range 12–451 days). Twenty-two patients (29%) had died, and 52 patients (68%) were alive and in treatment. In patients who did not die, culture conversion was documented in 52/54 patients (96%). One patient had defaulted, and one patient had transferred out. Death occurred after a median of 66 days in treatment (range 12–374 days).Conclusions/SignificanceIn a region where clinicians and program managers are increasingly confronted by drug-resistant tuberculosis, this report provides sobering evidence of the difficulty of MDR-TB treatment in high HIV-prevalence settings. In Lesotho, an innovative community-based treatment model that involved social and nutritional support, twice-daily directly observed treatment and early empiric use of second-line TB drugs was successful in reducing mortality of MDR-TB patients. Further research is urgently needed to improve MDR-TB treatment outcomes in high HIV-prevalence settings.

Determinants of multidrug-resistant tuberculosis (MDR-TB) in South Africa

Objectives: Multidrug-resistant tuberculosis (MDR-TB), a global public health threat, is established throughout South Africa following a serious escalation of TB compounded by the HIV epidemic. A national MDR-TB prevalence survey incorporating HIV testing was conducted to establish provincial estimates of MDR-TB prevalence and identify associated risk factors. Design: Cross-sectional population-based survey involving TB diagnostic centres as primary sampling units in a multistage stratified cluster design employing PPS sampling. Setting: Primary health care setting in the nine Provinces of South Africa. Subjects: Demographic details and treatment history were obtained in structured interviews of 5866 culture-confirmed TB patients. Sputum specimens from these patients underwent unlinked HIV testing. Outcome measures: Estimates of anti-TB drug resistance prevalence, with multiple logistic regression models elucidating risk factors for MDR-TB. Results: HIV co-infection rate was 55% (range 28-72%). Low MDR-TB prevalence of 2.9% overall (1.6% in new cases; 6.7% in retreatment cases) translates into at least 6000 MDR-TB patients per year. MDR-TB risk factors included previous TB treatment, poor treatment outcome (default or failure), hospitalisation, and HIV infection. Conclusions: A multi-faceted approach, including HIV treatment programmes and appropriate infection control, is required to avert a large-scale MDR-TB epidemic.

Tuberculosis control in Latvia: integrated DOTS and DOTS-plus programmes.

From 1991 until the end of 1998, the number of patients with tuberculosis in Latvia increased 2.5 times with a simultaneous increase of drug resistant and multidrug resistant tuberculosis (MDR-TB). Descriptive analysis of different TB programme services, activities and strategies including Directly Observed Therapy Short-course (DOTS) for tuberculosis and treatment of MDR-TB, were performed. Data from the state tuberculosis registry, drug resistance surveillance, and the national MDR-TB database were used. The state-funded national tuberculosis control programme (NTAP, Nacionâlâ Tuberkulozes Apkarodanas Programma), based on WHO recommended DOTS strategy, was introduced in Latvia in 1996. The NTAP includes TB control in prisons. Treatment of MDR-TB using second line drugs was started in 1997. Cure rates for TB patients increased from 59.5% in 1996 to 77.5% in 2003. Between 1996 and 2003, more than 200 patients began MDR-TB treatment each year, and the cure rate was between 66% and 73%. Numbers of MDR-TB patients were reduced by more than half during this period. Treatment results including MDR-TB reached the WHO target, with cure rates 85% of newly diagnosed patients. These results demonstrate that MDR-TB treatment and management using the individualised treatment approach can be effectively provided within the overall TB programme on a national scale, to successfully treat a large number of MDR-TB patients. Rapid diagnostic methods combined with early intensified case finding, isolation and infection control measures could decrease transmission of TB and MDR-TB in hospitals and in the community. Highly important that MDR-TB management follows WHO recommendations in order to stop creating drug resistance to first and to second line drugs.