Multidrug-resistant Tuberculosis Programme Research Articles

1400. Pretomanid in the Treatment of Patients with Tuberculosis in the United States: the Bedaquiline, Pretomanid and Linezolid (BPaL) Accelerated Monitoring (BAM) Project

BackgroundIn August 2019 the U.S. FDA approved pretomanid as part of a 6-month all-oral BPaL (bedaquiline, pretomanid, and linezolid) regimen for treating pulmonary extensively drug-resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis (TB). In the study supporting approval, 89% of patients had a favorable outcome, and all reported ≥ 1 adverse event. We describe the reported use of BPaL in the United States.MethodsUsing the 2020 CDC Report of a Verified Case of Tuberculosis (RVCT) MDR TB supplemental form, TB programs and providers submitted data for patients who began taking BPaL between Aug 1, 2019 and May 1, 2020, for retrospective descriptive analysis.ResultsPrograms and providers reported 17 TB patients aged a mean of 41 years (range 23–76) who received BPaL: 11 (65%) were male; 15 (88%) were non-U.S. born; 15 (88%) had pulmonary TB disease only; two (12%) had both pulmonary and extrapulmonary disease. Of all patients, 16 had Mycobacterium tuberculosis isolated from sputum and 7 (44%) had cavitary disease. The preliminary drug susceptibilities were 8 MDR patterns, 8 pre-XDR, and 1 unreported. Three patients received BPaL as their only treatment; six first received treatment for drug-susceptible TB, and eight received other regimens for MDR TB before BPaL. Eleven (65%) patients had ≥ 1 side effect reported during any TB treatment, including peripheral neuropathy (n=5), depression (n=4), vestibular dysfunction (n=3), and vision changes (n=3). Timing related to specific TB drug use was not reported. Sixteen (94%) patients received less than the approved initial dose of 1200 mg linezolid daily, and 15 (88%) patients underwent monitoring of linezolid exposure. All 16 patients with M. tuberculosis in initial sputa converted to negative culture results within 6 months of starting treatment. At 12 months after BPaL initiation, all patients had completed treatment, without TB recurrences or deaths reported.ConclusionIn the early period after FDA approval, most U.S. patients received BPaL off-label with an initial linezolid dose lower than the approved 1200mg yet still achieved good outcomes. Most reported patients underwent some monitoring of linezolid exposure. Monitoring of BPaL use is important and should continue.Disclosures All Authors: No reported disclosures

Programmatic Challenges in Managing Multidrug-Resistant Tuberculosis in Malawi

Background:Multidrug-resistant tuberculosis (MDR-TB) is one of the most urgent challenges that Malawi tends to take a firm public health action. A recent increase in multidrug MDR-TB cases, a decrease in treatment success rate, and a double increase of lost-to-follow-up call into question the country’s programmatic management of MDR-TB (PMDT). As such, the study aimed at exploring programmatic challenges in managing MDR-TB in Malawi.Methods:A comprehensive and nonsystematic search was made in PubMed and Google Scholar using mainly the keywords “MDR-TB” “extensively drug-resistant TB,” Malawi. The study reviewed existing guidelines and gray literature and reviewed data obtained from the national TB program (NTP) as well.Results:The study found the following challenges affecting PMDT: decrease in funding, partial access to GeneXpert, delay in diagnosis, long treatment duration, lack of adequate personal protective equipment, the long turnaround time of culture results, failure to initiate all diagnosed patients on treatment, absence of alternative second-line medicines, and lack of transport from health facilities to patient homes.Conclusion:If the Malawi NTP is to achieve a vision of a “TB-free Malawi,” rigorous efforts at all levels must be made, including mobilizing domestic resources for improved MDR-TB program performance. Developing partners should continue providing the much-needed funding to the Malawi government to stand in the wake of the MDR-TB crisis.

Prevalence and factors associated with non-adherence to multi-drug resistant tuberculosis (MDR-TB) treatment at Mulago National Referral Hospital, Kampala, Uganda.

In Uganda, 12% of previously treated TB cases and 1.6% of new cases have MDR-TB and require specialized treatment and care. Adherence is crucial for improving MDR-TB treatment outcomes. There is paucity of information on the extent to which these patients adhere to treatment and what the drivers of non-adherence are. We conducted a cohort study using retrospectively collected routine program data for patients treated for MDR-TB between January 2012 - May 2016 at Mulago Hospital. We extracted anonymized data on non-adherence (missing 10% or more of DOT), socio-economic, demographic, and treatment characteristics of the patients. All participants were sensitive to MDR-TB drugs after second line Drug Susceptible Testing (DST) at entry into the study. Factors associated with non-adherence to MDR-TB treatment were determined using generalized linear models for the binomial family with log link and robust standard errors. We considered a p- value less than 0.05 as statistically significant. The records of 227 MDR- TB patients met the inclusion criteria, 39.4% of whom were female, 32.6% aged between 25 - 34 years, and 54.6% living with HIV/AIDS. About 11.9% of the patients were non-adherent. The main driver for non-adherence was history of previous DR-TB treatment; previously treated DR-TB patients were 3.46 (Adjusted prevalence ratio: 3.46, 95 % CI: 1.68 - 7.14) times more likely to be non-adherent. One in 10 MDR-TB patients treated at Mulago hospital is non-adherent to treatment. History of previous DRTB treatment was significantly associated with non-adherence in this study. MDR-TB program should strengthen adherence counselling, strengthen DST surveillance, and close monitoring for previously treated DR-TB patients.

Person-centred care in practice: perspectives from a short course regimen for multi-drug resistant tuberculosis in Karakalpakstan, Uzbekistan

IntroductionPerson-centred care, an internationally recognised priority, describes the involvement of people in their care and treatment decisions, and the consideration of their needs and priorities within service delivery. Clarity is required regarding how it may be implemented in practice within different contexts. The standard multi-drug resistant tuberculosis (MDR-TB) treatment regimen is lengthy, toxic and insufficiently effective. 2019 World Health Organisation guidelines include a shorter (9–11-month) regimen and recommend that people with MDR-TB be involved in the choice of treatment option. We examine the perspectives and experiences of people with MDR-TB and health-care workers (HCW) regarding person-centred care in an MDR-TB programme in Karakalpakstan, Uzbekistan, run by Médecins Sans Frontières and the Ministry of Health.MethodsA qualitative study comprising 48 interviews with 24 people with MDR-TB and 20 HCW was conducted in June–July 2019. Participants were recruited purposively to include a range of treatment-taking experiences and professional positions. Interview data were analysed thematically using coding to identify emerging patterns, concepts, and categories relating to person-centred care, with Nvivo12.ResultsPeople with MDR-TB were unfamiliar with shared decision-making and felt uncomfortable taking responsibility for their treatment choice. HCW were viewed as having greater knowledge and expertise, and patients trusted HCW to act in their best interests, deferring the choice of appropriate treatment course to them. HCW had concerns about involving people in treatment choices, preferring that doctors made decisions. People with MDR-TB wanted to be involved in discussions about their treatment, and have their preference sought, and were comfortable choosing whether treatment was ambulatory or hospital-based. Participants felt it important that people with MDR-TB had knowledge and understanding about their treatment and disease, to foster their sense of preparedness and ownership for treatment. Involving people in their care was said to motivate sustained treatment-taking, and it appeared important to have evidence of treatment need and effect.ConclusionsThere is a preference for doctors choosing the treatment regimen, linked to shared decision-making unfamiliarity and practitioner-patient knowledge imbalance. Involving people in their care, through discussions, information, and preference-seeking could foster ownership and self-responsibility, supporting sustained engagement with treatment.

Treatment outcomes of multidrug-resistant tuberculosis in Hangzhou, China, 2011 to 2015.

Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging. More research is needed to understand treatment outcomes and associated factors.A retrospective cohort study was conducted to assess trends and predictors of treatment success among 398 MDR-TB and extensively drug resistant TB patients who started treatment in 2011 to 2015 in Hangzhou, China. Sociodemographic and clinical characteristic data were obtained from the national reporting database. Chi-square test for trend was used to evaluate changes in treatment success rates over the study years, and Cox regression analysis was used to identify predictors for poor treatment outcomes.The treatment success rate was 76% (301/398) for all participants, 77% (298/387) for MDR-TB cases and 27% (3/11) for extensively drug-resistant tuberculosis -TB cases. Treatment success increased significantly from 66% among patients who started treatment in 2011 to 85% in 2015 (P < .01). Of the 97 (24.4%) patients with unsuccessful treatment outcomes, 10 (2.5%) died, 64 (16.1%) failed treatment, and 23 (5.8%) were lost to follow-up. Patients who started treatment in 2013 to 2015 were less likely to have unsuccessful outcomes than those who started in 2011–2012 (adjusted odds ratio [AOR] 0.4, 95% confidence interval [CI] 0.3–0.6), patients ≥25 years were more likely to have unsuccessful outcomes than younger patients (AOR 1.6, 95% CI 1.3–2.1), and cases with kanamycin resistance was associated with three times the odds of having unsuccessful outcomes than kanamycin-susceptible cases (AOR 3.0, 95% CI 1.5–5.8).With proper case management of MDR-TB, patients can achieve a high treatment success rate. Hangzhou's program offers clinical evidence that can be used to inform MDR-TB programs elsewhere in China and abroad.

Predictors of treatment outcome among adult patients with multi-drug resistant tuberculosis in Kano, Nigeria

Background: Emergence of multidrug-resistant tuberculosis (MDR-TB) continues to threaten global tuberculosis (TB) treatment, care, and prevention, and it remains a major global health problem in many low- and middle-income countries with high morbidity and mortality. Objectives: The present study assessed MDR-TB treatment outcome and its predictors among adult patients in Kano, Nigeria. Methods: We conducted a secondary data analysis involving 283 adult patients treated for MDR-TB using routine data for MDR-TB programme in Kano State between August 2014 and September 2018. Results: The mean age (±standard deviation) of the respondents was 33.4 ± 11.6 years and up to 40% of them were within the age group of 25–34 years. About three-quarters of the participants 72.4% (205) were males; up to 63.6% (180) of the patients live in the urban areas, and mean duration of treatment initiation was 21 days after the diagnosis. Up to 66.8% (95% confidence interval [CI] = 61.1–72.4), patients had successful treatment, (cured) while 33.2% (95% CI = 27.6–38.9) died. After adjusting for confounding, gender and HIV status were found to be independent predictors of MDR-TB treatment outcome among MDR-TB patients in Kano. Male patients (adjusted odds ratio aOR = 0.38, 95% CI = 0.22–0.66, P = 0.001) and HIV-negative patients (aOR = 0.49, 95% CI = 0.28–0.87, P = 0.015) were less likely to die from MDR-TB. Conclusion: The study found a moderate treatment success rate for MDR-TB in Kano. Early initiation of treatment, control of HIV epidemic, and enhanced treatment supervision would likely improve treatment outcome.

RpoB Mutations Causing Discordant Rifampicin Susceptibility in Mycobacterium tuberculosis: Retrospective Analysis of Prevalence, Phenotypic, Genotypic, and Treatment Outcomes.

BackgroundDiscordant genotypic/phenotypic rifampicin susceptibility testing in Mycobacterium tuberculosis is a significant challenge, yet there are limited data on its prevalence and how best to manage such patients. Whether to treat isolates with rpoB mutations not conferring phenotypic resistance as susceptible or multidrug-resistant tuberculosis (MDR-TB) is unknown. We describe phenotypic and genotypic characteristics of discordant isolates and clinical characteristics and treatment outcomes of affected patients in KwaZulu-Natal, South Africa.MethodsWe analyzed clinical isolates showing rifampicin resistance on GenoType MTBDRplus while susceptible on 1% agar proportion method. We measured rifampicin minimum inhibitory concentrations (MICs) using Middlebrook 7H10 agar dilution and BACTEC MGIT 960. Sensititre MYCOTB plates were used for drug-susceptibility testing, and rpoB gene sequencing was performed on all isolates. Local MDR-TB program data were reviewed for clinical information and patient outcomes.ResultsDiscordant isolates constituted 4.6% (60) of 1302 rifampicin-resistant cases over the study period. Of these, 62% remained susceptible to isoniazid and 98% remained susceptible to rifabutin. Rifampicin MICs were close to the critical concentration of 1 µg/mL (0.5–2 µg/mL) for 83% of isolates. The most frequent rpoB mutations were Q513P (25.3%), D516V (19.2%), and D516Y (13.3%). Whereas 70% were human immunodeficiency virus infected, the mean CD4 count was 289 cells/mm3 and 87% were receiving antiretroviral therapy. Standard therapy for MDR-TB was used and 53% achieved successful treatment outcomes.ConclusionsRifampicin-discordant TB is not uncommon and sequencing is required to confirm results. The high susceptibility to rifabutin and isoniazid and poor treatment outcomes with the current regimen suggest a potential utility for rifabutin-based therapy.

Extensively drug resistant tuberculosis in Mali: a case report

BackgroundDrug resistant tuberculosis presents a major public health challenge.Case presentationWe present here the first two patients diagnosed with extensively drug resistant tuberculosis in Bamako, Mali. Genotypic findings suggest possible nosocomial transmission from the first patient to the second one, resulting in superinfection of the second patient. After being diagnosed with extensively drug resistant tuberculosis in August 2016, the patients only started receiving appropriate treatment 10 months later.ConclusionThe identification of these patients highlights the need for improved diagnostic and treatment algorithms for better surveillance and management of drug resistance in Mali. In the interest of these as well as future patients suffering from resistant tuberculosis, all steps recommended for programmatic management of drug resistant tuberculosis must be urgently prioritized in order to strengthen the multidrug resistant tuberculosis program.

Outcomes from the first multidrug-resistant tuberculosis programme in Kenya.

In March 2006, the first multidrug-resistant tuberculosis (MDR-TB) treatment programme was implemented in Kenya. To describe patients' treatment outcomes and adverse events. A retrospective case note review of patients started on MDR-TB treatment at two Médecins Sans Frontières-supported sites and the national referral hospital of Kenya was undertaken. Sites operated an ambulatory model of care. Patients were treated for a minimum of 24 months with at least 4-5 drugs for the intensive phase of treatment, including an injectable agent. Of 169 patients, 25.6% were human immunodeficiency virus (HIV) positive and 89.3% were culture-positive at baseline. Adverse events occurred in 67.4% of patients: 45.9% had nausea/vomiting, 43.9% electrolyte disturbance, 41.8% dyspepsia and 31.6% hypothyroidism. The median time to culture conversion was 2 months. Treatment outcomes were as follows: 76.6% success, 14.5% deaths, 8.3% lost to follow-up and 0.7% treatment failure. HIV-positive individuals (adjusted odds ratio [aOR] 3.51, 95% confidence interval [CI] 1.12-11.03) and women (aOR 2.73, 95%CI 1.01-7.39) had a higher risk of unfavourable outcomes, while the risk was lower in those with culture conversion at 6 months (aOR 0.11, 95%CI 0.04-0.32). In Kenya, where an ambulatory model of care is used for MDR-TB treatment, treatment success was high, despite high rates of HIV. Almost half of the patients experienced electrolyte disturbance and one third had hypothyroidism; this supports the view that systematic regular biochemical monitoring is needed in Kenya.

Recurrence after Successful Treatment of Multidrug-Resistant Tuberculosis in Taiwan.

Recurrence after successful treatment for multidrug-resistant tuberculosis (MDR-TB) is challenging because of limited retreatment options. This study aimed to determine rates and predictors of MDR-TB recurrence after successful treatment in Taiwan. Recurrence rates were analyzed by time from treatment completion in 295 M DR-TB patients in a national cohort. Factors associated with MDR-TB recurrence were examined using a multivariate Cox regression analysis. Ten (3%) patients experienced MDR-TB recurrence during a median follow-up of 4.8 years. The overall recurrence rate was 0.6 cases per 1000 person-months. Cavitation on chest radiography was an independent predictor of recurrence (adjusted hazard ratio [aHR] = 6.3; 95% CI, 1.2–34). When the analysis was restricted to 215 patients (73%) tested for second-line drug susceptibility, cavitation (aHR = 10.2; 95% CI, 1.2–89) and resistance patterns of extensively drug-resistant TB (XDR-TB) or pre-XDR-TB (aHR = 7.3; 95% CI, 1.2–44) were associated with increased risk of MDR-TB recurrence. In Taiwan, MDR-TB patients with cavitary lesions and resistance patterns of XDR-TB or pre-XDR-TB are at the highest risk of recurrence. These have important implications for MDR-TB programs aiming to optimize post-treatment follow-up and early detection of recurrent MDR-TB.

Concordance of programmatic and laboratory-based multidrug-resistant tuberculosis treatment outcomes in Peru

Confirmation of cure for multidrug-resistant tuberculosis (MDR-TB) patients requires laboratory tests for Mycobacterium tuberculosis growth on culture media. Outcome decisions dictate patient management, and inaccuracies place patients at an increased risk of morbidity and mortality, and may contribute to continued transmission of MDR-TB. To examine concordance between programmatic and laboratory-based MDR-TB treatment outcomes. The study population included 1658 MDR-TB patients in Peru treated between 1996 and 2002 with both program and laboratory-based outcomes. Laboratory-based outcomes were assigned according to international standards requiring at least five consecutive negative cultures in the last 12 months of treatment to confirm cure. Compared to the global culture-defined standard classification, only 1.1% of treatment successes, but 54.3% of failures, were misclassified programmatically. Overall, 10.4% of patients identified by a clinician as having a successful treatment outcome still had cultures positive for MDR-TB. Most patients with successful treatment outcomes by strict culture definitions were also classified by clinicians as having successful outcomes. However, many culture-confirmed failures were missed. In light of delays and incomplete access to culture in MDR-TB programs, efforts should be made to improve the accuracy of programmatically determined treatment outcomes.

Bacteriologic monitoring of multidrug-resistant tuberculosis patients in five DOTS-Plus pilot projects

Multidrug-resistant tuberculosis programs in DOTS-Plus pilot sites in five countries. To calculate sputum conversion time and its relationship to treatment outcome, document the frequency of culture reversions and examine concordance of smear and culture to assess the potential consequences of monitoring by smear microscopy alone. Retrospective cohort analysis of 1926 patients receiving individualized, second-line therapy. Among 1385 sputum culture-positive cases at baseline, 1146 (83%) experienced at least one culture conversion during treatment. Conversion, however, was not sustained in all patients: 201 (15%) experienced initial culture conversion and at least one subsequent culture reversion to positive; 1064 (77%) achieved sustained culture conversion. Median time to culture conversion was 3 months. Among 206 patients whose nal conversion occurred 7-18 months after the initiation of therapy, 71% were cured or had completed treatment. Prolonged treatment for patients with delayed conversion may be beneficial, as 71% of late converters still achieved cure or completed treatment. This has implications for programs with de ned end points for treatment failure. The interval between rst and nal conversion among patients whose initial con- version is not sustained raises concern with respect to the ongoing debate regarding duration of treatment and the definition of cure.

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.

The Demographic and Clinical Characteristics of Multidrug-resistant Tuberculosis Patients in Taiwan

Background: There are approximately 400 multidrug-resistant tuberculosis (MDRTB) patients in Taiwan currently. A new MDR-TB treatment program based on DOTS-plus was started in May, 2007 by the Centers for Disease Control (CDC), Taiwan. The demographics and clinical characteristics of these participants have not been described. To describe the demographics, clinical characteristics and resistance patterns of patients enrolled in the MDR-TB treatment program. Method: The inclusion criteria for the new MDR-TB treatment program include patients who were (1) sputum culture positive after Jan 1, 2007 (2) had Mycobacterium tuberculosis isolate showed isoniazid and rifampin resistance confirmed by the Centers for Research and Diagnostics, Taiwan or other CDC contract laboratories. We collected and analyzed demographics, clinical characteristics, medical history, and isolate drug susceptibility tests of patients enrolled between May and November, 2007. The patients were classified according to WHO guideline. Results: A total of 171 patients were enrolled in the MDRTB program between May and November, 2007. Mean age of the patients was 50.6 years; 137 (80.1%) were men. There were 46 (28.2%) aboriginals, 3 (1.8%) incarcerated, and 3 (1.8%) living in a long term care facility. Forty-one (24.0%) were new patients and 83 (48.5%) had treatment failure or relapse. Exclude the new patients of our MDR program, 25 (19.8%) developed both isoniazid and rifampin resistance within one year of starting anti-tuberculosis treatment, and 81 (64.3%) developed resistance after more than two years of treatment. Drug resistance was highest against fluoroquinolone (49%). Conclusion: Having prior treatment with poor compliance was considered the major determinant of developing MDR-TB. However, 24% of our MDR-TB patients were new patients, indicating possible transmission of MDR-TB in Taiwan. Aggressive TB control efforts are needed to prevent further development and spread of MDR-TB.

Is DOTS-Plus a Feasible and Cost-Effective Strategy?

Multidrug-resistant tuberculosis (MDR-TB) is on the increase with several Eastern European countries having a prevalence of more than ten percent. This resistance means that patients may not be cured with standard regimens even if they adhere well to treatment. An MDR-TB programme requires advanced medical care infection control measures counselling and good follow-up as one centre in the Philippines reports in a study published in PLoS Medicine. The DOTS-Plus (directly observed treatment short-course) project is run by the Makati Medical Center supported by the Tropical Disease Foundation. The Center has exceptional management capacity and was one of the first few nongovernmental organizations to be a principal recipient of grants from the Global Fund to Fight AIDS Tuberculosis and Malaria (known as the Global Fund). The Center itself provides high-quality tertiary care. Within this setting clinicians from the Makati Medical Center used drug history and sensitivity testing to provide individualised regimens of expensive second-line drugs estimated to cost more than US$1500 per patient. The authors report on a cohort of 171 patients with MDR-TB of whom 117 were enrolled and analysed with 61 percent cured. Indirect outcome data from patients from other countries were then combined with local cost data to estimate the number of premature deaths and secondary cases averted in order to provide an estimate of the mean cost per disability-adjusted life year gained. (excerpt)