MSF Access Campaign Drug-Resistant Tuberculosis Research and Development Case Study May 2020

Two novel drugs, bedaquiline and delamanid, have recently become available to treat drug resistant tuberculosis (DR-TB) after many decades of little innovation in the field of DR-TB treatment. Despite evidence of improved efficacy and reduced toxicity of multi-drug regimens including the two agents, access to bedaquiline and delamanid has been very limited in many settings with a high burden of DR-TB and consistently poor treatment outcomes. Aside from regulatory, logistic, and cost barriers at country level, uptake of the novel agents was complicated by gaps in knowledge for optimal use in clinical practice after initial market approval. The main incentives of the current pharmaceutical research and development paradigm are structured around obtaining regulatory approval, which in turn requires efficacy and safety data generated by clinical trials. Recently completed and ongoing clinical trials did not answer critical questions of how to provide shorter, less toxic treatment DR-TB treatment regimens containing bedaquiline and delamanid and improve patient outcomes. Voluntary generation of evidence that is not part of this process – yet essential from a clinical or policy perspective – has been left to non-sponsor partners and researchers, often without collaborative efforts to improve post-regulatory approval access to life saving drugs. Additionally, these efforts are currently not recognized in the value chain of the research and development process, and there are no incentives to make this critical research happen in a coordinated way.

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Abstract #1036 Hypothyroidism Induced by Multi Drug Resistant Tuberculosis (MDR-TB) Treatment

Endocrine Practice ◽

10.1016/s1530-891x(20)47401-4 ◽

2018 ◽

Vol 24 ◽

pp. 236

Author(s):

Rulli Rosandi

Keyword(s):

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multi Drug Resistant Tuberculosis ◽

Mdr Tb

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Novel drugs against tuberculosis: a clinician's perspective

European Respiratory Journal ◽

10.1183/09031936.00162314 ◽

2014 ◽

Vol 45 (4) ◽

pp. 1119-1131 ◽

Cited By ~ 39

Author(s):

Ioana Diana Olaru ◽

Florian von Groote-Bidlingmaier ◽

Jan Heyckendorf ◽

Wing Wai Yew ◽

Christoph Lange ◽

...

Keyword(s):

Clinical Trials ◽

Phase Ii ◽

Multidrug Resistant ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Phase Ii Clinical Trials ◽

Multidrug Resistant Tuberculosis ◽

Novel Drugs ◽

Phase Ii And Iii

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.

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Addressing the drug resistant tuberculosis challenge through implementing a mixed model of care in Uganda, 2012- 2017

10.21203/rs.2.10568/v1 ◽

2019 ◽

Author(s):

Samuel Kasozi ◽

Nicholas Sebuliba Kirirabwa ◽

Derrick Kimuli ◽

Henry Luwaga ◽

Enock Kizito ◽

...

Keyword(s):

Mixed Model ◽

Treatment Initiation ◽

Treatment Success ◽

Scale Up ◽

Sub Saharan Africa ◽

Drug Resistant ◽

Model Of Care ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis

Abstract Background Worldwide, Drug resistant Tuberculosis (DR-TB) remains a big problem; the diagnostic capacity has superseded the DR-TB clinical management capacity thereby causing ethical challenges. In Sub-Saharan Africa, treatment is either inadequate or lacking and some diagnosed patients are on treatment waiting lists. In Uganda, various health system challenges impeded scale up of DR-TB care in 2012; only three treatment initiation facilities existed, with only 41 of the estimated 1010 cases enrolled on treatment yet 300 were on the waiting list and there was no DR-TB treatment scale up plan. To scale up care, National TB/Leprosy Program (NTLP) with partners rolled out a DR-TB mixed model of care. In this paper, we share achievements and outcomes resulting from the implementation of this mixed Model of DR-TB care. Methods Routine NTLP DR-TB program data from 2013 to 2017 cohorts was collected from all the 15 DR-TB treatment initiation sites and analyzed using STATA version 14.2. We presented outcomes as the number of patient backlog cleared, DR-TB initiation sites, cumulative patients enrolled, percentage of co-infected patients on co-trimoxazole preventive therapy (CPT) and antiretroviral therapy (ART) as well as the six, twelve interim and 24 months treatment outcomes as per the Uganda NTLP 2016 Programmatic Management of drug Resistant Tuberculosis (PMDT) guidelines. Results Over the period 2013-2017, DR-TB treatment initiation sites increased from three to 15, cumulative patient enrollment rose from 41 to 1,311 and the 300-patient backlog was cleared. Treatment success rate (TSR) of 73% was achieved above the global TSR average rate of 50%. Conclusions The Uganda DR-TB mixed model of care coupled with early application of continuous improvement approaches, enhanced cohort reviews and use of multi-disciplinary teams allowed for rapid DR-TB program expansion, rapid clearance of patient backlog, attainment of high cumulative enrollment and high treatment success rates. Sustainability of these achievements is needed to further reduce the DR-TB burden in the country. We highly recommend this mixed model of care in settings with similar challenges.

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

African Health Sciences ◽

10.4314/ahs.v21i1.12 ◽

2021 ◽

Vol 21 (1) ◽

pp. 238-47

Author(s):

Charles Batte ◽

Martha S Namusobya ◽

Racheal Kirabo ◽

John Mukisa ◽

Susan Adakun ◽

...

Keyword(s):

Mulago Hospital ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Factors Associated ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multi Drug Resistant Tuberculosis ◽

Mdr Tb ◽

History Of ◽

Previously Treated

Background: 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. Methods: 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 sen- sitive 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. Results: The records of 227 MDR- TB patients met the inclusion criteria, 39.4% of whom were female, 32.6% aged be- tween 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 prev- alence ratio: 3.46, 95 % CI: 1.68 - 7.14) times more likely to be non-adherent. Conclusion: One in 10 MDR-TB patients treated at Mulago hospital is non-adherent to treatment. History of previous DR- TB 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. Keywords: Non-adherence; multi-drug resistant tuberculosis; treatment.

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Adverse Drug Reactions in Patients put on Multi Drug Resistant Tuberculosis (MDR-TB) Treatment in Seven Districts of Central Gujarat

Journal of Young Pharmacists ◽

10.5530/jyp.2015.4s.3 ◽

2015 ◽

Vol 7 (4s) ◽

pp. 425-431 ◽

Cited By ~ 2

Author(s):

Sangita Vashrambhai Patel ◽

Nimavat Kapil Bhikhubhai ◽

Alpesh Bhimabhai patel ◽

Kalpita Samrat Shringarpure ◽

Kedar Gautambhai Mehta ◽

...

Keyword(s):

Adverse Drug Reactions ◽

Drug Resistant ◽

Drug Reactions ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multi Drug Resistant Tuberculosis ◽

Mdr Tb

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The burden of drug resistant tuberculosis in a predominantly nomadic population in Uganda: a mixed methods study

BMC Infectious Diseases ◽

10.1186/s12879-021-06675-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Brenda Nakafeero Simbwa ◽

Achilles Katamba ◽

Elizabeth B. Katana ◽

Eva A. O. Laker ◽

Sandra Nabatanzi ◽

...

Keyword(s):

Mixed Methods ◽

Low Income ◽

Conditional Logistic Regression ◽

Drug Resistant ◽

Cross Sectional ◽

Drug Resistant Tuberculosis ◽

Public Health Burden ◽

Factors Associated ◽

Tb Treatment ◽

Resistant Tuberculosis

Abstract Background Emergence of drug resistant tuberculosis (DR-TB) has aggravated the tuberculosis (TB) public health burden worldwide and especially in low income settings. We present findings from a predominantly nomadic population in Karamoja, Uganda with a high-TB burden (3500 new cases annually) and sought to determine the prevalence, patterns, factors associated with DR-TB. Methods We used mixed methods of data collection. We enrolled 6890 participants who were treated for tuberculosis in a programmatic setting between January 2015 and April 2018. A cross sectional study and a matched case control study with conditional logistic regression and robust standard errors respectively were used to the determine prevalence and factors associated with DR-TB. The qualitative methods included focus group discussions, in-depth interviews and key informant interviews. Results The overall prevalence of DR-TB was 41/6890 (0.6%) with 4/64,197 (0.1%) among the new and 37/2693 (1.4%) among the previously treated TB patients respectively. The drug resistance patterns observed in the region were mainly rifampicin mono resistant (68.3%) and Multi Drug-Resistant Tuberculosis (31.7%). Factors independently associated with DR-TB were previous TB treatment, adjusted odds ratio (aOR) 13.070 (95%CI 1.552–110.135) and drug stock-outs aOR 0.027 (95%CI 0.002–0.364). The nomadic lifestyle, substance use, congested homesteads and poor health worker attitudes were a great challenge to effective treatment of TB. Conclusion Despite having the highest national TB incidence, Karamoja still has a low DR-TB prevalence. Previous TB treatment and drug stock outs were associated with DR-TB. Regular supply of anti TB medications and health education may help to stem the burden of TB disease in this nomadic population.

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Aminoglycoside-induced Hearing Loss Among Patients Being Treated for Drug-resistant Tuberculosis in South Africa: A Prediction Model

Clinical Infectious Diseases ◽

10.1093/cid/ciz289 ◽

2019 ◽

Vol 70 (5) ◽

pp. 917-924 ◽

Cited By ~ 2

Author(s):

Hyejeong Hong ◽

David W Dowdy ◽

Kelly E Dooley ◽

Howard W Francis ◽

Chakra Budhathoki ◽

...

Keyword(s):

South Africa ◽

Hearing Loss ◽

Prediction Model ◽

Predictive Value ◽

Characteristic Curve ◽

Hearing Threshold ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis

Abstract Background Individuals treated for drug-resistant tuberculosis (DR-TB) with aminoglycosides (AGs) in resource-limited settings often experience permanent hearing loss, yet there is no practical method to identify those at higher risk. We sought to develop a clinical prediction model of AG-induced hearing loss among patients initiating DR-TB treatment in South Africa. Methods Using nested, prospective data from a cohort of 379 South African adults being treated for confirmed DR-TB with AG-based regimens we developed the prediction model using multiple logistic regression. Predictors were collected from clinical, audiological, and laboratory evaluations conducted at the initiation of DR-TB treatment. The outcome of AG-induced hearing loss was identified from audiometric and clinical evaluation by a worsened hearing threshold compared with baseline during the 6-month intensive phase. Results Sixty-three percent of participants (n = 238) developed any level of hearing loss. The model predicting hearing loss at frequencies from 250 to 8000 Hz included weekly AG dose, human immunodeficiency virus status with CD4 count, age, serum albumin, body mass index, and pre-existing hearing loss. This model demonstrated reasonable discrimination (area under the receiver operating characteristic curve [AUC] = 0.71) and calibration (χ2[8] = 6.10, P = .636). Using a cutoff of 80% predicted probability of hearing loss, the positive predictive value of this model was 83% and negative predictive value was 40%. Model discrimination was similar for ultrahigh-frequency hearing loss (frequencies >9000 Hz; AUC = 0.81) but weaker for clinically determined hearing loss (AUC = 0.60). Conclusions This model may identify patients with DR-TB who are at highest risk of developing AG-induced ototoxicity and may help prioritize patients for AG-sparing regimens in clinical settings where access is limited.

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Recruitment challenges for clinical trials with novel regimens for drug-resistant tuberculosis

European Respiratory Journal ◽

10.1183/13993003.01330-2015 ◽

2015 ◽

Vol 47 (2) ◽

pp. 670-672 ◽

Cited By ~ 1

Author(s):

Sweetness Siwendu ◽

Melissa Mitchell ◽

Andreas H. Diacon ◽

Florian von Groote-Bidlingmaier

Keyword(s):

Clinical Trials ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Resistant Tuberculosis ◽

Recruitment Challenges

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Prevalence and risk factors of multi-drug resistant tuberculosis in Dalian, China

Journal of International Medical Research ◽

10.1177/0300060516687429 ◽

2017 ◽

Vol 45 (6) ◽

pp. 1779-1786 ◽

Cited By ~ 9

Author(s):

Xin-Tong Lv ◽

Xi-Wei Lu ◽

Xiao-Yan Shi ◽

Ling Zhou

Keyword(s):

Risk Factors ◽

Population History ◽

Drug Resistant ◽

Drug Resistant Tuberculosis ◽

Tb Treatment ◽

Resistant Tuberculosis ◽

Multi Drug Resistant Tuberculosis ◽

Mdr Tb ◽

Previously Treated Patients ◽

Previously Treated

Objectives To investigate the prevalence and risk factors associated with multi-drug resistant tuberculosis (MDR–TB) in Dalian, China. Methods This was a retrospective review of data from patients attending a TB clinic in Dalian, China between 2012 and 2015. Demographic and drug susceptibility data were retrieved from TB treatment cards. Univariate logistic analysis was used to assess the association between risk factors and MDR–TB. Results Among the 3552 patients who were smear positive for Mycobacterium tuberculosis (MTB), 2918 (82.2%) had positive MTB cultures and 1106 (31.1%) had isolates that showed resistance to at least one drug. The overall prevalence of MDR–TB was 10.1% (359/3552; 131/2261 [5.8%] newly diagnosed and 228/1291 [17.7%] previously treated patients). Importantly, 75 extensively drug-resistant TB isolates were detected from 25 newly treated and 50 previously treated patients. In total, 215 (6.1%) patients were infected with a poly-resistant strain of MTB. Previously treated patients and older patients were more likely to develop MDR–TB. Conclusions The study showed a high prevalence of MDR–TB among the study population. History of previous TB treatment and older age were associated with MDR–TB.

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