October 2017 Newsletter

1. The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation.
J Invest Dermatol. 2017 Oct 14. pii: S0022-202X(17)33040-3. doi: 10.1016/j.jid.2017.09.031. [Epub ahead of print]
Murashov MD(1), LaLone V(1), Rzeczycki PM(1), Keswani RK(1), Yoon GS(1), Sud S(1), Rajeswaran W(2), Larsen S(2), Stringer KA(3), Rosania GR(4).

ABSTRACT: Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug’s red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation. Despite the absence of detectable CLDIs in mice, administration of this analog still led to significant skin pigmentation. In clofazimine treated mice, skin cryosections revealed no evidence of CLDIs when analyzed with a microscopic imaging system specifically designed for detecting clofazimine aggregates. Rather, the reflectance spectra of the skin revealed a signal corresponding to the soluble, free base form of the drug. Consistent with the low concentrations of clofazimine in the skin, these results suggest that clofazimine-induced skin pigmentation is not due to clofazimine precipitation and CLDI formation, but rather to the partitioning of the circulating, free base form of the drug into subcutaneous fat.

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2. Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.
Eur J Cardiothorac Surg. 2017 Oct 10. doi:10.1093/ejcts/ezx350.
Marfina GY(1), Vladimirov KB(2), Avetisian AO(1), Starshinova AA(1), Kudriashov GG(1), Sokolovich EG(1), Yablonskii PK(1)(3).

OBJECTIVES: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB.
METHODS: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient’s susceptibility to drugs for Mycobacterium tuberculosis.
RESULTS: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11(68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015).
CONCLUSIONS: Thoracic surgery may significantly improve patients’ outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves.

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3. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance.
BMC Genomics. 2017 Oct 11;18(1):769. doi: 10.1186/s12864-017-4146-z.
Sheen P(1), Requena D(1), Gushiken E(1), Gilman RH(2), Antiparra R(1), Lucero B(1), Lizárraga P(1), Cieza B(1), Roncal E(1), Grandjean L(3), Pain A(4), McNerney R(5), Clark TG(5)(6), Moore D(5), Zimic M(7).

BACKGROUND: Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.
RESULTS: We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.
CONCLUSIONS: These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

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4. Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study.
Clin Infect Dis. 2017 Oct 15;65(8):1364-1370. doi: 10.1093/cid/cix556.
Farhat MR(1)(2), Jacobson KR(3), Franke MF(4), Kaur D(5), Murray M(4)(6), Mitnick CD(4)(7).

BACKGROUND: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.
METHODS: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.
RESULTS: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, “high-level” gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with “intermediate-level” gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.
CONCLUSIONS: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.

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5. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?
Int J Tuberc Lung Dis. 2017 Nov 1;21(11):1114-1126. doi: 10.5588/ijtld.17.0468.
Reuter A(1), Tisile P(2), von Delft D(2), Cox H(3), Cox V(4), Ditiu L(5), Garcia-Prats A(6), Koenig S(7), Lessem E(8), Nathavitharana R(9), Seddon JA(10), Stillo J(11), von Delft A(12), Furin J(7).

ABSTRACT: For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

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September 2017 Newsletter

1. The TB Portals: An open-access, web-based platform for global drug-resistant tuberculosis data sharing and analysis.
J Clin Microbiol. 2017 Sep 13. pii: JCM.01013-17. doi: 10.1128/JCM.01013-17. [Epub ahead of print]
Rosenthal A(1), Gabrielian A(2), Engle E(2), Hurt DE(2), Alexandru S(3), Crudu V(3), Sergueev E(4), Kirichenko V(4), Lapitskii V(4), Snezhko E(4), Kovalev V(4), Astrovko A(5), Skrahina A(5), Taaffe J(2), Harris M(2), Long A(2), Wollenberg K(2), Akhundova I(6), Ismayilova S(6), Skrahin A(7), Mammadbayov E(6), Gadirova H(6), Abuzarov R(6), Seyfaddinova M(6), Avaliani Z(6), Strambu I(8), Zaharia D(8), Muntean A(8), Ghita E(8), Bogdan M(8), Mindru R(8), Spinu V(8), Sora A(8), Ene C(8), Vashakidze S(9), Shubladze N(9), Nanava U(9), Tuzikov A(4), Tartakovsky M(2).

ABSTRACT: The TB Portals Program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug-resistant tuberculosis working with data scientists and IT professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis and backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), of which 976 (75.1%) are multi- or extensively drug resistant, and 38.2%, 51.9%, and 36.3% of cases contain X-ray, CT scan, and  genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and SNPs that confer resistance to isoniazid, rifampicin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics, while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations in our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at: https://tbportals.niaid.nih.gov.

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2. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.
N Engl J Med. 2017 Sep 14;377(11):1043-1054. doi: 10.1056/NEJMoa1614915.
Xie YL(1), Chakravorty S(1), Armstrong DT(1), Hall SL(1), Via LE(1), Song T(1), Yuan X(1), Mo X(1), Zhu H(1), Xu P(1), Gao Q(1), Lee M(1), Lee J(1), Smith LE(1), Chen RY(1), Joh JS(1), Cho Y(1), Liu X(1), Ruan X(1), Liang L(1), Dharan N(1), Cho SN(1), Barry CE 3rd(1), Ellner JJ(1), Dorman SE(1), Alland D(1).

BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid.
METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M.tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions.
RESULTS: Among the 308 participants who were culture-positive for M.tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.
CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; ClinicalTrials.gov number, NCT02251327).

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3. Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.
PLoS One. 2017 Sep 7;12(9):e0184270. doi: 10.1371/journal.pone.0184270. eCollection 2017.
Khaparde S(1), Raizada N(2), Nair SA(3), Denkinger C(4), Sachdeva KS(1), Paramasivan CN(2), Salhotra VS(5), Vassall A(6)(7), Hoog AV(6).

BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India.
METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients.
RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US $1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099).
CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

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4.Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada.
BMC Infect Dis. 2017 Sep 4;17(1):604. doi: 10.1186/s12879-017-2706-0.
Romanowski K(1), Chiang LY(1), Roth DZ(1), Krajden M(2), Tang P(2)(3), Cook VJ(1)(4), Johnston JC(5)(6).

BACKGROUND: Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by physicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated under programmatic conditions in British Columbia, Canada.
METHODS: Medical charts were retrospectively reviewed for cases of culture-confirmed INH mono-resistant TB reported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and strain characteristics, and clinical outcomes were analysed.
RESULTS: One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatment regimens were prescribed. Median treatment duration was 10.5 months (IQR 9-12 months) and treatment was extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverse event that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatment outcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse (n = 4; 2.4%) or all cause mortality (n = 6; 3.6%).
CONCLUSION: Our treatment outcomes, while consistent with findings reported from other studies in high resource settings, raise concerns about current recommendations for INH resistant TB treatment. Only a small proportion of patients completed the recommended treatment regimens. High quality studies to confirm the effectiveness of standardized regimens are urgently needed, with special consideration given to trials utilizing fluoroquinolones.

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August 2017 Newsletter

1. Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis.
Bull World Health Organ. 2017 Aug 1;95(8):584-593. doi: 10.2471/BLT.17.193375.
Ho J(1), Byrne AL(1), Linh NN(2), Jaramillo E(2), Fox GJ(3).

OBJECTIVE: To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches.
METHODS: We searched ClinicalTrials.gov, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization’s portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses.
FINDINGS: Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes.  The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01-1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38-1.13), for death RR: 1.01 (95% CI: 0.67-1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48-2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models.
CONCLUSION: Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

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2. A systematic review of national policies for the management of persons exposed to tuberculosis.
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):935-940. doi: 10.5588/ijtld.17.0061.
Rodriguez CA(1), Sasse S(1), Yuengling KA(2), Azzawi S(1), Becerra MC(3), Yuen CM(3).

OBJECTIVE: To describe mandates and policy gaps in tuberculosis (TB) contact investigation and management.
DESIGN: We conducted a systematic review of national TB policy documents obtained using a systematic internet search and by contacting national TB programs. We included policies published in English, Spanish, and French, and abstracted data using a standardized form.
RESULTS: We reviewed policy documents for 68 of 216 (31%) countries and territories. All countries recommended performing contact investigations, but 40% did not specify how contacts enter the health system for evaluation or who was responsible for this process. All countries recommended preventive therapy for contacts, but in 14 (21%) countries only young children were eligible. While four preventive therapy regimens exist, 48 (71%) countries recommended only isoniazid monotherapy. In addition, 28 (41%) countries lacked guidance on whether to give preventive therapy to contacts exposed to drug-resistant TB. Policies in 28 (41%) countries lacked recommendations for managing contacts with the human immunodeficiency virus (HIV) after new TB exposure.
CONCLUSION: Policies recommending contact investigation and preventive therapy for contacts are widespread, but policy gaps exist in the areas of ensuring accountability and the management of vulnerable populations such as people living with HIV and those exposed to drug-resistant TB.

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3. What happened to patients with RMP-resistant/MDR-TB in Zambia reported as lost to follow-up from 2011 to 2014?
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):887-893. doi: 10.5588/ijtld.16.0933.
Kasapo CC(1), Chimzizi R(1), Simwanza SC(1), Mzyece J(1), Chizema E(2), Mariandyshev A(3), Lee HY(4), Harries AD(5), Kapata N(6).

SETTING: University Teaching Hospital, Lusaka, and Ndola Central Hospital, Ndola, Zambia, which implemented active tracing of multidrug-resistant tuberculosis (MDR-TB) patients reported as lost to follow-up (LTFU).
OBJECTIVE: To determine 1) the number of patients treated for MDR-TB between 2011 and 2014; 2) the number, proportion, month when LTFU and characteristics of patients registered as LTFU; and 3) final outcomes observed following active patient tracing.
DESIGN: Retrospective cohort study.
RESULTS: Of 184 patients treated for confirmed MDR-TB, 76 (41%) were reported as LTFU. From 2011 to 2014, the proportions reported each year as LTFU were respectively 21%, 47%, 51% and 39%. Of patients who were LTFU, 43 (57%) had stopped attending the clinic during the intensive phase. These patients were predominantly male, aged 15-44 years, had pulmonary disease and had failed previous treatment. Of 57 (75%) patients with known human immunodeficiency virus (HIV) status, 42 (74%) were HIV-positive, 57% of whom were on antiretroviral treatment. After active patient tracing, 29 (38%) patients could not be found and the observed outcome remained LTFU. Of the remaining 47 patients, 29 (62%) were alive and had completed or were still on treatment, 14 (30%) were alive but had stopped treatment and 4 (8%) had died.
CONCLUSION: Zambia has been underreporting its favourable outcomes for MDR-TB treatment and should continue with active tracing of LTFU patients.

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4. Addressing the tuberculosis-depression syndemic to end the tuberculosis epidemic.
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):852-861. doi: 10.5588/ijtld.16.0584.
Sweetland AC(1), Kritski A(2), Oquendo MA(3), Sublette ME(1), Norcini Pala A(1), Silva LRB(4), Karpati A(5), Silva EC(6), Moraes MO(4), Silva JRLE(7), Wainberg ML(1).

ABSTRACT: Tuberculosis (TB) and depression act synergistically via social, behavioral, and biological mechanisms to magnify the burden of disease. Clinical depression is a common, under-recognized, yet treatable condition that, if comorbid with TB, is associated with increased morbidity, mortality, community TB transmission, and drug resistance. Depression may increase risk of TB reactivation, contribute to disease progression, and/or inhibit the physiological response to anti-tuberculosis treatment because of poverty, undernutrition, immunosuppression, and/or negative coping behaviors, including substance abuse.
Tuberculous infection and/or disease reactivation may precipitate depression as a result of the inflammatory response and/or dysregulation of the hypothalamic-pituitary-adrenal axis. Clinical depression may also be triggered by TB-related stigma, exacerbating other underlying social vulnerabilities, and/or may be attributed to the side effects of anti-tuberculosis treatment. Depression may negatively impact health behaviors such as diet, health care seeking, medication adherence, and/or treatment completion, posing a significant challenge for global TB elimination. As several of the core symptoms of TB and depression overlap, depression often goes unrecognized in individuals with active TB, or is dismissed as a normative reaction to situational stress. We used evidence to reframe TB and depression comorbidity as the ‘TB-depression syndemic’, and identified critical research gaps to further elucidate the underlying mechanisms. The World Health Organization’s Global End TB Strategy calls for integrated patient-centered care and prevention linked to social protection and innovative research. It will require multidisciplinary approaches that consider conditions such as TB and depression together, rather than as separate problems and diseases, to end the global TB epidemic.

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5. Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval
by the US Food and Drug Administration
JAMA. 2017;318(7):626-636. doi:10.1001/jama.2017.9415
Huseyin Naci, PhD, MHS; Katelyn R. Smalley, BSc; Aaron S. Kesselheim, MD, JD, MPH

IMPORTANCE: Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements.
OBJECTIVE: To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval.
DESIGN AND SETTING: Publicly available FDA documents were reviewed to identify the pre-approval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA’s database of post-marketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017.
EXPOSURES: Granting of accelerated approval.
MAIN OUTCOMES AND MEASURES: Characteristics of pre-approval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized.
RESULTS: The FDA granted accelerated approval to 22 drugs for 24 indications (19for indications involving cancer treatment) between 2009 and 2013. A total of 30 pre-approval studies supported the 24 indications. The median number of participants enrolled in the pre-approval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, −15% to 46%; P = .31). Post-approval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit
in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.
CONCLUSIONS AND RELEVANCE: Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in post-approval trials a minimum of 3 years after approval, although confirmatory trials and pre-approval trials had similar design elements, including reliance on surrogate measures as outcomes.

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July 2017 Newsletter

1. Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.
PLoS One. 2017 Jul 10;12(7):e0180916. doi: 10.1371/journal.pone.0180916. eCollection 2017.
Magee MJ(1), Sun YV(2), Brust JCM(3), Shah NS(4), Ning Y(3), Allana S(2), Campbell A(2), Hui Q(2), Mlisana K(5), Moodley P(5), Gandhi NR(2)(6)(7).

BACKGROUND: Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.
METHODS: We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.
RESULTS: Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%),  were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67).
CONCLUSIONS: Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in
South Africa.

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2. Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia.
BMC Infect Dis. 2017 Jul 12;17(1):491. doi: 10.1186/s12879-017-2594-3.
Sengstake S(1)(2), Bergval IL(3)(4), Schuitema AR(3), de Beer JL(5), Phelan J(6), de Zwaan R(5), Clark TG(6)(7), van Soolingen D(5), Anthony RM(3)(5).

BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region.
METHODS: Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates.
RESULTS: Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94-32 and 100-32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region.
CONCLUSION: In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.

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3. The sterilizing effect of ertapenem-clavulanate in a hollow fiber model of tuberculosis and implications on clinical dosing.
Antimicrob Agents Chemother. 2017 Jul 10. pii: AAC.02039-16. doi: 10.1128/AAC.02039-16. [Epub ahead of print]
van Rijn SP(1), Srivastava S(2), Wessels MA(1), van Soolingen D(3)(4), Alffenaar JC(5), Gumbo T(2).

ABSTRACT: Carbapenems are now being explored for treatment of multi-drug resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day, and lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once a day dose for clinical use. We utilized the hollow fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time-points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid Emax modeling was used to identify the relationship between total bacterial burden and the drug exposure, and identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose-fractionation hollow fiber study, efficacy was linked to percentage of the 24 hour dosing interval of ertapenem concentration persisting above MIC (%TMIC).  We performed a 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed %TMIC ≥40%. We identified an intravenous dose of 2 grams once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC 2 mg/L was identified for that dose. An ertapenem dose of 2g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.

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4. Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice.
Int J Tuberc Lung Dis. 2017 Jul 1;21(7):774-777. doi: 10.5588/ijtld.16.0949.
Turkova A(1), Tebruegge M(2), Brinkmann F(3), Tsolia M(4), Mouchet F(5), Kampmann B(6), Seddon JA(7).

ABSTRACT: The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related  to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33-12.5).

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5. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.
Lancet Infect Dis. 2017 Jul;17(7):707-715. doi: 10.1016/S1473-3099(17)30247-5. Epub 2017 May 9.
Sharma A, Hill A, Kurbatova E, van der Walt M, Kvasnovsky C, Tupasi TE, Caoili JC, Gler MT, Volchenkov GV, Kazennyy BY, Demikhova OV, Bayona J, Contreras C, Yagui M, Leimane V, Cho SN, Kim HJ, Kliiman K, Akksilp S, Jou R, Ershova J, Dalton T, Cegielski P; Global Preserving Effective TB Treatment Study Investigators.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa.
METHODS: We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa.
FINDINGS: The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4-16·2) in India, 8·9% (4·5-11·7) in the Philippines, 32·5% (27·0-35·8) in Russia, and 5·7% (3·0-7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1-12·9) in India, 9·0% (4·0-14·7) in the Philippines, 9·0% (4·8-14·2) in Russia, and 8·5% (2·5-14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000-40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040.
INTERPRETATION: MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis.
FUNDING: US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.

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June 2017 Newsletter

1. Cryptic Micro-heteroresistance Explains M. tuberculosis Phenotypic Resistance.
Am J Respir Crit Care Med. 2017 Jun 14. doi: 10.1164/rccm.201703-0556OC. [Epub ahead of print]
Metcalfe JZ(1), Streicher E(2), Theron G(3), Colman RE(4), Allender C(5), Lemmer
D(6), Warren R(7), Engelthaler DM(8).

BACKGROUND: Minority resistant M. tuberculosis subpopulations can be associated with phenotypic resistance, but are poorly detected by Sanger sequencing or commercial molecular diagnostic assays. The role of targeted next generation sequencing (NGS) in resolving these minor variant subpopulations is unclear.
METHODS: We utilized Single Molecule-Overlapping Reads (SMOR), a targeted NGS approach that dramatically reduces sequencing error, to analyze primary cultured isolates phenotypically resistant to rifampin, fluoroquinolones, or aminoglycosides, but for which Sanger sequencing found no resistance-associated variants (RAVs) within respective resistance determining regions (RDRs) (Study Group). Isolates also underwent single-colony selection on antibiotic-containing agar, blinded to sequencing results. As a positive control, isolates with multiple co-localizing chromatogram peaks were also analyzed (Control Group).
RESULTS: Among 61 primary culture isolates (25 study group and 36 control group), SMOR described 82 (54%) and 61 (40%) of 151 total heteroresistant RAVs at frequencies <5% and <1% of the total mycobacterial population, respectively. In the study group, SMOR detected minor resistant variant subpopulations in 84% (n=21/25) of isolates with no Sanger-identified RAVs (median subpopulation size 4.1%, interquartile range 2.6-7.5%). Single-colony selection on drug-containing media corroborated SMOR results for 91% (n=19/21) of RAV-containing specimens, and the absence of RAVs in 75% (n=3/4) of isolates. Overall, Sanger sequencing was concordant with SMOR for 77% (n=53/69) of macro-heteroresistant (5-95% total population), but only 4% of micro-heteroresistant (<5%) subpopulations (n=3/82) across both groups.
CONCLUSION: Cryptic minor variant mycobacterial subpopulations exist below the resolving capability of current DST methodologies, and may explain an important proportion of false-negative resistance determinations.

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2. Treatment outcomes of MDR-TB and HIV co-infection in Europe.
Eur Respir J. 2017 Jun 8;49(6). pii: 1602363. doi: 10.1183/13993003.02363-2016. Print 2017 Jun.
Magis-Escurra C(1)(2), Günther G(3)(4)(2), Lange C(5)(4)(6)(7)(2), Alexandru
S(8), Altet N(9), Avsar K(10), Bang D(11), Barbuta R(12), Bothamley G(13),
Ciobanu A(8), Crudu V(8)(14), Davilovits M(15), Dedicoat M(16)(17), Duarte
R(18)(19), Gualano G(20), Kunst H(21)(22), de Lange W(23)(24), Leimane V(25),
McLaughlin AM(26), Muylle I(27), Polcová V(28), Popa C(29), Rumetshofer R(30),
Skrahina A(31), Solodovnikova V(31), Spinu V(29), Tiberi S(22)(32)(33), Viiklepp
P(34), van Leth F(35)(36)(2); for TBnet.

EXTRACT: The ongoing HIV epidemic and the increasing number of patients with drug-resistant tuberculosis (TB) are seriously hampering global TB-control activities, including those in the World Health Organization (WHO) Region Europe. Overall, the prevalence of HIV co-infection in TB patients increased from 3.4% in 2008 to 8% in 2014 in the region. The prevalence of multidrug-resistant (MDR)-TB (drug resistance against at least isoniazid and rifampicin) reported for Europe – 15% in newly diagnosed TB patients and 48% in previously treated TB patients – is the highest in the world.

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3. In vitro and in vivo activity of biapenem against drug-susceptible and
rifampicin-resistant Mycobacterium tuberculosis.
J Antimicrob Chemother. 2017 Jun 1. doi: 10.1093/jac/dkx152. [Epub ahead of
Kaushik A(1), Ammerman NC(1), Tasneen R(1), Story-Roller E(1), Dooley KE(1),
Dorman SE(1), Nuermberger EL(1), Lamichhane G(1).

BACKGROUND: Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis.
OBJECTIVES: Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis, in vitro and in the mouse model.
METHODS: Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis: strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo, we first conducted a dose-ranging experiment with biapenem against H37Rvin the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain.
RESULTS: In vitro, synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo , biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains.
CONCLUSIONS: Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a ‘new’ – and desperately needed – drug for the treatment of drug-resistant TB.

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4.Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.
Eur Respir J. 2017 May 21;49(5). pii: 1700387. doi: 10.1183/13993003.00387-2017.
Print 2017 May.
Borisov SE(1)(2), Dheda K(3)(2), Enwerem M(4)(2), Romero Leyet R(5)(2),
D’Ambrosio L(6)(7)(2), Centis R(6)(2), Sotgiu G(8)(2), Tiberi S(9)(10)(2),
Alffenaar JW(11)(2), Maryandyshev A(12)(2), Belilovski E(1)(2), Ganatra S(13)(2),
Skrahina A(14)(2), Akkerman O(15)(16), Aleksa A(17), Amale R(13), Artsukevich
J(17), Bruchfeld J(18), Caminero JA(19)(20), Carpena Martinez I(21), Codecasa
L(22), Dalcolmo M(23), Denholm J(24), Douglas P(25), Duarte R(26), Esmail A(27),
Fadul M(27), Filippov A(1), Davies Forsman L(18), Gaga M(28), Garcia-Fuertes
JA(29), García-García JM(30), Gualano G(31), Jonsson J(32), Kunst H(10), Lau
JS(33), Lazaro Mastrapa B(34), Teran Troya JL(34), Manga S(35), Manika K(36),
González Montaner P(37), Mullerpattan J(13), Oelofse S(27), Ortelli M(38),
Palmero DJ(37), Palmieri F(31), Papalia A(39), Papavasileiou A(40), Payen MC(41),
Pontali E(42), Robalo Cordeiro C(43), Saderi L(8), Sadutshang TD(44), Sanukevich
T(17), Solodovnikova V(14), Spanevello A(45)(46), Topgyal S(44), Toscanini F(47),
Tramontana AR(48), Farokh Udwadia Z(13), Viggiani P(39), White V(49), Zumla
A(50), Migliori GB(51)(2).

ABSTRACT: Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

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May 2017 eNewsletter

1. Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug Resistant Tuberculosis patients.
Antimicrob Agents Chemother. 2017 May 15. pii: AAC.00343-17. doi: 10.1128/AAC.00343-17. [Epub ahead of print]
Van’t Boveneind-Vrubleuskaya N(1,)(2), Seuruk T(3), van Hateren K(2), van der Laan T(4), Kosterink JGW(2), van der Werf TS(5), van Soolingen D(4,)(6), van den Hof S(2,)(7), Skrahina A(3), Alffenaar JC(8).

ABSTRACT: Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily. Blood samples obtained at steady state before- and 1, 2, 3, 4, 7, and 12 hrs after drug administration were measured by validated a liquid chromatography-tandem mass spectrometry. MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 (IQR; 27-35) years were enrolled in this study. The median AUC0-24h was 98.8 mg/h/L (IQR; 84.8-159.6). The MIC median value for LFX was 0,5 mg/L with a range of 0.25 to 2.0 mg/L and the median fAUC0-24/MIC ratio was 109.5 (IQR; 48.5-399.4). In four of the 20 patients the value was below the target value of ≥100. When a MIC of 0.25, 0.5, 1.0 and 2.0 mg/L were applicable, 19, 18, 3 and no patients, respectively, had a fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. A fAUC0-24/MIC of ≥ 100 was only observed in case MIC values for LFX were 0.25-0.5 mg/L. Dosages exceeding 15mg/kg should be considered for target attainment if exposures are assumed to be safe.

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2. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.
Lancet Infect Dis. 2017 May 9. pii: S1473-3099(17)30247-5. doi:10.1016/S1473-3099(17)30247-5. [Epub ahead of print]
Sharma A(1), Hill A(2), Kurbatova E(2), van der Walt M(3), Kvasnovsky C(4), Tupasi TE(5), Caoili JC(5), Gler MT(5), Volchenkov GV(6), Kazennyy BY(7), Demikhova OV(8), Bayona J(9), Contreras C(9), Yagui M(10), Leimane V(11), Cho SN(12), Kim HJ(13), Kliiman K(14), Akksilp S(15), Jou R(16), Ershova J(2), Dalton T(2), Cegielski P(2); Global Preserving Effective TB Treatment Study Investigators.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries.We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa.
METHODS: We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa.
FINDINGS: The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4-16·2) in India, 8·9% (4·5-11·7) in the Philippines, 32·5% (27·0-35·8) in Russia, and 5·7% (3·0-7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1-12·9) in India, 9·0% (4·0-14·7) in the Philippines, 9·0% (4·8-14·2) in Russia, and 8·5% (2·5-14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000-40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040.
INTERPRETATION: MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis.
FUNDING: US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.

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3. A combination of baseline plasma immune markers can predict therapeutic response in multidrug resistant tuberculosis.
PLoS One. 2017 May 2;12(5):e0176660. doi: 10.1371/journal.pone.0176660. eCollection 2017.
Ferrian S(1), Manca C(2), Lubbe S(3), Conradie F(4), Ismail N(5), Kaplan G(6), Gray CM(1), Fallows D(2).

OBJECTIVE: To identify plasma markers predictive of therapeutic response in patients with multidrug resistant tuberculosis (MDR-TB).
METHODS: Fifty HIV-negative patients with active pulmonary MDR-TB were analysed for six soluble analytes in plasma at the time of initiating treatment (baseline) and over six months thereafter. Patients were identified as sputum culture positive or negative at baseline. Culture positive patients were further stratified by the median time to sputum culture conversion (SCC) as fast responders (< 76 days) or slow responders (≥ 76 days). Chest X-ray scores, body mass index, and sputum smear microscopy results were obtained at baseline.
RESULTS: Unsupervised hierarchical clustering revealed that baseline plasma levels of IP-10/CXCL10, VEGF-A, SAA and CRP could distinguish sputum culture and  cavitation status of patients. Among patients who were culture positive at baseline, there were significant positive correlations between plasma levels of CRP, SAA, VEGF-A, sIL-2Rα/CD40, and IP-10 and delayed SCC. Using linear discriminant analysis (LDA) and Receiver Operating Curves (ROC), we showed that a combination of MCP-1/CCL2, IP-10, sIL-2Rα, SAA, CRP and AFB smear could distinguish fast from slow responders and were predictive of delayed SCC with high sensitivity and specificity.
CONCLUSION: Plasma levels of specific chemokines and inflammatory markers measured before MDR-TB treatment are candidate predictive markers of delayed SCC. These findings require validation in a larger study.

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4. Population implications of the use of bedaquiline in people with extensively drug-resistant tuberculosis: are fears of resistance justified?
Lancet Infect Dis. 2017 May 19. pii: S1473-3099(17)30299-2. doi: 10.1016/S1473-3099(17)30299-2. [Epub ahead of print]
Kunkel A(1), Furin J(2), Cohen T(3).

ABSTRACT: Global rollout of the new antituberculosis drug bedaquiline has been slow, in part reflecting concerns about spread of bedaquiline resistance. Acquired resistance to bedaquiline is especially likely in patients with extensively drug-resistant (XDR) tuberculosis. However, the very high mortality rates of patients with XDR not receiving bedaquiline, and promising cohort study results, suggest these patients also have greatest need for the drug. In this Personal View, we argue that resistance concerns should not forestall use of bedaquiline in patients with XDR tuberculosis. Our position in favour of increased access to bedaquiline for these patients is based on three arguments. First, the use of drug combinations that include bedaquiline might prevent spread of XDR disease to others in the community. Second, until new combination regimens of novel drugs for XDR tuberculosis become available, patients with XDR disease and their infected contacts will face equivalent outcomes if bedaquiline is either not provided because of policy, or not effective because of resistance. Finally, because resistance to bedaquiline and other antituberculosis drugs is caused by mutations within a single bacterial chromosome, use of bedaquiline in patients with XDR tuberculosis will not substantially increase the risk of bedaquiline resistance in patients with drug-susceptible or multidrug-resistant (non‑XDR) tuberculosis strains.

Read free TB Online article here 

April 2017 eNewsletter

1. Adverse drug reactions during drug-resistant TB treatment in high HIV prevalence  settings: a systematic review and meta-analysis.
J Antimicrob Chemother. 2017 Apr 16. doi: 10.1093/jac/dkx107. [Epub ahead of print]
Schnippel K(1,)(2), Firnhaber C(2,)(3), Berhanu R(4,)(5), Page-Shipp L(6), Sinanovic E(1).

OBJECTIVES: To estimate the prevalence of adverse drug reactions or events (ADR) during drug-resistant TB (DR-TB) treatment in the context of settings with high HIV prevalence (at least 20% of patients).
METHODS: We conducted a systematic review and meta-analysis of articles in PubMed and Scopus. Pooled proportions of patients experiencing adverse events and relative risk with 95% CI were calculated.
RESULTS: The search yielded 24 studies, all observational cohorts. Ten reported on the number of patients experiencing ADR and were included in the meta-analysis representing 2776 study participants of whom 1943 were known to be HIV infected (70.0%). An average of 83% (95% CI: 82%-84%) of patients experienced one or more ADR. Among the seven articles ( n  =   664 study participants) with information on occurrence of severe ADR, 24% (95% CI: 21%-27%) of patients experienced at least one severe ADR during drug-resistant TB treatment. Sixteen of the 24 studies analysed the relative risk of ADR by HIV infection, nine of which found no statistically significant association between HIV infection and occurrence of drug-related ADR. There was insufficient information to disaggregate risk by concomitant treatment with HIV antiretrovirals or by immunosuppression (CD4 count).
CONCLUSIONS: No randomized clinical trials were found for WHO-recommended treatment of drug-resistant TB treatment where at least 20% of the cohort was coinfected with HIV. Nearly all patients (83%) experience ADR during DR-TB treatment. While no significant association between ADR and HIV coinfection was found, further research is needed to determine whether concomitant antiretrovirals or immunosuppression increases the risks for HIV-infected patients.

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2. Increased Tuberculosis Patient Mortality Associated with Mycobacterium tuberculosis Mutations Conferring Resistance to Second-line Antituberculous Drugs.
J Clin Microbiol. 2017 Apr 12. pii: JCM.00152-17. doi: 10.1128/JCM.00152-17. [Epub ahead of print]
Georghiou SB(1), Seifert M(2), Catanzaro DG(3), Garfein RS(2), Rodwell TC(2).

ABSTRACT: Rapid molecular diagnostics have great potential to limit the spread of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). These technologies detect mutations in the Mycobacterium tuberculosis (Mtb) genome that confer phenotypic drug resistance. However, there is little data published regarding the relationships between the detected Mtb resistance mutations and M/XDR-TB treatment outcomes, limiting our current ability to exploit the full potential of molecular diagnostics. We analyzed clinical, microbiological and sequencing data  for 451 patients and their clinical isolates collected in a multinational, observational cohort study to determine if there was an association between Mtb resistance mutations and patient mortality. Presence of an rrs 1401G mutation was associated with significantly higher odds of patient mortality [adj OR=5.72 (95% CI 1.65 to 19.84)] after adjusting for relevant patient clinical characteristics and all other resistance mutations. Further analysis of mutations, categorized by associated resistance level, indicated that the detection of mutations associated with high-level fluoroquinolone [OR 3.99 (95% CI 1.10-14.40)] and kanamycin [OR 5.47 (95% CI 1.64-18.24)] resistance were also significantly associated with higher odds of patient mortality, even after accounting for clinical site, patient age, reported smoking, BMI, diabetes, HIV, and all other resistance mutations. Specific gyrA and rrs resistance mutations, associated with high-level resistance, were associated with patient mortality when identified in clinical Mtb in a diverse M/XDR-TB patient population from three high burden clinical sites. These results have important implications for the interpretation of molecular diagnostics, including identifying patients at increased risk for mortality during treatment.

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3. Delamanid Kills Dormant Mycobacteria in Vitro and in the Guinea Pig Model of Tuberculosis.
Antimicrob Agents Chemother. 2017 Apr 3. pii: AAC.02402-16. doi: 10.1128/AAC.02402-16. [Epub ahead of print]
Chen X(1), Hashizume H(1), Tomishige T(1), Nakamura I(1), Matsuba M(1), Fujiwara M(1), Kitamoto R(1), Hanaki E(1), Ooba Y(1), Matsumoto M(2).

ABSTRACT: TB treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug-susceptibility. Drugs with broad activity are urgently needed. The study aimed to evaluate delamanid’s activity against growing or dormant bacilli in vitro as well as in vivo Culture of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic condition was used to study delamanid’s activity against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above the concentrations of 0.016 and 0.4 mg/L, respectively. To evaluate delamanid’s anti-tuberculosis activity in vivo, we used a chronic tuberculosis infection guinea pig model with lung lesions similar to those in human TB disease. In the guinea pig TB model, daily dose of 100 mg/kg delamanid for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampicin and pyrazinamide, or with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampicin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials in pulmonary MDR-TB patients. Delamanid may be an important drug for consideration when constructing new regimens to shorten TB treatment duration.

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4. Additional Drug Resistance Patterns among Multidrug-Resistant Tuberculosis Patients in Korea: Implications for Regimen Design.
J Korean Med Sci. 2017 Apr;32(4):636-641. doi: 10.3346/jkms.2017.32.4.636.
Mok JH(1), Kang BH(2), Lee T(3), Lee HK(4), Jang HJ(5), Cho YJ(6), Jeon D(7,)(8).

ABSTRACT: Detailed information on additional drug resistance patterns of multidrug-resistant tuberculosis (MDR-TB) is essential to build an effective treatment regimen; however, such data are scarce in Korea. We retrospectively analyzed the results of phenotypic drug susceptibility testing (DST) of culture confirmed-TB patients from January 2010 to December 2014 in 7 university hospitals in Korea. MDR-TB was identified among 6.8% (n = 378) of 5,599 isolates. A total of 57.1% (n = 216) of the MDR-TB patients had never been treated for TB. Strains from MDR-TB patients showed additional resistance to pyrazinamide (PZA) (35.7%), any second-line injectable drug (19.3%), and any fluoroquinolone (26.2%). Extensively drug resistant TB comprised 12.4% (n = 47) of the MDR-TB patients. Of 378 MDR-TB patients, 50.3% (n = 190) were eligible for the shorter MDR-TB regimen, and 50.0% (n = 189) were fully susceptible to the 5 drugs comprising the standard conventional regimen (PZA, kanamycin, ofloxoacin, prothionamide, and cycloserine). In conclusion, the proportion of new patients and the levels of additional drug resistance were high in MDR-TB patients. Considering the high levels of drug resistance, the shorter MDR-TB treatment regimen may not be feasible; instead, an individually tailored regimen based on the results of molecular and phenotypic DST may be more appropriate in MDR-TB patients in Korea.

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March 2017 eNewsletter

1. MDR-TB treatment as prevention: The projected population-level impact of expanded treatment for multidrug-resistant tuberculosis.
PLoS One. 2017 Mar 8;12(3):e0172748. doi: 10.1371/journal.pone.0172748. eCollection 2017.
Kendall EA(1), Azman AS(2), Cobelens FG(3), Dowdy DW(2).

BACKGROUND: In 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality.
METHODS: We constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology. RESULTS: Despite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4-52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naïve as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6-55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20-74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025.
CONCLUSIONS: Expansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.

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2. Outcomes from the first multidrug-resistant tuberculosis programme in Kenya.
Int J Tuberc Lung Dis. 2017 Mar 1;21(3):314-319. doi: 10.5588/ijtld.16.0661.
Huerga H(1), Bastard M(1), Kamene M(2), Wanjala S(3), Arnold A(4), Oucho N(5), Chikwanha I(6), Varaine F(6).

SETTING: In March 2006, the first multidrug-resistant tuberculosis (MDR-TB) treatment programme was implemented in Kenya.
OBJECTIVE: To describe patients’ treatment outcomes and adverse events.
DESIGN: 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.
RESULTS: 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).
CONCLUSION: In Kenya, where an ambulatory model of care is used for MDR-TBtreatment, 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.

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3. Latent tuberculous infection in household contacts of multidrug-resistant and newly diagnosed tuberculosis.
Int J Tuberc Lung Dis. 2017 Mar 1;21(3):297-302. doi: 10.5588/ijtld.16.0576.
Fox GJ(1), Anh NT(1), Nhung NV(2), Loi NT(1), Hoa NB(3), Ngoc Anh LT(4), Cuong NK(5), Buu TN(6), Marks GB(7), Menzies D(8).

BACKGROUND: Differences in the prevalence of latent tuberculous infection (LTBI) and tuberculosis (TB) disease among contacts of patients with multidrug-resistant TB(MDR-TB) and drug-susceptible TB are not well understood.
OBJECTIVE: To compare the prevalence of tuberculin skin test (TST) positivity in household contacts of patients with MDR-TB and in contacts of patients never previously treated for TB (‘new TB‘).
DESIGN: Consecutive patients with MDR-TB and their household contacts at nine urban district clinics in Viet Nam were screened for TB and LTBI, and followed up for 6 months. LTBI was defined as a TST result of at least 10 mm.
RESULTS: A total of 167 patients with TB and their 337 household contacts were recruited. A total of 167/180 (25.8%) contacts of new TB patients and 60/147 (40.8%) contacts of MDR-TB patients were TST-positive (odds ratio [OR] 2.0, 95%CI 1.3-3.2). Contacts of MDR-TB patients were more likely to have baseline chest radiograph findings consistent with TB (OR 2.6, 95%CI 1.4-5.0).
CONCLUSION: Contacts of MDR-TB patients have a high risk of developing TB. Measures to reduce Mycobacterium tuberculosis transmission and accelerate the detection of disease among high-risk contacts should be prioritised to curb the MDR-TB epidemic.

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4. The risk of global epidemic replacement with drug-resistant Mycobacterium tuberculosis strains.
Int J Infect Dis. 2017 Mar;56:14-20. doi: 10.1016/j.ijid.2017.01.031. Epub 2017 Feb 2.
McBryde ES(1), Meehan MT(2), Doan TN(3), Ragonnet R(4), Marais BJ(5), Guernier V(2), Trauer JM(6).

OBJECTIVES: Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model.
METHODS: This model considers two TB strains, one with and one without an MDR phenotype. It was considered that intrinsic transmissibility may be different between the two strains, as may the control response including the detection, treatment failure, and default rates. The outcomes were explored in terms of the incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain.
RESULTS AND CONCLUSIONS: The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility was modestly reduced (to between 50% and 100% as transmissible as the DS-TB strain). This model suggests that it may take decades or more for strain replacement to occur. It was also found that while the amplification of resistance is the early cause of MDR-TB, this will rapidly give way to person-to-person transmission.

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February 2017 e-Newsletter

1. Delays and loss to follow-up before treatment of drug-resistant tuberculosis following implementation of Xpert MTB/RIF in South Africa: A retrospective cohort study.
PLoS Med. 2017 Feb 21;14(2):e1002238. doi: 10.1371/journal.pmed.1002238. eCollection 2017.
Cox H(1,)(2), Dickson-Hall L(1), Ndjeka N(3), Van’t Hoog A(4,)(5), Grant
A(6,)(7,)(8), Cobelens F(4,)(5), Stevens W(9), Nicol M(1,)(2,)(10).

BACKGROUND: South Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for tuberculosis (TB) diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow-up) between the numbers of patients with laboratory-confirmed RR-TB and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa.
METHODS AND FINDINGS: A nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory-diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from the years 2011 and 2013, i.e., before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 mo and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with health care staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of the percentage of patients who initiated treatment and time to treatment were weighted to account for the sampling design. There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts, respectively; 92% were newly diagnosed with RR-TB (no prior RR-TB diagnoses). Nationally, among the 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53%-57%) and 63% (95% CI 61%-65%), respectively, started treatment within 6 mo of laboratory receipt of their diagnostic specimen (p < 0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at 6 mo between the 1,368 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59%-65%) and the 943 diagnosed by other methods (64%, 95% CI 61%-67%) (p = 0.39). The median time to treatment decreased from 44 d (interquartile range [IQR] 20-69) in 2011 to 22 d (IQR 2-43) in 2013 (p < 0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51%-73% by 6 mo) and median time to treatment (range 15-36 d, n = 1,450), and only 53% of the 1,448 new RR-TB patients who received treatment were recorded in the national RR-TB register. This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients.
CONCLUSIONS: In 2013, there was a large treatment gap for RR-TB in South Africa that varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, a larger proportion of RR-TB patients overall have received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required.

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2. Multidrug-resistant TB in Eastern region of the EU: is the shorter regimen an exception or a rule?
Thorax. 2017 Feb 16. pii: thoraxjnl-2016-209841. doi:10.1136/thoraxjnl-2016-209841. [Epub ahead of print]
Balabanova Y(1,)(2,)(3), Fiebig L(3), Ignatyeva O(4), Riekstina V(5), Danilovits
M(6), Jaama K(6), Davidaviciene E(7), Radiulyte B(7), Popa CM(8), Nikolayevskyy
V(1,)(2,)(9), Drobniewski F(1,)(2).

ABSTRACT: WHO recently recommended the use of a shorter multidrug-resistant TB (MDR-TB) regimen under programmatic conditions. We assessed eligibility for this regimen in a cohort of 737 adult patients with MDR-TB from Latvia, Lithuania, Estonia and Bucharest city recruited in 2007 and 2009. Only 4.2% of the patients were eligible for this regimen. Ethambutol (64%), pyrazinamide resistance (58%) and previous exposure to second-line TB drugs were major reasons for non-eligibility. High-level resistance to isoniazid is expected due to widespread prevalence of katG mutations. In Eastern Europe, the use of the shorter regimen might be an exception rather than a rule.

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3. Has universal screening with Xpert® MTB/RIF increased the proportion of multidrug-resistant tuberculosis cases diagnosed in a routine operational setting?
PLoS One. 2017 Feb 15;12(2):e0172143. doi: 10.1371/journal.pone.0172143. eCollection 2017.
Naidoo P(1), Dunbar R(1), Caldwell J(2), Lombard C(3), Beyers N(1).

SETTING: Primary health services in Cape Town, South Africa where the introduction of Xpert® MTB/RIF (Xpert) enabled simultaneous screening for tuberculosis (TB) and drug susceptibility in all presumptive cases.
STUDY AIM: To compare the proportion of TB cases with drug susceptibility tests undertaken and multidrug-resistant tuberculosis (MDR-TB) diagnosed pre-treatment and during the course of 1st line treatment in the previous smear/culture and the newly introduced Xpert-based algorithms.
METHODS: TB cases identified in a previous stepped-wedge study of TB yield in five sub-districts over seven one-month time-points prior to, during and after the introduction of the Xpert-based algorithm were analysed. We used a combination of patient identifiers to identify all drug susceptibility tests undertaken from electronic laboratory records. Differences in the proportions of DST undertaken and MDR-TB cases diagnosed between algorithms were estimated using a binomial regression model.
RESULTS: Pre-treatment, the probability of having a DST undertaken (RR = 1.82)(p<0.001) and being diagnosed with MDR-TB (RR = 1.42)(p<0.001) was higher in the Xpert-based algorithm than in the smear/culture-based algorithm. For cases evaluated during the course of 1st-line TB treatment, there was no significant difference in the proportion with DST undertaken (RR = 1.02)(p = 0.848) or MDR-TB diagnosed (RR = 1.12)(p = 0.678) between algorithms.
CONCLUSION: Universal screening for drug susceptibility in all presumptive TB cases in the Xpert-based algorithm resulted in a higher overall proportion of MDR-TB cases being diagnosed and is an important strategy in reducing transmission. The previous strategy of only screening new TB cases when 1st line treatment failed did not compensate for cases missed pre-treatment.

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4. Landmark legal ruling sees Indian girl prescribed bedaquiline for XDR-TB.
Lancet Respir Med. 2017 Feb 3. pii: S2213-2600(17)30042-5. doi: 10.1016/S2213-2600(17)30042-5. [Epub ahead of print]
Kirby T.

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January 2017 e-Newsletter

1. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time.
Nat Commun. 2017 Jan 24;8:14183. doi: 10.1038/ncomms14183.
Lee BY(1), Clemens DL(1), Silva A(2), Dillon BJ(1), Masleša-Galić S(1), Nava S(1), Ding X(3), Ho CM(2,)(4), Horwitz MA(1).

ABSTRACT: The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

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2. Reasons for Non-Enrollment in Treatment among Multi-Drug Resistant Tuberculosis Patients in Hunan Province, China.
PLoS One. 2017 Jan 23;12(1):e0170718. doi: 10.1371/journal.pone.0170718. eCollection 2017.
Xu Z(1), Xiao T(1), Li Y(1), Yang K(2), Tang Y(1), Bai L(3).

ABSTRACT: In 2015, only 49% of notified multi-drug resistant tuberculosis (MDR-TB) patients in China were estimated to have initiated treatment, compared with 90% of those worldwide. A case-control study was conducted to identify the reasons for non-enrollment in treatment among MDR-TB patients in Hunan province, China. All detected MDR-TB patients registered in designated MDR-TB hospitals in Hunan province from 2011 to 2014 were included and followed until June 2015 to determine their treatment status. Approximately 33.8% (482/1425) of patients were not enrolled in standardized treatment. Factors associated with lower enrollment rate were: age greater than 60 years, living in rural area, unemployed or occupation unreported. Of those who were not enrolled in MDR-TB treatment, the primary reasons for non-enrollment included economic hardship (23.0%), out-migration for work (18.0%), concerns about work and studies (13.7%), and the belief that they were cured after undergoing drug-sensitive TB treatment (12.4%).
Therefore, comprehensive strategies targeting priority populations, especially those enhancing treatment affordability and availability, need to be implemented to improve MDR-TB control.

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3. Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.
Nat Genet. 2017 Jan 16. doi: 10.1038/ng.3767. [Epub ahead of print]
Manson AL(1), Cohen KA(1,)(2,)(3), Abeel T(1,)(4), Desjardins CA(1), Armstrong DT(5), Barry CE 3rd(6), Brand J(7); TBResist Global Genome Consortium, Chapman SB(1), Cho SN(8), Gabrielian A(9), Gomez J(1), Jodals AM(10), Joloba M(11), Jureen P(12), Lee JS(8), Malinga L(7), Maiga M(13), Nordenberg D(14), Noroc E(15), Romancenco E(15), Salazar A(1,)(4), Ssengooba W(11), Velayati AA(16), Winglee K(5), Zalutskaya A(17), Via LE(6), Cassell GH(18), Dorman SE(5), Ellner J(19), Farnia P(16), Galagan JE(1,)(20), Rosenthal A(9), Crudu V(15), Homorodean D(10), Hsueh PR(21), Narayanan S(22), Pym AS(2), Skrahina A(17), Swaminathan S(22), Van der Walt M(7), Alland D(23), Bishai WR(2,)(5), Cohen T(24,)(25), Hoffner S(12), Birren BW(1), Earl AM(1).
COLLABORATORS: Brand J, Jureen P, Malinga L, Nordenberg D, Velayati AA, Cassell GH, Farnia P, Homorodean D, Van der Walt M, Hoffner S.

ABSTRACT: Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

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4. Estimated generic prices for novel treatments for drug-resistant tuberculosis.
J Antimicrob Chemother. 2017 Jan 10. pii: dkw522. doi: 10.1093/jac/dkw522. [Epub ahead of print]
Gotham D(1), Fortunak J(2), Pozniak A(3), Khoo S(4), Cooke G(5), Nytko FE 3rd(2), Hill A(3).

BACKGROUND: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course.
OBJECTIVES: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture.
METHODS: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines.
RESULTS: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen.
CONCLUSIONS: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

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5. Reduced chance of hearing loss associated with Therapeutic Drug Monitoring of Aminoglycosides in the treatment of Multidrug Resistant Tuberculosis.
Antimicrob Agents Chemother. 2017 Jan 9. pii: AAC.01400-16. doi: 10.1128/AAC.01400-16. [Epub ahead of print]
van Altena R(1,)(2), Dijkstra JA(3), van der Meer ME(3), Borjas Howard JF(4), Kosterink JG(3,)(5), van Soolingen D(6,)(7), van der Werf TS(2,)(4), Alffenaar JW(8).

ABSTRACT: Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-) toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 – 2012. Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including Cmax, Cmin and audiometry data were extracted from the patients’ medical charts. 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratio obtained from 57 patients was 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg a correlation was found between the dose per kg bodyweight during daily dosing and the extent of hearing loss in dB at 8000 Hz. This study suggests that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

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