February 2019 Newsletter


TB activists for first time challenge TB drug patent in India
February 6, 2019 – Médecins Sans Frontières (MSF) is supporting a patent challenge filed in India this week by two tuberculosis survivors, to prevent pharmaceutical corporation Johnson & Johnson (J&J) from extending its monopoly on the tuberculosis drug bedaquiline.

The development of bedaquiline benefited from considerable public investment, and the evidence for its potential to improve cure rates with fewer side-effects was the result of a collective effort of the global TB community. MSF is urging J&J to refrain from attempts to extend its monopoly that will further delay the availability of quality-assured generic versions of bedaquiline in India, South Africa and other countries.

As patients challenge patent, J&J commits to tackling drug-resistant TB
February 17, 2019 – While Bedaquiline patent is contested, firm denies its monopoly would get extended.

Johnson & Johnson has tripled its commitment on tuberculosis drug Bedaquiline by offering 90,000 doseages to its global donation programme that ends in March, Paul Stoffels, J&J’s Vice-Chair of the Executive Committee and Chief Scientific Officer, said, on a programme that has given medicines to India as well.



1.  Major depression and household food insecurity among individuals with multidrug-resistant tuberculosis (MDR-TB) in South Africa.
Soc Psychiatry Psychiatr Epidemiol. 2019 Feb 13.
doi: 10.1007/s00127-019-01669-y.
Tomita A, Ramlall S, Naidu T, Mthembu SS, Padayatchi N, Burns JK.

PURPOSE: Household food insecurity in South Africa is a pervasive public health challenge. Although its link to chronic health conditions is well established, its relationship to mental illness, particularly major depression, is not well-understood. Despite KwaZulu-Natal Province being the epicenter of the drug-resistant tuberculosis (MDR-TB) epidemic, and having the largest share of poverty in South Africa, this relationship remains unexamined. This study investigated the association between major depressive episode (MDE) and household food insecurity among individuals with MDR-TB.
METHODS: We enrolled and interviewed 141 newly admitted microbiologically confirmed MDR-TB inpatients at a specialized TB hospital in KwaZulu-Natal Province, South Africa. Logistic regression models were fitted to assess the relationship between MDE and household food insecurity, while accounting for socio-demographic status (e.g., age, gender, education, marital status, social grant status, income, and preference for living in one’s community).
RESULTS: The prevalence of MDE and household food insecurity was 11.35% and 21.01%, respectively. MDE was significantly associated with household food insecurity (aOR 4.63, 95% CI 1.17-18.38). Individuals who are female (aOR 6.29, 95% CI 1.13-35.03), young (aOR 8.86, 95% CI 1.69-46.34), have low educational attainment (aOR 6.19, 95% CI 1.70-22.59) and receive social grants (aOR 7.60, 95% CI 2.36-24.48) were most at risk of household food insecurity.
CONCLUSIONS: MDE in individuals with MDR-TB was significantly associated with household food insecurity, independent of socio-economic status. Although MDR-TB is not exclusively a disease of the poor, individuals from socio-economically disadvantaged backgrounds (e.g., female, young adults, low education, and social grant recipients) were more likely to experience household food insecurity. Our study underscores the need to address the co-occurring cycles of food insecurity and untreated MDE in South Africa.

This article is available with open access here.

2. Underestimated pyrazinamide resistance may compromise outcomes of pyrazinamide containing regimens for treatment of drug susceptible and multi-drug-resistant tuberculosis in Tanzania.
BMC Infect Dis. 2019 Feb 7;19(1):129. doi: 10.1186/s12879-019-3757-1.
Juma SP, Maro A, Pholwat S, Mpagama SG, Gratz J, Liyoyo A, Houpt ER, Kibiki GS, Mmbaga BT, Heysell SK.

BACKGROUND: Tuberculosis (TB) is the leading cause of death from an infectious
disease and the roll-out of rapid molecular diagnostics for rifampin resistance has resulted in a steady rise in the number of patients with multidrug-resistant (MDR)-TB referred for treatment. Pyrazinamide is used in susceptible TB treatment for 6 months when used in combination with rifampin, isoniazid and ethambutol and is an important companion drug in novel MDR-TB trials. This study was undertaken to determine the prevalence of pyrazinamide resistance by either phenotypic or pncA testing among patients admitted to a referral hospital in Tanzania for
drug-susceptible and MDR-TB treatment.
METHODS: Surveillance sputa were sent among subjects beginning TB therapy at the national MDR-TB referral hospital during a 6 month period in 2013-2014. Mycobacterial cultures of pretreatment sputa were performed at the Kilimanjaro Clinical Research Institute (KCRI) in the BACTEC mycobacterial growth indicator tubes (MGIT) 960 system. Speciation of M. tuberculosis complex was confirmed by MTBc assay. Isolates were sub-cultured on to Lowenstein-Jensen (LJ) slants. Phenotypic resistance to pyrazinamide was performed in the MGIT system while a
real-time PCR with High Resolution Melt (HRM) technique was used to determine mutation in the pncA gene from the same pure subculture. Sputa were then collected monthly to determine the time to culture negativity. Final treatment outcome was determined.
RESULTS: Ninety-one M. tuberculosis isolates from individual patients were available for analysis of which 30 (32.9%) had MDR-TB, the mean (±SD) age was 33 ± 10 years, and the majority 23 (76.7%) were males. Of the 30 MDR-TB patients, 15(50%) had isolates with pyrazinamide resistance by conventional MGIT testing. This proportion expectedly exceeded the number with pyrazinamide resistance in the 61 patients without MDR-TB, 13 (21.3%) (p = 0.008). Six (20%) of MDR-TB patients had a poor outcome including treatment failure. Among patients with treatment failure, 5 (83%) had pyrazinamide resistance compared to only 10 (41.6%) with treatment success (p = 0.08). Two patients died, and both had isolates with pyrazinamide resistance. No other pretreatment characteristic was associated with treatment outcome.
CONCLUSION: Pyrazinamide susceptibility appears to be important in clinical outcomes for MDR-TB patients, and susceptibility testing appears to be a critical adjunct to TB care. The high proportion of PZA resistance in non-MDR TB cases calls for further local investigation.

This article is available with open access here.

3. Using Changes in Weight-for-Age z Score to Predict Effectiveness of Childhood Tuberculosis Therapy.
J Pediatric Infect Dis Soc. 2019 Feb 1. doi: 10.1093/jpids/piy138.
Chiang SS, Park S, White EI, Friedman JF, Cruz AT, Del Castillo H, Lecca L, Becerra MC, Seddon JA.

BACKGROUND: International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain.
METHODS: We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2-5 for group 1, and between baseline and months 2-8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment
failure or death.
RESULTS: Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3-5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%-90% sensitivity and 60%-86% specificity in months 2-5 for group 1 and months 7-8 for group 2. All successfully treated children-except group 2 participants with unknown microbiologic confirmation status-achieved catch-up weight gain.
CONCLUSIONS: Weight change early in therapy can predict the outcome of childhood TB treatment.

This article is not available for open access.

4. Effect of financial support on reducing the incidence of catastrophic costs among tuberculosis-affected households in Indonesia: eight simulated scenarios.
Infect Dis Poverty. 2019 Feb 2;8(1):10. doi: 10.1186/s40249-019-0519-7.
Fuady A, Houweling TAJ, Mansyur M, Burhan E, Richardus JH.

BACKGROUND: The World Health Organization’s End Tuberculosis Strategy states that no tuberculosis (TB)-affected households should endure catastrophic costs due to TB. To achieve this target, it is essential to provide adequate social protection. As only a few studies in many countries have evaluated social-protection programs to determine whether the target is being reached, we assessed the effect of financial support on reducing the incidence of catastrophic costs due to TB in Indonesia.
METHODS: From July to September 2016, we interviewed adult patients receiving treatment for TB in 19 primary health centres in urban, sub-urban and rural area of Indonesia, and those receiving multidrug-resistant (MDR) TB treatment in an Indonesian national referral hospital. Based on the needs assessment, we developed eight scenarios for financial support. We assessed the effect of each simulated scenario by measuring reductions in the incidence of catastrophic costs.
RESULTS: We analysed data of 282 TB and 64 MDR-TB patients. The incidences of catastrophic costs in affected households were 36 and 83%, respectively. Patients’ primary needs for social protection were financial support to cover costs related to income loss, transportation, and food supplements. The optimum scenario, in which financial support would be provided for these three items, would reduce the respective incidences of catastrophic costs in TB and MDR-TB-affected households to 11 and 23%. The patients experiencing catastrophic costs in this scenario would, however, have to pay high remaining costs (median of USD 910; [interquartile range (IQR) 662] in the TB group, and USD 2613; [IQR3442] in the MDR-TB group).
CONCLUSIONS: Indonesia’s current level of social protection is not sufficient to mitigate the socioeconomic impact of TB. Financial support for income loss, transportation costs, and food-supplement costs will substantially reduce the incidence of catastrophic costs, but financial support alone will not be sufficient to achieve the target of 0% TB-affected households facing catastrophic costs. This would require innovative social-protection policies and higher levels of domestic and external funding.

This article is available via open access here.

5. Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.
Am J Respir Crit Care Med. 2019 Jan 29. doi: 10.1164/rccm.201807-1361OC.
Dheda K, Lenders L, Srivastava S, Magombedze G, Wainwright H, Raj P, Bush SJ, Pollara G, Steyn R, Davids M, Pooran A, Pennel T, Linegar A, McNerney R, Moodley L, Pasipanodya JG, Turner CT, Noursadeghi M, Warren RM, Wakeland E, Gumbo T.

RATIONALE: There is poor understanding about protective immunity and the pathogenesis of cavitation in tuberculosis patients.
OBJECTIVES: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.
METHODS: Biopsies were obtained from eight pre-determined locations within lung cavities of multidrug-resistant tuberculosis patients undergoing therapeutic surgical resection (n=14) and healthy lung tissue from non-tuberculosis controls (n=10). RNA sequencing, immunohistochemistry, and bacterial load determination was performed at each cavity position. Differentially expressed genes were normalized to non-tuberculosis controls, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.
RESULTS: The median (range) lung cavity volume on PET-CT scans was 50cm3 (15-389cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple pro-inflammatory pathways were upregulated in the cavity wall, while a downregulation ‘sink’ in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, TREM-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and TREM-1 pathways, as well as macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r>0.6), while T-helper effector systems did not.
CONCLUSION: These data provide novel insights into host immunity to drug-resistant Immune Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

This article can be found via open access here.

6. DeepAMR for predicting co-occurrent resistance of Mycobacterium tuberculosis.
Bioinformatics. 2019 Jan 28. doi: 10.1093/bioinformatics/btz067.
Walker TM, Walker AS, Wilson DJ, Peto TEA, Crook DW, Shamout F; CRyPTIC consortium, Zhu T, Clifton DA.

MOTIVATION: Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages.
METHODS: We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data.
RESULTS: The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs (i.e., isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)), multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA, and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. T-SNE visualisation shows that DeepAMR_cluster captures lineage-related clusters in the latent space.
AVAILABILITY: The details of source code are provided at http://www.robots.ox.ac.uk/davidc/code.php.

This article is available via open access here.