BEAT TB: A ground breaking DR-TB program in South Africa

A ground breaking new programme, BEAT Tuberculosis, was launched in Port Elizabeth, South Africa. It is a world first in the fight against Drug Resistant Tuberculosis (DR TB) that is expected to slash treatment time-frames, make taking treatment far easier and minimise devastating side-effects. The program is supported by USAID in collaboration with the Wits Health Consortium.

It is a global first and will be conducted in Port Elizabeth, an area in South Africa which bears a disproportionally high burden of RR TB. It is expected to lead to a safer, more tolerable and more effective all-oral regimen for the treatment of DR TB.

Click here for the full article.

Click here for a informational video (~4 minutes).

March 2019 Newsletter

NEWS ANNOUNCEMENTS

 

WHO consolidated guidelines on drug-resistant tuberculosis treatment
These Consolidated guidelines include a comprehensive set of WHO recommendations for the treatment and care of DR-TB, derived from these WHO guidelines documents. The consolidated guidelines include policy recommendations on treatment regimens for isoniazid-resistant TB (Hr-TB) and MDR/RR-TB, including longer and shorter regimens, culture monitoring of patients on treatment, the timing of antiretroviral therapy (ART) in MDR/RR-TB patients infected with the human immunodeficiency virus (HIV), use of surgery for patients receiving MDR-TB treatment, and optimal models of patient support and care.
Access the full guidelines and WHO report here.
Download the guidelines directly here.

Upcoming RESIST-TB Webinar
On Friday, April 12th from 08:30 to 9:30 EST (14:30-15:30 CEST and SAST), RESIST-TB will be hosting a webinar on two presentations from the 2019 Conference on Retroviruses and Opportunistic Infections (CROI):
THE INHindsight Trial
(Early bactericidal activity of high-dose isonizaid against multidrug-resistant TB)
by Kelly E. DooleyThe DELIBERATE Trial
(QT effects of bedaquiline, delamanid or both in MDR-TB patients)
by Gary Maartens*An announcement will sent out soon with details on how to join the webinar.

PUBLICATIONS

1. Treatment outcomes of patients switching from an injectable drug to bedaquiline during short standardized MDR-TB treatment in Mozambique
Clin Infect Dis. 2019 Mar 11. pii: ciz196. doi: 10.1093/cid/ciz196.
Bastard M, Molfino L, Mutaquiha C, Galindo MA, Zindoga P, Vaz D, Mahinça I, du Cros P, Rusch B, Telnov A

ABSTRACT: Bedaquiline was recommended by WHO as the preferred option in treatment of MDR-TB patients with long regimen. However, no recommendation was given for the short MDR-TB regimen. Data from our small cohort of patients who switched injectable dug to bedaquiline suggest that bedaquiline based short regimen is effective and safe.

This article is unavailable via open access.

2. A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.
N Engl J Med. 2019 Mar 13. doi: 10.1056/NEJMoa1811867.
Nunn AJ, Phillips PPJ, Meredith SK, et. al.

BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.
METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive
a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.
RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group – a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia’s formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.
CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.

Read the full article here.

3. Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with
Tuberculosis.

Antimicrob Agents Chemother. 2019 Mar 11. pii: AAC.00055-19. doi: 10.1128/AAC.00055-19.
Alghamdi WA, Alsultan A, Al-Shaer MH, An G, Ahmed S, Alkabab Y, Banu S, Barbakadze K, Houpt E, Kipiani M, Mikiashvili L, Schmidt S, Heysell SK, Kempker RR, Cegielski JP, Peloquin CA.

BACKGROUND: Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on
cycloserine in tuberculosis (TB) patients. We pooled several studies into a large
PK dataset to estimate the population PK parameters for cycloserine in TB
patients. We also performed simulations to provide insight into optimizing the
dosing of cycloserine.
METHODS: TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC ≥30% and ≥64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve ≥90% of PTA.
RESULTS: Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA was achieved as the total daily dose was increased. The
highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/L. For MICs >16 mg/L, doses of at least 500 mg three times daily or 750 mg twice daily were needed.
CONCLUSIONS: The current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs >16mg/L. Further studies are needed regarding the efficacy and tolerability of daily doses >1000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimized exposure, which can potentially reduce the drug adverse effects.

Read the full article here.

4. Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.
Lancet HIV. 2019 Mar;6(3):e201-e204. doi: 10.1016/S2352-3018(19)30035-9.
O’Donnell MR, Padayatchi N, Daftary A, Orrell C, Dooley KE, Rivet Amico K, Friedland G.

ABSTRACT: Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa
and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.

Read the full article here (will require a free Lancet account).

 

5. Health care gaps in the global burden of drug-resistant tuberculosis.                                                                                                  Int J Tuberc Lung Dis. 2019 Feb 1;23(2):125-135. doi: 10.5588/ijtld.18.0866.                                                                                                               Cox V, Cox H, Pai M, Stillo J, Citro B, Brigden G.

ABSTRACT: The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

World Tuberculosis Day 2019

Each year, we commemorate World Tuberculosis (TB) Day on March 24 to raise public awareness about the devastating health, social and economic consequences of TB, and to step up efforts to end the global TB epidemic. March 24 marks the day in 1882 when Dr. Robert Koch announced that he had discovered Mycobacterium tuberculosis, the bacterium that causes TB, which opened the way towards diagnosing and curing this disease.

It is a day to educate the public about the impact of TB around the world, sharing successes in TB prevention and control, and raising awareness of the challenges that hinder our progress toward the elimination of this devastating disease.

Click the following links to learn more about World TB Day 2019 (WHO, CDC)

CROI 2019 Presentations on the DELIBERATE Trial and the INHindsight Trial

On April 12th RESIST-TB hosted a webinar on two presentations from the 2019 Conference on Retroviruses and Opportunistic Infections (CROI):

EARLY BACTERICIDAL ACTIVITY OF HIGH-DOSE ISONIAZID AGAINST MULTIDRUG-RESISTANT TB

Presented by Kelly Dooley

High-dose isoniazid (INH) may be useful in treating multidrug-resistant tuberculosis (MDR-TB), particularly when INH resistance is mediated by inhA mutations. Although the World Health Organization (WHO) recommends ‘high-dose’ INH as part of the new shorter MDR-TB regimen, the optimal dose and its efficacy are not established.

AIDS Clinical Trials Group (ACTG) A5312 is a Phase 2A randomized, open-label trial in which individuals with smear-positive pulmonary MDR-TB with INH resistance mediated by an inhA mutation (Group 1) were randomized to receive INH doses of 5, 10 or 15 mg/kg daily for 7 days. Controls with drug-sensitive TB (Group 2) received the standard INH dose of 5 mg/kg/day. Sputum cultures were collected daily, beginning at baseline. The early bactericidal activity of INH, estimated as the average daily change in log10 colony forming units (CFU) on solid media (EBACFU0-7) or average daily change in time to positivity (TTP) in hours on liquid media (EBATTP0-7) over 7 days of treatment was estimated using nonlinear mixed effects models. Safety data were collected from study entry through Day 21.

 

Dr. Dooley’s webinar presentation: INHindsight Trial

 

QT EFFECTS OF BEDAQUILINE, DELAMANID OR BOTH IN MDR-TB PATIENTS: THE DELIBERATE TRIAL

Presented by Gary Maartens

Bedaquiline and delamanid are the first drugs of new classes approved for tuberculosis (TB) in 40 years. Both are oral, well-tolerated, and recommended for treatment of multidrug resistant (MDR) TB by WHO. However, these drugs and/or their metabolites have long half-lives, and each prolongs the QT interval with maximum effects weeks after drug initiation. The cardiac safety of these drugs given together as part of multidrug therapy has not been established.

AIDS Clinical Trials Group (ACTG) A5343 is a phase 2, open-label trial randomizing adults with MDR-TB receiving multidrug background treatment (MBT) 1:1:1 to receive bedaquiline (BDQ arm), delamanid (DLM arm) or both (BDQ+DLM arm) for 24 weeks. Patients with QTcF >450ms or CD4 count < 100 cells/mm3 were excluded. HIV-infected participants received dolutegravir-based ART. Clofazimine was not allowed, and levofloxacin was given in place of moxifloxacin. Three electrocardiograms (ECG) were performed at baseline, every two weeks for 24 weeks, then week 28. QTcF (in ms) was calculated by a core laboratory blinded to treatment. The mean QTcF change from baseline (averaged over weeks 8-24) was defined in each arm, and the QTcF change in the BDQ+DLM arm was compared to QTcF changes in the BDQ and the DLM arms. Grade 3 QTcF prolongation was defined as >500ms or >480ms with increase from baseline >60ms. Grade 4 was life-threatening dysrhythmia.

Dr. Maarten’s webinar presentation: DELIBERATE Trial

 

Due to technical complications during the webinar, the event was unable to be recorded.

We apologize for the inconvenience.

 

 

TB CAB statement on safety of using bedaquiline and delamanid together

The Global TB Community Advisory Board (TB CAB) welcomes the important finding from the AIDS Clinical Trials Group Deliberate Trial that newer drugs bedaquiline and delamanid are safe to use together. These findings should erase any remaining reluctance to use these two important drugs together, as the benefits of these safer drugs outweigh the risks–especially for patients with drug-resistant TB who have few other treatment options.

Click here to read the full article.

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

TB Alliance’s new drug application (NDA) for the novel tuberculosis (TB) drug candidate pretomanid has been accepted for review by the United States Food and Drug Administration (FDA). The application is for the use of pretomanid as part of a new regimen, in combination with bedaquiline and linezolid, for the treatment of extensively drug-resistant (XDR) TB, treatment intolerant multidrug-resistant (MDR) TB, and treatment non-responsive MDR-TB.

The NDA for pretomanid has been granted Priority Review by FDA. The Prescription Drug User Fee Act (PDUFA) action date for an FDA decision is in third quarter 2019.

Statement by TB Alliance

Statement by Treatment Action Group (TAG)

The MDR-TB epidemic—a status report

RESIST-TB authored (C. R. Horsburgh, Jr, C. D. Mitnick, C. Lange) editorial in the International Journal of Tuberculosis and Lung Disease February edition:

 

Despite its recognition over 28 years ago, the magnitude of the impact of drug resistance of M. tuberculosis on TB control has long been under-appreciated. We now realize that MDR strains of M. tuberculosis are spreading by primary transmission and not merely developing through therapeutic misadventure, that cure rates are abysmal,4,5andthat the level of resistance to drugs in addition to INH and RMP is often astonishingly high.

Click here to access this article (download available for free).

 

February 2019 Newsletter

NEWS

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.

 

PUBLICATIONS

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.

January 2019 Newsletter

NEWS AND ANNOUNCEMENTS

FIND WEBINAR SERIES 2019
FIND, the World Health Organization, the New Diagnostics Working Group and MSF Access Campaign are co-organizing a four-part webinar series on the use and implementation of next-generation sequencing (NGS) for drug-resistant TB (DR-TB). The series will take place on 5, 12, 19, and 26 February 2019. More information about these webinars and their specific times can be found here.

PUBLICATIONS

1. Ambient air pollution exposures and risk of drug-resistant tuberculosis.
Environ Int. 2019 Jan 11;124:161-169. doi: 10.1016/j.envint.2019.01.013. [Epub ahead of print]
Yao L, LiangLiang C, JinYue L, WanMei S, Lili S, YiFan L, HuaiChen L.

BACKGROUND: Few epidemiological studies have explored the effects of air pollution on the risk of drug-resistant tuberculosis (DR-TB).
OBJECTIVE: To investigate the short and long term residential concentrations of ambient air pollutants (particulate matter <10 μm in diameter (PM10) and particulate matter≤2.5 μm in diameter (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)) in relation to the risk of DR-TB in a typical air pollution city, Jinan city, China.
METHODS: A total of 752 new culture-confirmed TB cases reported in TB prevention and control institutions of Jinan from January 1, 2014 to December 31, 2015 were included. Average individual-level concentrations of air pollution for 5 different exposure windows, vary from 90 days to 720 days to diagnosis were estimated using measurements from monitor closest to the patient home addresses. Logistic regression model adjusted for potential confounders was employed to evaluate correlation between air pollution and DR-TB risk at different five exposure windows individually.
RESULTS: There were substantially increased mono-drug resistance and poly-drug resistance risks for ambient PM2.5, PM10, O3, and CO exposures. High exposure to PM2.5, PM10, and CO was also significantly associated with increased incidence of multi-drug resistance (MDR) both in the single- and multi-pollutants regression models. The dominant positive associations for PM2.5was observed at 540 days exposure, for O3 was observed at 180 days exposure, and for PM10 and CO was observed from 90 days to 540 days exposures.
CONCLUSIONS: Our finding suggest that exposure to ambient air pollution (PM2.5, PM10, O3, and CO) are associated with increased risk of DR-TB. We provided epidemiological evidence of association between pollution exposure and mono-, poly- and multi-drug resistance.

This article is available for open access here.

2. Interventions to improve retention-in-care and treatment adherence among patients with drug-resistant tuberculosis: a systematic review.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801030. doi: 10.1183/13993003.01030-2018.
Print 2019 Jan.
Law S, Daftary A, O’Donnell M, Padayatchi N, Calzavara L, Menzies D.

ABSTRACT: The global loss to follow-up (LTFU) rate among drug-resistant tuberculosis (DR-TB) patients remains high at 15%. We conducted a systematic review to explore interventions to reduce LTFU during DR-TB treatment.We searched for studies published between January 2000 and December 2017 that provided any form of psychosocial or material support for patients with DR-TB. We estimated point estimates and 95% confidence intervals of the proportion LTFU. We performed subgroup analyses and pooled estimates using an exact binomial likelihood approach.We included 35 DR-TB cohorts from 25 studies, with a pooled proportion LTFU of 17 (12-23)%.  Cohorts that received any form of psychosocial or material support had lower LTFU rates than those that received standard care. Psychosocial support throughout treatment, via counselling sessions or home visits, was associated with lower LTFU rates compared to when support was provided through a limited number of visits or not at all.Our review suggests that psychosocial support should be provided throughout DR-TB treatment in order to reduce treatment LTFU. Future studies should explore the potential of providing self-administered therapy complemented with psychosocial support during the continuation phase.

This article is available for open access here.

3. Such a long journey: What health seeking pathways of patients with drug resistant tuberculosis in Mumbai tell us.
PLoS One. 2019 Jan 17;14(1):e0209924. doi: 10.1371/journal.pone.0209924. eCollection 2019.
Bhattacharya Chakravarty A, Rangan S, Dholakia Y, Rai S, Kamble S, Raste T, Shah S, Shah S, Mistry N.

INTRODUCTION: The Indian Tuberculosis (TB) Programme currently faces the dual challenges of tackling increasing numbers of drug resistant (DR) TB cases and regulating practices of a pluralistic private sector catering to TB patients. A study of health seeking behaviour of DR-TB patients in such a situation, offers an opportunity to understand the problems patients face while interacting with health systems.
METHODOLOGY: Forty-six DR-TB patients drawn from 15 high TB burden wards in Mumbai were interviewed using an open ended interview tool. Interviews were audio recorded and transcribed. Pathway schematics developed from analysis of patient records, were linked to transcripts. Open coding was used to analyse these units and themes were derived after collating the codes.
RESULTS AND DISCUSSION: The paper presents themes interwoven with narratives in the discussions. These include awareness-action gap among patients, role of neighbourhood providers, responsiveness of health systems, the not-such a ‘merry go round’ that patients go/are made to go on while seeking care, costs of diagnostics and treatment, and how DR-TB is viewed as the ‘big TB’.
CONCLUSION: The recommendations are based on a preventative ethos which is sustainable, compared to interventions with top-down approaches, which get piloted, but fail to sustain impact when scaled up.

This article is available for open access here.

4. Pharmacokinetics, safety, and dosing of novel pediatric levofloxacin dispersible  tablets in children with multidrug-resistant tuberculosis exposure.
Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01865-18. doi: 10.1128/AAC.01865-18. [Epub ahead of print]
Garcia-Prats AJ, Purchase SE, Osman M, Draper HR, Schaaf HS, Wiesner L, Denti P, Hesseling AC.

ABSTRACT: This study characterized the pharmacokinetics of novel 100 mg levofloxacin dispersible tablets in 24 children aged <5 years with household MDR-TB exposure. Data was pooled with previously published data from children (n=109) with MDR-TB receiving adult (250 mg) levofloxacin tablets, using nonlinear mixed-effect modelling. The adult 250 mg tablets had 41% lower bioavailability compared to thenovel dispersible tablets, resulting in much higher exposures with the dispersible tablets with the same mg/kg dose.

This article is available for open access here.

5. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial.
Lancet Respir Med. 2019 Jan 7. pii: S2213-2600(18)30426-0. doi: 10.1016/S2213-2600(18)30426-0. [Epub ahead of print]
von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V Jr, Ticona E, Segura P, Cadena E, Yu C, Cirule A, Lizarbe V, Davidaviciene E, Domente L, Variava E, Caoili J, Danilovits M, Bielskiene V, Staples S, Hittel N, Petersen C, Wells C, Hafkin J, Geiter LJ, Gupta R.

BACKGROUND: Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.

METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia,  Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670.                FINDINGS: Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen
[placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the
placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91-1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one
serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid.
INTERPRETATION: The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care.
FUNDING: Otsuka Pharmaceutical.

This article is not available for open access.

6. Compassionate use of delamanid in combination with bedaquiline for the treatment of multidrug-resistant tuberculosis.
Eur Respir J. 2019 Jan 10;53(1). pii: 1801154. doi: 10.1183/13993003.01154-2018. Print 2019 Jan. Hafkin J, Hittel N, Martin A, Gupta R.

SUMMARY: Updated data from the Otsuka compassionate use program show that regimens combining delamanid and bedaquiline appear effective in MDR-TB cases with limited treatment options.This article is available here

Webinar: Introduction of the ICN/Curry Center Nursing guide for managing side effects to drug-resistant TB treatment (RECORDING AVAILABLE)

On January 16th, RESIST-TB and The Union’s Nurses and Allied Professionals Sub-Section (NAPS) hosted a webinar to discuss the ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment. Nurses are often the first to hear of a patient’s side effects during TB treatment, making them well positioned to intervene. The information presented in this guide, which is the topic of this webinar, was developed to help nurses assess for and respond appropriately to side effects related to anti-TB medications.

The ICN/CITC Nursing Guide for Management of Side Effects of DR-TB Treatment is available in English, Chinese and Russian.

For those of you who were unable to join the webinar, below is a recording. The slides used can be found here.

Key speakers: Bob Horsburgh, Carrie Tudor, Linette McElroy

*Speaking first is Bob Horsburgh (RESIST-TB), who introduces the key presenter Carrie Tudor (ICN)