May 2019 Newsletter

News

Advocates raise serious concerns about errors in the WHO guidelines for the treatment of drug-resistant TB
On 23 April 2019, TB advocates sent an open letter to Dr. Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization (WHO), expressing their serious concerns about the WHO Global TB Program’s ability to issue evidence-based guidelines for the treatment of drug-resistant TB.

Community capacity building modules to accelerate DR-TB response
Affected communities and community-based organizations can play a crucial role and work with national programmes in ensuring a person-centred and human rights-based approach in the management of drug-resistant TB in countries in the South-East Asia Region, provided their capacity is built with appropriate training to understand the science and management of DR-TB. This article explores the recent developments made at the WHO South-East Asia Regional Meeting of National TB Program Managers and Partners.

It’s Time to End Drug-Resistant Tuberculosis: The Case for Action
NEW BRUNSWICK, N.J., MAY 7, 2019 — A new report published today by The Economist Intelligence Unit (EIU), and with support from Johnson & Johnson, emphasizes the urgent need for focused global action to address the growing threat of drug-resistant tuberculosis (DR-TB). DR-TB is the leading contributor to deaths from antimicrobial resistance (AMR).

 

Publications

1. What will it take to eliminate drug-resistant tuberculosis?
Int J Tuberc Lung Dis. 2019 May 1;23(5):535-546. doi: 10.5588/ijtld.18.0217.
Kendall EA, Sahu S, Pai M, Fox GJ, Varaine F, Cox H, Cegielski JP, Mabote L, Vassall A, Dowdy DW.

ABSTRACT: Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

This article is not available via open access.

2. Improved treatment outcomes with bedaquiline when substituted for second-line injectable agents in multidrug resistant tuberculosis: a retrospective cohort study.
Clin Infect Dis. 2018 Aug 24. doi: 10.1093/cid/ciy727.
Zhao Y, Fox T, Manning K, Stewart A, Tiffin N, Khomo N, Leslie J, Boulle A, Mudaly V, Kock Y, Meintjes G, Wasserman S.

BACKGROUND: Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant tuberculosis (MDR-TB), butthe efficacy and safety of this strategy is unknown.
METHODS: We performed a retrospective cohort study to evaluate treatment outcomes for MDR-TB patients who substituted bedaquiline for SLIs. Adults receiving bedaquiline substitution for MDR-TB therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic TB register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow up, or failure to achieve sustained culture conversion at 12 months of treatment.
RESULTS: Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were HIV-infected. Unfavorable outcomes occurred in 35/146 (23.9%) patients in the bedaquiline group versus 51/141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval [CI], 0.46 to 0.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient, 0.8%) compared to controls (12 patients, 10.3%; P = 0.001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio, 1.5; 95% CI, 1.1 – 1.9, for every 30-day delay). Mortality was similar at 12 months (11 deaths in each group; P = 0.973).
CONCLUSIONS: Substituting bedaquiline for SLIs in MDR-TB treatment resulted in improved outcomes at 12 months compared with patients who remained on SLIs, supporting the use of bedaquiline for MDR-TB treatment in programmatic settings.

Read the full article here.

3. Linezolid interruption in patients with fluoroquinolone-resistant tuberculosis receiving a bedaquiline-based treatment regimen. 
Int J Infect Dis. 2019 May 14. pii: S1201-9712(19)30199-7. doi: 10.1016/j.ijid.2019.04.028.
Olayanju O, Esmail A, Limberis J, Gina P, Dheda K.

BACKGROUND: Treatment outcomes of extensively drug-resistant tuberculosis (XDR-TB) patients are sub-optimal and treatment options remain limited. Linezolid is associated with improved outcomes but also substantial toxicity, and details about the relationship between these are lacking from resource-poor HIV-endemic
settings.
METHODS: We prospectively followed up 63 South African XDR-TB patients (58.7% HIV-infected; median CD4 131 cells/µl) between 2014 and 2018. The frequency and severity of linezolid-associated adverse events and the impact on treatment outcomes were compared between linezolid interrupters and non-interrupters.
RESULTS: Twenty-two patients (34.9%) discontinued or underwent dose reduction due to presumed linezolid-associated toxicity. Anaemia (77.3% versus 7.3%; p < 0.001), peripheral neuropathy (63.6% versus 14.6%; p = 0.003), and optic neuritis (18.2% versus 9.8%; p = 0.34) occurred more frequently in linezolid interrupters than in non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at a median of 5, 18 and 23 weeks, respectively, after treatment initiation. Linezolid interruption was not associated with unfavourable outcomes but was strongly associated with HIV co-infection (aHR 4.831 (1.526-15.297); p = 0.007) and bacterial load (culture days to positivity; aHR = 0.824 (0.732- 0.927); p = 0.001).
CONCLUSION: Linezolid-related treatment interruption is common, is strongly associated with HIV co-infection, and system-specific toxicity occurs within predictable time frames. These data inform the clinical management of patients with drug resistant TB.

Read the full article here.

4. Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies.
PLoS Med. 2019 Apr 30;16(4):e1002789. doi: 10.1371/journal.pmed.1002789. eCollection 2019 Apr.
Garcia-Prats AJ, Schaaf HS, Draper HR, Garcia-Cremades M, Winckler J, Wiesner L, Hesseling AC, Savic RM.

BACKGROUND: Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB.
METHODS AND FINDINGS: Children routinely treated for MDR-TB in 2 observational studies (2011-2015, 2016-2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data.
CONCLUSIONS: Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

Read the full article here.

5. Bedaquiline and delamanid in combination for treatment of drug-resistant tuberculosis.
Lancet Infect Dis. 2019 May;19(5):470. doi: 10.1016/S1473-3099(19)30168-9.
Mohr E, Ferlazzo G, Hewison C, De Azevedo V, Isaakidis P.

SUMMARY: Here we report on the final outcomes for the cohort of 28 patients from Armenia, India, and South Africa who initiated regimens containing the combination of bedaquiline and delamanid from January to August, 2016, for the treatment of multidrug-resistant tuberculosis in our cohort study.

Read the full article here.

What will it take to eliminate drug-resistant tuberculosis?

This is the third article in our State of the Art series, with senior RESIST-TB editors Bob Horsburgh, Carole Mitnick and Christoph Lange.

Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Read the full article here.

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.