Low-Level Delamanid and Bedaquiline Resistancein Extensively Drug-Resistant TB

In a brief report published in Clinical Infectious Diseases, researchers reported a case of drug resistance against 2 recently approved antitubercular medications: delamanid and bedaquiline. Researchers presented a patient with extensively drug-resistant tuberculosis (TB), and highlighted the potential for the emergence and transmission of resistant Mycobacterium tuberculosis complex strains with more frequent use of these relatively new drugs
Read the full article here.

April 2019 Newsletter


NEWS

Low-Level Delamanid and Bedaquiline Resistancein Extensively Drug-Resistant TB

In a brief report published in Clinical Infectious Diseases, researchers reported a case of drug resistance against 2 recently approved antitubercular medications: delamanid and bedaquiline. Researchers presented a patient with extensively drug-resistant tuberculosis (TB), and highlighted the potential for the emergence and transmission of resistant Mycobacterium tuberculosis complex strains with more frequent use of these relatively new drugs
Read the full article here.

PUBLICATIONS

1. Feasibility of Identifying Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.
Clin Infect Dis. 2019 Mar 28. pii: ciz235. doi: 10.1093/cid/ciz235.
Gupta A, Swindells S, Kim S, Hughes MD, Naini L, Wu X, Dawson R, Mave V, Sanchez J, Mendoza A, Gonzales P, Kumarasamy N, Comins K,

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial.
METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in eight high-TB-burden  countries. HHCs underwent symptom screening, chest radiography (CXR), sputum TB bacteriology, TB infection (TBI) testing (tuberculin skin test and interferon gamma release assay) and HIV testing.
RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were acid fast bacilli sputum smear-positive and 43% had cavitary disease; at study entry 35% remained smear-positive after a median MDR-TB treatment duration of 8.8 weeks. Nine HHCs were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. 121 (12%) HHC had new TB identified: 17 (2%) were confirmed; 33 (3%) probable; and 71 (7%) possible TB. TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) <5 years; 63 (6%) 5 and HIV-infected; and 610 (61%) 5 years, HIV-negative/unknown, and TBI positive. Only 21 (2%) HHCs were on preventive therapy.
CONCLUSIONS: The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel preventive therapies are urgently needed to inform treatment policy and practice.

This article is unavailable via open access.

2. Gridlock from diagnosis to treatment of multidrug-resistant tuberculosis in Tanzania: low accessibility of molecular diagnostic services and lack of healthcare worker empowerment in 28 districts of 5 high burden TB regions with mixed methods evaluation.
BMC Public Health. 2019 Apr 11;19(1):395. doi: 10.1186/s12889-019-6720-6.
Mpagama SG, Mbelele PM, Chongolo AM, Lekule IA, Lyimo JJ, Kibiki GS, Heysell SK.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) outcomes are adversely
impacted by delay in diagnosis and treatment.
METHODS: Mixed qualitative and quantitative approaches were utilized to identify
healthcare system related barriers to implementation of molecular diagnostics for
MDR-TB. Randomly sampled districts from the 5 highest TB burden regions were
enrolled during the 4th quarter of 2016. District TB & Leprosy Coordinators
(DTLCs), and District AIDS Coordinators (DACs) were interviewed, along with staff
from all laboratories within the selected districts where molecular diagnostics
tests for MDR-TB were performed. Furthermore, the 2015 registers were audited for
all drug-susceptible but retreatment TB cases and TB collaborative practices in
HIV clinics, as these patients were in principal targeted for drug susceptibility
testing by rapid molecular diagnostics.
RESULTS: Twenty-eight TB districts from the 5 regions had 399 patients reviewed
for retreatment with a drug-susceptible regimen. Only 160 (40%) had specimens
collected for drug-susceptibility testing, and of those specimens only 120 (75%)
had results communicated back to the clinic. MDR-TB was diagnosed in 16 (13.3%)
of the 120 specimens but only 12 total patients were ultimately referred for
treatment. Furthermore, among the HIV/AIDS clinics served in 2015, the median
number of clients with TB diagnosis was 92 cases [IQR 32-157] yet only 2 people
living with HIV were diagnosed with MDR-TB throughout the surveyed districts.
Furthermore, the districts generated 53 front-line healthcare workers for
interviews. DTLCs with intermediate or no knowledge on the clinical application
of XpertMTB/RIF were 3 (11%), and 10 (39%), and DACs with intermediate or no
knowledge were 0 (0%) and 2 (8%) respectively (p = 0.02). Additionally, 11 (100%)
of the laboratories surveyed had only the 4-module XpertMTB/RIF equipment. The
median time that XpertMTB/RIF was not functional in the 12 months prior to the
investigation was 2 months (IQR 1-4).
CONCLUSIONS: Underutilization of molecular diagnostics in high-risk groups was a
function of a lack of front-line healthcare workforce empowerment and training,
and a lack of equipment access, which likely contributed to the observed delay in
MDR-TB diagnosis in Tanzania.

Read the full article here.

3. Impact of universal drug susceptibility testing and effective management of
multidrug-resistant tuberculosis in Taiwan.

PLoS One. 2019 Apr 2;14(4):e0214792. doi: 10.1371/journal.pone.0214792.
eCollection 2019.
Lee PH, Chan PC, Peng YT, Chu PW, Wu MH, Jou R, Yu MC, Lin CJ, Huang YW, Chien ST, Lee JJ, Chiang CY.

BACKGROUND: The treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC.
METHODOLOGY/PRINCIPLE FINDINGS: We analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007-2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007-2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001).
CONCLUSIONS: We concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan.

Read the full article here.

4. Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.
Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: e02516-18. doi: 10.1128/AAC.02516-18.
Sarathy J, Blanc L, Alvarez-Cabrera N, O’Brien P, Dias-Freedman I, Mina M, Zimmerman M, Kaya F, Ho Liang HP, Prideaux B, Dietzold J, Salgame P, Savic RM, Linderman J, Kirschner D, Pienaar E, Dartois V.

ABSTRACT: Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of “universal” drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens.

Read the full article here.

5. Treatment as prevention and other interventions to reduce transmission of multidrug-resistant tuberculosis.
Int J Tuberc Lung Dis. 2019 Apr 1;23(4):396-404. doi: 10.5588/ijtld.18.0276.
Nathavitharana RR, Lederer P, Tierney DB, Nardell E.

ABSTRACT: Drug-resistant tuberculosis (DR-TB) represents a major programmatic challenge at the national and global levels. Only ∼30% of patients with multidrug-resistant TB (MDR-TB) were diagnosed, and ∼25% were initiated on treatment for MDR-TB in 2016. Increasing evidence now points towards primary transmission of DR-TB, rather than inadequate treatment, as the main driver of the DR-TB epidemic. The cornerstone of DR-TB transmission prevention should be earlier diagnosis and prompt initiation of effective treatment for all patients with DR-TB. Despite the extensive scale-up of Xpert® MTB/RIF testing, major implementation barriers continue to limit its impact. Although there is longstanding evidence in support of the rapid impact of treatment on patient infectiousness, delays in the initiation of effective DR-TB treatment persist, resulting in ongoing transmission. However, it is also imperative to address the burden of latent drug-resistant tuberculous infection because it is estimated that many DR-TB patients will become infectious before seeking care and encounter various diagnostic delays before treatment. Addressing latent DR-TB primarily consists of identifying, treating and following the contacts of patients with MDR-TB, typically through household contact evaluation. Adjunctive measures, such as improved ventilation and use of germicidal ultraviolet technology can further reduce TB transmission in high-risk congregate settings. Although many gaps remain in our biological understanding of TB transmission, implementation barriers to early diagnosis and rapid initiation of effective DR-TB treatment can and must be overcome if we are to impact DR-TB incidence in the short and long term.

This article is unavailable via open access.


BEAT TB: A groundbreaking 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).

Union Symposium Presentations (2017)

Presentation 1 by Elizabeth Schnaubelt, MD, Global Tuberculosis Branch Division of Global HIV and TB

Manufacturing XDR TB: Timing of Acquired Resistance to Fluoroquinolones and Second-line Injectable Drugs during MDR TB Treatment in 9 Countries, 2005–2010, Preserving Effective TB Treatment Study (PETTS)

To view this presentation click here.


Presentation 2 by Isaac Chikwanha, MD, TB/HIV/HCV advisor, Access Campaign, MSF Geneva

The Role of Policy Adoption and Implementation for Elimination of MDR-TB

To view this presentation click here.


Presentation 3 by Gavin Churchyard, (MBBCh, FCP (SA), FRCP (Edin), MMED, PhD) Co-Chair of PHOENIx Feasibility Study and Main Trial

Accessing MDR-TB exposed Households: the PHOENiX MDR-TB Feasibility Study

To view this presentation click here.


Presentation 4 by Emily A. Kendall, MD Assistant Professor, Infectious Diseases, Johns Hopkins University School of MedicineMDR-TB

Elimination: What will it cost?

To view this presentation click here.

Webinar: TREAT TB

TREAT TB will hosted a capacity building webinar on community engagement in MDR-TB clinical trials.

It will feature a presentation from Ezio Tavora dos Santos Filho, STREAM Community Engagement Coordinator from REDE-TB, followed by a question and answer session.

The presentation will highlight the importance and objectives of community engagement in clinical research, how to implement community engagement before a trial begins, as well as how to bring community engagement into an existing trial. To join the webinar, click here. To join by phone, please dial +1 855 880 1246 US Toll-free or +1 877 853 5257 US Toll-free. For international numbers, click here. Meeting ID: 912 316 884

A recording of the webinar and slides will be available on the TREAT TB website approximately one week after (available around (12/12/18)) the webinar.

TREAT TB’s MDR-TB clinical trial capacity building webinar series will continue over the coming months, with webinars scheduled for January, March, and May 2019. Future topics to be addressed include regulatory requirements, institutional review boards and ethics approval, as well as laboratory strengthening.

Has compassionate use ever sunk a drug?

Click here to read a recent International Union Against Tuberculosis and Lung Disease Editorial by RESIST-TB members, Sarah McAnaw, Carole Mitnick, and Bob Horsburgh.

“New treatments for a serious disease generate understandable excitement among patients with life-threatening conditions. As pharmaceutical companies consider compassionate use of experimental drugs, one factor is commonly cited as a barrier to such use: fear that adverse events incurred by patients during Compassionate Use/Expanded Access (CU/EA) will impede regulatory approval of the drug. Such concerns stem from the obligation to report adverse events—that are serious, unexpected, and suspected to be related to the investigational drug— experienced by patients during treatment under CU/ EA programs.1 Such reports, it is feared, will damage the future of the drug, particularly since adverse events may not be related to the experimental drug and patients taking such drugs are typically sicker than the average patient.2 Existing evidence, however, does not support the notion that such events jeopardize regulatory approval.” Click here to read the article in full. 

Unitaid extends key research grant as part of a strong counterattack on tuberculosis

Unitaid is intensifying its commitment to fighting tuberculosis with a US$ 21 million investment in extending endTB, a global research project that is improving treatment regimens for patients with multidrug-resistant tuberculosis (MDR-TB). This project has been piloting bedaquiline and delamanid in 17 countries with the goal of providing countries and funding agencies with effective drugs to tackle MDR-TB on a large scale. 

Long-used treatments for MDR-TB can take up to two years, succeed in only about half the cases, and can cause major side effects. With endTB’s extension, a new clinical trial will be added to develop a treatment regimen for patients with fluoroquinolone-resistant MDR-TB. These regimens have the potential to cure 119,000 more patients, save 56,000 more lives and avert 239,000 drug-resistant infections from 2019 to 2027.

The endTB project’s original term was 2015-2019 and its budget US$ 60 million, but with the extension it will run through the end of 2022, with Unitaid support of up to US$ 81 million. 

To read the full article, click here.

TREAT TB Clinical Trial Capacity Building Webinar Series

RESIST-TB invites you to join TREAT TB for the second webinar in its series to promote capacity building for high quality clinical trials for MDR-TB.

On September 28th at 8 AM EST, Dr. Jan Komrska, senior pharmacist at Vital Strategies, will present a webinar on supply chain management for MDR-TB trials.

Connection details below.

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For more information about connection details and future webinars, click here.

To join the webinar from a PC, Mac, Linux, iOS or Android, click here.

To join by phone, please dial: US (toll free):  +1 855 880 1246 (Toll Free) or +1 877 853 5257 (Toll Free).

For international numbers, click here.

Meeting ID: 912 316 884

Complete makeover in fight of MDR-TB

An international collaborative study led by Dr. Dick Menzies at McGill University has shown that several new medicines, including bedaquiline, linezolid, and the later generation fluoroquinolones, have produced consistently better cure rates for MDR-TB patients and have been proven to be more effective at treating XDR-TB than currently used treatments. 

The World Health Organization (WHO) has already responded to this study’s findings by announcing landmark changes in line with this MDR-TB regimen and, also, positioning fully oral regimens over injectable agents. “The guidelines committee simply erased the old treatment recommendations and started over. They gave the treatment guidelines a complete make-over,” says Dr. Menzies.

To read the full article, click here.

SimpliciTB clinical trial launched with first patients in Tbilisi, Georgia

TB Alliance has started a new, four month clinical trial, SimpliciTB, to test the efficacy of the BPaMZ treatment regimen consisting of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in people with drug-sensitive TB against the standard six-month treatment regimen. SimpliciTB is looking to see if this regimen can shorten the duration of treatment by one third. BPaMZ was previously studied in a Phase 2b study, NC-005, in which MDR-TB patients saw improvement three times faster than those enrolled on the standard treatment. SimpliciTB is currently enrolling patients in Tbilisi, Georgia at the at the National Center for Tuberculosis and Lung Disease. 150 of the total 450 patients that will be enrolled are expected to have MDR-TB across 26 centers in 10 countries. 

To read the full article, click here.