1. Precision medicine for drug-resistant tuberculosis in high-burden countries: is individualised treatment desirable and feasible?

Lancet Infect Dis. 2018 Mar 13. pii: S1473-3099(18)30104-X. doi:10.1016/S1473-3099(18)30104-X. [Epub ahead of print]

Cox H(1), Hughes J(2), Black J(3), Nicol MP(4).

ABSTRACT: Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management. We argue that a balance is required between the need to improve treatment access and the imperative to minimise resistance amplification and provide the highest standard of care, through a precision medicine approach. In tuberculosis, as in other diseases, we should aim to reduce the entrenched inequalities that manifest as different standards of care in different settings.

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2. Bedaquiline and Delamanid for the Treatment of Multidrug-resistant Tuberculosis: A Multi-center Cohort Study in Korea.

Eur Respir J. 2018 Mar 15. pii: 1702467. doi: 10.1183/13993003.02467-2017. [Epub ahead of print]

Tae Kim C(1), Kim TO(2), Shin HJ(2), Chun Ko Y(3), Hun Choe Y(4), Kim HR(5), Kwon YS(2).

ABSTRACT: Relatively little is known about the efficacy and safety of the programmatic use of bedaquiline and delamanid in multidrug-resistant tuberculosis (MDR-TB) treatment. This study evaluated 61 patients with MDR-TB treated with bedaquiline (n=39), delamanid (n=11), or both, either sequentially (n=10) or in co-administration (n=1), for more than 1 month, combined with a World Health Organization-recommended regimen. Of these, 49 (80.3%) were men and 12 (19.7%) were women. The median age was 53 years (interquartile range [IQR]=38.5-61.0 years). Forty-two (68.9%) patients had fluoroquinolone-resistant MDR-TB and 16 (26.2%) had extensively drug-resistant TB. The median duration of treatment with bedaquiline and/or delamanid was 168 days (IQR 166.5-196.5 days), with 33 (54.1%) receiving linezolid for median 673 days (IQR 171-736 days). Of the 55 patients with positive sputum cultures at the start of bedaquiline and/or delamanid treatment, 39 (70.9%) achieved sputum culture conversion within a median of 119 days. Treatment was halted in four patients (6.6%) because of prolonged corrected QT interval. In conclusion, bedaquiline and delamanid were effective and safe for treating MDR-TB, with initial evidence of sequential administration of these two drugs as a viable treatment strategy for patients when an adequate treatment regimen cannot be constructed.

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3. Clinical Management of Multidrug-resistant Tuberculosis in 16 European Countries.

Am J Respir Crit Care Med. 2018 Mar 6. doi: 10.1164/rccm.201710-2141OC. [Epub ahead of print]

Günther G(1), van Leth F(2), Alexandru S(3), Altet N(4), Avsar K(5), Bang D(6), Barbuta R(7), Bothamley G(8), Ciobanu A(3), Crudu V(3), Danilovits M(9), Dedicoat M(10), Duarte R(11), Gualano G(12), Kunst H(13), de Lange W(14), Leimane V(15), McLaughlin AM(16), Magis-Escurra C(17), Muylle I(18), Polcová V(19), Popa C(20),  Rumetshofer R(21), Skrahina A(22), Solodovnikova V(23), Spinu V(24), Tiberi S(25), Viiklepp P(26), Lange C(27); for TBNET.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less and cure rates are even lower.

METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by WHO and alternative simplified definitions.

RESULTS: 380 patients with MDR-TB were recruited and followed-up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median 111 vs. 28 days), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying WHO outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include one year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%) and high- incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6).

CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared to individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by WHO outcome definitions.

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4. Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):407-412. doi: 10.5588/ijtld.17.0706.

Cox V(1), Brigden G(2), Crespo RH(3), Lessem E(4), Lynch S(5), Rich ML(6), Waning B(3), Furin J(7).

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up

Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.

RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.

CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

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