September 2018 Newsletter

1. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.
Lancet. 2018 Sep 8;392(10150):821-834. doi: 10.1016/S0140-6736(18)31644-1.
Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017, Ahmad N(1), Ahuja SD(2), Akkerman OW(3), Alffenaar JC(4), Anderson LF(5), Baghaei P(6), Bang D(7), Barry PM(8), Bastos ML(9), Behera D(10), Benedetti A(11), Bisson GP(12), Boeree MJ(13), Bonnet M(14), Brode SK(15), Brust  JCM(16), Cai Y(17), Caumes E(18), Cegielski JP(19), Centis R(20), Chan PC(21), Chan ED(22), Chang KC(23), Charles M(24), Cirule A(25), Dalcolmo MP(26), D’Ambrosio L(27), de Vries G(28), Dheda K(29), Esmail A(29), Flood J(8), Fox GJ(30), Fréchet-Jachym M(31), Fregona G(32), Gayoso R(26), Gegia M(5), Gler MT(33), Gu S(34), Guglielmetti L(35), Holtz TH(19), Hughes J(36), Isaakidis P(37), Jarlsberg L(38), Kempker RR(39), Keshavjee S(40), Khan FA(11), Kipiani M(41), Koenig SP(42), Koh WJ(43), Kritski A(44), Kuksa L(45), Kvasnovsky CL(46),  Kwak N(47), Lan Z(11), Lange C(48), Laniado-Laborín R(49), Lee M(50), Leimane V(25), Leung CC(23), Leung EC(23), Li PZ(11), Lowenthal P(8), Maciel EL(32), Marks SM(51), Mase S(52), Mbuagbaw L(53), Migliori GB(20), Milanov V(54), Miller AC(55), Mitnick CD(55), Modongo C(56), Mohr E(36), Monedero I(57), Nahid P(38), Ndjeka N(58), O’Donnell MR(59), Padayatchi N(60), Palmero D(61), Pape JW(62), Podewils LJ(19), Reynolds I(34), Riekstina V(25), Robert J(63), Rodriguez M(64),  Seaworth B(65), Seung KJ(66), Schnippel K(67), Shim TS(68), Singla R(69), Smith SE(19), Sotgiu G(70), Sukhbaatar G(71), Tabarsi P(6), Tiberi S(72), Trajman A(73), Trieu L(2), Udwadia ZF(74), van der Werf TS(75), Veziris N(63), Viiklepp P(76), Vilbrun SC(77), Walsh K(77), Westenhouse J(8), Yew WW(78), Yim JJ(47), Zetola NM(56), Zignol M(5), Menzies D(79).

BACKGROUND:Treatment outcomes for multidrug-resistant tuberculosis remain poor.
We aimed to estimate the association of treatment success and death with the use
of individual drugs, and the optimal number and duration of treatment with those
drugs in patients with multidrug-resistant tuberculosis.
METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment
completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic,  or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.
FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for  number of drugs and durations analyses.
INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for  treatment of multidrug resistant tuberculosis. These findings emphasise the need  for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.
FUNDING:American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

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2. Time to act on injectable-free regimens for children with multidrug-resistant tuberculosis.
Lancet Respir Med. 2018 Sep;6(9):662-664. doi: 10.1016/S2213-2600(18)30329-1.
Seddon JA(1), Schaaf HS(2), Marais BJ(3), McKenna L(4), Garcia-Prats AJ(2), Hesseling AC(2), Hughes J(2), Howell P(5), Detjen A(6), Amanullah F(7), Singh U(8), Master I(9), Perez-Velez CM(10), Misra N(9), Becerra MC(11), Furin JJ(11).

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3. 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. [Epub ahead of print]
Zhao Y(1), Fox T(1), Manning K(1), Stewart A(2), Tiffin N(3)(4)(5), Khomo N(1), Leslie J(1), Boulle A(3), Mudaly V(6), Kock Y(6), Meintjes G(1)(5), Wasserman S(1)(5).

BACKGROUND:Bedaquiline is used as a substitute for second-line injectable (SLI)
intolerance in the treatment of multidrug-resistant tuberculosis (MDR-TB), but
the 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.

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4. Using routinely collected laboratory data to identify high rifampicin-resistant tuberculosis burden communities in the Western Cape Province, South Africa: A retrospective spatiotemporal analysis.
PLoS Med. 2018 Aug 21;15(8):e1002638. doi: 10.1371/journal.pmed.1002638. eCollection 2018 Aug.
McIntosh AI(1), Jenkins HE(1), White LF(1), Barnard M(2), Thomson DR(3), Dolby T(2), Simpson J(2), Streicher EM(4), Kleinman MB(5), Ragan EJ(5), van Helden PD(4), Murray MB(3), Warren RM(4), Jacobson KR(5).

BACKGROUND:South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data.
METHODS AND FINDINGS:We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing (n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location (n= 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage  by clinic, and estimated average size and direction of change was mapped. We
identified 799,779 individuals who had specimens submitted from mappable clinics  for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27-44), and 10,255 (4.6%, 95% CI: 4.6-4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among
these individuals was 11.4% (95% CI: 10.7-12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm.
CONCLUSIONS:Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions.

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