July 2018 Newsletter

1. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study.
Lancet Respir Med. 2018 Jul 9. pii: S2213-2600(18)30235-2. doi: 10.1016/S2213 2600(18)30235-2. [Epub ahead of print]
Schnippel K(1), Ndjeka N(2), Maartens G(3), Meintjes G(4), Master I(5), Ismail N(6), Hughes J(7), Ferreira H(8), Padanilam X(9), Romero R(10), Te Riele J(11), Conradie F(12).

BACKGROUND: Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis  Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.
METHODS: In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We  excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively
drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or
rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of  sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment.
FINDINGS: 24,014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to  743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28-0·46) and extensively drug-resistant tuberculosis (0·26, 0·18-0·38) compared with standard regimens.
INTERPRETATION: Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen.

Read abstract here.

2. Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.
PLoS Med. 2018 Jul 11;15(7):e1002591. doi: 10.1371/journal.pmed.1002591.eCollection 2018 Jul.
Harausz EP(1)(2), Garcia-Prats AJ(1), Law S(3), Schaaf HS(1), Kredo T(4), Seddon  JA(5), Menzies D(3), Turkova A(6), Achar J(7), Amanullah F(8), Barry P(9), Becerra M(10), Chan ED(11), Chan PC(12), Ioana Chiotan D(13), Crossa A(14), Drobac PC(10), Fairlie L(15), Falzon D(16), Flood J(9), Gegia M(17), Hicks RM(18), Isaakidis P(19), Kadri SM(20), Kampmann B(21)(22), Madhi SA(23), Marais E(24), Mariandyshev A(25), Méndez-Echevarría A(26), Moore BK(27), Nargiza P(28), Ozere I(29), Padayatchi N(30), Ur-Rehman S(31), Rybak N(32), Santiago-Garcia B(33), Shah NS(18), Sharma S(34), Shim TS(35), Skrahina A(36), Soriano-Arandes A(37), van den Boom M(38), van der Werf MJ(39), van der Werf TS(40), Williams B(41), Yablokova E(25), Yim JJ(42), Furin J(43), Hesseling AC(1); Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in MDR-TB.

BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children.
METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data  were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome.In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician’s perception of illness, with resulting potential for bias.
CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children.  Our findings of individual drug effects on treatment outcome should be further evaluated.

Read full study here. 

3. Relative bioavailability of bedaquiline tablets suspended in water: implications for dosing in children.
Br J Clin Pharmacol. 2018 Jun 27. doi: 10.1111/bcp.13696. [Epub ahead of print]
Svensson EM(1)(2), du Bois J(3), Kitshoff R(3), de Jager VR(3), Wiesner L(4), Norman J(4), Nachman S(5), Smith B(6), Diacon A(3), Hesseling AC(7), Garcia-Prats AJ(7).

OBJECTIVES: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared  to whole tablets.
METHODS: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48 hours was conducted at two occasions 14 days apart in each participant after administration of 400 mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.
RESULTS: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.
CONCLUSIONS: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat MDR-TB in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.

Read full study here.

4. Increased Doses Lead to Higher Drug Exposures of Levofloxacin for the Treatment of Tuberculosis.
Antimicrob Agents Chemother. 2018 Jul 16. pii: AAC.00770-18. doi: 10.1128/AAC.00770-18. [Epub ahead of print]
Peloquin CA(1), Phillips PPJ(2)(3), Mitnick CD(4), Eisenach K(5), Patientia RF(6), Lecca L(7), Gotuzzo E(8), Gandhi NR(9), Butler D(10), Diacon AH(6), Martel B(7), Santillan J(8), Hunt KR(10), Vargas D(7), von Groote-Bidlingmaier F(6), Seas C(8), Dianis N(10), Moreno-Martinez A(11)(12), Kaur P(13), Horsburgh CR Jr(13)(14).

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to weight-banded nominal doses of 11, 14, 17 or 20 mg/kg/day levofloxacin (minimum 750 mg) in combination with other second-line agents. 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median AUC0-24 were 109.49, 97.86, 145.33 and 207.04 h*mcg/ml. Median Cmax were 11.90, 12.02, 14.86, and 19.17 mcg/ml. Higher levofloxacin doses, up to 1500 mg daily, resulted in higher exposures. ClinicalTrials.gov Identifier: NCT01918397.

Read manuscript here.

5. Can patients afford the cost of treatment for multidrug-resistant tuberculosis in Ethiopia?
Int J Tuberc Lung Dis. 2018 Aug 1;22(8):905-911. doi: 10.5588/ijtld.17.0837.
Collins D(1), Beyene D(2), Tedla Y(3), Mesfin H(4), Diro E(5).

SETTING: Ethiopia has a high prevalence of tuberculosis (TB) and is one of the countries with the highest burden of multidrug-resistant TB (MDR-TB).
OBJECTIVE: To understand the costs that patients incur in obtaining diagnosis and treatment  for MDR-TB.
DESIGN: In March 2013, interviews were conducted with 169 MDR-TB patients at three hospitals in Ethiopia to identify the cost to patients and the impact on employment and family income.
RESULTS: The average MDR-TB patient incurred a total cost of US$1378, which represented 25 months of a mid-treatment household income of US$54. The impact on the patient’s employment and on overall patient and family income was generally catastrophic: 74% of all respondents reported losing their jobs, 66% of patients lost household income, and household income was reduced by 38%. To help cover the costs, 38% of patients sold some type of property, while 7% leased out property and 41% took out loans, any of which could jeopardize their future financial situation even further.
CONCLUSION: Despite services being officially free of charge, most patients incurred catastrophic costs and suffered significant income loss as a result of obtaining diagnosis and treatment for MDR-TB.

Read abstract here.