Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

What is the best culture conversion prognostic marker for patients treated for multidrug-resistant tuberculosis?

INTRODUCTION: Identification of good prognostic marker for tuberculosis (TB) treatment response is a necessary step on the path towards a surrogate marker to reduce TB trial duration.METHODS: We performed a retrospective analysis on routinely collected data in 6 drug-resistant TB (DRTB) programs. Culture conversion, defined as two consecutive negative cultures, was assessed, and performance of culture conversion at Month 2 and Month 6 to predict treatment success were explored. To explore factors associated with positive predicted value (PPV) and the specificity of culture conversion, a multinomial logistic regression was fitted.RESULTS: This study included 634 patients: 68.5% were males; the median age was 35 years, 75.2% were previously treated for TB, 59.4% were resistant only to isoniazid and rifampicin and 18.1% resistant to fluoroquinolones. Culture conversion at Month 2 and 6 showed similar PPV while specificity was much higher for culture conversion at Month 2: 91.3% (95%CI 86.1-95.1). PPV of culture conversion at Month 2 did not vary strongly according to patients' characteristics, while specificity was slightly higher among patients with fluoroquinolone-resistant strains.CONCLUSION: Culture conversion at Month 2 is an acceptable prognostic marker for MDR-TB treatment. Considering the advantage of using an earlier marker, further evaluation as a surrogate marker is warranted to shorten TB trials.

IPT during HIV treatment in Myanmar: high rates of coverage, completion and drug adherence.

Setting: A southern Myanmar district providing isoniazid preventive therapy (IPT) in one of the last countries to formally recommend it as part of human immunodeficiency virus (HIV) care. Objective: To assess coverage and adherence and the feasibility of IPT scale-up in a routine care setting in Myanmar. Design: A retrospective analysis of people living with HIV (PLHIV) screened for tuberculosis (TB) and enrolled in IPT over a 3-year period (July 2011-June 2014) using clinical databases. Results: Among 3377 patients under HIV care and screened for TB, 2740 (81.1%) initiated IPT, with 2651 (96.8%) completing a 6- or 9-month course of IPT; 83 (3.1%) interrupted treatment for different reasons, including loss to follow-up (n = 41), side effects (n = 15) or drug adherence issues (n = 9); 6 (0.2%) died. Among the IPT patients, 33 (1.2%) were diagnosed with TB, including 9 (0.3%) while on IPT and 24 (0.9%) within 1 year of completion of therapy. Among the PLHIV who completed IPT, one case of isoniazid resistance was detected. Conclusion: Scaling up IPT in Myanmar HIV settings is feasible with high rates of drug adherence and completion, and a low rate of discontinuation due to side effects. IPT scale-up should be prioritised in HIV clinical settings in Myanmar.

Contexte : Un district du sud du Myanmar fournissant le traitement préventif par isoniazide (IPT) dans l'un des derniers pays à le recommander formellement comme élément de la prise en charge de l'infection par le virus de l'immunodéficience humaine (VIH).Objectif : Evaluer la couverture, l'adhérence et la faisabilité d'une accélération de l'IPT dans un contexte de soins de routine au Myanmar.Schéma : Analyse rétrospective de personnes vivant avec le VIH (PVVIH) dépistés pour la tuberculose (TB) et enrôlés dans l'IPT sur une période de 3 ans, de juillet 2011 à juin 2014, grâce à des bases de données cliniques.Résultats : Sur 3377 patients pris en charge pour le VIH et dépistés pour la TB, 2740 (81,1%) ont mis en route le TPI, dont 2651 (96,8%) ont achevé un traitement préventif de 6 ou 9 mois ; 83 (3,1%) ont interrompu leur traitement pour différentes raisons incluant les pertes de vue (n = 41), les effets secondaires (n = 15) ou des problèmes d'adhérence au médicament (n = 9), et six (0,2%) sont décédés. Parmi les patients IPT, 33 (1,2%) ont eu un diagnostic de TB, dont 9 (0,3%) pendant la prophylaxie et 24 (0,9%) dans l'année qui a suivi la fin de l'IPT. Un cas de résistance à l'isoniazide a été détecté parmi les PVVIH qui ont achevé l'IPT.Conclusion: L'accélération de l'IPT dans les structures VIH du Myanmar est faisable, avec un taux élevé d'adhérence au médicament et d'achèvement et un taux faible d'arrêt du traitement dû à des effets secondaires. L'accélération de l'IPT devrait être considérée comme une priorité dans les structures cliniques VIH du Myanmar.

Marco de referencia: Un distrito del sur de Birmania que provee el tratamiento preventivo con isoniazida (IPT). Birmania es uno de los últimos países que incluyó esta profilaxis en las recomendaciones formales de atención de la infección por el virus de la inmunodeficiencia humana (VIH).Objetivo: Evaluar la cobertura, el cumplimiento terapéutico y la factibilidad de ampliar la escala de aplicación del IPT en un entorno de tratamiento corriente en Birmania.Método: Fue este un análisis retrospectivo de personas con infección por el VIH, en quienes se practicó la detección sistemática de la tuberculosis (TB) y se registraron para recibir el IPT. Se obtuvo la información a partir de las bases de datos clínicos durante un período de 3 años, de julio del 2011 hasta junio del 2014.Resultados: De los 3377 pacientes que recibían atención por infección por el VIH, con investigación sistemática de la TB, 2740 iniciaron el TPI (81,1%) y 2651 completaron un esquema de 6 o 9 meses de profilaxis (96,8%). Ochenta y tres pacientes interrumpieron por razones diversas el tratamiento (3,1%), entre ellas, la pérdida durante el seguimiento (n = 41), los efectos secundarios (n = 15) o los problemas de cumplimiento terapéutico (n = 9) y seis pacientes fallecieron (0,2%). De los pacientes que recibieron IPT, en 33 se diagnosticó TB (1,2%), en 9 de ellos durante la profilaxis (0,3%) y en 24 casos durante el primer año después de haber completado el esquema (0,9%). Se detectó un caso de resistencia a isoniazida en las personas infectadas por el VIH que completaron el IPT.Conclusiôn: La ampliación de escala del IPT en los entornos de atención de la infección por el VIH es factible en Birmania y se pueden alcanzar altas tasas de cumplimiento terapéutico y compleción del esquema, con una baja tasa de interrupción debida a efectos colaterales. Es importante dar prioridad a la ampliación de escala del IPT en los medios de atención de la infección por el VIH en el país.

Identification of patients who could benefit from bedaquiline or delamanid: a multisite MDR-TB cohort study.

BACKGROUND: The World Health Organization recommends adding bedaquiline or delamanid to multidrug-resistant tuberculosis (MDR-TB) regimens for which four effective drugs are not available, and delamanid for patients at high risk of poor outcome. OBJECTIVE: To identify patients at risk of unfavourable outcomes who may benefit from the new drugs. METHODS: Retrospective cohort study of treatment outcomes involving four to five effective drugs for 15-24 months in programmes in Uzbekistan, Georgia, Armenia, Swaziland and Kenya between 2001 and 2011. RESULTS: Of 1433 patients, 48.5% had body mass index (BMI) <18.5 kg/m(2), 72.9% had a high bacillary load, 16.7% were resistant to two injectables, 2.9% were resistant to ofloxacin (OFX) and 3.0% had extensively drug-resistant TB (XDR-TB). Treatment success ranged from 59.7% (no second-line resistance) to 27.0% (XDR-TB). XDR-TB (aOR 8.16, 95%CI 3.22-20.64), resistance to two injectables (aOR 1.90, 95%CI 1.00-3.62) or OFX (aOR 5.56, 95%CI 2.15-14.37), past incarceration (aOR 1.88, 95%CI 1.11-3.2), history of second-line treatment (aOR 3.24, 95%CI 1.53-6.85), low BMI (aOR 2.22, 95%CI 1.56-3.12) and high bacillary load (aOR 2.32, 95%CI 1.15-4.67) were associated with unfavourable outcomes. Patients started on capreomycin rather than kanamycin were more likely to have an unfavourable outcome (aOR 1.54, 95%CI 1.04-2.28). CONCLUSION: In our cohort, patients who may benefit from bedaquiline and delamanid represented up to two thirds of all MDR-TB patients.

[The Médicins sans Frontières HIV/AIDS programme in Ukraine]. / Het hiv/aidsprogramma van Artsen zonder Grenzen in Oekraïne.

In 1999, Médicins sans Frontières started an HIV/AIDS programme in Ukraine, a country with an estimated 410,000 people with HIV (1.4% prevalence), including 53,000 in urgent need of antiretroviral therapy. Between 1999 and 2004, a comprehensive HIV/AIDS programme was implemented in close collaboration with the Ministry of Health in AIDS centres in Odessa, Mikolaev and Simferopol. Initial activities included prevention and treatment advocacy campaigns, which were later followed by prevention of mother-to-child transmission, treatment of opportunistic infections, antiretroviral therapy for infants and adults and palliative care. This programme has served as a model and has led to meaningful improvements in HIV/AIDS care in Ukraine. It demonstrates that adequate care for patients with HIV or AIDS is possible in countries like Ukraine.

Measurements of CP-violating asymmetries in B0-->K(0)(s)pi(0) decays.

We present a measurement of the time-dependent CP-violating (CPV) asymmetries in B0-->K(0)(S)pi(0) decays based on 124x10(6) Upsilon(4S)-->BB decays collected with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. In a sample containing 122+/-16 signal decays, we obtain the magnitudes of the direct CPV asymmetry CK(0)(S)(pi(0))=0.40(+0.27)(-0.28)+/-0.09 and of the CPV asymmetry in the interference between mixing and decay SK(0)(S)(pi(0))=0.48(+0.38)(-0.47)+/-0.06 where the first error is statistical and the second systematic.

Search for B+/--->[K(-/+)pi(+/-)](D)K+/- and upper limit on the b-->u amplitude in B+/--->DK+/-.

We search for B+/--->[K(-/+)pi(+/-)](D)K+/- decays, where [K(-/+)pi(+/-)](D) indicates that the K-/+pi(+/-) pair originates from the decay of a D0 or D (0). Results are based on 120x10(6) Upsilon(4S)-->BB decays collected with the BABAR detector at SLAC. We set an upper limit on the ratio R(Kpi) identical with[Gamma(B+-->[K(-)pi(+)](D)K+)+Gamma(B--->[K(+)pi(-)](D)K-)][Gamma(B+-->[K(+)pi(-)](D) / K+)+Gamma(B--->[K(-)pi(+)](D)K-)]<0.026 (90% C.L.). This constrains the amplitude ratio r(B) identical with|A(B--->D 0K-)/A(B--->D0K-)|<0.22 (90% C.L.), consistent with expectations. The small value of r(B) favored by our analysis suggests that the determination of the Cabibbo-Kobayashi-Maskawa phase gamma from B-->DK will be difficult.

Study of high momentum eta' production in B --> eta'Xs.

We measure the branching fraction for the charmless semi-inclusive process B --> eta'Xs, where the eta' meson has a momentum in the range 2.0 to 2.7 GeV/c in the upsilon4S center-of-mass frame and Xs represents a system comprising a kaon and zero to four pions. We find B(B --> eta'Xs) = [3.9 +/- 0.8(stat) +/- 0.5(syst) +/- 0.8(model)] x 10(-4). We also obtain the Xs mass spectrum and find that it fits models predicting high masses.

Measurement of branching fractions and charge asymmetries in B+/--->rho+/-pi0 and B+/--->rho0pi+/- decays, and search for B0-->rho0pi0.

We present measurements of branching fractions and charge asymmetries in B-meson decays to rho(+)pi(0), rho(0)pi(+), and rho(0)pi(0). The data sample comprises 89x10(6) Upsilon(4S)-->BBmacr; decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We find the charge-averaged branching fractions B(B+-->rho(+)pi(0))=[10.9+/-1.9(stat)+/-1.9(syst)]x10(-6) and B(B+-->rho(0)pi(+))=(9.5+/-1.1+/-0.9)x10(-6), and we set a 90% confidence-level upper limit B(B0-->rho(0)pi(0))<2.9x10(-6). We measure the charge asymmetries ACP(pi(0))(rho(+))=0.24+/-0.16+/-0.06 and ACP(pi(+))(rho(0))=-0.19+/-0.11+/-0.02.

Observation of the decay B-->J/psietaK and search for X(3872)-->J/psieta.

We report the observation of the B meson decay B+/- -->J/psietaK+/- and evidence for the decay B0-->J/psietaK0S, using 90 x 10(6) BB; events collected at the Upsilon(4S) resonance with the BABAR detector at the SLAC PEP-II e+e- asymmetric-energy storage ring. We obtain branching fractions of B(B+/- -->J/psietaK+/-) = [10.8 +/- 2.3(stat) +/- 2.4(syst)] x 10(-5) and B(B0-->J/psietaK0S) = [8.4 +/- 2.6(stat) +/- 2.7(syst)] x 10(-5). We search for the new narrow mass state, the X(3872), recently reported by the Belle Collaboration, in the decay B+/- -->X(3872)K+/-,X(3872)-->J/psieta and determine an upper limit of B[B +/- -->X(3872)K+/- -->J/psietaK+/-] < 7.7 x 10(-6) at 90% confidence level.

Measurement of the time-dependent CP asymmetry in the B0-->phiK0 decay.

We present a measurement of the time-dependent CP asymmetry for the neutral B-meson decay B0-->phiK0. We use a sample of approximately 114 x 10(6) B-meson pairs taken at the Upsilon(4S) resonance with the BABAR detector at the PEP-II B-meson factory at SLAC. We reconstruct the CP eigenstates phiK0S and phiK0L, where phi-->K+K-, K0S-->pi+pi-, and K0L is observed via its hadronic interactions. The other B meson in the event is tagged as either a B0 or Bbar0 from its decay products. The values of the CP-violation parameters are SphiK=0.47+/-0.34(stat)+0.08-0.06(syst) and CphiK=0.01+/-0.33(stat)+/-0.10(syst).

Measurement of time-dependent CP asymmetries in B0-->D(*)+/-pi-/+ decays and constraints on sin(2beta+gamma).

We present a measurement of CP-violating asymmetries in fully reconstructed B0-->D(*)+/-pi-/+ decays in approximately 88 x 10(6) upsilon(4S)-->BBmacr; decays collected with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. From a time-dependent maximum-likelihood fit we obtain the following for the CP-violating parameters: a=-0.022+/-0.038 (stat)+/-0.020 (syst), a*=-0.068+/-0.038 (stat)+/-0.020 (syst), c(lep)=+0.025+/-0.068 (stat)+/-0.033 (syst), and c*(lep)=+0.031+/-0.070 (stat)+/-0.033 (syst). Using other measurements and theoretical assumptions we interpret the results in terms of the angles of the Cabibbo-Kobayashi-Maskawa unitarity triangle, and find |sin((2beta+gamma)|>0.69 at 68% confidence level. We exclude the hypothesis of no CP violation [sin(2beta+gamma)=0] at 83% confidence level.

Measurement of time-dependent CP asymmetries and constraints on sin(2beta+gamma) with partial reconstruction of B0-->D*-/+pi+/- decays.

We present a measurement of time-dependent CP-violating asymmetries in decays of neutral B mesons to the final states D(*-/+)pi(+/-), using approximately 82x10(6) BBmacr; events recorded by the BABAR experiment at the PEP-II e(+)e(-) storage ring. Events containing these decays are selected with a partial reconstruction technique, in which only the high-momentum pi(+/-) from the B decay and the low-momentum pi(-/+) from the D(*-/+) decay are used. We measure the amplitude of the asymmetry to be -0.063+/-0.024(stat)+/-0.014(syst) and compute bounds on |sin((2beta+gamma)|.

Study of B+/ --> J/psi pi+/- and B+/ -->J/psi K+/- decays: measurement of the ratio of branching fractions and search for direct CP violation.

We study B+/ --> J/psi pi(+/-) and B+/ --> J/psi K+/- decays in a sample of about 89 x 10(6) BB pairs collected with the BABAR detector at the PEP-II asymmetric B factory at SLAC. We observe a signal of 244+/-20 B+/ --> J/psi pi(+/-) events and determine the ratio B(B+/ --> J/psi pi(+/-))/B(B+/ --> J/psi K+/-) to be [5.37+/-0.45(stat)+/-0.11(syst)]%. The charge asymmetries for the B+/ --> J/psi pi(+/-) and B+/ --> J/psi K+/- decays are determined to be A(pi)=0.123+/-0.085(stat)+/-0.004(syst) and A(K)=0.030+/-0.015(stat)+/-0.006(syst), respectively.

Search for the rare leptonic decay B+-->mu(+)nu(mu).

We have performed a search for the rare leptonic decay B+-->mu(+)nu(mu) with data collected at the Upsilon(4S) resonance by the BABAR experiment at the PEP-II storage ring. In a sample of 88.4 x 10(6) BB pairs, we find no significant evidence for a signal and set an upper limit on the branching fraction B(B+-->my(+)nu(my))< 6.6 x 10(-6) at the 90% confidence level.

Measurements of branching fractions and CP-violating asymmetries in B meson decays to charmless two-body states containing a K(0).

We present measurements of branching fractions and CP-violating asymmetries in decays of B mesons to two-body final states containing a K0. The results are based on a data sample of approximately 88 x 10(6) Upsilon(4S)-->BB decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We measure B(B+-->K(0)pi(+))=(22.3+/-1.7+/-1.1)x10(-6), B(B0-->K(0)pi(0)=(11.4+/-1.7+/-0.8)x10(-6), B(B+-->K(0)K+)<2.5 x 10(-6), and B(B0-->K(0)K(0)<1.8 x 10(-6), where the first uncertainty is statistical and the second is systematic, and the upper limits are at the 90% confidence level. In addition, the following CP-violating asymmetries have been measured: A(CP)(B+-->K(0)pi(+))=-0.05+/-0.08+/-0.01 and A(CP)(B0-->K(0)pi(0)=0.03+/-0.36+/-0.11.

Measurement of the branching fractions and CP asymmetry of B--->D(0)((CP))K- decays with the BABAR detector.

We present a study of B--->D(0)(CP)K- decays, where D(0)(CP) is reconstructed in CP-even channels, based on a sample of 88.8 x 10(6) Upsilon(4S)-->BB decays collected with the BABAR detector at the PEP-II e(+)e(-) storage ring. We measure the ratio of Cabibbo-suppressed to Cabibbo-favored branching fractions B(B--->D(0)(CP)K-)/B(B--->D(0)(CP)pi(-))=[8.8+/-1.6(stat)+/-0.5(syst)]x10(-2) and the CP asymmetry A(CP)=0.07+/-0.17(stat)+/-0.06(syst). We also measure B(B--->D0K-)/B(B--->D0pi(-))=[8.31+/-0.35(stat)+/-0.20(syst)]x10(-2) using a sample of 61.0 x 10(6) BB pairs.

Limits on the decay-rate difference of neutral B mesons and on CP, T, and CPT violation in B(0-0)B oscillations.

Using events in which one of two neutral B mesons from the decay of an Upsilon(4S) meson is fully reconstructed, we determine parameters governing decay (DeltaGamma(d)/Gamma(d)), CP, and T violation (|q/p|), and CP and CPT violation (Re z,Im z). The results, obtained from an analysis of 88 x 10(6) Upsilon(4S) decays recorded by BABAR, are sgn(Re lambda(CP))DeltaGamma(d)/Gamma(d)=-0.008+/-0.037(stat)+/-0.018(syst)[-0.084,0.068],|q/p|=1.029+/-0.013(stat)+/-0.011(syst)[1.001,1.057],(Re lambda(CP)/|lambda(CP)|) Re z=0.014+/-0.035(stat)+/-0.034(syst)[-0.072,0.101],Im z=0.038+/-0.029(stat)+/-0.025(syst)[-0.028,0.104]. The values inside the square brackets indicate the 90% confidence-level intervals. These results are consistent with standard model expectations.

Search for the radiative decays B-->rhogamma and B0-->omegagamma.

A search of the exclusive radiative decays B-->rho(770)gamma and B0-->omega(782)gamma is performed on a sample of about 84x10(6) BBmacr; events collected by the BABAR detector at the SLAC PEP-II asymmetric-energy e+e- storage ring. No significant signal is seen in any of the channels. We set upper limits on the branching fractions B of B(B0-->rho(0)gamma)<1.2 x 10(-6), B(B+-->rho+gamma)<2.1 x 10(-6), and B(B0-->omegagamma)<1.0 x 10(-6) at 90% confidence level (C.L.). Using the assumption that Gamma(B-->rhogamma)=Gamma(B+-->rho(+)gamma)=2 x Gamma(B0-->rho(0)gamma), we find the combined limit B(B-->rhogamma)<1.9 x 10(-6), corresponding to B(B-->rhogamma)/B(B-->K*gamma)<0.047 at 90% C.L.

Measurement of the branching fraction and polarization for the decay B--->D*0K*-.

We present a study of the decay B--->D(*0)K(*-) based on a sample of 86 x 10(6) Upsilon(4S)-->BBmacr; decays collected with the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We measure the branching fraction B(B--->D(*0)K(*-))=(8.3+/-1.1(stat)+/-1.0(syst)) x 10(-4), and the fraction of longitudinal polarization in this decay to be Gamma(L)/Gamma=0.86+/-0.06(stat)+/-0.03(syst).