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.

[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.

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.

Observation of a significant excess of pi0pi0 events in B meson decays.

We present a study of the decay B0-->pi(0)pi(0) based on a sample of 124 x 10(6) BB pairs recorded by the BABAR detector at the PEP-II asymmetric-energy B Factory at SLAC. We observe 46+/-13+/-3 events, where the first error is statistical and the second is systematic, corresponding to a significance of 4.2 standard deviations including systematic uncertainties. We measure the branching fraction B(B0-->pi(0)pi(0))=(2.1+/-0.6+/-0.3)x10(-6), averaged over B0 and B(0) decays.

Evidence for the rare decay B-->K*l+l- and measurement of the B-->Kl+l- branching fraction.

We present evidence for the flavor-changing neutral current decay B-->K*l+l- and a measurement of the branching fraction for the related process B-->K l+l-, where l+l- is either an epsilon+epsilon- or a mu+mu- pair. These decays are highly suppressed in the standard model, and they are sensitive to contributions from new particles in the intermediate state. The data sample comprises 123 x 10(6) Upsilon(4S)-->B(-)B decays collected with the BABAR detector at the SLAC PEP-II epsilon+epsilon- storage ring. Averaging over K(*) isospin and lepton flavor, we obtain the branching fractions B(B-->Kl+l-)=(0.65(+0.14)(-0.13)+/-0.04)x10(-6) and B(B-->K*l+l-)=(0.88(+0.33)(-0.29)+/-0.10)x10(-6), where the uncertainties are statistical and systematic, respectively. The significance of the B-->Kl+l- signal is over 8sigma, while for B-->K*l+l- it is 3.3sigma.

Measurements of branching fractions and CP-violating asymmetries in B0-->rho(+/-)h(-/+) decays.

We present measurements of branching fractions and CP-violating asymmetries in B0-->rho(+/-)pi(-/+) and B0-->rho-K+ decays. The results are obtained from a data sample of 88.9 x 10(6) Upsilon(4S)-->BB decays collected with the BABAR detector at the SLAC PEP-II asymmetric-energy B Factory. From a time-dependent maximum likelihood fit we measure the branching fractions B(B0-->rho(+/-)pi(-/+))=[22.6+/-1.8 (stat)+/-2.2 (syst)]x10(-6) and B(B0-->rho-K+)=(7.3 -1.2( +1.3)+/-1.3)x10(-6), and the CP-violating charge asymmetries A(rhopi)(CP)=-0.18+/-0.08+/-0.03 and A(rhoK)(CP)=0.28+/-0.17+/-0.08, the direct CP violation parameter C(rhopi)=0.36+/-0.18+/-0.04 and the mixing-induced CP violation parameter S(rhopi)=0.19+/-0.24+/-0.03, and the dilution parameters DeltaC(rhopi)=0.28 -0.19( +0.18)+/-0.04 and DeltaS(rhopi)=0.15+/-0.25+/-0.03.

Measurement of the CP asymmetry amplitude sin2beta with B0 mesons.

We present results on time-dependent CP asymmetries in neutral B decays to several CP eigenstates. The measurements use a data sample of about 88 x 10(6) Upsilon(4S)-->B(-)B decays collected between 1999 and 2002 with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. We study events in which one neutral B meson is fully reconstructed in a final state containing a charmonium meson and the other B meson is determined to be either a B(0) or B(-0) from its decay products. The amplitude of the CP asymmetry, which in the standard model is proportional to sin2beta, is derived from the decay-time distributions in such events. We measure sin2beta=0.741+/-0.067(stat)+/-0.034(syst) and |lambda|=0.948+/-0.051(stat)+/-0.030(syst). The magnitude of lambda is consistent with unity, in agreement with the standard model expectation of no direct CP violation in these modes.

Measurements of branching fractions and CP-violating asymmetries in B0-->pi+pi-, K+pi-, K+K- decays.

We present measurements of branching fractions and CP-violating asymmetries for two-body neutral B meson decays to charged pions and kaons based on a sample of about 88x10(6) Upsilon(4S)-->BB decays. From a time-independent fit we measure the charge-averaged branching fractions B(B0-->pi+pi-)=(4.7+/-0.6+/-0.2)x10(-6), B(B0-->K+pi-)=(17.9+/-0.9+/-0.7)x10(-6), and the direct CP-violating charge asymmetry A(Kpi)=-0.102+/-0.050+/-0.016 [-0.188,-0.016], where the ranges in square brackets indicate the 90% confidence intervals. From a time-dependent fit we measure the B0-->pi+pi- CP-violating parameters S(pipi)=0.02+/-0.34+/-0.05 [-0.54,+0.58] and C(pipi)=-0.30+/-0.25+/-0.04 [-0.72,+0.12].

Measurement of the B0-->J/psipi+pi- branching fraction.

We present a measurement of the branching fraction for the decay of the neutral B meson into the final state J/psipi(+)pi(-). The data set contains approximately 56 x 10(6) BB pairs produced at the Upsilon(4S) resonance and recorded with the BABAR detector at the PEP-II asymmetric-energy e(+)e(-) storage ring. The result of this analysis is B(B0-->J/psipi(+)pi(-))=(4.6+/-0.7+/-0.6) x 10(-5), where the first error is statistical and the second is systematic. In addition, we measure B(B0-->J/psirho(0))=(1.6+/-0.6+/-0.4) x 10(-5).

Measurement of the Cabibbo-Kobayashi-Maskawa matrix element V(ub) with B-->rhoenu decays.

We present a measurement of the branching fraction for the rare decays B-->rhoenu and extract a value for the magnitude of V(ub), one of the smallest elements of the Cabibbo-Kobayashi-Maskawa quark-mixing matrix. The results are given for five different calculations of form factors used to para-metrize the hadronic current in semileptonic decays. Using a sample of 55 x 10(6) BB meson pairs recorded with the BABAR detector at the PEP-II e(+)e(-) storage ring, we obtain B(B0-->rho(-)e(+)nu)=(3.29+/-0.42+/-0.47+/-0.55) x 10(-4) and |V(ub)|=(3.64+/-0.22+/-0.25(+0.39)(-0.56)) x 10(-3), where the uncertainties are statistical, systematic, and theoretical, respectively.

Study of the rare decays B0-->D((*)+)(s)pi(-) and B0-->D((*)-)(s)K+.

We report evidence for the decays B0-->D(+)(s)pi(-) and B0-->D(-)(s)K+ and the results of a search for B0-->D(*+)(s)pi(-) and B0-->D(*-)(s)K+ in a sample of 84 x 10(6) upsilon(4S) decays into BB pairs collected with the BABAR detector at the PEP-II asymmetric-energy e(+)e(-) storage ring. We measure the branching fractions B(B0-->D(+)(s)pi(-))=[3.2+/-0.9(stat)+/-1.0(syst)] x 10(-5) and B(B0-->D(-)(s)K+)=[3.2+/-1.0(stat)+/-1.0(syst)] x 10(-5). We also set 90% C.L. limits B(B0-->D(*+)(s)pi(-))<4.1 x 10(-5) and B(B0-->D(*-)(s)K+)<2.5 x 10(-5).

Observation of a narrow meson state decaying to D(+)(s)pi(0) at a mass of 2.32 GeV/c(2).

We have observed a narrow state near 2.32 GeV/c(2) in the inclusive D(+)(s)pi(0) invariant mass distribution from e(+)e(-) annihilation data at energies near 10.6 GeV. The observed width is consistent with the experimental resolution. The small intrinsic width and the quantum numbers of the final state indicate that the decay violates isospin conservation. The state has natural spin-parity and the low mass suggests a J(P)=0(+) assignment. The data sample corresponds to an integrated luminosity of 91 fb(-1) recorded by the BABAR detector at the SLAC PEP-II asymmetric-energy e(+)e(-) storage ring.

Evidence for B+-->J/psip(-)Lambda; and search for B0-->J/psip(-)p.

We have performed a search for the decays B+-->J/psip(-)Lambda; and search for B0-->J/psip(-)p. in a data set of (88.9+/-1.0) x 10(6) Upsilon(4S) decays collected by the BABAR experiment at the PEP-II e(+)e(-) storage ring at the Stanford Linear Accelerator Center. Four charged B candidates have been observed with an expected background of 0.21+/-0.14 events. The corresponding branching fraction is (12(+9)(-6)) x 10(-6), where statistical and systematic uncertainties have been combined. The result can be interpreted as a 90% confidence level (C.L.) upper limit of 26 x 10(-6). We also find one B0 candidate, with an expected background of 0.64+/-0.17 events, implying a 90% C.L. upper limit of 1.9 x 10(-6).

Measurement of the branching fraction, and bounds on the CP-violating asymmetries, of neutral B decays to D*+/- D-/+.

We present measurements of the branching fraction and CP-violating asymmetries for neutral B decays to D(*+/-)D-/+. The measurement uses a data sample of approximately 88x10(6) Upsilon(4S)-->BBmacr; decays collected with the BABAR detector at the SLAC PEP-II asymmetric-energy e(+)-e(-) collider. By fully reconstructing the D(*+/-)D-/+ decay products, we measure the branching fraction to be (8.8+/-1.0+/-1.3)x10(-4) and the time-integrated CP-violating asymmetry between the rates to D(*-)D+ and D(*+)D- to be A=-0.03+/-0.11+/-0.05. We also measure the time-dependent CP-violating asymmetry parameters to be S(-+)=-0.24+/-0.69+/-0.12, C(-+)=-0.22+/-0.37+/-0.10 for B-->D(*-)D+ and S(+-)=-0.82+/-0.75+/-0.14, C(+-)=-0.47+/-0.40+/-0.12 for B-->D(*+)D-. In each case, the first error is statistical and the second error is systematic.

Measurement of time-dependent CP asymmetries and the CP-odd fraction in the decay B0-->D(*+)D(*-).

We present a measurement of time-dependent CP asymmetries and an updated determination of the CP-odd fraction in the decay B0-->D(*+)D(*-) using a data sample of 88x10(6)BB pairs collected by the BABAR detector at the PEP-II B Factory at SLAC. We determine the CP-odd fraction to be 0.063+/-0.055(stat)+/-0.009(syst). The time-dependent CP asymmetry parameters Im(lambda(+)) and /lambda(+)/ are determined to be 0.05+/-0.29(stat)+/-0.10(syst) and 0.75+/-0.19(stat)+/-0.02(syst), respectively. The standard model predicts these parameters to be -sin(2beta and 1, respectively, in the absence of penguin diagram contributions.

Limits on D0-macro D0 mixing and CP violation from the ratio of lifetimes for decay to K-pi+, K-K+, and pi- pi+.

We present a measurement of D0-macro D0 mixing parameters using the ratios of lifetimes extracted from samples of D0 mesons decaying to K-pi(+), K-K+, and pi(-)pi(+). Using 91 fb(-1) of data collected by the BABAR detector at the PEP-II asymmetric-energy B Factory, we obtain a value Y=[0.8+/-0.4(stat.)(+0.5)(-0.4)(syst.)]%, which, in the limit of CP conservation, corresponds to the mixing parameter y=Delta Gamma/2 Gamma. Using the difference in lifetimes of D0 and macro D0 mesons, we obtain the CP-violation parameter Delta Y=[-0.8+/-0.6(stat.)+/-0.2(syst.)]%.

Rates, polarizations, and asymmetries in charmless vector-vector B meson decays.

With a sample of approximately 89 x 10(6) B(-)B pairs collected with the BABAR detector, we perform a search for B meson decays into pairs of charmless vector mesons (phi, rho, and K*). We measure the branching fractions, determine the degree of longitudinal polarization, and search for CP violation asymmetries in the processes B+-->phiK(*+), B0-->phiK(*0), B+-->rho(0)K(*+), and B+-->rho(0)rho(+). We also set an upper limit on the branching fraction for the decay B0-->rho(0)rho(0).

Search for D0-D(-)0 mixing and a measurement of the doubly Cabibbo-suppressed decay rate in D0-->Kpi decays.

We present results of a search for D0-D(-)0 mixing and a measurement of R(D), the ratio of doubly Cabibbo-suppressed decays to Cabibbo-favored decays, using D0-->K+pi- decays from 57.1 fb(-1) of data collected near sqrt[s]=10.6 GeV with the BABAR detector at the PEP-II collider. At the 95% confidence level, allowing for CP violation, we find the mixing parameters x('2)<0.0022 and -0.056