Acceptability of levofloxacin dispersible and non-dispersible tablet formulations in children receiving TB preventive treatment.

BACKGROUND: We evaluated the palatability and acceptability of a 100 mg dispersible and a non-dispersible 250 mg levofloxacin (LVX) tablet formulation in children. METHODS: Perform was a randomised, open-label, cross-over trial of the relative bioavailability of LVX dispersible vs. crushed non-dispersible tablets in children aged <6 years routinely receiving TB preventive treatment. Children and caregivers completed Likert- and ranking-type measures on the acceptability of both formulations. We used summary, comparative and ranking statistics to characterise formulation acceptability. RESULTS: A total of 25 children were enrolled (median age: 2.6 years, IQR 1.6-4.0). Caregivers reported frequent challenges with preventive therapy in routine care prior to study entry, including taste of tablets (n = 14, 56%), vomiting/spitting out medicines (n = 11, 44%), and children refusing medicines (n = 10, 40%). Caregivers reported that the dispersible formulation was easier for their child to take than the non-dispersible formulation (P = 0.0253). Mean ranks for caregiver's formulation preferences (dispersible tablets: 1.48, SD ±0.71; non-dispersible tablets: 2.12, SD ±0.67; routinely available formulations: 2.40 SD ±0.82) differed significantly (Friedman's F 11.120; P < 0.0038); post-hoc testing showed dispersible tablets were preferred over non-dispersible (P = 0.018) and routinely available LVX formulations (P < 0.001). CONCLUSIONS: The dispersible LVX 100 mg tablet formulation was preferred and should be prioritised for integration into routine care.

CONTEXTE: Nous avons évalué la palatabilité et l'acceptabilité d'un comprimé dispersible de 100 mg et d'un comprimé non dispersible de 250 mg de lévofloxacine (LVX) chez les enfants. MÉTHODES: Perform était un essai randomisé, ouvert et croisé de la biodisponibilité relative des comprimés dispersibles LVX par rapport aux comprimés non dispersibles écrasés chez des enfants âgés de moins de 6 ans recevant régulièrement un traitement préventif contre la TB. Les enfants et les soignants ont rempli des questionnaires de type Likert et de classement sur la tolérance des deux formulations. Nous avons utilisé des statistiques sommaires, comparatives et de classement pour caractériser la tolérance à la formulation. RÉSULTATS: Au total, 25 enfants ont été recrutés (âge médian : 2,6 ans ; IQR 1,6­4,0). Les soignants ont signalé des problèmes fréquents liés au traitement préventif dans le cadre des soins de routine avant le début de l'étude, notamment le goût des comprimés (n = 14, 56%), le fait de vomir ou de recracher les médicaments (n = 11, 44%) et le fait que les enfants refusent les médicaments (n = 10, 40%). Les soignants ont déclaré que la formulation dispersible était plus facile à prendre pour leur enfant que la formulation non dispersible (P = 0,0253). Les classements moyens pour les préférences de formulation des soignants (comprimés dispersibles : 1,48 ; SD ±0,71 ; comprimés non dispersibles : 2,12 ; SD ±0,67 ; formulations couramment disponibles : 2,40 ; SD ±0,82) différaient de manière significative (Friedman's F 11,120 ; P < 0,0038) ; les tests post-hoc ont montré que les comprimés dispersibles étaient préférés aux comprimés non dispersibles (P = 0,018) et aux formulations LVX couramment disponibles (P < 0,001). CONCLUSION: La formulation dispersible des comprimés de LVX 100 mg a été préférée et devrait être intégrée en priorité dans les soins de routine.

Treatment outcomes and safety in children with rifampicin-resistant TB.

BACKGROUND: The treatment of rifampicin-resistant TB (RR-TB) in children is evolving rapidly. As newer regimens are introduced into routine care, it is vital to compare their outcome and safety with well-characterised clinical cohorts treated with historical regimens.METHODS: Study sample comprised a prospective observational cohort of children on routine RR-TB treatment, enrolled from 2011 to 2015 in Cape Town, South Africa. Children were followed for safety, treatment response and outcome.RESULTS: Of 136 children included, 27 (19.9%) were living with HIV and 48 (37.8%) had severe TB. The median time-to-culture conversion in children with bacteriological confirmation (n = 44) was 28.5 days (IQR 14.5-45). Overall, 118/129 (91.5%) had favourable TB treatment outcomes. Of 106 (77.9%) children who received an injectable drug, 9 (8.5%) developed hearing loss and 7/136 (5.1%) developed other Grade 3 or higher adverse events likely related to treatment.CONCLUSIONS: In this cohort with a substantial proportion of children with severe manifestations of TB and with HIV, TB treatment outcomes were excellent. Apart from hearing loss, few children developed severe adverse events related to treatment. This study provides robust reference data for future evaluation of shorter, injectable-sparing regimens.

Pharmacokinetics of high-dose isoniazid in children affected by multidrug-resistant TB.

BACKGROUND: High-dose isoniazid (INHH) (15-20 mg/kg/day) could be administered to overcome low-level INH resistance, but pharmacokinetic data are sparse.METHODS: This observational study included South African children (<15 years) receiving INHH as preventive therapy, or treatment for multidrug-resistant TB (MDR-TB) exposure or disease. Pharmacokinetic sampling was performed after an INH dose of 20 mg/kg. Non-compartmental analysis and multivariable regression models were used to evaluate associations of key covariates with area under the curve (AUC0-24) and maximum concentration (Cmax). AUC and Cmax values were compared against proposed adult targets.RESULTS: Seventy-seven children were included, with median age of 3.7 years; 51 (66%) had MDR-TB disease and 26 (34%) had MDR-TB exposure. Five were HIV-positive, of whom four were ≥5 years old. The median AUC0-24 was 19.46 µgh/mL (IQR 10.76-50.06) and Cmax was 5.14 µg/mL (IQR 2.69-13.2). In multivariable analysis of children aged <5 years, MDR-TB disease (vs. exposure) was associated with considerably lower AUC0-24 (geometric mean ratio GMR 0.19, 95% CI 0.15-0.26; P < 0.001) and Cmax (GMR 0.20, 95% CI 0.15-0.26; P < 0.001).CONCLUSIONS: INH concentrations in children with MDR-TB disease were much lower than expected, but comparable to previous reports in children with MDR-TB exposure. Further studies should confirm these findings and explore possible causes.

What drives 'first-time testers' to test for HIV at community-based HIV testing services?

Drivers of and barriers to testing are not well understood for those who have never been tested previously and now self-initiate at a community-based human immuno-deficiency virus (HIV) testing service (CB-HTS). This descriptive study enrolled 229 first-time testers. Participants completed an electronic questionnaire. The majority reported fear and (non) accessibility of HTS as barriers to testing (40% and 24%, respectively). Wanting 'to know my status' and the immediate opportunity to test were reported as drivers of testing (41% and 35%, respectively). Addressing fear of testing and providing an easily accessible opportunity to test may go some way to encouraging those previously untested individuals to test.

Les facteurs qui amènent à réaliser un test et ceux qui les entravent ne sont pas bien compris pour ceux qui n'ont jamais été testés auparavant et en prennent l'initiative dans un service de test pour le virus de l'immunodéficience humaine (VIH) basé en communauté (CB-HTS). Cette étude descriptive a enrôlé 229 patients testés pour la première fois. Les participants ont rempli un questionnaire électronique. La majorité a déclaré que la crainte et la (non) accessibilité du HTS étaient des entraves au test (40% et 24%, respectivement). Vouloir « connaître son statut ¼ et l'opportunité de faire le test immédiatement ont été les moteurs de la réalisation du test (41% et 35%, respectivement). Répondre aux craintes individuelles de se faire tester et offrir une opportunité facilement accessible de le réaliser contribueraient à amener au test ceux qui ne l'ont jamais fait.

No se conocen plenamente los impulsores y los obstáculos a la práctica de las pruebas diagnósticas de la infección por el virus de la inmunodeficiencia humana (VIH), en las personas que nunca han recibido la prueba y que ahora, por iniciativa propia, acuden a los servicios comunitarios que la ofrecen. En el presente estudio descriptivo se incorporaron 229 personas que recibían la prueba diagnóstica por primera vez. Los participantes completaron un cuestionario en formato electrónico. La mayoría refirió como obstáculos a la práctica de la prueba el temor (40%) y la (falta de) accesibilidad de los servicios que la ofrecen (24%). Los factores referidos como impulsores de la búsqueda de la prueba fueron el hecho de 'querer conocer su estado' (41%) y la oportunidad inmediata de hacerla (35%). Abordar el temor de las personas y ofrecer una oportunidad fácilmente accesible de realizar la prueba diagnóstica del VIH puede contribuir a que las personas que nunca han realizado la prueba, la acepten.

Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children.

SETTING: Isoniazid-resistant rifampicin-susceptible (HRRS) tuberculosis (TB) is the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes, but has been poorly described in children. OBJECTIVE: To characterise the clinical presentation, treatment, and clinical and microbiological outcomes among children with culture-confirmed HRRS TB. DESIGN: Retrospective hospital-based cohort study. RESULTS: Of the 72 children included in the study, the median age was 50.1 months (IQR 21.5-102.5); 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed HRRS TB. Of 66 tested, 12 (17%) were human immunodeficiency virus (HIV) infected, and 36 (60%) of the 60 with pulmonary TB (PTB) had severe disease. Seventy children had treatment data; the median total duration of treatment was 11.3 months (IQR 9-12.3); 25 (36%) initiated treatment with a three-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 children with known outcomes, 55 (88%) had a favourable outcome, 1 died and 3 had treatment failure. Ten had positive follow-up cultures at ⩾2 months after starting treatment. Older age (P = 0.008), previous anti-tuberculosis treatment (P = 0.023) and severe PTB (P = 0.018) were associated with failure to culture-convert at ⩾2 months. CONCLUSIONS: Although overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasise the need for additional attention to the management of children with HRRS TB.

Pharmacokinetics of Rifampin, Isoniazid, Pyrazinamide, and Ethambutol in Infants Dosed According to Revised WHO-Recommended Treatment Guidelines.

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 µg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 µg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 µg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children.

Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.

Pharmacokinetics of isoniazid in low-birth-weight and premature infants.

Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N-acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 µg/ml, the time after drug administration to reach CmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2-5) was 13.56 µg · h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h(-1). The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants.

Factors influencing increased expertise for a sustainable workforce at a research centre in South Africa.

SETTING: The Desmond Tutu Tuberculosis (TB) Centre (DTTC), Stellenbosch University, South Africa. OBJECTIVES: 1) To determine whether access to designated funding is associated with the development of expertise in employees, and 2) which other factors are associated with the development of expertise in employees. DESIGN: This was a retrospective study. The target population consisted of all employees at the DTTC during the period 1 January 2004 to 31 December 2011. Improvement in expertise during employment was the primary outcome; the secondary outcome was an increase in educational level linked to the National Qualifications Framework. RESULTS: There was no association between access to funding and expertise development, but an association between the number of months employed and improvement of expertise during employment was observed (OR 1.03, 95%CI 1.02-1.04, P < 0.001), controlling for age at appointment, sex, access to designated funding and education level. CONCLUSION: The study shows that almost a third of employees increased their expertise, more than 90% had access to designated funding and personnel employed for a longer duration were more likely to experience improvements in expertise. We encourage research organisations in low- and middle-income countries to implement strategies to retain employees in order to build their expertise.

Contexte : Le Centre Antituberculeux Desmond Tutu (DTTC), à l'Université de Stellenbosch, en Afrique du Sud.Objectifs : 1) Déterminer si l'accès au financement est associé au développement d'une expertise chez les employés, et 2) déterminer quels autres facteurs sont associés au développement de l'expertise des employés.Schéma : Cette étude était rétrospective. La population cible était constituée par les employés du DTTC entre le 1e janvier 2004 et le 31 décembre 2011. L'amélioration de l'expertise pendant la période de fonction était le premier résultat attendu ; le deuxième était une augmentation du niveau de connaissances en relation avec le Cadre National de Certification.Résultats : Il n'a pas été démontré d'association entre l'accès au financement et le développement de l'expertise, mais on a mis en évidence une association entre le nombre de mois de travail et cette amélioration (OR 1.03 ; IC95% 1,02­1.04 ; P< 0,001), en contrôlant l'âge lors de l'entrée en fonction, le sexe, l'accès au financement et le niveau d'instruction.Conclusion : L'étude montre que près d'un tiers du personnel a accru son expertise, plus de 90% ont eu accès au financement et que les personnes employées pendant une durée plus longue avaient davantage de chances d'améliorer leur expertise. Nous encourageons les organismes de recherche des pays à revenu faible et moyen à mettre en œuvre des stratégies visant à retenir leur personnel afin de renforcer leur expertise.

Marco de referencia: El Centro Desmond Tutu de atención de la tuberculosis (DTTC) de la Universidad Stellenbosch en Suráfrica.Objetivos: 1) Determinar si la obtención de atribución de financiamientos contribuye a perfeccionar la competencia profesional de los empleados; y 2) definir los demás factores que fomentan el mejoramiento de la pericia de los profesionales.Método: Fue este un estudio retrospectivo de los empleados del DTTC del 1° de enero del 2004 al 31 de diciembre del 2011. El principal criterio de evaluación fue el perfeccionamiento de la competencia profesional de los empleados durante el tiempo de ocupación del cargo. El criterio secundario fue el progreso académico de los profesionales, según los criterios del Marco Nacional de Cualificaciones.Resultados: No se observó ninguna asociación entre el acceso al financiamiento y el mejoramiento de las competencias, pero la duración en meses en el empleo se asoció con un progreso en los conocimientos y la experiencia de los empleados (OR 1,03; IC95% de 1,02 a 1,04; P < 0,001), una vez corregidos los datos en función de la edad del nombramiento, el sexo, el acceso a la atribución de financiamiento y el grado de instrucción.Conclusión: Los resultados del estudio ponen de manifiesto que cerca de un tercio de los empleados perfeccionó sus competencias, más del 90% contaba con acceso a la atribución de financiamiento y que era más probable que las personas empleadas por períodos más prolongados mejorasen sus conocimientos teóricos y prácticos. Se recomienda a las organizaciones de investigación de los países con recursos medianos y bajos que introduzcan estrategias encaminadas a fidelizar a sus empleados, con el fin de mejorar y consolidar las competencias.

Factors affecting treatment outcomes in drug-resistant tuberculosis cases in the Northern Cape, South Africa.

The Northern Cape Province has low cure rates (21%) for multidrug-resistant tuberculosis (TB). We audited the programme to identify factors affecting treatment outcomes. Cases admitted to two drug-resistant TB units from 2007 to 2009 had data extracted from clinical folders. Unfavourable treatment outcomes were found in 58% of the 272 cases. A multivariable regression analysis found that male sex was associated with unfavourable outcome (P = 0.009). Weight at diagnosis (P < 0.001) and oral drug adherence (P < 0.001) were also associated with an unfavourable outcome; however, injectable drug adherence was not (P = 0.395). Positive baseline smear and human immunodeficiency virus positive status were not associated with unfavourable outcome. Shorter, more patient-friendly regimens may go a long way to improving adherence and outcomes.

La province du Nord du Cap a des taux de réussite thérapeutique faibles (21%) pour les tuberculoses (TB) multirésistantes. Nous avons effectué un audit du programme afin d'identifier les facteurs affectant les résultats du traitement. Les dossiers cliniques des cas admis dans deux unités de traitement de la TB pharmacorésistante de 2007 à 2009 ont permis d'extraire les données requises. Sur 272 patients, 58% ont eu un échec thérapeutique. Une analyse de régression multivariée a constaté que le sexe masculin était associé à un résultat défavorable (P = 0,009). Le poids au moment du diagnostic (P < 0,001) et l'adhérence au traitement oral (P < 0,001) étaient également associés à un mauvais résultat, mais l'adhérence aux médicaments injectables ne l'était pas (P = 0,395). Un frottis positif au départ et un statut du virus de l'immunodéficience humaine positif n'étaient pas associés à un mauvais résultat. En bref, des protocoles mieux adaptés aux patients ont du chemin à faire pour améliorer l'adhérence et les résultats.

La Provincia Septentrional del Cabo presenta bajas tasas de curación (21%) de la tuberculosis (TB) multidrogorresistente. Se practicó una auditoría del programa con el fin de detectar los factores que influyen sobre los desenlaces terapéuticos. Se analizaron los casos hospitalizados entre el 2007 y el 2009 en dos unidades de atención de la TB resistente a partir de los datos de las historias clínicas. Se observaron desenlaces desfavorables en 58% de los 272 casos. Un análisis de regresión multifactorial puso en evidencia que el sexo masculino se asociaba con desenlaces desfavorables (P = 0,009). El peso en el momento del diagnóstico (P < 0,001) y el cumplimiento con el tratamiento por vía oral (P < 0,001) se asociaron con un desenlace desfavorable, pero no así el cumplimiento con el tratamiento intravenoso (P = 0,395). Los resultados iniciales de la baciloscopia del esputo y de la serología frente al virus de la inmunodeficiencia humana no se asociaron con desenlaces desfavorables. La utilización de regímenes de tratamiento más cortos y más centrados en el paciente podría contribuir a mejorar considerablemente el cumplimiento y los desenlaces terapéuticos.

A comparative study of tuberculosis patients initiated on ART and receiving different models of TB-HIV care.

SETTING: Although health policy in South Africa calls for the integration of services, the effectiveness of different models of integration on patient outcomes has not been well demonstrated. OBJECTIVE: To evaluate the outcomes of coinfected patients starting antiretroviral treatment (ART) in a tuberculosis (TB) hospital who received different models of ongoing care. DESIGN: This cohort study compared outcomes for 271 coinfected patients who started ART in a TB hospital in the Western Cape. After discharge, one group of patients received anti-tuberculosis treatment and ART from different providers, in the same or in different clinics (vertical care). The other group received anti-tuberculosis treatment and ART at the same visit from the same service provider (integrated care). Demographic and clinical data and TB and ART outcomes were compared. RESULTS: The vertical care model had more unfavourable outcomes for anti-tuberculosis treatment (28.7% vs. 5.9%, P < 0.001) and ART (30.1% vs. 7.4%, P < 0.001) than the integrated care model. The vertical care model showed no difference whether services were provided by two service providers in the same or in geographically separate primary health care clinics. CONCLUSION: Patient outcomes were better when TB and HIV care was received from the same service provider at the same visit.

Seroprevalence of hepatitis B in a cohort of HIV-infected children and adults in Swaziland.

Hepatitis B virus (HBV) is an important co-morbidity in the HIV epidemic. A retrospective chart review was performed of HIV-infected patients with no previous antiretroviral history enrolled in a Swaziland clinic from January 2009 to May 2011. The seroprevalence of HBV surface antigen (HBsAg) was calculated and the data were analyzed using Mann-Whitney U and Fisher's exact tests. A total of 1282 patients were included in analysis. Five hundred were children aged <15 years. Overall HBsAg seroprevalence was 3.7% (1.4% of children and 5.1% of adults). Prevalence in under-5s was low (0.4%). Among adult women and men, prevalence was 4.2% and 9.8%, respectively (P = 0.022). Median alanine aminotransferase level was 19 U/L in the HBsAg-negative adults and 25 U/L in the HBsAg-positive adults (P = 0.005). Given the number of patients found to be HBsAg-positive, especially among adults, it is important for antiretroviral programmes to consider universal screening and strategically utilize medications that have been found effective in treating both HBV and HIV.