Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

L'Organisation mondiale de la santé a élaboré des profils de produits cibles contenant des cibles minimales et optimales pour les caractéristiques principales des essais destinés au suivi et à l'optimisation du traitement de la tuberculose. L'optimisation du traitement de la tuberculose fait référence à l'instauration d'un régime de traitement efficace de la tuberculose ou à l'adoption d'un tel régime, avec une probabilité élevée d'obtenir de bons résultats thérapeutiques. Les profils de produits cibles couvrent également les essais de guérison effectués à l'issue du traitement. Les profils de produits cibles ont été élaborés sur la base d'un sondage auprès des parties prenantes, d'une analyse coût-efficacité et d'une analyse du parcours de soins du patient. Des retours supplémentaires des parties prenantes ont été obtenus au moyen d'un processus créé selon la méthode Delphi, d'une consultation technique et d'un appel à commentaires publics sur un projet de document. Un groupe d'élaboration scientifique s'est mis d'accord sur les objectifs finaux lors d'une réunion de concertation. En ce qui concerne les caractéristiques jugées les plus importantes, le document énumère ce qui suit: (i) une grande précision diagnostique (sensibilité et spécificité); (ii) un délai idéal d'obtention des résultats ≤ 2 heures et au maximum de 1 jour; (iii) le type d'échantillon requis doit être peu invasif et facile à obtenir, comme l'urine, l'haleine ou le sang capillaire, ou bien un échantillon respiratoire au-delà des expectorations; (iv) idéalement, l'essai pourrait avoir lieu dans un établissement de santé périphérique sans laboratoire ; et (v) l'essai devrait être abordable pour les pays à revenu faible et intermédiaire et permettre un accès large et équitable ainsi qu'une mise à l'échelle. L'utilisation de ces profils de produits cibles devrait faciliter la mise au point de nouveaux essais de surveillance et d'optimisation du traitement de la tuberculose qui soient précis et accessibles à toutes les personnes suivant un traitement pour la tuberculose.

La Organización Mundial de la Salud ha elaborado perfiles de productos objetivo que contienen objetivos mínimos y óptimos para las características principales de las pruebas de seguimiento y optimización del tratamiento de la tuberculosis. La optimización del tratamiento de la tuberculosis consiste en iniciar o cambiar a un régimen eficaz de tratamiento de la tuberculosis que ofrezca una alta probabilidad de un buen resultado terapéutico. Los perfiles de productos objetivo también abarcan las pruebas de curación realizadas al final del tratamiento. La elaboración de los perfiles de los productos objetivo se basó en una encuesta a las partes interesadas, un análisis de rentabilidad y un análisis de la vía de atención al paciente. Se obtuvo información adicional de las partes interesadas mediante un proceso tipo Delphi, una consulta técnica y una convocatoria de comentarios públicos sobre un borrador del documento. Un grupo de desarrollo científico acordó los objetivos finales en una reunión de consenso. Para las características clasificadas de mayor importancia, el documento enumera: (i) alta precisión diagnóstica (sensibilidad y especificidad); (ii) tiempo hasta el resultado de óptimamente ≤ 2 horas y no más de 1 día; (iii) el tipo de muestra requerida debe ser mínimamente invasiva, fácil de obtener, como orina, aliento o sangre capilar, o una muestra respiratoria que vaya más allá del esputo; (iv) idealmente la prueba podría realizarse en un centro sanitario periférico sin laboratorio; y (v) la prueba debe ser asequible para los países de ingresos bajos y medios y permitir un acceso amplio y equitativo y su expansión. El uso de estos perfiles de producto objetivo debería facilitar el desarrollo de pruebas nuevas de seguimiento y optimización del tratamiento de la tuberculosis que sean precisas y accesibles para todas las personas que reciben tratamiento antituberculoso.

Middlebrook 7h11 reduces invalid results and turnaround time of phenotypic drug-susceptibility testing of M. tuberculosis.

Background: Phenotypic drug-susceptibility testing (pDST), which relies on growth inhibition in the drug-containing media, remains a challenge for fastidious Mycobacterium tuberculosis complex (MTBc) isolates due to insufficient growth on the growth controls (GC). Middlebrook 7H11 (M7H11) medium contains casein hydrolysate, which may favor the growth of such strains. Method: In this study, we tested whether M7H11 reduces invalid results due to insufficient growth on the GCs and the turnaround time (TAT) of pDST for MTBc compared to Middlebrook 7H10 (M7H10) without affecting the accuracy of the pDST results and how it differs between rifampicin- and isoniazid-susceptible non multi-drug resistant (non-MDR), MDR and MDR with additional resistance to fluoroquinolones (Pre-XDR) MTBc isolates. We compared the proportions of invalid pDST results due to lack of growth on the GCs, TATs of valid parallel drug-susceptibility testings as an indicator of speed of MTBc growth, and colony-forming unit (CFU) count on the most diluted GC of the parallel pDSTs after equal incubation periods as an indicator of growth abundance on M7H11 and M7H10. We also analyzed the agreement between the pDST results of the same drug or drugs in the same drug class, tested in parallel on both media. Results: For MDR and pre-XDR isolates, relative to M7H10, M7H11 significantly reduced the occurrence of invalid pDST results due to insufficient growth on the GCs (odds ratio [OR] = ∞ [95% confidence interval (CI) 1.9-∞], P = 0.004 for MDR, OR = ∞ [95% CI 3.3-∞], P = 0.0001 for pre-XDR) and the TAT of pDSTs (OR = 17 [95% CI 2.6-710.4], P = 0.0001 for MDR, OR = 9.3 [95% CI 4.0-26.5], P < 0.0001 for pre-XDR). The growth abundance of MTBc on M7H11 was significantly higher compared to M7H10 (17 CFU on M7H10 vs. 28 on M7H11), irrespective of drug-resistance profiles. The agreement between the pDST results between the two media was high (Cohen's k > 0.98). Conclusion: Our study findings suggest that M7H11 is preferred over M7H10 for pDSTs of MTBc isolates.

Selection bias in multidrug-resistant tuberculosis cohort studies assessing sputum culture conversion.

BACKGROUND: Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or "baseline" culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval. METHODS: We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion. RESULTS: In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites. CONCLUSION: Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

Concomitant Treatment of Chronic Hepatitis C With Direct-Acting Antivirals and Multidrug-Resistant Tuberculosis Is Effective and Safe.

We assessed effectiveness and safety of concomitant chronic hepatitis C virus (HCV) treatment with direct-acting antivirals (DAAs) and multidrug-resistant tuberculosis (MDR-TB). Of 322 MDR-TB patients (19.4% HCV), 30 were treated concomitantly (23.3% human immunodeficiency virus-positive). Overall, 76.7% achieved HCV treatment success (95.8% among tested). One patient (3.3%) experienced a serious adverse event.

Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study.

Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for nonconversion.Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with conversion.Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.

Outcomes of HIV-infected versus HIV-non-infected patients treated for drug-resistance tuberculosis: Multicenter cohort study.

BACKGROUND: The emergence of resistance to anti-tuberculosis (DR-TB) drugs and the HIV epidemic represent a serious threat for reducing the global burden of TB. Although data on HIV-negative DR-TB treatment outcomes are well published, few data on DR-TB outcomes among HIV co-infected people is available despite the great public health importance. METHODS: We retrospectively reported and compared the DR-TB treatment outcomes of HIV-positive and HIV-negative patients treated with an individualized regimen based on WHO guidelines in seven countries: Abkhazia, Armenia, Colombia, Kenya, Kyrgyzstan, Swaziland and Uzbekistan. RESULTS: Of the 1,369 patients started DRTB treatment, 809 (59.1%) were multi-drug resistant (MDR-TB) and 418 (30.5%) were HIV-positive. HIV-positive patients were mainly from African countries (90.1%) while HIV-negative originated from Former Soviet Union (FSU) countries. Despite a higher case fatality rate (19.0% vs 9.4%), HIV-positive MDR-TB patients had a 10% higher success rate than HIV-negative patients (64.0% vs 53.2%, p = 0.007). No difference in treatment success was found among polydrug-resistant (PDR-TB) patients. Overall, lost to follow-up rate was much higher among HIV-negative (22.0% vs. 8.4%). Older age and not receiving ART were the only factors associated with unfavorable treatment outcome among HIV-positive patients. CONCLUSIONS: As already known for HIV-negative patients, success rate of DR-TB HIV-positive patients remains low and requires more effective DR-TB regimen using new drugs also suitable to HIV-infected patients on ART. The study also confirms the need of ART introduction in HIV co-infected patients.

Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis.

We describe 27 children and adolescents <18 years of age who received bedaquiline during treatment for multidrug-resistant tuberculosis. We report good treatment responses and no cessation attributable to adverse effects. Bedaquiline could be considered for use with this age group for multidrug-resistant tuberculosis when treatment options are limited.

Six-Month Response to Delamanid Treatment in MDR TB Patients.

Delamanid, recently available for the treatment of multidrug-resistant tuberculosis (MDR TB), has had limited use outside clinical trials. We present the early treatment results for 53 patients from 7 countries who received a delamanid-containing treatment for MDR TB. Results show good tolerability and treatment response at 6 months.

Nontuberculous Mycobacteria Infections at a Provincial Reference Hospital, Cambodia.

Prevalence of nontuberculous mycobacteria (NTM) disease is poorly documented in countries with high prevalence of tuberculosis (TB). We describe prevalence, risk factors, and TB program implications for NTM isolates and disease in Cambodia. A prospective cohort of 1,183 patients with presumptive TB underwent epidemiologic, clinical, radiologic, and microbiologic evaluation, including >12-months of follow-up for patients with NTM isolates. Prevalence of NTM isolates was 10.8% and of disease was 0.9%; 217 (18.3%) patients had TB. Of 197 smear-positive patients, 171 (86.8%) had TB confirmed (167 by culture and 4 by Xpert MTB/RIF assay only) and 11 (5.6%) had NTM isolates. HIV infection and past TB were independently associated with having NTM isolates. Improved detection of NTM isolates in Cambodia might require more systematic use of mycobacterial culture and the use of Xpert MTB/RIF to confirm smear-positive TB cases, especially in patients with HIV infection or a history of TB.

New developments in the treatment of drug-resistant tuberculosis: clinical utility of bedaquiline and delamanid.

The current treatment for drug-resistant tuberculosis (TB) is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB). Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis.

Effects of treatment interruption patterns on treatment success among patients with multidrug-resistant tuberculosis in Armenia and Abkhazia.

BACKGROUND: The success of the current treatment regimen for multidrug-resistant (MDR) tuberculosis is poor partly owing to a high default rate. Many studies have explored predictors of poor outcomes, but very few have assessed the effects of treatment interruptions on treatment outcomes for MDR tuberculosis. METHODS: We conducted a retrospective analysis among patients with MDR tuberculosis enrolled in 2 MDR tuberculosis programs using regimens recommended by the World Health Organization under directly observed therapy. Treatment outcomes were defined as successful if the patient was cured or completed treatment and unsuccessful if the patient died or defaulted from treatment or if treatment failed. The effect of patterns of interruptions on treatment outcomes was assessed through multivariate logistic regression. RESULTS: A total of 393 patients with MDR tuberculosis were included in the study; 171 (43.5%) had a successful outcome, and 222 (56.5%) an unsuccessful outcome: 39 (9.9%) died, 56 (14.3%) had failed treatment, and 127 (32.3%) defaulted from treatment. In multivariate analysis, long interruptions (≥3 days) (adjusted odds ratio, 3.87; 95% confidence interval, 1.66-8.98) and short gaps (<10 days) between interruptions (3.94; 1.76-8.81) were independently associated with an unsuccessful treatment outcome. DISCUSSION: This study shows that in a directly observed therapy-based MDR tuberculosis program, treatment interruptions at short intervals of ≥3 days directly affect treatment outcome.

Field evaluation of a simple fluorescence method for detection of viable Mycobacterium tuberculosis in sputum specimens during treatment follow-up.

Simple tuberculosis (TB) treatment monitoring tools are needed. We assessed the performance of fluorescein-diacetate (FDA) smear microscopy for detection of viable Mycobacterium tuberculosis in sputum specimens (n = 288) of TB cases under treatment compared to culture (17.4% culture positivity). FDA sensitivity was moderate (83.7% [95% confidence interval {CI}, 70.3 to 92.6]), and specificity was low (66.1% [59.5 to 72.2]). The good negative predictive value (94.8% [90.1 to 97.8]) and negative likelihood ratio (0.2) suggest using this method to rule out treatment failure in settings without access to culture.

Safety and effectiveness of first line eflornithine for Trypanosoma brucei gambiense sleeping sickness in Sudan: cohort study.

OBJECTIVE: To assess the safety and effectiveness of eflornithine as first line treatment for human African trypanosomiasis. DESIGN: Cohort study. SETTING: Control programme in Ibba, southern Sudan. PARTICIPANTS: 1055 adults and children newly diagnosed with second stage disease in a 16 month period. MAIN OUTCOME MEASURES: Deaths, severe drug reactions, and cure at 24 months. RESULTS: 1055 patients received eflornithine for 14 days (400 mg/kg/day in adults and 600 mg/kg/day in a subgroup of 96 children). Overall, 2824 drug reactions (2.7 per patient) occurred during hospital stay, 1219 (43.2%) after the first week. Severe reactions affected 138 (13.1%) patients (mainly seizures, fever, diarrhoea, and bacterial infections), leading to 15 deaths. Risk factors for severe reactions included cerebrospinal fluid leucocyte counts > or =100x10(9)/l (adults: odds ratio 2.6, 95% confidence interval 1.5 to 4.6), seizures (adults: 5.9, 2.0 to 13.3), and stupor (children: 9.3, 2.5 to 34.2). Children receiving higher doses did not experience increased toxicity. Follow-up data were obtained for 924 (87.6%) patients at any follow-up but for only 533 (50.5%) at 24 months. Of 924 cases followed, 16 (1.7%) died during treatment, 70 (7.6%) relapsed, 15 (1.6%) died of disease, 403 (43.6%) were confirmed cured, and 420 (45.5%) were probably cured. The probability of event free survival at 24 months was 0.88 (0.86 to 0.91). Most (65.8%, 52/79) relapses and disease related deaths occurred after 12 months. Risk factors for relapse included being male (incidence rate ratio 2.42, 1.47 to 3.97) and cerebrospinal fluid leucocytosis: 20-99x10(9)/l (2.35, 1.36 to 4.06); > or =100x10(9)/l (1.87, 1.07 to 3.27). Higher doses did not yield better effectiveness among children (0.87 v 0.85, P=0.981). Conclusions Eflornithine shows acceptable safety and effectiveness as first line treatment for human African trypanosomiasis. Relapses did occur more than 12 months after treatment. Higher doses in children were well tolerated but showed no advantage in effectiveness.

Tuberculosis after HAART initiation in HIV-positive patients from five countries with a high tuberculosis burden.

BACKGROUND: HAART reduces tuberculosis (TB) incidence in people living with HIV/AIDS but those starting HAART may develop active TB or subclinical TB may become apparent in the immune reconstitution inflammatory syndrome. OBJECTIVE: To measure the incidence rate of notified TB in people receiving HAART in five HIV programmes occurring in low-resource countries with a high TB/HIV burden. METHODS: A retrospective review in five Médecins Sans Frontières programmes (Cambodia, Thailand, Kenya, Malawi and Cameroon) allowed incidence rates of notified TB to be calculated based on follow-up time after HAART initiation. RESULT: Among 3151 patients analysed, 90% had a CD4 cell count of < 200 cells/mul. Median follow-up time ranged from 3.7 months in Thailand or Kenya to 11.1 months in Cambodia. Incidence rates were 7.6, 10.4, 17.6, 14.3 and 4.8/100 person-years for pulmonary TB and 12.7, 4.3, 6.9, 2.1 and 0/100 person-years for extra-pulmonary TB in the programmes in Cambodia, Thailand, Kenya, Malawi and Cameroon, respectively. Overall, 62.3% of pulmonary TB and 54.9% of extra-pulmonary TB were diagnosed within 3 months after HAART initiation. CONCLUSION: High incidence rates of notified TB under HAART in programmes held in poor-resource countries were observed; these were likely to include both undiagnosed prevalent TB at HAART initiation and subclinical TB developing during the immune reconstitution inflammatory syndrome. This raises operational issues concerning TB diagnosis and treatment of TB/HIV-coinfected patients and prompts for urgent TB and HIV care integration.

Working in a war zone. The impact on humanitarian health workers.

BACKGROUND: The work challenges faced by doctors, nurses and other health professionals in the humanitarian field are overwhelming. OBJECTIVE: This article highlights the psychological effects on humanitarian workers and the support available, both while on a 'mission' and on return home. DISCUSSION: It is impossible not to be psychologically affected by witnessing gross acts of violence, starvation, epidemics, displacement and despair, or hearing tales of slaughter, rape and killing. Just as those populations who are subjected to traumatic experiences develop post-traumatic psychological problems, so too can those humanitarian workers who assist them.