Electronic pillbox-enabled self-administered therapy versus standard directly observed therapy for tuberculosis medication adherence and treatment outcomes in Ethiopia (SELFTB): protocol for a multicenter randomized controlled trial.

BACKGROUND: To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives. METHODS: This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers. DISCUSSION: This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Severe disseminated tuberculosis in HIV-negative refugees.

In high-income countries, the presentation of tuberculosis is changing, primarily because of migration, and understanding the specific health needs of susceptible populations is becoming increasingly important. Although disseminated tuberculosis is well documented in HIV-positive patients, the disease is poorly described and less expected in HIV-negative individuals. In this Grand Round, we report eight HIV-negative refugees, who presented with extensively disseminated tuberculosis. We discuss the multifactorial causes, such as deprivations during long journeys, precarious living conditions, and the experience of violence, which might add to nutritional factors and chronic disorders, eventually resulting in a state of predisposition to immune deficiency. We also show that disseminated tuberculosis is often difficult to diagnose when pulmonary symptoms are absent. Communication difficulties between refugees and health-care workers are another major hurdle, and every effort should be made to get a valid patient history. This medical history is crucial to guide imaging and other diagnostic procedures to establish a definite diagnosis, which should be confirmed by a positive tuberculosis culture. Because many of these patients are at risk for multidrug-resistant tuberculosis, drug susceptibility testing is imperative to guide therapy. In the absence of treatment guidelines for this entity, clinicians can determine treatment duration according to recommendations provided for extrapulmonary tuberculosis and affected organs. Paradoxical expansion of tuberculous lesions during therapy should be treated with corticosteroids. In many cases, treatment duration must be individualised and might even exceed 12 months.

Improving treatment outcome assessment in a mouse tuberculosis model.

Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (RpZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal Emax model in favor over linear or conventional Emax models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and RpZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.

Effects on type 2 diabetes complicated with pulmonary tuberculosis: regiment of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol versus the regiment plus Qi-boosting and Yin-nourishing decoction of Traditional Chinese Medicine.

OBJECTIVE: To observe the clinical effect on type 2 diabetes mellitus (T2DM) complicated with pulmonary tuberculosis (TB) of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol (conventional medication) administered together with Qi-boosting and Yin-nourishing decoction derived from Traditional Chinese Medicine (TCM). METHODS: A total of 60 patients with T2DM complicated with pulmonary TB were randomly and equally divided into positive control group and treatment group. The control group was treated with Western conventional regiment (WCR): insulin, isoniazid, rifampicin, pyrazinamide, and ethambutol, whereas the treatment group was given both WCR and Qi-boosting and Yin-nourishing decoction prepared from TCM. RESULTS: After the treatment, 20 (66.7%) and 11 (36.7%) cases showed sputum bacteria negative conversion in the WCR plus TCM group and WCM group respectively (P < 0.05). A total of 25 (83.3%) and 18 (60%) cases showed improvement in lung lesion in the WCR plus TCM group and WCM group respectively (P < 0.05). Compared with WCR group, fasting plasma glucose and 2-hour postprandial blood glucose levels in the WCR plus TCM group significantly decreased (P < 0.05 and P < 0.01, respectively). CONCLUSION: Qi-boosting and Yin-nourishing decoction combined with the Western medication showed better curative effect in treating T2DM complicated with pulmonary TB compared with the group using the conventional Western Medicine alone.

Pulmonary mycobacterial spindle cell pseudotumor in a lung transplant patient: progression without therapy and response to therapy.

Mycobacterial spindle cell pseudotumor (MSP) represents a rare, non-malignant, mass-forming reaction to various mycobacterial infections, typically occurring in immunocompromised patients. It is characterized by the proliferation of spindle-shaped fibrohistiocytic cells without the formation of epithelioid granulomas. Without staining for acid-fast bacilli, histological distinction from other spindle cell lesions, including malignancy, can be difficult. Most of the MSP cases reported in the literature have involved lymph nodes, skin, spleen, or bone marrow, but rarely involve the lung. MSP predominately occurs in patients who are immunosuppressed. We present a patient with MSP of the transplanted lung caused by non-tuberculous mycobacteria, in whom both the natural course of the untreated pseudotumor as well as the response to antimycobacterial treatments were observed.

Effect of micronutrient supplementation on treatment outcomes in children with intrathoracic tuberculosis: a randomized controlled trial.

BACKGROUND: Micronutrients play an important role in immune function. To our knowledge, there have been no comprehensive studies on the role of micronutrient supplementation in children with tuberculosis. OBJECTIVE: We assessed the effect of micronutrient supplementation in children treated with antituberculosis therapy (ATT). DESIGN: A randomized, double-blind, placebo-controlled trial that used a 2 × 2 factorial design was undertaken at 2 teaching hospitals in Delhi. Children with newly diagnosed intrathoracic tuberculosis were enrolled, and they received ATT together with daily supplementation for 6 mo with either zinc alone, micronutrients without zinc, micronutrients in combination with zinc, or a placebo. Main outcomes were weight gain and an improvement in a chest X-ray (CXR) lesion assessed at 6 mo of treatment. RESULTS: A total of 403 children were enrolled and randomly assigned. A microbiological diagnosis of tuberculosis was confirmed in 179 children (44.4%). The median (95% CI) increase in weight-for-age z score at 6 mo was not significantly different between subjects who received micronutrients [0.75 (0.66, 0.84)] and those who did not receive micronutrients [0.76 (0.67, 0.85)] and between subjects who received zinc [0.76 (0.68, 0.85)] and those who did not receive zinc [0.75 (0.66, 0.83)]. An improvement in CXR was observed in 285 children, but there was no difference between those receiving zinc and no zinc or between those receiving micronutrients and no micronutrients after 6 mo of ATT. However, children who received micronutrients had a faster gain in height over 6 mo than did those who did not receive micronutrients (height-for-age z score Δ = 0.08; P = 0.014). CONCLUSIONS: Micronutrient supplementation did not modify the weight gain or clearance of lesions on CXR in children with intrathoracic tuberculosis. However, micronutrient supplementation during treatment may improve height gain in children with intrathoracic tuberculosis. This trial was registered at clinicaltrials.gov as NCT00801606.

Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial.

BACKGROUND: In contrast to drug-sensitive tuberculosis, the guidelines for the treatment of multi-drug-resistant tuberculosis (MDR-TB) have a very poor evidence base; current recommendations, based on expert opinion, are that patients should be treated for a minimum of 20 months. A series of cohort studies conducted in Bangladesh identified a nine-month regimen with very promising results. There is a need to evaluate this regimen in comparison with the currently recommended regimen in a randomized controlled trial in a variety of settings, including patients with HIV-coinfection. METHODS/DESIGN: STREAM is a multi-centre randomized trial of non-inferiority design comparing a nine-month regimen to the treatment currently recommended by the World Health Organization in patients with MDR pulmonary TB with no evidence on line probe assay of fluoroquinolone or kanamycin resistance. The nine-month regimen includes clofazimine and high-dose moxifloxacin and can be extended to 11 months in the event of delay in smear conversion. The primary outcome is based on the bacteriological status of the patients at 27 months post-randomization. Based on the assumption that the nine-month regimen will be slightly more effective than the control regimen and, given a 10% margin of non-inferiority, a total of 400 patients are required to be enrolled. Health economics data are being collected on all patients in selected sites. DISCUSSION: The results from the study in Bangladesh and cohorts in progress elsewhere are encouraging, but for this regimen to be recommended more widely than in a research setting, robust evidence is needed from a randomized clinical trial. Results from the STREAM trial together with data from ongoing cohorts should provide the evidence necessary to revise current recommendations for the treatment for MDR-TB. TRIAL REGISTRATION: This trial was registered with clincaltrials.gov (registration number: ISRCTN78372190) on 14 October 2010.

Therapeutic drug monitoring in the treatment of Mycobacterium avium complex lung disease.

RATIONALE: Little is known regarding the application of therapeutic drug monitoring for treatment of Mycobacterium avium complex (MAC) lung disease. OBJECTIVES: To evaluate drug interactions of multidrug regimens and clinical usefulness of therapeutic drug monitoring in the management of MAC lung disease. METHODS: A total of 130 patients with MAC lung disease and 60 patients with Mycobacterium abscessus complex lung disease were enrolled in this study. All of the MAC patients were treated with multidrug regimens that included clarithromycin (CLR), rifampin (RIF) or rifabutin (RFB), and ethambutol (EMB), and the plasma drug concentrations of CLR, RIF, and EMB were measured. MEASUREMENTS AND MAIN RESULTS: Peak plasma CLR concentrations were lower in patients with MAC lung disease who received daily (median, 0.3 µg/ml) or intermittent (median, 0.2 µg/ml) therapy with CLR in conjunction with RIF in both groups, compared with those diagnosed with M. abscessus complex lung disease who received CLR without RIF (median, 3.8 µg/ml; P < 0.05). The proportion of patients with MAC lung disease who received daily therapy and whose plasma CLR levels were below the target range of 2 µg/ml was 97% (96 of 99), and this rate was 100% (21 of 21) among patients with MAC lung disease who received intermittent therapy. The peak plasma drug concentrations and the peak plasma drug concentration/minimal inhibitory concentration ratios of CLR, RIF, and EMB did not differ between patients with unfavorable treatment outcomes and those with favorable outcomes. CONCLUSIONS: Low plasma CLR concentrations were common in patients treated for MAC lung disease. However, there was no association between low plasma CLR concentrations and treatment outcomes. Therefore, therapeutic drug monitoring may not be beneficial in managing the therapy of patients with MAC lung disease.

Tuberculose: como eu trato / Tuberculosis: how I deal

Historicamente, o Brasil teve papel pioneiro na organização das ações de controle da tuberculose. Desde os primeiros anos do século XX, por meio de estratégias diagnósticas e terapêuticas padronizadas simples e efetivas, baseadas na patobiologia da doença e nas características do agente etiológico, o Programa de Controle da Tuberculose vem contribuindo para o controle da doença e para a organização do sistema público de saúde. A padronização terapêutica em todo o território nacional, associada à garantia de fornecimento gratuito dos medicamentos a todos os doentes identificados, são instrumentos fundamentais para a redução do impacto da tuberculose na população. Os esquemas medicamentosos padronizados para cada situação, previamente testados e validados, possibilitam a cura da maior parte dos doentes. Atualmente, os maiores obstáculos ao controle desejado da doença incluem a infecção pelo HIV e o desenvolvimento de bacilos resistentes aos principais agentes quimioterápicos.

Historically, Brazil has had a major role in the organization of tuberculosis control activities. Since the beginning of the XX Century, using simple and effective standardized diagnostic and therapeutic strategies, based on an understanding of the pathophysiology of the disease and on the characteristics of the etiologic agent, the Tuberculosis Control Program has contributed to the control of the disease and to the organization of the public health system. Nationwide standardization of the treatment, along with the quarantee of free medicines to all patients, are fundamental tools for reducing the impact of the disease. A structured approach to care lead to the cure of the majority of the patients. At present, the major obstacles to the desired level of tuberculosis control include HIV infection and the development of Mycobacterium tuberculosis strains resistant to the most important anti tubercular drugs.

Outcomes of a standardized triple-drug regimen for the treatment of nontuberculous mycobacterial pulmonary infection.

The treatment of fibrocavitatory pulmonary infection due to Mycobacterium avium complex and Mycobacterium malmoense poses a challenge. This study assessed microbial, inflammatory, radiographic, and clinical outcomes for a standardized 24-month triple-drug regime. Following treatment completion, all patients had fewer symptoms, experienced a reduction in systemic inflammation, and had negative sputum mycobacterial culture results.

Outcome of multi-drug resistant tuberculosis cases treated by individualized regimens at a tertiary level clinic.

AIM: To determine the clinical, radiological and drug resistance profile as well as the factors associated with treatment outcome of Multi-Drug Resistant Tuberculosis (MDR-TB). MATERIAL AND METHODS: All newly diagnosed patients with pulmonary MDR-TB from August 2002 to December 2004 enrolled at New Delhi Tuberculosis Centre, were included in the study. They were followed up clinically, radiologically and bacteriologically by sputum smear, culture and Drug Susceptibility Testing (DST) at regular intervals. According to their DST pattern and previous history of Anti-Tubercular Treatment (ATT), individualized treatment regimens were tailored for each patient. RESULTS: Out of total 27 bacteriologically proven cases of MDR-TB included in this study, 19 were males (mean age and weight 38.5 years and 52.6 kgs, respectively) and eight females (mean age and weight 34.3 years and 40.7 kgs, respectively). A majority (18) were residents of Delhi and the rest hailed from different parts of North India. All of them had a history of previous treatment ranging from six to 34 months. Cavity on chest X-rays was seen in 81%, while 44% showed extensive involvement. The patients received at least four "second line drugs" during their treatment with a mean of 6.2 anti-tubercular drugs during their intensive phase. Of the 27 patients, 13 were cured, 10 defaulted, one died, one is still on treatment and two were referred for surgery. Radiological improvement was observed in two third of cases and chest X-ray of two patients showed a complete resolution. Six predictors were identified for successful outcome of MDR-TB. They include weight gain at six months, culture conversion, radiological improvement during treatment, disease with M. tuberculosis strains exhibiting resistance to less than or up to three anti-tubercular drugs, use of less than or up to three second line drugs in treatment and no change of regimen during treatment. CONCLUSION: Default from treatment was observed to be a major challenge in the treatment of MDR-TB due to long duration and expense of ATT.

[Isoniazid induced neuropathy: consider prevention]. / Neuropathie toxique induite par l'isoniazide: pensez à la prévention.

INTRODUCTION: Antituberculous treatment is effective but has numerous side effects. Among these isoniazid induced neuropathy is easily preventable. CASE REPORT: A female patient of 42 years, infected with HIV, presented with general deterioration associated with an interstitial pulmonary infiltrate and mediastinal lymphadenopathy. Tuberculosis was not confirmed bacteriologically but she responded to antituberculous treatment. Three months later she developed distal leg pains extending proximally. There was superficial sensory impairment up to the groins and loss of the ankle reflexes. The dose of isoniazid was reduced from 5 to 2.5 mg/kg/day on account of slow acetylator status and treatment with pyridoxine 250 mg/day commenced. The clinical signs resolved in a few weeks. CONCLUSIONS: Isoniazid neuropathy develops in the presence of risk factors (HIV, alcoholism, diabetes, renal failure, malnutrition, pregnancy and lactation, neurotoxic medication) and manifests itself initially by burning feet. Pyridoxine is preventative in low dosage and curative in high dosage. The development of symptoms should lead to measurement of acetylator status, and a reduction of the isoniazid dose to 3 mg/kg/day or even less in slow acetylators.

Adverse drug reactions observed during DOTS.

A total of 8.37% of the 1195 patients treated at NDTB Centre with DOTS under RNTCP between January 2002 to June 2003 presented with adverse drug reactions. Patients showing any sort of adverse reactions were studied in detail by personal interviews and a semi-structured questionnaire. The profile of patients presenting with adverse reactions showed that majority of the patients (53%) had gastrointestinal reactions, the commonest presenting complaint being nausea and vomiting. General aches and pains were complained by about 35% and giddiness was the presenting complaint in 27% irrespective of the use of streptomycin, although giddiness was observed more often in Category II patients (59%). Skin rash and itching was complained by about 17% of patients and 11% complained of arthralgia, while only 1% had hepatotoxicity during treatment. Majority of the adverse reactions (67%) were observed within the first four weeks of treatment and only 0.25% of patients treated with DOTS had interruption of treatment for short periods.

[Miss-management in treatment failure of pulmonary tuberculosis].

PURPOSE: To investigate the risk factor of treatment failure of pulmonary tuberculosis excluding multi-drug resistant cases from the standpoint of both clinical management and tuberculosis control. OBJECT AND METHOD: Retrospective chart review of patients who admitted to Fukujuji Hospital for treatment failure of pulmonary tuberculosis excluding multi-drug resistant cases from Jan. 1993 to Dec. 2003. RESULTS: Out of 24 treatment failure cases available for analysis, 4 cases were associated with chronic tuberculous empyema with broncho-pleural fistula, and among them, chronic empyema was considered to be the main cause of treatment failure in one case. In 6 cases, poor adherence to medication was confirmed or suspected, and 2 of these 6 cases was also associated with miss-management. In 9 cases miss-management was found without poor adherence or chronic empyema, and in 8 out of these 9 cases, miss-management was considered to be the main cause of treatment failure. In 5 cases no apparent risk factor was found, but in 2 out of these 5 cases the ignorance of the results of drug sensitivity tests (and, therefore, miss-management) was strongly suspected. Summing up, in 10 out of 24 cases (41.7%), the miss-management was considered to be the main cause of treatment failure, and it was more frequently seen than poor adherence to medication. CONCLUSION: Clinicians should be aware of these risk factors of treatment failure such as chronic empyema, weak regimen in bacteriological negative cases, rifampicin+ethambutol regimen, and miss-management of drug adverse effect. From the standpoint of tuberculosis control in Japan we considered that, in addition to DOT, strategy to secure the quality of tuberculosis treatment is by all means needed.

[The morphological reactions in the lungs during the chemotherapy of experimental tuberculosis]. / Morfologicheskie reaktsii v legkikh pri khimioterapii éksperimental'nogo tuberkuleza.

Histological, histochemical, and electron microscopic studies were used to examine cellular and subcellular responses in the lung to the development of tuberculous inflammation and its drug treatment. In early inflammation, they are induced by higher capillary and cellular permeabilities, cell ultrastructural changes in the air-blood barrier. The period of granuloma formation is characterized by a larger count of hypertrophic alveolar parenchymal cells, type 2 alveolocytes in particular, that synthesize a surfactant, and by higher macrophagal activity. During therapy, there are increases in the count of multinuclear giant cells in the granuloma, in the resolution of inflammatory changes or in the isolation of a tuberculous focus. Morphological signs that show the inefficiency of treatment are identified.

A retrospective study of the addition of ciprofloxacin to clarithromycin and ethambutol in the treatment of disseminated Mycobacterium avium complex infection.

Disseminated Mycobacterium avium complex (DMAC) infection is associated with increased morbidity and mortality in HIV-infected individuals. The combination antibiotic regimens containing clarithromycin can decrease symptoms and improve survival in patients with DMAC, however, optimal therapy remains to be defined. Quinolones have been widely used in the treatment of DMAC but their utility has not been established. A retrospective cohort study of DMAC infection was established in a metropolitan hospital providing comprehensive care to over 3000 HIV-infected individuals. Medical records of patients with DMAC diagnosed at the Parkland Memorial Hospital from 1991 to 1994 were reviewed for therapeutic regimens for DMAC, concomitant therapy for HIV and Pneumocystis carinii prophylaxis and date of death. Subjects were included if they were treated with clarithromycin and ethambutol. Cases were defined as those patients who received more than 30 days of ciprofloxacin as therapy for DMAC in addition to the other drugs that they received. The primary endpoint was the time to death from the data of DMAC diagnosis. Covariates effecting survival were analysed through the Cox proportional hazards model. Eighty-nine subjects with DMAC who were treated with clarithromycin and ethambutol were identified. Fifty-eight received ciprofloxacin in addition to clarithromycin and ethambutol. The time to death was significantly better in those subjects who were treated with ciprofloxacin than those who were not (489 days vs 281 days, P=0.01). The sole significant predictor of improved survival on Cox proportional hazards model was ciprofloxacin therapy. Subjects treated with combination of clarithromycin, ethambutol and ciprofloxacin had improved survival over those treated with clarithromycin and ethambutol alone.

Evaluation of an intensive intermittent-induction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG).

This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates.