Tuberculosis Contact Investigation Using Interferon-Gamma Release Assay with Chest X-Ray and Computed Tomography

Between September 2009 and January 2010, 6 members of the Japanese Eastern Army, who had completed the same training program, were diagnosed with active tuberculosis (TB) on different occasions. The Ministry of Defense conducted a contact investigation of all members who had come into contact with the infected members. The purpose of this study was to verify the efficacy of the TB screening protocol used in this investigation. A total of 884 subjects underwent interferon-gamma release assay (IGRA) and chest X-ray. The 132 subjects who were IGRA positive or with X-ray findings suggestive of TB subsequently underwent chest computer tomography (CT). Chest CT was performed for 132 subjects. Based on CT findings, 24 (2.7%) subjects were classified into the active TB group, 107 (12.1%) into the latent tuberculosis infection (LTBI) group, and 753 (85.2%) into the non-TB group. The first 2 groups underwent anti-TB therapy, and all 3 groups were followed for 2 years after treatment. Although one subject in the active TB group experienced relapse during the follow-up period, no patient in the LTBI or non-TB groups developed TB. IGRA and chest X-ray, followed by chest CT for those IGRA positive or with suspicious X-ray findings, appears to be an effective means of TB contact screening and infection prevention.     

A case report of a 24-year-old male with a large hemorrhagic pericardiai effusion

Although bloody pericardial effusion often suggests neoplasia,such an event is not rare in tuberculosis (TB),especially in those countries with a high TB disease burden.Meanwhile,TB accounts for 50％ and greater than 90％ of large pericardial effusions in human immunodeficiency virus (HIV)-negative and HIV-positive patients,respectively.Here we report a case of a 24-year-old HIV-negative male who presented with fever and hemorrhagic pericardial effusion.The patient was given presumptive anti-TB treatment before diagnosis was established.Eventually the patient responded well to the anti-TB treatment at the last follow-up and the diagnosis was confirmed by aspirated pericardial fluid culture on LowensteinJensen (LJ) medium.     

Nine- to Twelve-Month Anti-Tuberculosis Treatment Is Associated with a Lower Recurrence Rate than 6–9-Month Treatment in Human Immunodeficiency Virus-Infected Patients: A Retrospective Population-Based Cohort Study in Taiwan

Background

Human immunodeficiency virus (HIV)-infected patients are at an increased risk of tuberculosis (TB) and its recurrence following completion of anti-TB treatment. We investigated whether extending anti-TB treatment to 9 months or longer reduces TB recurrence.

Methods

HIV-infected patients who were diagnosed with pulmonary TB between 1997 and 2009 and who received anti-TB treatment for a duration between 5.5 and 12.5 months were identified from the National Health Insurance Research Database in Taiwan. Those who received any non-fluoroquinolone second-line anti-TB drug for >28 days were excluded. Factors associated with TB recurrence within 2 years after completion of anti-TB treatment were explored using Cox regression analysis. Sensitivity analysis was performed for a subpopulation fulfilling strict diagnostic criteria for HIV infection.

Results

TB recurrence was observed in 18 (3.5%) of 508 HIV-infected patients. The recurrence rate declined from 5.4% to 1.0% after the implementation of directly observed therapy, short course (DOTS) in 2006 (p = 0.014). The recurrence rate was 5.9%, 5.2%, and 1.6% in patients who received anti-TB treatment for <195, 195–270, and >270 days, respectively (p = 0.066). Cox regression analysis revealed that TB diagnosed in the DOTS era (hazard ratio [HR]: 0.18 [0.04–0.77]) and anti-TB treatment for >270 days (HR: 0.24 [0.06–0.89]) were associated with a reduced risk of TB recurrence. Sensitivity analysis of 449 selected patients revealed that anti-TB treatment for >270 days was a significant factor.

Conclusion

In Taiwan, the 2-year TB recurrence rate in HIV-infected patients declined after implementation of DOTS. The risk of TB recurrence in HIV-infected patients can be further reduced by extending anti-TB treatment to 9–12.5 months.     

A case report of a 24-year-old male with a large hemorrhagic pericardial effusion

Although bloody pericardial effusion often suggests neoplasia, such an event is not rare in tuberculosis (TB), especially in those countries with a high TB disease burden. Meanwhile, TB accounts for 50% and greater than 90% of large pericardial effusions in human immunodeficiency virus (HIV)-negative and HIV-positive patients, respectively. Here we report a case of a 24-year-old HIV-negative male who presented with fever and hemorrhagic pericardial effusion. The patient was given presumptive anti-TB treatment before diagnosis was established. Eventually the patient responded well to the anti-TB treatment at the last follow-up and the diagnosis was confirmed by aspirated pericardial fluid culture on Lowenstein-Jensen (LJ) medium.     

纳米材料在结核病诊疗中的应用

结核病是由结核分枝杆菌引起的慢性感染性疾病,经过呼吸道感染后侵犯机体器官,严重威胁全球公共卫生。传统结核诊疗手段存在诊断效率低、易误诊漏诊、易产生耐药、治疗效果和患者依从性差等瓶颈问题,亟需开发快速、准确的结核即时诊断（POC）方法和安全、高效的结核治疗方案,切实解决结核防治难题。本文总结了纳米材料在结核病诊疗领域的研究进展及应用前景,旨在为开发新一代安全、快速、有效的结核病诊疗方法提供参考。     

Transmission of MDR and XDR Tuberculosis in Shanghai,China

Background

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are global health problems. We sought to determine the characteristics, prevalence, and relative frequency of transmission of MDR and XDR TB in Shanghai, one of the largest cities in Asia.

Methods

TB is diagnosed in district TB hospitals in Shanghai, China. Drug susceptibility testing for first-line drugs was performed for all culture positive TB cases, and tests for second-line drugs were performed for MDR cases. VNTR-7 and VNTR-16 were used to genotype the strains, and prior treatment history and treatment outcomes were determined for each patient.

Results

There were 4,379 culture positive TB cases diagnosed with drug susceptibility test results available during March 2004 through November 2007. 247 (5.6%) were infected with a MDR strain of M. tuberculosis and 11 (6.3%) of the 175 MDR patients whose isolate was tested for susceptibility to second-line drugs, were XDR. More than half of the patients with MDR and XDR were newly diagnosed and had no prior history of TB treatment. Nearly 57% of the patients with MDR were successfully treated.

Discussion

Transmission of MDR and XDR strains is a serious problem in Shanghai. While a history of prior anti-TB treatment indicates which individuals may have acquired MDR or XDR TB, it does not accurately predict which TB patients have disease caused by transmission of MDR and XDR strains. Therefore, universal drug susceptibility testing is recommended for new and retreatment TB cases.     

Cotrimoxazole Prophylaxis and Tuberculosis Risk among People Living with HIV

Objectives

Many randomized and cohort studies have reported a survival benefit with cotrimoxazole prophylaxis without detecting a difference in tuberculosis (TB) incidence by cotrimoxazole status. However, several in vitro studies have reported that cotrimoxazole possesses anti-TB activity. We sought to compare TB incidence and TB diagnostic yield by cotrimoxazole use among participants in a well characterized cohort of HIV-infected adults living in a high TB prevalence region.

Methods

We analyzed prospective data from a long-term longitudinal cohort of adults receiving HIV care and TB investigations in Soweto, South Africa. Using longitudinal analysis, we compared total and laboratory confirmed TB incidence by cotrimoxazole status as well as all-cause mortality. In addition, we compared TB culture results by cotrimoxazole status.

Results

In a multivariable analysis, adjusted for sex, body mass index, WHO clinical stage, time-updated CD4 count, and antiretroviral therapy status, we observed an association between cotrimoxazole and an increase in TB incidence (hazard ratio 1.7, 95% CI: 1.2, 2.2). However, when restricted to laboratory-confirmed TB, there was no association between cotrimoxazole and TB incidence (hazard ratio: 0.97, 95% CI: 0.39, 2.4). In TB cases, we found no difference in the proportion of positive sputum cultures or days to culture positivity by cotrimoxazole status. Cotrimoxazole was associated with a reduction in mortality.

Conclusions

In this cohort with a mortality benefit from cotrimoxazole, we found an increased risk of all TB among individuals using cotrimoxazole, likely a result of residual confounding, but no association between use of cotrimoxazole and laboratory-confirmed TB. Cotrimoxazole did not compromise TB diagnosis.     

Culture Conversion Rate at 2 Months of Treatment According to Diagnostic Methods among Patients with Culture-Positive Pulmonary Tuberculosis

Introduction

The culture-negative conversion rate of sputum after 2 months of treatment in patients with pulmonary tuberculosis (TB) is used as a reliable surrogate marker for relapse after completion of treatment. We hypothesized that culture conversion of sputum at 2 months of anti-TB treatment and the time to culture conversion are different among pulmonary TB patients who are diagnosed using different methods.

Methods

Culture-confirmed pulmonary TB patients who were diagnosed between 1 January, 2011 and 31 December, 2012 were classified into three groups based on the diagnostic method that prompted treatment initiation: positive acid-fast bacilli (AFB) staining of sputum (smear-positive group), negative AFB staining, but Mycobacterium tuberculosis was cultured from sputum (culture-positive group), and positive AFB staining, positive polymerase chain reaction (PCR) for M. tuberculosis, or culture of M. tuberculosis from a bronchoscopic specimen (bronchoscopy group). Rates of negative mycobacterial culture conversion at 2 months of anti-TB treatment and the time to negative culture conversion of sputum were compared among the three groups.

Results

A total of 203 patients with culture-confirmed pulmonary TB were included in the final analysis. TB patients in the culture-positive group (94.1%) and the bronchoscopy group (97.6%) showed a higher culture conversion rate at 2 months of treatment than those in the smear-positive group (78.7%, P = 0.001). Additionally, the time to culture conversion was longer in the smear-positive group (median, 40 days) than in the culture-positive (median, 19 days; P = 0.009) and bronchoscopy groups (median, 29 days; P = 0.004).

Conclusions

The higher culture conversion rate at 2 months and the shorter time to culture conversion among pulmonary TB patients with a negative AFB smear suggests the feasibility of shortening treatment duration and isolation in these patients.     

Anti-Tuberculosis Drug Resistance among New and Previously Treated Sputum Smear-Positive Tuberculosis Patients in Uganda: Results of the First National Survey

Background

Multidrug resistant and extensively drug resistant tuberculosis (TB) have become major threats to control of tuberculosis globally. The rates of anti-TB drug resistance in Uganda are not known. We conducted a national drug resistance survey to investigate the levels and patterns of resistance to first and second line anti-TB drugs among new and previously treated sputum smear-positive TB cases.

Methods

Sputum samples were collected from a nationally representative sample of new and previously treated sputum smear-positive TB patients registered at TB diagnostic centers during December 2009 to February 2011 using a weighted cluster sampling method. Culture and drug susceptibility testing was performed at the national TB reference laboratory.

Results

A total of 1537 patients (1397 new and 140 previously treated) were enrolled in the survey from 44 health facilities. HIV test result and complete drug susceptibility testing (DST) results were available for 1524 (96.8%) and 1325 (85.9%) patients, respectively. Of the 1209 isolates from new cases, resistance to any anti-TB drug was 10.3%, 5% were resistant to isoniazid, 1.9% to rifampicin, and 1.4% were multi drug resistant. Among the 116 isolates from previously treated cases, the prevalence of resistance was 25.9%, 23.3%, 12.1% and 12.1% respectively. Of the 1524 patients who had HIV testing 469 (30.7%) tested positive. There was no association between anti-TB drug resistance (including MDR) and HIV infection.

Conclusion

The prevalence of anti-TB drug resistance among new patients in Uganda is low relative to WHO estimates. The higher levels of MDR-TB (12.1%) and resistance to any drug (25.3%) among previously treated patients raises concerns about the quality of directly observed therapy (DOT) and adherence to treatment. This calls for strengthening existing TB control measures, especially DOT, routine DST among the previously treated TB patients or periodic drug resistance surveys, to prevent and monitor development and transmission of drug resistant TB.     

Functional and phenotypic changes in monocytes from patients with tuberculosis are reversed with treatment

Alterations of monocyte/macrophages have been reported in patients with tuberculosis (TB), but their significance is poorly understood. Blood mononuclear cells from patients with different clinical forms of TB, at various times of anti-TB treatment, and healthy tuberculin positive individuals, were double-stained for CD14 plus CD206, TLR-2, IFN-gammaR1, CD40, HLA-DR, CD36 and CD163, and analyzed by flow cytometry. Monocytes were infected with Mycobacterium tuberculosis H37Rv and 24h later the phenotype, induction of necrosis and apoptosis and production of tumor necrosis factor TNFalpha, interleukin (IL)-10 and IL-12p40 were determined. TB patients presented higher percentage of CD14+ cells but lower percentage of CD14+DR+ and CD14+CD36+ cells. Expression of CD14, HLA-DR and CD36 was decreased in TB patients. Normal percentages and expression were restored during anti-TB treatment. Monocytes from TB patients underwent necrosis and apoptosis after M. tuberculosis infection, whereas monocytes from healthy controls exhibited only apoptosis. Anti-TB treatment reverted necrosis. There were no differences between the various clinical forms of TB. In vitro M. tuberculosis infection decreased expression of the membrane molecules studied. HLA-DR and CD36 inhibition correlated with induction of apoptosis. Restoration of monocyte alterations during anti-TB treatment suggests that such alterations may be caused by the high M. tuberculosis load present during active disease.     

Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts’ body weight, metabolic processing of the drug, malabsorption and/or drug–drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen’s physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.     

定西市2007—2010年外出务工人员肺结核线索调査情况分析

目的为了了解外出务工人群的结核病疫情状况,进一步加强对这部分人群结核病的控制工作。方法利用大多外出务工人员春节前集中返乡与家人团聚的时机,对有咳嗽、咳痰超过3周等可疑肺结核病症状者进行摸底调查和造册登记,并由县(区)疾控中心组织免费检查,对确诊患者进行免费抗结核治疗。结果 4年中调查返乡务工人员102万余人次,有可疑肺结核症状者占2.56%,共确诊活动性肺结核患者346例,其中涂阳108例,初治涂阴238例,男女之比为2.15∶1,以青壮年人群为主,20～39岁占73.99%;年均涂阳和活动性肺结核登记率分别为10.59/10万和33.92/10万,涂阳比例为31.21%,其中初治涂阳比例为95.37%。结论外出务工人员是结核病的高发人群,应加强外出务工人员的结核病防治工作,利用外出务工人员春节集中返乡的有利时机开展肺结核病线索调查是主动发现病人的有效方法。     

Access to Bacteriologic-Based Diagnosis in Smear Positive Retreatment Tuberculosis Patients in Rural China: A Cross-Sectional Study in Three Geographic Varied Provinces

Objective

To determine factors influencing the utilization and accessibility to bacteriologic-based tuberculosis (TB) diagnosis among sputum smear positive (SS+) retreatment TB patients, and to develop strategies for improving the case detection rate of MDR-TB in rural China.

Study Design and Setting

A cross-sectional study of SS+ TB retreatment patients was conducted in eight counties from three provinces with different implementation period and strategy of MDR-TB program in China. Demographic and socioeconomic parameters were collected by self-reporting questionnaires. Sputum samples were collected and cultured by the laboratory of county-designated TB clinics and delivered to prefectural Centers for Disease Prevention and Control (CDC) labs for DST with 4 first-line anti-TB drugs.

Results

Among the 196 SS+ retreatment patients, 61.22% received culture tests during current treatment. Patients from more developed regions (OR = 24.0 and 3.6, 95% CI: 8.6–67.3 and 1.1–11.6), with better socio-economic status (OR = 3. 8, 95% CI: 1.3–10.7), who had multiple previous anti-TB treatments (OR = 5.0, 95% CI: 1.6–15.9), and who failed in the most recent anti-TB treatment (OR = 2.6, 95% CI: 1.0–6.4) were more likely to receive culture tests. The percentage of isolates resistant to any of first-line anti-TB drugs and MDR-TB were 50.0% (95% CI: 39.8%-60.2%) and 30.4% (95% CI: 21.0%-39.8%) respectively.

Conclusions

Retreatment SS+ TB patients, high risk MDR-TB population, had poor utilization of access to bacteriologic-based TB diagnosis, which is far from optimal. The next step of anti-TB strategy should be focused on how to make bacteriological-based diagnosis cheaper, safer and more maneuverable, and how to assure the DST-guided treatment for these high-risk TB patients.     

Clinical and epidemiological profiles of individuals with drug-resistant tuberculosis

Drug-resistant tuberculosis (TB) is a growing global threat. Approximately 450,000 people developed multidrug-resistant TB worldwide in 2012 and an estimated 170,000 people died from the disease. This paper describes the sociodemographic, clinical-epidemiological and bacteriological aspects of TB and correlates these features with the distribution of anti-TB drug resistance. Mycobacterium tuberculosis (MT) cultures and drug susceptibility testing were performed according to the BACTEC MGIT 960 method. The results demonstrated that MT strains from individuals who received treatment for TB and people who were infected with human immunodeficiency virus were more resistant to TB drugs compared to other individuals (p < 0.05). Approximately half of the individuals received supervised treatment, but most drug-resistant cases were positive for pulmonary TB and exhibited positive acid-fast bacilli smears, which are complicating factors for TB control programs. Primary healthcare is the ideal level for early disease detection, but tertiary healthcare is the most common entry point for patients into the system. These factors require special attention from healthcare managers and professionals to effectively control and monitor the spread of TB drug-resistant cases.     

Prevalence of pulmonary tuberculosis (PTB) among people living with HIV/AIDS (PLWHA) in Keffi and its environs

Coinfection with HIV and Mycobacterium tuberculosis is known to be a lethal combination especially with its attendant mortality and morbidity. The need to have a baseline data in an environment like Keffi with a HIV/AIDS prevalence of 38.6% necessitated this study. Three hundred and ninety people living with HIV/AIDS (PLWHA) were screened for pulmonary tuberculosis. Results of this study showed 16.7% prevalence of coinfection in the population. Gender-related prevalence of coinfection was 19.4% and 14.4% among males and females respectively (P>0.05). Age-related prevalence of coinfection was least among respondents of age below 20 years (13.3%) and highest among those of age above 40 years (20.2%) (P>0.05). Even though statistically insignificant by both parameters, these findings are of public health significance. There is therefore an urgent need for immediate intervention to allow for early TB diagnosis, institution of anti-TB treatment and provision of prophylaxis against TB among TB-negative PLWHA.     

Factors associated with anti-tuberculosis medication adverse effects: a case-control study in Lima, Peru

Background

Long-term exposure to anti-tuberculosis medication increases risk of adverse drug reactions and toxicity. The objective of this investigation was to determine factors associated with anti-tuberculosis adverse drug reactions in Lima, Peru, with special emphasis on MDR-TB medication, HIV infection, diabetes, age and tobacco use.

Methodology and Results

A case-control study was performed using information from Peruvian TB Programme. A case was defined as having reported an anti-TB adverse drug reaction during 2005–2010 with appropriate notification on clinical records. Controls were defined as not having reported a side effect, receiving anti-TB therapy during the same time that the case had appeared. Crude, and age- and sex-adjusted models were calculated using odds ratios (OR) and 95% confidence intervals (95%CI). A multivariable model was created to look for independent factors associated with side effect from anti-TB therapy. A total of 720 patients (144 cases and 576 controls) were analyzed. In our multivariable model, age, especially those over 40 years (OR = 3.93; 95%CI: 1.65–9.35), overweight/obesity (OR = 2.13; 95%CI: 1.17–3.89), anemia (OR = 2.10; IC95%: 1.13–3.92), MDR-TB medication (OR = 11.1; 95%CI: 6.29–19.6), and smoking (OR = 2.00; 95%CI: 1.03–3.87) were independently associated with adverse drug reactions.

Conclusions

Old age, anemia, MDR-TB medication, overweight/obesity status, and smoking history are independent risk factors associated with anti-tuberculosis adverse drug reactions. Patients with these risk factors should be monitored during the anti-TB therapy. A comprehensive clinical history and additional medical exams, including hematocrit and HIV-ELISA, might be useful to identify these patients.     

A case of strongyloidiasis accompanied by duodenal ulcer]

A 58-year-old chronic alcoholism patient, who complained of epigastric discomfort, nausea, and frequent loose stool was diagnosed as strongyloidiasis accompanied by duodenal ulcer. The symptoms first appeared two years ago and aggravated during the recent 3 months, and he lost 4 kg of his body weight. Stool examination revealed rhabditoid nematode larvae, which were confirmed as those of Strongyloides stercoralis after cultivation of them to filariform larvae. At duodenoscopy, duodenal ulcer was found. The patient was treated with albendazole (200 mg, bid, for 14 days) for strongyloidiasis and with colloidal bismuth sulfate (240 mg, bid, for 6 weeks) for duodenal ulcer. After the medication, the symptoms of loose stool and epigastric discomfort were much improved and he was discharged with no clinical problems. This is an interesting case which suggests that S. stercoralis infection could be related with ulceration of the duodenal mucosa.     

A review of medicinal plant of Middle East and North Africa (MENA) region as source in tuberculosis drug discovery

Tuberculosis (TB) is a disease that affects one-third of the world’s population. Although currently available TB drugs have many side effects, such as nausea, headache and gastrointestinal discomfort, no new anti-TB drugs have been produced in the past 30 years. Therefore, the discovery of a new anti-TB agent with minimal or no side effects is urgently needed. Many previous works have reported the effects of medicinal plants against Mycobacterium tuberculosis (MTB). However, none have focused on medicinal plants from the Middle Eastern and North African (MENA) region. This review highlights the effects of medicinal plants from the MENA region on TB. Medicinal plants from the MENA region have been successfully used as traditional medicine and first aid against TB related problems. A total of 184 plants species representing 73 families were studied. Amongst these species, 93 species contained more active compounds with strong anti-MTB activity (crude extracts and/or bioactive compounds with activities of 0–100 µg/ml). The extract of Inula helenium, Khaya senegalensis, Premna odorata and Rosmarinus officinalis presented the strongest anti-MTB activity. In addition, Boswellia papyrifera (Del) Hochst olibanum, Eucalyptus camaldulensis Dehnh leaves (river red gum), Nigella sativa (black cumin) seeds and genus Cymbopogon exhibited anti-TB activity. The most potent bioactive compounds included alantolactone, octyl acetate, 1,8-cineole, thymoquinone, piperitone, α- verbenol, citral b and α-pinene. These compounds affect the permeability of microbial plasma membranes, thus kill the mycobacterium spp. As a conclusion, plant species collected from the MENA region are potential sources of novel drugs against TB.     

Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion

Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.     

Adherence to Tuberculosis Therapy among Patients Receiving Home-Based Directly Observed Treatment: Evidence from the United Republic of Tanzania

Background

Non-adherence to tuberculosis (TB) treatment is the leading contributor to the selection of drug-resistant strains of Mycobacterium tuberculosis and subsequent treatment failure. Tanzania introduced a TB Patient Centred Treatment (PCT) approach which gives new TB patients the choice between home-based treatment supervised by a treatment supporter of their own choice, and health facility–based treatment observed by a medical professional. The aim of this study was to assess the extent and determinants of adherence to anti-TB therapy in patients opting for home-based treatment under the novel PCT approach.

Methods

In this cross-sectional study, the primary outcome was the percentage of patients adherent to TB therapy as detected by the presence of isoniazid in urine (IsoScreen assay). The primary analysis followed a non-inferiority approach in which adherence could not be lower than 75%. Logistic regression was used to examine the influence of potentially predictive factors.

Results

A total of 651 new TB patients were included. Of these, 645 (99.1%) provided urine for testing and 617 patients (95.7%; 90%CI 94.3–96.9) showed a positive result. This result was statistically non-inferior to the postulated adherence level of 75% (p<0.001).

Conclusions

Adherence to TB therapy under home-based Directly Observed Treatment can be ensured in programmatic settings. A reliable supply of medication and the careful selection of treatment supporters, who preferably live very close to the patient, are crucial success factors. Finally, we recommend a cohort study to assess the rate of adherence throughout the full course of TB treatment.