Starting Tuberculosis Treatment Research Articles

Contact tracing versus facility-based screening for active TB case finding in rural South Africa: A pragmatic cluster-randomized trial (Kharitode TB).

BackgroundThere is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa.Methods and findingsWe conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83–1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64–1.27; p = 0.78) and 1.23 (95% CI 0.87–1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66–1.37; p = 0.93) and 1.08 (95% CI 0.74–1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82–1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80–1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies.ConclusionsContact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting.Trial registrationClinicalTrials.gov NCT02808507.

Delay in tuberculosis diagnosis and treatment in Amhara state, Ethiopia

BackgroundDelayed presentation is a major problem contributing to the high burden and transmission of tuberculosis (TB) in developing countries. The delay may be due to patient delay if the patient visits health-facility for diagnosis after the onset of symptoms of more than 3 weeks or health system delay if the patient is not diagnosed and treated at the time of the first visit. Ethiopia, where no more than two-thirds of TB cases are detected is no exception. Therefore, the aim of this study was to assess delay in diagnosis of tuberculosis among patients taking anti-TB treatment in North Shoa Zone, Ethiopia.MethodsInstitution based cross-sectional study was conducted from 01 to 30 December 2017. All TB patients who took their treatment in the health facilities of the seven selected districts of North Shoa Zone were included. Data was entered into EPI INFO version 3.5.1 statistical software and transferred into SPSS version 20.0 for further analysis. Bivariate and multivariate analysis was used to identify associated factors for delayed TB diagnosis.ResultsOut of 170 tuberculosis patients included, 162 patients were studied with a response rate of 95.3%. The proportion of tuberculosis patients who had delayed diagnosis was 59.9%. The mean time of health-seeking after developing the symptom of tuberculosis was 7.6 weeks. Tuberculosis patients with extra pulmonary site involvements were about four times more likely to be delayed in seeking health services (OR: 4.00, 95% CI: 1.77–9.03) as compared to patients with pulmonary TB. New patients were about three times more likely to come lately for TB diagnosis (OR: 2.94, 95% CI: 1.26–6.84) as compared to patients who had previous-history of treatment. Patients who had no information about TB before they started TB treatment were also around three times to be delayed (OR: 3.37, 95% CI: 1.43–8.00) as compared to those who had the information.ConclusionsMore than 50% of TB patients reported in health-seeking relatively a longer time. Strengthening the health education activities for the community about tuberculosis and capacity building of the health care provider to increase suspicion of identifying tuberculosis and early diagnosis is crucial.

The shift in tuberculosis timing among people living with HIV in the course of antiretroviral therapy scale-up in Malawi.

IntroductionAlthough the use of antiretroviral therapy (ART) reduces HIV‐associated tuberculosis (TB), patients living with HIV receiving ART remain at a higher risk of developing TB compared to those without HIV. We investigated the incidence of TB and the proportion of HIV‐associated TB cases among patients living with HIV who are receiving ART.MethodsThe study used TB registration and ART programme data collected between 2008 and 2017 from an integrated, public clinic in urban Lilongwe, Malawi. ART initiation was based on either WHO clinical staging or CD4 cell count. The CD4 thresholds for ART initiation eligibility was initially 250 cells/μL then changed to 350 cells/μL in 2011, 500 cells/μL in 2014 and to universal treatment upon diagnosis from 2016. Using TB registration data, we calculated the proportion of TB/HIV patients who were already on ART when they registered for TB treatment by year of TB registration. ART registration data were used to examine TB incidence by calendar year of ART follow‐up and by time on ART.ResultsThe overall proportion of TB/patients living with HIV who started TB treatment while on ART increased from 21% in 2008 to 81% in 2017 but numbers remained relatively constant at 500 TB cases annually. The overall incidence rate of TB among patients on ART was 1.35/100 person‐years (95% CI 1.28 to 1.42). The incidence of TB by time on ART decreased from 6.4/100 person‐years in the first three months of ART to 0.4/100 person‐years after eight years on ART. TB incidence was highest in the first month on ART. The annual rate of TB among patients on ART rapidly decreased each calendar year and stabilized at 1% after 2013. Although the risk of developing TB decreased with year of ART initiation in univariable analysis, there was no significant association after adjusting for sex, age and reason for ART eligibility.ConclusionsThe decline in TB incidence over calendar years suggests protective effects of early ART initiation. The high TB incidence within the first month of ART highlights the need for more sensitive tools such as X‐ray and GeneXpert to identify patients living with HIV who have clinical and subclinical TB disease at ART initiation.

Mortality in the first six months among HIV-positive and HIV-negative patients empirically treated for tuberculosis

BackgroundEmpirical treatment of tuberculosis (TB) may be necessary in patients with negative or no Xpert MTB/RIF results. In a context with access to Xpert, we assessed mortality in the 6 months after the initial TB consultation among HIV-positive and HIV-negative patients who received empirical TB treatment or TB treatment based on bacteriological confirmation and we compared it with the mortality among those who did not receive TB treatment.MethodsThis prospective cohort study included consecutively adult patients with signs and symptoms of TB attending an outpatient TB clinic in Western Kenya. At the first consultation, patients received a clinical exam and chest X-ray. Sputum was collected for microscopy, Xpert and Mycobacterium tuberculosis complex (MTB) culture. Patients not started on TB treatment were reassessed after 5 days. All patients bacteriologically confirmed (positive Xpert or culture) received TB treatment. Empirical treatment was defined as a decision to start TB treatment without bacteriological confirmation. Patients were reassessed after 6 months.ResultsOf 606 patients included, 344/606 (56.8%) were women. Median age was 35 years [Interquartile Range (IQR):27–47] and 398/594 (67.0%) were HIV-positive. In total, 196/606 (32.3%) patients were Xpert- or culture-positive and 331/606 (54.6%) started TB treatment. Overall, 100/398 (25.1%) HIV-positive and 31/196 (15.8%) HIV-negative patients received empirical treatment. Mortality in the 6 months following the first consultation was 1.6 and 0.8/100 patient-months among HIV-positive and HIV-negative patients respectively. In the multivariate analyses, TB treatment - whether empirical or based on bacteriological confirmation- was not associated with increased mortality among HIV-positive patients (aHR:2.51, 95%CI:0.79–7.90 and aHR:1.25, 95%CI:0.37–4.21 respectively). However, HIV-negative patients who received empirical treatment had a higher risk of mortality (aHR:4.85, 95%CI:1.08–21.67) compared to those not started on treatment. HIV-negative patients treated for TB based on bacteriological confirmation did not have a different risk of mortality (aHR:0.77, 95%CI:0.08–7.41).ConclusionsOur findings suggest that in a context with access to Xpert, clinicians should continue using empirical TB treatment in HIV-positive patients with signs and symptoms of TB and negative Xpert results. However, differential diagnoses other than TB should be actively sought before initiating empirical TB treatment, particularly in HIV-negative patients.

Referral and treatment outcomes of tuberculosis patients who crossed the border from Japan to the philippines.

The referral and treatment outcomes of tuberculosis (TB) patients referred from Japan to the Philippines have not yet been systematically reported. This study aimed to describe the cross-border referral process for TB patients referred from Japan to the Philippines. This is a retrospective descriptive review of the referral process between the two countries. The data on the pathways of Filipino patients with TB or latent TB infection initially treated in Japan from 2009 to mid-2018 were summarized. We calculated the proportion of the referred-and-accessed and that of the successfully treated in the health facilities in the Philippines. The Chi-square test or Fisher's exact test was applied to test significant differences between categorical data. Among the 36 Filipino TB patients referred, 83.3% (30 patients) were successful in accessing any of the health facilities. Among these, 28 patients confirmed that they had started TB treatment in the Philippines. Age groups (P = 0.17), gender (P = 0.76), planned place of residence (P = 0.44), bacteriological results (P = 0.81), and TB patient types (P = 0.96) did not show any significant differences in the referred-and-access rate. The treatment success rate among the 23 TB patients (excluding five patients who were still receiving treatment as of writing) was 91.3%. However, only three out of five multidrug-resistant TB patients successfully started treatment. The current cross-border TB patient referral mechanism between Japan and the Philippines indicated successful results. However, it needs to be enhanced by strengthening the mechanism to track referral outcomes systemically.

Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS

BackgroundEarly initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)–infected patients who have tuberculosis reduces mortality among patients with low CD4 counts, but it increases the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS).MethodsWe conducted this randomized, double-blind, placebo-controlled trial to assess whether prophylactic prednisone can safely reduce the incidence of paradoxical tuberculosis-associated IRIS in patients at high risk for the syndrome. We enrolled HIV-infected patients who were initiating ART (and had not previously received ART), had started tuberculosis treatment within 30 days before initiating ART, and had a CD4 count of 100 cells or fewer per microliter. Patients received either prednisone (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) or placebo. The primary end point was the development of tuberculosis-associated IRIS within 12 weeks after initiating ART, as adjudicated by an independent committee.ResultsAmong the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P=0.03). Open-label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P=1.00). Severe infections (acquired immunodeficiency syndrome–defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P=0.23). One case of Kaposi’s sarcoma occurred in the placebo group.ConclusionsPrednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of tuberculosis-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers. (Funded by the European and Developing Countries Clinical Trials Partnership and others; PredART ClinicalTrials.gov number, NCT01924286.)

Health-seeking behaviour and treatment delay in patients with pulmonary tuberculosis in Switzerland: some slip through the net.

To assess the health-seeking behaviour, the patient delay (onset of symptoms to first consultation) and the health system delay (first consultation to start of tuberculosis treatment) among patients with pulmonary tuberculosis (TB) diagnosed in Switzerland, and to assess the predictors of the various types of delay. A survey among pulmonary TB patients was carried out in six cantons, covering 42% of all pulmonary adult TB cases notified in Switzerland. Data were collected by collaborators of the cantonal lung associations in charge of the follow-up of TB patients to investigate treatment seeking behaviour and to establish various delays and its predictors. Predictors of percentiles of delay (median and 75th percentile) were assessed using quantile regression. Among 252 eligible patients, 162 patients could be interviewed. Of these, 20.4% were born in Switzerland. Cough as a symptom was mentioned by 76% of the interviewed patients. Almost half of the 162 patients (46%) consulted first a general practitioner in an ambulatory care setting and 26% approached a hospital first. The median delay between symptom onset and first healthcare contact (patient delay) was 5.2 weeks, which is slightly longer than findings in other low prevalence countries. The interquartile range was 1.6 to 14.2 weeks. The median delay between first consultation in Switzerland and the start of TB treatment (health system delay) was 2 weeks. The interquartile range was 0.6 to 7.1 weeks. There were no clear predictors of patient delay. The main predictors of a longer median health system delay were the presence of fever (1.6 weeks, 95% confidence interval [CI] 0.5 to 2.6 weeks), having visited first a general practitioner or a paediatrician (1 week, 95% CI 0.1 to 1.9 weeks) and having seen three or four doctors before beginning TB treatment (2.9 weeks, 95% CI 0.7 to 5.1 weeks). A clear predictor of a shorter median health system delay was having undergone an X-ray at the first consultation (-2.9 weeks, 95% CI -4.8 to -0.9 weeks). Marginally significant for shorter delay was male sex (-2.6 weeks, 95% CI -5.4 to 0.1 weeks). No predictor of patient delay was found among the variables collected. For one fourth of the patients, the health system delay was longer than 7 weeks. General practitioners are commonly approached first, and they have to consider TB, also for patients not considered at high-risk for TB.

HIV, TB, inflammation and other correlates of serum phosphate: A cross-sectional study

There is little information about serum phosphate levels among patients with pulmonary tuberculosis (TB) and HIV infection. We aimed to assess the role of TB, HIV, inflammation and other correlates on serum phosphate levels. A cross-sectional study was conducted among TB patients and age- and sex-matched non-TB controls. Pulmonary TB patients were categorized as sputum -negative and -positive, based on culture. Age- and sex-matched non-TB controls were randomly selected among neighbours to sputum-positive TB patients. Data on age, sex, alcohol and smoking habits were obtained. HIV status, serum phosphate, and the acute phase reactants C-reactive protein (serum CRP) and α1-acid glycoprotein (serum AGP) were determined. Linear regression analysis was used to identify correlates of serum phosphate. Of 1605 participants, 355 (22.1%) were controls and 1250 (77.9%) TB patients, of which 9.9% and 50.4% were HIV-infected. Serum phosphate was determined before start of TB treatment in 44%, and 1-14 days after start of treatment in 56%. Serum phosphate was up to 0.10mmol/L higher 1-3 days after start of TB treatment, and lowest 4 days after treatment, after which it increased. In multivariable analysis, TB patients had 0.09 (95% CI: 0.05; 0.13) mmol/L higher serum phosphate than controls, and those with HIV had 0.05 (95% CI: 0.01; 0.08) mmol/L higher levels than those without. Smoking was also a positive correlate of serum phosphate, whereas male sex and age were negative correlates. While HIV and TB are associated with higher serum phosphate, our data suggest that TB treatment is followed by transient reductions in serum phosphate, which may reflect hypophosphataemia in some patients.

Evaluation of a medication monitor-based treatment strategy for drug-sensitive tuberculosis patients in China: study protocol for a cluster randomised controlled trial

BackgroundTreatment for drug-sensitive tuberculosis (TB) is taken for at least 6 months and problems with adherence are common. Therefore, there is substantial interest in the possible use of eHealth interventions to support patients to take their treatment. Electronic medication monitors have been shown to improve adherence to TB medication, but the impact on clinical outcomes is unknown. We aim to evaluate the impact of a medication monitor-based treatment strategy for drug-sensitive TB patients on a composite poor outcome measured over 18 months from start of TB treatment.Methods/designWe will conduct an open, pragmatic, cluster randomised superiority trial, with 24 counties/districts in three provinces in China, randomised 1:1 to implement the intervention or standard of care. Adults (aged ≥ 18 years) with a new episode of GeneXpert-positive and rifampicin-sensitive pulmonary TB, who plan to be in the study area for the next 18 months, and will receive daily fixed-dose combination tablets for 6 months of treatment are eligible. The intervention is centred around a medication monitor that holds a 1-month supply of medication and has three key functions: as an audio and visual reminder for patients to take their daily medication; reminds patients of upcoming monthly visit; and records date and time whenever the box is opened. At the monthly follow-up visit, the doctor downloads these data to generate a graphical display of the last month’s adherence record for discussion with the patient and potentially to switch the patient to more intensive management. The primary outcome is a composite poor outcome measured over 18 months from start of TB treatment, defined as either of poor outcome at the end of treatment (death, treatment failure, or loss to follow-up) or subsequent recurrence (culture positive for TB at 12 or 18 months or re-starting TB treatment in the follow-up period). An economic evaluation will also be conducted as part of this study.DiscussionThis trial will assess whether a medication monitor-based treatment strategy can improve clinical outcomes for TB patients. Several trials of other eHealth interventions for TB treatment are ongoing and are summarised in this paper. This trial will provide an important part of the emerging evidence base for the potential of eHealth to improve TB treatment outcomes.Trial registrationThis trial was registered with Current Controlled Trials (identifier: ISRCTN35812455). Registered on May 19, 2016.

Missed opportunities for tuberculosis prevention among patients accessing a UK HIV service.

United Kingdom guidelines recommend screening for and treatment of latent tuberculosis infection (LTBI) in HIV-positive patients at high risk of active tuberculosis (TB) disease, but implementation is suboptimal. We investigated potential missed opportunities to identify and treat LTBI among HIV-positive patients accessing a large HIV outpatient service in London. Case records of all adult patients attending our service for HIV care diagnosed with active TB between 2011 and 2015 were reviewed to determine whether they met criteria for LTBI screening and whether screening was undertaken. Twenty-five patients were treated for TB. Of 15 (60%) patients who started TB treatment ≥6 months after HIV diagnosis, 14 (93%) met UK guideline-recommended criteria for LTBI screening and treatment; only one (7%) had been screened for LTBI. Eight of these 15 (53%) patients had additional risk factors for TB which are not reflected in current UK guidelines. Of 15 patients treated for TB ≥6 months after diagnosis of HIV, 14 (93%) had not been screened for LTBI, suggesting missed opportunities for TB prevention. People living with HIV may benefit from a broader approach to LTBI screening which takes into account additional recognised TB risk factors and ongoing TB exposure.

The utility of repeat Xpert MTB/RIF testing to diagnose tuberculosis in HIV-positive adults with initial negative result.

Background: Amongst HIV-positive adults in South Africa with initial negative Xpert results, we compared the yield from repeating Xpert MTB/RIF ("Xpert") on sputum to guideline-recommended investigation for tuberculosis (TB). Methods: A systematic sample of adults attending for HIV care were enrolled in a cohort exploring TB investigation pathways. This substudy was restricted to those at highest risk of TB (CD4<200 cells/mm 3 or unknown) who had a negative initial Xpert result. At attendance for the Xpert result, a repeat sputum sample was stored, and further investigations facilitated per national guidelines. Participants were reviewed monthly, with reinvestigation if indicated, for at least three months, when sputum and blood were cultured for mycobacteria, and the stored sputum tested using Xpert. We defined TB as "confirmed" if Xpert, line probe assay or Mycobacterium tuberculosis culture within six months of enrolment were positive, and "clinical" if TB treatment was started without microbiological confirmation. Results: Amongst 227 participants with an initial negative Xpert result (63% female, median age 37 years, median CD4 count 100 cells/mm 3), 28 (12%) participants had TB diagnosed during study follow-up (16 confirmed, 12 clinical); stored sputum tested positive on Xpert in 5/227 (2%). Amongst 27 participants who started TB treatment, the basis was bacteriological confirmation 11/27 (41%); compatible imaging 11/27 (41%); compatible symptoms 2/27 (7%); and unknown 3/27 (11%). Conclusions: Amongst HIV-positive individuals at high risk of active TB with a negative Xpert result, further investigation using appropriate diagnostic modalities is more likely to lead to TB treatment than immediately repeating sputum for Xpert. TB diagnostic tests with improved sensitivity are needed.

Differences in response to antiretroviral therapy in HIV-positive patients being treated for tuberculosis in Eastern Europe, Western Europe and Latin America

BackgroundEfavirenz-based antiretroviral therapy (ART) regimens are preferred for treatment of adult HIV-positive patients co-infected with tuberculosis (HIV/TB). Few studies have compared outcomes among HIV/TB patients treated with efavirenz or non-efavirenz containing regimens.MethodsHIV-positive patients aged ≥16 years with a diagnosis of tuberculosis recruited to the TB:HIV study between Jan 1, 2011, and Dec 31, 2013 in 19 countries in Eastern Europe (EE), Western Europe (WE), and Latin America (LA) who received ART concomitantly with TB treatment were included. Patients either received efavirenz-containing ART starting between 15 days prior to, during, or within 90 days after starting tuberculosis treatment, (efavirenz group), or other ART regimens (non-efavirenz group). Patients who started ART more than 90 days after initiation of TB treatment, or who experienced ART interruption of more than 15 days during TB treatment were excluded. We describe rates and factors associated with death, virological suppression, and loss to follow up at 12 months using univariate, multivariate Cox, and marginal structural models to compare the two groups of patients.ResultsOf 965 patients (647 receiving efavirenz-containing ART, and 318 a non-efavirenz regimen) 50% were from EE, 28% from WE, and 22% from LA. Among those not receiving efavirenz-containing ART, regimens mainly contained a ritonavir-boosted protease inhibitor (57%), or raltegravir (22%). At 12 months 1.4% of patients in WE had died, compared to 20% in EE: rates of virological suppression ranged from 21% in EE to 61% in WE. After adjusting for potential confounders, rates of death (adjusted Hazard Ratio; aHR, 95%CI: 1.13, 0.72–1.78), virological suppression (aHR, 95%CI: 0.97, 0.76–1.22), and loss to follow up (aHR, 95%CI: 1.17, 0.81–1.67), were similar in patients treated with efavirenz and non-efavirenz containing ART regimens.ConclusionIn this large, prospective cohort, the response to ART varied significantly across geographical regions, whereas the ART regimen (efavirenz or non-efavirenz containing) did not impact on the proportion of patients who were virologically-suppressed, lost to follow up or dead at 12 months.

Hyperglycaemia is inversely correlated with live M. bovis BCG-specific CD4+ T cell responses in Tanzanian adults with latent or active tuberculosis.

IntroductionThe rising prevalence of Diabetes mellitus (DM) in high TB‐endemic countries may adversely affect sustainability of TB control since DM constitutes a risk factor for development of active tuberculosis (TB). The impact of DM on TB specific adaptive immune responses remains poorly addressed, particularly in people living in Sub‐Saharan countries. We performed a functional characterization of TB specific cellular immune response in Tanzanian subjects with active or latent Mycobacterium tuberculosis (Mtb) infection stratified by their diabetic status.MethodsHIV negative active TB patients (≥18 years) with Xpert MTB/RIF positive pulmonary TB were included before starting TB treatment in Dar es Salaam, Tanzania between April and December 2013. HIV negative healthy controls latently infected with TB but without past TB history were also included. Active and latent TB patients were stratified in two groups according to their diabetic status. Peripheral Blood Mononuclear cells were stimulated with either live M. bovis BCG or Mtb‐specific peptide pools and analyzed by intracellular cytokine staining and polychromatic flow cytometry.ResultsOur results show a lower frequency of IFN‐γ CD4+ T cells in patients with active TB and DM compared to patients with active TB only after live M. bovis BCG (p = 0.04) but not after Mtb peptide pools re‐stimulation. Irrespective of TB status, level of glycaemia is selectively inversely correlated with IFN‐γ and TNF‐α CD4+ T cell production (p = 0.02 and p = 0.03) after live M. bovis BCG stimulation.ConclusionsThese results support the hypothesis that hyperglycaemia negatively impacts antigen processing and/or presentation of whole mycobacteria delaying secretion of key cytokines involved in TB immunity.

An assessment of the isoniazid preventive therapy programme for children in a busy primary healthcare clinic in Nelson Mandela Bay Health District, Eastern Cape Province, South Africa.

Tuberculosis (TB) is a significant contributor to the international and national burden of disease. Global estimates suggest that there were 10.4 million new cases of TB in 2015. Children accounted for ~10% of these cases, although in South Africa (SA) this figure is thought to be higher. Despite clear evidence that isoniazid preventive therapy (IPT) can reduce the risk of progression from TB infection to disease in TB contacts, IPT has been poorly implemented in SA national TB control programmes. To determine current practices regarding the identification and management of child contacts (&lt;5 years of age) at a primary care clinic in the Nelson Mandela Bay Health District, Eastern Cape Province, SA. A cross-sectional descriptive study was conducted using a retrospective record review of infectious TB index patients aged ≥15 years. Folders of index patients with bacteriologically confirmed pulmonary TB, who started TB treatment between 21 October 2011 and 28 February 2014, were included. A sample size of 246 child contacts was required to obtain adequate power. A 95% confidence interval (CI) was used to determine statistically significant results. Index patient records (N=491) were assessed and 261 child contacts identified. In a high percentage of index patient folders (87.5%; n=430), contacts were documented, although only 0.53 child contacts were identified per index patient. Of the 261 child contacts identified, 184 (70.5%) were screened for TB, 2 started TB treatment and 108/184 (58.7%) started IPT. For the remaining 74 (40.2%) children, there was no documentation of further management. Only 4 (3.7%) children completed the 24-week IPT course. Male patients reported fewer child contacts (χ2 =7.31; p=0.01; odds ratio (OR) 0.6; 95% CI 0.42 - 0.86) and were less likely to bring contacts for screening (χ2=8.98; p=0.003; OR 0.41; 95% CI 0.24 - 0.72). Retreatment index patients were also less likely to bring contacts for screening (χ2=6.37; p=0.01; OR 0.45; 95% CI 0.25 - 0.81) and those who were screened were less likely to initiate IPT (χ2=4.05; p=0.04; OR 0.54; 95% CI 0.3 - 0.95). Despite contacts being well documented, child contacts were poorly identified. The fall-out of children at each step from identification to IPT completion was unacceptably high. Contacts of male patients and retreatment index patients were at greater risk of poor management. Recommendations to improve IPT delivery at national and local level include a review of the national IPT guidelines, considering the relative success of shorter courses of TB prophylaxis, the use of standardised IPT stationery, staff training and the involvement of community health workers in contact management.

Infection of multiple Mycobacterium tuberculosis strains among tuberculosis/human immunodeficiency virus co-infected patients: A molecular study in Myanmar.

Background:Appearance of Mycobacterium tuberculosis (MTB) in the sputum of a tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected patient under treatment may indicate either failure or new infection. This study aims to evaluate whether TB treatment failure among TB/HIV co-infected patients is a real failure.Methods:A prospective cohort study was conducted among 566 TB/HIV co-infected patients who started TB treatment in 12 townships in the upper Myanmar. Among the 566 participants, 16 (2.8%) resulted in treatment failure. We performed a molecular study using mycobacterial interspersed repetitive-unit-variable number of tandem repeat (MIRU-VNTR) genotyping for them. The MIRU-VNTR profiles were analyzed using the web server, MIRU-VNTRplus. All data were entered into EpiData version 3.1 and analyzed using R version 3.4.3.Results:Among 16 failure patients, seven had incomplete laboratory results. Of the nine remaining patients, nobody had exactly the same MIRU-VNTR pattern between the initial and final isolates. Four patients had persistent East-African Indian (EAI) lineages and one each had persistent Beijing lineage, changing from EAI to Beijing, from Beijing to EAI, NEW-1 to Beijing, and NEW-1 to X strains. Female patients have significantly larger genetic difference between MTB of the paired isolates than male patients (t-test, P = 0.04).Conclusion:Thus, in our study patients, infection of multiple MTB strains is a possible cause of TB treatment failure. Explanation for the association between gender and distance of genotypes from the initial to subsequent MTB infection needs further studies.

Gaps in the child tuberculosis care cascade in 32 rural communities in Uganda and Kenya

BackgroundReducing tuberculosis (TB) deaths among children requires a better understanding of the gaps in the care cascade from TB diagnosis to treatment completion. We sought to assess the child TB care cascade in 32 rural communities in Uganda and Kenya using programmatic data. MethodsThis is a retrospective cohort study of 160,851 children (ages < 15 years) living in 12 rural communities in Kenya and 22 in Uganda. We reviewed national TB registries from health centers in and adjacent to the 32 communities, and we included all child TB cases recorded from January 1, 2013 to June 30, 2016. To calculate the first step of the child TB care cascade, the number of children with active TB, we divided the number of reported child TB diagnoses by the 2015 World Health Organization (WHO) child TB case detection ratio for Africa of 27%. The remaining components of the Child TB Care Cascade were ascertained directly from the TB registries and included: diagnosed with TB, started on TB treatment, and completed TB treatment. ResultsIn two and a half years, a total of 42 TB cases were reported among children living in 32 rural communities in Uganda and Kenya. 40% of the children were co-infected with HIV. Using the WHO child TB case detection ratio, we calculated that 155 children in this cohort had TB during the study period. Of those 155 children, 42 were diagnosed and linked to TB care, 42 were started on treatment, and 31 completed treatment. Among the 42 children who started TB treatment, reasons for treatment non-completion were loss to follow up (7%), death (5%), and un-recorded reasons (5%). Overall, 20% (31/155) of children completed the child TB care cascade. ConclusionIn 32 rural communities in Uganda and Kenya, we estimate that 80% of children with TB fell off the care cascade. Reducing morbidity and mortality from child TB requires strengthening of the child TB care cascade from diagnosis through treatment completion.

IP-10 Kinetics in the First Week of Therapy are Strongly Associated with Bacteriological Confirmation of Tuberculosis Diagnosis in HIV-Infected Patients

Simple effective tools to monitor the long treatment of tuberculosis (TB) are lacking. Easily measured host derived biomarkers have been identified but need to be validated in larger studies and different population groups. Here we investigate the early response in IP-10 levels (between day 0 and day 7 of TB therapy) to identify bacteriological status at diagnosis among 127 HIV-infected patients starting TB treatment. All participants were then classified as responding or not responding to treatment blindly using a previously described IP-10 kinetic algorithm. There were 77 bacteriologically confirmed cases and 41 Xpert MTB/RIF® and culture negative cases. Most participants had a measurable decline in IP-10 during the first 7 days of therapy. Bacteriologically confirmed cases were more likely to have high IP-10 levels at D0 and had a steeper decline than clinically diagnosed cases (mean decline difference 2231 pg/dl, 95% CI: 897–3566, p = 0.0013). Bacteriologically confirmed cases were more likely to have a measurable decline in IP-10 at day 7 than clinically diagnosed cases (48/77 (62.3%) vs 13/41 (31.7%), p < 0.001). This study confirms the association between a decrease in IP-10 levels during the first week of treatment and a bacteriological confirmation at diagnosis in a large cohort of HIV positive patients.

L’issue du traitement, la survie et ses facteurs de risque chez les nouveaux tuberculeux co-infectés par le VIH pendant l’épidémie d’Ebola à Conakry

BackgroundMortality among TB/HIV co-infected patients remains high in Africa. The study aimed to estimate survival and associated factors in a cohort of TB/HIV co-infected patients who started tuberculosis treatment during the Ebola outbreak in Conakry, Guinea. MethodsA prospective cohort study was conducted from April 2014 to December 2015. TB patients with HIV co-infection were enrolled at the University Hospital of Conakry. Survival and risk factors were analyzed according to Kaplan–Meier's method, log-rank test and Cox's regression. ResultsData from 573 patients were analyzed. From these, 86 (15.0%) died before the end of treatment, 52% occurring within eight weeks of treatment onset. Survival at 4, 12 and 24 weeks after the beginning of the TB treatment was 92%, 86% and 83%, respectively. Independent risk factors associated with death were in the cell CD4 <200 cells/mm3 [adjusted hazard ratio (AHR): 2.25; 95% CI (confidence intervals): 1.16–4.37], opportunistic infections other than TB [AHR: 2.89; 95% CI: 1.39–6.02], and comorbidities [AHR: 4.12; 95% CI: 2.10–8.10]. An increase of one unit in hemoglobin [AHR: 0.81; 95% CI: 0.75–0.91] was protective of death. ConclusionTB/HIV co-infected patients had a higher fatality rate during treatment of tuberculosis. Prevention of opportunistic infections, anemia and proper management of tuberculosis treatment in early comorbidities may improve survival for TB/HIV co-infected patients in restoring immune function.

Deaths during tuberculosis treatment among paediatric patients in a large tertiary hospital in Nigeria.

BackgroundDespite availability of effective cure, tuberculosis (TB) remains a leading cause of death in children. In many high-burden countries, childhood TB is underdiagnosed and underreported, and care is often accessed too late, resulting in adverse treatment outcomes. In this study, we examined the time to death and its associated factors among a cohort of children that commenced TB treatment in a large treatment centre in northern Nigeria.MethodsThis is a retrospective cohort study of children that started TB treatment between 2010 and 2014. We determined mortality rates per 100 person-months of treatment, as well as across treatment and calendar periods. We used Cox proportional hazards regression to determine adjusted hazard ratios (aHR) for factors associated with mortality.ResultsAmong 299 children with a median age 4 years and HIV prevalence of 33.4%; 85 (28.4%) died after 1,383 months of follow-up. Overall mortality rate was 6.1 per 100 person-months. Deaths occurred early during treatment and declined from 42.4 per 100 person-months in the 1st week of treatment to 2.2 per 100 person-months after at the 3rd month of treatment. Mortality was highest between October to December period (9.1 per 100 pm) and lowest between July and September (2.8 per 100 pm). Risk factors for mortality included previous TB treatment (aHR 2.04:95%CI;1.09–3.84); HIV infection (aHR 1.66:95%CI;1.02–2.71), having either extra-pulmonary disease (aHR 2.21:95%CI;1.26–3.89) or both pulmonary and extrapulmonary disease (aHR 3.03:95%CI;1.70–5.40).ConclusionsMortality was high and occurred early during treatment in this cohort, likely indicative of poor access to prompt TB diagnosis and treatment. A redoubling of efforts at improving universal health coverage are required to achieve the End TB Strategy target of zero deaths from TB.

Tuberculosis Case Finding With Combined Rapid Point-of-Care Assays (Xpert MTB/RIF and Determine TB LAM) in HIV-Positive Individuals Starting Antiretroviral Therapy in Mozambique.

Tuberculosis is a major health concern in several countries, and effective diagnostic algorithms for use in human immunodeficiency virus (HIV)-positive patients are urgently needed. At prescription of antiretroviral therapy, all patients in 3 Mozambican health centers were screened for tuberculosis, with a combined approach: World Health Organization (WHO) 4-symptom screening (fever, cough, night sweats, and weight loss), a rapid test detecting mycobacterial lipoarabinomannan in urine (Determine TB LAM), and a molecular assay performed on a sputum sample (Xpert MTB/RIF; repeated if first result was negative). Patients with positive LAM or Xpert MTB/RIF results were referred for tuberculosis treatment. Among 972 patients with a complete diagnostic algorithm (58.5% female; median CD4 cell count, 278/μL; WHO HIV stage I, 66.8%), 98 (10.1%) tested positive with Xpert (90, 9.3%) or LAM (34, 3.5%) assays. Compared with a single-test Xpert strategy, dual Xpert tests improved case finding by 21.6%, LAM testing alone improved it by 13.5%, and dual Xpert tests plus LAM testing improved it by 32.4%. Rifampicin resistance in Xpert-positive patients was infrequent (2.5%). Among patients with positive results, 22 of 98 (22.4%) had no symptoms at WHO 4-symptom screening. Patients with tuberculosis diagnosed had significantly lower CD4 cell counts and hemoglobin levels, more advanced WHO stage, and higher HIV RNA levels. Fifteen (15.3%) did not start tuberculosis treatment, mostly owing to rapidly deteriorating clinical conditions or logistical constraints. The median interval between start of the diagnostic algorithm and start of tuberculosis treatment was 7 days. The prevalence of tuberculosis among Mozambican HIV-positive patients starting antiretroviral therapy was 10%, with limited rifampicin resistance. Use of combined point-of-care tests increased case finding, with a short time to treatment. Interventions are needed to remove logistical barriers and prevent presentation in very advanced HIV/tuberculosis disease.