Do We Need to Detect Isoniazid Resistance in Addition to Rifampicin Resistance in Diagnostic Tests for Tuberculosis?

Background

Multidrug-resistant tuberculosis (MDR-TB) is resistant to both rifampicin (RIF) and isoniazid (INH). Whereas many TB diagnostics detect RIF-resistance, few detect INH-monoresistance, which is common and may increase risk of acquired MDR-TB. Whether inclusion of INH-resistance in a first-line rapid test for TB would have an important impact on MDR-TB rates remains uncertain.

Methods

We developed a transmission model to evaluate three tests in a population similar to that of India: a rapid molecular test for TB, the same test plus RIF-resistance detection (“TB+RIF”), and detection of RIF and INH-resistance (“TB+RIF/INH”). Our primary outcome was the prevalence of INH-resistant and MDR-TB at ten years.

Results

Compared to the TB test alone and assuming treatment of all diagnosed MDR cases, the TB+RIF test reduced the prevalence of MDR-TB among all TB cases from 5.5% to 3.8% (30.6% reduction, 95% uncertainty range, UR: 17–54%). Despite using liberal assumptions about the impact of INH-monoresistance on treatment outcomes and MDR-TB acquisition, expansion from TB+RIF to TB+RIF/INH lowered this prevalence only from 3.8% to 3.6% further (4% reduction, 95% UR: 3–7%) and INH-monoresistant TB from 15.8% to 15.1% (4% reduction, 95% UR: (-8)-19%).

Conclusion

When added to a rapid test for TB plus RIF-resistance, detection of INH-resistance has minimal impact on transmission of TB, MDR-TB, and INH-monoresistant TB.     

Profile and Treatment Outcomes of Tuberculosis in the Elderly in Southeastern Nigeria, 2011–2012

Background

The demographic transition and increasing life expectancy in Africa has lead to a rising elderly population. In Nigeria, little is known about the profile of and treatment outcomes of tuberculosis (TB) in the elderly.

Methods

Retrospective cohort study of adult TB patients treated between January 2011 and December 2012 in two large health facilities in Nigeria. The demographic, clinical and treatment outcomes of patients aged 60 and older were compared with those aged 15 to 59 years.

Results

Elderly (≥60 years) TB patients accounted for 12.7% of all (1668) adult TB enrolled. Elderly patients had a higher proportion of men compared to non-elderly (64.2% vs 56.8%; p = 0.043); but a lower proportion of smear-positive TB at baseline (40.7% vs 65.8%; p<0.001). A higher proportion of elderly patients failed to smear convert after the intensive phase of treatment (23.7% vs 19.8%; p = 0.06), and overall elderly patients had lower treatment success rates (68.9% vs 77.1%; p = 0.009). Unsuccessful outcomes were mainly due to higher default and deaths in the elderly. The risk factors for unsuccessful outcomes in the elderly were: extrapulmonary TB case (adjusted odds ratio (aOR) 10.9; 95% confidence interval (CI) 1.1–108), and HIV co-infection (aOR 3.6; CI 1.1–11.7).

Conclusions

Treatment outcomes of elderly TB patients were inferior to non-elderly adults with higher death and default rates being implicated. With the rising elderly population, specific strategies are needed to quickly address TB management in the elderly in resource-limited settings.     

Linkage of Presumptive Multidrug Resistant Tuberculosis (MDR-TB) Patients to Diagnostic and Treatment Services in Cambodia

Setting

National Tuberculosis Programme, Cambodia.

Objective

In a cohort of TB patients, to ascertain the proportion of patients who fulfil the criteria for presumptive MDR-TB, assess whether they underwent investigation for MDR-TB, and the results of the culture and drug susceptibility testing (DST).

Methods

A cross sectional record review of TB patients registered for treatment between July-December 2011.

Results

Of 19,236 TB patients registered, 409 (2%) fulfilled the criteria of presumptive MDR-TB; of these, 187 (46%) were examined for culture. This proportion was higher among relapse, failure, return after default (RAD) and non-converters at 3 months of new smear positive TB patients (>60%) as compared to non-converters at 2 months of new TB cases (<20%). Nearly two thirds (n = 113) of the samples were culture positive; of these, three-fourth (n = 85) grew Mycobacterium tuberculosis complex (MTBc) and one-fourth (n = 28) grew non-tuberculous Mycobacteria. DST results were available for 96% of the MTBc isolates. Overall, 21 patients were diagnosed as MDR-TB (all diagnosed among retreatment TB cases and none from non-converters) and all of them were initiated on MDR-TB treatment.

Conclusion

There is a need to strengthen mechanisms for linking patients with presumptive MDR-TB to culture centers. The policy of testing non-converters for culture and DST needs to be reviewed.     

Is IP-10 a Better Biomarker for Active and Latent Tuberculosis in Children than IFNγ?

Background

The blood based interferon-gamma release assays (IGRA) for the diagnosis of tuberculosis do not discriminate between active TB disease and latent TB infection (LTBI). The search for distinguishing biomarkers therefore continues, as the accurate diagnosis of tuberculosis is particularly challenging in children. IFN-γ-inducible protein 10 (IP-10/CXCL10) has recently been evaluated as a marker for active TB in adults with promising results.

Aim

To investigate this new biomarker for active TB and LTBI in paediatrics.

Method

We measured IP-10 levels using ELISA in supernatants of whole blood samples stimulated with TB-specific-antigens and negative control antigen.

Results

IP-10 is produced in high levels following mycobacterial antigen stimulation in active TB (n = 17) and LTBI (n = 16) compared to controls (n = 16) and to IFN-γ. The baseline levels of IP-10 are increased in active TB and in LTBI, but there is no significant difference of stimulated levels of IP-10 between active TB and LTBI.

Conclusions

IP-10 is a biomarker for tuberculosis in children. However like IFNγ, IP-10 also does not distinguish between active TB and LTBI.     

Patterns of Treatment Interruption among Patients with Multidrug-Resistant TB (MDR TB) and Association with Interim and Final Treatment Outcomes

Background

The reasons that patients with multidrug-resistant tuberculosis (MDR TB) miss treatment are multi-factorial and complex. Identifying patterns of treatment interruption that predict poor outcomes can be used to target program activities aiming to improve treatment adherence.

Objective

To characterize patterns of treatment interruption among MDR TB patients and determine the association between patterns and treatment outcomes.

Methods

Retrospective analysis of MDR TB patients. A treatment interruption was defined as any time that a patient missed a prescribed dose of treatment for at least 1 day but for a period of less than 2 consecutive months. Patients were characterized by the number, length and variability of interruptions, variability of time between interruptions, and percent of missed doses. Final treatment outcome was dichotomized as a successful (cured or completed) or poor outcome (defaulted, failed, or died). Risk ratios were calculated to determine the association between characteristics of treatment interruption and treatment outcomes. All analyses were conducted in 6 month treatment intervals.

Results

Only 7.0% of 583 patients completed treatment without interruption. Of the remaining 542 patients, the median time to the first interruption was 2 ½ months (70 days). In multivariate analysis, patients who had longer interruptions with sporadic variability during the 6–12 month or the 12–18 month treatment period had a significantly increased risk for poor outcomes compared to patients who had short, regular interruptions (RR_adj 4.37, 95% CI 1.2–15.8;  = 0.03 and RR_adj 3.38, 95% CI 1.6–7.1; p = 0.001, respectively). In addition, missing 10% or more of the prescribed doses during any 6 month period in the initial 18 months of therapy significantly increased the risk for poor outcomes (RR_adj range 1.55–2.35; p-value range 0.01–0.005).

Conclusion

Patients that miss more consecutive days of treatment with sporadic interruption patterns or a greater proportion of treatment are at an increased risk for poor treatment outcomes.     

Soluble Markers of the Toll-Like Receptor 4 Pathway Differentiate between Active and Latent Tuberculosis and Are Associated with Treatment Responses

Background

Biomarkers to differentiate between active tuberculosis (TB) and latent TB infection (LTBI) and to monitor treatment responses are requested to complement TB diagnostics and control, particularly in patients with multi-drug resistant TB. We have studied soluble markers of the Toll-like-receptor 4 (TLR-4) pathway in various stages of TB disease and during anti-TB treatment.

Methods

Plasma samples from patients with culture confirmed drug-sensitive TB (n = 19) were collected before and after 2, 8 and 24 weeks of efficient anti-TB treatment and in a LTBI group (n = 6). Soluble (s) CD14 and myeloid differentiation-2 (MD-2) were analyzed by the Enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) was analyzed by the Limulus Amebocyte Lysate colorimetric assay. Nonparametric statistics were applied.

Results

Plasma levels of sCD14 (p<0.001), MD-2 (p = 0.036) and LPS (p = 0.069) were elevated at baseline in patients with untreated active TB compared to the LTBI group. MD-2 concentrations decreased after 2 weeks of treatment (p = 0.011), while LPS levels decreased after 8 weeks (p = 0.005). In contrast, sCD14 levels increased after 2 weeks (p = 0.047) with a subsequent modest decrease throughout the treatment period. There was no significant difference in concentrations of any of these markers between patients with pulmonary and extrapulmonary TB or between patients with or without symptoms.

Conclusion

Our data suggest that plasma levels of LPS, MD-2 and sCD14 can discriminate between active TB and LTBI. A decline in LPS and MD-2 concentrations was associated with response to anti-TB treatment. The clinical potential of these soluble TLR-4 pathway proteins needs to be further explored.     

Socio-Demographic and Clinical Differences in Subjects with Tuberculosis with and without Diabetes Mellitus in Brazil – A Multivariate Analysis

Background

Several studies have evaluated the relationship between diabetes mellitus (DM) and tuberculosis (TB), but the nature of this relationship is not fully understood. TB incidence may be influenced by immunosuppression from DM, but this association may be confounded by other clinical and socioeconomic factors. We aimed to assess socio-demographic and clinical differences in TB patients with and without DM.

Methods

Using the Brazilian national surveillance system (SINAN), we compared 1,797 subjects with TB and DM with 29,275 subjects diagnosed with TB only in 2009. We performed multivariate analysis to identify factors associated with the presence of DM among TB patients.

Results

Subjects with TB – DM were older; have initial positive sputum smear test (OR = 1.42, 95% CI 1.26–1.60), and were more likely to die from TB (OR = 1.44, 95% CI 1.03–2.01). They were less likely to have been institutionalized [in prison, shelter, orphanage, psychiatric hospital (OR = 0.74, 95% CI 0.60–0.93)]; developed extra pulmonary TB (OR = 0.62, 95% CI 0.51–0.75) and to return to TB treatment after abandonment (OR = 0.66, 95% CI 0.51–0.86).

Conclusions

Prevalence of NCD continues to rise in developing countries, especially with the rise of elderly population, the prevention and treatment of infectious diseases will be urgent. DM and TB represent a critical intersection between communicable and non-communicable diseases in these countries and the effect of DM on TB incidence and outcomes provide numerous opportunities for collaboration and management of these complex diseases in the national public health programs.     

Beneficial Effect of Isoniazid Preventive Therapy and Antiretroviral Therapy on the Incidence of Tuberculosis in People Living with HIV in Ethiopia

Background

IPT with or without concomitant administration of ART is a proven intervention to prevent tuberculosis among PLHIV. However, there are few data on the routine implementation of this intervention and its effectiveness in settings with limited resources.

Objectives

To measure the level of uptake and effectiveness of IPT in reducing tuberculosis incidence in a cohort of PLHIV enrolled into HIV care between 2007 and 2010 in five hospitals in southern Ethiopia.

Methods

A retrospective cohort analysis of electronic patient database was done. The independent effects of no intervention, “IPT-only,” “IPT-before-ART,” “IPT-and-ART started simultaneously,” “ART-only,” and “IPT-after-ART” on TB incidence were measured. Cox-proportional hazards regression was used to assess association of treatment categories with TB incidence.

Results

Of 7,097 patients, 867 were excluded because they were transferred-in; a further 823 (12%) were excluded from the study because they were either identified to have TB through screening (292 patients) or were on TB treatment (531). Among the remaining 5,407 patients observed, IPT had been initiated for 39% of eligible patients. Children, male sex, advanced disease, and those in Pre-ART were less likely to be initiated on IPT. The overall TB incidence was 2.6 per 100 person-years. As compared to those with no intervention, use of “IPT-only” (aHR = 0.36, 95% CI = 0.19–0.66) and “ART-only” (aHR = 0.32, 95% CI = 0.24–0.43) were associated with significant reduction in TB incidence rate. Combining ART and IPT had a more profound effect. Starting IPT-before-ART (aHR = 0.18, 95% CI = 0.08–0.42) or simultaneously with ART (aHR = 0.20, 95% CI = 0.10–0.42) provided further reduction of TB at ∼80%.

Conclusions

IPT was found to be effective in reducing TB incidence, independently and with concomitant ART, under programme conditions in resource-limited settings. The level of IPT provision and effectiveness in reducing TB was encouraging in the study setting. Scaling up and strengthening IPT service in addition to ART can have beneficial effect in reducing TB burden among PLHIV in settings with high TB/HIV burden.     

Randomized Clinical Trial of Thrice-Weekly 4-Month Moxifloxacin or Gatifloxacin Containing Regimens in the Treatment of New Sputum Positive Pulmonary Tuberculosis Patients

Background

Shortening tuberculosis (TB) treatment duration is a research priority. This paper presents data from a prematurely terminated randomized clinical trial, of 4-month moxifloxacin or gatifloxacin regimens, in South India.

Methods

Newly diagnosed, sputum-positive HIV-negative pulmonary TB patients were randomly allocated to receive gatifloxacin or moxifloxacin, along with isoniazid and rifampicin for 4 months with pyrazinamide for first 2 months (G or M) or isoniazid and rifampicin for 6 months with ethambutol and pyrazinamide for first 2 months (C). All regimens were administered thrice-weekly. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post-treatment. The Data and Safety Monitoring Board recommended termination of the trial due to high TB recurrence rates in the G and M regimens.

Results

Of 416 patients in intent-to-treat analysis, 6 (5%) of 124, 2 (2%) of 110 and 2 (2%) of 137 patients with drug-susceptible TB in the G, M and C arms respectively had unfavorable response at the end of treatment; during the next 24 months, 17 (15%) of 115, 11 (11%) of 104 and 8 (6%) of 132 patients respectively, had TB recurrence. Of 38 drug-resistant patients 1 of 8 and 3 of 26 in the G and C arms respectively had unfavourable response at the end of treatment; and TB recurrence occurred in 2 of 7 and 2 of 23 patients, respectively. The differences in TB recurrence rates between the G and C arms was statistically significant (p = 0.02). Gastro-intestinal symptoms occurred in 23%, 22% and 9% of patients in the G, M and C arms respectively, but most reactions were mild and manageable with symptomatic measures; 1% required regimen modification.

Conclusions

4-month thrice-weekly regimens of gatifloxacin or moxifloxacin with isoniazid, rifampicin and pyrazinamide, were inferior to standard 6-month treatment, in patients with newly diagnosed sputum positive pulmonary TB.

Trial Registration

Clinical Trials Registry of India CTRI/2012/10/003060     

Opportunities for Tuberculosis Diagnosis and Prevention among Persons Living with HIV: A Cross-Sectional Study of Policies and Practices at Four Large Ryan White Program-Funded HIV Clinics

Objective

We describe the frequency and attributes of tuberculosis testing and treatment at four publicly-funded HIV clinics.

Methods

We abstracted medical records from a random sample of 600 HIV-infected patients having at least one clinic visit in 2009 at four clinics in New York and Los Angeles Metropolitan Statistical areas. We described testing and treatment for tuberculosis infection (TBI), 2008–2010, and estimated adjusted odds ratios (aORs). We interviewed key informants and described clinic policies and practices.

Results

Of 600 patients, 500 were eligible for testing, and 393 (79%) were tested 2008–2010; 107 (21%) did not receive at least one tuberculin skin test or interferon gamma release assay. Results were positive in 20 (5%) patients, negative in 357 (91%), and unknown in 16 (4%). Fourteen (70%) of 20 patients with TBI initiated treatment at the clinics; only three were documented to have completed treatment. Three hundred twenty three (54%) patients had chest radiography, 346 (58%) had tuberculosis symptom screening, and three had tuberculosis disease (117 per 100,000 person-years, 95% confidence interval (CI) = 101–165). Adjusting for site, non-Hispanic ethnicity (aOR = 4.9, 95% CI = 2.6–9.5), and employment (aOR = 1.9, 95% CI = 1.0–3.4) were associated with TBI testing; female gender (aOR = 2.0, 95% CI = 1.4–3.3), non-black race (aOR = 1.7, 95% CI = 1.3–2.5), and unemployment (aOR = 1.5, 95% CI = 1.1–2.1) were associated with chest radiography. Clinics evaluated TBI testing performance annually and identified challenges to TB prevention.

Conclusions

Study clinics routinely tested patients for TBI, but did not always document treatment. In a population with a high TB rate, ensuring treatment of TBI may enhance TB prevention.     

Treatment Outcomes in Tuberculosis Patients with Diabetes: A Polytomous Analysis Using Brazilian Surveillance System

Background

The impact of non-communicable diseases on tuberculosis incidence has received significant attention. It has been suggested that the risk of tuberculosis is higher among subjects with diabetes and these subjects also has poor TB treatment outcomes.This study was aimed at assessing the socio-demographic and clinical factors that may influence different outcome of TB in patients with DM (TB-DM) identified in the Brazilian national database from 2001 to 2011.

Methods

TB-DM cases reported in the Brazilian information system were identified and compared.Covariates associated with the outcomes of interest (cure, default, deaths, and development of TB MDR) were included in a hierarchical regression model.

Results

TB-DM cases increased from 380/100,000/year in 2001 to 6,150/100,000/year in 2011. Some of the main associations found are pointed. The odds of default was higher among those in the age group 20–39 years (OR = 2.07, 95%CI 1.32–3.24); alcoholics (OR = 2.17, 95%CI 1.86–2.54), and HIV/AIDS (OR = 2.16, 95%CI 1.70–2.74);positive monitoring smear (OR = 1.94, 95%CI 1.55–2.43); prior default (OR = 5.41, 95%CI 4.47–6.54), and unknown type of treatment (OR = 3.33, 95%CI 1.54–7.22). The odds of death was greater for subjects ≥60 years old (OR = 2.74, 95%CI 1.74–4.29); institutionalized in shelter (OR = 2.69, 95%CI 1.07–6.77); alcoholics (OR = 2.70, 95%CI 2.27–3.22); HIV/AIDS (OR = 2.87, 95%CI 2.13–3.86); pulmonary+extrapulmonary TB (OR = 2.49, 95%CI 1.79–3.46); with unknown type of treatment (OR = 14.12, 95%CI 7.04–28.32).Development of MDR TB was more related to relapse (OR = 9.60, 95%CI 6.07–15.14);previous default (OR = 17.13, 95%CI 9.58–30.63); and transfer of treatment center (OR = 7.87, 95%CI 4.74–13.07).

Conclusions

Older subjects and those with comorbidities and with a previous treatment of TB had poorest outcomes. TB control program in Brazil will need to expand efforts to focus on treatment of TB-DM patients to improve their cure rates in order to achieve the goals of tuberculosis elimination.     

Month 2 Culture Status and Treatment Duration as Predictors of Tuberculosis Relapse Risk in a Meta-Regression Model

Background

New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.

Objective

The goal of the present study was to infer the required duration of these treatments.

Method

A meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect.

Results

The model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for ≥5 months.

Conclusions

This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.     

Impact of Xpert MTB/RIF Testing on Tuberculosis Management and Outcomes in Hospitalized Patients in Uganda

Rationale

The clinical impact of Xpert MTB/RIF for tuberculosis (TB) diagnosis in high HIV-prevalence settings is unknown.

Objective

To determine the diagnostic accuracy and impact of Xpert MTB/RIF among high-risk TB suspects.

Methods

We prospectively enrolled consecutive, hospitalized, Ugandan TB suspects in two phases: baseline phase in which Xpert MTB/RIF results were not reported to clinicians and an implementation phase in which results were reported. We determined the diagnostic accuracy of Xpert MTB/RIF in reference to culture (solid and liquid) and compared patient outcomes by study phase.

Results

477 patients were included (baseline phase 287, implementation phase 190). Xpert MTB/RIF had high sensitivity (187/237, 79%, 95% CI: 73–84%) and specificity (190/199, 96%, 95% CI: 92–98%) for culture-positive TB overall, but sensitivity was lower (34/81, 42%, 95% CI: 31–54%) among smear-negative TB cases. Xpert MTB/RIF reduced median days-to-TB detection for all TB cases (1 [IQR 0–26] vs. 0 [IQR 0–1], p<0.001), and for smear-negative TB (35 [IQR 22–55] vs. 22 [IQR 0–33], p = 0.001). However, median days-to-TB treatment was similar for all TB cases (1 [IQR 0–5] vs. 0 [IQR 0–2], p = 0.06) and for smear-negative TB (7 [IQR 3–53] vs. 6 [IQR 1–61], p = 0.78). Two-month mortality was also similar between study phases among 252 TB cases (17% vs. 14%, difference +3%, 95% CI: −21% to +27%, p = 0.80), and among 87 smear-negative TB cases (28% vs. 22%, difference +6%, 95% CI: −34 to +46%, p = 0.77).

Conclusions

Xpert MTB/RIF facilitated more accurate and earlier TB diagnosis, leading to a higher proportion of TB suspects with a confirmed TB diagnosis prior to hospital discharge in a high HIV/low MDR TB prevalence setting. However, our study did not detect a decrease in two-month mortality following implementation of Xpert MTB/RIF possibly because of insufficient powering, differences in empiric TB treatment rates, and disease severity between study phases.     

Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis

Rationale

Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients.

Methods

Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv.

Results

All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy''s criteria for serious liver injury.

Conclusions

The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01225640","term_id":"NCT01225640"}}NCT01225640     

The Impact of Antiretroviral Therapy on Mortality in HIV Positive People during Tuberculosis Treatment: A Systematic Review and Meta-Analysis

Objective

To quantify the impact of antiretroviral therapy (ART) on mortality in HIV-positive people during tuberculosis (TB) treatment.

Design

We conducted a systematic literature review and meta-analysis. Studies published from 1996 through February 15, 2013, were identified by searching electronic resources (Pubmed and Embase) and conference books, manual searches of references, and expert consultation. Pooled estimates for the outcome of interest were acquired using random effects meta-analysis.

Subjects

The study population included individuals receiving ART before or during TB treatment.

Main Outcome Measures

Main outcome measures were: (i) TB-case fatality ratio (CFR), defined as the proportion of individuals dying during TB treatment and, if mortality in HIV-positive people not on ART was also reported, (ii) the relative risk of death during TB treatment by ART status.

Results

Twenty-one studies were included in the systematic review. Random effects pooled meta-analysis estimated the CFR between 8% and 14% (pooled estimate 11%). Among HIV-positive TB cases, those receiving ART had a reduction in mortality during TB treatment of between 44% and 71% (RR = 0.42, 95%CI: 0.29–0.56).

Conclusion

Starting ART before or during TB therapy reduces the risk of death during TB treatment by around three-fifths in clinical settings. National programmes should continue to expand coverage of ART for HIV positive in order to control the dual epidemic.     

Clinical Deterioration during Antitubercular Treatment at a District Hospital in South Africa: The Importance of Drug Resistance and AIDS Defining Illnesses

Background

Clinical deterioration on drug therapy for tuberculosis is a common cause of hospital admission in Africa. Potential causes for clinical deterioration in settings of high HIV-1 prevalence include drug resistant Mycobacterium tuberculosis (M.tb), co-morbid illnesses, poor adherence to therapy, tuberculosis associated-immune reconstitution inflammatory syndrome (TB-IRIS) and subtherapeutic antitubercular drug levels. It is important to derive a rapid diagnostic work-up to determine the cause of clinical deterioration as well as specific management to prevent further clinical deterioration and death. We undertook this study among tuberculosis (TB) patients referred to an adult district level hospital situated in a high HIV-1 prevalence setting to determine the frequency, reasons and outcome for such clinical deterioration.

Method

A prospective observational study conducted during the first quarter of 2007. We defined clinical deterioration as clinical worsening or failure to stabilise after 14 or more days of antitubercular treatment, resulting in hospital referral. We collected data on tuberculosis diagnosis and treatment, HIV-1 status and antiretroviral treatment, and investigated reasons for clinical deterioration as well as outcome.

Results

During this period, 352 TB patients met inclusion criteria; 296 were admitted to hospital accounting for 17% of total medical admissions (n = 1755). Eighty three percent of TB patients (291/352) were known to be HIV-1 co-infected with a median CD4 count of 89cells/mm³ (IQR 38–157). Mortality among TB patients admitted to hospital was 16% (n = 48). The median duration of hospital admission was 9.5 days (IQR 4–18), longer than routine in this setting (4 days). Among patients in whom HIV-1 status was known (n = 324), 72% of TB patients (n = 232) had an additional illness to tuberculosis; new AIDS defining illnesses (n = 80) were the most frequent additional illnesses (n = 208) in HIV-1 co-infected patients (n = 291). Rifampin-resistant M.tb (n = 41), TB-IRIS (n = 51) and drug resistant bacterial infections (n = 12) were found in 12%, 14% and 3.4% of the 352 cases, respectively.

Interpretation

In our setting, new AIDS defining illnesses, drug resistant M.tb and other drug resistant bacteria are important reasons for clinical deterioration in HIV-1 co-infected patients receiving antitubercular treatment. HIV-1 co-infected patients may be at increased risk of acquiring nosocomial drug resistant pathogens because profound immune suppression results in co-morbid illnesses that require prolonged inpatient admissions. Routine infection control is essential and needs to be strengthened in our setting.     

Outcomes of Bronchial Artery Embolization for Life-Threatening Hemoptysis Secondary to Tuberculosis

Objective

To appraise the immediate and long-term outcomes of bronchial arterial embolization for life-threatening hemoptysis secondary to tuberculosis.

Methods

112 patients with life-threatening hemoptysis due to tuberculosis underwent bronchial artery embolization from January 2004 to February 2014. Life-threatening hemoptysis was defined as expectoration of at least 400 ml of blood in 24 hour. The median follow-up is 20 months, ranging from 2 to 52 months.

Results

The hemoptysis control rate was 86.6% at 14 days, 84.8% at 30 days, 78.6% at 240 days, 75.9% at 360 days, respectively. None of these characteristics, including gender, age and tuberculosis status, was significantly associated with immediate control of bleeding. Patients with active tuberculosis had a significantly longer recurrence-free duration than did patients with inactive tuberculosis (P = 0.040), which was further confirmed by Cox regression hazards model (P = 0.046). There was no spinal cord complication or mortality related to bronchial artery embolization. The most common complication was transient chest pain.

Conclusion

Bronchial arterial embolization is an effective and safe technique in the management of life-threatening hemoptysis secondary to tuberculosis. Active tuberculosis may be associated with a lower rate of recurrence of hemoptysis.     

The Impact of Isoniazid Resistance on the Treatment Outcomes of Smear Positive Re-Treatment Tuberculosis Patients in the State of Andhra Pradesh,India

Background

Multi drug resistant and rifampicin resistant TB patients in India are treated with the World Health Organization (WHO) recommended standardized treatment regimens but no guidelines are available for the management of isoniazid (INH) resistant TB patients. There have been concerns that the standard eight-month retreatment regimen being used in India (2H₃R₃Z₃E₃S₃/1H₃R₃Z₃E₃/5H₃R₃E₃; H-Isoniazid; R-Rifampicin; Z-Pyrazinamide; E-Ethambutol; S-Streptomycin) may be inadequate to treat INH resistant TB cases and leads to poor treatment outcomes. We aimed to assess if INH resistance is associated with unfavorable treatment outcomes (death, default, failure and transferred out) among a cohort of smear positive retreatment TB patients registered in three districts of Andhra Pradesh, India.

Methods

We conducted a retrospective record review of all smear positive retreatment TB patients without rifampicin resistance registered during April–December 2011.

Results

Of 1,947 TB patients, 1,127 (58%) were tested with LPA—50 (4%) were rifampicin resistant, 933 (84%) were sensitive to INH and rifampicin and 144 (12%) were INH resistant. Of 144 INH resistant cases, 64 (44%) had poor treatment outcomes (25 (17%) default, 22 (15%) death, 12 (8%) failure and 5 (3%) transfer out) as compared to 287 (31%) among INH sensitive cases [aRR 1.46; 95%CI (1.19–1.78)].

Conclusion

Our study confirms that INH resistance is independently associated with unfavorable treatment outcomes among smear positive retreatment TB patients, indicating that the current treatment regimen may be inadequate. These findings call for an urgent need for randomized controlled trials to discover the most effective treatment regimen for managing INH resistant TB.     

Association of Major Depressive Episode with Negative Outcomes of Tuberculosis Treatment

Background

Pulmonary tuberculosis (TB) persists an important contributor to the burden of diseases in developing countries. TB control success is based on the patient’s compliance to the treatment. Depressive disorders have been negatively associated with compliance of therapeutic schemes for chronic diseases. This study aimed to estimate the significance and magnitude of major depressive episode as a hazard factor for negative outcomes (NO), including abandon or death in patients receiving TB treatment.

Methodology/Principal Findings

A longitudinal study was conducted to evaluate the association of major depressive episode (MDE), as measured by a 5-item version of the Center for Epidemiological Studies Depression Scale (CES-D) with NO to TB treatment. Patients with confirmed TB were enrolled before the start of TB treatment. Baseline measurements included socio-demographic variables as well as the CES-D, which was also applied every month until the end of the treatment. Death and treatment default were assessed monthly. Survivor function (SF) for NO according to MDE status (CES-D≥6) at baseline (MDEb) was estimated. Cox’s Regression was performed for bivariate analyses as well as for the multivariate model. A total of 325 patients accepted to participate in the study, of which 34 where excluded for diagnosis of MDR-TB. NO was observed in 24 patients (8.2%); 109 (37%) presented MDEb. Statistically significant difference was found on the SF of patients with and without MDEb (0.85 vs. 0.96, p-value = 0.002). The hazard ratio for NO, controlled for age, sex, marital status and instruction level was 3.54 (95%CI 1.43–8.75; p-value = 0.006).

Conclusion

The presence of MDE at baseline is associated to NO of TB treatment. Targeting detection and treatment of MDE may improve TB treatment outcomes.     

Vitamin D Deficiency in Medical Patients at a Central Hospital in Malawi: A Comparison with TB Patients from a Previous Study

Objectives

To determine the prevalence of vitamin D deficiency (VDD) in adult medical, non-tuberculous (non-TB) patients. To investigate associations with VDD. To compare the results with a similar study in TB patients at the same hospital.

Design

Cross-sectional sample.

Setting

Central hospital in Malawi.

Participants

Adult non-TB patients (n = 157), inpatients and outpatients.

Outcome Measures

The primary outcome was the prevalence of VDD. Potentially causal associations sought included nutritional status, in/outpatient status, HIV status, anti-retroviral therapy (ART) and, by comparison with a previous study, a diagnosis of tuberculosis (TB).

Results

Hypovitaminosis D (≤75 nmol/L) occurred in 47.8% (75/157) of patients, 16.6% (26/157) of whom had VDD (≤50 nmol/L). None had severe VDD (≤25 nmol/L). VDD was found in 22.8% (23/101) of in-patients and 5.4% (3/56) of out-patients. In univariable analysis in-patient status, ART use and low dietary vitamin D were significant predictors of VDD. VDD was less prevalent than in previously studied TB patients in the same hospital (68/161 = 42%). In multivariate analysis of the combined data set from both studies, having TB (OR 3.61, 95%CI 2.02–6.43) and being an in-patient (OR 2.70, 95%CI 1.46–5.01) were significant independent predictors of VDD.

Conclusions

About half of adult medical patients without TB have suboptimal vitamin D status, which is more common in in-patients. VDD is much more common in TB patients than non-TB patients, even when other variables are controlled for, suggesting that vitamin D deficiency is associated with TB.