Impact and Cost-Effectiveness of Culture for Diagnosis of Tuberculosis in HIV-Infected Brazilian Adults

Background

Culture of Mycobacterium tuberculosis currently represents the closest “gold standard” for diagnosis of tuberculosis (TB), but operational data are scant on the impact and cost-effectiveness of TB culture for human immunodeficiency (HIV-) infected individuals in resource-limited settings.

Methodology/Principal Findings

We recorded costs, laboratory results, and dates of initiating TB therapy in a centralized TB culture program for HIV-infected patients in Rio de Janeiro, Brazil, constructing a decision-analysis model to estimate the incremental cost-effectiveness of TB culture from the perspective of a public-sector TB control program. Of 217 TB suspects presenting between January 2006 and March 2008, 33 (15%) had culture-confirmed active tuberculosis; 23 (70%) were smear-negative. Among smear-negative, culture-positive patients, 6 (26%) began TB therapy before culture results were available, 11 (48%) began TB therapy after culture result availability, and 6 (26%) did not begin TB therapy within 180 days of presentation. The cost per negative culture was US$17.52 (solid media)–$23.50 (liquid media). Per 1,000 TB suspects and compared with smear alone, TB culture with solid media would avert an estimated eight TB deaths (95% simulation interval [SI]: 4, 15) and 37 disability-adjusted life years (DALYs) (95% SI: 13, 76), at a cost of $36 (95% SI: $25, $50) per TB suspect or $962 (95% SI: $469, $2642) per DALY averted. Replacing solid media with automated liquid culture would avert one further death (95% SI: −1, 4) and eight DALYs (95% SI: −4, 23) at $2751 per DALY (95% SI: $680, dominated). The cost-effectiveness of TB culture was more sensitive to characteristics of the existing TB diagnostic system than to the accuracy or cost of TB culture.

Conclusions/Significance

TB culture is potentially effective and cost-effective for HIV-positive patients in resource-constrained settings. Reliable transmission of culture results to patients and integration with existing systems are essential.     

Rapid Molecular Testing for TB to Guide Respiratory Isolation in the U.S.: A Cost-Benefit Analysis

Background

Respiratory isolation of inpatients during evaluation for TB is a slow and costly process in low-burden settings. Xpert MTB/RIF (Xpert) is a novel molecular test for tuberculosis (TB) that is faster and more sensitive but substantially more expensive than smear microscopy. No previous studies have examined the costs of molecular testing as a replacement for smear microscopy in this setting.

Methods

We conducted an incremental cost–benefit analysis comparing the use of a single negative Xpert versus two negative sputum smears to release consecutive adult inpatients with presumed TB from respiratory isolation at an urban public hospital in the United States. We estimated all health-system costs and patient outcomes related to Xpert implementation, diagnostic evaluation, isolation, hospitalization, and treatment. We performed sensitivity and probabilistic uncertainty analyses to determine at what threshold the Xpert strategy would become cost-saving.

Results

Among a hypothetical cohort of 234 individuals undergoing evaluation for presumed active TB annually, 6.4% had culture-positive TB. Compared to smear microscopy, Xpert reduced isolation bed utilization from an average of 2.7 to 1.4 days per patient, leading to a 48% reduction in total annual isolation bed usage from 632 to 328 bed-days. Xpert saved an average of $2,278 (95% uncertainty range $1582–4570) per admission, or $533,520 per year, compared with smear microscopy.

Conclusions

Molecular testing for TB could provide substantial savings to hospitals in high-income countries by reducing respiratory isolation usage and overall length of stay.     

Can Follow-Up Examination of Tuberculosis Patients Be Simplified? A Study in Chhattisgarh,India

Background

Each follow-up during the course of tuberculosis treatment currently requires two sputum examinations. However, the incremental yield of the second sputum sample during follow-up of different types of tuberculosis patients has never been determined precisely.

Objectives

To assess the incremental yield of the second sputum sample in the follow-up of tuberculosis patients under the Revised National Tuberculosis Control Programme (RNTCP) in Chhattisgarh, India.

Methodology

A record review of tuberculosis (TB) patients registered in 2009 using a structured proforma from two sources, Tuberculosis and Laboratory Register, was undertaken in the six districts of Chhattisgarh, India.

Results

In smear positive cases, of 10,048 follow-up examinations, 45 (0.5%) were found to be smear positive only on the second sputum when the result of the first sample was negative. In smear negative pulmonary and extra pulmonary TB patients, of 6,206 follow-up smear examinations, 11(0.2%) were found to be smear positive.

Conclusions

The incremental yield of a second smear examination was very low, indicating that examination of one sputum sample is enough during follow-up among TB patients. There is insufficient yield to support sputum smear microscopy for monitoring smear negative pulmonary TB and extra pulmonary TB patients. These results indicate that the follow-up smear microscopy can be substantially simplified with favourable resource implications.     

A toolbox for tuberculosis diagnosis: an Indian multicentric study (2006-2008): microbiological results

Background

The aim of this multicentric prospective study in India was to assess the value of several microbiological tools that contribute to the diagnosis of tuberculosis (TB) according to HIV status.

Methods

Standard microbiological tools on individual specimens were analyzed.

Results

Among the 807 patients with active TB, 131 were HIV-infected, 316 HIV-uninfected and 360 had HIV-unknown status. Among the 980 non-active TB subjects, 559 were at low risk and 421 were at high risk of M. tuberculosis (Mtb) exposure. Sensitivity of smear microscopy (SM) was significantly lower in HIV-infected (42.2%) than HIV-uninfected (75.9%) (p = 0.0001) and HIV-unknown pulmonary TB patients (61.4%) (p = 0.004). Specificity was 94.5% in non-TB patients and 100% in health care workers (HCW) and healthy family contacts. Automated liquid culture has significantly higher diagnostic performances than solid culture, measured by sensitivity (74.7% vs. 55.9%) (p = 0.0001) and shorter median time to detection (TTD) (12.0 vs. 34.0 days) (p = 0.0001). Specificity was 100% in HCW and cured-TB patients, but was lower in non-TB patients (89%) due to isolation of Mycobacteria other than tuberculosis (MOTT). TTD by both methods was related to AFB score. Contamination rate was low (1.4%). AccuProbe hybridization technique detected Mtb in almost all culture-positive specimens, but MOTT were found in 4.7% with a significantly higher frequency in HIV-infected (15%) than HIV-uninfected TB patients (0.5%) (p = 0.0007). Pre-test classification significantly increased the diagnostic value of all microbiological tests in pulmonary TB patients (p<0.0001) but to a lesser degree in extrapulmonary TB patients.

Conclusions

Conventional microbiological tools led to results similar to those already described in India special features for HIV-infected TB patients included lower detection by SM and culture. New microbiological assays, such as the automated liquid culture system, showed increased accuracy and speed of detection.     

Serological testing versus other strategies for diagnosis of active tuberculosis in India: a cost-effectiveness analysis

Background

Undiagnosed and misdiagnosed tuberculosis (TB) drives the epidemic in India. Serological (antibody detection) TB tests are not recommended by any agency, but widely used in many countries, including the Indian private sector. The cost and impact of using serology compared with other diagnostic techniques is unknown.

Methods and Findings

Taking a patient cohort conservatively equal to the annual number of serological tests done in India (1.5 million adults suspected of having active TB), we used decision analysis to estimate costs and effectiveness of sputum smear microscopy (US$3.62 for two smears), microscopy plus automated liquid culture (mycobacterium growth indicator tube [MGIT], US$20/test), and serological testing (anda-tb ELISA, US$20/test). Data on test accuracy and costs were obtained from published literature. We adopted the perspective of the Indian TB control sector and an analysis frame of 1 year. Our primary outcome was the incremental cost per disability-adjusted life year (DALY) averted. We performed one-way sensitivity analysis on all model parameters, with multiway sensitivity analysis on variables to which the model was most sensitive.If used instead of sputum microscopy, serology generated an estimated 14,000 more TB diagnoses, but also 121,000 more false-positive diagnoses, 102,000 fewer DALYs averted, and 32,000 more secondary TB cases than microscopy, at approximately four times the incremental cost (US$47.5 million versus US$11.9 million). When added to high-quality sputum smears, MGIT culture was estimated to avert 130,000 incremental DALYs at an incremental cost of US$213 per DALY averted. Serology was dominated by (i.e., more costly and less effective than) MGIT culture and remained less economically favorable than sputum smear or TB culture in one-way and multiway sensitivity analyses.

Conclusions

In India, sputum smear microscopy remains the most cost-effective diagnostic test available for active TB; efforts to increase access to quality-assured microscopy should take priority. In areas where high-quality microscopy exists and resources are sufficient, MGIT culture is more cost-effective than serology as an additional diagnostic test for TB. These data informed a recently published World Health Organization policy statement against serological tests. Please see later in the article for the Editors'' Summary     

High Prevalence of Tuberculosis and Insufficient Case Detection in Two Communities in the Western Cape,South Africa

Background

In South Africa the estimated incidence of all forms of tuberculosis (TB) for 2008 was 960/100000. It was reported that all South Africans lived in districts with Directly Observed Therapy, Short-course. However, the 2011 WHO report indicated South Africa as the only country in the world where the TB incidence is still rising.

Aims

To report the results of a TB prevalence survey and to determine the speed of TB case detection in the study communities.

Methods

In 2005 a TB prevalence survey was done to inform the sample size calculation for the ZAMSTAR (Zambia South Africa TB and AIDS Reduction) trial. It was a cluster survey with clustering by enumeration area; all households were visited within enumeration areas and informed consent obtained from eligible adults. A questionnaire was completed and a sputum sample collected from each adult. Samples were inoculated on both liquid mycobacterium growth indicator tube (MGIT) and Löwenstein-Jensen media. A follow-up HIV prevalence survey was done in 2007.

Results

In Community A, the adjusted prevalence of culture positive TB was 32/1000 (95%CI 25–41/1000) and of smear positive TB 8/1000 (95%CI 5–13/1000). In Community B, the adjusted prevalence of culture positive TB was 24/1000 (95%CI 17–32/1000) and of smear positive TB 9/1000 (95%CI 6–15/1000). In Community A the patient diagnostic rate was 0.38/person-year while in community B it was 0.30/person-year. In both communities the adjusted HIV prevalence was 25% (19–30%).

Discussion

In both communities a higher TB prevalence than national estimates and a low patient diagnostic rate was calculated, suggesting that cases are not detected at a sufficient rate to interrupt transmission. These findings may contribute to the rising TB incidence in South Africa. The TB epidemic should therefore be addressed rapidly and effectively, especially in the presence of the concurrently high HIV prevalence.     

Real-World Efficiency of Pharmacogenetic Screening for Carbamazepine-Induced Severe Cutaneous Adverse Reactions

Objectives

We evaluated the cost and efficiency of routine HLA-B*15∶02 screening to prevent carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (CBZ-SJS/TEN) in Hong Kong.

Methods

Data were extracted from patients who commenced CBZ as the first-ever AED treatment or tested for HLA-B*15∶02 allele in three years before policy implementation (pre-policy: 16 September 2005 to 15 September 2008) and three years after (post-policy: 16 September 2008 to 15 September 2011). Using published unit costs, we estimated the cost of screening by comparing the costs to prevent and treat CBZ-SJS/TEN. We compared the number of person-tests needed and the cost to prevent resultant death with cancer screening programs.

Results

The number of screening tests needed to prevent one case of CBZ-SJS/TEN was 442, and to prevent one resultant death was 1,474 to 8,840. The screening cost was $332 per person, of which 42% was attributed to an additional consultation to review result and prescribe appropriate medication. HLA-B*15∶02 screening expended $146,749 to prevent a case of CBZ-SJS/TEN, and $489,386– $2,934,986 to prevent a resultant death. The corresponding numbers of tests and costs for mammography and Pap smear to prevent death due to breast and cervical cancers were 7,150 and 7,000, and $614,900 and $273,000, respectively. Comparing to the SJS/TEN treatment cost, HLA-B*15∶02 screening would become cost saving if a point-of-care test of less than $37 was available.

Conclusions

HLA-B*15∶02 screening is as efficient as mammography and Pap smear in preventing death. Development of point-of-care testing will vastly improve efficiency.     

A Pilot Study of Short-Duration Sputum Pretreatment Procedures for Optimizing Smear Microscopy for Tuberculosis

Background

Direct sputum smear microscopy for tuberculosis (TB) lacks sensitivity for the detection of acid fast bacilli. Sputum pretreatment procedures may enhance sensitivity. We did a pilot study to compare the diagnostic accuracy and incremental yield of two short-duration (<1 hour) sputum pretreatment procedures to optimize direct smears among patients with suspected TB at a referral hospital in India.

Methodology/Findings

Blinded laboratory comparison of bleach and universal sediment processing (USP) pretreated centrifuged auramine smears to direct Ziehl-Neelsen (ZN) and direct auramine smears and to solid (Loweinstein-Jensen (LJ)) and liquid (BACTEC 460) culture. 178 pulmonary and extrapulmonary TB suspects were prospectively recruited during a one year period. Thirty six (20.2%) were positive by either solid or liquid culture. Direct ZN smear detected 22 of 36 cases and direct auramine smears detected 26 of 36 cases. Bleach and USP centrifugation detected 24 cases each, providing no incremental yield beyond direct smears. When compared to combined culture, pretreated smears were not more sensitive than direct smears (66.6% vs 61.1 (ZN) or 72.2 (auramine)), and were not more specific (92.3% vs 93.0 (ZN) or 97.2 (auramine).

Conclusions/Significance

Short duration sputum pretreatment with bleach and USP centrifugation did not increase yield as compared to direct sputum smears. Further work is needed to confirm this in a larger study and also determine if longer duration pre-treatment might be effective in optimizing smear microscopy for TB.     

Cost Analysis of a Nucleic Acid Amplification Test in the Diagnosis of Pulmonary Tuberculosis at an Urban Hospital with a High Prevalence of TB/HIV

Introduction

The Centers for Disease Control and Prevention has recommended using a nucleic acid amplification test (NAAT) for diagnosing pulmonary tuberculosis (TB) but there is a lack of data on NAAT cost-effectiveness.

Methods

We conducted a prospective cohort study that included all patients with an AFB smear-positive respiratory specimen at Grady Memorial Hospital in Atlanta, GA, USA between January 2002 and June 2008. We determined the sensitivity, specificity, and positive and negative predictive value of a commercially available and FDA-approved NAAT (amplified MTD, Gen-Probe) compared to the gold standard of culture. A cost analysis was performed and included costs related to laboratory tests, hospital charges, anti-TB medications, and contact investigations. Average cost per patient was calculated under two conditions: (1) using a NAAT on all AFB smear-postive respiratory specimens and (2) not using a NAAT. One-way sensitivity analyses were conducted to determine sensitivity of cost difference to reasonable ranges of model inputs.

Results

During a 6 1/2 year study period, there were 1,009 patients with an AFB smear-positive respiratory specimen at our public urban hospital. We found the NAAT to be highly sensitive (99.6%) and specific (99.1%) on AFB smear-positive specimens compared to culture. Overall, the positive predictive value (PPV) of an AFB smear-positive respiratory specimen for culture-confirmed TB was 27%. The PPV of an AFB smear-positive respiratory specimen for culture-confirmed TB was significantly higher for HIV-uninfected persons compared to those who were HIV-seropositive (152/271 [56%] vs. 85/445 [19%]; RR = 2.94, 95% CI 2.36–3.65, p<0.001). The cost savings of using the NAAT was $2,003 per AFB smear-positive case.

Conclusions

Routine use of the NAAT on AFB smear-positive respiratory specimens was highly cost-saving in our setting at a U.S. urban public hospital with a high prevalence of TB and HIV because of the low PPV of an AFB smear for culture-confirmed TB.     

Rapid diagnosis of tuberculosis with the Xpert MTB/RIF assay in high burden countries: a cost-effectiveness analysis

Background

Xpert MTB/RIF (Xpert) is a promising new rapid diagnostic technology for tuberculosis (TB) that has characteristics that suggest large-scale roll-out. However, because the test is expensive, there are concerns among TB program managers and policy makers regarding its affordability for low- and middle-income settings.

Methods and Findings

We estimate the impact of the introduction of Xpert on the costs and cost-effectiveness of TB care using decision analytic modelling, comparing the introduction of Xpert to a base case of smear microscopy and clinical diagnosis in India, South Africa, and Uganda. The introduction of Xpert increases TB case finding in all three settings; from 72%–85% to 95%–99% of the cohort of individuals with suspected TB, compared to the base case. Diagnostic costs (including the costs of testing all individuals with suspected TB) also increase: from US$28–US$49 to US$133–US$146 and US$137–US$151 per TB case detected when Xpert is used “in addition to” and “as a replacement of” smear microscopy, respectively. The incremental cost effectiveness ratios (ICERs) for using Xpert “in addition to” smear microscopy, compared to the base case, range from US$41–$110 per disability adjusted life year (DALY) averted. Likewise the ICERS for using Xpert “as a replacement of” smear microscopy range from US$52–$138 per DALY averted. These ICERs are below the World Health Organization (WHO) willingness to pay threshold.

Conclusions

Our results suggest that Xpert is a cost-effective method of TB diagnosis, compared to a base case of smear microscopy and clinical diagnosis of smear-negative TB in low- and middle-income settings where, with its ability to substantially increase case finding, it has important potential for improving TB diagnosis and control. The extent of cost-effectiveness gain to TB programmes from deploying Xpert is primarily dependent on current TB diagnostic practices. Further work is required during scale-up to validate these findings. Please see later in the article for the Editors'' Summary     

The High Cost of Free Tuberculosis Services: Patient and Household Costs Associated with Tuberculosis Care in Ebonyi State,Nigeria

Objective

Poverty is both a cause and consequence of tuberculosis. The objective of this study is to quantify patient/household costs for an episode of tuberculosis (TB), its relationships with household impoverishment, and the strategies used to cope with the costs by TB patients in a resource-limited high TB/HIV setting.

Methods

A cross-sectional study was conducted in three rural hospitals in southeast Nigeria. Consecutive adults with newly diagnosed pulmonary TB were interviewed to determine the costs each incurred in their care-seeking pathway using a standardised questionnaire. We defined direct costs as out-of-pocket payments, and indirect costs as lost income.

Results

Of 452 patients enrolled, majority were male 55% (249), and rural residents 79% (356), with a mean age of 34 (±11.6) years. Median direct pre-diagnosis/diagnosis cost was $49 per patient. Median direct treatment cost was $36 per patient. Indirect pre-diagnostic and treatment costs were $416, or 79% of total patient costs, $528. The median total cost of TB care per household was $592; corresponding to 37% of median annual household income pre-TB. Most patients reported having to borrow money 212(47%), sell assets 42(9%), or both 144(32%) to cope with the cost of care. Following an episode of TB, household income reduced increasing the proportion of households classified as poor from 54% to 79%. Before TB illness, independent predictors of household poverty were; rural residence (adjusted odds ratio [aOR] 2.8), HIV-positive status (aOR 4.8), and care-seeking at a private facility (aOR 5.1). After TB care, independent determinants of household poverty were; younger age (≤35 years; aOR 2.4), male gender (aOR 2.1), and HIV-positive status (aOR 2.5).

Conclusion

Patient and household costs for TB care are potentially catastrophic even where services are provided free-of-charge. There is an urgent need to implement strategies for TB care that are affordable for the poor.     

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.     

The cost-effectiveness of tuberculosis preventive therapy for HIV-infected individuals in southern India: a trial-based analysis

Background

Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India.

Methods

We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm³, and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH).

Results

Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence.

Conclusions

Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care.     

Comparison of the efficacies of loop-mediated isothermal amplification, fluorescence smear microscopy and culture for the diagnosis of tuberculosis

Background

Despite the advent of novel diagnostic techniques, smear microscopy remains as the most practical test available in resource-limited settings for tuberculosis (TB) diagnosis. Due to the low sensitivity of microscopy and the long time required for culture, feasible and accessible rapid diagnostic methods are urgently needed. Loop-mediated Isothermal Amplification (LAMP) is a promising nucleic-acid amplification assay, which could be accessible, cost-effective and more suited for use with unpurified samples.

Methodology/Principal Findings

In the current study, the objective was to assess the efficacy of a LAMP assay for tuberculosis compared with fluorescence smear microscopy as well as Löwenstein-Jensen (LJ) and Mycobacteria Growth Indicator Tube (MGIT) cultures for the diagnosis of pulmonary tuberculosis using sputum samples. Smear microscopy and culture were performed for decontaminated and concentrated sputum from TB suspects and the LAMP was also performed on these specimens. The LAMP and smear microscopy were compared, in series and in parallel, to culture. LAMP and smear microscopy showed sensitivities of 79.5% and 82.1% respectively and specificities of 93.8% and 96.9% respectively, compared to culture. LAMP and smear in series had sensitivity and specificity of 79.5% and 100.0% respectively. LAMP and smear in parallel had sensitivity and specificity of 82.1% and 90.6% respectively.

Conclusions/Significance

The overall efficacies of LAMP and fluorescence smear microscopy in the current study were high and broadly similar. LAMP and smear in series had high specificity (100.0%) and can be used as a rule-in test combination. However, the performance of LAMP in smear negative samples was found to be insufficient.     

Costs of a Motivational Enhancement Therapy Coupled with Cognitive Behavioral Therapy versus Brief Advice for Pregnant Substance Users

Objectives

To determine and compare costs of a nurse-administered behavioral intervention for pregnant substance users that integrated motivational enhancement therapy with cognitive behavioral therapy (MET-CBT) to brief advice (BA) administered by an obstetrical provider. Both interventions were provided concurrent with prenatal care.

Methods

We conducted a micro-costing study that prospectively collected detailed resource utilization and unit cost data for each of the two intervention arms (MET-CBT and BA) within the context of a randomized controlled trial. A three-step approach for identifying, measuring and valuing resource utilization was used. All cost estimates were inflation adjusted to 2011 U.S. dollars.

Results

A total of 82 participants received the MET-CBT intervention and 86 participants received BA. From the societal perspective, the total cost (including participants’ time cost) of the MET-CBT intervention was $120,483 or $1,469 per participant. In contrast, the total cost of the BA intervention was $27,199 or $316 per participant. Personnel costs (nurse therapists and obstetric providers) for delivering the intervention sessions and supervising the program composed the largest share of the MET-CBT intervention costs. Program set up costs, especially intervention material design and training costs, also contributed substantially to the overall cost.

Conclusions

Implementation of an MET-CBT program to promote drug abstinence in pregnant women is associated with modest costs. Future cost effectiveness and cost benefit analyses integrating costs with outcomes and benefits data will enable a more comprehensive understanding of the intervention in improving the care of substance abusing pregnant women.     

Use of Anti-Retroviral Therapy in Tuberculosis Patients on Second-Line Anti-TB Regimens: A Systematic Review

Introduction

Use of antiretroviral therapy (ART) during treatment of drug susceptible tuberculosis (TB) improves survival. However, data from HIV infected individuals with drug resistant TB are lacking. Second line TB drugs when combined with ART may increase drug interactions and lead to higher rates of toxicity and greater noncompliance. This systematic review sought to determine the benefit of ART in the setting of second line drug therapy for drug resistant TB.

Methods

We included individual patient data from studies that evaluated treatment of drug-resistant tuberculosis in HIV-1 infected individuals published between January 1980 and December of 2009. We evaluated the effect of ART on treatment outcomes, time to smear and culture conversion, and adverse events.

Results

Ten observational studies, including data from 217 subjects, were analyzed. Patients using ART during TB treatment had increased likelihood of cure (hazard ratio (HR) 3.4, 95% CI 1.6–7.4) and decreased likelihood of death (HR 0.4, 95% CI 0.3–0.6) during treatment for drug resistant TB. These associations remained significant in patients with a CD4 less than 200 cells/mm³ and less than 50 cells/mm³, and when correcting for drug resistance pattern.

Limitations

We identified only observational studies from which individual patient data could be drawn. Limitations in study design, and heterogeneity in a number of the outcomes of interest had the potential to introduce bias.

Discussion

While there are insufficient data to determine if ART use increases adverse drug interactions when used with second line TB drugs, ART use during treatment of drug resistant TB appears to improve cure rates and decrease risk of death. All individuals with HIV appear to benefit from ART use during treatment for TB.     

Performance Characteristics of the Cepheid Xpert MTB/RIF Test in a Tuberculosis Prevalence Survey

Background

Xpert MTB/RIF (“Xpert”) is a molecular test for detection of Mycobacterium tuberculosis (MTB) in sputum. Performance characteristics have been established for its use during passive tuberculosis (TB) case detection in symptomatic TB suspects, but Xpert performance has not been assessed in other settings. Objectives were to determine Xpert performance and costs in the context of a TB prevalence survey.

Methodology/Principal Findings

This was a diagnostic sub-study of a TB prevalence survey conducted in gold mining companies in South Africa. Sputa (one per participant) were tested using smear microscopy, liquid culture (reference comparator), and Xpert. Costs were collected using an ingredients approach and analyzed using a public health program perspective. 6893 participants provided a sputum specimen. 187/6893 (2.7%) were positive for MTB in culture, 144/6893 (2.1%) were positive for MTB by Xpert, and 91/6893 (1.3%) were positive for acid fast bacilli by microsocopy. Sensitivity, specificity, positive predictive value, and negative predictive value for detection of MTB by Xpert were 62.6% (95% confidence interval [CI] 55.2, 69.5), 99.6% (99.4, 99.7), 81.3% (73.9, 87.3), and 98.9 (98.6, 98.8); agreement between Xpert and culture was 98.5% (98.2, 98.8). Sensitivity of microscopy was 17.6% (12.5, 23.9). When individuals with a history of TB treatment were excluded from the analysis, Xpert specificity was 99.8 (99.7, 99.9) and PPV was 90.6 (83.3, 95.4) for detection of MTB. For the testing scenario of 7000 specimens with 2.7% of specimens culture positive for MTB, costs were $165,690 for Xpert and $115,360 for the package of microscopy plus culture.

Conclusion

In the context of a TB prevalence survey, the Xpert diagnostic yield was substantially higher than that of microscopy yet lower than that of liquid culture. Xpert may be useful as a sole test for TB case detection in prevalence surveys, particularly in settings lacking capacity for liquid culture.     

Sensitivity of the Quantiferon-Gold In-Tube Assay in Sputum Smear Positive TB Cases in Indonesia

Background

As part of a formal evaluation of the Quantiferon-Gold in-tube assay (QFT-IT) for latent TB infection we compared its sensitivity to the tuberculin skin test (TST) in confirmed adult TB cases in Indonesia. Smear-positive TB disease was used as a proxy gold standard for latent TB infection.

Methods and Findings

We compared the sensitivity of QFT-IT and TST in 98 sputum smear and chest x-ray positive TB cases and investigated risk factors for negative and discordant results in both tests. Both tests showed high sensitivity; (QFT-IT; 88.7%: TST; 94.9%), not significantly different from each other (p value 0.11). Very high sensitivity was seen when tests were combined (98.9%). There were no variables significantly associated with discordant results or with a negative TST. For QFT-IT which particular staff member collected blood was significantly associated with test positivity (p value 0.01). Study limitations include small sample size and lack of culture confirmation or HIV test results.

Conclusions

The QFT-IT has similar sensitivity in Indonesian TB cases as in other locations. However, QFT-IT, like the TST cannot distinguish active TB disease from LTBI. In countries such as Indonesia, with high background rates of LTBI, test specificity for TB disease will likely be low. While our study was not designed to evaluate the QFT-IT in the diagnosis of active TB disease in TB suspects, the data suggest that a combination of TST and QFT-IT may prove useful for ruling out TB disease. Further research is required to explore the clinical role of QFT-IT in combination with other TB diagnostic tests.     

Retooling National TB Control Programmes (NTPs) with New Diagnostics: The NTP Perspective

Background

A delay is evident between the development of new policies on TB diagnostics and their implementation at country level. The Stop TB Partnership would benefit from information from national TB program (NTP) managers on progress towards implementation of new recommendations as well as the opportunities and challenges encountered in the process.

Methods and Findings

To solicit information on the introduction of new TB diagnostics at country level, questionnaires were sent out to NTP managers of high-burden TB countries and a subset of managers was interviewed. The results indicate that about 50% of high-burden TB countries are using the TB diagnostic tools newly recommended by the World Health Organization (WHO). Most NTP managers reported that new diagnostics would only be implemented when officially endorsed by the WHO. All countries have plans to adopt newly endorsed diagnostics at reference laboratory level, while approaches to optimize smear microscopy at lower levels of the health service are given less attention. NTP managers reported diverse challenges to the implementation of new diagnostics.

Conclusions

More information on the obstacles and advantages of introducing new diagnostic tools should be provided to NTP managers to ensure the rational adoption of new diagnostics. A single recommendation covering the introduction of a package of diagnostic tools might be preferable to NTP managers and facilitate implementation in high-burden TB countries.     

Population Based National Tuberculosis Prevalence Survey among Adults (>15 Years) in Pakistan, 2010–2011

Background

We aimed to determine the prevalence of pulmonary tuberculosis (TB) amongst the adult population in 2010–2011 in Pakistan.

Method

A nationwide cross-sectional survey with multistage cluster sampling was conducted among adults (≥15 years) in 95 clusters in 2010–2011. All consenting participants were screened for cough and by chest X-ray. Participants with presumptive TB submitted two sputum samples for smear microscopy, culture, and molecular testing if needed. The TB prevalence estimates were adjusted for missing data and the cluster design.

Result

Of 131,329 eligible individuals, 105,913 (81%) participated in the survey, of whom 10,471 (9.9%) were eligible for sputum examination. We found 341 bacteriologically positive TB cases of whom 233 had sputum smear-positive TB. The adjusted prevalence estimates for smear and bacteriologically positive TB were 270/100,000 (95% confidence interval (CI) 217–323), and 398/100,000 (95% CI 333–463), respectively. Only 61% of the diagnosed TB cases screened positive on symptoms (cough >2wks), whereas the other TB cases were detected based on X-ray abnormalities. The TB prevalence increased with age and was 1.8 times higher among men than women. The prevalence-to-notification ratio of smear-positive TB was 3.1 (95% CI 2.5–3.7), was higher among men than women, and increased with age.

Conclusion

Our data suggest that there is under-detection and/or -notification of TB, especially among men and elderly. TB control should be strengthened specifically in these risk groups. X-ray examination should be combined with symptom screening to enhance case detection.