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RationaleThe recommended tuberculosis (TB) intensified case finding (ICF) algorithm for people living with HIV (symptom-based screening followed by Xpert MTB/RIF [Xpert] testing) is insufficiently sensitive and results in unnecessary Xpert testing.ObjectivesTo evaluate whether novel ICF algorithms combining C-reactive protein (CRP)-based screening with urine Determine TB-LAM (TB-LAM), sputum Xpert, and/or sputum culture could improve ICF yield and efficiency.MethodsWe compared the yield and efficiency of novel ICF algorithms inclusive of point-of-care CRP-based TB screening and confirmatory testing with urine TB-LAM (if CD4 count ≤100 cells/μl), sputum Xpert, and/or a single sputum culture among consecutive people living with HIV with CD4 counts less than or equal to 350 cells/μl initiating antiretroviral therapy in Uganda.Measurements and main resultsOf 1,245 people living with HIV, 203 (16%) had culture-confirmed TB including 101 (49%) patients with CD4 counts less than or equal to 100 cells/μl. Compared with the current ICF algorithm, point-of-care CRP-based TB screening followed by Xpert testing had similar yield (56% [95% confidence interval, 49-63] vs. 59% [95% confidence interval, 51-65]) but consumed less than half as many Xpert assays per TB case detected (9 vs. 4). Addition of TB-LAM did not significantly increase diagnostic yield relative to the current ICF algorithm but provided same-day diagnosis for 26% of TB patients with advanced HIV. Addition of a single culture to TB-LAM and Xpert substantially improved ICF yield, identifying 78% of all TB cases.ConclusionsPoint-of-care CRP-based screening can improve ICF efficiency among people living with HIV. Addition of TB-LAM and a single culture to Xpert confirmatory testing could enable HIV programs to increase the speed of TB diagnosis and ICF yield.

BackgroundClinical tuberculosis diagnosis and empiric treatment have traditionally been common among patients with negative bacteriologic test results. Increasing availability of rapid molecular diagnostic tests, including Xpert MTB/RIF and the new Xpert Ultra cartridge, may alter the role of empiric treatment.MethodsWe prospectively enrolled outpatients age > = 15 who were evaluated for pulmonary tuberculosis at three health facilities in Kampala, Uganda. Using sputum mycobacterial culture, interviews, and clinical record abstraction, we estimated the accuracy of clinical diagnosis relative to Xpert and sputum culture and assessed the contribution of clinical diagnosis to case detection.ResultsOver a period of 9 months, 99 patients were diagnosed with pulmonary tuberculosis and subsequently completed sputum culture; they were matched to 196 patients receiving negative tuberculosis evaluations in the same facilities. Xpert was included in the evaluation of 291 (99%) patients. Compared to culture, Xpert had a sensitivity of 92% (95% confidence interval 83-97%) and specificity of 95% (92-98%). Twenty patients with negative Xpert were clinically diagnosed with tuberculosis and subsequently had their culture status determined; two (10%) were culture-positive. Considering all treated patients regardless of Xpert and culture data completeness, and considering treatment initiations before a positive Xpert (N = 4) to be empiric, 26/101 (26%) tuberculosis treatment courses were started empirically. Compared to sputum smear- or Xpert-positive patients with positive cultures, empirically-treated, Xpert-negative patients with negative cultures had higher prevalence of HIV (67% versus 37%), shorter duration of cough (median 4 versus 8 weeks), and lower inflammatory markers (median CRP 7 versus 101 mg/L).ConclusionJudged against sputum culture in a routine care setting of high HIV prevalence, the accuracy of Xpert was high. Clinical judgment identified a small number of additional culture-positive cases, but with poor specificity. Although clinicians should continue to prescribe tuberculosis treatment for Xpert-negative patients whose clinical presentations strongly suggest pulmonary tuberculosis, they should also carefully consider alternative diagnoses.

BackgroundIntegrating home-based HIV counseling and testing (HCT) with tuberculosis (TB) evaluation could improve the uptake of HIV testing among household contacts of patients with active TB. We sought to identify the facilitators of and barriers to HCT during household contact investigation for TB in Kampala, Uganda.MethodsWe nested semi-structured interviews with 28 household contacts who were offered home-based HCT in a household-randomized trial of home-based strategies for TB contact investigation. Respondents reflected on their experiences of the home visit, the social context of the household, and their decision to accept or decline HIV testing. We used content analysis to identify and evaluate facilitators of and barriers to testing, then categorized the emergent themes using the Capability, Opportunity, Motivation, and Behavior (COM-B) model.ResultsFacilitators included a preexisting desire to confirm HIV status or to show support for the index TB patient; a perception that home-based services are convenient; and positive perceptions of lay health workers. Key barriers included fear of results and feeling psychologically unprepared to receive results. The social influence of other household members operated as both a facilitator and a barrier.ConclusionsPreexisting motivation, psychological readiness to test, and the social context of the household are major contributors to the decision to test for HIV at home. Uptake might be improved by providing normalizing information about HCT before the visit, by offering a second HCT opportunity, by offering self-tests with follow-up counseling, or by introducing HCT using "opt-out" language.

BackgroundThe World Health Organization recommends routine household tuberculosis contact investigation in high-burden countries but adoption has been limited. We sought to identify barriers to and facilitators of TB contact investigation during its introduction in Kampala, Uganda.MethodsWe collected cross-sectional qualitative data through focus group discussions and interviews with stakeholders, addressing three core activities of contact investigation: arranging household screening visits through index TB patients, visiting households to screen contacts and refer them to clinics, and evaluating at-risk contacts coming to clinics. We analyzed the data using a validated theory of behavior change, the Capability, Opportunity, and Motivation determine Behavior (COM-B) model, and sought to identify targeted interventions using the related Behavior Change Wheel implementation framework.ResultsWe led seven focus-group discussions with 61 health-care workers, two with 21 lay health workers (LHWs), and one with four household contacts of newly diagnosed TB patients. We, in addition, performed 32 interviews with household contacts from 14 households of newly diagnosed TB patients. Commonly noted barriers included stigma, limited knowledge about TB among contacts, insufficient time and space in clinics for counselling, mistrust of health-center staff among index patients and contacts, and high travel costs for LHWs and contacts. The most important facilitators identified were the personalized and enabling services provided by LHWs. We identified education, persuasion, enablement, modeling of health-positive behaviors, incentivization, and restructuring of the service environment as relevant intervention functions with potential to alleviate barriers to and enhance facilitators of TB contact investigation.ConclusionsThe use of a behavioral theory and a validated implementation framework provided a comprehensive approach for systematically identifying barriers to and facilitators of TB contact investigation. The behavioral determinants identified here may be useful in tailoring interventions to improve implementation of contact investigation in Kampala and other similar urban settings.

BackgroundSymptom-based screening for tuberculosis is recommended for all people living with HIV. This recommendation results in unnecessary Xpert MTB/RIF testing in many individuals living in tuberculosis-endemic areas and thus poor implementation of intensified case finding and tuberculosis preventive therapy. Novel approaches to tuberculosis screening are needed to help achieve global targets for tuberculosis elimination. We assessed the performance of C-reactive protein (CRP) measured with a point-of-care assay as a screening tool for active pulmonary tuberculosis.MethodsFor this prospective study, we enrolled adults (aged ≥18 years) living with HIV with CD4 cell count less than or equal to 350 cells per μL who were initiating antiretroviral therapy (ART) from two HIV/AIDS clinics in Uganda. CRP concentrations were measured at study entry with a point-of-care assay using whole blood obtained by fingerprick (concentration ≥10 mg/L defined as screen positive for tuberculosis). Sputum samples were collected for Xpert MTB/RIF testing and culture. We calculated the sensitivity and specificity of point-of-care CRP and WHO symptom-based screening in reference to culture results. We repeated the sensitivity analysis with Xpert MTB/RIF as the reference standard.FindingsBetween July 8, 2013, and Dec 15, 2015, 1237 HIV-infected adults were enrolled and underwent point-of-care CRP testing. 60 (5%) patients with incomplete or contaminated cultures were excluded from the analysis. Of the remaining 1177 patients (median CD4 count 165 cells per μL [IQR 75-271]), 163 (14%) had culture-confirmed tuberculosis. Point-of-care CRP testing had 89% sensitivity (145 of 163, 95% CI 83-93) and 72% specificity (731 of 1014, 95% CI 69-75) for culture-confirmed tuberculosis. Compared with WHO symptom-based screening, point-of-care CRP testing had lower sensitivity (difference -7%, 95% CI -12 to -2; p=0·002) but substantially higher specificity (difference 58%, 95% CI 55 to 61; p

SETTING:Seven public tuberculosis (TB) units in Kampala, Uganda, where Uganda's national TB program recently introduced household contact investigation, as recommended by 2012 guidelines from WHO. OBJECTIVE:To apply a cascade analysis to implementation of household contact investigation in a programmatic setting. DESIGN:Prospective, multi-center observational study. METHODS:We constructed a cascade for household contact investigation to describe the proportions of: 1) index patient households recruited; 2) index patient households visited; 3) contacts screened for TB; and 4) contacts completing evaluation for, and diagnosed with, active TB. RESULTS:338 (33%) of 1022 consecutive index TB patients were eligible for contact investigation. Lay health workers scheduled home visits for 207 (61%) index patients and completed 104 (50%). Among 287 eligible contacts, they screened 256 (89%) for symptoms or risk factors for TB. 131 (51%) had an indication for further TB evaluation. These included 59 (45%) with symptoms alone, 58 (44%) children

In this Perspective on the research article by William Rudgard and colleagues, Priya Shete and coauthor discuss the challenges of measuring the impact of social protection programs such as cash transfers.

BackgroundSystematic screening is often proposed as a way to improve case finding for tuberculosis (TB), but the cost-effectiveness of specific strategies for systematic screening remains poorly studied.MethodsWe constructed a Markov-based decision analytic model to analyse the cost-effectiveness of triage testing for TB in Uganda, compared against passive case detection with Xpert MTB/RIF. We assumed a triage algorithm whereby all adults presenting to healthcare centres would be screened for cough, and those with cough of at least 2 weeks would receive the triage test, with positive triage results confirmed by Xpert MTB/RIF. We adopted the perspective of the TB control sector, using a primary outcome of the cost per year of life gained (YLG) over a lifetime time horizon.ResultsSystematic screening in a population with a 5% underlying prevalence of TB was estimated to cost US$610 per YLG (95% uncertainty range US$200-US$1859) with chest X-ray (CXR) (US$5 per test, specificity 0.67), or US$588 (US$221-US$1746) with C reactive protein (CRP) (US$3 per test, specificity 0.59). In addition to the cost and specificity of the triage test, cost-effectiveness was most sensitive to the underlying prevalence of TB, monthly risk of mortality in people with untreated TB and the proportion of patients with TB who would be treated in the absence of systematic screening.ConclusionsTo optimise the cost-effectiveness of facility-based systematic screening of TB with a triage test, it must be carried out in a high-risk population, or use triage tests that are cheaper or more specific than CXR or CRP.

Healthcare workers (HCWs) in low-incidence settings are often serially tested for latent TB infection (LTBI) with the QuantiFERON-TB Gold In-Tube (QFT) assay, which exhibits frequent conversions and reversions. The clinical impact of such variability on serial testing remains unknown. We used a microsimulation Markov model that accounts for major sources of variability to project diagnostic outcomes in a simulated North American HCW cohort. Serial testing using a single QFT with the recommended conversion cutoff (IFN-g > 0.35 IU/mL) resulted in 24.6% (95% uncertainty range, UR: 23.8-25.5) of the entire population testing false-positive over ten years. Raising the cutoff to >1.0 IU/mL or confirming initial positive results with a (presumed independent) second test reduced this false-positive percentage to 2.3% (95%UR: 2.0-2.6%) or 4.1% (95%UR: 3.7-4.5%), but also reduced the proportion of true incident infections detected within the first year of infection from 76.5% (95%UR: 66.3-84.6%) to 54.8% (95%UR: 44.6-64.5%) or 61.5% (95%UR: 51.6-70.9%), respectively. Serial QFT testing of HCWs in North America may result in tremendous over-diagnosis and over-treatment of LTBI, with nearly thirty false-positives for every true infection diagnosed. Using higher cutoffs for conversion or confirmatory tests (for initial positives) can mitigate these effects, but will also diagnose fewer true infections.

Background.  The effect of Xpert MTB/RIF (Xpert) scale-up on patient outcomes in low-income settings with a high tuberculosis (TB) burden has not been established. We sought to characterize the effectiveness of Xpert as implemented across different levels of the healthcare system in Uganda. Methods.  We reviewed laboratory records from 2012 to 2014 at 18 health facilities throughout Uganda. In 8 facilities, Xpert had been implemented onsite since 2012, and in 10 sites Xpert was available as an offsite referral test from another facility. We describe Xpert testing volumes by facility, Xpert and smear microscopy results, and downtime due to malfunction and cartridge stockouts. We compare TB treatment initiation as well as time to treatment between facilities implementing Xpert and those that did not. Results.  The median number of Xpert assays run at implementing facilities was 25/month (interquartile range [IQR], 10-63), amounting to 8% of total capacity. Among 1251 assays run for a new TB diagnosis, 19% were positive. Among 1899 patients with smear-negative presumptive TB, the proportion starting TB treatment was similar between Xpert facilities (11%; 95% confidence interval [CI], 9%-13%) and non-Xpert facilities (9%; 95% CI, 8%-11%; P = .325). In Xpert facilities, a positive Xpert preceded TB treatment initiation in only 12 of 70 (17%) smear-negative patients initiated on treatment. Conclusions.  Xpert was underutilized in Uganda and did not significantly increase the number of patients starting treatment for TB. Greater attention must be paid to appropriate implementation of novel diagnostic tests for TB if these new tools are to impact patient important outcomes.

1 | INTRODUCTION The HIV epidemic in Kenya is one of the largest globally, with an estimated 1.6 million people living with HIV (PLHIV) in 2018 [1]. According to the [...], Introduction: As people with HIV age, prevention and management of other communicable and non-communicable diseases (NCDs) will become increasingly important. Integration of screening and treatment for HIV and NCDs is a promising approach for addressing the dual burden of these diseases. The aim of this study was to assess the epidemiological impact and cost-effectiveness of a community-wide integrated programme for screening and treatment of HIV, hypertension and diabetes in Kenya. Methods: Coupling a microsimulation of cardiovascular diseases (CVDs) with a population-based model of HIV dynamics (the Spectrum), we created a hybrid HIV/CVD model. Interventions were modelled from year 2019 (baseline) to 2023, and population was followed to 2033. Analyses were carried at a national level and for three selected regions (Nairobi, Coast and Central). Results: At a national level, the model projected 7.62 million individuals living with untreated hypertension, 692,000 with untreated diabetes and 592,000 individuals in need of ART in year 2018. Improving ART coverage from 68% at baseline to 88% in 2033 reduced HIV incidence by an estimated 64%. Providing NCD treatment to 50% of diagnosed cases from 2019 to 2023 and maintaining them on treatment afterwards could avert 116,000 CVD events and 43,600 CVD deaths in Kenya over the next 15 years. At a regional level, the estimated impact of expanded HIV services was highest in Nairobi region (averting 42,100 HIV infections compared to baseline) while Central region experienced the highest impact of expanded NCD treatment (with a reduction of 22,200 CVD events). The integrated HIV/NCD intervention could avert 7.76 million disability-adjusted-life-years (DALYs) over 15 years at an estimated cost of $6.68 billion ($445.27 million per year), or $860.30 per DALY averted. At a cost-effectiveness threshold of $2,010 per DALY averted, the probability of cost-effectiveness was 0.92, ranging from 0.71 in Central to 0.92 in Nairobi region. Conclusions: Integrated screening and treatment of HIV and NCDs can be a cost-effective and impactful approach to save ives of people with HIV in Kenya, although important variation exists at the regional level. Containing the substantial costs required for scale-up will be critical for management of HIV and NCDs on a national scale. Keywords: HIV; diabetes mellitus; hypertension; Kenya; cost-benefit analysis; computer simulation

The year 2020 is the designated date for achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets for human immunodeficiency virus (HIV) diagnosis, treatment and viral suppression [1]; it [...], Keywords: human immunodeficiency virus; integrated care; health systems; mathematical models

ObjectiveThe association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain.DesignNested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm).MethodsWe measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis.ResultsSeventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB.ConclusionIncident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.

RationaleInterferon gamma (IFN-γ) release assays for latent tuberculosis infection result in a larger-than-expected number of conversions and reversions in occupational screening programs, and reproducibility of test results is a concern.ObjectivesKnowledge of the relative contribution and extent of the individual sources of variability (immunological, preanalytical, or analytical) could help optimize testing protocols.MethodsWe performed a systematic review of studies published by October 2013 on all potential sources of variability of commercial IFN-γ release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB). The included studies assessed test variability under identical conditions and under different conditions (the latter both overall and stratified by individual sources of variability). Linear mixed effects models were used to estimate within-subject SD.Measurements and main resultsWe identified a total of 26 articles, including 7 studies analyzing variability under the same conditions, 10 studies analyzing variability with repeat testing over time under different conditions, and 19 studies reporting individual sources of variability. Most data were on QuantiFERON (only three studies on T-SPOT.TB). A considerable number of conversions and reversions were seen around the manufacturer-recommended cut-point. The estimated range of variability of IFN-γ response in QuantiFERON under identical conditions was ±0.47 IU/ml (coefficient of variation, 13%) and ±0.26 IU/ml (30%) for individuals with an initial IFN-γ response in the borderline range (0.25-0.80 IU/ml). The estimated range of variability in noncontrolled settings was substantially larger (±1.4 IU/ml; 60%). Blood volume inoculated into QuantiFERON tubes and preanalytic delay were identified as key sources of variability.ConclusionsThis systematic review shows substantial variability with repeat IFN-γ release assays testing even under identical conditions, suggesting that reversions and conversions around the existing cut-point should be interpreted with caution.

(1) | INTRODUCTION In the last decade, Zambia has restructured much of the way it provides ART care in the form of task-shifting by increasing the role of nurses (e.g. [...], Introduction: Accurate costing is key for programme planning and policy implementation. Since 2011, there have been major changes in eligibility criteria and treatment regimens with price reductions in ART drugs, programmatic changes resulting in clinical task-shifting and decentralization of ART delivery to peripheral health centres making existing evidence on ART care costs in Zambia out-of-date. As decision makers consider further changes in ART service delivery, it is important to understand the current drivers of costs for ART care. This study provides updates on costs of ART services for HIV-positive patients in Zambia. Methods: We evaluated costs, assessed from the health systems perspective and expressed in 2016 USD, based on an activity-based costing framework using both top-down and bottom-up methods with an assessment of process and capacity. We collected primary site-level costs and resource utilization data from government documents, patient chart reviews and time-and-motion studies conducted in 10 purposively selected ART clinics. Results: The cost of providing ART varied considerably among the ten clinics. The average per-patient annual cost of ART service was $116.69 (range: $59.38 to $145.62) using a bottom-up method and $130.32 (range: $94.02 to $162.64) using a top-down method. ART drug costs were the main cost driver (67% to 7% of all costs) and are highly sensitive to the types of patient included in the analysis (long-term vs. all ART patients, including those recently initiated) and the data sources used (facility vs. patient level). Missing capacity costs made up 57% of the total difference between the top-down and bottom-up estimates. Variability in cost across the ten clinics was associated with operational characteristics. Conclusions: Real-world costs of current routine ART services in Zambia are considerably lower than previously reported estimates and sensitive to operational factors and methods used. We recommend collection and monitoring of resource use and capacity data to periodically update cost estimates. Keywords: AIDS; HIV; antiretroviral therapy; costs and cost analysis; low-resource setting; Zambia

Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis. Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

BackgroundStark racial/ethnic disparities in health outcomes exist among those living with HIV in the United States. One of 3 primary goals of the National HIV/AIDS Strategy is to reduce HIV-related disparities and health inequities.MethodsUsing data from HIV-infected women participating in the Women's Interagency HIV Study from April 2006 to March 2011, we measured virologic failure (HIV RNA >200 copies/mL) after suppression (HIV RNA < 80 copies/mL) on highly active antiretroviral therapy. We identified predictors of virologic failure using discrete time survival analysis and calculated racial/ethnic-specific population-attributable fractions (PAFs).ResultsOf 887 eligible women, 408 (46%) experienced virologic failure during the study period. Hispanic and white women had significantly lower hazards of virologic failure than African American women [Hispanic hazard ratio, (HR) = 0.8, 95% confidence interval: (0.6 to 0.9); white HR = 0.7 (0.5 to 0.9)]. The PAF of virologic failure associated with low income was higher in Hispanic [adjusted hazard ratios (aHR) = 2.2 (0.7 to 6.5), PAF = 49%] and African American women [aHR = 1.8 (1.1 to 3.2), PAF = 38%] than among white women [aHR = 1.4 (0.6 to 3.4), PAF = 16%]. Lack of health insurance compared with public health insurance was associated with virologic failure only among Hispanic [aHR = 2.0 (0.9 to 4.6), PAF = 22%] and white women [aHR = 1.9 (0.7 to 5.1), PAF = 13%]. By contrast, depressive symptoms were associated with virologic failure only among African-American women [aHR = 1.6 (1.2 to 2.2), PAF = 17%].ConclusionsIn this population of treated HIV-infected women, virologic failure was common, and correlates of virologic failure varied by race/ethnicity. Strategies to reduce disparities in HIV treatment outcomes by race/ethnicity should address racial/ethnic-specific barriers including depression and low income to sustain virologic suppression.

David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions.