TB Modeling and Translational Epi Group

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- August 2014 -

Reply to "at the crossroads between early or delayed antiretroviral therapy initiation during TB/HIV coinfection". (2014). Saraceni V., Durovni B., Pacheco AG., Chaisson RE., Golub JE, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 18, 578-9

- July 2014 -

Factors associated with tuberculosis by HIV status in the Brazilian national surveillance system: a cross sectional study. (2014). do Prado TN., Miranda AE., de Souza FM., Dias Edos S., Sousa LK., Arakaki-Sanchez D., Sanchez MN., Golub JE., Maciel EL, BMC infectious diseases, 14, 415

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BACKGROUND: Over the last decade tuberculosis (TB) incidence and mortality in Brazil have been steadily declining. However, this downward trend has not been observed among HIV-infected patients. We describe the epidemiological and clinical profile of TB patients by HIV status using the Brazilian National Surveillance System. METHODS: All TB diagnoses with HIV status information between January 1, 2007 and December 31, 2011 were categorized as either HIV or non-HIV at time of TB diagnosis. Co-infected patients (TB-HIV) were compared to TB patients with no HIV-infection using a hierarchical logistic regression model using Stata 13.0. RESULTS: The prevalence of TB-HIV co-infection was 19% among adults >/= 15 years of age. We analyzed data from 243,676 individuals, of whom 46,466 were TB-HIV and 197,210 were only TB cases. The following factors increased risk of co-infection: male sex (OR: 1.06, 95% CI 1.03-1.10), 20 to 39 years of age (OR = 4.82, 95% CI 4.34-5.36), black (OR = 1.08, 95% CI 1.04-1.13), 4-7 years of education (OR = 1.13, 95% CI 1.19-1.28), diagnosed following default (OR = 2.65, 95% CI 1.13-6.25), presenting with pulmonary and extra-pulmonary forms of TB simultaneously (OR = 2.80, 95% CI 1.56-5.02), presenting with histopathologic examination suggestive of TB (OR = 2.15, 95% CI 1.13-4.07). Co-infected patients were less likely to live in rural areas (OR = 0.45, 95% CI 0.42-0.48), have diabetes (OR = 0.45, 95% CI 0.40-0.50) and be smear positive (OR = 0.55, 95% CI 0.32-0.95), and co-infected patients had higher risk of default (OR = 2.96, 95% CI 2.36-3.71) and death from TB (OR = 5.16, 95% CI 43.04-5.77). CONCLUSIONS: The prevalence of co-infection with HIV among TB patients is 19% in Brazil. By identifying predictors of co-infection targeted interventions can be developed to prevent both TB and HIV, and to diagnose each disease earlier and ultimately decrease poor treatment outcomes and death.

The importance of implementation strategy in scaling up Xpert MTB/RIF for diagnosis of tuberculosis in the Indian health-care system: a transmission model. (2014). Salje H., Andrews JR., Deo S., Satyanarayana S., Sun AY., Pai M., Dowdy DW, PLoS medicine, 11, e1001674

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BACKGROUND: India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited. METHODS AND FINDINGS: We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research. CONCLUSIONS: The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

Transforming the fight against tuberculosis: targeting catalysts of transmission. (2014). Dowdy DW., Azman AS., Kendall EA., Mathema B, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 59, 1123-9

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The global tuberculosis control community has committed itself to ambitious 10-year targets. To meet these targets, biomedical advances alone will be insufficient; a more targeted public health tuberculosis strategy is also needed. We highlight the role of "tuberculosis transmission catalysts," defined as variabilities in human behavior, bacillary properties, and host physiology that fuel the propagation of active tuberculosis at the local level. These catalysts can be categorized as factors that increase contact rates, infectiousness, or host susceptibility. Different catalysts predominate in different epidemiological and sociopolitical settings, and public health approaches are likely to succeed only if they are tailored to target the major catalysts driving transmission in the corresponding community. We argue that global tuberculosis policy should move from a country-level focus to a strategy that prioritizes collection of data on key transmission catalysts at the local level followed by deployment of "catalyst-targeted" interventions, supported by strengthened health systems.

- June 2014 -

Prevalent tuberculosis at HIV diagnosis in Rio de Janeiro, Brazil: the TB/HIV in Rio (THRio) Cohort. (2014). Saraceni V., Cohn S., Cavalcante SC., Pacheco AG., Moulton LH., Chaisson RE., Durovni B., Golub JE, Journal of acquired immune deficiency syndromes (1999), 67, 98-101

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BACKGROUND: Although Brazil has model HIV care programs, many patients continue to present late to care. We studied the frequency of tuberculosis (TB) diagnosed at HIV diagnosis in Rio de Janeiro, Brazil, to quantify missed opportunities for TB prevention. METHODS: People living with HIV (PLHIV) and enrolled in the TB/HIV in Rio study between September 1, 2005, and August 31, 2009, were included. Prevalent TB was defined as TB diagnosed within 60 days of HIV diagnosis or HIV diagnosis during TB therapy. Survival was measured from HIV diagnosis. We conducted Kaplan-Meier survival plots and Cox regression analyses. RESULTS: Four thousand five hundred forty-eight newly diagnosed PLHIV were enrolled: 476 (10.5%) with prevalent TB. Individuals with prevalent TB were older, had lower CD4 counts, and higher viral loads than did those without TB. Median time to receiving highly active antiretroviral therapy (HAART) in those with prevalent TB was 99 days (interquartile range = 58-191) vs. 126 days (interquartile range = 63-301) in those without TB (P = 0.021). Among those with prevalent TB, 17% died during follow-up compared with 8% among those without TB (P < 0.001). After adjustment for sex, age, baseline CD4, and baseline viral load, the risk of occurrence of death remained significantly higher among those with prevalent TB [adjusted hazard ratio = 1.72 (confidence interval 95% 1.19 to 2.48)]. CONCLUSIONS: More than 10% of new PLHIV in our study presented to care with concurrent active TB disease and thus missed the opportunity for undergoing TB preventive therapy. Despite initiating HAART more quickly, these individuals were at a significantly greater risk of death. Earlier HIV diagnosis is necessary to provide earlier initiation of HAART and TB preventive therapy to reduce morbidity and mortality in PLHIV.

Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis. (2014). Dowdy DW., van't Hoog A., Shah M., Cobelens F, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 647-54

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BACKGROUND: Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. OBJECTIVE: To evaluate the potential cost-effectiveness of rapid DST for SLDs. DESIGN: We constructed a decision analysis model of Xpert MTB/RIF-based TB diagnosis in East and South-East Asia to compare culture-based DST vs. a hypothetical rapid SLD DST system for specimens resistant to rifampin. Our primary outcomes were the effectiveness and incremental cost-effectiveness of a rapid SLD DST assay relative to culture-based DST. RESULTS: For rapid SLD DST to be more effective than culture-based DST, treating individuals with pre-XDR/XDR-TB with a standardized MDR-TB regimen while awaiting culture-based DST must incur at least 30% excess XDR-TB mortality (100% = treatment with first-line drugs); rapid SLD DST should attain an aggregate sensitivity and specificity for all pre-XDR/XDR mutations of 88% and 96%, respectively. The unit cost of the rapid SLD DST assay must approach that of culture to achieve common thresholds for cost-effectiveness in low-income countries. CONCLUSION: Rapid SLD DST has the potential to be cost-effective, but must meet stringent criteria for accuracy and costs, and requires that standardized second-line treatment for pre-XDR/XDR-TB incur substantial excess mortality before the return of culture results.

Body mass index predictive of sputum culture conversion among MDR-TB patients in Indonesia. (2014). Putri FA., Burhan E., Nawas A., Soepandi PZ., Sutoyo DK., Agustin H., Isbaniah F., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 564-70

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SETTING: Programmatic management of drug-resistant tuberculosis at Persahabatan Hospital, Jakarta, Indonesia. OBJECTIVE: To evaluate the association between body mass index (BMI) and sputum culture conversion during treatment for multidrug-resistant tuberculosis (MDR-TB). DESIGN: We conducted a retrospective cohort study of 212 MDR-TB patients. MDR-TB was confirmed using culture in liquid medium and line-probe assay. Patients were treated with a standardised regimen unless they were resistant to any of the drugs tested. Study outcomes were time to culture conversion (primary) and probability of conversion within 4 months (secondary). Data were analysed using Kaplan-Meier curves, discrete time-survival analysis and Poisson regression. RESULTS: Compared to patients with normal weight (BMI >/=18.5 kg/m(2)), severely underweight patients (BMI <16 kg/m(2)) had longer time to initial conversion (adjusted hazard ratio [aHR] 0.55, 95%CI 0.37-0.84) and a lower probability of sputum culture conversion within 4 months (adjusted relative risk 0.67, 95%CI 0.54-0.83). Other predictors for longer sputum culture conversion were female sex (aHR 0.55, 95%CI 0.39-0.78), resistance to injectables (aHR 0.59, 95%CI 0.42-0.83) and high baseline smear grade (aHR 0.33, 95%CI 0.18-0.60). CONCLUSION: Severe underweight was associated with longer time to initial sputum culture conversion among MDR-TB patients.

How can mathematical models advance tuberculosis control in high HIV prevalence settings? (2014). Houben RM., Dowdy DW., Vassall A., Cohen T., Nicol MP., Granich RM., Shea JE., Eckhoff P., Dye C., Kimerling ME., White RG, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 18, 509-14

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Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

A user-friendly, open-source tool to project impact and cost of diagnostic tests for tuberculosis. (2014). Dowdy DW., Andrews JR., Dodd PJ., Gilman RH, eLife, 3

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Most models of infectious diseases, including tuberculosis (TB), do not provide results customized to local conditions. We created a dynamic transmission model to project TB incidence, TB mortality, multidrug-resistant (MDR) TB prevalence, and incremental costs over 5 years after scale-up of nine alternative diagnostic strategies. A corresponding web-based interface allows users to specify local costs and epidemiology. In settings with little capacity for up-front investment, same-day microscopy had the greatest impact on TB incidence and became cost-saving within 5 years if delivered at $10/test. With greater initial investment, population-level scale-up of Xpert MTB/RIF or microcolony-based culture often averted 10 times more TB cases than narrowly-targeted strategies, at minimal incremental long-term cost. Xpert for smear-positive TB had reasonable impact on MDR-TB incidence, but at substantial price and little impact on overall TB incidence and mortality. This user-friendly modeling framework improves decision-makers' ability to evaluate the local impact of TB diagnostic strategies.

Point-of-Care Tests for HIV, Related Coinfections, and Blood-Borne Infections. (2014). Pant Pai N., Peeling RW., Smith BD., Dowdy D, AIDS research and treatment, 2014, 625082

- May 2014 -

Impact of isoniazid preventive therapy for HIV-infected adults in Rio de Janeiro, Brazil: an epidemiological model. (2014). Dowdy DW., Golub JE., Saraceni V., Moulton LH., Cavalcante SC., Cohn S., Pacheco AG., Chaisson RE., Durovni B, Journal of acquired immune deficiency syndromes (1999), 66, 552-8

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BACKGROUND: The potential epidemiological impact of isoniazid preventive therapy (IPT), delivered at levels that could be feasibly scaled up among people living with HIV (PLHIV) in modern, moderate-burden settings, remains uncertain. METHODS: We used routine surveillance and implementation data from a cluster-randomized trial of IPT among HIV-infected clinic patients with good access to antiretroviral therapy in Rio de Janeiro, Brazil, to populate a parsimonious transmission model of tuberculosis (TB)/HIV. We modeled IPT delivery as a constant process capturing a proportion of the eligible population every year. We projected feasible reductions in TB incidence and mortality in the general population and among PLHIV specifically at the end of 5 years after implementing an IPT program. RESULTS: Data on time to IPT fit an exponential curve well, suggesting that IPT was delivered at a rate covering 20% (95% confidence interval: 16% to 24%) of the 2500 eligible individuals each year. By the end of year 5 after modeled program rollout, IPT had reduced TB incidence by 3.0% [95% uncertainty range (UR): 1.6% to 7.2%] in the general population and by 15.6% (95% UR: 15.5% to 36.5%) among PLHIV. Corresponding reductions in TB mortality were 4.0% (95% UR: 2.2% to 10.3%) and 14.3% (14.6% to 33.7%). Results were robust to wide variations in parameter values on sensitivity analysis. CONCLUSIONS: TB screening and IPT delivery can substantially reduce TB incidence and mortality among PLHIV in urban, moderate-burden settings. In such settings, IPT can be an important component of a multi-faceted strategy to feasibly reduce the burden of TB in PLHIV.

RE: Severe mental illness at ART initiation is associated with worse retention in care among HIV-infected Ugandan adults by JM Nachega et al. (2013), TMIH 18, pp 53-57. (2014). Nakimuli-Mpungu E., Dowdy DW., Nachega JB, Tropical medicine & international health : TM & IH, 19, 133-4

Population-level impact of shorter-course regimens for tuberculosis: a model-based analysis. (2014). Fofana MO., Knight GM., Gomez GB., White RG., Dowdy DW, PloS one, 9, e96389

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Despite current control efforts, global tuberculosis (TB) incidence is decreasing slowly. New regimens that can shorten treatment hold promise for improving treatment completion and success, but their impact on population-level transmission remains unclear. Earlier models projected that a four-month regimen could reduce TB incidence by 10% but assumed that an entire course of therapy must be completed to derive any benefit. We constructed a dynamic transmission model of TB disease calibrated to global estimates of incidence, prevalence, mortality, and treatment success. To account for the efficacy of partial treatment, we used data from clinical trials of early short-course regimens to estimate relapse rates among TB patients who completed one-third, one-half, two-thirds, and all of their first-line treatment regimens. We projected population-level incidence and mortality over 10 years, comparing standard six-month therapy to hypothetical shorter-course regimens with equivalent treatment success but fewer defaults. The impact of hypothetical four-month regimens on TB incidence after 10 years was smaller than estimated in previous modeling analyses (1.9% [95% uncertainty range 0.6-3.1%] vs. 10%). Impact on TB mortality was larger (3.5% at 10 years) but still modest. Transmission impact was most sensitive to the proportion of patients completing therapy: four-month therapy led to greater incidence reductions in settings where 25% of patients leave care ("default") over six months. Our findings remained robust under one-way variation of model parameters. These findings suggest that novel regimens that shorten treatment duration may have only a modest effect on TB transmission except in settings of very low treatment completion.

A comparative assessment of the price, brands and pack characteristics of illicitly traded cigarettes in five cities and towns in South Africa. (2014). Wherry AE., McCray CA., Adedeji-Fajobi TI., Sibiya X., Ucko P., Lebina L., Golub JE., Cohen JE., Martinson NA, BMJ open, 4, e004562

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OBJECTIVE: The prevalence of illicitly traded cigarettes in South Africa has been reported to be 40-50%. However, these estimates do not account for the more nuanced characteristics of the illicit cigarette trade. With the goal of better understanding contraband cigarettes in South Africa, this study piloted three methods for assessing the price, brands, pack features and smoker's views about illicit cigarettes in five cities/towns. Data were collected in June and July 2012. SETTING: A convenience sample of three South African cities (Johannesburg, Durban and Nelspruit) and two smaller towns (Musina and Ficksburg) were chosen for this study. OUTCOME MEASURES: Three cross-sectional approaches were used to assess the characteristics of contraband cigarettes: (1) a dummy purchase of cigarettes from informal retailers, (2) the collection of discarded cigarette packs and (3) a survey of tobacco smokers. PARTICIPANTS: For the purposes of the survey, 40 self-reported smokers were recruited at taxi ranks in each downtown site. Adults who were over the age of 18 were asked to verbally consent to participate in the study and answer a questionnaire administered by a researcher. RESULTS: The leading reason for labelling a pack as illicit in each city/town was the absence of an excise stamp (28.6% overall), and the least common reason was an illegal tar or nicotine level (11.1% overall). The overall proportion of informal vendors who sold illicit cigarettes was 41%. Singles and packs of 20 were consistently cheaper at informal vendors. Survey participants' responses reflected varied perspectives on illicit cigarettes and purchasing preferences. CONCLUSIONS: Each approach generated an interesting insight into physical aspects of illicit cigarettes. While this pilot study cannot be used to generate generalisable statistics on illicit cigarettes, more systematic surveys of this nature could inform researchers' and practitioners' initiatives to combat illicit and legal cigarette sales and usage.

Survival of HIV patients with tuberculosis started on simultaneous or deferred HAART in the THRio cohort, Rio de Janeiro, Brazil. (2014). Saraceni V., Durovni B., Cavalcante SC., Cohn S., Pacheco AG., Moulton LH., Chaisson RE., Golub JE, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 18, 491-5

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BACKGROUND: The timing of highly active antiretroviral therapy (HAART) after a tuberculosis diagnosis in HIV-infected patients can affect clinical outcomes and survival. We compared survival after tuberculosis diagnosis in HIV-infected adults who initiated HAART and tuberculosis therapy simultaneously to those who delayed the start of HAART for at least two months. METHODS: The THRio cohort includes 17,983 patients receiving HIV care in 29 public clinics in Rio de Janeiro, Brazil. HAART-naive patients at the time of a new TB diagnosis between September 2003 and June 2008 were included. Survival was measured in days from diagnosis of TB. We compared survival among patients who initiated HAART within 60 days of TB treatment (simultaneous - ST) to those who started HAART >60 days of TB treatment or never started (deferred - DT). Kaplan-Meier plots and Cox proportional hazards regression analyses were conducted. RESULTS: Of 947 patients diagnosed with TB, 572 (60%) were HAART naive at the time of TB diagnosis; 135 were excluded because of missing CD4 count results. Among the remaining 437 TB patients, 56 (13%) died during follow-up: 25 (10%) among ST patients and 31 (16%) in DT group (p=0.08). ST patients had lower median CD4 counts at TB diagnosis than DT patients (106 vs. 278, p<0.001). Cox proportional hazards utilizing propensity score analysis showed that DT patients were more likely to die (adjusted HR=1.89; 95% CI: 1.05-3.40; p=0.03). CONCLUSION: HAART administered simultaneously with TB therapy was associated with improved survival after TB diagnosis. HAART should be given to patients with HIV-related TB as soon as clinically feasible.

- February 2014 -

Timing of tuberculosis transmission and the impact of household contact tracing. An agent-based simulation model. (2014). Kasaie P., Andrews JR., Kelton WD., Dowdy DW, American journal of respiratory and critical care medicine, 189, 845-52

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RATIONALE: Household contact tracing has recently been endorsed for global tuberculosis (TB) control, but its potential population-level impact remains uncertain. OBJECTIVES: To project the maximum impact of household contact tracing for TB in a moderate-burden setting. METHODS: We developed a stochastic, agent-based simulation model of a simplified TB epidemic, calibrated to a setting of moderate TB incidence. We used data from the literature to generate "community-driven" and "household-driven" scenarios in which 22 and 50% of TB transmission occurred within the household, respectively. In each scenario, we simulated an intervention in which the household members are screened and treated for TB at the time of an index patient's active TB diagnosis. MEASUREMENTS AND MAIN RESULTS: By the time of TB diagnosis, 75 to 95% of initial household infections had already occurred, but only 1.5 to 3.0% of contacts had sufficient time to progress to active TB. With 100% sensitive tracing of all contacts for 5 consecutive years, TB incidence declined by 10 to 15%, with a mean year-over-year decline of 2% per year. Effects were sustained for many years after stopping the intervention. Providing preventive therapy with contact tracing nearly doubled this impact (17-27% decline in incidence). Impact was proportional to sensitivity and coverage; thus, if 50% of contacts were screened with a 50% sensitive test, TB incidence declined by only 0.5% per year. CONCLUSIONS: Household contact tracing is unlikely to transform TB epidemiology in isolation but has the potential, especially with provision of preventive therapy, to augment a comprehensive package of interventions that could substantially reduce the population-level burden of TB.

- January 2014 -

Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. (2014). Schroeder LF., Robilotti E., Peterson LR., Banaei N., Dowdy DW, Journal of clinical microbiology, 52, 489-96

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Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea in health care settings, and for patients presumed to have CDI, their isolation while awaiting laboratory results is costly. Newer rapid tests for CDI may reduce this burden, but the economic consequences of different testing algorithms remain unexplored. We used decision analysis from the hospital perspective to compare multiple CDI testing algorithms for adult inpatients with suspected CDI, assuming patient management according to laboratory results. CDI testing strategies included combinations of on-demand PCR (odPCR), batch PCR, lateral-flow diagnostics, plate-reader enzyme immunoassay, and direct tissue culture cytotoxicity. In the reference scenario, algorithms incorporating rapid testing were cost-effective relative to nonrapid algorithms. For every 10,000 symptomatic adults, relative to a strategy of treating nobody, lateral-flow glutamate dehydrogenase (GDH)/odPCR generated 831 true-positive results and cost $1,600 per additional true-positive case treated. Stand-alone odPCR was more effective and more expensive, identifying 174 additional true-positive cases at $6,900 per additional case treated. All other testing strategies were dominated by (i.e., more costly and less effective than) stand-alone odPCR or odPCR preceded by lateral-flow screening. A cost-benefit analysis (including estimated costs of missed cases) favored stand-alone odPCR in most settings but favored odPCR preceded by lateral-flow testing if a missed CDI case resulted in less than $5,000 of extended hospital stay costs and <2 transmissions, if lateral-flow GDH diagnostic sensitivity was >93%, or if the symptomatic carrier proportion among the toxigenic culture-positive cases was >80%. These results can aid guideline developers and laboratory directors who are considering rapid testing algorithms for diagnosing CDI.

Tuberculosis: progress and challenges in product development and delivery. (2014). Pai M., Dowdy D, The Lancet. Respiratory medicine, 2, 25-7

Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: A meta-analysis of randomized controlled trials. (2014). Nachega JB., Parienti JJ., Uthman OA., Gross R., Dowdy DW., Sax PE., Gallant JE., Mugavero MJ., Mills EJ., Giordano TP, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 58, 1297-307

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BACKGROUND: Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes. METHODS: A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool. RESULTS: Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates (P = .004) and worse virological suppression (P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing. CONCLUSIONS: Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.

Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings? (2014). Theron G., Peter J., Dowdy D., Langley I., Squire SB., Dheda K, The Lancet. Infectious diseases, 14, 527-32

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In tuberculosis-endemic settings, patients are often treated empirically, meaning that they are placed on treatment based on clinical symptoms or tests that do not provide a microbiological diagnosis (eg, chest radiography). New tests for tuberculosis, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), are being implemented at substantial cost. To inform policy and rationally drive implementation, data are needed for how these tests affect morbidity, mortality, transmission, and population-level tuberculosis burden. If people diagnosed by use of new diagnostics would have received empirical treatment a few days later anyway, then the incremental benefit might be small. Will new diagnostics substantially improve outcomes and disease burden, or simply displace empirical treatment? Will the extent and accuracy of empirical treatment change with the introduction of a new test? In this Personal View, we review emerging data for how empirical treatment is frequently same-day, and might still be the predominant form of treatment in high-burden settings, even after Xpert implementation; and how Xpert might displace so-called true-positive, rather than false-positive, empirical treatment. We suggest types of studies needed to accurately assess the effect of new tuberculosis tests and the role of empirical treatment in real-world settings. Until such questions can be addressed, and empirical treatment is appropriately characterised, we postulate that the estimated population-level effect of new tests such as Xpert might be substantially overestimated.

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