Publications by authors named "James J Lewis"

72 Publications

Cost-Effectiveness of Automated Digital Microscopy for Diagnosis of Active Tuberculosis.

PLoS One 2016 20;11(6):e0157554. Epub 2016 Jun 20.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.

Background: Automated digital microscopy has the potential to improve the diagnosis of tuberculosis (TB), particularly in settings where molecular testing is too expensive to perform routinely. The cost-effectiveness of TB diagnostic algorithms using automated digital microscopy remains uncertain.

Methods: Using data from a demonstration study of an automated digital microscopy system (TBDx, Applied Visual Systems, Inc.), we performed an economic evaluation of TB diagnosis in South Africa from the health system perspective. The primary outcome was the incremental cost per new TB diagnosis made. We considered costs and effectiveness of different algorithms for automated digital microscopy, including as a stand-alone test and with confirmation of positive results with Xpert MTB/RIF ('Xpert', Cepheid, Inc.). Results were compared against both manual microscopy and universal Xpert testing.

Results: In settings willing to pay $2000 per incremental TB diagnosis, universal Xpert was the preferred strategy. However, where resources were not sufficient to support universal Xpert, and a testing volume of at least 30 specimens per day could be ensured, automated digital microscopy with Xpert confirmation of low-positive results could facilitate the diagnosis of 79-84% of all Xpert-positive TB cases, at 50-60% of the total cost. The cost-effectiveness of this strategy was $1280 per incremental TB diagnosis (95% uncertainty range, UR: $340-$3440) in the base case, but improved under conditions likely reflective of many settings in sub-Saharan Africa: $677 per diagnosis (95% UR: $450-$935) when sensitivity of manual smear microscopy was lowered to 0.5, and $956 per diagnosis (95% UR: $40-$2910) when the prevalence of multidrug-resistant TB was lowered to 1%.

Conclusions: Although universal Xpert testing is the preferred algorithm for TB diagnosis when resources are sufficient, automated digital microscopy can identify the majority of cases and halve the cost of diagnosis and treatment when resources are more scarce and multidrug-resistant TB is not common.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913947PMC
July 2017

Household HIV Testing Uptake among Contacts of TB Patients in South Africa.

PLoS One 2016 19;11(5):e0155688. Epub 2016 May 19.

The Aurum Institute, Johannesburg, South Africa.

Background: In high HIV prevalence settings, offering HIV testing may be a reasonable part of contact tracing of index tuberculosis (TB) patients. We evaluated the uptake of HIV counselling and testing (HCT) among household contacts of index TB patients and the proportion of newly diagnosed HIV-infected persons linked into care as part of a household TB contact tracing study.

Methods: We recruited index TB patients at public health clinics in two South African provinces to obtain consent for household contact tracing. During scheduled household visits we offered TB symptom screening to all household members and HCT to individuals ≥14years of age. Factors associated with HCT uptake were investigated using a random effects logistic regression model.

Results & Discussion: Out of 1,887 listed household members ≥14 years old, 984 (52%) were available during a household visit and offered HCT of which 108 (11%) self-reported being HIV infected and did not undergo HCT. Of the remaining 876, a total of 304 agreed to HCT (35%); 26 (8.6%) were newly diagnosed as HIV positive. In multivariable analysis, factors associated with uptake of HCT were prior testing (odds ratio 1.6; 95% confidence interval [CI]: 1.1-2.3) and another member in the household testing (odds ratio 2.4; 95% CI: 1.7-3.4). Within 3 months of testing HIV-positive, 35% reported initiating HIV care.

Conclusion: HCT as a component of household TB contact tracing reached individuals without prior HIV testing, however uptake of HIV testing was poor. Strategies to improve HIV testing in household contacts should be evaluated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155688PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873208PMC
July 2017

The timing of tuberculosis after isoniazid preventive therapy among gold miners in South Africa: a prospective cohort study.

BMC Med 2016 Mar 23;14:45. Epub 2016 Mar 23.

TB Centre, London School of Hygiene & Tropical Medicine, London, UK.

Background: The durability of isoniazid preventive therapy (IPT) in preventing tuberculosis (TB) is limited in high-prevalence settings. The underlying mechanism (reactivation of persistent latent TB or reinfection) is not known. We aimed to investigate the timing of TB incidence during and after IPT and associated risk factors in a very high TB and HIV-prevalence setting, and to compare the observed rate with a modelled estimate of TB incidence rate after IPT due to reinfection.

Methods: In a post-hoc analysis of a cluster-randomized trial of community-wide IPT among South African gold miners, all intervention arm participants that were dispensed IPT for at least one of the intended 9 months were included. An incident TB case was defined as any participant with a positive sputum smear or culture, or with a clinical TB diagnosis assigned by a senior study clinician. Crude TB incidence rates were calculated during and after IPT, overall and by follow-up time. HIV status was not available. Multivariable Cox regression was used to analyse risk factors by follow-up time after IPT. Estimates from a published mathematical model of trial data were used to calculate the average reinfection TB incidence in the first year after IPT.

Results: Among 18,520 participants (96% male, mean age 41 years, median follow-up 2.1 years), 708 developed TB. The TB incidence rate during the intended IPT period was 1.3/100 person-years (pyrs; 95% confidence interval (CI), 1.0-1.6) and afterwards 2.3/100 pyrs (95% CI, 1.9-2.7). TB incidence increased within 6 months followed by a stable rate over time. There was no evidence for changing risk factors for TB disease over time after miners stopped IPT. The average TB incidence rate attributable to reinfection in the first year was estimated at 1.3/100 pyrs, compared to an observed rate of 2.2/100 pyrs (95% CI, 1.8-2.7).

Conclusions: The durability of protection by IPT was lost within 6-12 months in this setting with a high HIV prevalence and a high annual risk of M. tuberculosis infection. The observed rate was higher than the modelled rate, suggesting that reactivation of persistent latent infection played a role in the rapid return to baseline TB incidence.
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http://dx.doi.org/10.1186/s12916-016-0589-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804575PMC
March 2016

Effectiveness and safety of misoprostol distributed to antenatal women to prevent postpartum haemorrhage after child-births: a stepped-wedge cluster-randomized trial.

BMC Pregnancy Childbirth 2015 Nov 26;15:315. Epub 2015 Nov 26.

Department of Obstetrics and Gynaecology, Makerere University College of Health Sciences, PO Box 7072, Kampala, Uganda.

Background: Oral misoprostol, administered by trained health-workers is effective and safe for preventing postpartum haemorrhage (PPH). There is interest in expanding administration of misoprostol by non-health workers, including task-shifting to pregnant women themselves. However, the use of misoprostol for preventing PPH in home-births remains controversial, due to the limited evidence to support self-administration or leaving it in the hands of non-health workers. This study aimed to determine if antenatally distributing misoprostol to pregnant women to self-administer at home birth reduces PPH.

Methods: Between February 2013 and March 2014, we conducted a stepped-wedge cluster-randomized trial in six health facilities in Central Uganda. Women at 28+ weeks of gestation attending antenatal care were eligible. Women in the control-arm received the standard-of-care; while the intervention-arm were offered 600 mcg of misoprostol to swallow immediately after birth of baby, when oxytocin was not available. The primary outcome (PPH) was a drop in postpartum maternal haemoglobin (Hb) by ≥ 2 g/dl, lower than the prenatal Hb. Analysis was by intention-to-treat at the cluster level and we used a paired t-tests to assess whether the mean difference between the control and intervention groups was statistically significant.

Results: 97% (2466/2545) of eligible women consented to participate; 1430 and 1036 in the control and intervention arms respectively. Two thousand fifty-seven of the participants were successfully followed up and 271 (13.2%) delivered outside a health facility. There was no significant difference between the study group in number of women who received a uterotonic at birth (control 80.4% vs intervention 91.4%, mean difference = -11.0%, 95% confidence interval [CI] -25.7% to 3.6%, p = 0.11). No woman took misoprostol before their baby's birth. Shivering and fever were 14.9% in the control arm compared to 22.2% in the intervention arm (mean difference = -7.2%, 95% CI -11.1% to -3.7%), p = 0.005). There was a slight, but non-significant, reduction in the percentage of women with Hb drop ≥ 2g/dl from 18.5% in the control arm to 11.4% in the intervention arm (mean difference = 7.1%, 95% CI -3.1% to 17.3%, p = 0.14). Similarly, there was no significant difference between the groups in the primary outcome in the women who delivered at home (control 9.6% vs intervention 14.5%, mean difference -4.9; 95% CI -12.7 to 2.9), p = 0.17).

Conclusion: This study was unable to detect a significant reduction in PPH following the antenatal distribution of misoprostol. The study was registered with Pan-African Clinical Trials Network ( PACTR201303000459148, on 19/11/2012).
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http://dx.doi.org/10.1186/s12884-015-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662032PMC
November 2015

Effectiveness of Electronic Reminders to Improve Medication Adherence in Tuberculosis Patients: A Cluster-Randomised Trial.

PLoS Med 2015 Sep 15;12(9):e1001876. Epub 2015 Sep 15.

MRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: Mobile text messaging and medication monitors (medication monitor boxes) have the potential to improve adherence to tuberculosis (TB) treatment and reduce the need for directly observed treatment (DOT), but to our knowledge they have not been properly evaluated in TB patients. We assessed the effectiveness of text messaging and medication monitors to improve medication adherence in TB patients.

Methods And Findings: In a pragmatic cluster-randomised trial, 36 districts/counties (each with at least 300 active pulmonary TB patients registered in 2009) within the provinces of Heilongjiang, Jiangsu, Hunan, and Chongqing, China, were randomised using stratification and restriction to one of four case-management approaches in which patients received reminders via text messages, a medication monitor, combined, or neither (control). Patients in the intervention arms received reminders to take their drugs and reminders for monthly follow-up visits, and the managing doctor was recommended to switch patients with adherence problems to more intensive management or DOT. In all arms, patients took medications out of a medication monitor box, which recorded when the box was opened, but the box gave reminders only in the medication monitor and combined arms. Patients were followed up for 6 mo. The primary endpoint was the percentage of patient-months on TB treatment where at least 20% of doses were missed as measured by pill count and failure to open the medication monitor box. Secondary endpoints included additional adherence and standard treatment outcome measures. Interventions were not masked to study staff and patients. From 1 June 2011 to 7 March 2012, 4,292 new pulmonary TB patients were enrolled across the 36 clusters. A total of 119 patients (by arm: 33 control, 33 text messaging, 23 medication monitor, 30 combined) withdrew from the study in the first month because they were reassessed as not having TB by their managing doctor (61 patients) or were switched to a different treatment model because of hospitalisation or travel (58 patients), leaving 4,173 TB patients (by arm: 1,104 control, 1,008 text messaging, 997 medication monitor, 1,064 combined). The cluster geometric mean of the percentage of patient-months on TB treatment where at least 20% of doses were missed was 29.9% in the control arm; in comparison, this percentage was 27.3% in the text messaging arm (adjusted mean ratio [aMR] 0.94, 95% CI 0.71, 1.24), 17.0% in the medication monitor arm (aMR 0.58, 95% CI 0.42, 0.79), and 13.9% in the combined arm (aMR 0.49, 95% CI 0.27, 0.88). Patient loss to follow-up was lower in the text messaging arm than the control arm (aMR 0.42, 95% CI 0.18-0.98). Equipment malfunction or operation error was reported in all study arms. Analyses separating patients with and without medication monitor problems did not change the results. Initiation of intensive management was underutilised.

Conclusions: This study is the first to our knowledge to utilise a randomised trial design to demonstrate the effectiveness of a medication monitor to improve medication adherence in TB patients. Reminders from medication monitors improved medication adherence in TB patients, but text messaging reminders did not. In a setting such as China where universal use of DOT is not feasible, innovative approaches to support patients in adhering to TB treatment, such as this, are needed.

Trial Registration: Current Controlled Trials, ISRCTN46846388.
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http://dx.doi.org/10.1371/journal.pmed.1001876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570796PMC
September 2015

Brief Report: The Effect of Antiretroviral Therapy and CD4 Count on Markers of Infectiousness in HIV-Associated Tuberculosis.

J Acquir Immune Defic Syndr 2015 Sep;70(1):104-8

*Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom; †Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; ‡The Aurum Institute, Johannesburg, South Africa; §Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom; and ‖School of Public Health, University of Witwatersrand, Johannesburg, South Africa.

Clinical features of tuberculosis influence infectiousness. This cross-sectional study examined the effect of combination antiretroviral therapy (cART) and CD4 on sputum smear-positivity (SS+) and pulmonary cavitation among 1589 (1185/1589 HIV-positive) miners in South Africa. Proportions SS+ varied nonlinearly by CD4 with greatest proportions SS+ (55.3%) in the lowest stratum (<100 cells/μL). Adjusted prevalence ratio for SS+; on vs. off cART was 0.90 (95% confidence interval: 0.73 to 1.11). Proportions with cavitation varied linearly with CD4, with no independent cART effect (adjusted prevalence ratio 1.17; 95% confidence interval: 0.80 to 1.71). cART did not independently affect SS+ or cavitation but may increase infectiousness through CD4 recovery.
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http://dx.doi.org/10.1097/QAI.0000000000000684DOI Listing
September 2015

Designing and implementing a socioeconomic intervention to enhance TB control: operational evidence from the CRESIPT project in Peru.

BMC Public Health 2015 Aug 21;15:810. Epub 2015 Aug 21.

Innovación Por la Salud Y Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, Peru.

Background: Cash transfers are key interventions in the World Health Organisation's post-2015 global TB policy. However, evidence guiding TB-specific cash transfer implementation is limited. We designed, implemented and refined a novel TB-specific socioeconomic intervention that included cash transfers, which aimed to support TB prevention and cure in resource-constrained shantytowns in Lima, Peru for: the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project.

Methods: Newly-diagnosed TB patients from study-site healthposts were eligible to receive the intervention consisting of economic and social support. Economic support was provided to patient households through cash transfers on meeting the following conditions: screening for TB in household contacts and MDR TB in patients; adhering to TB treatment and chemoprophylaxis; and engaging with CRESIPT social support (household visits and community meetings). To evaluate project acceptability, quantitative and qualitative feedback was collected using a mixed-methods approach during formative activities. Formative activities included consultations, focus group discussions and questionnaires conducted with the project team, project participants, civil society and stakeholders.

Results: Over 7 months, 135 randomly-selected patients and their 647 household contacts were recruited from 32 impoverished shantytown communities. Of 1299 potential cash transfers, 964 (74 %) were achieved, 259 (19 %) were not achieved, and 76 (7 %) were yet to be achieved. Of those achieved, 885/964 (92 %) were achieved optimally and 79/964 (8 %) sub-optimally. Key project successes were identified during 135 formative activities and included: strong multi-sectorial collaboration; generation of new evidence for TB-specific cash transfer; and the project being perceived as patient-centred and empowering. Challenges included: participant confidence being eroded through cash transfer delays, hidden account-charges and stigma; access to the initial bank-provider being limited; and conditions requiring participation of all TB-affected household members (e.g. community meetings) being hard to achieve. Refinements were made to improve project acceptability and future impact: the initial bank-provider was changed; conditional and unconditional cash transfers were combined; cash transfer sums were increased to a locally-appropriate, evidence-based amount; and cash transfer size varied according to patient household size to maximally reduce mitigation of TB-related costs and be more responsive to household needs.

Conclusions: A novel TB-specific socioeconomic intervention including conditional cash transfers has been designed, implemented, refined and is ready for impact assessment, including by the CRESIPT project. The lessons learnt during this research will inform policy-makers and decision-makers for future implementation of related interventions.
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http://dx.doi.org/10.1186/s12889-015-2128-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546087PMC
August 2015

Designing a stepped wedge trial: three main designs, carry-over effects and randomisation approaches.

Trials 2015 Aug 17;16:352. Epub 2015 Aug 17.

Department of Social and Environmental Health Research, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK.

Background: There is limited guidance on the design of stepped wedge cluster randomised trials. Current methodological literature focuses mainly on trials with cross-sectional data collection at discrete times, yet many recent stepped wedge trials do not follow this design. In this article, we present a typology to characterise the full range of stepped wedge designs, and offer guidance on several other design aspects.

Methods: We developed a framework to define and report the key characteristics of a stepped wedge trial, including cluster allocation and individual participation. We also considered the relative strengths and weaknesses of trials according to this framework. We classified recently published stepped wedge trials using this framework and identified illustrative case studies. We identified key design choices and developed guidance for each.

Results: We identified three main stepped wedge designs: those with a closed cohort, an open cohort, and a continuous recruitment short exposure design. In the first two designs, many individuals experience both control and intervention conditions. In the final design, individuals are recruited in continuous time as they become eligible and experience either the control or intervention condition, but not both, and then provide an outcome measurement at follow-up. While most stepped wedge trials use simple randomisation, stratification and restricted randomisation are often feasible and may be useful. Some recent studies collect outcome information from individuals exposed a long time before or after the rollout period, but this contributes little to the primary analysis. Incomplete designs should be considered when the intervention cannot be implemented quickly. Carry-over effects can arise in stepped wedge trials with closed and open cohorts.

Conclusions: Stepped wedge trial designs should be reported more clearly. Researchers should consider the use of stratified and/or restricted randomisation. Trials should generally not commit resources to collect outcome data from individuals exposed a long time before or after the rollout period. Though substantial carry-over effects are uncommon in stepped wedge trials, researchers should consider their possibility before conducting a trial with closed or open cohorts.
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http://dx.doi.org/10.1186/s13063-015-0842-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538756PMC
August 2015

Five questions to consider before conducting a stepped wedge trial.

Trials 2015 Aug 17;16:350. Epub 2015 Aug 17.

Institute for Global Health, University College London, London, UK.

Researchers should consider five questions before starting a stepped wedge trial. Why are you planning one? Researchers sometimes think that stepped wedge trials are useful when there is little doubt about the benefit of the intervention being tested. However, if the primary reason for an intervention is to measure its effect, without equipoise there is no ethical justification for delaying implementation in some clusters. By contrast, if you are undertaking pragmatic research, where the primary reason for rolling out the intervention is for it to exert its benefits, and if phased implementation is inevitable, a stepped wedge trial is a valid option and provides better evidence than most non-randomized evaluations. What design will you use? Two common stepped wedge designs are based on the recruitment of a closed or open cohort. In both, individuals may experience both control and intervention conditions and you should be concerned about carry-over effects. In a third, continuous-recruitment, short-exposure design, individuals are recruited as they become eligible and experience either control or intervention condition, but not both. How will you conduct the primary analysis? In stepped wedge trials, control of confounding factors through secular variation is essential. 'Vertical' approaches preserve randomization and compare outcomes between randomized groups within periods. 'Horizontal' approaches compare outcomes before and after crossover to the intervention condition. Most analysis models used in practice combine both types of comparison. The appropriate analytic strategy should be considered on a case-by-case basis. How large will your trial be? Standard sample size calculations for cluster randomized trials do not accommodate the specific features of stepped wedge trials. Methods exist for many stepped wedge designs, but simulation-based calculations provide the greatest flexibility. In some scenarios, such as when the intracluster correlation coefficient is moderate or high, or the cluster size is large, a stepped wedge trial may require fewer clusters than a parallel cluster trial. How will you report your trial? Stepped wedge trials are currently challenging to report using CONSORT principles. Researchers should consider how to demonstrate balance achieved by randomization and how to describe trends for outcomes in both intervention and control clusters.
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http://dx.doi.org/10.1186/s13063-015-0841-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538743PMC
August 2015

Stepped wedge randomised controlled trials: systematic review of studies published between 2010 and 2014.

Trials 2015 Aug 17;16:353. Epub 2015 Aug 17.

Institute for Global Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.

Background: In a stepped wedge, cluster randomised trial, clusters receive the intervention at different time points, and the order in which they received it is randomised. Previous systematic reviews of stepped wedge trials have documented a steady rise in their use between 1987 and 2010, which was attributed to the design's perceived logistical and analytical advantages. However, the interventions included in these systematic reviews were often poorly reported and did not adequately describe the analysis and/or methodology used. Since 2010, a number of additional stepped wedge trials have been published. This article aims to update previous systematic reviews, and consider what interventions were tested and the rationale given for using a stepped wedge design.

Methods: We searched PubMed, PsychINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Web of Science, the Cochrane Library and the Current Controlled Trials Register for articles published between January 2010 and May 2014. We considered stepped wedge randomised controlled trials in all fields of research. We independently extracted data from retrieved articles and reviewed them. Interventions were then coded using the functions specified by the Behaviour Change Wheel, and for behaviour change techniques using a validated taxonomy.

Results: Our review identified 37 stepped wedge trials, reported in 10 articles presenting trial results, one conference abstract, 21 protocol or study design articles and five trial registrations. These were mostly conducted in developed countries (n = 30), and within healthcare organisations (n = 28). A total of 33 of the interventions were educationally based, with the most commonly used behaviour change techniques being 'instruction on how to perform a behaviour' (n = 32) and 'persuasive source' (n = 25). Authors gave a wide range of reasons for the use of the stepped wedge trial design, including ethical considerations, logistical, financial and methodological. The adequacy of reporting varied across studies: many did not provide sufficient detail regarding the methodology or calculation of the required sample size.

Conclusions: The popularity of stepped wedge trials has increased since 2010, predominantly in high-income countries. However, there is a need for further guidance on their reporting and analysis.
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http://dx.doi.org/10.1186/s13063-015-0839-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538902PMC
August 2015

Analysis and reporting of stepped wedge randomised controlled trials: synthesis and critical appraisal of published studies, 2010 to 2014.

Trials 2015 Aug 17;16:358. Epub 2015 Aug 17.

Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

Background: Stepped wedge cluster randomised trials introduce interventions to groups of clusters in a random order and have been used to evaluate interventions for health and wellbeing. Standardised guidance for reporting stepped wedge trials is currently absent, and a range of potential analytic approaches have been described.

Methods: We systematically identified and reviewed recently published (2010 to 2014) analyses of stepped wedge trials. We extracted data and described the range of reporting and analysis approaches taken across all studies. We critically appraised the strategy described by three trials chosen to reflect a range of design characteristics.

Results: Ten reports of completed analyses were identified. Reporting varied: seven of the studies included a CONSORT diagram, and only five also included a diagram of the intervention rollout. Seven assessed the balance achieved by randomisation, and there was considerable heterogeneity among the approaches used. Only six reported the trend in the outcome over time. All used both 'horizontal' and 'vertical' information to estimate the intervention effect: eight adjusted for time with a fixed effect, one used time as a condition using a Cox proportional hazards model, and one did not account for time trends. The majority used simple random effects to account for clustering and repeat measures, assuming a common intervention effect across clusters. Outcome data from before and after the rollout period were often included in the primary analysis. Potential lags in the outcome response to the intervention were rarely investigated. We use three case studies to illustrate different approaches to analysis and reporting.

Conclusions: There is considerable heterogeneity in the reporting of stepped wedge cluster randomised trials. Correct specification of the time-trend underlies the validity of the analytical approaches. The possibility that intervention effects vary by cluster or over time should be considered. Further work should be done to standardise the reporting of the design, attrition, balance, and time-trends in stepped wedge trials.
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http://dx.doi.org/10.1186/s13063-015-0838-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538923PMC
August 2015

Logistic, ethical, and political dimensions of stepped wedge trials: critical review and case studies.

Trials 2015 Aug 17;16:351. Epub 2015 Aug 17.

Institute for Global Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.

Background: Three arguments are usually invoked in favour of stepped wedge cluster randomised controlled trials: the logistic convenience of implementing an intervention in phases, the ethical benefit of providing the intervention to all clusters, and the potential to enhance the social acceptability of cluster randomised controlled trials. Are these alleged benefits real? We explored the logistic, ethical, and political dimensions of stepped wedge trials using case studies of six recent evaluations.

Methods: We identified completed or ongoing stepped wedge evaluations using two systematic reviews. We then purposively selected six with a focus on public health in high, middle, and low-income settings. We interviewed their authors about the logistic, ethical, and social issues faced by their teams. Two authors reviewed interview transcripts, identified emerging issues through qualitative thematic analysis, reflected upon them in the context of the literature, and invited all participants to co-author the manuscript.

Results: Our analysis raises three main points. First, the phased implementation of interventions can alleviate problems linked to simultaneous roll-out, but also brings new challenges. Issues to consider include the feasibility of organising intervention activities according to a randomised sequence, estimating time lags in implementation and effects, and accommodating policy changes during the trial period. Second, stepped wedge trials, like parallel cluster trials, require equipoise: without it, randomising participants to a control condition, even for a short time, remains problematic. In stepped wedge trials, equipoise is likely to lie in the degree of effect, effectiveness in a specific operational milieu, and the balance of benefit and harm, including the social value of better evaluation. Third, the strongest arguments for a stepped wedge design are logistic and political rather than ethical. The design is advantageous when simultaneous roll-out is impractical and when it increases the acceptability of using counterfactuals.

Conclusions: The logistic convenience of phased implementation is context-dependent, and may be vitiated by the additional requirements of phasing. The potential for stepped wedge trials to enhance the social acceptability of cluster randomised trials is real, but their ethical legitimacy still rests on demonstrating equipoise and its configuration for each research question and setting.
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http://dx.doi.org/10.1186/s13063-015-0837-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538739PMC
August 2015

Clinical Relevance of Nontuberculous Mycobacteria Isolated from Sputum in a Gold Mining Workforce in South Africa: An Observational, Clinical Study.

Biomed Res Int 2015 28;2015:959107. Epub 2015 May 28.

London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.

Background: The clinical relevance of nontuberculous mycobacteria (NTM), detected by liquid more than solid culture in sputum specimens from a South African mining workforce, is uncertain. We aimed to describe the current spectrum and relevance of NTM in this population.

Methods: An observational study including individuals with sputum NTM isolates, recruited at workforce tuberculosis screening and routine clinics. Symptom questionnaires were administered at the time of sputum collection and clinical records and chest radiographs reviewed retrospectively.

Results: Of 232 individuals included (228 (98%) male, median age 44 years), M. gordonae (60 individuals), M. kansasii (50), and M. avium complex (MAC: 38) were the commonest species. Of 38 MAC isolates, only 2 (5.3%) were from smear-positive sputum specimens and 30/38 grew in liquid but not solid culture. MAC was especially prevalent among symptomatic, HIV-positive individuals. HIV prevalence was high: 57/74 (77%) among those tested. No differences were found in probability of death or medical separation by NTM species.

Conclusions: M. gordonae, M. kansasii, and MAC were the commonest NTM among miners with suspected tuberculosis, with most MAC from smear-negative specimens in liquid culture only. HIV testing and identification of key pathogenic NTM in this setting are essential to ensure optimal treatment.
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http://dx.doi.org/10.1155/2015/959107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477445PMC
April 2016

Performance of a Novel Algorithm Using Automated Digital Microscopy for Diagnosing Tuberculosis.

Am J Respir Crit Care Med 2015 Jun;191(12):1443-9

3 London School of Hygiene and Tropical Medicine, London, United Kingdom.

Rationale: TBDx automated microscopy is a novel technology that processes digital microscopic images to identify acid-fast bacilli (AFB). Use of TBDx as part of a diagnostic algorithm could improve the diagnosis of tuberculosis (TB), but its performance characteristics have not yet been formally tested.

Objectives: To evaluate the performance of the TBDx automated microscopy system in algorithms for diagnosis of TB.

Methods: Prospective samples from patients with presumed TB were processed in parallel with conventional smear microscopy, TBDx microscopy, and liquid culture. All TBDx-positive specimens were also tested with the Xpert MTB/RIF (GXP) assay. We evaluated the sensitivity and specificity of two algorithms-(1) TBDx-GXP (TBDx with positive specimens tested by Xpert MTB/RIF) and (2) TBDx alone-against the gold standard liquid media culture.

Measurements And Main Results: Of 1,210 samples, 1,009 were eligible for evaluation, of which 109 were culture positive for Mycobacterium tuberculosis. The TBDx system identified 70 specimens (68 culture positive) as having 10 or more putative AFB (high positive) and 207 (19 culture positive) as having 1-9 putative AFB (low positive). An algorithm in which "low-positive" results on TBDx were confirmed by GXP had 78% sensitivity (85 of 109) and 99.8% specificity (889 of 900), requiring 21% (207 of 1,009) specimens to be processed by GXP. As a stand-alone test, a "high-positive" result on TBDx had 62% sensitivity and 99.7% specificity.

Conclusions: TBDx used in diagnostic algorithms with GXP provided reasonable sensitivity and high specificity for active TB while dramatically reducing the number GXP tests performed. As a stand-alone microscopy system, its performance was equivalent to that of a highly experienced TB microscopist.
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http://dx.doi.org/10.1164/rccm.201502-0390OCDOI Listing
June 2015

Tuberculosis control in South African gold mines: mathematical modeling of a trial of community-wide isoniazid preventive therapy.

Am J Epidemiol 2015 Apr 19;181(8):619-32. Epub 2015 Mar 19.

A recent major cluster randomized trial of screening, active disease treatment, and mass isoniazid preventive therapy for 9 months during 2006-2011 among South African gold miners showed reduced individual-level tuberculosis incidence but no detectable population-level impact. We fitted a dynamic mathematical model to trial data and explored 1) factors contributing to the lack of population-level impact, 2) the best-achievable impact if all implementation characteristics were increased to the highest level achieved during the trial ("optimized intervention"), and 3) how tuberculosis might be better controlled with additional interventions (improving diagnostics, reducing treatment delay, providing isoniazid preventive therapy continuously to human immunodeficiency virus-positive people, or scaling up antiretroviral treatment coverage) individually and in combination. We found the following: 1) The model suggests that a small proportion of latent infections among human immunodeficiency virus-positive people were cured, which could have been a key factor explaining the lack of detectable population-level impact. 2) The optimized implementation increased impact by only 10%. 3) Implementing additional interventions individually and in combination led to up to 30% and 75% reductions, respectively, in tuberculosis incidence after 10 years. Tuberculosis control requires a combination prevention approach, including health systems strengthening to minimize treatment delay, improving diagnostics, increased antiretroviral treatment coverage, and effective preventive treatment regimens.
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http://dx.doi.org/10.1093/aje/kwu320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388015PMC
April 2015

Molecular epidemiology of Mycobacterium tuberculosis among South African gold miners.

Ann Am Thorac Soc 2015 Jan;12(1):12-20

1 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.

Rationale: HIV-associated tuberculosis remains a major health problem among the gold-mining workforce in South Africa. We postulate that high levels of recent transmission, indicated by strain clustering, are fueling the tuberculosis epidemic among gold miners.

Objectives: To combine molecular and epidemiologic data to describe Mycobacterium tuberculosis genetic diversity, estimate levels of transmission, and examine risk factors for clustering.

Methods: We conducted a cross-sectional study of culture-positive M. tuberculosis isolates in 15 gold mine shafts across three provinces in South Africa. All isolates were subject IS6110-based restriction fragment length polymorphisms, and we performed spoligotyping analysis and combined it with basic demographic and clinical information.

Measurements And Main Results: Of the 1,602 M. tuberculosis patient isolates, 1,240 (78%) had genotyping data available for analysis. A highly diverse bacillary population was identified, comprising a total of 730 discrete genotypes. Four genotypic families (Latin American Mediterranean spoligotype family; W-Beijing; AH or X; and T1-T4) accounted for over 50% of all strains. Overall, 45% (560/1,240) of strains were genotypically clustered. The minimum estimate for recent transmission (n - 1 method) was 32% (range, 27-34%). There were no individual-level risk factors for clustering, apart from borderline evidence for being non-South African and having self-reported HIV infection.

Conclusions: The high M. tuberculosis genetic diversity and lack of risk factors for clustering are indicative of a universal risk for disease among gold miners and likely mixing with nonmining populations. Our results underscore the urgent need to intensify interventions to interrupt transmission across the entire gold-mining workforce in South Africa.
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http://dx.doi.org/10.1513/AnnalsATS.201404-150OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342800PMC
January 2015

Systematic review of strategies to increase men's HIV-testing in sub-Saharan Africa.

AIDS 2014 Sep;28(14):2133-45

Objective: This systematic review summarizes evidence on the effectiveness of strategies to increase men's HIV-testing in sub-Saharan Africa.

Methods: Medline, EmBase, Africa-Wide Information and Global Health were searched. Cluster and individually randomized trials evaluating interventions to increase the proportion of adults (≥ 15 years) testing for HIV were eligible if they were conducted in sub-Saharan Africa, included men in the study population, and reported HIV-testing data by sex. References were independently screened.

Results: Of the 1852 references, 15 papers including 16 trials were eligible. Trials were judged too heterogeneous to combine in meta-analysis. Three interventions invited men to attend antenatal care-based HIV-testing via pregnant partners, of which two showed a significant effect on partner-testing. One intervention invited men to HIV-test through pregnant partners and showed an increase in HIV-testing when it was offered in bars compared with health facilities. A trial of notification to partners of newly diagnosed HIV-positive patients showed an increase in testing where notification was by healthcare providers compared with notification by the patient. Three interventions reached men already at health facilities and eight reported the effects of community-based HIV testing. Mobile-testing had a significant effect on HIV-testing compared with standard voluntary counselling and testing. Home-based testing also had a significant effect, but reached smaller numbers of men than mobile-testing.

Discussion: Interventions to encourage HIV-testing can increase men's levels of HIV testing. Community-based programmes in particular had a large effect on population levels of HIV-testing. More data on costs and potential population impact of these approaches over different time-horizons would aid policy-makers in planning resource allocation to increase male HIV-testing.
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http://dx.doi.org/10.1097/QAD.0000000000000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819892PMC
September 2014

The seasonality of tuberculosis, sunlight, vitamin D, and household crowding.

J Infect Dis 2014 Sep 4;210(5):774-83. Epub 2014 Mar 4.

IFHAD: Innovation For Health and Development, United Kingdom Laboratorio de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Perú Infectious Diseases and Immunity, Imperial College London Wellcome Trust Imperial College Centre for Global Health Research, London.

Background: Unlike other respiratory infections, tuberculosis diagnoses increase in summer. We performed an ecological analysis of this paradoxical seasonality in a Peruvian shantytown over 4 years.

Methods: Tuberculosis symptom-onset and diagnosis dates were recorded for 852 patients. Their tuberculosis-exposed cohabitants were tested for tuberculosis infection with the tuberculin skin test (n = 1389) and QuantiFERON assay (n = 576) and vitamin D concentrations (n = 195) quantified from randomly selected cohabitants. Crowding was calculated for all tuberculosis-affected households and daily sunlight records obtained.

Results: Fifty-seven percent of vitamin D measurements revealed deficiency (<50 nmol/L). Risk of deficiency was increased 2.0-fold by female sex (P < .001) and 1.4-fold by winter (P < .05). During the weeks following peak crowding and trough sunlight, there was a midwinter peak in vitamin D deficiency (P < .02). Peak vitamin D deficiency was followed 6 weeks later by a late-winter peak in tuberculin skin test positivity and 12 weeks after that by an early-summer peak in QuantiFERON positivity (both P < .04). Twelve weeks after peak QuantiFERON positivity, there was a midsummer peak in tuberculosis symptom onset (P < .05) followed after 3 weeks by a late-summer peak in tuberculosis diagnoses (P < .001).

Conclusions: The intervals from midwinter peak crowding and trough sunlight to sequential peaks in vitamin D deficiency, tuberculosis infection, symptom onset, and diagnosis may explain the enigmatic late-summer peak in tuberculosis.
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http://dx.doi.org/10.1093/infdis/jiu121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130318PMC
September 2014

A trial of mass isoniazid preventive therapy for tuberculosis control.

N Engl J Med 2014 Jan;370(4):301-10

From the Aurum Institute (G.J.C., L.C.) and the School of Public Health, University of the Witwatersrand (G.J.C.) - both in Johannesburg; the London School of Hygiene and Tropical Medicine, London (G.J.C., K.L.F., J.J.L., E.L.C., P.G.-F., R.J.H., A.D.G.); and the Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore (R.E.C.).

Background: Tuberculosis is epidemic among workers in South African gold mines. We evaluated an intervention to interrupt tuberculosis transmission by means of mass screening that was linked to treatment for active disease or latent infection.

Methods: In a cluster-randomized study, we designated 15 clusters with 78,744 miners as either intervention clusters (40,981 miners in 8 clusters) or control clusters (37,763 miners in 7 clusters). In the intervention clusters, all miners were offered tuberculosis screening. If active tuberculosis was diagnosed, they were referred for treatment; if not, they were offered 9 months of isoniazid preventive therapy. The primary outcome was the cluster-level incidence of tuberculosis during the 12 months after the intervention ended. Secondary outcomes included tuberculosis prevalence at study completion.

Results: In the intervention clusters, 27,126 miners (66.2%) underwent screening. Of these miners, 23,659 (87.2%) started taking isoniazid, and isoniazid was dispensed for 6 months or more to 35 to 79% of miners, depending on the cluster. The intervention did not reduce the incidence of tuberculosis, with rates of 3.02 per 100 person-years in the intervention clusters and 2.95 per 100 person-years in the control clusters (rate ratio in the intervention clusters, 1.00; 95% confidence interval [CI], 0.75 to 1.34; P=0.98; adjusted rate ratio, 0.96; 95% CI, 0.76 to 1.21; P=0.71), or the prevalence of tuberculosis (2.35% vs. 2.14%; adjusted prevalence ratio, 0.98; 95% CI, 0.65 to 1.48; P=0.90). Analysis of the direct effect of isoniazid in 10,909 miners showed a reduced incidence of tuberculosis during treatment (1.10 cases per 100 person-years among miners receiving isoniazid vs. 2.91 cases per 100 person-years among controls; adjusted rate ratio, 0.42; 95% CI, 0.20 to 0.88; P=0.03), but there was a subsequent rapid loss of protection.

Conclusions: Mass screening and treatment for latent tuberculosis had no significant effect on tuberculosis control in South African gold mines, despite the successful use of isoniazid in preventing tuberculosis during treatment. (Funded by the Consortium to Respond Effectively to the AIDS TB Epidemic and others; Thibela TB Current Controlled Trials number, ISRCTN63327174.).
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http://dx.doi.org/10.1056/NEJMoa1214289DOI Listing
January 2014

Eligibility for isoniazid preventive therapy in South African gold mines.

PLoS One 2013 14;8(11):e81376. Epub 2013 Nov 14.

London School of Hygiene and Tropical Medicine, London, United Kingdom ; The Aurum Institute for Health Research, Johannesburg, South Africa.

Setting: The "Thibela TB" cluster randomised trial of community-wide isoniazid preventive therapy (IPT) to reduce tuberculosis incidence in the South African gold mines.

Objectives: To determine the proportion of participants eligible for IPT and the reasons and risk factors for ineligibility, to inform the scale-up of IPT.

Design: Cross-sectional survey of participants in intervention clusters (mine shafts) consenting to tuberculosis screening and assessment for eligibility to start IPT.

Results: Among 27,126 consenting participants, 94.7% were male, the median age was 41 years, 12.2% reported previous tuberculosis, 0.6% reported ever taking IPT and 2.5% reported currently taking antiretroviral therapy. There were 24,430 (90.1%) assessed as eligible to start IPT, of whom 23,659 started IPT. The most common reasons for ineligibility were having suspected tuberculosis that was subsequently confirmed by a positive smear and/or culture (n=705), excessive alcohol consumption (n=427) and being on tuberculosis treatment at time of initial screen (n=241). Ineligibility was associated with factors including older age, female gender, prior history of tuberculosis and being in "HIV care". However, at least 78% were eligible for IPT in all of these sub-groups.

Conclusions: The vast majority of participants in this community-wide intervention were eligible for IPT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081376PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828258PMC
February 2015

Comparison of tenofovir, zidovudine, or stavudine as part of first-line antiretroviral therapy in a resource-limited-setting: a cohort study.

PLoS One 2013 14;8(5):e64459. Epub 2013 May 14.

The Aurum Institute, Johannesburg, South Africa.

Background: Tenofovir (TDF) is part of the WHO recommended first-line antiretroviral therapy (ART); however, there are limited data comparing TDF to other nucleoside reverse transcriptase inhibitors in resource-limited-settings. Using a routine workplace and community-based ART cohort in South Africa, we assessed single drug substitution, HIV RNA suppression, CD4 count increase, loss-from-care, and mortality between TDF, stavudine (d4T) 30 mg dose, and zidovudine (AZT).

Methods: In a prospective cohort study we included ART naïve patients aged ≥17 years-old who initiated ART containing TDF, d4T, or AZT between 2007 and 2009. For analysis of single drug substitutions we used a competing-risks time-to-event analysis; for loss-from-care, mixed-effect Poisson modeling; for HIV RNA suppression, competing-risks logistic regression; for CD4 count slope, mixed-effects linear regression; and for mortality, proportional hazards modeling.

Results: Of 6,196 patients, the initial drug was TDF for 665 (11%), d4T for 4,179 (68%), and AZT for 1,352 (22%). During the first 6 months of ART, the adjusted hazard ratio for a single drug substitution was 2.3 for d4T (95% confidence interval [CI]: 0.27, 19) and 5.2 for AZT (95% CI: 1.1, 23), compared to TDF; whereas, after 6 months, it was 10 (95% CI: 5.8, 18) and 4.4 (95% CI: 2.5, 7.8) for d4T and AZT, respectively. Virologic suppression was similar by agent; however, CD4 count rise was lowest for AZT. The adjusted hazard ratio for loss-from-care, when compared to TDF, was 1.5 (95% CI: 1.1, 1.9) for d4T and 1.2 (95% CI: 1.1, 1.4) for AZT. The adjusted hazard ratio for mortality, when compared to TDF, was 2.7 (95% CI: 2.0, 3.5) and 1.4 (95% CI: 1.3, 1.5) and for d4T and AZT, respectively.

Discussion: In routine care, TDF appeared to perform better than either d4T or AZT, most notably with less drug substitution and mortality than for either other agent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653880PMC
December 2013

Genomic architecture of adaptive color pattern divergence and convergence in Heliconius butterflies.

Genome Res 2013 Aug 14;23(8):1248-57. Epub 2013 May 14.

Smithsonian Tropical Research Institute, Panama City, Republic of Panama.

Identifying the genetic changes driving adaptive variation in natural populations is key to understanding the origins of biodiversity. The mosaic of mimetic wing patterns in Heliconius butterflies makes an excellent system for exploring adaptive variation using next-generation sequencing. In this study, we use a combination of techniques to annotate the genomic interval modulating red color pattern variation, identify a narrow region responsible for adaptive divergence and convergence in Heliconius wing color patterns, and explore the evolutionary history of these adaptive alleles. We use whole genome resequencing from four hybrid zones between divergent color pattern races of Heliconius erato and two hybrid zones of the co-mimic Heliconius melpomene to examine genetic variation across 2.2 Mb of a partial reference sequence. In the intergenic region near optix, the gene previously shown to be responsible for the complex red pattern variation in Heliconius, population genetic analyses identify a shared 65-kb region of divergence that includes several sites perfectly associated with phenotype within each species. This region likely contains multiple cis-regulatory elements that control discrete expression domains of optix. The parallel signatures of genetic differentiation in H. erato and H. melpomene support a shared genetic architecture between the two distantly related co-mimics; however, phylogenetic analysis suggests mimetic patterns in each species evolved independently. Using a combination of next-generation sequencing analyses, we have refined our understanding of the genetic architecture of wing pattern variation in Heliconius and gained important insights into the evolution of novel adaptive phenotypes in natural populations.
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http://dx.doi.org/10.1101/gr.150615.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730099PMC
August 2013

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

AIDS 2013 Jun;27(10):1603-13

Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Spain.

Objectives: To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings.

Design: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK.

Methods: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality.

Results: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log₁₀ copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/μl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77).

Conclusion: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.
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http://dx.doi.org/10.1097/QAD.0b013e328360a5a1DOI Listing
June 2013

Mortality associated with delays between clinic entry and ART initiation in resource-limited settings: results of a transition-state model.

J Acquir Immune Defic Syndr 2013 May;63(1):105-11

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Objective: To estimate the mortality impact of delay in antiretroviral therapy (ART) initiation from the time of entry into care.

Design: A state-transition Markov process model. This technique allows for assessing mortality before and after ART initiation associated with delays in ART initiation among a general population of ART-eligible patients without conducting a randomized trial.

Methods: We used patient-level data from 3 South African cohorts to determine transition probabilities for pre-ART CD4 count changes and pre-ART and on-ART mortality. For each parameter, we generated probabilities and distributions for Monte Carlo simulations with 1-week cycles to estimate mortality 52 weeks from clinic entry.

Results: We estimated an increase in mortality from 11.0% to 14.7% (relative increase of 34%) with a 10-week delay in ART for patients entering care with our pre-ART cohort CD4 distribution. When we examined low CD4 ranges, the relative increase in mortality delays remained similar; however, the absolute increase in mortality rose. For example, among patients entering with CD4 count 50-99 cells per cubic millimeter, 12-month mortality increased from 13.3% with no delay compared with 17.0% with a 10-week delay and 22.9% with a 6-month delay.

Conclusions: Delays in ART initiation, common in routine HIV programs, can lead to important increases in mortality. Prompt ART initiation for patients entering clinical care and eligible for ART, especially those with lower CD4 counts, could be a relatively low-cost approach with a potential marked impact on mortality.
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http://dx.doi.org/10.1097/QAI.0b013e3182893fb4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3647455PMC
May 2013

"Proof-of-concept" evaluation of an automated sputum smear microscopy system for tuberculosis diagnosis.

PLoS One 2012 29;7(11):e50173. Epub 2012 Nov 29.

London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: "TBDx" is an innovative smear microscopy system that automatically loads slides onto a microscope, focuses and digitally captures images and then classifies smears as positive or negative using computerised algorithms.

Objectives: To determine the diagnostic accuracy of TBDx, using culture as the gold standard, and compare this to a microscopist's diagnostic performance.

Methods: This study is nested within a cross-sectional study of tuberculosis suspects from South African gold mines. All tuberculosis suspects had one sputum sample collected, which was decontaminated prior to smear microscopy, liquid culture and organism identification. All slides were auramine-stained and then read by both a research microscopist and by TBDx using fluorescence microscopes, classifying slides based on the WHO classification standard of 100 fields of view (FoV) at 400× magnification.

Results: Of 981 specimens, 269 were culture positive for Mycobacterium tuberculosis (27.4%). TBDx had higher sensitivity than the microscopist (75.8% versus 52.8%, respectively), but markedly lower specificity (43.5% versus 98.6%, respectively). TBDx classified 520/981 smears (53.0%) as scanty positive. Hence, a proposed hybrid software/human approach that combined TBDx examination of all smears with microscopist re-examination of TBDx scanty smears was explored by replacing the "positive" result of slides with 1-9 AFB detected on TBDx with the microscopist's original reading. Compared to using the microscopist's original results for all 981 slides, this hybrid approach resulted in equivalent specificity, a slight reduction in sensitivity from 52.8% to 49.4% (difference of 3.3%; 95% confidence interval: 0.2%, 6.5%), and a reduction in the number of slides to be read by the microscopist by 47.0%.

Discussion: Compared to a research microscopist, the hybrid software/human approach had similar specificity and positive predictive value, but sensitivity requires further improvement. Automated microscopy has the potential to substantially reduce the number of slides read by microscopists.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050173PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510232PMC
June 2013

Performance characteristics of the Cepheid Xpert MTB/RIF test in a tuberculosis prevalence survey.

PLoS One 2012 15;7(8):e43307. Epub 2012 Aug 15.

Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043307PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419700PMC
February 2013

Genotype MTBDRplus for direct detection of Mycobacterium tuberculosis and drug resistance in strains from gold miners in South Africa.

J Clin Microbiol 2012 Apr 11;50(4):1189-94. Epub 2012 Jan 11.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

GenoType MTBDRplus is a molecular assay for detection of Mycobacterium tuberculosis and drug resistance. Assay performance as applied directly to consecutive unselected sputum samples has not been established. The objective of this study was to determine the accuracy of the MTBDRplus test for direct detection of M. tuberculosis (in sputum) and for drug resistance in consecutively submitted sputum samples. In this cross-sectional study in South Africa, one sputum specimen from each person suspected of having pulmonary tuberculosis was tested by smear microscopy, direct MTBDRplus, and Mycobacterial Growth Indicator Tube (MGIT) culture with MGIT drug susceptibility testing. MGIT results were the reference standard. We tested 2,510 sputum samples, and 529 (21.1%) were positive for M. tuberculosis by MGIT. Direct MTBDRplus identified M. tuberculosis in 256 of 529 specimens (sensitivity, 48.4%; 95% confidence interval [CI], 44.1, 52.7). The sensitivity of MTBDRplus for M. tuberculosis detection by sputum smear status was as follows: smear negative, 13.7% (95% CI, 9.8, 18.4); smear scanty, 46.2% (95% CI, 19.2, 74.9); smear 1+, 69.1% (95% CI, 55.2, 80.9); smear 2+, 86.3% (95% CI, 73.7, 94.3); smear 3+, 89.8% (95% CI, 83.7, 94.2). Direct MTBDRplus testing was negative for 1,594/1,612 sputum samples that were culture negative for M. tuberculosis (specificity, 98.9%; 95% CI, 98.2, 99.3). For specimens positive for M. tuberculosis by MTBDRplus, this assay's sensitivity and specificity for rifampin resistance were 85.7% (95% CI, 57.2, 98.2) and 96.6% (95% CI, 93.2, 98.6) and for isoniazid resistance they were 62.1% (95% CI, 42.3, 79.3) and 97.9% (95% CI, 94.8, 99.4). For sputum testing, the sensitivity of MTBDRplus is directly related to the specimen's bacillary burden. Our results support recommendations that the MTBDRplus test not be used for direct testing of smear-negative or paucibacillary sputum samples.
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http://dx.doi.org/10.1128/JCM.05723-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318561PMC
April 2012

Antiretroviral treatment cohort analysis using time-updated CD4 counts: assessment of bias with different analytic methods.

PLoS One 2011 17;6(11):e27763. Epub 2011 Nov 17.

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: Survival analysis using time-updated CD4+ counts during antiretroviral therapy is frequently employed to determine risk of clinical events. The time-point when the CD4+ count is assumed to change potentially biases effect estimates but methods used to estimate this are infrequently reported.

Methods: This study examined the effect of three different estimation methods: assuming i) a constant CD4+ count from date of measurement until the date of next measurement, ii) a constant CD4+ count from the midpoint of the preceding interval until the midpoint of the subsequent interval and iii) a linear interpolation between consecutive CD4+ measurements to provide additional midpoint measurements. Person-time, tuberculosis rates and hazard ratios by CD4+ stratum were compared using all available CD4+ counts (measurement frequency 1-3 months) and 6 monthly measurements from a clinical cohort. Simulated data were used to compare the extent of bias introduced by these methods.

Results: The midpoint method gave the closest fit to person-time spent with low CD4+ counts and for hazard ratios for outcomes both in the clinical dataset and the simulated data.

Conclusion: The midpoint method presents a simple option to reduce bias in time-updated CD4+ analysis, particularly at low CD4 cell counts and rapidly increasing counts after ART initiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027763PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219676PMC
May 2012

'Team up against TB': promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy.

AIDS 2010 Nov;24 Suppl 5:S37-44

Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK.

Objective: To describe a programme of community education and mobilization to promote uptake in a cluster-randomized trial of tuberculosis preventive therapy offered to all members of intervention clusters.

Setting And Participants: Gold mines in South Africa, where tuberculosis incidence is extremely high, despite conventional control measures. All employees in intervention clusters (mine shaft and associated hostel) were invited to enrol.

Main Outcome Measure: Cumulative enrolment in the study in intervention clusters.

Results: Key steps in communicating information relevant to the study included extensive consultation with key stakeholders; working with a communication company to develop a project 'brand'; developing a communication strategy tailored to each intervention site; and involving actors from a popular television comedy series to help inform communities about the study. One-to-one communications used peer educators along with study staff, and participant advisory groups facilitated two-way communication between study staff and participants. By contrast, treatment 'buddies' and text messaging to promote adherence proved less successful. Mean cumulative enrolment in the first four intervention clusters was 61.9%, increasing to 83.0% in the final four clusters.

Conclusion: A tailored communication strategy can facilitate a high level of enrolment in a community health intervention.
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http://dx.doi.org/10.1097/01.aids.0000391020.10661.ebDOI Listing
November 2010

Symptom and chest radiographic screening for infectious tuberculosis prior to starting isoniazid preventive therapy: yield and proportion missed at screening.

AIDS 2010 Nov;24 Suppl 5:S19-27

Aurum Institute for Health Research, Johannesburg, South Africa.

Objective: This analysis describes the prevalence of and risk factors for tuberculosis at screening prior to isoniazid preventive therapy (IPT); the additional yield of tuberculosis using chest radiography versus symptoms alone, and risk factors for tuberculosis missed by screening.

Design: Cross-sectional analysis of a trial of community-wide IPT in South African gold mines.

Methods: Participants were screened for tuberculosis prior to starting IPT using symptoms (cough >2 weeks, weight loss, night sweats) and chest radiography. Tuberculosis suspects had sputum collected for mycobacterial investigations. Those with a positive smear or culture with no speciation or culture identified as Mycobacterium tuberculosis were classified as having probable or definite tuberculosis, respectively. Among participants who were dispensed IPT, we defined a 'missed' case of active tuberculosis as one identified within 90 days of the enrolment screen.

Results: Between July 2006 and December 2008, among 23,286 participants with complete data, the prevalence of undiagnosed tuberculosis [definite (284) and probable (31)] was high (315/23 286; 1.4%). The addition of chest radiography to symptom screening increased the number of definite tuberculosis cases detected by 2.5-fold (113 to 281 cases). Among 19,609 individuals correctly screened for tuberculosis who started IPT and had more than 90 days of follow-up, only 39 (0.2%) active tuberculosis cases were missed. Risk factors for tuberculosis missed by screening included increasing age [adjusted odds ratio (aOR) 1.66/10 year increase, 95% confidence interval (CI) 1.07-2.56], non-South African, in HIV care (aOR 4.80, 95% CI 1.63-14.1), lower weight (aOR 2.07/10 kg decrease, 95% CI 1.23-3.49) and alcohol use (aOR 2.52, 95% CI 1.31-4.86), which were similar to risk factors for tuberculosis detected by screening.

Conclusion: Tuberculosis screening prior to IPT detects a substantial burden of tuberculosis and misses very few cases. Chest radiography significantly increased the yield of tuberculosis cases detected.
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http://dx.doi.org/10.1097/01.aids.0000391018.72542.46DOI Listing
November 2010
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