Baseline and primary data for the partner-provided HIV self-testing and linkage (PASTAL) adaptive multi-arm multi-stage cluster randomized trial in Blantyre, Malawi

Dataset containing details of 2,349 pregnant women accessing antenatal care in three primary health centres in urban Blantyre, Malawi who gave informed consent to participate in an adaptive multi-arm multi-stage cluster randomized trial. The unit of randomization was the antenatal care (ANC) clinic day. On a given ANC day, women could receive standard of care (SOC) of receiving just an invitation letter to deliver to their male partner who was absent at this ANC visit. Or, the women could receive SOC plus two oral self-test kits alone or in combination with a guaranteed financial incentive of $3 or$10 conditional on clinic attendance following self-testing for HIV care or prevention. Two other arms offered a lottery-based incentive with 10% chance of winning $30 to male partners achieving the primary outcome, or a phone call reminder to the male partner immediately following collection of kits by the woman repeated after five days. The dataset contains variables on baseline data for the women and their male partners as reported by the woman as well as data underlying the trial outcomes by arm. Recruitment and follow-up were completed between 8 August 2016 and 30 June 2017

An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse.

It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial

Data for: "The utility of repeat Xpert MTB/RIF testing to diagnose tuberculosis in HIV-positive adults with initial negative result"

The World Health Organization recommends regular tuberculosis screening of HIV-positive individuals with Xpert MTB/RIF as the first diagnostic test. Further evaluation of those who are HIV-positive and Xpert-negative comprises clinical reassessment, chest radiograph (if available), sputum for mycobacterial culture, and treatment with antibiotic if clinically indicated. The aim of our study was to describe the diagnostic yield from an immediate repeat sputum tested with Xpert, compared to sequential further investigation guided by South African recommendations , amongst HIV-positive adults in South Africa being investigated for TB whose initial sputum Xpert result is negative. It was a sub-study of “Xpert for people attending HIV/AIDS care: test or review?” (XPHACTOR), a prospective cohort study evaluating a risk-based algorithm to prioritise Xpert testing amongst adults attending for routine HIV care in South Africa. This dataset contains data for 227 adults attending for routine HIV care who have an initial negative sputum Xpert result. It includes basic demographics, TB diagnoses, mycobacteriology and chest radiograph results. Data was collected for the purpose of HIV and TB research and can only be reused for related research, in accordance with the participant consent agreement

Modulation of NKG2D expression in human CD8(+) T cells corresponding with tuberculosis drug cure.

BACKGROUND: Biomarkers predicting tuberculosis treatment response and cure would facilitate drug development. This study investigated expression patterns of the co-stimulation molecule NKG2D in human tuberculosis and treatment to determine its potential usefulness as a host biomarker of tuberculosis drug efficacy. METHODS: Tuberculosis patients (n = 26) were recruited in Lahore, Pakistan, at diagnosis and followed up during treatment. Household contacts (n = 24) were also recruited. NKG2D expression was measured by qRT-PCR in RNA samples both ex vivo and following overnight mycobacterial stimulation in vitro. Protein expression of NKG2D and granzyme B was measured by flow cytometry. RESULTS: NKG2D expression in newly diagnosed tuberculosis patients was similar to household contacts in ex vivo RNA, but was higher following in vitro stimulation. The NKG2D expression was dramatically reduced by intensive phase chemotherapy, in both ex vivo blood RNA and CD8(+) T cell protein expression, but then reverted to higher levels after the continuation phase in successfully treated patients. CONCLUSION: The changes in NKG2D expression through successful treatment reflect modulation of the peripheral cytotoxic T cell response. This likely reflects firstly in vivo stimulation by live Mycobacterium tuberculosis, followed by the response to dead bacilli, antigen-release and finally immunopathology resolution. Such changes in host peripheral gene expression, alongside clinical and microbiological indices, could be developed into a biosignature of tuberculosis drug-induced cure to be used in future clinical trials

The optimal design of stepped wedge trials with equal allocation to sequences and a comparison to other trial designs.

Background/Aims We sought to optimise the design of stepped wedge trials with an equal allocation of clusters to sequences and explored sample size comparisons with alternative trial designs. Methods We developed a new expression for the design effect for a stepped wedge trial, assuming that observations are equally correlated within clusters and an equal number of observations in each period between sequences switching to the intervention. We minimised the design effect with respect to (1) the fraction of observations before the first and after the final sequence switches (the periods with all clusters in the control or intervention condition, respectively) and (2) the number of sequences. We compared the design effect of this optimised stepped wedge trial to the design effects of a parallel cluster-randomised trial, a cluster-randomised trial with baseline observations, and a hybrid trial design (a mixture of cluster-randomised trial and stepped wedge trial) with the same total cluster size for all designs. Results We found that a stepped wedge trial with an equal allocation to sequences is optimised by obtaining all observations after the first sequence switches and before the final sequence switches to the intervention; this means that the first sequence remains in the control condition and the last sequence remains in the intervention condition for the duration of the trial. With this design, the optimal number of sequences is [Formula: see text], where [Formula: see text] is the cluster-mean correlation, [Formula: see text] is the intracluster correlation coefficient, and m is the total cluster size. The optimal number of sequences is small when the intracluster correlation coefficient and cluster size are small and large when the intracluster correlation coefficient or cluster size is large. A cluster-randomised trial remains more efficient than the optimised stepped wedge trial when the intracluster correlation coefficient or cluster size is small. A cluster-randomised trial with baseline observations always requires a larger sample size than the optimised stepped wedge trial. The hybrid design can always give an equally or more efficient design, but will be at most 5% more efficient. We provide a strategy for selecting a design if the optimal number of sequences is unfeasible. For a non-optimal number of sequences, the sample size may be reduced by allowing a proportion of observations before the first or after the final sequence has switched. Conclusion The standard stepped wedge trial is inefficient. To reduce sample sizes when a hybrid design is unfeasible, stepped wedge trial designs should have no observations before the first sequence switches or after the final sequence switches

Trends in silicosis prevalence and the healthy worker effect among gold miners in South Africa: a prevalence study with follow up of employment status.

BACKGROUND: Given the intimate association between silicosis and tuberculosis, understanding the epidemiology of the South African gold mining industry silicosis epidemic is essential to current initiatives to control both silicosis and tuberculosis in this population, one of the most heavily affected globally. The study's objectives were to compare the prevalence of silicosis among working black gold miners in South Africa during 2004-2009 to that of previous studies, including autopsy series, and to analyse the influence of silicosis and/or tuberculosis on exiting employment. METHODS: Routine chest radiographs from a cohort of gold miners were read for silicosis by an experienced reader (I), and a subset re-read by a B-trained reader (II). Two methods of presenting the readings were used. Additionally, with baseline status of silicosis and previous or active tuberculosis as predictors, survival analysis examined the probability of exiting the workforce for any reason during 2006-2011. RESULTS: Reader I read 11 557 chest radiographs and reader II re-read 841. Overall, silicosis prevalence (ILO ≥ 1/0: 5.7 and 6.2% depending on reader method) was similar to the age adjusted prevalence found in a large study in 1984 (5.0%). When comparison was restricted to a single mine shaft previously studied in 2000, a decline in prevalence (ILO ≥ 1/1) was suggested for one of the reading methods (duration adjusted 20.5% vs. 13.0% in the current study). These findings are discordant with a long-term rising autopsy prevalence of silicosis over this period. Overall, relative to miners with neither disease, the adjusted hazard ratio for exiting employment during the follow-up period was 1.54 for baseline silicosis [95% confidence interval (CI) 1.17, 2.04], 1.71 for tuberculosis (95% CI 1.51, 1.94) and 1.53 for combined disease (95% CI 1.20, 1.96). CONCLUSIONS: This study found, a) there was no significant decline in overall silicosis prevalence among working black miners in the South African gold mining industry between 1984 and 2004-2009, and b) a possible decline at one mine shaft more recently. In the absence of evidence of declining respirable silica concentrations between the 1980s and 2000s, the trends found are plausibly due to a healthy worker survivor effect, which may be accelerating

XPHACTOR Clinical Score dataset

The World Health Organization (WHO) recommendation for regular tuberculosis (TB) screening of HIV-positive individuals with Xpert MTB/RIF as the first diagnostic test has major resource implications. The aim of our study was to develop a score, comprising elements readily available in primary care, to predict probability of TB in adults attending for routine HIV care screened for TB and found WHO tool positive. We used data collected for “Xpert for people attending HIV/AIDS care: test or review?” (XPHACTOR), a prospective cohort study evaluating a risk-based algorithm to prioritise Xpert MTB/RIF testing amongst adults attending for routine HIV care in South Africa, to develop and validate our clinical score. This dataset contains data for 1,048 HIV-positive adults attending for routine HIV care and reporting ≥1 symptom on the WHO screening tool. The dataset is split 50:50 to derive, and internally validate the prediction model. It includes basic demographics, TB diagnoses, and candidate predictors considered for the score. Data was collected for the purpose of HIV and TB research and can only be reused for related research, in accordance with the participant consent agreement

Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals.

OBJECTIVE: To assess the adequacy of reporting of non-inferiority trials alongside the consistency and utility of current recommended analyses and guidelines. DESIGN: Review of randomised clinical trials that used a non-inferiority design published between January 2010 and May 2015 in medical journals that had an impact factor >10 (JAMA Internal Medicine, Archives Internal Medicine, PLOS Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet and New England Journal of Medicine). DATA SOURCES: Ovid (MEDLINE). METHODS: We searched for non-inferiority trials and assessed the following: choice of non-inferiority margin and justification of margin; power and significance level for sample size; patient population used and how this was defined; any missing data methods used and assumptions declared and any sensitivity analyses used. RESULTS: A total of 168 trial publications were included. Most trials concluded non-inferiority (132; 79%). The non-inferiority margin was reported for 98% (164), but less than half reported any justification for the margin (77; 46%). While most chose two different analyses (91; 54%) the most common being intention-to-treat (ITT) or modified ITT and per-protocol, a large number of articles only chose to conduct and report one analysis (65; 39%), most commonly the ITT analysis. There was lack of clarity or inconsistency between the type I error rate and corresponding CIs for 73 (43%) articles. Missing data were rarely considered with (99; 59%) not declaring whether imputation techniques were used. CONCLUSIONS: Reporting and conduct of non-inferiority trials is inconsistent and does not follow the recommendations in available statistical guidelines, which are not wholly consistent themselves. Authors should clearly describe the methods used and provide clear descriptions of and justifications for their design and primary analysis. Failure to do this risks misleading conclusions being drawn, with consequent effects on clinical practice

Stable incidence rates of tuberculosis (TB) among human immunodeficiency virus (HIV)-negative South African gold miners during a decade of epidemic HIV-associated TB.

During the last decade, annual tuberculosis (TB) case-notification rates increased 4-fold, to >4000 cases/100000 person-years, in the study workforce, among whom prevalence of human immunodeficiency virus (HIV) was 30% in 2000. Three separate cohort studies, totalling 6454 HIV-negative participants, were combined and analyzed for time trends. Observed incidence of TB varied between 962 (1991-1994) and 1589 (1999-2000) cases/100000 person-years (P=.17, test for trend). There was, however, a progressive increase in age, and, for each period, older age was associated with increased incidence rates of TB (P<.001). Having adjusted for age differences, there was no significant association between incidence of TB and calendar period (P=.81, test for trend). Relative to 1991-1994, multivariate-adjusted incidence-rate ratios were 0.94, for 1995-1997, 0.96, for 1998-1999, and 1.05, for 1999-2000. Preventing a secondary epidemic of TB among HIV-negative individuals may be achievable with conventional means, even in settings with a high burden of HIV-associated TB