Xpert MTB/RIF - why the lack of morbidity and mortality impact in intervention trials?

: Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings.<br/

Strategies to Accelerate HIV Care and Antiretroviral Therapy Initiation After HIV Diagnosis: A Randomized Trial.

: Determine the effectiveness of strategies to increase linkage to care after testing HIV positive at mobile HIV testing in South Africa. : Unmasked randomized controlled trial. : Recruitment of adults testing HIV positive and not currently in HIV care occurred at 7 mobile HIV counseling and testing units in urban, periurban, and rural South Africa with those consenting randomized 1:1:1:1 into 1 of 4 arms. Three strategies were compared with standard of care (SOC): point-of-care CD4 count testing (POC CD4), POC CD4 plus longitudinal strengths-based counseling (care facilitation; CF), and POC CD4 plus transport reimbursement (transport). Participants were followed up telephonically and through clinic records and analyzed with an intention-to-treat analysis. : From March 2013 to October 2014, 2558 participants were enrolled, of whom 160 were excluded postrandomization. Compared with the SOC arm where 298 (50%) reported having entered care, linkage to care was 319 (52%) for POC CD4, hazard ratio (HR) 1.0 [95% confidence interval (CI): 0.89 to 1.2, P = 0.6]; 331 (55%) for CF, HR: 1.1 (95% CI: 0.84 to 1.3, P = 0.2); and 291 (49%) for transport, HR 0.97 (95% CI: 0.83 to 1.1, P = 0.7). Linkage to care verified with clinical records that occurred for 172 (29%) in the SOC arm; 187 (31%) in the POC CD4 arm, HR: 1.0 (95% CI: 0.86 to 1.3, P = 0.6); 225 (38%) in the CF arm, HR: 1.4 (95% CI: 1.1 to 1.7, P = 0.001); and 180 (31%) in the transport arm, HR: 1.1 (95% CI: 0.88 to 1.3, P = 0.5). : CF improved verified linkage to care from 29% to 38%.<br/

Does antiretroviral treatment increase the infectiousness of smear-positive pulmonary tuberculosis?

BACKGROUND: Understanding of the effects of human immunodeficiency virus (HIV) infection and antiretroviral treatment (ART) on Mycobacterium tuberculosis transmission dynamics remains limited. We undertook a cross-sectional study among household contacts of smear-positive pulmonary tuberculosis (TB) cases to assess the effect of established ART on the infectiousness of TB. METHOD: Prevalence of tuberculin skin test (TST) positivity was compared between contacts of index cases aged 2-10 years who were HIV-negative, HIV-positive but not on ART, on ART for <1 year and on ART for 1 year. Random-effects logistic regression was used to take into account clustering within households. RESULTS: Prevalence of M. tuberculosis infection in contacts of HIV-negative patients, HIV-positive patients on ART 1 year and HIV-positive patients not on ART/on ART <1 year index cases was respectively 44%, 21% and 22%. Compared to contacts of HIV-positive index cases not on ART or recently started on ART, the odds of TST positivity was similar in contacts of HIV-positive index cases on ART 1 year (adjusted OR [aOR] 1.0, 95%CI 0.3-3.7). The odds were 2.9 times higher in child contacts of HIV-negative index cases (aOR 2.9, 95%CI 1.0-8.2). CONCLUSIONS: We found no evidence that established ART increased the infectiousness of smear-positive, HIV-positive index cases

Cost of point-of-care lateral flow urine lipoarabinomannan antigen testing in HIV-positive adults in South Africa.

INTRODUCTION: The World Health Organization recommends point-of-care (POC) lateral flow urine lipoarabinomannan (LF-LAM) for tuberculosis (TB) diagnosis in selected human immunodeficiency virus (HIV) positive people. South Africa had 438 000 new TB episodes in 2016, 58.9% of which were contributed by HIV-positive people. LF-LAM is being considered for scale-up in South Africa. METHODS: We estimated the costs of using LF-LAM in HIV-positive adults with CD4 counts 150 cells/μl enrolled in the TB Fast Track Trial in South Africa. We also estimated costs of POC haemoglobin (Hb), as this was used in the study algorithm. Data on clinic-level (10 intervention clinics) and above-clinic-level costs were collected. RESULTS: A total of 1307 LF-LAM tests were performed at 10 clinics over 24 months. The mean clinic-level costs were US$12.80 per patient for LF-LAM and POC Hb; LF-LAM costs were US$11.49 per patient. The mean above-clinic-level unit costs for LF-LAM were US$12.06 for clinic preparation, training, coordination and mentoring. The mean total cost of LF-LAM was US$23.55 per patient. CONCLUSION: At clinic level, the cost of LF-LAM was comparable to other TB diagnostics in South Africa. It is important to consider above-clinic-level costs for POC tests, as these may be required to support roll-out and ensure successful implementation

Five questions to consider before conducting a stepped wedge trial.

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

Risk factors for Mycobacterium tuberculosis infection in 2-4 year olds in a rural HIV-prevalent setting.

BACKGROUND: Mycobacterium tuberculosis infection in children acts as a sentinel for infectious tuberculosis. OBJECTIVE: To assess risk factors associated with tuberculous infection in pre-school children. METHOD: We conducted a population-wide tuberculin skin test (TST) survey from January to December 2012 in Malawi. All children aged 2-4 years residing in a demographic surveillance area were eligible. Detailed demographic data, including adult human immunodeficiency virus (HIV) status, and clinical and sociodemographic data on all diagnosed tuberculosis (TB) patients were available. RESULTS: The prevalence of M. tuberculosis infection was 1.1% using a TST induration cut-off of 15 mm (estimated annual risk of infection of 0.3%). The main identifiable risk factors were maternal HIV infection at birth (adjusted OR [aOR] 3.6, 95%CI 1.1-12.2), having three or more adult members in the household over a lifetime (aOR 2.4, 95%CI 1.2-4.8) and living in close proximity to a known case of infectious TB (aOR 1.6, 95%CI 1.1-2.4), modelled as a linear variable across categories (>200 m, 100-200 m, <100 m, within household). Less than 20% of the infected children lived within 200 m of a known diagnosed case. CONCLUSION: Household and community risk factors identified do not explain the majority of M. tuberculosis infections in children in our setting

All nonadherence is equal but is some more equal than others? Tuberculosis in the digital era

Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress

Design and protocol for a cluster randomised trial of enhanced diagnostics for tuberculosis screening among people living with HIV in hospital in Malawi (CASTLE study)

BACKGROUND: People living with HIV (PLHIV) have a high risk of death if hospitalised in low-income countries. Tuberculosis has long been the leading cause of admission and death, in part due to suboptimal diagnostics. Two promising new diagnostic tools are digital chest Xray with computer-aided diagnosis (DCXR-CAD) and urine testing with Fujifilm SILVAMP LAM (FujiLAM). Neither test has been rigorously evaluated among inpatients. Test characteristics may be complementary, with FujiLAM especially sensitive for disseminated tuberculosis and DCXR-CAD especially sensitive for pulmonary tuberculosis, making combined interventions of interest. DESIGN AND METHODS: An exploratory unblinded, single site, two-arm cluster randomised controlled trial, with day of admission as the unit of randomisation. A third, smaller, integrated cohort arm (4:4:1 random allocation) contributes to understanding case-mix, but not trial outcomes. Participants are adults living with HIV not currently on TB treatment. The intervention (DCXR-CAD plus urine FujiLAM plus usual care) is compared to usual care alone. The primary outcome is proportion of participants started on tuberculosis treatment by day 56, with secondary outcomes of mortality (time to event) measured to to 56 days from enrolment, proportions with undiagnosed tuberculosis at death or hospital discharge and comparing proportions with enrolment-day tuberculosis treatment initiation. DISCUSSION: Both DCXR-CAD and FujiLAM have potential clinical utility and may have complementary diagnostic performance. To our knowledge, this is the first randomised trial to evaluate these tests among hospitalised PLHIV

Cost-effectiveness of a novel lipoarabinomannan test for tuberculosis in patients with HIV

BACKGROUND: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with HIV irrespective of symptoms. METHODS: We used a microsimulation model to project clinical and economic outcomes of three testing strategies: 1) sputum Xpert MTB/RIF (Xpert); 2) sputum Xpert plus urine AlereLAM (Xpert+AlereLAM); 3) sputum Xpert plus urine FujiLAM (Xpert+FujiLAM). The modelled cohort matched that of a two-country clinical trial. We applied diagnostic yields from a retrospective study (yields for Xpert/Xpert+AlereLAM/Xpert+FujiLAM among those with CD4<200/µL: 33%/62%/70%; among those with CD4≥200/µL: 33%/35%/47%). Costs of Xpert/AlereLAM/FujiLAM were USD15/3/6 (South Africa) and USD25/3/6 (Malawi). Xpert+FujiLAM was considered cost-effective if its incremental cost-effectiveness ratio (USD/year-of-life saved) was <$940 (South Africa) and <$750 (Malawi). We varied key parameters in sensitivity analysis and performed a budget impact analysis of implementing FujiLAM countrywide. RESULTS: Compared with Xpert+AlereLAM, Xpert+FujiLAM increased life expectancy by 0.2 years for those tested in South Africa and Malawi. Xpert+FujiLAM was cost-effective in both countries. Xpert+FujiLAM for all patients remained cost-effective compared with sequential testing and CD4-stratified testing strategies. FujiLAM use added 3.5% (South Africa) and 4.7% (Malawi) to five-year healthcare costs of tested patients, primarily reflecting ongoing HIV treatment costs among survivors. CONCLUSIONS: FujiLAM with Xpert for tuberculosis testing in hospitalized people with HIV is likely to increase life expectancy and be cost-effective at the currently anticipated price in South Africa and Malawi. Additional studies should evaluate FujiLAM in clinical practice settings

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014