Economic evaluation of novel Mycobacterium tuberculosis specific antigen-based skin tests for detection of TB infection: A modelling study

Evidence on the economic impact of novel skin tests for tuberculosis infection (TBST) is scarce and limited by study quality. We used estimates on the cost-effectiveness of the use of TBST compared to current tuberculosis infection (TBI) tests to assess whether TBST are affordable and feasible to implement under different country contexts. A Markov model parametrised to Brazil, South Africa and the UK was developed to compare the cost-effectiveness of three TBI testing strategies: (1) Diaskintest (DST), (2) TST test, and (3) IGRA QFT test. Univariate and probabilistic sensitivity analyses over unit costs and main parameters were performed. Our modelling results show that Diaskintest saves $5.60 and gains 0.024 QALYs per patient and$8.40, and 0.01 QALYs per patient in Brazil, compared to TST and IGRA respectively. In South Africa, Diaskintest is also cost-saving at $4.39, with 0.015 QALYs per patient gained, compared to TST, and$64.41, and 0.007 QALYs per patient, compared to IGRA. In the UK, Diaskintest saves $73.33, and gaines 0.0351 QALYs per patient, compared to TST. However, Diaskintest, compared to IGRA, showed an incremental cost of$521.45 (95% CI (500.94-545.07)) per QALY, below the willingness-to-pay threshold of $20.223 per QALY. Diaskintest potentially saves costs and results in greater health gains than the TST and IGRA tests in Brazil and South Africa. In the UK Diaskintest would gain health but also be more costly. Our results have potential external validity because TBST remained cost-effective despite extensive sensitivity analyses

A Systematic Review on the Safety of Mycobacterium tuberculosis-Specific Antigen-Based Skin Tests for Tuberculosis Infection Compared With Tuberculin Skin Tests

BACKGROUND: A systematic review showed that the accuracy of Mycobacterium tuberculosis antigen-based skin tests (TBSTs) for tuberculosis is similar to that of interferon γ release assay, but the safety of TBSTs has not been systematically reviewed. METHODS: We searched for studies reporting injection site reactions (ISRs) and systemic adverse events associated with TBSTs. We searched Medline, Embase, e-library, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure database for studies through 30 July 2021, and the database search was updated until 22 November 2022. RESULTS: We identified 7 studies for Cy-Tb (Serum Institute of India), 7 (including 2 found through the updated search) for C-TST (Anhui Zhifei Longcom), and 11 for Diaskintest (Generium). The pooled risk of any injection site reactions (ISRs) due to Cy-Tb (n = 2931; 5 studies) did not differ significantly from that for tuberculin skin tests (TSTs; risk ratio, 1.05 [95% confidence interval, .70-1.58]). More than 95% of ISRs were reported as mild or moderate; common ISRs included pain, itching, and rash. In 1 randomized controlled study, 49 of 153 participants (37.6%) given Cy-Tb experience any systemic adverse event (eg, fever and headache), compared with 56 of 149 participants (37.6%) given TST (risk ratio, 0.85 [95% confidence interval, .6-1.2]). In a randomized controlled study in China (n = 14 579), the frequency of systemic adverse events in participants given C-TST was similar to that for TST, and the frequency of ISRs was similar to or lower than that for TST. Reporting of the safety data on Diaskintest was not standardized, precluding meta-analysis. CONCLUSION: The safety profile of TBSTs appears similar to that of TSTs and is associated with mostly mild ISRs

Isoniazid Preventive Therapy Added to ART to Prevent TB: An Individual Participant Data Meta-Analysis

Background: Isoniazid preventive therapy prevents active tuberculosis in people with HIV, but previous studies have found no evidence of benefit in people with HIV who had a negative tuberculin skin test, and a non-significant effect on mortality. We aimed to estimate the effect of isoniazid preventive therapy given with antiretroviral therapy (ART) for the prevention of tuberculosis and death among people with HIV across population subgroups. Methods: We searched PubMed, Embase, the Cochrane database, and conference abstracts from database inception to Jan 15, 2019, to identify potentially eligible randomised trials. Eligible studies were trials that enrolled HIV-positive adults (age ≥15 years) taking ART who were randomly assigned to either daily isoniazid preventive therapy plus ART or ART alone and followed up longitudinally for outcomes of incident tuberculosis and mortality. We approached all authors of included trials and requested individual participant data: coprimary outcomes were relative risk of incident tuberculosis and all-cause mortality. We did a single-stage meta-analysis of individual participant data using stratified Cox-proportional hazards models. We did prespecified subgroup analyses by sex, CD4 cell count, and evidence of immune sensitisation to tuberculosis (indicated by tuberculin skin test or interferon-γ release assays [IGRAs]). We also assessed the relative risk of liver injury in an additional prespecified analysis. This study is registered with PROSPERO, CRD42019121400. Findings: Of 838 records, we included three trials with data for 2611 participants and 8584·8 person-years of follow-up for the outcome of incident tuberculosis, and a subset of 2362 participants with 8631·6 person-years of follow-up for the coprimary outcome of all-cause mortality. Risk for tuberculosis was lower in participants given isoniazid preventive therapy and ART than participants given ART alone (hazard ratio [HR] 0·68, 95% CI 0·49–0·95, p=0·02). Risk of all-cause mortality was lower in participants given isoniazid preventive therapy and ART than participants given ART alone, but this difference was non-significant (HR 0·69, 95% CI 0·43–1·10, p=0·12). Participants with baseline CD4 counts of less than 500 cells per μL had increased risk of tuberculosis, but there was no significant difference in the benefit of isoniazid preventive therapy with ART by sex, baseline CD4 count, or results of tuberculin skin test or IGRAs. 65 (2·5%) of 2611 participants had raised alanine aminotransferase, but data were insufficient to calculate an HR. Interpretation: Isoniazid preventive therapy with ART prevents tuberculosis across demographic and HIV-specific and tuberculosis-specific subgroups, which supports efforts to further increase use of isoniazid preventive therapy with ART broadly among people living with HIV. Funding: National Institutes of Health and National Institute of Allergy and Infectious Diseases

Effect of antiretroviral therapy on the diagnostic accuracy of symptom screening for intensified tuberculosis case finding in a South African HIV clinic.

BACKGROUND: Current symptom screening algorithms for intensified tuberculosis case finding or prior to isoniazid preventive therapy (IPT) in patients infected with human immunodeficiency virus (HIV) were derived from antiretroviral-naive cohorts. There is a need to validate screening algorithms in patients on antiretroviral therapy (ART). METHODS: We performed cross-sectional evaluation of the diagnostic accuracy of symptom screening, including the World Health Organization (WHO) algorithm, to rule out tuberculosis in HIV-infected individuals pre-ART and on ART undergoing screening prior to IPT. RESULTS: A total of 1429 participants, 54% on ART, had symptom screening and a sputum culture result available. Culture-positive tuberculosis was diagnosed in 126 patients (8.8%, 95% confidence interval [CI], 7.4%-10.4%). The WHO symptom screen in the on-ART compared with the pre-ART group had a lower sensitivity (23.8% vs 47.6%), but higher specificity (94.4% vs 79.8%). The effect of ART was independent of CD4(+) count in multivariable analyses. The posttest probability of tuberculosis following a negative WHO screen was 8.9% (95% CI, 7.4%-10.8%) and 4.4% (95% CI, 3.7%-5.2%) for the pre-ART and on-ART groups, respectively. Addition of body mass index to the WHO screen significantly improved discriminatory ability in both ART groups, which was further improved by adding CD4 count and ART duration. CONCLUSIONS: The WHO symptom screen has poor sensitivity, especially among patients on ART, in a clinic where regular tuberculosis screening is practiced. Consequently, a significant proportion of individuals with tuberculosis would inadvertently be placed on isoniazid monotherapy despite high negative predictive values. Until more sensitive methods of ruling out tuberculosis are established, it would be prudent to do a sputum culture prior to IPT where this is feasible

Community-based active-case finding for tuberculosis: navigating a complex minefield

Community-based active case finding (ACF) for tuberculosis (TB) involves an offer of screening to populations at risk of TB, oftentimes with additional health promotion, community engagement and health service strengthening. Recently updated World Health Organization TB screening guidelines conditionally recommend expanded offer of ACF for communities where the prevalence of undiagnosed pulmonary TB is greater than 0.5% among adults, or with other structural risk factors for TB. Subclinical TB is thought to be a major contributor to TB transmission, and ACF, particularly with chest X-ray screening, could lead to earlier diagnosis. However, the evidence base for the population-level impact of ACF is mixed, with effectiveness likely highly dependent on the screening approach used, the intensity with which ACF is delivered, and the success of community- and health-system participation. With recent changes in TB epidemiology due to the effective scale-up of treatment for HIV in Africa, the impacts of the COVID-19 pandemic, and the importance of subclinical TB, researchers and public health practitioners planning to implement ACF programmes must carefully and repeatedly consider the potential population and individual benefits and harms from these programmes. Here we synthesise evidence and experience from implementing ACF programmes to provide practical guidance, focusing on the selection of populations, screening algorithms, selecting outcomes, and monitoring and evaluation. With careful planning and substantial investment, community-based ACF for TB can be an impactful approach to accelerating progress towards elimination of TB in high-burden countries. However, ACF cannot and should not be a substitute for equitable access to responsive, affordable, accessible primary care services for all

Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive inpatients: A systematic review and individual participant data meta-analysis

BACKGROUND: WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV-positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test). METHODS: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively. FINDINGS: We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (<200 cells/μL) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (<8 g/dL), body mass index (<18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively. INTERPRETATION: WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis. FUNDING: None

Seroprevalence of SARS-CoV-2 in four states of Nigeria in October 2020: A population-based household survey

The observed epidemiology of SARS-CoV-2 in sub-Saharan Africa has varied greatly from that in Europe and the United States, with much lower reported incidence. Population-based studies are needed to estimate true cumulative incidence of SARS-CoV-2 to inform public health interventions. This study estimated SARS-CoV-2 seroprevalence in four selected states in Nigeria in October 2020. We implemented a two-stage cluster sample household survey in four Nigerian states (Enugu, Gombe, Lagos, and Nasarawa) to estimate age-stratified prevalence of SARS-CoV-2 antibodies. All individuals in sampled households were eligible for interview, blood draw, and nasal/oropharyngeal swab collection. We additionally tested participants for current/recent malaria infection. Seroprevalence estimates were calculated accounting for the complex survey design. Across all four states, 10,629 (96·5%) of 11,015 interviewed individuals provided blood samples. The seroprevalence of SARS-CoV-2 antibodies was 25·2% (95% CI 21·8–28·6) in Enugu State, 9·3% (95% CI 7·0–11·5) in Gombe State, 23·3% (95% CI 20·5–26·4) in Lagos State, and 18·0% (95% CI 14·4–21·6) in Nasarawa State. Prevalence of current/recent malaria infection ranged from 2·8% in Lagos to 45·8% in Gombe and was not significantly related to SARS-CoV-2 seroprevalence. The prevalence of active SARS-CoV-2 infection in the four states during the survey period was 0·2% (95% CI 0·1–0·4). Approximately eight months after the first reported COVID-19 case in Nigeria, seroprevalence indicated infection levels 194 times higher than the 24,198 officially reported COVID-19 cases across the four states; however, most of the population remained susceptible to COVID-19 in October 2020

Prevalence of non‐communicable diseases among household contacts of people with tuberculosis: a systematic review and individual participant data meta‐analysis

Objective: To investigate the prevalence of non‐communicable diseases among household contacts of people with tuberculosis. Methods: We conducted a systematic review and individual participant data meta‐analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non‐communicable disease among household contacts of people with clinical tuberculosis. We estimated the non‐communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta‐analyses. Furthermore, we compared age and sex‐standardised non‐communicable disease prevalence with national‐level estimates standardised for age and sex. Results: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta‐analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%–14.9%, four studies). Age‐and sex‐standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self‐report or medical records was 3.4% (95% CI 2.6%–4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta‐analysis. There were limited data for other non‐communicable diseases. Conclusion: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non‐communicable diseases and address shared risk factors

Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.

BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (2), and lymphadenopathy had high specificities (80-90%) but low sensitivities (29-43%). The WHO-recommended algorithm had a sensitivity of 58% (50-66) and a specificity of 99% (98-100); Xpert for all had a sensitivity of 68% (57-76) and a specificity of 99% (98-99). In the one study that assessed both, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62-81] vs 57% [47-67]) and specificities were similar (98% [96-98] vs 99% [98-100]). Among outpatients on ART (4309 [99·1%] of 4347 people on ART), W4SS sensitivity was 53% (35-71) and specificity was 71% (51-85). In this population, a parallel strategy (two tests done at the same time) of W4SS with any chest x-ray abnormality had higher sensitivity (89% [70-97]) and lower specificity (33% [17-54]; n=2670) than W4SS alone; at a tuberculosis prevalence of 5%, this strategy would require 379 more rapid diagnostic tests per 1000 people living with HIV than W4SS but detect 18 more tuberculosis cases. Among outpatients not on ART (11 160 [71·8%] of 15 541 outpatients), W4SS sensitivity was 85% (76-91) and specificity was 37% (25-51). C-reactive protein (≥10 mg/L) alone had a similar sensitivity to (83% [79-86]), but higher specificity (67% [60-73]; n=3187) than, W4SS and a sequential strategy (both test positive) of W4SS then C-reactive protein (≥5 mg/L) had a similar sensitivity to (84% [75-90]), but higher specificity than (64% [57-71]; n=3187), W4SS alone; at 10% tuberculosis prevalence, these strategies would require 272 and 244 fewer rapid diagnostic tests per 1000 people living with HIV than W4SS but miss two and one more tuberculosis cases, respectively.InterpretationC-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.FundingWorld Health Organization