The evaluation of different strategies to improve the diagnosis of tuberculosis in people living with HIV in resource-limited settings

Background The 2019 WHO screening and diagnostic algorithm for tuberculosis in people living with HIV (PLHIV) has 2 components: the WHO Xpert MTB/RIF (Xpert) algorithm and WHO Alere Determine TB-LAM (AlereLAM) algorithm. According to the WHO Xpert algorithm, WHO recommends that PLHIV be routinely screened for tuberculosis with the WHO foursymptom screen (W4SS; comprising any one of current cough, fever, night sweats, or weight loss) and, if the screen is positive, receive Xpert or Xpert MTB/RIF Ultra (Xpert Ultra) confirmatory testing. According to the WHO AlereLAM algorithm, WHO also recommends that PLHIV be routinely screened for tuberculosis using screening criteria and, if the screen is positive, receive urine lateral-flow lipoarabinomannan (LF-LAM) confirmatory testing with AlereLAM. We aimed: i. To determine the diagnostic accuracy of the W4SS and alternative screening tools and strategies in ambulatory PLHIV, including key subgroups, and to compare the diagnostic accuracy of the WHO Xpert algorithm with Xpert confirmatory testing for all ambulatory PLHIV ii. To determine the performance of the W4SS and alternative screening tools and strategies in HIV-positive inpatients and to compare the diagnostic accuracy of the WHO Xpert algorithm with Xpert confirmatory testing for all HIV-positive inpatients iii. To determine the performance of WHO screening criteria and alternative screening tools and strategies to guide LF-LAM testing in HIV-positive inpatients and to compare the performance of the WHO AlereLAM algorithm with AlereLAM and Fujifilm SILVAMP TB-LAM (FujiLAM; a novel LF-LAM test) confirmatory testing in all HIV-positive inpatients. iv. To develop and validate novel clinical prediction models (CPMs) for tuberculosis screening in outpatient PLHIV and to determine the clinical utility of these CPMs and WHO-recommended screening tools Methods We conducted a systematic review and individual participant data (IPD) meta-analysis. We updated a search of PubMed (MEDLINE), Embase, Cochrane Library, and conference 2 abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to August 2, 2019 (objectives i and iv) and March 1, 2020 (objectives ii and iii). We also screened reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional studies, observational studies, and randomized trials that enrolled adult and adolescent (age ≥10 years) PLHIV irrespective of symptoms and signs of tuberculosis. We also included studies that enrolled outpatient PLHIV with a positive W4SS (objective iv only). We extracted study-level data using a standardized data extraction form, and we requested IPD from study authors. The reference standards were culture (objectives i, ii, and iv) and culture or Xpert (objective iii). For screening tools and strategies, we also used separate reference standards of Xpert (objective i and ii), AlereLAM (objective iii), and FujiLAM (objective iii). We selected these confirmatory tests as reference standards since these tests are the most likely confirmatory tests used in practice. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy (i.e., sensitivity and specificity) by fitting random-effects bivariate models, and assessed diagnostic yield (i.e., proportion of total tuberculosis cases with a positive confirmatory test) descriptively. For CPMs, we first used logistic regression, allowing for non-linear relations, to develop an extended CPM (using backwards selection of C-reactive protein [CRP] and other predictors) and a CRP-only CPM (which only included CRP along with spline transformations); we then used internal-external cross-validation to evaluate discrimination, calibration, and clinical utility (i.e., decision curve analysis) of both CPMs and other screening strategies. Decision curve analysis plots net benefit across a range of risk thresholds. This systematic review has been registered with PROSPERO, CRD42020155895. Results i. We obtained data for 22 of 25 studies (n= 15,666 participants; 4,347 on antiretroviral therapy [ART]). W4SS sensitivity was 82% (95% CI 72, 89) and specificity was 42% (29, 57). CRP (≥10 mg/L) had similar sensitivity (77% [61, 88]), but higher specificity (74% [61, 83]; n=3571). Cough (lasting ≥2 weeks), haemoglobin (< 8 g/dL), body mass index (<18.5kg/m²), and lymphadenopathy had high specificities (80–90%) but low sensitivities (29–43%). The WHO Xpert algorithm had a sensitivity of only 58% (50,66) and a specificity of 99% (98, 100); Xpert for all had a sensitivity of 68% (57–76) and similar specificity. In the only study that compared both tests, the sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62, 81] vs 57% [47, 67]) and specificities were similar. Among outpatients on ART, W4SS sensitivity was 53% (35, 71) and specificity was 71% (51, 85). In this population, a parallel strategy (two or more screening tests offered 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=2,670) than W4SS alone; at a 5% tuberculosis prevalence, this strategy would require 379 more Xpert tests per 1,000 PLHIV than W4SS but detect 18 more cases. Among outpatients not on ART, W4SS sensitivity was 85% (76, 91) and specificity was 37% (25, 51). CRP (≥10 mg/L) had a similar sensitivity (83% [79, 86]), but higher specificity (67% [60, 73]; n=3,187) and a sequential strategy (second screening test offered only if first screening test is positive) of W4SS then CRP (≥5 mg/L) also had similar sensitivity (84% [75, 90]) but higher specificity (64% [57, 71]; n=3187); at 10% tuberculosis prevalence, these CRP-based strategies would require 272 and 244 fewer Xpert tests per 1,000 PLHIV than W4SS but miss two and one more cases, respectively. ii. We obtained data for all six eligible studies (n=3,660 participants). The pooled proportion of inpatients eligible for Xpert was 90% (89, 91; n=3,658). Among screening tools to guide Xpert testing, W4SS and CRP (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin (< 8 g/dL), body mass index (sensitivity of sputum Xpert Ultra was higher than sputum Xpert (73% [62, 81] vs 57% [47, 67]) and specificities were similar. Among outpatients on ART, W4SS sensitivity was 53% (35, 71) and specificity was 71% (51, 85). In this population, a parallel strategy (two or more screening tests offered 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=2,670) than W4SS alone; at a 5% tuberculosis prevalence, this strategy would require 379 more Xpert tests per 1,000 PLHIV than W4SS but detect 18 more cases. Among outpatients not on ART, W4SS sensitivity was 85% (76, 91) and specificity was 37% (25, 51). CRP (≥10 mg/L) had a similar sensitivity (83% [79, 86]), but higher specificity (67% [60, 73]; n=3,187) and a sequential strategy (second screening test offered only if first screening test is positive) of W4SS then CRP (≥5 mg/L) also had similar sensitivity (84% [75, 90]) but higher specificity (64% [57, 71]; n=3187); at 10% tuberculosis prevalence, these CRP-based strategies would require 272 and 244 fewer Xpert tests per 1,000 PLHIV than W4SS but miss two and one more cases, respectively. ii. We obtained data for all six eligible studies (n=3,660 participants). The pooled proportion of inpatients eligible for Xpert was 90% (89, 91; n=3,658). Among screening tools to guide Xpert testing, W4SS and CRP (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin (< 8 g/dL), body mass index (<18.5 kg/m²) and lymphadenopathy had higher specificities (61–90%) but low sensitivities (12–57%). The WHO Xpert algorithm had sensitivity of 76% (67, 84) and specificity of 93% (88, 96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (69, 85) and specificity was 93% (87, 96; n=639). We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM testing using WHO criteria was 93% (91, 95). Among screening tools to guide LF-LAM testing, WHO criteria, CRP (≥5 mg/L), and CD4 count (< 8 g/dL), body mass index (<18.5 kg/m2) lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM for all had the same sensitivity (62% [47, 75]) and specificity (88% [64, 97]) as WHO AlereLAM algorithm. Sensitivities of FujiLAM and AlereLAM were 69% and 48%, while specificities were 88% and 96%, respectively. In 2 studies that 4 collected sputum and non-sputum samples for Xpert and/or culture, diagnostic yield of sputum Xpert was 40–41%, 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 61%, 81%, and 92% of all cases, respectively. Conclusion These findings informed the updated 2021 WHO guidelines on tuberculosis screening in PLHIV. Among outpatient PLHIV, the WHO-recommended W4SS has suboptimal diagnostic accuracy and clinical utility. CRP reduces the need for further Xpert confirmatory testing compared with W4SS without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. CRP also shows utility when used in a CPM. However, CRP data were scarce for outpatients on ART, necessitating future research on the accuracy of CRP in this subgroup. Chest X-ray can be useful in outpatients on ART when combined with W4SS. The WHO Xpert algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and may be considered if resources permit. Among HIV-positive inpatients, WHO screening criteria and other potential screening tools to guide Xpert and AlereLAM testing have suboptimal performance. Based on these findings, WHO now strongly recommends Xpert testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%. The findings in this thesis also support that AlereLAM testing be implemented in all HIV-positive medical inpatients. 5 Routine FujiLAM testing in all HIV-positive medical inpatients may substantially improve tuberculosis diagnosis, but prospective evaluation of this novel assay is required

Systematic review of facility-based sexual and reproductive health services for female sex workers in Africa

Background: Several biological, behavioural, and structural risk factors place female sex workers (FSWs) at heightened risk of HIV, sexually transmitted infections (STIs), and other adverse sexual and reproductive health (SRH) outcomes. FSW projects in many settings have demonstrated effective ways of altering this risk, improving the health and wellbeing of these women. Yet the optimum delivery model of FSW projects in Africa is unclear. This systematic review describes intervention packages, service-delivery models, and extent of government involvement in these services in Africa. Methods: On 22 November 2012, we searched Web of Science and MEDLINE, without date restrictions, for studies describing clinical and non-clinical facility-based SRH prevention and care services for FSWs in low- and middle-income countries in Africa. We also identified articles in key non-indexed journals and on websites of international organizations. A single reviewer screened titles and abstracts, and extracted data from articles using standardised tools. Results: We located 149 articles, which described 54 projects. Most were localised and small-scale; focused on research activities (rather than on large-scale service delivery); operated with little coordination, either nationally or regionally; and had scanty government support (instead a range of international donors generally funded services). Almost all sites only addressed HIV prevention and STIs. Most services distributed male condoms, but only 10% provided female condoms. HIV services mainly encompassed HIV counselling and testing; few offered HIV care and treatment such as CD4 testing or antiretroviral therapy (ART). While STI services were more comprehensive, periodic presumptive treatment was only provided in 11 instances. Services often ignored broader SRH needs such as family planning, cervical cancer screening, and gender-based violence services. Conclusions: Sex work programmes in Africa have limited coverage and a narrow scope of services and are poorly coordinated with broader HIV and SRH services. To improve FSWs’ health and reduce onward HIV transmission, access to ART needs to be addressed urgently. Nevertheless, HIV prevention should remain the mainstay of services. Service delivery models that integrate broader SRH services and address structural risk factors are much needed. Government-led FSW services of high quality and scale would markedly reduce SRH vulnerabilities of FSWs in Africa

Systematic review of facility-based sexual and reproductive health services for female sex workers in Africa

Abstract Background: Several biological, behavioural, and structural risk factors place female sex workers (FSWs) at heightened risk of HIV, sexually transmitted infections (STIs), and other adverse sexual and reproductive health (SRH) outcomes. FSW projects in many settings have demonstrated effective ways of altering this risk, improving the health and wellbeing of these women. Yet the optimum delivery model of FSW projects in Africa is unclear. This systematic review describes intervention packages, service-delivery models, and extent of government involvement in these services in Africa. Methods: On 22 November 2012, we searched Web of Science and MEDLINE, without date restrictions, for studies describing clinical and non-clinical facility-based SRH prevention and care services for FSWs in low-and middle-income countries in Africa. We also identified articles in key non-indexed journals and on websites of international organizations. A single reviewer screened titles and abstracts, and extracted data from articles using standardised tools

Community empowerment and involvement of female sex workers in targeted sexual and reproductive health interventions in Africa: A systematic review

Background: Female sex workers (FSWs) experience high levels of sexual and reproductive health (SRH) morbidity, violence and discrimination. Successful SRH interventions for FSWs in India and elsewhere have long prioritised community mobilisation and structural interventions, yet little is known about similar approaches in African settings. We systematically reviewed community empowerment processes within FSW SRH projects in Africa, and assessed them using a framework developed by Ashodaya, an Indian sex worker organisation.Methods: In November 2012 we searched Medline and Web of Science for studies of FSW health services in Africa, and consulted experts and websites of international organisations. Titles and abstracts were screened to identify studies describing relevant services, using a broad definition of empowerment. Data were extracted on service-delivery models and degree of FSW involvement, and analysed with reference to a four-stage framework developed by Ashodaya. This conceptualises community empowerment as progressing from (1) initial engagement with the sex worker community, to (2) community involvement in targeted activities, to (3) ownership, and finally, (4) sustainability of action beyond the community.Results: Of 5413 articles screened, 129 were included, describing 42 projects. Targeted services in FSW 'hotspots' were generally isolated and limited in coverage and scope, mostly offering only free condoms and STI treatment. Many services were provided as part of research activities and offered via a clinic with associated community outreach. Empowerment processes were usually limited to peer-education (stage 2 of framework). Community mobilisation as an activity in its own right was rarely documented and while most projects successfully engaged communities, few progressed to involvement, community ownership or sustainability. Only a few interventions had evolved to facilitate collective action through formal democratic structures (stage 3). These reported improved sexual negotiating power and community solidarity, and positive behavioural and clinical outcomes. Sustainability of many projects was weakened by disunity within transient communities, variable commitment of programmers, low human resource capacity and general resource limitations.Conclusions: Most FSW SRH projects in Africa implemented participatory processes consistent with only the earliest stages of community empowerment, although isolated projects demonstrate proof of concept for successful empowerment interventions in African settings

Perspectives on the methods of a large systematic mapping of maternal health interventions.

BACKGROUND: Mapping studies describe a broad body of literature, and differ from classical systematic reviews, which assess more narrowly-defined questions and evaluate the quality of the studies included in the review. While the steps involved in mapping studies have been described previously, a detailed qualitative account of the methodology could inform the design of future mapping studies. OBJECTIVES: Describe the perspectives of a large research team on the methods used and collaborative experiences in a study that mapped the literature published on maternal health interventions in low- and middle-income countries (2292 full text articles included, after screening 35,048 titles and abstracts in duplicate). METHODS: Fifteen members of the mapping team, drawn from eight countries, provided their experiences and perspectives of the study in response to a list of questions and probes. The responses were collated and analysed thematically following a grounded theory approach. RESULTS: The objectives of the mapping evolved over time, posing difficulties in ensuring a uniform understanding of the purpose of the mapping among the team members. Ambiguity of some study variables and modifications in data extraction codes were the main threats to the quality of data extraction. The desire for obtaining detailed information on a few topics needed to be weighed against the benefits of collecting more superficial data on a wider range of topics. Team members acquired skills in systematic review methodology and software, and a broad knowledge of maternal health literature. Participation in analysis and dissemination was lower than during the screening of articles for eligibility and data coding. Though all respondents believed the workload involved was high, study outputs were viewed as novel and important contributions to evidence. Overall, most believed there was a favourable balance between the amount of work done and the project's outputs. CONCLUSIONS: A large mapping of literature is feasible with a committed team aiming to build their research capacity, and with a limited, simplified set of data extraction codes. In the team's view, the balance between the time spent on the review, and the outputs and skills acquired was favourable. Assessments of the value of a mapping need, however, to take into account the limitations inherent in such exercises, especially the exclusion of grey literature and of assessments of the quality of the studies identified

Mapping of research on maternal health interventions in low- and middle-income countries: a review of 2292 publications between 2000 and 2012.

BACKGROUND: Progress in achieving maternal health goals and the rates of reductions in deaths from individual conditions have varied over time and across countries. Assessing whether research priorities in maternal health align with the main causes of mortality, and those factors responsible for inequitable health outcomes, such as health system performance, may help direct future research. The study thus investigated whether the research done in low- and middle-income countries (LMICs) matched the principal causes of maternal deaths in these settings. METHODS: Systematic mapping was done of maternal health interventional research in LMICs from 2000 to 2012. Articles were included on health systems strengthening, health promotion; and on five tracer conditions (haemorrhage, hypertension, malaria, HIV and other sexually transmitted infections (STIs)). Following review of 35,078 titles and abstracts in duplicate, data were extracted from 2292 full-text publications. RESULTS: Over time, the number of publications rose several-fold, especially in 2004-2007, and the range of methods used broadened considerably. More than half the studies were done in sub-Saharan Africa (55.4 %), mostly addressing HIV and malaria. This region had low numbers of publications per hypertension and haemorrhage deaths, though South Asia had even fewer. The proportion of studies set in East Asia Pacific dropped steadily over the period, and in Latin America from 2008 to 2012. By 2008-2012, 39.1 % of articles included health systems components and 30.2 % health promotion. Only 5.4 % of studies assessed maternal STI interventions, diminishing with time. More than a third of haemorrhage research included health systems or health promotion components, double that of HIV research. CONCLUSION: Several mismatches were noted between research publications, and the burden and causes of maternal deaths. This is especially true for South Asia; haemorrhage and hypertension in sub-Saharan Africa; and for STIs worldwide. The large rise in research outputs and range of methods employed indicates a major expansion in the number of researchers and their skills. This bodes well for maternal health if variations in research priorities across settings and topics are corrected

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

Local and foreign authorship of maternal health interventional research in low- and middle-income countries: systematic mapping of publications 2000-2012.

BACKGROUND: Researchers in low- and middle-income countries (LMICs) are under-represented in scientific literature. Mapping of authorship of articles can provide an assessment of data ownership and research capacity in LMICs over time and identify variations between different settings. METHODS: Systematic mapping of maternal health interventional research in LMICs from 2000 to 2012, comparing country of study and of affiliation of first authors. Studies on health systems or promotion; community-based activities; and haemorrhage, hypertension, HIV/STIs and malaria were included. Following review of 35,078 titles and abstracts, 2292 full-text publications were included. Data ownership was measured by the proportion of articles with an LMIC lead author (author affiliated with an LMIC institution). RESULTS: The total number of papers led by an LMIC author rose from 45.0/year in 2000-2003 to 98.0/year in 2004-2007, but increased only slightly thereafter to 113.1/year in 2008-2012. In the same periods, the proportion of papers led by a local author was 58.4 %, 60.8 % and 60.1 %, respectively. Data ownership varies markedly between countries. A quarter of countries led more than 75 % of their research; while in 10 countries, under 25 % of publications had a local first author. Researchers at LMIC institutions led 56.6 % (1297) of all papers, but only 26.8 % of systematic reviews (65/243), 29.9 % of modelling studies (44/147), and 33.2 % of articles in journals with an Impact Factor ≥5 (61/184). Sub-Saharan Africa authors led 54.2 % (538/993) of studies in the region, while 73.4 % did in Latin America and the Caribbean (223/304). Authors affiliated with United States (561) and United Kingdom (207) institutions together account for a third of publications. Around two thirds of USAID and European Union funded studies had high-income country leads, twice as many as that of Wellcome Trust and Rockefeller Foundation. CONCLUSIONS: There are marked gaps in data ownership and these have not diminished over time. Increased locally-led publications, however, does suggest a growing capacity in LMIC institutions to analyse and articulate research findings. Differences in author attribution between funders might signal important variations in funders' expectations of authorship and discrepancies in how funders understand collaboration. More stringent authorship oversight and reconsideration of authorship guidelines could facilitate growth in LMIC leadership. Left unaddressed, deficiencies in research ownership will continue to hinder alignment between the research undertaken and knowledge needs of LMICs