Background Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy. Objectives To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction. Selection criteria We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays. Data collection and analysis Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results. Main results We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1). Authors' conclusions Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

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Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis

Background
Tuberculosis is a leading cause of infectious disease‐related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one‐third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection.

Objectives
To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high‐risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough).

To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high‐risk groups and in the general population.

Search methods
We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies.

Selection criteria
Cross‐sectional and cohort studies in which adults (15 years and older) in high‐risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture‐based drug susceptibility testing and line probe assays.

Data collection and analysis
Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS‐2. We used a bivariate random‐effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high‐risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high‐risk groups combined.

Main results
We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV‐burden countries. We judged most studies to have low risk of bias in all four QUADAS‐2 domains and low concern for applicability.

Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis

In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate‐certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high‐certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF‐positive; of these, 9 (22%) would not have tuberculosis (false‐positives); and 960 would be Xpert MTB/RIF‐negative; of these, 19 (2%) would have tuberculosis (false‐negatives).

In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low‐certainty evidence) and 98% (97 to 99) (503 participants; moderate‐certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra‐positive; of these, 19 (36%) would not have tuberculosis (false‐positives); and 947 would be Xpert Ultra‐negative; of these, 16 (2%) would have tuberculosis (false‐negatives).

In non‐hospitalized people in high‐risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low‐certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate‐certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF‐positive; of these, 12 (63%) would not have tuberculosis (false‐positives); and 981 would be Xpert MTB/RIF‐negative; of these, 3 (0%) would have tuberculosis (false‐negatives).

We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population.

Xpert MTB/RIF as a screening test for rifampicin resistance

Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low‐certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate‐certainty evidence).

Authors' conclusions
Of the high‐risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non‐hospitalized people in high‐risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high‐risk for tuberculosis, or in the general population.

Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms

Introduction Most sub-Saharan African countries endure a high burden of communicable infections but also face a rise of non-communicable diseases (NCDs). Interventions targeting particular epidemics are often executed within vertical programmes. We establish an Adaptive Diseases control Expert Programme in Tanzania (ADEPT) model with three domains; stepwise training approach, integration of communicable and NCDs and a learning system. The model aims to shift traditional vertical programmes to an adaptive diseases management approach through integrating communicable and NCDs using the tuberculosis (TB) and diabetes mellitus (DM) dual epidemic as a case study. We aim to describe the ADEPT protocol with underpinned implementation and operational research on TB/DM. Methods and analysis The model implement a collaborative TB and DM services protocol as endorsed by WHO in Tanzania. Evaluation of the process and outcomes will follow the logic framework. A mixed research design with both qualitative and quantitative approaches will be used in applied research action. Anticipated implementation research outcomes include at the health facilities level for organising TB/DM services, pathways of patients with TB/DM seeking care in different health facilities, factors in service delivery that need deimplementation and the ADEPT model implementation feasibility, acceptability and fidelity. Expected operational research outcomes include additional identified patients with dual TB/DM, the prevalence of comorbidities like hypertension in patients with TB/DM and final treatment outcomes of TB/DM including treatment-related complications. Findings will inform the future policies and practices for integrating communicable and NCDs services. Ethics and dissemination Ethical approval was granted by The National Research Health Ethical Committee (Ref-No. NIMR/HQ/R.8a/Vol.IX/2988) and the implementation endorsed by the government authorities. Findings will be proactively disseminated through multiple mechanisms including peer-reviewed journals, and engagement with various stakeholders’ example in conferences and social media.

https://bmjopen.bmj.com/content/bmjopen/11/4/e041521.full.pdf

Protocol for establishing an Adaptive Diseases control Expert Programme in Tanzania (ADEPT) for integrating care of communicable and non-communicable diseases using tuberculosis and diabetes as a case study.

Introduction Digital Adherence Tools (DAT) to promote adherence to antiretroviral treatment (ART) for HIV are being increasingly adopted globally, however their effectiveness and acceptability in limited resource settings has been challenging. In this study, we examine the acceptability of DATs to improve adherence to ART. Methods This study was part of a three-arm randomized controlled trial (REMIND) which investigated the effect of two different DAT's: SMS text messages (SMS) or real-time medication monitoring (RTMM) on treatment adherence; compared to standard of care. Exit interviews and in-depth interviews were conducted at 48 weeks follow-up, to collect data on their experiences (successes, challenges, and barriers) and behaviours regarding the implementation of the interventions. Translated transcripts, memos and field notes were imported to NVivo software version 12. We used a thematic framework analysis which drew from Sekhon's theoretical framework of acceptability (TFA), which comprises of seven constructs (affective attitude, perceived burden, perceived effectiveness, ethicality, self-efficacy, intervention coherence and opportunity costs). Results Of the 166 participants enrolled, 143 (86%) were interviewed (68 in the SMS arm and 75 in the RTMM arm). Participants were highly satisfied (98%) with the DAT system and the majority of them reported it motivated them to take their medication (99%). The majority of participants reported they were confident in their ability to comply with the intervention and understood how the intervention worked (97%). Very few reported negatively about the devices (carrying the device), with only 6% reporting that they did not feel comfortable and 8% had ethical concerns with the SMS-content A few participants reported challenges with their connectivity/network and that the visits were too time-consuming. A few participants reported that they incurred extra cost for the sake of the study. Conclusion Overall, the acceptability of these DATs was high. However, several factors may hamper their acceptability including the content and number of SMS, carrying the devices and the network availability.

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"I Wish to Continue Receiving the Reminder Short Messaging Service": A Mixed Methods Study on the Acceptability of Digital Adherence Tools Among Adults Living with HIV on Antiretroviral Treatment in Tanzania.

The number of human immunodeficiency virus (HIV) positive adolescents in secondary school has increased over the years. Little is known on how the students cope to the pressures and demands of their academic and health lives in the boarding secondary schools. This study explored the factors surrounding their anti-retroviral therapy adherence as well as their experiences. We did a qualitative study that employed in-depth interviews amongst purposively selected 19 HIV positive adolescent students in boarding secondary school and seven key informants. Key informants were members of boarding secondary school staff directly taking care of the adolescents living with human immune virus and had spent at least two academic terms in that school. The study participants were recruited from four health facilities in Bushenyi district, southwestern Uganda, and key informants from five boarding secondary schools in Bushenyi. These were engaged in in-depth interviews using an interview guide. Data was transcribed, coded and the content analyzed thematically. Adolescents living with human immunodeficiency virus in boarding secondary school face challenges similar to adolescents outside boarding school settings. However, some challenges are unique to them. Students faced numerous barriers which made it difficult to adhere to their medication. Stigmatization in its different forms was also a major challenge amongst students. Willingness disclosure of serostatus was beneficial to the students since it guaranteed support while at school; facilitating adherence and better living. However, students were uneasy to disclose their status. Some students adopted negative coping mechanisms such as telling lies, escaping from school, and class to access medication. Adolescents in boarding secondary schools face similar challenges as compared to their counterparts with some being unique to them. Few school mechanisms help these students to cope while at school. Limited disclosure has proven useful but some adolescents have opted not to disclose their status and hence used negative coping mechanisms. These challenges need to be addressed and a safe environment to encourage limited disclosure should be made.

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Influence of boarding secondary school environment on HIV positive students in South Western Uganda.

Background: Despite effort to diagnose tuberculosis (TB) in the Human Immunodeficiency Virus (HIV) infected population, 45% of adults with HIV that had a previously unknown reason for death, demonstrated TB was the cause by autopsy examination. We aimed to assess the clinical outcomes of implementation a new algorithm for diagnosis and treatment of tuberculosis (TB) related sepsis among PLHIV presenting with life-threatening illness. Methods: This study is a prospective cohort conducted in three-referral hospitals in Kilimanjaro, recruited 97 PLHIV from February through June 2018. Patients provided urine and sputum samples for testing lateral flow – lipoarabinomannan (LF-LAM) and Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) assays, respectively. Anti-TB was prescribed to patients with positive LF-LAM or Xpert MTB/RIF or received broad-spectrum antibiotics but deteriorated. Results: Of 97 patients, 84 (87%) provided urine and sputa, and 13 (13%) provided only urine. The mean age (95% confidence interval) was 40 (38–43) years and 52 (54%) were female. In 84 patients, LF-LAM increased TB detection from 26 (31%) by Xpert MTB/RIF to 41 (55%) by both tests. Of 97 patients, 69 (71%) prescribed anti-TB, 67% (46/69) and 33% (23/69) had definitive and probable TB respectively. Sixteen (16.5%) patients died, of which one died before treatment, 73% (11/15) died within 7 days of admission. The 30-day survival was similar in both treatment groups (log rank = 0.1574). Mortality was significantly higher among hospitalized patients compared to outpatients (P ≤ 0.027). Conclusion: Implementation of new algorithm increased TB case detection in patients that could have been missed by Xpert MTB/RIF assay. Survival of PLHIV with confirmed or probable TB was comparable to those of PLHIV that were treated with broad-spectrum antibiotics alone. Further work should focus on the optimal timing and content of the immediate antimicrobial regimen for sepsis among PLHIV in TB-endemic settings.

Clinical outcomes of new algorithm for diagnosis and treatment of Tuberculosis sepsis in HIV patients.

Introduction Despite improvements in treatment (eg, reduction in pill intake), antiretroviral therapy (ART) is dispensed in socially inefficient and uneconomical packaging. To make pills less conspicuous and decrease the risk of being stigmatized, people living with HIV (PLWH) often engage in self-repackaging - the practice of transferring ART from original packaging to alternative containers. This behavior has been associated with ART nonadherence and failure to achieve viral load suppression. While much of the literature on ART packaging has centered around medication adherence, patients stated preferences for ART packaging and packaging attributes that influence the observed ART nonadherence are understudied. Methods We conducted a qualitative study to elucidate perceptions of ART packaging among PLWH at two large referral hospitals in Northern Tanzania. Interviews were conducted until thematic saturation was reached. Interviews were audio-recorded, transcribed and coded. Results Of the 16 participants whose data were used in the final analysis, a majority were between 36 and 55 years of age (Mean 45.5 years SD: 11.1), had primary-level education (n=11, 68.8%), were self-employed (n=9, 56.3%), reported that they had self-repacked ART (n=14, 88%), and were taking ART for more than 6 years (n=11, 68.8%). Participants identified three attributes of ART packaging that increased anticipated HIV stigma and prompted self-repackaging, including visual identification, bulkiness, and the rattling noise produced by ART pill bottles. Conclusion Given the drastic reduction in the number of pills required for HIV treatment, there is an opportunity to not only assess the cost-effectiveness of innovative ART packaging but also evaluate the acceptability of such packaging among PLWH in order to address stigma and improve ART adherence.

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Does Antiretroviral Therapy Packaging Matter? Perceptions and Preferences of Antiretroviral Therapy Packaging for People Living with HIV in Northern Tanzania.

Seleman K Semvua

Papers

Clinical outcomes of new algorithm for diagnosis and treatment of Tuberculosis sepsis in HIV patients.

Does Antiretroviral Therapy Packaging Matter? Perceptions and Preferences of Antiretroviral Therapy Packaging for People Living with HIV in Northern Tanzania.