Integrated TB and HIV care for Mozambican children: temporal trends, site-level determinants of performance, and recommendations for improved TB preventive treatment.

BACKGROUND: Pediatric tuberculosis (TB), human immunodeficiency virus (HIV), and TB-HIV co-infection are health problems with evidence-based diagnostic and treatment algorithms that can reduce morbidity and mortality. Implementation and operational barriers affect adherence to guidelines in many resource-constrained settings, negatively affecting patient outcomes. This study aimed to assess performance in the pediatric HIV and TB care cascades in Mozambique. METHODS: A retrospective analysis of routine PEPFAR site-level HIV and TB data from 2012 to 2016 was performed. Patients 0-14 years of age were included. Descriptive statistics were used to report trends in TB and HIV indicators. Linear regression was done to assess associations of site-level variables with performance in the pediatric TB and HIV care cascades using 2016 data. RESULTS: Routine HIV testing and cotrimoxazole initiation for co-infected children in the TB program were nearly optimal at 99% and 96% in 2016, respectively. Antiretroviral therapy (ART) initiation was lower at 87%, but steadily improved from 2012 to 2016. From the HIV program, TB screening at the last consultation rose steadily over the study period, reaching 82% in 2016. The percentage of newly enrolled children who received either TB treatment or isoniazid preventive treatment (IPT) also steadily improved in all provinces, but in 2016 was only at 42% nationally. Larger volume sites were significantly more likely to complete the pediatric HIV and TB care cascades in 2016 (p value range 0.05 to < 0.001). CONCLUSIONS: Mozambique has made significant strides in improving the pediatric care cascades for children with TB and HIV, but there were missed opportunities for TB diagnosis and prevention, with IPT utilization being particularly problematic. Strengthened TB/HIV programming that continues to focus on pediatric ART scale-up while improving delivery of TB preventive therapy, either with IPT or newer rifapentine-based regimens for age-eligible children, is needed.

Sociocultural understanding of Tuberculosis and implications for care-seeking among adults in the province of Zambezia, Mozambique: Qualitative research.

INTRODUCTION: Mozambique has a high burden of Tuberculosis (TB) with an incidence of 368 per 100,000 population in 2020, coupled with a low all-form TB detection rate. The COVID-19 pandemic has exacerbated delays in timely diagnosis and treatment of new TB cases. Promoting active TB case finding is a national priority in Mozambique. We conducted qualitative research to explore factors influencing TB testing in Zambezia province in Mozambique. MATERIALS AND METHODS: One-to-one, semi-structured, audio-recorded telephone interviews were conducted to explore TB-related knowledge, and barriers and facilitators to TB testing. A sample of two TB Program staff, two community providers of TB services, and 19 community members (10 women and 9 men) was recruited, with support from provincial government TB staff, from four districts in Zambezia with a high TB burden. Interviews were transcribed verbatim, and thematic analysis was conducted. The Mozambican National Bioethics Committee for Health approved the study protocol. RESULTS: Our study highlights that knowledge about TB symptoms and its causes is low, which could delay timely TB testing. Sociocultural beliefs often implicate certain types of sexual activity and women as causes of TB symptoms; for example, having sex with a widow who has not been traditionally purified, or with a woman who has had an abortion. Therefore, people usually tend to first seek care from traditional healers instead of going to a health facility. Additionally, stigma associated with HIV and TB also delays care seeking. Gender-related disparities in TB care seeking were also evident. CONCLUSIONS: This study provides valuable insights into how healthcare seeking for TB is influenced by sociocultural understanding of symptoms and gender dynamics. Therefore, interventions to promote timely and appropriate care seeking for TB should be contextually tailored, culturally appropriate, and gender sensitive.

Emergence of bedaquiline-resistant tuberculosis and of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains with rpoB Ile491Phe mutation not detected by Xpert MTB/RIF in Mozambique: a retrospective observational study.

BACKGROUND: In 2021, an estimated 4800 people developed rifampicin-resistant tuberculosis in Mozambique, 75% of which went undiagnosed. Detailed molecular data on rifampicin-resistant and multidrug-resistant (MDR) tuberculosis are not available. Here, we aimed at gaining precise data on the determinants of rifampicin-resistant and MDR tuberculosis in Mozambique. METHODS: In this retrospective observational study, we performed whole-genome sequencing of 704 rifampicin-resistant Mycobacterium tuberculosis complex (Mtbc) strains submitted to the National Tuberculosis Reference Laboratory (NTRL) in Maputo, Mozambique, between 2015 and 2021. Phylogenetic strain classification, genomic resistance prediction, and cluster analysis were performed. FINDINGS: Between Jan 1, 2015, and July 31, 2021, 2606 Mtbc isolates with an isoniazid or rifampicin resistance were identified in the NTRL biobank, of which, 1483 (56·9%) were from men, 1114 (42·7%) from women, and nine (0·4%) were unknown. Genome-based drug-resistant prediction classified 704 Mtbc strains as rifampicin resistant. 628 (89%) of the 704 Mtbc strains were classified MDR; of those, 146 (23%) were pre-extensively drug resistant (pre-XDR; additional fluoroquinolone resistance), and 24 (4%) extensively drug resistant (XDR; combined fluoroquinolone and bedaquiline resistance). Overall, 61 (9%) of 704 strains revealed resistance to bedaquiline: five (7%) of 76 rifampicin resistant plus bedaquiline resistant, 32 (7%) of 458 MDR plus bedaquiline resistant, and 24 (100%) of 24 XDR. Prevalence of bedaquiline resistance increased from 3% in 2016 to 14% in 2021. The cluster rate (12 single-nucleotide polymorphism threshold) was 42% for rifampicin-resistant strains, 78% for MDR strains, 94% for pre-XDR strains, and 96% for XDR Mtbc strains. 31 (4%) of 704 Mtbc strains, belonging to a diagnostic escape outbreak strain previously described in Eswatini (group_56), had an rpoB Ile491Phe mutation which is not detected by Xpert MTB/RIF (no other rpoB mutation). Of these, 23 (74%) showed additional resistance to bedaquiline, 13 (42%) had bedaquiline and fluoroquinolone resistance, and two (6%) were bedaquiline, fluoroquinolone, and delamanid resistant. INTERPRETATION: Pre-XDR resistance is highly prevalent among MDR Mtbc strains in Mozambique and so is bedaquiline resistance; and the frequency of bedaquiline resistance quadrupled over time and was found even in Mtbc strains without fluoroquinolone resistance. Importantly, strains with Ile491Phe mutation were frequent, accounting for 31% (n=10) of MDR plus bedaquiline-resistant strains and 54% (n=13) of XDR Mtbc strains. Given the current diagnostic algorithms and treatment regimens, both the emergence of rifampicin resistance due to Ile491Phe and bedaquiline resistance might jeopardise MDR tuberculosis prevention and care unless sequencing-based technology is rolled out. The potential cross border spread of diagnostic escape strains needs further investigation. FUNDING: The German Ministry of Health through the Seq_MDRTB-Net project, the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy Precision Medicine in Inflammation and the Research Training Group 2501 TransEvo, the Leibniz Science Campus Evolutionary Medicine of the Lung, and the German Ministry of Education and Research via the German Center for Infection Research.

Evaluation of radiological capacity and usage in paediatric TB diagnosis: A mixed-method protocol of a comparative study in Mozambique, South Africa and Spain.

INTRODUCTION: Tuberculosis remains one of the top ten causes of mortality globally. Children accounted for 12% of all TB cases and 18% of all TB deaths in 2022. Paediatric TB is difficult to diagnose with conventional laboratory tests, and chest radiographs remain crucial. However, in low-and middle-income countries with high TB burden, the capacity for radiological diagnosis of paediatric TB is rarely documented and data on the associated radiation exposure limited. METHODS: A multicentre, mixed-methods study is proposed in three countries, Mozambique, South Africa and Spain. At the national level, official registry databases will be utilised to retrospectively compile an inventory of licensed imaging resources (mainly X-ray and Computed Tomography (CT) scan equipment) for the year 2021. At the selected health facility level, three descriptive cross-sectional standardised surveys will be conducted to assess radiology capacity, radiological imaging diagnostic use for paediatric TB diagnosis, and radiation protection optimization: a site survey, a clinician-targeted survey, and a radiology staff-targeted survey, respectively. At the patient level, potential dose optimisation will be assessed for children under 16 years of age who were diagnosed and treated for TB in selected sites in each country. For this component, a retrospective analysis of dosimetry will be performed on TB and radiology data routinely collected at the respective sites. National inventory data will be presented as the number of units per million people by modality, region and country. Descriptive analyses will be conducted on survey data, including the demographic, clinical and programmatic characteristics of children treated for TB who had imaging examinations (chest X-ray (CXR) and/or CT scan). Dose exposure analysis will be performed by children's age, gender and disease spectrum. DISCUSSION: As far as we know, this is the first multicentre and multi-national study to compare radiological capacity, radiation protection optimization and practices between high and low TB burden settings in the context of childhood TB management. The planned comparative analyses will inform policy-makers of existing radiological capacity and deficiencies, allowing better resource prioritisation. It will inform clinicians and radiologists on best practices and means to optimise the use of radiological technology in paediatric TB management.

Improving tuberculosis case detection through contact risk stratification by Xpert MTB/RIF Ultra and spatial parameters: Evaluation of an innovative active case finding strategy in Mozambique (Xpatial-TB).

Prompt diagnosis is critical for tuberculosis (TB) control, as it enables early treatment which in turn, reduces transmission and improves treatment outcomes. We investigated the impact on TB diagnosis of introducing Xpert Ultra as the frontline diagnostic test, combined with an innovative active-case finding (ACF) strategy (based on Xpert Ultra semi-quantitative results and spatial parameters), in a semi-rural district of Southern Mozambique. From January-December 2018 we recruited incident TB-cases (index cases, ICs) and their household contacts (HCs). Recruitment of close community contacts (CCs) depended on IC´s Xpert Ultra results, and the population density of their area. TB-contacts, either symptomatic or people living with HIV, were asked to provide a spot sputum for lab-testing. Trends on TB case notification were compared to the previous years and to those of two districts in the south of the Maputo province (control area), using an interrupted time series analysis with and without control (CITS/ITS). A total of 1010 TB ICs (37.1% laboratory-confirmed) were recruited; 3165 HCs and 4730 CCs were screened for TB. Eighty-nine additional TB cases were identified through the ACF intervention (52.8% laboratory-confirmed). The intervention increased by 8.2% all forms of TB cases detected in 2018. Xpert Ultra trace positive results accounted for a high proportion of laboratory confirmations in the ACF cohort (51.1% vs 13.7% of those passively diagnosed). The Number Needed to Screen to find a TB case differed widely among HCs (55) and CCs (153). During the intervention period, a reversal of the previous negative trend in lab-confirmed case notifications was observed in the district. However, the CITS model did not show any statistically significant difference compared to the control area. Paediatric population benefited the most from the ACF strategy and HCs screening seemed an effective intervention to find microbiological confirmed cases in early stages of the disease.

Evaluation of the multidrug-resistant tuberculosis surveillance system in Maputo City, Mozambique in the period 2017-2018.

Introduction: multidrug-resistant tuberculosis (MDR-TB) remains a public health problem worldwide. In Mozambique, cases of MDR-TB have increased annually. In 2018, 1,206 cases were reported, as compared to 943 cases in 2017. The aim of this study was to assess the surveillance system for multidrug-resistant tuberculosis in Maputo City. Methods: an extract from the national database was considered for a cut-out of the City of Maputo in the period 2017-2018; the study was conducted per the guidelines of the Centers for Disease Control and Prevention, where the description of the system was carried out, and evaluation of the attributes. Each attribute was evaluated according to the established criteria and parameters. Results: the surveillance system is based on the collection of data in health centers. Four hundred and six cases of MDR-TB were notified, of which 56.8% (231/406) were male and 95.9% (386/406) were ≥15 years. The system was complex with 4 levels of information transmission. With regard to flexibility, there was no changing the variables in the database. Acceptability was good. The quality of the data was regular with discrepancy of data of 14.5%. The system was considered stable as there was no system interruption. Timeliness with case notification monthly. The system sensitivity was 72.9%, the positive predictive value (PPV) was 2.3% and regarding utility the system has fulfilled its objectives. Conclusion: the system was not flexible, the data quality was regular, had moderate sensitivity and low positive predictive value. Continuous assessment of data and scale up the diagnosis for the detection of cases of MDR-TB is recommended.

Extrapulmonary tuberculosis mortality according to clinical and point of care ultrasound features in Mozambique.

In resource-limited settings, point-of-care ultrasound (POCUS) has great potential to support the timely diagnosis of extrapulmonary tuberculosis (EPTB). We aim to determine the in-hospital mortality due to EPTB according to clinical and POCUS features and risk factors in newly diagnosed patients hospitalized for EPTB in Chókwè district, Mozambique. We analyzed routinely collected data from paper medical files and electronic POCUS records of EPTB in infected patients aged 15 years or older and admitted to Carmelo Hospital of Chókwè from 2016 to 2020. Kaplan-Meier survival curves and adjusted Cox regression analyses were used to model predictors of mortality and time to death. The 390 included in-patients with EPTB and POCUS data contributed a total of 6240 in-hospital person-days of observation. The overall mortality rate was 2.16 per 100 person-days. Adjusted Cox regression showed a higher risk of death in those with abdominal tenderness (adjusted hazard ratio [aHR] 1.61, 95% confidence interval [CI] 1.00-2.82, p = 0.050), antiretroviral treatment (ART) for more than 90 days (aHR 4.03, 95% CI 1.50-10.78, p = 0.006), and mixed patterns on kidney POCUS (aHR 2.91, 95% CI 1.38-6.10, p = 0.005). An optimal immunovirological response to ART was a protective factor against death [aHR] 0.12, 95% CI 0.04-0.35, p < 0.001). Variables associated with an increased risk of death were male gender, abdominal pain, ART for more than three months (with immunovirological failure or non-response to ART) and having a mixed pattern of kidney POCUS characteristics. Early detection of these risk factors may have a direct impact on reducing TB mortality, and the POCUS approach as a complementary diagnostic method for EPTB provides a simple, feasible and affordable intervention in resource-limited settings like Mozambique.