Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status.

Potential Mycobacterium tuberculosis (Mtb) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92% and 90% at presentation, 87% and 74% at 2 wk, 54% and 44% at 2 mo and 32% and 20% at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93%, 70%, 48% and 22% at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in ~30% of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.

Stability in care and risk of loss to follow-up among clients receiving community health worker-led differentiated HIV care: Results from a prospective cohort study in northern Tanzania.

BACKGROUND: HIV services in Tanzania are facility-based but facilities are often overcrowded. Differentiated care models (DCM) have been introduced into the National Guidelines. We piloted a Community Health Worker (CHW)-led HIV treatment club model (CHW-DCM) in an urban region, and assessed its effectiveness in comparison to the standard of care (SoC, facility-based model), in terms of stability in care, loss to follow-up (LTFU) and treatment adherence. METHODS: In two clinics in the Shinyanga region, clients established on ART (defined as stable clients by national guidelines as on first-line ART >6 months, undetectable viral load, no opportunistic infections or pregnancy, and good adherence) were offered CHW-DCM. This prospective cohort study included all stable clients who enrolled in CHW-DCM between July 2018 and March 2020 (CHW-DCM) and compared them to stable clients who remained in SoC during that period. Multivariable Cox regression models were used to analyse factors associated with continued stability in care and the risk of LTFU during 18 months of follow-up; treatment adherence was assessed by pill count and compared using Chi-square tests. RESULTS: Of 2472 stable clients, 24.5% received CHW-DCM and 75.5% SoC. CHW-DCM clients were slightly older (mean 42.8 vs. 37.9 years) and more likely to be female (36.2% vs. 32.2%). Treatment adherence was better among CHW-DCM than SoC: 96.6% versus 91.9% and 98.5% versus 92.2%, respectively (both p = 0.001). SoC clients were more likely to not remain stable over time than CHW-DCM (adjusted Hazard ratio [AHR] = 2.68; 95% CI: 1.86-3.90). There was no difference in LTFU (adjusted hazard ratio [AHR] = 1.54; 95%CI: 0.82-2.93). CONCLUSION: Clients attending CHW-DCM demonstrated better stability in care and treatment adherence than SoC, and the risk of LTFU was not increased. These findings demonstrate the potential of CHW in delivering community-based HIV services in the local Tanzanian context. These results could be used to extend this CHW-DCM model to similar settings.

Repurposing of anti-malarial drugs for the treatment of tuberculosis: realistic strategy or fanciful dead end?

BACKGROUND: Drug repurposing offers a strategic alternative to the development of novel compounds, leveraging the known safety and pharmacokinetic profiles of medications, such as linezolid and levofloxacin for tuberculosis (TB). Anti-malarial drugs, including quinolones and artemisinins, are already applied to other diseases and infections and could be promising for TB treatment. METHODS: This review included studies on the activity of anti-malarial drugs, specifically quinolones and artemisinins, against Mycobacterium tuberculosis complex (MTC), summarizing results from in vitro, in vivo (animal models) studies, and clinical trials. Studies on drugs not primarily developed for TB (doxycycline, sulfonamides) and any novel developed compounds were excluded. Analysis focused on in vitro activity (minimal inhibitory concentrations), synergistic effects, pre-clinical activity, and clinical trials. RESULTS: Nineteen studies, including one ongoing Phase 1 clinical trial, were analysed: primarily investigating quinolones like mefloquine and chloroquine, and, to a lesser extent, artemisinins. In vitro findings revealed high MIC values for anti-malarials versus standard TB drugs, suggesting a limited activity. Synergistic effects with anti-TB drugs were modest, with some synergy observed in combinations with isoniazid or pyrazinamide. In vivo animal studies showed limited activity of anti-malarials against MTC, except for one study of the combination of chloroquine with isoniazid. CONCLUSIONS: The repurposing of anti-malarials for TB treatment is limited by high MIC values, poor synergy, and minimal in vivo effects. Concerns about potential toxicity at effective dosages and the risk of antimicrobial resistance, especially where TB and malaria overlap, further question their repurposing. These findings suggest that focusing on novel compounds might be both more beneficial and rewarding.

Post-tuberculosis treatment paradoxical reactions.

Paradoxical reactions (PR) to tuberculosis (TB) treatment are common during treatment, but have also been described after treatment. A presentation with recurrent signs or symptoms of TB after cure or completion of prior treatment needs to be differentiated between microbiological relapse and a paradoxical reaction. We searched all published literature on post-treatment PR, and present a synthesis of 30 studies, focusing on the epidemiology, diagnosis and management of this phenomenon. We report an additional case vignette. The majority of studies were of lymph node TB (LN-TB), followed by central nervous system TB (CNS-TB). A total of 112 confirmed and 42 possible post-treatment PR cases were reported. The incidence ranged between 3 and 14% in LN-TB and was more frequent than relapses, and between 0 and 2% in all TB. We found four reports of pulmonary or pleural TB post-treatment PR cases. The incidence did not differ by length of treatment, but was associated with younger age at initial diagnosis, and having had a PR (later) during treatment. Post-treatment PR developed mainly within the first 6 months after the end of TB treatment but has been reported many years later (longest report 10 years). The mainstays of diagnosis and management are negative mycobacterial cultures and anti-inflammatory treatment, respectively. Due to the favourable prognosis in LN-TB recurrent symptoms, a short period of observation is warranted to assess for spontaneous regression. In CNS-TB with recurrent symptoms, immediate investigation and anti-inflammatory treatment with the possibility of TB retreatment should be undertaken.

A stool based qPCR for the diagnosis of TB in children and people living with HIV in Uganda, Eswatini and Mozambique (Stool4TB): a protocol for a multicenter diagnostic evaluation.

BACKGROUND: Tuberculosis (TB) is a major cause of mortality worldwide. Children and people living with HIV (PLHIV) have an increased risk of mortality, particularly in the absence of rapid diagnosis. The main challenges of diagnosing TB in these populations are due to the unspecific and paucibacillary disease presentation and the difficulty of obtaining respiratory samples. Thus, novel diagnostic strategies, based on non-respiratory specimens could improve clinical decision making and TB outcomes in high burden TB settings. We propose a multi-country, prospective diagnostic evaluation study with a nested longitudinal cohort evaluation to assess the performance of a new stool-based qPCR, developed by researchers at Baylor College of Medicine (Houston, Texas, USA) for TB bacteriological confirmation with promising results in pilot studies. METHODS: The study will take place in high TB/HIV burden countries (Mozambique, Eswatini and Uganda) where we will enroll, over a period of 30 months, 650 PLHIV (> 15) and 1295 children under 8 years of age (irrespective of HIV status) presenting pressumptive TB. At baseline, all participants will provide clinical history, complete a physical assessment, and undergo thoracic chest X-ray imaging. To obtain bacteriological confirmation, participants will provide respiratory samples (1 for adults, 2 in children) and 1 stool sample for Xpert Ultra MTB/RIF (Cepheid, Sunnyvale, CA, USA). Mycobacterium tuberculosis (M.tb) liquid culture will only be performed in respiratory samples and lateral flow lipoarabinomannan (LF-LAM) in urine following WHO recommendations. Participants will complete 2 months follow-up if they are not diagnosed with TB, and 6 months if they are. For analytical purposes, the participants in the pediatric cohort will be classified into "confirmed tuberculosis", "unconfirmed tuberculosis" and "unlikely tuberculosis". Participants of the adult cohort will be classified as "bacteriologically confirmed TB", "clinically diagnosed TB" or "not TB". We will assess accuracy of the novel qPCR test compared to bacteriological confirmation and Tb diagnosis irrespective of laboratory results. Longitudinal qPCR results will be analyzed to assess its use as treatment response monitoring. DISCUSSION: The proposed stool-based qPCR is an innovation because both the strategy of using a non-sputum based sample and a technique specially designed to detect M.tb DNA in stool. PROTOCOL REGISTRATION DETAILS: ClinicalTrials.gov Identifier: NCT05047315.

A prospective randomised controlled trial investigating household SARS-CoV-2 transmission in a densely populated community in Cape Town, South Africa - the transmission of COVID-19 in crowded environments (TRACE) study.

BACKGROUND: South Africa's first SARS-CoV-2 case was identified 5th March 2020 and national lockdown followed March 26th. Households are an important location for secondary SARS-CoV-2 infection. Physical distancing and sanitation - infection mitigation recommended by the World Health Organization (WHO) at the time - are difficult to implement in limited-resource settings because of overcrowded living conditions. METHODS: This study (ClinicalTrials.gov NCT05119348) was conducted from August 2020 to September 2021 in two densely populated, low socioeconomic Cape Town community sub-districts. New COVID-19 index cases (ICs) identified at public clinics were randomised to an infection mitigation intervention (STOPCOV) delivered by lay community health workers (CHWs) or standard of care group. STOPCOV mitigation measures included one initial household assessment conducted by a CHW in which face masks, sanitiser, bleach and written information on managing and preventing spread were provided. This was followed by regular telephonic follow-up from CHWs. SARS-CoV-2 PCR and IgM/IgG serology was performed at baseline, weeks 1, 2, 3 and 4 of follow-up. RESULTS: The study randomised 81 ICs with 245 HHCs. At baseline, no HHCs in the control and 7 (5%) in the intervention group had prevalent SARS-CoV-2. The secondary infection rate (SIR) based on SARS-CoV-2 PCR testing was 1.9% (n = 2) in control and 2.9% (n = 4) in intervention HHCs (p = 0.598). At baseline, SARS-CoV-2 antibodies were present in 15% (16/108) of control and 38% (52/137) of intervention participants. At study end incidence was 8.3% (9/108) and 8.03% (11/137) in the intervention and control groups respectively. Antibodies were present in 23% (25/108) of control HHCs over the course of the study vs. 46% (63/137) in the intervention arm. CHWs made twelve clinic and 47 food parcel referrals for individuals in intervention households in need. DISCUSSION: Participants had significant exposure to SARS-CoV-2 infections prior to the study. In this setting, household transmission mitigation was ineffective. However, CHWs may have facilitated other important healthcare and social referrals.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Effectiveness of provider-initiated versus client-initiated HIV testing by different health facility departments in Northern Tanzania.

BACKGROUND: HIV prevalence in Tanzania is still high at 4.7% among adults. Regular HIV testing is consistently advocated in the country to increase the level of awareness of HIV status, thus contributing to national HIV prevention. We report findings from three years of implementation of an HIV Test and Treat project utilizing provider-initiated and client-initiated testing and counselling (PITC and CITC). This study compared the effectiveness of PITC versus CITC in HIV case detection by the different departments of health facilities. METHOD: This retrospective cross-sectional study used health facility-based HIV testing data collected from adults aged 18 years and above between June 2017 - July 2019 in the Shinyanga region, Tanzania. Chi-square and logistic regression analysis were used to assess determinants of yield (HIV positivity). RESULTS: A total of 24,802 HIV tests were performed of which 15,814 (63.8%) were by PITC and 8,987 (36.2%) by CITC. Overall HIV positivity was 5.7%, higher among CITC at 6.6% than PITC at 5.2%. TB and IPD departments had the highest HIV positivity 11.8% and 7.8% respectively. Factors associated with a positive test were testing at a department in the facility compared to CITC, first-time test, and being or having been married compared to being single. CONCLUSION: Success in identifying HIV + patients was highest among people visiting the clinic for HIV testing (CITC) and first-time testers. With PITC, HIV + patient detection differed between departments, suggesting divergent risk profiles of respective clients and/or divergent HIV alertness of staff. This underscores the importance of increased targeting for PITC to identify HIV + patients.

Beyond viral suppression: Quality of life among stable ART clients in a differentiated service delivery intervention in Tanzania.

BACKGROUND: With antiretroviral therapy, more people living with HIV (PLHIV) in resource-limited settings are virally suppressed and living longer. WHO recommends differentiated service delivery (DSD) as an alternative, less resource-demanding way of expanding HIV services access. Monitoring client's health-related quality of life (HRQoL) is necessary to understand patients' perceptions of treatment and services but is understudied in sub-Saharan Africa. We assessed HRQoL among ART clients in Tanzania accessing two service models. METHODS: Cross-sectional survey from May-August 2019 among stable ART clients randomly sampled from clinics and clubs in the Shinyanga region providing DSD and clinic-based care. HRQoL data were collected using a validated HIV-specific instrument-Functional Assessment of HIV infection (FAHI), in addition to socio-demographic, HIV care, and service accessibility data. Descriptive analysis of HRQoL, logistic regression and a stepwise multiple linear regression were performed to examine HRQoL determinants. RESULTS: 629 participants were enrolled, of which 40% accessed DSD. Similar HRQoL scores [mean (SD), p-value]; FAHI total [152.2 (22.2) vs 153.8 (20.6), p 0.687] were observed among DSD and clinic-based care participants. Accessibility factors contributed more to emotional wellbeing among DSD participants compared to the clinic-based care participants (53.4% vs 18.5%, p = < 0.001). Satisfactory (> 80% of maximum score) HRQoL scoring was associated with (OR [95% CI], p-value) being male (2.59 [1.36-4.92], p 0.004) among clinic participants and with urban residence (4.72 [1.70-13.1], p 0.001) among DSD participants. CONCLUSIONS: Similar HRQoL was observed in DSD and clinic-based care. Our research highlights focus areas to identify supporting interventions, ultimately optimizing HRQoL among PLHIV.

High Rates of Recurrent Tuberculosis Disease: A Population-level Cohort Study.

BACKGROUND: Retreatment tuberculosis (TB) disease is common in high-prevalence settings. The risk of repeated episodes of recurrent TB is unknown. We calculated the rate of recurrent TB per subsequent episode by matching individual treatment episodes over a period of 13 years. METHODS: All recorded TB episodes in Cape Town between 2003 and 2016 were matched by probabilistic linkage of personal identifiers. Among individuals with a first episode notified in Cape Town and who completed their prior treatment successfully we estimated the recurrence rate stratified by subsequent episode and HIV status. We adjusted person-time to background mortality by age, sex, and HIV status. RESULTS: A total of 292 915 TB episodes among 263 848 individuals were included. The rate of recurrent TB was 16.4 per 1000 person-years (95% CI, 16.2-16.6), and increased per subsequent episode (8.4-fold increase, from 14.6 to 122.7 per 1000 from episode 2 to 6, respectively). These increases were similar stratified by HIV status. Rates among HIV positives were higher than among HIV negatives for episodes 2 and 3 (2- and 1.5-fold higher, respectively), and the same thereafter. CONCLUSIONS: TB recurrence rates were high and increased per subsequent episode, independent of HIV status. This suggests that HIV infection is insufficient to explain the high burden of recurrence; it is more likely due to a high annual risk of infection combined with an increased risk of infection or progression to disease associated with a previous TB episode. The very high recurrence rates would justify increased TB surveillance of patients with >1 episode.

Determine TB-LAM point-of-care tuberculosis assay predicts poor outcomes in outpatients during their first year of antiretroviral therapy in South Africa.

BACKGROUND: Determine TB-LAM is the first point-of-care test (POC) for HIV-associated tuberculosis (TB) and rapidly identifies TB in those at high-risk for short-term mortality. While the relationship between urine-LAM and mortality has been previously described, the outcomes of those undergoing urine-LAM testing have largely been assessed during short follow-up periods within diagnostic accuracy studies. We therefore sought to assess the relationship between baseline urine-LAM results and subsequent hospitalization and mortality under real-world conditions among outpatients in the first year of ART. METHODS: Consecutive, HIV-positive adults with a CD4 count < 100 cells/uL presenting for ART initiation were enrolled. TB diagnoses and outcomes (hospitalization, loss-to-follow and mortality) were recorded during the first year following enrolment. Baseline urine samples were retrospectively tested using the urine-LAM POC assay. Kaplan Meier survival curves were used to assess the cumulative probability of hospitalization or mortality in the first year of follow-up, according to urine-LAM status. Cox regression analyses were performed to determine independent predictors of hospitalization and mortality at three months and one year of follow-up. RESULTS: 468 patients with a median CD4 count of 59 cells/uL were enrolled. There were 140 patients (29.9%) with newly diagnosed TB in the first year of follow-up of which 79 (56.4%) were microbiologically-confirmed. A total of 18% (n = 84) required hospital admission and 12.2% (n = 57) died within a year of study entry. 38 out of 468 (8.1%) patients retrospectively tested urine-LAM positive - including 19.0% of those with microbiologically-proven TB diagnoses (n = 15/79) and 23.0% (n = 14/61) of those with clinical-only TB diagnoses; 9 of 38 (23.7%) of patients retrospectively testing LAM positive were never diagnosed with TB under routine program conditions. Among all patients (n = 468) in the first year of follow-up, a positive urine-LAM result was strongly associated with all-cause hospitalization and mortality with a corresponding adjusted hazard ratio (aHR) of 3.7 (95%CI, 1.9-7.1) and 2.6 (95%, 1.2-5.7), respectively. CONCLUSIONS: Systematic urine-LAM testing among ART-naïve HIV-positive outpatients with CD4 counts < 100 cells/uL detected TB cases that were missed under routine programme conditions and was highly predictive for subsequent hospitalization and mortality in the first year of ART.

Detection, survival and infectious potential of Mycobacterium tuberculosis in the environment: a review of the evidence and epidemiological implications.

Much remains unknown about Mycobacterium tuberculosis transmission. Seminal experimental studies from the 1950s demonstrated that airborne expulsion of droplet nuclei from an infectious tuberculosis (TB) patient is the primary route of transmission. However, these findings did not rule out other routes of M. tuberculosis transmission. We reviewed historical scientific evidence from the late 19th/early 20th century and contemporary studies investigating the presence, persistence and infectiousness of environmental M. tuberculosis We found both experimental and epidemiological evidence supporting the presence and viability of M. tuberculosis in multiple natural and built environments for months to years, presumably following contamination by a human source. Furthermore, several studies confirm M. tuberculosis viability and virulence in the environment using guinea pig and mouse models. Most of this evidence was historical; however, several recent studies have reported consistent findings of M. tuberculosis detection and viability in the environment using modern methods. Whether M. tuberculosis in environments represents an infectious threat to humans requires further investigation; this may represent an untapped source of data with which to further understand M. tuberculosis transmission. We discuss potential opportunities for harnessing these data to generate new insights into TB transmission in congregate settings.

The differential impact of HIV and antiretroviral therapy on gender-specific tuberculosis rates.

OBJECTIVE: To assess the impact of the HIV epidemic and the rollout of antiretroviral therapy (ART) from 2004 on the gender-specific TB burden in Cape Town, we investigated temporal changes in TB notification rates, the HIV-associated relative risk of TB and the population attributable risk fraction (PAF) of HIV by gender. METHODS: Annual TB notifications, mid-year population and HIV prevalence estimates were used to calculate rates per 100 000 population stratified by gender and HIV. Annual rate ratios (RR) of TB associated with HIV and PAF were calculated by gender. RESULTS: Pre-HIV TB notification rates were lower among women than men (146/100 000 vs. 247/100 000). With the onset of the HIV, epidemic rates increased 5.3-fold in women (to 778/100 000) and 3.7-fold in men (to 917/100 000) to a peak in 2008, after which they declined by 25% in women (to 634/100 000) and 18% in men (to 755/100 000) by 2014. The HIV-associated RR of TB was 25% higher in women than in men in 2006 (25 vs. 20), but decreased to the same level in 2014. HIV PAF declined between 2008 and 2014 from 56% to 50% and from 40% to 38% in women and men, respectively. CONCLUSIONS: The HIV epidemic led to greater relative increases in TB rates among women than men. The increased HIV-associated TB risk in women could be compatible with removal of the biological protection of female gender by HIV infection. The decline in RR and PAF in HIV-positive women could be explained by increasing ART usage reversing female gender-related susceptibility.

OBJECTIF: Afin d'évaluer l'impact de l'épidémie du VIH et le déploiement du traitement antirétroviral (ART depuis 2004) sur la charge de la tuberculose (TB) spécifique au sexe, à Cape Town, nous avons examiné les changements temporels dans les taux de notification de la TB, le risque relatif de TB associé au VIH et la fraction de risque attribuable à la population (FAP) du VIH par sexe. MÉTHODES: Les notifications annuelles de la TB, les estimations de la population en milieu d'année et de la prévalence du VIH ont été utilisées pour calculer les taux par 100.000 habitants stratifiés par sexe et VIH. Les rapports de risque (RR) annuels de TB associé au VIH et la FAP ont été calculés par sexe. RÉSULTATS: Les taux de notification de la TB avant le VIH étaient plus faibles chez les femmes que chez les hommes (146 sur 100.000 contre 247 sur 100.000). Avec le début de l'épidémie de VIH, les taux ont augmenté de 5,3 fois chez les femmes (à 778/100.000) et de 3,7 fois chez les hommes (à 917/100.000) pour atteindre un pic en 2008. Puis, ils ont diminué de 25% chez les femmes (à 634/100.000) et de 18% chez les hommes (à 755/100.000) en 2014. Les RR de TB associés au VIH étaient 25% plus élevés chez les femmes que chez les hommes en 2006 (25 contre 20), mais ont diminué au même niveau en 2014. La FAP du VIH a diminué entre 2008 et 2014, passant de 56% à 50% et de 40% à 38% chez les femmes et les hommes, respectivement. CONCLUSIONS: L'épidémie du VIH a entraîné une augmentation relative du taux de TB chez les femmes supérieure à celle des hommes. L'augmentation du risque de TB associé au VIH chez les femmes pourrait être compatible avec la suppression de la protection biologique du sexe féminin par l'infection au VIH. La baisse des RR et de la FAP chez les femmes VIH positives pourrait être expliquée par une augmentation de l'utilisation de l'ART inversant la sensibilité liée au sexe féminin.

Drivers of Seasonal Variation in Tuberculosis Incidence: Insights from a Systematic Review and Mathematical Model.

BACKGROUND: Seasonality in tuberculosis incidence has been widely observed across countries and populations; however, its drivers are poorly understood. We conducted a systematic review of studies reporting seasonal patterns in tuberculosis to identify demographic and ecologic factors associated with timing and magnitude of seasonal variation. METHODS: We identified studies reporting seasonal variation in tuberculosis incidence through PubMed and EMBASE and extracted incidence data and population metadata. We described key factors relating to seasonality and, when data permitted, quantified seasonal variation and its association with metadata. We developed a dynamic tuberculosis natural history and transmission model incorporating seasonal differences in disease progression and/or transmission rates to examine magnitude of variation required to produce observed seasonality in incidence. RESULTS: Fifty-seven studies met inclusion criteria. In the majority of studies (n=49), tuberculosis incidence peaked in spring or summer and reached a trough in late fall or winter. A standardized seasonal amplitude was calculated for 34 of the studies, resulting in a mean of 17.1% (range: 2.7-85.5%) after weighting by sample size. Across multiple studies, stronger seasonality was associated with younger patients, extrapulmonary disease, and latitudes farther from the Equator. The mathematical model was generally able to reproduce observed levels of seasonal case variation; however, substantial variation in transmission or disease progression risk was required to replicate several extreme values. CONCLUSIONS: We observed seasonal variation in tuberculosis, with consistent peaks occurring in spring, across countries with varying tuberculosis burden. Future research is needed to explore and quantify potential gains from strategically conducting mass screening interventions in the spring.

HIV and TB co-infection in the ART era: CD4 count distributions and TB case fatality in Cape Town.

BACKGROUND: In Cape Town, the roll-out of antiretroviral therapy (ART) has increased over the last decade with an estimated coverage of 63% of HIV- positive patients in 2013. The influence of ART on the characteristics of the population of HIV-positive patients presenting to the primary care TB programme is unknown. In this study, we examined trends in CD4 count distribution, ART usage and treatment outcomes among HIV-positive TB patients in Cape Town from 2009 to 2013. METHODS: Data from the electronic TB register on all newly registered drug-sensitive TB patients ≥18 years were analyzed retrospectively. Descriptive statistics were used to compare baseline characteristics, the CD4 count distribution and TB treatment outcomes both by year of treatment and ART status at the start of TB treatment. Survival analyses were used to assess the change in mortality risk during TB treatment over time, stratified by ART status at start of TB treatment. RESULTS: 118,989 patients were treated over 5 years. HIV prevalence among TB patients decreased from 50.9% in 2009 to 49.0% in 2013. The absolute number of HIV-positive TB cases declined by 13.2% between 2010 and 2013. More patients entered the TB programme on ART in 2013 compared to 2009 (30.0% vs 9.9%). Among these, the CD4 count distribution showed a year by year shift to higher CD4 counts. In 2013, over 75% of ART-naïve TB patients still had a CD4 count < 350 cells/mm3. ART initiation among ART-naive patients increased from 37.0 to 77.7% and TB case fatality declined from 7.4 to 5.2% (p < 0.001). In multivariate analysis a decrease in TB mortality was most strongly associated with CD4 count (Adjusted HR 0.82 per increase of 50 cells/mm3, 95% CI: 0.81-0.83, p < 001) and the initiation of ART during TB treatment (Adjusted HR 0.39, 95% CI: 0.35-0.42, p < 0.001). CONCLUSION: Comprehensive changes in the ART and TB treatment programmes resulted in incremental increases in ART coverage for HIV-positive TB patients and a subsequent decrease in TB case fatality due to increased ART uptake in HIV-positive ART-naïve patients. However TB still remained a major presenting opportunistic infection with the majority of cases occurring at low CD4 counts.

"Tuberculosis in advanced HIV infection is associated with increased expression of IFNγ and its downstream targets".

BACKGROUND: Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV. METHODS: We conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4+ T cell count of ≤ 100 cells/µl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels. RESULTS: Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNγ, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNγ, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB-IRIS. CONCLUSIONS: Gene expression of FcGR1A and BATF2, and plasma protein levels of IFNγ and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB.

The impact of the roll-out of rapid molecular diagnostic testing for tuberculosis on empirical treatment in Cape Town, South Africa.

OBJECTIVE: To investigate the impact of introducing a rapid test as the first-line diagnostic test for drug-sensitive tuberculosis in Cape Town, South Africa. METHODS: Xpert® MTB/RIF (Xpert®), an automated polymerase-chain-reaction-based assay, was rolled out between 2011 and 2013. Data were available on 102 007 adults treated for pulmonary tuberculosis between 2010 and 2014. Tuberculosis notification rates per 100 000 population were calculated for each calendar year and for each year relative to the test roll-out locally, overall and by bacteriological confirmation. Empirical treatment was defined as treatment given without bacteriological confirmation by Xpert®, sputum smear microscopy or sputum culture. FINDINGS: Between 2010 and 2014, the proportion of human immunodeficiency virus (HIV)-negative patients treated empirically for tuberculosis declined from 23% (2445/10 643) to 11% (1149/10 089); in HIV-positive patients, it declined from 42% (4229/9985) to 27% (2364/8823). The overall tuberculosis notification rate decreased by 12% and 19% among HIV-negative and HIV-positive patients, respectively; the rate of bacteriologically confirmed cases increased by 1% and 3%, respectively; and the rate of empirical treatment decreased by 56% and 49%, respectively. These changes occurred gradually following the test's introduction and stabilized after 3 years. CONCLUSION: Roll-out of the rapid test in a setting with a high prevalence of pulmonary tuberculosis and HIV infection was associated with a halving of empirical treatment that occurred gradually after the test's introduction, possibly reflecting the time needed for full implementation. More than a quarter of HIV-positive patients with tuberculosis were still treated empirically, highlighting the diagnostic challenge in these patients.

Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the Xpert™ MTB/RIF era: a cohort study.

BACKGROUND: The Xpert™ MTB/RIF (XP) has a higher sensitivity than sputum smear microscopy (70% versus 35%) for TB diagnosis and has been endorsed by the WHO for TB high burden countries to increase case finding among HIV co-infected presumptive TB patients. Its impact on the diagnosis of smear-negative TB in a routine care setting is unclear. We determined the change in diagnosis, treatment and mortality of smear-negative presumptive TB with routine use of Xpert MTB/RIF (XP). METHODS: Prospective cohort study of HIV-positive smear-negative presumptive TB patients during a 12-month period after XP implementation in a well-staffed and trained integrated TB/HIV clinic in Kampala, Uganda. Prior to testing clinicians were asked to decide whether they would treat empirically prior to Xpert result; actual treatment was decided upon receipt of the XP result. We compared empirical and XP-informed treatment decisions and all-cause mortality in the first year. RESULTS: Of 411 smear-negative presumptive TB patients, 175 (43%) received an XP; their baseline characteristics did not differ. XP positivity was similar in patients with a pre-XP empirical diagnosis and those without (9/29 [17%] versus 14/142 [10%], P = 0.23). Despite XP testing high levels of empirical treatment prevailed (18%), although XP results did change who ultimately was treated for TB. When adjusted for CD4 count, empirical treatment was not associated with higher mortality compared to no or microbiologically confirmed treatment. CONCLUSIONS: XP usage was lower than expected. The lower sensitivity of XP in smear-negative HIV-positive patients led experienced clinicians to use XP as a "rule-in" rather than "rule-out" test, with the majority of patients still treated empirically.

The timing of tuberculosis after isoniazid preventive therapy among gold miners in South Africa: a prospective cohort study.

BACKGROUND: The durability of isoniazid preventive therapy (IPT) in preventing tuberculosis (TB) is limited in high-prevalence settings. The underlying mechanism (reactivation of persistent latent TB or reinfection) is not known. We aimed to investigate the timing of TB incidence during and after IPT and associated risk factors in a very high TB and HIV-prevalence setting, and to compare the observed rate with a modelled estimate of TB incidence rate after IPT due to reinfection. METHODS: In a post-hoc analysis of a cluster-randomized trial of community-wide IPT among South African gold miners, all intervention arm participants that were dispensed IPT for at least one of the intended 9 months were included. An incident TB case was defined as any participant with a positive sputum smear or culture, or with a clinical TB diagnosis assigned by a senior study clinician. Crude TB incidence rates were calculated during and after IPT, overall and by follow-up time. HIV status was not available. Multivariable Cox regression was used to analyse risk factors by follow-up time after IPT. Estimates from a published mathematical model of trial data were used to calculate the average reinfection TB incidence in the first year after IPT. RESULTS: Among 18,520 participants (96% male, mean age 41 years, median follow-up 2.1 years), 708 developed TB. The TB incidence rate during the intended IPT period was 1.3/100 person-years (pyrs; 95% confidence interval (CI), 1.0-1.6) and afterwards 2.3/100 pyrs (95% CI, 1.9-2.7). TB incidence increased within 6 months followed by a stable rate over time. There was no evidence for changing risk factors for TB disease over time after miners stopped IPT. The average TB incidence rate attributable to reinfection in the first year was estimated at 1.3/100 pyrs, compared to an observed rate of 2.2/100 pyrs (95% CI, 1.8-2.7). CONCLUSIONS: The durability of protection by IPT was lost within 6-12 months in this setting with a high HIV prevalence and a high annual risk of M. tuberculosis infection. The observed rate was higher than the modelled rate, suggesting that reactivation of persistent latent infection played a role in the rapid return to baseline TB incidence.

Factors associated with acceleration of clinical development for infectious diseases: a cross-sectional analysis of 10-year EMA registration data.

Background: Clinical trials feature centrally in the development of drugs and vaccines to determine safety and efficacy. Clinical development can be slow and may have a duration of more than ten years. Global public health threats such as Ebola virus disease (EVD) and COVID-19 have demonstrated that it is possible to accelerate clinical trials while maintaining safety and efficacy. We investigated acceleration in clinical trials over the past decade and identified factors associated with acceleration for drugs targeting infectious diseases. Methods: A cross-sectional study was performed of all medicinal compounds targeting infectious diseases that received marketing authorisation by the European Medicines Agency (EMA) between 2012 and 2022. We calculated median clinical development time in years between the first phase 1 trial enrolment date and the authorisation date. Multivariable linear regression analysis was performed to identify factors associated with shorter development times. Findings: Eighty-one trajectories were included. The median clinical development time was 7.3 years (IQR 4.4-12.3). The fastest times belonged to drugs and vaccines targeting COVID-19 (1.3 years, IQR 0.8-1.6), EVD (5.5 years, IQR 5.1-5.8), and Hepatitis A-E (5.5 years, IQR 3.9-8.2). Factors associated with shorter development times were outbreak setting (-5.4 years [95% CI, -8.2 to -2.6]), accelerated assessment status (-4.0 years [95% CI, -7.6 to -0.5]), and drugs with combined compounds (-2.7 years [95% CI, -4.9 to -0.4]). Interpretation: Clinical development time for infectious disease-related drugs and vaccines was relatively short, and outbreak setting and accelerated EMA assessment were associated with shorter development times. Funding: Amsterdam Public Health research institute.