The association between the magnitude of T-cell interferon-gamma responses to Mycobacterium tuberculosis specific antigens and risk of progression to tuberculosis in household contacts tested with QuantiFERON-TB Gold In-Tube Assay.

Background Household contacts (HHCs) of pulmonary TB patients are at high risk of Mycobacterium tuberculosis (Mtb) infection and early disease development. Tuberculin skin test (TST) has been traditionally used to identify infected individuals; however, its use is limited by low specificity in populations with high levels of BCG vaccination or significant exposure to non-tuberculosis mycobacteria (NTM), and reduced sensitivity in immunocompromised individuals. Interferon-gamma release assays (IGRAs) such as QuantiFERON-TB Gold In-Tube (QFT-GIT) using Mtb specific antigens provide an alternative to TST for infection detection. IGRAs are now widely used for the detection of Mtb infection and are included in the guidelines of many countries with a low incidence of TB. Despite a growing body of literature on IGRAs, the relationship between the magnitude of T-cell Interferon-γ responses to Mtb specific antigens and risk of progression to disease has not been studied. Objective The main objective of this study was to determine whether HHCs with high (≥10 IU/ml) levels of IFN-γ in response to Mtb specific antigens (ESAT-6, CFP-10 or TB 7.7) in the QFT-GIT assay are at higher risk of developing TB compared to those with low (> 0.35-<10 IU/ml) levels. Other secondary objectives included to determine the following: the performance and operational characteristics of QFT-GIT in a field setting; risk factors associated with positive QFT-GIT results; concordance between the two tests; incidence rates of TB in HHCs with positive and negative QFT-GIT and TST results at baseline as well as positive and negative predictive values. Method This study was nested within a large community randomized trial called ZAMSTAR implemented in 16 communities in Zambia and 8 communities in the Western Cape Province of South Africa. A cohort of HIV-positive and HIV-negative adult (≥ 15 years) HHCs were prospectively followed for 2-4 years. Consenting HHCs had blood drawn for HIV antibodies. QFT-GIT test was performed according to the manufacturer's instructions. TST were performed according to the standard IUATLD protocol. A standardized questionnaire was used to collect information on risk factors for TB and TB treatment information (for those with TB). Results The feasibility studies showed three main findings. Firstly, the sensitivity of QFT-GIT was greater than that of TST overall, at all the standard TST cut-offs and when stratified by HIV status. The sensitivity of QFT-GIT was 85.6% (95%CI: 77.0-91.9) (indeterminate results excluded) compared to that of TST at 51.6% (95% CI: 40.9-62.2) at a cut-off of ≥ 10 mm. Secondly, test-retest reproducibility of QFT-GIT was high at 91.74% (ICC: 0.90; 95% CI 0.82-0.97). Thirdly, in this setting, some biological and operational factors that affected the performance of QFT-GIT were identified such as HIV positivity, low CD4+ T-lymphocytes, delayed incubation of blood samples and power outages. 8 For the main study, the study population at baseline consisted of 1,789 HHCs who were predominantly women (71%); median age was 28 years (IQR: 21-43); HIV positivity rate was 27.9%. Prevalence of tuberculous infection was 63.7% as measured by QFT-GIT and 39.6% by TST. There was a low level of agreement between the tests regardless of TST cut-off point (% agreement=59.7%; kappa=0.24). QFT+/TST- discordance (575/719; 80%) was more frequent than QFT-/TST+ discordance (144/719; 20%) at TST ≥10 mm. Risk factors associated with QFT-GIT positivity were identified at baseline. In multivariable analysis adjusted for sex, age, and community, HIV status was negatively associated with QFTGIT positivity (aOR: 0.48; 95% CI: 0.37–0.63; p<0.001) whereas residing in an urban area (aOR: 2.37; 95% CI: 1.10–5.13; p<0.03), smear status of index (OR: 1.26; 95% CI: 0.91-1.76; p=0.15) and country (aOR: 1.93; 95% CI: 1.48–2.51; p<0.001) were positively associated with QFT-GIT positivity. Similar results were obtained for TST. From a total of 1789 HHCs seen at baseline, 1113 (62.2%) HHCs entered follow-up and were included in the main analysis. The overall incidence rate of TB was 20.96/1000 pyrs (95% CI: 15.93-27.58). TB incidence rate was higher among test positive HHCs compared to those who were negative (IRR for QFT-GIT: 1.65; 95% CI: 0.86-3.37; p=0.06) and for TST (IRR: 1.88; 95%CI: 1.04-3.41; p=0.01). Results were similar in univariable analysis (QFT-GIT: 1.66 (95%CI: 0.88-3.11; p=0.11) and TST: 1.89 (95%CI: 1.09-3.28; p=0.02)) and multivariable analysis adjusted for sex, age and HIV (QFT-GIT: 2.20 (95%CI: 1.14-4.25; p=0.02) and TST: 2.19 (95%CI: 1.24-3.86; p=0.007)). Overall, PPV for QFT-GIT was 5.38% (95%CI: 3.84-7.31), compared to TST, 6.57% (95% CI: 4.41- 9.36). Overall for QFT-GIT, the IRR was higher among HIV negative HHCs (IRR: 3.85; 95%CI: 0.90-34.51; p=0.07) compared to HIV positives (IRR; 1.93; 95%CI: 0.88-4.57; p=0.04). Overall for TST, the IRR for HIV negatives (IRR: 2.21; 95%CI: 0.78-6.72; p=0.05) was similar to that among HIV positives (IRR: 2.32; 95%CI: 1.09-5.00; p=0.009). Univariable analysis showed similar results for both tests. In multivariable analyses adjusted for age, sex and country as an effect modifier, the HR for developing TB was 4.72 (95%CI: 1.35-16.46; p=0.01) in HIV positive QFT-GIT positives compared to 2.13 (95%CI: 0.81-5.60; p=0.12) in HIV positives TST positive HHCs. Risk factors for TB were identified. In multivariable analyses, adjusted for age, sex , HIV status and country there was strong evidence that occasional smoking, (HR: 4.07; 95%CI:1.31-12.63), HIV positivity (HR: 4.60; 95%CI:2.48-8.56), smear positivity of the index (HR: 2.00 ; 95%CI:1.04- 3.87) and country (HR: 1.79 ; 95%1.02-3.15; p=0.04) ) were associated with incidence of TB. Out of the 1,113 HHCs who entered follow-up, 406 HHCs had IFN-γ levels <0.35 IU/ml and were excluded leaving 707 HHCs in analysis for the primary objective. Out of these 536 (75.8%) had IFN-gamma levels ≥ 0.35 and <10 IU/ml (low IFN-γ levels) while 171 (24.2%) HHCs had ≥ 10 IU/ml (high IFN-γ levels). Out of the 707 HHCs that entered follow-up, 38 (5.4%) HHCs developed active TB over 1558.0 person-years (pyrs) of follow-up, giving an incidence rate of 24.39/1000 pyrs (95% CI: 17.75- 33.52).TB incidence rates were 24.51/1000 pyrs (9 cases/367.2 pyrs) in HHCs with high levels and 24.35 (29 cases/1190.7 pyrs) among those with low levels of IFN-γ, giving an IRR of 1.0 (95% CI: 0.42-2.18; p=0.48). Overall, unadjusted HR in HHCs with high IFN-γ levels was 1.02 (95%CI: 0.48-2.15; p=0.96) while in multivariable analysis adjusted for age, sex, country and HIV as an effect modifier, HR was 1.74 (95%CI: 0.63-4.79; p=0.29). TB incidence rates in HIV positives was 51.94/1000 pyrs (3 cases/57.8 pyrs) in HHCs with high levels and 65.29/1000 pyrs (19 cases/291.0 pyrs) among those with low levels of IFN-γ, giving an IRR of 0.79 (95%CI: 0.15-2.70; p=0.38).TB incidence rates in HIV negatives were 19.56/1000 pyrs (6 cases/306.7 pyrs) in HHCs with high levels and 11.47 (10 cases/871.7 pyrs) among those with low levels of IFN-γ, giving an IRR of 1.70 (95%CI: 0.51-5.18, p=0.16). Unadjusted HR among HIV negative HHCs was 1.73 (95%CI: 0.63-4.77; p=0.29) and 0.75 (95%0.22-2.55; p=0.65) among HIV positive ones respectively. In multivariable analysis adjusted for age, sex and country, the HR remained similar as unadjusted analysis for both HIV negatives and positives. For all the groups used for sensitivity analysis of the primary question, HHCs with the highest IFN-γ levels had increased IRRs ranging from 1.5 to 2 compared to the reference sub-group. For HIV negatives, HHCs with the highest IFN-γ levels had the highest IRRs in all groups apart from one group. HIV negative HHCs with the highest IFN-γ levels had increased IRRs ranging from 4 to 5-fold compared to the reference sub-group. In comparison, HIV positive HHCs with the highest IFN-γ levels had increased IRRs ranging from 1.6 to 2.6 compared to the reference sub-group. Conclusions The principal finding in this study is that there was no difference in incidence rates between HHCs with low and high levels (overall IRR: 1.0 (95% CI: 0.42-2.18)). Another principal finding was that there was strong evidence of a five-fold increased risk of TB in HIV positive QFT-GIT positive HHCs compared to HIV positive QFT-GIT negative ones (aHR : 4.72; 95%CI: 1.35-16.46; P=0.01). For all the groups used in the sensitivity analysis of the primary question, HHCs with the highest IFN-γ levels had increased IRRs ranging from 1.5 to 2 compared to the reference sub-group. The feasibility studies emphasized the need for stringent sample collection and processing techniques to ensure the accuracy of QFT-GIT results

Coverage of clinic-based TB screening in South Africa may be low in key risk groups

The South African Ministry of Health has proposed screening all clinic attendees for tuberculosis (TB). Amongst other factors, male sex and bar attendance are associated with higher TB risk. We show that 45% of adults surveyed in Western Cape attended a clinic within 6 months, and therefore potentially a relatively high proportion of the population could be reached through clinic-based screening. However, fewer than 20% of all men aged 18–25 years, or men aged 26–45 who attend bars, attended a clinic. The population-level impact of clinic-based screening may be reduced by low coverage among key risk groups

Assessing usability of QIAreach QuantiFERON-TB platform in a high tuberculosis prevalence, low-resource setting.

QIAreach QuantiFERON-TB is a portable IGRA with the potential to improve accessibility of TB infection diagnosis in low-resource settings https://bit.ly/3nTzolf

HIV Care Cascade Among Adolescents in a "Test and Treat" Community-Based Intervention: HPTN 071 (PopART) for Youth Study.

PURPOSE: The PopART for Youth (P-ART-Y) study was nested within the HPTN 071 (PopART) trial, a three-arm community randomized trial in 21 communities in Zambia and South Africa. The P-ART-Y study evaluated the acceptability and uptake of a combination HIV prevention package among young people. We report on the HIV care cascade for adolescents aged 10-19 years from 14 communities receiving the full HIV prevention package in Zambia and South Africa. METHODS: Adolescents were offered participation in the PopART intervention, which included universal home-based HIV testing, linkage to care, antiretroviral therapy (ART) adherence, and other services. Data were collected from September 2016 to December 2017, covering the third round (R3) of the intervention. RESULTS: We enumerated (listed) 128,241 adolescents (Zambia: 95,295 and South Africa: 32,946). Of the adolescents offered HIV testing, 81.9% accepted in Zambia and 70.3% in South Africa. Knowledge of HIV status was higher among older adolescents and increased from 31.4% before R3 to 88.3% at the end of R3 in Zambia and from 28.3% to 79.5% in South Africa. Overall, there were 1,710 (1.9%) adolescents identified as living with HIV by the end of R3 (515 new diagnoses and 1,195 self-reported). Of the new diagnoses, 335 (65.0%) were girls aged 15-19 years. The median time to initiate ART was 5 months. ART coverage before and after R3 increased from 61.3% to 78.7% in Zambia and from 65.6% to 87.8% in South Africa, with boys having higher uptake than girls in both countries. CONCLUSIONS: The PopART intervention substantially increased coverage toward the first and second UNAIDS 90-90-90 targets in adolescents

Comparison of indoor contact time data in Zambia and Western Cape, South Africa suggests targeting of interventions to reduce Mycobacterium tuberculosis transmission should be informed by local data.

BACKGROUND: In high incidence settings, the majority of Mycobacterium tuberculosis (M.tb) transmission occurs outside the household. Little is known about where people's indoor contacts occur outside the household, and how this differs between different settings. We estimate the number of contact hours that occur between adults and adult/youths and children in different building types in urban areas in Western Cape, South Africa, and Zambia. METHODS: Data were collected from 3206 adults using a cross-sectional survey, on buildings visited in a 24-h period, including building function, visit duration, and number of adults/youths and children (5-12 years) present. The mean numbers of contact hours per day by building function were calculated. RESULTS: Adults in Western Cape were more likely to visit workplaces, and less likely to visit shops and churches than adults in Zambia. Adults in Western Cape spent longer per visit in other homes and workplaces than adults in Zambia. More adults/youths were present at visits to shops and churches in Western Cape than in Zambia, and fewer at homes and hairdressers. More children were present at visits to shops in Western Cape than in Zambia, and fewer at schools and hairdressers. Overall numbers of adult/youth indoor contact hours were the same at both sites (35.4 and 37.6 h in Western Cape and Zambia respectively, p = 0.4). Child contact hours were higher in Zambia (16.0 vs 13.7 h, p = 0.03). Adult/youth and child contact hours were highest in workplaces in Western Cape and churches in Zambia. Compared to Zambia, adult contact hours in Western Cape were higher in workplaces (15.2 vs 8.0 h, p = 0.004), and lower in churches (3.7 vs 8.6 h, p = 0.002). Child contact hours were higher in other peoples' homes (2.8 vs 1.6 h, p = 0.03) and workplaces (4.9 vs 2.1 h, p = 0.003), and lower in churches (2.5 vs 6.2, p = 0.004) and schools (0.4 vs 1.5, p = 0.01). CONCLUSIONS: Patterns of indoor contact between adults and adults/youths and children differ between different sites in high M.tb incidence areas. Targeting public buildings with interventions to reduce M.tb transmission (e.g. increasing ventilation or UV irradiation) should be informed by local data

Acceptability and feasibility of genital self-sampling for the diagnosis of female genital schistosomiasis: a cross-sectional study in Zambia

Background: Female genital schistosomiasis (FGS) is a neglected and disabling gynaecological disorder that is difficult to diagnose and is part of the wider spectrum of urogenital disease caused by the waterborne parasite Schistosoma haematobium. Over 90% of human schistosomiasis cases are found in sub-Saharan Africa with 3.8 million people infected with schistosomes in Zambia. Reported FGS prevalence ranges from 33-75% of those with urinary schistosomiasis in endemic areas, suggesting a potentially high FGS burden in Zambia alone. The Bilharzia and HIV (BILHIV) study evaluated home self-sampling genital collection methods for the diagnosis of FGS. Methods: Eligible participants included non-pregnant, sexually active women aged 18-31 who were previously recruited for the HPTN 071 (PopART) trial in Livingstone, Zambia. Household demographic and symptom questionnaires were administered by community workers. Participants were offered vaginal and cervical self-swabs and a urine cup. Cervicovaginal lavage (CVL) was performed in clinic by midwives. Information was collected from participants on the acceptability and feasibility of genital self-sampling. Results: From January-August 2018, 603 women were enrolled, and 87.3% (527/603) completed clinic follow up. A high proportion of participants indicated that self-collection of specimens was “easy” or “very easy” on a 5-point Likert scale. A high proportion of women would be willing to self-collect all three specimens again in future: vaginal swab 96.7% (583/603), cervical swab 96.5% (582/603), and urine 96.2% (580/603). Home-based self-sampling was preferred over provider-based sampling in the clinic due to greater privacy 58.5% (353/603), convenience 46.3% (279/603) and need for transportation 15.9% (96/603). Conclusions: Home based genital self-sampling for FGS diagnosis is highly acceptable. This scalable method may inform future efforts for community-based diagnosis of FGS.</ns4:p

Age- and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection: Interview Questionnaire

Questionnaire used in a study of Mycobacterium tuberculosis infection incidences among adults in the Western Cape, South Africa. The questionnaire was piloted in Zambia in early 2011, before being used in face-to-face interviews with random selected adults who were enrolled in the Zambia-South Africa TB and AIDS Reduction (ZAMSTAR) Study

Sociological variety and the transmission efficiency of Mycobacterium tuberculosis: a secondary analysis of qualitative and quantitative data from 15 communities in Zambia

Objectives: Selected Zambian communities formed part of a cluster randomised trial: the Zambia and South Africa TB and AIDS Reduction study (ZAMSTAR). There was wide variability in the prevalence of Mycobacterium tuberculosis infection and tuberculosis (TB) disease across these communities. We sought to clarify whether specific communities could have been more/less vulnerable to M. tuberculosis transmission as a result of sociological variety relevant to transmission efficiency. Design: We conducted a mixed methods secondary analysis using existing data sets. First, we analysed qualitative data to categorise and synthesise patterns of socio-spatial engagement across communities. Second, we compared emergent sociological variables with a measure of transmission efficiency: the ratio of the annual risk of infection to TB prevalence. Setting: ZAMSTAR communities in urban and peri-urban Zambia, spanning five provinces. Participants Fifteen communities, each served by a health facility offering TB treatment to a population of at least 25 000. TB notification rates were at least 400 per 100 000 per annum and HIV seroprevalence was estimated to be high. Results: Crowding, movement, livelihoods and participation in recreational activity differed across communities. Based on 12 socio-spatial indicators, communities were qualitatively classified as more/less spatially crowded and as more/less socially ‘open’ to contact with others, with implications for the presumptive risk of M. tuberculosis transmission. For example, watching video shows in poorly ventilated structures posed a presumptive risk in more socially open communities, while outdoor farming and/or fishing were particularly widespread in communities with lower transmission measures. Conclusions: A dual dynamic of ‘social permeability’ and crowding appeared relevant to disparities in M. tuberculosis transmission efficiency. To reduce transmission, certain socio-spatial aspects could be adjusted (eg, increasing ventilation on transport), while more structural aspects are less malleable (eg, reliance on public transport). We recommend integrating community level typologies with genome sequencing techniques to further explore the significance of ‘social permeability’. Trial registration number: ISRCTN36729271

Age- and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection.

We aimed to model the incidence of infection with Mycobacterium tuberculosis among adults using data on infection incidence in children, disease prevalence in adults, and social contact patterns. We conducted a cross-sectional face-to-face survey of adults in 2011, enumerating "close" (shared conversation) and "casual" (shared indoor space) social contacts in 16 Zambian communities and 8 South African communities. We modeled the incidence of M. tuberculosis infection in all age groups using these contact patterns, as well as the observed incidence of M. tuberculosis infection in children and the prevalence of tuberculosis disease in adults. A total of 3,528 adults participated in the study. The reported rates of close and casual contact were 4.9 per adult per day (95% confidence interval: 4.6, 5.2) and 10.4 per adult per day (95% confidence interval: 9.3, 11.6), respectively. Rates of close contact were higher for adults in larger households and rural areas. There was preferential mixing of close contacts within age groups and within sexes. The estimated incidence of M. tuberculosis infection in adults was 1.5-6 times higher (2.5%-10% per year) than that in children. More than 50% of infections in men, women, and children were estimated to be due to contact with adult men. We conclude that estimates of infection incidence based on surveys in children might underestimate incidence in adults. Most infections may be due to contact with adult men. Treatment and control of tuberculosis in men is critical to protecting men, women, and children from tuberculosis

Creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding, observations from cross-sectional studies in Lesotho and Zambia

BACKGROUND: The health impact of the COVID-19 pandemic largely depends on the ability of the healthcare systems to develop effective and adaptable preparedness and mitigation strategies. A collaborative initiative (BRCCH-EDCTP COVID-19 Initiative) was set up between Lesotho and Zambia early on in the pandemic, to jointly conduct a project to investigate creating access to SARS-CoV-2 screening and testing through community-based COVID-19 case-finding. METHODS: Two different community case-finding strategies were deployed. In Lesotho, an approach was implemented whereby a community (village) health worker screened community members at their home or during community gatherings for COVID-19 signs and symptoms. All community members who screened positive were then offered SARS-CoV-2 testing. In Zambia, so-called community hubs, staffed by community health care workers, were set up at different locations in the community for people to walk in and get tested for SARS-CoV-2. Hubs changed location from week-to-week and targeted transmission hotspots. All persons visiting the hubs were offered testing for SARS-CoV-2 irrespective of self-reported signs and symptoms of COVID-19 though information was collected on occurrence of these. Testing in both approaches was done using SARS-CoV-2 rapid antigen tests. RESULTS: Setting up testing in the community setting was feasible in both countries. In Lesotho in the village health worker approach, over a period of 46 weeks, 7221 persons were screened, and 49 (11.4%) SARS-COV-2 cases identified among 428 COVID-19 screen positive participants. In the community hubs among 3150 people tested, 166 (5.3%) SARS-CoV-2 cases were identified in a period of 26 weeks. From the community hubs approach, where all seen were offered COVID-19 testing it was learned that people screening positive for COVID-19 signs and symptoms were more likely to test SARS-COV-2 positive, especially those reporting classic COVID-19 symptoms like loss of sense/smell for a short period of time (1-3 days). CONCLUSIONS: In conclusion, in this project we learned that implementing COVID-19 screening and testing by lay health workers in the community is possible. Characteristics of the population screened, tested, and identified to have SARS-CoV-2 are described to help guide development of future testing strategies