Time to care-seeking for TB symptoms.

BACKGROUND: Early presentation to healthcare facilities is critical for early diagnosis and treatment of TB. We studied self-reported time to care-seeking from the onset of TB symptoms among primary healthcare clinic (PHC) attendees in Limpopo Province, South Africa.METHODS: We used data from participants enrolled in a cluster-randomized trial of TB case finding in 56 PHC clinics across two health districts. We fitted log-normal accelerated failure time regression models and we present time ratios (TRs) for potential risk factors.RESULTS: We included 2,160 participants. Among the 1,757 (81%) diagnosed with active TB, the median time to care-seeking was 30 days (IQR 14-60); adults sought care later than children/adolescents (adjusted TR aTR 1.47, 95% CI 1.10-1.96). Among those not diagnosed with TB, the median was 14 days (IQR 7-60); being HIV-positive (aTR 1.57, 95% CI 1.03-2.40); having less than grade 8 education and currently smoking were associated with longer time to care-seeking. In the combined analysis, living with HIV and having underlying active TB was associated with faster care-seeking (TB status x HIV interaction: TR 0.68, 95% CI 0.48-0.96).CONCLUSION: Delay in care-seeking was associated with age, lower education and being a current smoker. TB awareness campaigns targeting these population groups may improve care-seeking behavior and reduce community TB transmission.

A position statement and practical guide to the use of particulate filtering facepiece respirators (N95, FFP2, or equivalent) for South African health workers exposed to respiratory pathogens including Mycobacterium tuberculosis and SARS-CoV-2.

SUMMARY: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is transmitted mainly by aerosol in particles <10 µm that can remain suspended for hours before being inhaled. Because particulate filtering facepiece respirators ('respirators'; e.g. N95 masks) are more effective than surgical masks against bio-aerosols, many international organisations now recommend that health workers (HWs) wear a respirator when caring for individuals who may have COVID-19. In South Africa (SA), however, surgical masks are still recommended for the routine care of individuals with possible or confirmed COVID-19, with respirators reserved for so-called aerosol-generating procedures. In contrast, SA guidelines do recommend respirators for routine care of individuals with possible or confirmed tuberculosis (TB), which is also transmitted via aerosol. In health facilities in SA, distinguishing between TB and COVID-19 is challenging without examination and investigation, both of which may expose HWs to potentially infectious individuals. Symptom-based triage has limited utility in defining risk. Indeed, significant proportions of individuals with COVID-19 and/or pulmonary TB may not have symptoms and/or test negative. The prevalence of undiagnosed respiratory disease is therefore likely significant in many general clinical areas (e.g. waiting areas). Moreover, a proportion of HWs are HIV-positive and are at increased risk of severe COVID-19 and death. RECOMMENDATIONS: Sustained improvements in infection prevention and control (IPC) require reorganisation of systems to prioritise HW and patient safety. While this will take time, it is unacceptable to leave HWs exposed until such changes are made. We propose that the SA health system adopts a target of 'zero harm', aiming to eliminate transmission of respiratory pathogens to all individuals in every healthcare setting. Accordingly, we recommend: the use of respirators by all staff (clinical and non-clinical) during activities that involve contact or sharing air in indoor spaces with individuals who: (i) have not yet been clinically evaluated; or (ii) are thought or known to have TB and/or COVID-19 or other potentially harmful respiratory infections;the use of respirators that meet national and international manufacturing standards;evaluation of all respirators, at the least, by qualitative fit testing; andthe use of respirators as part of a 'package of care' in line with international IPC recommendations. We recognise that this will be challenging, not least due to global and national shortages of personal protective equipment (PPE). SA national policy around respiratory protective equipment enables a robust framework for manufacture and quality control and has been supported by local manufacturers and the Department of Trade, Industry and Competition. Respirator manufacturers should explore adaptations to improve comfort and reduce barriers to communication. Structural changes are needed urgently to improve the safety of health facilities: persistent advocacy and research around potential systems change remain essential.

Venous thromboembolic disease in adults admitted to hospital in a setting with a high burden of HIV and TB.

BACKGROUND: HIV and tuberculosis (TB) independently cause an increased risk for venous thromboembolic disease (VTE): deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Data from high HIV and TB burden settings describing VTE are scarce. The Wells' DVT and PE scores are widely used but their utility in these settings has not been reported on extensively. OBJECTIVES: To evaluate new onset VTE, compare clinical characteristics by HIV status, and the presence or absence of TB disease in our setting. We also calculate the Wells' score for all patients. METHODS: A prospective cohort of adult in-patients with radiologically confirmed VTE were recruited into the study between September 2015 and May 2016. Demographics, presence of TB, HIV status, duration of treatment, CD4 count, viral load, VTE risk factors, and parameters to calculate the Wells' score were collected. RESULTS: We recruited 100 patients. Most of the patients were HIV-infected (n=59), 39 had TB disease and 32 were HIV/TB co-infected. Most of the patients had DVT only (n=83); 11 had PE, and 6 had both DVT and PE. More than a third of patients on antiretroviral treatment (ART) (43%; n=18/42) were on treatment for <6 months. Half of the patients (51%; n=20/39) were on TB treatment for <1 month. The median (interquartile range (IQR)) DVT and PE Wells' score in all sub-groups was 3.0 (1.0 - 4.0) and 3.0 (2.5 - 4.5), respectively. CONCLUSION: HIV/TB co-infection appears to confer a risk for VTE, especially early after initiation of ART and/or TB treatment, and therefore requires careful monitoring for VTE and early initiation of thrombo-prophylaxis.

Choice architecture-based prescribing tool for TB preventive therapy: a pilot study in South Africa.

BACKGROUND: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach. SETTING: Primary care clinics in Matlosana, South Africa. DESIGN: This was a mixed-methods implementation study. METHODS: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers. RESULTS: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe. CONCLUSIONS: This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision.

Subclinical tuberculosis and adverse infant outcomes in pregnant women with HIV.

BACKGROUND: Tuberculosis (TB) in pregnant women with HIV is associated with adverse maternal and infant outcomes. Previous studies have described a substantial prevalence of subclinical TB in this group, but little is known about the impact of subclinical TB on maternal and pediatric outcomes.METHODS: The Tshepiso Study recruited 235 HIV-infected pregnant women with TB (and matched HIV-positive, TB-negative pregnant controls), in Soweto, South Africa, from 2011 to 2014. During enrolment screening, some women initially recruited as controls were subsequently diagnosed with prevalent TB. We therefore assessed the prevalence of subclinical TB, associated participant characteristics and outcomes.RESULTS: Of 162 women initially recruited as TB-negative controls, seven (4.3%) were found to have TB on sputum culture. All seven had negative WHO symptom screens, and six (86%) were smear-negative. Of their seven infants, one was diagnosed with TB, and three (43%) experienced complications compared to zero infants with TB and 11% experiencing complications in the control group of TB-negative mothers (P = 0.045).CONCLUSION: We discovered an appreciable prevalence of subclinical TB in HIV-infected pregnant women in Soweto, which had not been detected by screening algorithms based solely on symptoms. Infants of HIV-infected mothers with subclinical TB appear to have a higher risk of adverse outcomes than those of TB-negative mothers.

Priorities among HIV-positive individuals for tuberculosis preventive therapies.

BACKGROUND: There has been slow uptake of isoniazid preventive therapy (IPT) among people living with HIV (PLWH).METHODS: We surveyed adults recently diagnosed with HIV in 14 South African primary health clinics. Based on the literature and qualitative interviews, sixteen potential barriers and facilitators related to preventive therapy among PLWH were selected. Best-worst scaling (BWS) was used to quantify the relative importance of the attributes. BWS scores were calculated based on the frequency of participants' selecting each attribute as the best or worst among six options (across multiple choice sets) and rescaled from 0 (always selected as worst) to 100 (always selected as best) and compared by currently receiving IPT or not.RESULTS: Among 342 patients surveyed, 33% (n = 114) were currently taking IPT. Having the same standard of life as someone without HIV was most highly prioritized (BWS score = 67.3, SE = 0.6), followed by trust in healthcare providers (score, 66.3 ± 0.6). Poor standard of care in public clinics (score, 30.6 ± 0.6) and side effects of medications (score, 33.7 ± 0.6) were least prioritized. BWS scores differed by IPT status for few attributes, but overall ranking was similar (spearman's rho = 0.9).CONCLUSION: Perceived benefits of preventive therapy were high among PLWH. IPT prescription by healthcare providers should be encouraged to enhance IPT uptake among PLWH.

Tuberculosis patients with higher levels of poverty face equal or greater costs of illness.

SETTING: Fifty-six public clinics in Limpopo Province, South Africa.OBJECTIVE: To evaluate the association between tuberculosis (TB) patient costs and poverty as measured by a multidimensional poverty index.DESIGN: We performed cross-sectional interviews of consecutive patients with TB. TB episode costs were estimated from self-reported income, travel costs, and care-seeking time. Poverty was assessed using the South African Multidimensional Poverty Index (SAMPI) deprivation score (a 12-item household-level index), with higher scores indicating greater poverty. We used multivariable linear regression to adjust for age, sex, human immunodeficiency virus status and travel time.RESULTS: Among 323 participants, 108 (33%) were 'deprived' (deprivation score >0.33). For each 0.1-unit increase in deprivation score, absolute TB episode costs were 1.11 times greater (95%CI 0.97-1.26). TB episode costs were 1.19 times greater with each quintile of higher deprivation score (95%CI 1.00-1.40), but lower by a factor of 0.54 with each quintile of lower self-reported income (higher poverty, 95%CI 0.46-0.62).CONCLUSION: Individuals experiencing multidimensional poverty and the cost of tuberculosis illness in Limpopo, South Africa faced equal or higher costs of TB than non-impoverished patients. Individuals with lower self-reported income experienced higher costs as a proportion of household income but lower absolute costs. Targeted interventions are needed to reduce the economic burden of TB on patients with multidimensional poverty.

Lessons learnt conducting minimally invasive autopsies in private mortuaries as part of HIV and tuberculosis research in South Africa.

Current estimates of the burden of tuberculosis (TB) disease and cause-specific mortality in human immunodeficiency virus (HIV) positive people rely heavily on indirect methods that are less reliable for ascertaining individual-level causes of death and on mathematical models. Minimally invasive autopsy (MIA) is useful for diagnosing infectious diseases, provides a reasonable proxy for the gold standard in cause of death ascertainment (complete diagnostic autopsy) and, used routinely, could improve cause-specific mortality estimates. From our experience in performing MIAs in HIV-positive adults in private mortuaries in South Africa (during the Lesedi Kamoso Study), we describe the challenges we faced and make recommendations for the conduct of MIA in future studies or surveillance programmes, including strategies for effective communication, approaches to obtaining informed consent, risk management for staff and efficient preparation for the procedure.

Les estimations actuelles du poids de la tuberculose (TB) maladie et de la mortalité qui lui est due parmi les patients positifs à l'infection par le virus de l'immunodéficience humaine (VIH) dépendent beaucoup de méthodes indirectes, qui sont moins fiables pour vérifier les causes de décès au niveau individuel et de modèles mathématiques. Une autopsie peu invasive (MIA) est utile au diagnostic de maladies infectieuses, fournit une approximation raisonnable de l'étalon or de la vérification de la cause du décès c'est-à-dire une autopsie diagnostique complète. Si elle est utilisée en routine, elle pourrait améliorer les estimations de mortalité spécifique d'une cause. A partir de nos expériences de MIA sur des adultes positifs au VIH dans des morgues privées d'Afrique du Sud (au cours de l'étude Lesedi Kamoso), nous décrivons les défis rencontrés et faisons des recommandations pour la réalisation de MIA dans des études futures ou des programmes de surveillance, incluant des stratégies de communication efficaces, des approches visant à obtenir un consentement éclairé, une prise en charge du risque pour le personnel et une préparation efficace de la procédure.

Las estimaciones actuales de morbilidad por tuberculosis (TB) y de mortalidad por causas específicas en las personas positivas frente al virus de la inmunodeficiencia humana (VIH) se fundamentan en su mayor parte en métodos indirectos que son menos fiables para determinar las causas de muerte individuales y en modelizaciones matemáticas. La autopsia mínimamente invasiva (MIA) es útil en el diagnóstico de las enfermedades infecciosas, ofrece un sustituto aceptable al método de referencia para determinar la causa de muerte (que es la autopsia diagnóstica completa), y cuando se usa de manera sistemática, mejora las estimaciones de la mortalidad por causas específicas. A partir de su experiencia con la MIA en adultos con infección por el VIH en empresas fúnebres privadas en Suráfrica (durante el estudio Lesedi Kamoso), los autores describen las dificultades que encontraron y formulan recomendaciones que se pueden aplicar en el futuro al realizar la autopsia mínimamente invasiva en estudios de investigación o en programas de vigilancia; se preconizan estrategias de comunicación efectivas, métodos de obtención del consentimiento informado, la gestión de riesgos para el personal y la preparación eficiente del procedimiento.

Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure.

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 µg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.

Latent tuberculous infection in schoolchildren and contact tracing in Matlosana, North West Province, South Africa.

This is a cross-sectional study to estimate the prevalence of latent tuberculous infection (LTBI) and the annual risk of tuberculous infection (ARTI) among a sample of children aged 5 and 7 years in Matlosana, South Africa. LTBI prevalence was significantly higher in children aged 7 years (n = 704) (19.7%, 95%CI 16.75-22.65) than in those aged 5 years (212/1401, 15.1%, 95%CI 13.23-16.97) (P = 0.0075). The ARI was 2.9% (95%CI 2.2-3.6).

The effect of topical calcipotriol or zinc on tuberculin skin tests in hospitalised South African children.

BACKGROUND: The tuberculin skin test (TST) is used to help diagnose tuberculosis (TB) in acutely ill hospitalised children. OBJECTIVE To investigate the potential augmentative effect of topical calcipotriol (a vitamin D analogue) or zinc on TST induration. METHODS: Three TSTs were performed among 64 hospitalised children; each site was covered with topical aqueous cream (control), calcipotriol or zinc and assessed 24 and 48 h later by investigators blinded to all topical applications. RESULTS: TSTs were reactive in 15 (23.4%) children, of whom 13 (20.3%) were TST-positive. Topical calcipotriol and zinc induced TST positivity in two children with reactive but negative control TSTs. These treatments, however, did not significantly increase TST positivity rates. In children with reactive TSTs, the median 48 h induration diameter was not significantly different between the control, calcipotriol- or zinc-treated groups, which were respectively 12.0 (25%-75% IQR 5.0 - 18.0), 14.0 (25%-75% IQR 10.0 - 15.0) and 12.0 (25%-75% IQR 8.0 - 15.0) mm. Topical treatments did not induce TST reactivity or TST positivity in children with culture-confirmed TB disease (n = 4), human immunodeficiency virus infection (n= 18) or kwashiorkor (n = 9). CONCLUSIONS: Topical calcipotriol or zinc does not induce TST reactivity or significantly increase TST positivity rates in acutely ill hospitalised children. However, further studies are required to assess the effects of topical treatments on TST positivity in severely malnourished children.

Prevalence and associations with hepatitis B and hepatitis C infection among HIV-infected adults in South Africa.

We assessed prevalence and factors associated with hepatitis B in a cross section of HIV-infected primary care and antinatal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years and median CD4 count was 354 cells/mm(3). HBsAg enzyme-linked immunosorbent assay (ELISA), anti-hepatitis B core (HBc) antibodies and hepatitis C virus antibody were positive among 4.2%, 37% and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines and higher CD4 counts; HBsAg positivity was associated with lower CD4. Compared with the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found that subjects with HBsAg positivity had lower CD4 counts.

QuantiFERON-TB Gold In-Tube for the detection of Mycobacterium tuberculosis infection in children with household tuberculosis contact.

SETTING: Improved strategies are needed for detecting Mycobacterium tuberculosis infection in children in TB-endemic settings. OBJECTIVE: To determine the prevalence of M. tuberculosis infection by tuberculin skin testing (TST) and by the QuantiFERON-TB Gold In-Tube (QFT-GIT) test in children with an adult household contact with pulmonary TB in South Africa. DESIGN: Cross-sectional study. RESULTS: A total of 167 adult pulmonary TB cases (153/167, 92% human immunodeficiency virus [HIV] infected) and 270 pediatric contacts (median age 6 years, 14/270, 5% HIV-infected) were enrolled. All children completed QFT-GIT testing and 254 (94.1%) completed TST testing. Prevalence of M. tuberculosis infection was 28% (71/254, 95%CI 23-34) using TST (5 mm cut-off) and 29% (79/270, 95%CI 24-35) using QFT-GIT (P = 0.49). Agreement between TST and QFT-GIT was 81% (kappa 0.58). Nineteen (7%) QFT-GIT results were indeterminate. Children aged <2 years were more likely than older children to have indeterminate QFT-GIT results (aOR 5.7, 95%CI 1.5-22, P = 0.01) and discordant QFT-GIT and TST results (aOR 3.5, 95%CI 1.7-7.6, P = 0.001). CONCLUSION: Prevalence of M. tuberculosis infection in pediatric contacts was high regardless of the diagnostic method used. TST should not be excluded for the detection of pediatric M. tuberculosis infection in this setting, but QFT-GIT may be a feasible alternative in children aged ≥ 2 years.

Intention to quit smoking among human immunodeficiency virus infected adults in Johannesburg, South Africa.

Although smoking is common in human immunodeficiency virus (HIV) infected individuals, in resource-constrained, high HIV prevalence settings, information on smoking cessation intent and acceptability is limited. Of 150 self-reported current smokers surveyed in two South African HIV clinics, 62 (42%) reported intent to quit smoking in the next year, while 86 (58%) were not interested in quitting or had no plan to quit; 132 (82%) had attempted to quit at least once in the past. Respondents' preferred cessation strategies were counseling and nicotine replacement. A high proportion of HIV-infected smokers want to quit, and interventions should be provided as part of HIV care.