•Rifampicin concentrations were low in all continuously fed critically ill patients.•Dose escalation increased drug exposure and achieved target concentrations.•Therapeutic drug monitoring should be ...implemented in critically ill patients to improve dose optimization.•Further research is required to determine the impact of therapeutic drug monitoring on clinical outcomes.
Critically ill patients with tuberculosis (TB) face a high mortality risk and require effective treatment. There is a paucity of data on rifampicin pharmacokinetics, the impact of continuous enteral feeding on drug absorption, and the potential of therapeutic drug monitoring (TDM) to optimize drug exposure in these patients.
We performed a sequential pharmacokinetic study to determine the impact of feeding and TDM with rifampicin dose escalation in critically ill patients with TB. Noncompartmental pharmacokinetic analysis was performed.
Among 20 critically ill patients (40% were HIV-infected), median rifampicin Cmax (maximum serum concentration) in the fasted and fed states were 5.1 µg/ml versus 3.3 µg/ml, respectively (P <0.0001; geometric mean ratio 1.95; 90% confidence interval 1.46-2.60). The proportion of patients with low rifampicin concentrations in the fasted and fed states was 80% vs 100% (P-value = 0.1336). Optimized dosing led to a per-patient median rifampicin dosing of 24.6 mg/kg and a median Cmax increase from 2.4 µg/ml to 17.8 µg/ml (P-value = 0.0005; geometric mean ratio 8.29; 90% confidence interval 3.88-17.74). TDM-guided dose escalation increased the proportion of patients achieving the suggested target rifampicin concentration compared with standard dosing (83% vs 0%, P-value = 0.004).
We found low rifampicin concentrations in all patients receiving continuous enteral feeding. TDM-guided dose escalation provided an effective strategy to achieve target drug exposure in these critically ill patients with TB.
•Community-based integration of TB and COVID-19 screening is feasible.•Point-of-care molecular and radiological screening tools have high diagnostic yield.•This active case-finding strategy detects ...individuals with probably infectious TB.
To evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF).
Community-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert Ultra) and COVID-19 (nasopharyngeal swabs; Xpert SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals.
Six hundred and one participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 1.4% had concurrent TB/COVID-19). Seven (7/16 43.8%) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area under the curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have ‘good’ user-friendliness.
Integrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons.
COVID-19 self-testing strategy (COVIDST) can rapidly identify symptomatic and asymptomatic SARS-CoV-2-infected individuals and their contacts, potentially reducing transmission. In this living ...systematic review, we evaluated the evidence for real-world COVIDST performance. Two independent reviewers searched six databases (PubMed, Embase, Web of Science, World Health Organization database, Cochrane COVID-19 registry, Europe PMC) for the period April 1st, 2020, to January 18th, 2023. Data on studies evaluating COVIDST against laboratory-based conventional testing and reported on diagnostic accuracy, feasibility, acceptability, impact, and qualitative outcomes were abstracted. Bivariate random effects meta-analyses of COVIDST accuracy were performed (n = 14). Subgroup analyses (by sampling site, symptomatic/asymptomatic infection, supervised/unsupervised strategy, with/without digital supports) were conducted. Data from 70 included studies, conducted across 25 countries with a median sample size of 817 (range: 28-784,707) were pooled. Specificity and DOR was high overall, irrespective of subgroups (98.37-99.71%). Highest sensitivities were reported for: a) symptomatic individuals (73.91%, 95%CI: 68.41-78.75%; n = 9), b) mid-turbinate nasal samples (77.79%, 95%CI: 56.03-90.59%; n = 14), c) supervised strategy (86.67%, 95%CI: 59.64-96.62%; n = 13), and d) use of digital interventions (70.15%, 95%CI: 50.18-84.63%; n = 14). Lower sensitivity was attributed to absence of symptoms, errors in test conduct and absence of supervision or a digital support. We found no difference in COVIDST sensitivity between delta and omicron pre-dominant period. Digital supports increased confidence in COVIDST reporting and interpretation (n = 16). Overall acceptability was 91.0-98.7% (n = 2) with lower acceptability reported for daily self-testing (39.5-51.1%). Overall feasibility was 69.0-100.0% (n = 5) with lower feasibility (35.9-64.6%) for serial self-testing. COVIDST decreased closures in school, workplace, and social events (n = 4). COVIDST is an effective rapid screening strategy for home-, workplace- or school-based screening, for symptomatic persons, and for preventing transmission during outbreaks. These data will guide COVIDST policy. Our review demonstrates that COVIDST has paved the way for self-testing in pandemics worldwide.
With a prevalence almost twice as high as the national average, people living in South African townships are particularly impacted by the HIV epidemic. Yet, it remains unclear how socioeconomic ...factors impact the risk of HIV infection within township populations. Our objective was to estimate the extent to which socioeconomic factors (dwelling situation, education, employment status, and monthly income) explain the risk of HIV in South African township populations, after controlling for behavioural and individual risk factors. Using Bayesian logistic regression, we analysed secondary data from a quasi-randomised trial which recruited participants (N = 3095) from townships located across three subdistricts of Cape Town. We controlled for individual factors (age, sex, marital status, testing history, HIV exposure, comorbidities, and tuberculosis infection) and behavioural factors (unprotected sex, sex with multiple partners, with sex workers, with a partner living with HIV, under the influence of alcohol or drugs), and accounted for the uncertainty due to missing data through multiple imputation. We found that residing in informal dwellings and not having post-secondary education increased the odds of HIV (aOR, 89% CrI: 1.34, 1.07-1.68 and 1.82, 1.29-2.61, respectively), after controlling for subdistrict of residence, individual, and behavioural factors. Additionally, our results suggest different pathways for how socioeconomic status (SES) affect HIV infection in males and female participants: while socioeconomic factors associated with lower SES seem to be associated with a decreased likelihood of having recently sough HIV testing among male participants, they are associated with increased sexual risk taking which, among female participants, increase the risk of HIV. Our analyses demonstrate that social determinants of health are at the root of the HIV epidemic and affect the risk of HIV in multiple ways. These findings stress the need for the deployment of programs that specifically address social determinants of health.
IntroductionImplementation data for digital unsupervised HIV self-testing (HIVST) are sparse. We evaluated the impact of an app-based, personalised, oral HIVST program offered by healthcare workers ...in Western Cape, South Africa.MethodsIn a quasirandomised study (n=3095), we recruited consenting adults with undiagnosed HIV infection from township clinics. To the HIVST arm participants (n=1535), we offered a choice of an offsite (home, office or kiosk based), unsupervised digital HIVST program (n=962), or an onsite, clinic-based, supervised digital HIVST program (n=573) with 24/7 linkages services.With propensity score analyses, we compared outcomes (ie, linkages, new HIV infections and test referrals) with conventional HIV testing (ConvHT) arm participants (n=1560), recruited randomly from geographically separated clinics.ResultsIn both arms, participants were young (HIVST vs ConvHT) (mean age: 28.2 years vs 29.2 years), female (65.0% vs 76.0%) and had monthly income <3000 rand (80.8% vs 75%).Participants chose unsupervised HIVST (62.7%) versus supervised HIVST and reported multiple sex partners (10.88% vs 8.7%), exposure to sex workers (1.4% vs 0.2%) and fewer comorbidities (0.9% vs 1.9%). Almost all HIVST participants were linked (unsupervised HIVST (99.7%), supervised HIVST (99.8%) vs ConvHT (98.5%)) (adj RR 1.012; 95% CI 1.005 to 1.018) with new HIV infections: overall HIVST (9%); supervised HIVST (10.9%) and unsupervised HIVST (7.6%) versus ConvHT (6.79%) (adj RR 1.305; 95% CI 1.023 to 1.665); test referrals: 16.7% HIVST versus 3.1% ConvHT (adj RR 5.435; 95% CI 4.024 to 7.340).ConclusionsOur flexible, personalised, app-based HIVST program, offered by healthcare workers, successfully linked almost all HIV self-testers, detected new infections and increased referrals to self-test. Data are relevant for digital HIVST initiatives worldwide.
•In the diagnosis of tuberculosis, adjuvant urine lipopolysaccharide lipoarabinomannan (LAM) did not reduce the number of diagnostic sputum samples, need for additional imaging, or hospital ...readmission rate.•Adjunctive urine LAM was associated with a more rapid rate of disease resolution in the severely ill subgroup.•Higher urine LAM grade was associated with lower use of ultrasound, lower CD4 cell count, and shorter time to tuberculosis culture positivity.
The World Health Organization (WHO) recommends the use of adjunctive urine lipopolysaccharide lipoarabinomannan (LAM) testing in hospitalized HIV-infected persons with suspected tuberculosis (TB) and a CD4 count <100cells/ml. However, the recommendation is conditional, and uptake by individual treatment programmes depends on perceived additional benefit. The aim of this study was to determine whether adjunctive LAM testing has additional clinical benefits including a reduction in healthcare-related use of resources.
A post hoc analysis was performed of a published multicentre, multi-country, randomized controlled trial that showed an approximate 20% mortality benefit in HIV-infected hospitalized patients who underwent adjunctive LAM testing as part of their diagnostic workup. In that parent study, adult HIV-infected hospitalized patients with suspected TB (n=2528) were randomly allocated to either routine diagnostics (smear microscopy, Xpert MTB/RIF, and culture; n=1271), or routine diagnostics plus adjunctive urine LAM testing (n=1257). Data were further analyzed to determine whether there were other potential benefits of LAM usage based on CD4 count and illness severity. Aspects evaluated included: (1) the reduction in number of diagnostic sputum samples tested, (2) the utilization of additional imaging, (3) disease resolution based on follow-up signs and symptoms of illness severity, and (4) the reduction in hospital readmission.
Adjuvant LAM did not reduce the number of diagnostic sputum samples requested, the need for additional imaging, or the hospital readmission rate. However, adjunctive LAM was associated with a more rapid rate of disease resolution (dyspnoea) in the severely ill subgroup. Higher LAM grade (grades 4 and 5), compared to lower grade positivity (≤3), was associated with lower use of ultrasound, lower Karnofsky performance score, lower CD4 cell count, and shorter time to culture positivity.
Although, adjunct LAM was associated with a mortality benefit in the parent study, no benefit could be demonstrated in the secondary analysis with respect to the number of diagnostic sputum samples requested, the use of additional imaging, or hospital readmission rates. However, given the limitations of the present study, further appropriately designed studies are required to determine the effect of adjunct urine LAM on the utilization of healthcare resources.
Feasibility and acceptability research for HIV self-testing (HIVST) often emphasises the importance of good test conduct and correct test interpretation for knowing one’s HIV result while overlooking ...the ways in which different uncertainties and meanings emerge around testing. Using empirical examples from a quantitative study assessing an app-based strategy in Cape Town, South Africa, this research article explores the practice of HIVST and how people deal with uncertainties while using the app in question, named ‘HIVSmart!’. We use the concept of ‘living under’ to explore the practices of HIV testing for those who fit the definition of being ‘at risk’ of HIV (note that an individual’s HIV status must be unknown in order for them to fit this definition) and to understand how an app-based HIVST strategy fits within these practices. We show how the app and oral self-test—as well as knowledge around HIV risk behaviours, comparisons between different testing methods, and the guidance and presence of healthcare staff—alleviate as well as generate uncertainty and constitute HIV status as an ongoing process. The effective implementation of new strategies for HIVST requires consideration of multiple aspects of the testing process, including local understandings of HIV risk, access to healthcare staff, and the meaning of certain test methods within a particular context.
There are few prospective data about the incidence and mortality associated with pulmonary tuberculosis in intensive care units (ICUs), and none on the accuracy and clinical effect of the ...Xpert-MTB/RIF assay in this setting. We aimed to measure the frequency of culture-positive tuberculosis in ICUs in Cape Town, South Africa and to assess the performance and effect on patient outcomes of Xpert MTB/RIF versus smear microscopy for diagnosis of tuberculosis.
We did a prospective burden of disease study with a randomised controlled substudy at the ICUs of four hospitals in Cape Town. Mechanically ventilated adults (≥18 years) with suspected pulmonary tuberculosis admitted between Aug 1, 2010, and July 31, 2013 (irrespective of the reason for admission), were prospectively investigated by culture, and by Xpert-MTB/RIF testing or smear microscopy, of tracheal aspirate samples. In the substudy, patients were randomly assigned (1:1), via a computer-generated allocation list, to smear microscopy or Xpert MTB/RIF. Participants, caregivers, and outcome assessors were not masked to group assignment. Only the laboratory staff were blinded to the clinical details of the participants. In November, 2012, Xpert MTB/RIF was adopted as the initial diagnostic test for respiratory samples in Western Cape province. Thereafter, patients received Xpert MTB/MIF and culture as standard of care. For the whole study cohort, the primary outcome was the frequency of bacteriologically confirmed tuberculosis. The primary endpoint of the randomised substudy was the proportion of culture-positive patients on treatment at 48 h after enrolment. The randomised substudy is registered with ClinicalTrials.gov, number NCT01530568.
We investigated 341 patients for suspected pulmonary tuberculosis out of a total of 2309 ICU admissions. 46 (15%) of 317 patients included in the final analysis had a positive test for tuberculosis (Xpert MTB/RIF or culture). Culture-positive patients who failed to initiate treatment (adjusted HR 4·49, 95% CI 1·45-13·89) or who received inotropes (4·33, 1·49-12·60) were more likely to die. However, tuberculosis status was not associated with 28-day or 90-day mortality. In the substudy, we randomly assigned 115 patients to smear microscopy and 111 to Xpert MTB/RIF. Smear microscopy detected six (43%) of 14 culture-positive patients, and Xpert MTB/RIF detected 11 (100%) of 11 culture-positive patients (p=0·002). The proportion of culture-positive patients on treatment at 48 h was higher in the Xpert MTB/RIF group than in the smear microscopy group (11 92% of 12 vs nine 53% of 17; p=0·043), although use of Xpert MTB/RIF had no effect on mortality or other patient outcomes.
Tuberculosis is fairly common in ICUs in high-burden settings, and clinicians should screen and test patients for tuberculosis with Xpert MTB/RIF where available. This test improves diagnostic yield and rates of treatment initiation, and reduces unnecessary treatment, but might not increase the total number of patients on treatment when empirical treatment is widely used. A suspected diagnosis of pulmonary tuberculosis should not exclude patients from ICU care in resource-limited settings because mortality is unaffected by the presence of this disease.
European and Developing Countries Clinical Trials Partnership, South African Medical Research Council, and the Discovery Foundation.
There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are ...unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline-delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5%
81.8%; p=0.26) and 18-month favourable outcome rate (63.4%
67.5%; p=0.66) in the bedaquiline
the bedaquiline-delamanid combination group, despite the latter having more advanced drug resistance (3.7%
22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2%
52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.A bedaquiline-delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.
A double-blind randomized trial in South Africa documented poor efficacy of two doses of the ChAdOx1 nCoV-19 vaccine against the B.1.351 variant of SARS-CoV-2 that emerged in South Africa. Infections ...occurred in 3.2% of placebo recipients and in 2.5% of vaccine recipients. Thirty-nine of the 42 virus isolates were the B.1.351 variant. None of the cases led to hospitalization or death.
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