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.

Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: A comparative analysis between a multi-country tracing study and linkage to a health information exchange.

OBJECTIVES: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. METHODS: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correcting mortality estimates for all children, adolescents and young adults with HIV. RESULTS: We found substantial variations of mortality estimates among children, adolescents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI(asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. CONCLUSIONS: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out-of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.

Tobacco smoking, smoking cessation and life expectancy among people with HIV on antiretroviral therapy in South Africa: a simulation modelling study.

INTRODUCTION: As access to effective antiretroviral therapy (ART) has improved globally, tobacco-related illnesses, including cardiovascular disease, cancer and chronic respiratory conditions, account for a growing proportion of deaths among people with HIV (PWH). We estimated the impact of tobacco smoking and smoking cessation on life expectancy among PWH in South Africa. METHODS: In a microsimulation model, we simulated 18 cohorts of PWH with virologic suppression, each homogenous by sex, initial age (35y/45y/55y) and smoking status (current/former/never). Input parameters were from data sources published between 2008 and 2022. We used South African data to estimate age-stratified mortality hazard ratios: 1.2-2.3 (females)/1.1-1.9 (males) for people with current versus never smoking status; and 1.0-1.3 (females)/1.0-1.5 (males) for people with former versus never smoking status, depending on age at cessation. We assumed smoking status remains unchanged during the simulation; people who formerly smoked quit at model start. Simulated PWH face a monthly probability of disengagement from care and virologic non-suppression. In sensitivity analysis, we varied smoking-associated and HIV-associated mortality risks. Additionally, we estimated the total life-years gained if a proportion of all virologically suppressed PWH stopped smoking. RESULTS: Forty-five-year-old females/males with HIV with virologic suppression who smoke lose 5.3/3.7 life-years compared to PWH who never smoke. Smoking cessation at age 45y adds 3.4/2.4 life-years. Simulated PWH who continue smoking lose more life-years from smoking than from HIV (females, 5.3 vs. 3.0 life-years; males, 3.7 vs. 2.6 life-years). The impact of smoking and smoking cessation increase as smoking-associated mortality risks increase and HIV-associated mortality risks, including disengagement from care, decrease. Model results are most sensitive to the smoking-associated mortality hazard ratio; varying this parameter results in 1.0-5.1 life-years gained from cessation at age 45y. If 10-25% of virologically suppressed PWH aged 30-59y in South Africa stopped smoking now, 190,000-460,000 life-years would be gained. CONCLUSIONS: Among virologically suppressed PWH in South Africa, tobacco smoking decreases life expectancy more than HIV. Integrating tobacco cessation interventions into HIV care, as endorsed by the World Health Organization, could substantially improve life expectancy.

Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting.

Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months' follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8% (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months' longitudinal sampling, only 2% (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.

Laparoscopic-Assisted Transvaginal Cholecystectomy - the US Military Experience With Long-Term Follow Up.

Objectives: We present our initial clinical experience applying Natural Orifice Transluminal Endoscopic Surgical (NOTES) technique to perform cholecystectomy in ten patients at a military institution. Methods: A posterior colpotomy was created to accommodate a single site working port used to facilitate dissection and gallbladder mobilization under direct visualization via an infraumbilical port. The specimen was retrieved through the vagina and the colpotomy was closed with absorbable suture under direct visualization. Long-term follow up was performed over the phone to assess quality of life with 2 widely used health-related quality of life (HRQoL) surveys including RAND-36 Health Item Survey (Version 1.0),1 and the Female Sexual Function Index (FSFI).2. Results: Ten women underwent a laparoscopic-assisted transvaginal cholecystectomy (TVC) with 7 available for long-term follow-up. The average age was 28.9 years (20-37) and the indications for surgery included symptomatic cholelithiasis (9) and biliary dyskinesia (1). The mean operative time was 129 mins (95-180), and median blood loss was 34 ml (5-400). There were no conversions and the average length of stay was 9.98 hours (2.4-28.8). Pain (analogue scale 1-10) on postoperative day three was minimal (mean 2.3) and was limited to the infraumbilical incision. On average patients returned to work by postoperative day six and resumed normal daily activities at seven days. Immediate postoperative complications included one incident of postoperative urinary retention requiring bladder catheterization. One intra-operative cholangiogram was successfully performed due to elevated preoperative liver enzymes without significant findings. Long-term complications included one asymptomatic incisional hernia repair at the infraumbilical port site. The RAND-36 survey demonstrated an average physical and mental health summary score of 82.2 and 63.7 with an average general health score of 63.6. The average FSFI total score was 21.8. Conclusion: TVC is safe and effective. Implementation may improve operational readiness by returning service members to normal activities more expeditiously than conventional laparoscopy.

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.

Self-transfers, Hospital Admissions and Mortality Among Children and Adolescents Lost to Follow-up From Antiretroviral Therapy Programs in the Western Cape, South Africa Between 2004 and 2019: Linkage to Provincial Records.

BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy <15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

Airborne transmission risks of tuberculosis and COVID-19 in schools in South Africa, Switzerland, and Tanzania: Modeling of environmental data.

The COVID-19 pandemic renewed interest in airborne transmission of respiratory infections, particularly in congregate indoor settings, such as schools. We modeled transmission risks of tuberculosis (caused by Mycobacterium tuberculosis, Mtb) and COVID-19 (caused by SARS-CoV-2) in South African, Swiss and Tanzanian secondary schools. We estimated the risks of infection with the Wells-Riley equation, expressed as the median with 2.5% and 97.5% quantiles (credible interval [CrI]), based on the ventilation rate and the duration of exposure to infectious doses (so-called quanta). We computed the air change rate (ventilation) using carbon dioxide (CO2) as a tracer gas and modeled the quanta generation rate based on reported estimates from the literature. The share of infectious students in the classroom is determined by country-specific estimates of pulmonary TB. For SARS-CoV-2, the number of infectious students was estimated based on excess mortality to mitigate the bias from country-specific reporting and testing. Average CO2 concentration (parts per million [ppm]) was 1,610 ppm in South Africa, 1,757 ppm in Switzerland, and 648 ppm in Tanzania. The annual risk of infection for Mtb was 22.1% (interquartile range [IQR] 2.7%-89.5%) in South Africa, 0.7% (IQR 0.1%-6.4%) in Switzerland, and 0.5% (IQR 0.0%-3.9%) in Tanzania. For SARS-CoV-2, the monthly risk of infection was 6.8% (IQR 0.8%-43.8%) in South Africa, 1.2% (IQR 0.1%-8.8%) in Switzerland, and 0.9% (IQR 0.1%-6.6%) in Tanzania. The differences in transmission risks primarily reflect a higher incidence of SARS-CoV-2 and particularly prevalence of TB in South Africa, but also higher air change rates due to better natural ventilation of the classrooms in Tanzania. Global comparisons of the modeled risk of infectious disease transmission in classrooms can provide high-level information for policy-making regarding appropriate infection control strategies.

Computational Models as Predictors of HIV Treatment Outcomes for the Phidisa Cohort in South Africa

Background: Selecting the optimal combination of HIV drugs for an individual in resourcelimited settings is challenging because of the limited availability of drugs and genotyping.Objective: The evaluation as a potential treatment support tool of computational models that predict response to therapy without a genotype; using cases from the Phidisa cohort in South Africa.Methods: Cases from Phidisa of treatment change following failure were identified that had the following data available: baseline CD4 count and viral load; details of failing and previous antiretroviral drugs; drugs in new regimen and time to follow-up. The HIV Resistance Response Database Initiative's (RDI's) models used these data to predict the probability of a viral load 50 copies/mL at follow-up. The models were also used to identify effective alternative combinations of three locally available drugs.Results: The models achieved accuracy (area under the receiver-operator characteristic curve) of 0.72 when predicting response to therapy; which is less accurate than for an independent global test set (0.80) but at least comparable to that of genotyping with rules-based interpretation. The models were able to identify alternative locally available three-drug regimens that were predicted to be effective in 69% of all cases and 62% of those whose new treatment failed in the clinic.Conclusion: The predictive accuracy of the models for these South African patients together with the results of previous studies suggest that the RDI's models have the potential to optimise treatment selection and reduce virological failure in different patient populations; without the use of a genotype

The clinical and economic impact of point-of-care CD4 testing in mozambique and other resource-limited settings: a cost-effectiveness analysis

Background: Point-of-care CD4 tests at HIV diagnosis could improve linkage to care in resource-limited settings. Our objective is to evaluate the clinical and economic impact of point-of-care CD4 tests compared to laboratory-based tests in Mozambique. Methods and findings: We use a validated model of HIV testing, linkage, and treatment (CEPAC-International) to examine two strategies of immunological staging in Mozambique: (1) laboratory-based CD4 testing (LAB-CD4) and (2) point-of-care CD4 testing (POC-CD4). Model outcomes include 5-y survival, life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs). Input parameters include linkage to care (LAB-CD4, 34%; POC-CD4, 61%), probability of correctly detecting antiretroviral therapy (ART) eligibility (sensitivity: LAB-CD4, 100%; POC-CD4, 90%) or ART ineligibility (specificity: LAB-CD4, 100%; POC-CD4, 85%), and test cost (LAB-CD4, US$10; POC-CD4, US$24). In sensitivity analyses, we vary POC-CD4-specific parameters, as well as cohort and setting parameters to reflect a range of scenarios in sub-Saharan Africa. We consider ICERs less than three times the per capita gross domestic product in Mozambique (US$570) to be cost-effective, and ICERs less than one times the per capita gross domestic product in Mozambique to be very cost-effective. Projected 5-y survival in HIV-infected persons with LAB-CD4 is 60.9% (95% CI, 60.9%-61.0%), increasing to 65.0% (95% CI, 64.9%-65.1%) with POC-CD4. Discounted life expectancy and per person lifetime costs with LAB-CD4 are 9.6 y (95% CI, 9.6-9.6 y) and US$2,440 (95% CI, US$2,440-US$2,450) and increase with POC-CD4 to 10.3 y (95% CI, 10.3-10.3 y) and US$2,800 (95% CI, US$2,790-US$2,800); the ICER of POC-CD4 compared to LAB-CD4 is US$500/year of life saved (YLS) (95% CI, US$480-US$520/YLS). POC-CD4 improves clinical outcomes and remains near the very cost-effective threshold in sensitivity analyses, even if point-of-care CD4 tests have lower sensitivity/specificity and higher cost than published values. In other resource-limited settings with fewer opportunities to access care, POC-CD4 has a greater impact on clinical outcomes and remains cost-effective compared to LAB-CD4. Limitations of the analysis include the uncertainty around input parameters, which is examined in sensitivity analyses. The potential added benefits due to decreased transmission are excluded; their inclusion would likely further increase the value of POC-CD4 compared to LAB-CD4. Conclusions: POC-CD4 at the time of HIV diagnosis could improve survival and be cost-effective compared to LAB-CD4 in Mozambique, if it improves linkage to care. POC-CD4 could have the greatest impact on mortality in settings where resources for HIV testing and linkage are most limited. Please see later in the article for the Editors' Summary.

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