COVID-19 outbreaks in residential aged care facilities: an agent-based modeling study.

Introduction: A disproportionate number of COVID-19 deaths occur in Residential Aged Care Facilities (RACFs), where better evidence is needed to target COVID-19 interventions to prevent mortality. This study used an agent-based model to assess the role of community prevalence, vaccination strategies, and non-pharmaceutical interventions (NPIs) on COVID-19 outcomes in RACFs in Victoria, Australia. Methods: The model simulated outbreaks in RACFs over time, and was calibrated to distributions for outbreak size, outbreak duration, and case fatality rate in Victorian RACFs over 2022. The number of incursions to RACFs per day were estimated to fit total deaths and diagnoses over time and community prevalence.Total infections, diagnoses, and deaths in RACFs were estimated over July 2023-June 2024 under scenarios of different: community epidemic wave assumptions (magnitude and frequency); RACF vaccination strategies (6-monthly, 12-monthly, no further vaccines); additional non-pharmaceutical interventions (10, 25, 50% efficacy); and reduction in incursions (30% or 60%). Results: Total RACF outcomes were proportional to cumulative community infections and incursion rates, suggesting potential for strategic visitation/staff policies or community-based interventions to reduce deaths. Recency of vaccination when epidemic waves occurred was critical; compared with 6-monthly boosters, 12-monthly boosters had approximately 1.2 times more deaths and no further boosters had approximately 1.6 times more deaths over July 2023-June 2024. Additional NPIs, even with only 10-25% efficacy, could lead to a 13-31% reduction in deaths in RACFs. Conclusion: Future community epidemic wave patterns are unknown but will be major drivers of outcomes in RACFs. Maintaining high coverage of recent vaccination, minimizing incursions, and increasing NPIs can have a major impact on cumulative infections and deaths.

The relative effectiveness of three and four doses of COVID-19 vaccine in Victoria, Australia: A data linkage study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic led to extensive vaccination campaigns worldwide, including in Australia. Immunity waning and the emergence of new viral variants pose challenges to the effectiveness of vaccines. Our study aimed to assess the relative effectiveness (rVE) of 3 and 4 compared with 2 doses of COVID-19 vaccine. The study focuses on the Victorian population, a majority of whom had no prior exposure to the virus before vaccination. METHODS: We used routinely collected data for the state of Victoria, Australia, to assess rVE during an Omicron-dominant period, 1 June 2022 to 1 March 2023. Immunisation, notifications, hospitalisations and mortality data for residents aged 65 years and older were linked for analysis. Cox proportional hazard regression was used to estimate the rVE against COVID-19 hospitalisation or death, accounting for key confounders with vaccination as a time-varying covariate. RESULTS: In 1,070,113 people 65 years or older who had received their second dose, a third and fourth dose of a COVID-19 vaccine significantly reduced the hazard of hospitalisation or death compared to two doses. rVE was highest within two weeks from administration at 40 % (95 % CI: 0 % to 64 %) and 66 % (95 % CI: 60 % to 71 %) for a third and fourth dose, respectively. Additional protection conferred by third and fourth doses waned over time from administration. CONCLUSIONS: Our findings underscore the need for additional vaccine doses and updated vaccine strategies. These findings have implications for public health advice and COVID-19 vaccine strategies. Further research and monitoring of vaccine effectiveness in real-world settings are warranted to inform ongoing pandemic response efforts.

Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study.

Background: Oral Antiviral (OAV) COVID-19 treatments are widely used, but evidence for their effectiveness against the Omicron variant in higher risk, vaccinated individuals is limited. Methods: Retrospective study of two vaccinated cohorts of COVID-19 cases aged ≥70 years diagnosed during a BA.4/5 Omicron wave in Victoria, Australia. Cases received either nirmatrelvir-ritonavir or molnupiravir as their only treatment. Data linkage and logistic regression modelling was used to evaluate the association between treatment and death and hospitalisation and compared with no treatment. Findings: Of 38,933 individuals in the mortality study population, 13.5% (n = 5250) received nirmatrelvir-ritonavir, 51.3% (n = 19,962) received molnupiravir and 35.2% (n = 13,721) were untreated. Treatment was associated with a 57% (OR = 0.43, 95% CI 0.36-0.51) reduction in the odds of death, 73% (OR = 0.27, 95% CI 0.17-0.40) for nirmatrelvir-ritonavir and 55% (OR = 0.45, 95% CI 0.38-0.54) for molnupiravir. Treatment was associated with a 31% (OR = 0.69, 95% CI 0.55-0.86) reduction in the odds of hospitalisation, 40% (OR = 0.60, 95% CI 0.43-0.83) for nirmatrelvir-ritonavir and 29% (OR = 0.71, 95% CI 0.58-0.87) for molnupiravir. Cases treated within 1 day of diagnosis had a 61% reduction in the odds of death (OR = 0.39, 95% CI 0.33-0.46) compared with 33% reduction for a delay of 4 or more days (OR = 0.67, 95% CI 0.44-0.97). Interpretation: Treatment with both nirmatrelvir-ritonavir or molnupiravir was associated with a reduction in death and hospitalisation in vaccinated ≥70 years individuals during the Omicron era. Timely, equitable treatment with OAVs is an important tool in the fight against COVID-19. Funding: There was no funding for this study.

Beyond patient delay, navigating structural health system barriers to timely care and treatment in a high burden TB setting in Papua New Guinea.

Tuberculosis (TB) is a major public health issue in Papua New Guinea, with incidence rates particularly high in the South Fly District of Western Province. We present three case studies, along with additional vignettes, that were derived from interviews and focus groups carried out between July 2019 and July 2020 of people living in rural areas of the remote South Fly District depicting their challenges accessing timely TB diagnosis and care; most services within the district are only offered offshore on Daru Island. The findings detail that rather than 'patient delay' attributed to poor health seeking behaviours and inadequate knowledge of TB symptoms, many people were actively trying to navigate structural barriers hindering access to and utilisation of limited local TB services. The findings highlight a fragile and fragmented health system, a lack of attention given to primary health services, and undue financial burdens placed on people living in rural and remote areas associated with costly transportation to access functioning health services. We conclude that a person-centred and effective decentralised model of TB care as outlined in health policies is imperative for equitable access to essential health care services in Papua New Guinea.

Detecting Mycobacterium tuberculosis Infection in Children Migrating to Australia.

In 2015, Australia updated premigration screening for tuberculosis (TB) disease in children 2-10 years of age to include testing for infection with Mycobacterium tuberculosis and enable detection of latent TB infection (LTBI). We analyzed TB screening results in children <15 years of age during November 2015-June 2017. We found 45,060 child applicants were tested with interferon-gamma release assay (IGRA) (57.7% of tests) or tuberculin skin test (TST) (42.3% of tests). A total of 21 cases of TB were diagnosed: 4 without IGRA or TST, 10 with positive IGRA or TST, and 7 with negative results. LTBI was detected in 3.3% (1,473/44,709) of children, for 30 applicants screened per LTBI case detected. LTBI-associated factors included increasing age, TB contact, origin from a higher TB prevalence region, and testing by TST. Detection of TB and LTBI benefit children, but the updated screening program's effect on TB in Australia is likely to be limited.

Exploring Tuberculosis Riskscapes in a Papua New Guinean 'Hotspot'.

This article explores socio-spatial dimensions of risk and how they can enhance understanding of a high burden tuberculosis (TB) context in the South Fly District of Papua New Guinea. We report on select findings from a qualitative study that included 128 semi-structured in-depth interviews and 10 focus group discussions with a wide range of South Fly District community members. Using the conceptual framework of 'riskscapes' to examine emic perspectives on risk, space and practice, we map key elements of TB riskscapes on Daru Island, South Fly District, along with solutions for navigating through these riskscapes. Overcrowding, lack of water, sanitation and hygiene, as well as food insecurity and undernutrition, were identified as common elements within participants' riskscapes, that compounded upon each other to create the perception of an assemblage of risk favourable to TB transmission.

Evolution and spread of a highly drug resistant strain of Mycobacterium tuberculosis in Papua New Guinea.

BACKGROUND: Molecular mechanisms determining the transmission and prevalence of drug resistant tuberculosis (DR-TB) in Papua New Guinea (PNG) are poorly understood. We used genomic and drug susceptibility data to explore the evolutionary history, temporal acquisition of resistance and transmission dynamics of DR-TB across PNG. METHODS: We performed whole genome sequencing on isolates from Central Public Health Laboratory, PNG, collected 2017-2019. Data analysis was done on a composite dataset that also included 100 genomes previously sequenced from Daru, PNG (2012-2015). RESULTS: Sampled isolates represented 14 of the 22 PNG provinces, the majority (66/94; 70%) came from the National Capital District (NCD). In the composite dataset, 91% of strains were Beijing 2.2.1.1, identified in 13 provinces. Phylogenetic tree of Beijing strains revealed two clades, Daru dominant clade (A) and NCD dominant clade (B). Multi-drug resistance (MDR) was repeatedly and independently acquired, with the first MDR cases in both clades noted to have emerged in the early 1990s, while fluoroquinolone resistance emerged in 2009 (95% highest posterior density 2000-2016). We identified the presence of a frameshift mutation within Rv0678 (p.Asp47fs) which has been suggested to confer resistance to bedaquiline, despite no known exposure to the drug. Overall genomic clustering was significantly associated with rpoC compensatory and inhA promoter mutations (p < 0.001), with high percentage of most genomic clusters (12/14) identified in NCD, reflecting its role as a potential national amplifier. CONCLUSIONS: The acquisition and evolution of drug resistance among the major clades of Beijing strain threaten the success of DR-TB treatment in PNG. With continued transmission of this strain in PNG, genotypic drug resistance surveillance using whole genome sequencing is essential for improved public health response to outbreaks. With occurrence of resistance to newer drugs such as bedaquiline, knowledge of full drug resistance profiles will be important for optimal treatment selection.

Tuberculosis in migrants to Australia: Outcomes of a national screening program.

BACKGROUND: Few low-incidence countries are on track to achieve the ambitious target of reaching TB pre-elimination by 2035. Australia is a high-income country with a low burden of TB, which is particularly concentrated in migrant populations. As part of Australia's migration program, permanent, provisional and humanitarian visa applicants are screened for TB, along with some applicants for temporary visas. METHODS: We calculated the prevalence of all forms of active TB and bacteriologically-confirmed TB among onshore and offshore applicants for visas to Australia from July 2014 to June 2017, and investigated associated risk factors using logistic regression. FINDINGS: Visa applicants were predominantly young adults from various Asian countries. Among 2,381,217 applicants, 1263 cases of active TB were diagnosed, including 852 cases of bacteriologically-confirmed TB. Overall TB prevalence was 53.0 per 100,000, corresponding to one TB diagnosis for every 1887 applicants screened. TB rates increased with age and were higher among humanitarian applicants and those previously treated for TB, although most cases occurred in applicants without these risk factors. TB prevalence by country of origin was similar to WHO estimates for some countries, but considerably lower for others. For several highly represented countries of origin, rates appear to have fallen relative to earlier comparable studies. INTERPRETATION: Prevalence of TB among visa applicants to Australia and the consequent risk to the Australian community appear to be declining and remain low. In this context, support for TB control programs overseas and preventive interventions are likely to have the greatest impact on domestic TB burden. FUNDING: No specific funding was received for this study. JMT is a recipient of an Early Career Fellowship from the Australian National Health and Medical Research Council (APP1142638).

Telemedicine in Resource-Limited Settings to Optimize Care for Multidrug-Resistant Tuberculosis.

The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) poses a major threat to the global targets for TB control. In recent years, an evolving science and evidence base for MDR-TB has led to much needed changes in international guidelines promoting the use of newer TB drugs and regimens for MDR-TB, however, there remains a significant implementation gap. Due to the complexity of treating MDR-TB, management of cases is often supported by an expert multidisciplinary team, or clinical expert group. This service is often centralized, and may be delivered through a telemedicine platform. We have implemented a Web-based "store-and-forward" telemedicine service to optimize MDR-TB patient care in Daru, a remote and resource limited setting in Papua New Guinea (PNG). From April 2016 to February 2019, 237 cases were discussed using the service. This encompassed diagnostic (presumptive) and treatment cases, and more recently, support to the scale up of preventative therapy for latent TB infection. There were 75 cases in which the use of Bedaquiline was discussed or mentioned, with a high frequency of discussions occurring in the initial period (26 cases in the first 12 months), which has appeared to decrease as clinicians gained familiarity with use of the drug (15 cases in the last 12 months). This service has supported high quality clinical care and fostered collaboration between clinicians and technical experts in a shared learning environment.

Training for Tuberculosis Elimination in Indonesia: Achievements, Reflections, and Potential for Impact.

Indonesia has the third highest tuberculosis (TB) caseload internationally. A cornerstone for strengthening health systems to respond to TB is a well-trained workforce. In a partnership between Indonesian and Australian institutions, TB training was run during 2018 to strengthen the local capacity to meet End TB strategy targets. This paper aims to report on course design, delivery, training outcomes, and reflections. Seventy-six Indonesian healthcare workers, program staff, researchers, and policy-makers were selected from over 800 applicants. The structure comprised three trainings, each with a pre-course workshop (in Indonesia) to identify learning needs, a two-week block (Australia), and a post-course workshop (Indonesia). The training content delivered was a combination of TB technical knowledge and program/project theory, design, and logic, and the training utilised multiple teaching and learning methods. An innovative element of the training was participant-designed TB workplace projects focusing on context-specific priorities. Evaluation was undertaken using participant surveys and appraisal of the projects. Participants rated the course highly, while success in project implementation varied. Reflections include the importance of involving Indonesian experts in delivery of training, the need to understand participant learning requirements and adapt the training content accordingly, and the challenge of measuring tangible training outputs.

Early Success With Retention in Care Among People Living With HIV at Decentralized ART Satellite Sites in Yangon, Myanmar, 2015-2016.

Introduction: Myanmar is one of the countries in the Asia-Pacific region hit hardest by the HIV epidemic that is concentrated among urban areas and key populations. In 2014, the National AIDS Programme (NAP) launched a new model of decentralized service delivery with the establishment ART satellite sites with care delivered by HIV peer workers. Methods: ART satellite sites are implemented by non-government organizations to service high burden HIV areas and populations that suffer stigma or find access to public sector services difficult. They provide continuity of HIV care from outreach testing, counseling, linkage to care, and retention in care. Anti-retroviral (ART) initiation occurs at health facilities by specialist physicians. We conducted a retrospective cohort study of people living with HIV (PLHIV) who were initiated on ART from 2015 to 2016 at five ART satellite sites in Yangon, Myanmar to assess outcomes and time from enrolment to ART initiation. Results: Of 1,339 PLHIV on ART treatment in 2015-16, 1,157 (89%) were retained, and 5% were lost from care and 5% reported dead, at the end of March 2018. Attrition rates (death and lost-to-follow-up) were found to be significantly associated with a CD4 count ≤ 50 cells/mm3 and having baseline weight ≤ 50 kg. Median time taken from enrolment to ART initiation was 1.9 months (interquartile range: 1.4-2.5). Conclusion: We report high rates of retention in care of PLHIV in a new model of ART satellite sties in Yangon, Myanmar after 3 years of follow-up. The delays identified in time taken from enrolment to ART initiation need to be explored further and addressed. This initial study supports continuation of plans to scale-up ART satellite sites in Myanmar. To optimize outcomes for patients and the program and accelerate progress to reduce HIV transmission and end the HIV epidemic, operational research needs to be embedded within the response.

On the conditional distribution of a multivariate Normal given a transformation - the linear case.

We show that the orthogonal projection operator onto the range of the adjoint T ⁎ of a linear operator T can be represented as UT, where U is an invertible linear operator. Given a Normal random vector Y and a linear operator T, we use this representation to obtain a linear operator T ˆ such that T ˆ Y is independent of TY and Y - T ˆ Y is an affine function of TY. We then use this decomposition to prove that the conditional distribution of a Normal random vector Y given T Y , where T is a linear transformation, is again a multivariate Normal distribution. This result is equivalent to the well-known result that given a k-dimensional component of a n-dimensional Normal random vector, where k < n , the conditional distribution of the remaining ( n - k ) -dimensional component is a ( n - k ) -dimensional multivariate Normal distribution, and sets the stage for approximating the conditional distribution of Y given g ( Y ) , where g is a continuously differentiable vector field.

Are death and loss to follow-up still high in people living with HIV on ART after national scale-up and earlier treatment initiation? A large cohort study in government hospital-based setting, Myanmar: 2013-2016.

SETTING: Myanmar National AIDS Program has had significant scale-up of services and changes in CD4 eligibility criterion for ART initiation from 2013 to 2016. This study assessed early death within 6 months and attrition (death and loss to follow-up, LTFU) after ART initiation and their associated factors. DESIGN: A retrospective cohort study on people living with HIV (PLHIV >15 year of age) enrolled at three specialist hospitals in Yangon from 1st June 2013 to 30th June 2016. Cox regression was used to calculate hazard ratios (HRs) of early death and attrition. RESULTS: Of 11,727 adults enrolled, 11,186 (95%) were initiated on ART, providing 15,964 person-years of follow-up. At baseline, median age was 36 years [IQR: 30-43], 58% were men and median CD4 count was 151 cells/mm3 (IQR: 54-310). There were 733(6%) early deaths, 961(9%) total deaths and 1371 (12%) LTFU during the study period. Independent risk factors for early death were older age (41-50 and ≥51 years) [aHR 1.38, 1.07-1.78 and 1.68, 1.21-2.34], male (1.84, 1.44-2.35), low weight (2.06, 1.64-2.59), bedridden, (3.81, 2.57-5.66) and CD4 count ≤ 50 cells/mm3 (6.83, 2.52-18.57). In addition to above factors, high attrition was associated with an abacavir-based regimen. CONCLUSION: Although there was a low rate of early deaths, patients were being diagnosed late and there was a high attrition rate from specialist hospitals. Concerted effort is required to increase early diagnosis and ART initiation, and strengthen community systems for HIV care to achieve ambitious goal of ending AIDS epidemic by 2030.

Evaluation of a tuberculosis active case finding project in peri-urban areas, Myanmar: 2014-2016.

OBJECTIVES: We assessed the effect of an active case finding (ACF) project on tuberculosis (TB) case notification and the yields from a household and neigbourhood intervention (screening contacts of historical index TB patients diagnosed >24months ago) and a community intervention (screening attendants of health education sessions/mobile clinics). DESIGN: Cross-sectional analysis of project records, township TB registers and annual TB reports. RESULTS: In the household and neigbourhood intervention, of 56,709 people screened, 1,076 were presumptive TB and 74 patients were treated for active TB with a screening yield of 0.1% and a yield from presumptive cases of 6.9%. In the community intervention, of 162,881 people screened, 4,497 were presumptive TB and 984 were treated for active TB with a screening yield of 0.6% and yield from presumptive cases of 21.9%. Of active TB cases, 94% were new, 89% were pulmonary, 44% were bacteriologically-confirmed and 5% had HIV. Case notification rates per 100,000 in project townships increased from 142 during baseline (2011-2013) to 148 during intervention (2014-2016) periods. CONCLUSIONS: The yield from household and neigbourhood intervention was lower than community intervention. This finding highlights reconsidering the strategy of screening of contacts from historical index cases. Strategies to reach high-risk groups should be explored for future ACF interventions to increase yield of TB.

Multi-clonal evolution of multi-drug-resistant/extensively drug-resistant Mycobacterium tuberculosis in a high-prevalence setting of Papua New Guinea for over three decades.

An outbreak of multi-drug resistant (MDR) tuberculosis (TB) has been reported on Daru Island, Papua New Guinea. Mycobacterium tuberculosis strains driving this outbreak and the temporal accrual of drug resistance mutations have not been described. Whole genome sequencing of 100 of 165 clinical isolates referred from Daru General Hospital to the Supranational reference laboratory, Brisbane, during 2012-2015 revealed that 95 belonged to a single modern Beijing sub-lineage strain. Molecular dating suggested acquisition of streptomycin and isoniazid resistance in the 1960s, with potentially enhanced virulence mediated by an mycP1 mutation. The Beijing sub-lineage strain demonstrated a high degree of co-resistance between isoniazid and ethionamide (80/95; 84.2 %) attributed to an inhA promoter mutation combined with inhA and ndh coding mutations. Multi-drug resistance, observed in 78/95 samples, emerged with the acquisition of a typical rpoB mutation together with a compensatory rpoC mutation in the 1980s. There was independent acquisition of fluoroquinolone and aminoglycoside resistance, and evidence of local transmission of extensively drug resistant (XDR) strains from 2009. These findings underline the importance of whole genome sequencing in informing an effective public health response to MDR/XDR TB.

Extending 'Contact Tracing' into the Community within a 50-Metre Radius of an Index Tuberculosis Patient Using Xpert MTB/RIF in Urban, Pakistan: Did It Increase Case Detection?

BACKGROUND: Currently, only 62% of incident tuberculosis (TB) cases are reported to the national programme in Pakistan. Several innovative interventions are being recommended to detect the remaining 'missed' TB cases. One such intervention involved expanding contact investigation to the community using the Xpert MTB/RIF test. METHODS: This was a before and after intervention study involving retrospective record review. Passive case finding and household contact investigation was routinely done in the pre-intervention period July 2011-June 2013. Four districts with a high concentration of slums were selected as intervention areas; Lahore, Rawalpindi, Faisalabad and Islamabad. Here, in the intervention period, July 2013-June 2015, contact investigation beyond household was conducted: all people staying within a radius of 50 metres (using Geographical Information System) from the household of smear positive TB patients were screened for tuberculosis. Those with presumptive TB were investigated using smear microscopy and the Xpert MTB/RIF test was performed on smear negative patients. All the diagnosed TB patients were linked to TB treatment and care. RESULTS: A total of 783043 contacts were screened for tuberculosis: 23741(3.0%) presumptive TB patients were identified of whom, 4710 (19.8%) all forms and 4084(17.2%) bacteriologically confirmed TB patients were detected. The contribution of Xpert MTB/RIF to bacteriologically confirmed TB patients was 7.6%. The yield among investigated presumptive child TB patients was 5.1%. The overall yield of all forms TB patients among investigated was 22.3% among household and 19.1% in close community. The intervention contributed an increase of case detection of bacteriologically confirmed tuberculosis by 6.8% and all forms TB patients by 7.9%. CONCLUSION: Community contact investigation beyond household not only detected additional TB patients but also increased TB case detection. However, further long term assessments and cost-effectiveness studies are required before national scale-up.