"You'll come in and dose even in a global pandemic”: a qualitative study of adaptive opioid agonist treatment provision during the COVID-19 pandemic

Background Opioid agonist treatment (OAT) improves multiple health and social outcomes, yet requirements to attend for supervised dosing can be burdensome and stigmatising. The COVID-19 pandemic and associated restrictions threatened continuity of care and the wellbeing of people receiving OAT, risking a parallel health crisis. This study sought to understand how adaptations in the complex system of OAT provision impacted and responded to risk environments of people receiving OAT during the COVID-19 pandemic. Methods The analysis draws on semi-structured interviews with 40 people receiving and 29 people providing OAT located across Australia. The study considered the risk environments that produce COVID-19 transmission, treatment (non-)adherence, and adverse events for people receiving OAT. Drawing on theories of risk environments and complex adaptive systems, data were coded and analysed to understand how adaptations to the typically rigid system of OAT provision impacted and responded to risk environments during the COVID-19 pandemic. Results During COVID-19, the complex system of OAT provision demonstrated possibilities for responsive adaptation to the entangled features of risk environments of people receiving OAT. Structural stigma was evident in the services which stayed rigid during the pandemic, requiring people to attend for daily supervised dosing and risking fracturing therapeutic relationships. In parallel, there were several examples of services developing enabling environments by offering flexible care through increased takeaways, treatment subsidies, and home delivery. Conclusions Rigidity in the delivery of OAT has been an impediment to achieving health and wellbeing over past decades. To sustain health-promoting environments for people receiving OAT, the wider impacts of the complex system should be acknowledged beyond narrowly defined outcomes relating solely to the medication. Centring people receiving OAT in their own care plans will ensure adaptations in the complex system of OAT provision are responsive to the individual's risk environment.

COVID-19 vaccine attitudes and facilitators among people in Australia who inject drugs.

INTRODUCTION: We aimed to describe COVID-19 vaccination attitudes and identify potential facilitators for vaccine uptake among people who inject drugs. METHODS: People who inject drugs were recruited from all eight Australian capital cities (N = 884; 65% male, mean age 44 years) and interviewed face-to-face or via telephone in June-July 2021. COVID-19 and broader vaccination attitudes were used to model latent classes. Correlates of class membership were assessed through multinomial logistic regression. Probability of endorsing potential vaccination facilitators were reported by class. RESULTS: Three classes of participants were identified: 'vaccine acceptant' (39%), 'vaccine hesitant' (34%) and 'vaccine resistant' (27%). Those in the hesitant and resistant groups were younger, more likely to be unstably housed and less likely to have received the current season influenza vaccine than the acceptant group. In addition, hesitant participants were less likely to report a chronic medical condition than acceptant participants. Compared to vaccine acceptant and hesitant participants, vaccine-resistant participants were more likely to predominantly inject methamphetamine and to inject drugs more frequently in the past month. Both vaccine-hesitant and resistant participants endorsed financial incentives for vaccination and hesitant participants also endorsed facilitators related to vaccine trust. DISCUSSION AND CONCLUSION: People who inject drugs who are unstably housed or predominantly inject methamphetamine are subgroups that require targeted interventions to increase COVID-19 vaccination uptake. Vaccine-hesitant people may benefit from interventions that build trust in vaccine safety and utility. Financial incentives may improve vaccine uptake among both hesitant and resistant people.

"You'll come in and dose even in a global pandemic": A qualitative study of adaptive opioid agonist treatment provision during the COVID-19 pandemic.

BACKGROUND: Opioid agonist treatment (OAT) improves multiple health and social outcomes, yet requirements to attend for supervised dosing can be burdensome and stigmatising. The COVID-19 pandemic and associated restrictions threatened continuity of care and the wellbeing of people receiving OAT, risking a parallel health crisis. This study sought to understand how adaptations in the complex system of OAT provision impacted and responded to risk environments of people receiving OAT during the COVID-19 pandemic. METHODS: The analysis draws on semi-structured interviews with 40 people receiving and 29 people providing OAT located across Australia. The study considered the risk environments that produce COVID-19 transmission, treatment (non-)adherence, and adverse events for people receiving OAT. Drawing on theories of risk environments and complex adaptive systems, data were coded and analysed to understand how adaptations to the typically rigid system of OAT provision impacted and responded to risk environments during the COVID-19 pandemic. RESULTS: During COVID-19, the complex system of OAT provision demonstrated possibilities for responsive adaptation to the entangled features of risk environments of people receiving OAT. Structural stigma was evident in the services which stayed rigid during the pandemic, requiring people to attend for daily supervised dosing and risking fracturing therapeutic relationships. In parallel, there were several examples of services developing enabling environments by offering flexible care through increased takeaways, treatment subsidies, and home delivery. CONCLUSIONS: Rigidity in the delivery of OAT has been an impediment to achieving health and wellbeing over past decades. To sustain health-promoting environments for people receiving OAT, the wider impacts of the complex system should be acknowledged beyond narrowly defined outcomes relating solely to the medication. Centring people receiving OAT in their own care plans will ensure adaptations in the complex system of OAT provision are responsive to the individual's risk environment.

Evaluation of serological assays for SARS-CoV-2 antibody testing from dried blood spots collected from cohorts with prior SARS-CoV-2 infection.

Background: Dried blood spot (DBS) specimens are a useful serosurveillance tool particularly in hard-to-reach populations but their application for detecting SARS-CoV-2 infection is poorly characterised. Objectives: To compare detection of naturally acquired SARS-CoV-2 antibodies in paired DBS and serum specimens using commercially available serological immunoassays. Study Design: Specimens were collected through St Vincent's Hospital observational post COVID-19 cohort study (ADAPT). Laboratory spotted DBS from venepuncture were initially tested on seven assays, a DBS validation completed on three with clinically collected fingerstick DBSs tested on one. Results: Sensitivity for Euroimmun nucleocapsid (NCP) IgG ELISA from laboratory spotted DBS (n=145), Euroimmun spike, IgG ELISA from laboratory spotted DBS (n=161), and Binding Site total antibody ELISA from clinically collected fingerstick DBS (n=391) was 100% (95% CI: 95.8-100%), 100% (95% CI: 95.8-100%) and 92.9% (95% CI: 89.5-95.5%), respectively. Specificity was 66.2% (95% CI: 53.6-77.0%), 96% (95% CI: 88.7-99.1%) and 98.8% (95% CI: 93.3-99.9%), respectively. All three assays' results displayed a strong positive correlation between DBS compared to paired serum. Conclusions: The Binding Site™ spike total antibody and Euroimmun™ spike IgG ELISAs provided good analytical performance, demonstrating that DBS specimens could facilitate specimen collection in the epidemiological surveillance of SARS-CoV-2 infection. This is highly applicable in populations and settings where venepuncture is problematic (including community based regional/remote settings, nursing homes, prisons, and schools).

High titre neutralizing antibodies in response to SARS-CoV-2 infection require RBD-specific CD4 T cells that include proliferative memory cells.

Background: Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. Methods: We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Findings: Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)-specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, in contrast to the effector T-bet+, cytotoxic granzymes+ and perforin+ cells seen in RBD-specific memory CD4 T cells from high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects similarly revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, in individuals with high antibody levels. However, vaccination of low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Interpretation: Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD-region should be prioritized in booster vaccines.

A multinational Delphi consensus to end the COVID-19 public health threat.

Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic^1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches¹, while maintaining proven prevention measures using a vaccines-plus approach² that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities³ in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.

Nafamostat Mesylate for Treatment of COVID-19 in Hospitalised Patients: A Structured, Narrative Review.

The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only for continuous intravenous infusion. In vitro human lung cell line studies with nafamostat demonstrate high antiviral potency against SARS-CoV-2 (half maximal inhibitory concentration [IC50] of 0.0022 µM [compared to remdesivir 1.3 µM]), ostensibly via inhibition of the cellular enzyme transmembrane protease serine 2 (TMPRSS2) preventing viral entry into human cells. In addition, the established antithrombotic activity is hypothesised to be advantageous given thrombosis-associated sequelae of COVID-19. Clinical reports to date are limited, but indicate a potential benefit of nafamostat in patients with moderate to severe COVID-19. In this review, we will explore the pre-clinical, pharmacokinetic and clinical outcome data presently available for nafamostat as a treatment for COVID-19. The recruitment to ongoing clinical trials is a priority to provide more robust data on the safety and efficacy of nafamostat as a treatment for COVID-19.

Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-ß) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-ß, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.

Elimination versus mitigation of SARS-CoV-2 in the presence of effective vaccines.

There is increasing evidence that elimination strategies have resulted in better outcomes for public health, the economy, and civil liberties than have mitigation strategies throughout the first year of the COVID-19 pandemic. With vaccines that offer high protection against severe forms of COVID-19, and increasing vaccination coverage, policy makers have had to reassess the trade-offs between different options. The desirability and feasibility of eliminating SARS-CoV-2 compared with other strategies should also be re-evaluated from the perspective of different fields, including epidemiology, public health, and economics. To end the pandemic as soon as possible-be it through elimination or reaching an acceptable endemic level-several key topics have emerged centring around coordination, both locally and internationally, and vaccine distribution. Without coordination it is difficult if not impossible to sustain elimination, which is particularly relevant in highly connected regions, such as Europe. Regarding vaccination, concerns remain with respect to equitable distribution, and the risk of the emergence of new variants of concern. Looking forward, it is crucial to overcome the dichotomy between elimination and mitigation, and to jointly define a long-term objective that can accommodate different political and societal realities.

Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications.

Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia's progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.

Coordination, cooperation, and creativity within harm reduction networks in Iran: COVID-19 prevention and control among people who use drugs.

An unprecedented public health crisis confronts the world. Iran is among the hardest-hit countries, where effects of the COVID-19 pandemic are stretched across society and felt by the most marginalised people. Among people who use drugs, a comprehensive response to the crisis calls for broad collaboration, coordination, and creativity involving multiple government and non-government organisations. This commentary provides early insights into an unfolding experience, demonstrating the operational and policy impact of an initiative, bringing together a diverse array of harm reduction stakeholders to address the pandemic. In the context of lived experiences of social and economic marginalization, this initiative intends to lead efforts in developing an equitable response to the COVID-19 pandemic.

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

Whole of population-based cohort study of recovery time from COVID-19 in New South Wales Australia.

BACKGROUND: COVID-19 results in persisting symptoms but there is little systematically collected data estimating recovery time following infection. METHODS: We followed 94% of all COVID-19 cases diagnosed in the Australian state of New South Wales between January and May 2020 using 3-4 weekly telephone interviews and linkage to hospitalisation and death data to determine if they had recovered from COVID-19 based on symptom resolution. Proportional hazards models with competing risks were used to estimate time to recovery adjusted for age and gender. FINDINGS: In analyses 2904 cases were followed for recovery (median follow-up time 16 days, range 1-122, IQR 11-24).There were 2572 (88.6%) who reported resolution of symptoms (262/2572 were also hospitalised), 224 (7.8%) had not recovered at last contact (28/224 were also hospitalised), 51 (1.8%) died of COVID-19, and 57 (2.0%) were hospitalised without a documented recovery date. Of those followed, 20% recovered by 10 days, 60% at 20, 80% at 30, 91% at 60, 93% at 90 and 96% at 120 days. Compared to those aged 30-49 years, those 0-29 years were more likely to recover (aHR 1.22, 95%CI 1.10-1.34) while those aged 50-69 and 70+ years were less likely to recover (aHR respectively 0.74, 95%CI 0.67-0.81 and 0.63, 95%CI 0.56-0.71). Men were faster to recover than women (aHR 1.20, 95%CI 1.11-1.29) and those with pre-existing co-morbidities took longer to recover than those without (aHR 0.90, 95%CI 0.83-0.98). INTERPRETATION: In a setting where most cases of COVID-19 were ascertained and followed, 80% of those with COVID-19 recover within a month, but about 5% will continue to experience symptoms 3 months later. FUNDING: NSW Health Emergency Response Priority Research Projects.

Concomitant Marked Decline in Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Other Respiratory Viruses Among Symptomatic Patients Following Public Health Interventions in Australia: Data from St Vincent's Hospital and Associated Screening Clinics, Sydney, NSW.

Our Australian hospital tested almost 22 000 symptomatic people over 11 weeks for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a multiplex polymerase chain reaction (PCR) assay. Following travel bans and physical distancing, SARS-CoV-2 and other respiratory viruses diagnoses fell dramatically. Increasing rhinovirus diagnoses as social control measures were relaxed may indirectly indicate an elevated risk of coronavirus disease 2019 (COVID-19) resurgence.