Antiviral therapies for the management of persistent coronavirus disease 2019 in immunocompromised hosts: A narrative review.

Antiviral agents with activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have played a critical role in disease management; however, little is known regarding the efficacy of these medications in the treatment of SARS-CoV-2 infection in immunocompromised patients, particularly in the management of persistent SARS-CoV-2 positivity. This narrative review discusses the management of persistent coronavirus disease 2019 in immunocompromised hosts, with a focus on antiviral therapies. We identified 84 cases from the literature describing a variety of approaches, including prolonged antiviral therapy (n = 11), combination antivirals (n = 13), and mixed therapy with antiviral and antibody treatments (n = 60). A high proportion had an underlying haematologic malignancy (n = 67, 80%), and were in receipt of anti-CD20 agents (n = 51, 60%). Success was reported in 70 cases (83%) which varied according to the therapy type. Combination therapies with antivirals may be an effective approach for individuals with persistent SARS-CoV-2 positivity, particularly those that incorporate treatments aimed at increasing neutralizing antibody levels. Any novel approaches taken to this difficult management dilemma should be mindful of the emergence of antiviral resistance.

Serosurvey for Japanese encephalitis virus antibodies following an outbreak in an immunologically naïve population, Victoria, 2022: a cross-sectional study.

OBJECTIVES: To investigate the distribution and prevalence of Japanese encephalitis virus (JEV) antibody (as evidence of past infection) in northern Victoria following the 2022 Japanese encephalitis outbreak, seeking to identify groups of people at particular risk of infection; to investigate the distribution and prevalence of antibodies to two related flaviviruses, Murray Valley encephalitis virus (MVEV) and West Nile virus Kunjin subtype (KUNV). STUDY DESIGN: Cross-sectional serosurvey (part of a national JEV serosurveillance program). SETTING: Three northern Victorian local public health units (Ovens Murray, Goulburn Valley, Loddon Mallee), 8 August - 1 December 2022. PARTICIPANTS: People opportunistically recruited at pathology collection centres and by targeted recruitment through community outreach and advertisements. People vaccinated against or who had been diagnosed with Japanese encephalitis were ineligible for participation, as were those born in countries where JEV is endemic. MAIN OUTCOME MEASURES: Seroprevalence of JEV IgG antibody, overall and by selected factors of interest (occupations, water body exposure, recreational activities and locations, exposure to animals, protective measures). RESULTS: 813 participants were recruited (median age, 59 years [interquartile range, 42-69 years]; 496 female [61%]); 27 were JEV IgG-seropositive (3.3%; 95% confidence interval [CI], 2.2-4.8%) (median age, 73 years [interquartile range, 63-78 years]; 13 female [48%]); none were IgM-seropositive. JEV IgG-seropositive participants were identified at all recruitment locations, including those without identified cases of Japanese encephalitis. The only risk factors associated with JEV IgG-seropositivity were age (per year: prevalence odds ratio [POR], 1.07; 95% CI, 1.03-1.10) and exposure to feral pigs (POR, 21; 95% CI, 1.7-190). The seroprevalence of antibody to MVEV was 3.0% (95% CI, 1.9-4.5%; 23 of 760 participants), and of KUNV antibody 3.3% (95% CI, 2.1-4.8%; 25 of 761). CONCLUSIONS: People living in northern Victoria are vulnerable to future JEV infection, but few risk factors are consistently associated with infection. Additional prevention strategies, including expanding vaccine eligibility, may be required to protect people in this region from Japanese encephalitis.

Mpox diagnostics: Review of current and emerging technologies.

Mpox is a zoonotic disease caused by monkeypox virus (MPXV) from the Orthopoxvirus genus. Unprecedented transmission events have led to more than 70 000 cases reported worldwide by October 2022. The change in mpox epidemiology has raised concerns of its ability to establish endemicity beyond its traditional geographical locations. In this review, we discuss the current understanding of mpox virology and viral dynamics that are relevant to mpox diagnostics. A synopsis of the traditional and emerging laboratory technologies useful for MPXV detection and in guiding "elimination" strategies is outlined in this review. Importantly, development in MPXV genomics has rapidly advanced our understanding of the role of viral evolution and adaptation in the current outbreak.

Intra- and interhost genomic diversity of monkeypox virus.

The impact and frequency of infectious disease outbreaks demonstrate the need for timely genomic surveillance to inform public health responses. In the largest known outbreak of mpox, genomic surveillance efforts have primarily focused on high-incidence nations in Europe and the Americas, with a paucity of data from South-East Asia and the Western Pacific. Here we analyzed 102 monkeypox virus (MPXV) genomes sampled from 56 individuals in Melbourne, Australia. All genomes fell within the 2022 MPXV outbreak lineage (B.1), with likely onward local transmission detected. We observed within-host diversity and instances of co-infection, and highlight further examples of structural variation and apolipoprotein B editing complex-driven micro-evolution in the current MPXV outbreak. Updating our understanding of MPXV emergence and diversification will inform public health measures and enable monitoring of the virus' evolutionary trajectory throughout the mpox outbreak.

Survey of treatment practices for immunocompromised patients with COVID-19 in Australasia.

Coronavirus disease 2019 (COVID-19) in immunocompromised patients can lead to severe and prolonged illness. Data are limited with regard to management of COVID-19 in this setting, particularly in persistent or recrudescent infection. The authors conducted an online survey among infectious diseases doctors to determine current approaches to treatment across Australasia. There was marked variability in responses relating to the diagnostic modalities and use of antiviral agents in patients with immunocompromise, highlighting the need for high-quality studies to guide treatment decisions in this group.

Clinical and microbiological characteristics of Staphylococcus lugdunensis.

PURPOSE OF REVIEW: This review provides an update on recent findings about the clinical and microbiological characteristics of Staphylococcus lugdunensis . RECENT FINDINGS: European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) differ in their methodology and breakpoints for the detection of penicillin and oxacillin resistance in S. lugdunensis . The EUCAST method for beta-lactamase detection recommends a 1-unit penicillin disk and has demonstrated superior performance compared to the 10-unit penicillin disk recommended by CLSI. A similar outcome has been previously reported in Staphylococcus aureus. In addition, there is emerging oxacillin resistance in some geographical areas. Of particular concern is that oxacillin resistance in mecA positive isolates may not be reliably detected by current cefoxitin breakpoints. SUMMARY: Coagulase negative staphylococci are now recognised as a heterogenous group of organisms that do not microbiologically or clinically behave the same way. The spectrum of clinical disease is species dependent and is particularly true for S. lugdunensis , which causes an array of clinical infections like that of S. aureus. Further studies are needed to assess the performance of phenotypic tests to detect resistance, to ensure that appropriate antimicrobial therapy is delivered to patients.

Toxicity and in vitro activity of HIV-1 latency-reversing agents in primary CNS cells.

Despite the success of combination antiretroviral therapy (cART), HIV persists in long lived latently infected cells in the blood and tissue, and treatment is required lifelong. Recent clinical studies have trialed latency-reversing agents (LRA) as a method to eliminate latently infected cells; however, the effects of LRA on the central nervous system (CNS), a well-known site of virus persistence on cART, are unknown. In this study, we evaluated the toxicity and potency of a panel of commonly used and well-known LRA (panobinostat, romidepsin, vorinostat, chaetocin, disulfiram, hexamethylene bisacetamide [HMBA], and JQ-1) in primary fetal astrocytes (PFA) as well as monocyte-derived macrophages as a cellular model for brain perivascular macrophages. We show that most LRA are non-toxic in these cells at therapeutic concentrations. Additionally, romidepsin, JQ-1, and panobinostat were the most potent at inducing viral transcription, with greater magnitude observed in PFA. In contrast, vorinostat, chaetocin, disulfiram, and HMBA all demonstrated little or no induction of viral transcription. Together, these data suggest that some LRA could potentially activate transcription in latently infected cells in the CNS. We recommend that future trials of LRA also examine the effects of these agents on the CNS via examination of cerebrospinal fluid.

Prevention and post-exposure management of occupational exposure to Ebola virus.

There have been significant advances in the prevention and management of Ebola virus disease (EVD) caused by Zaire Ebola virus (ZEBOV), including the development of two effective vaccines, rVSV-ZEBOV and Ad26.ZEBOV/MVA-BN-Filo. In addition, ZEBOV monoclonal antibodies have become first-line therapy for EVD. However, the 2022-23 outbreak of Sudan Ebola virus (SUDV) in Uganda has highlighted the gap in current therapies and vaccines, whose efficacy is uncertain against non-ZEBOV species. Health-care and laboratory staff working in EVD treatment centres or Ebola virus diagnostic and research laboratories face unique risks relating to potential occupational exposure to Ebola viruses. Given the substantial morbidity and mortality associated with EVD, facilities should have strategies in place to manage occupational exposures, including consideration of post-exposure therapies. In this Review, we discuss currently available evidence for prevention and post-exposure prophylaxis of EVD, including therapies currently under evaluation for SUDV.

Characterising HIV-1 transmission in Victoria, Australia: a molecular epidemiological study.

Background: In Australia the incidence of HIV has declined steadily, yet sustained reduction of HIV transmission in this setting requires improved public health responses. As enhanced public health responses and prioritisation of resources may be guided by molecular epidemiological data, here we aimed to assess the applicability of these approaches in Victoria, Australia. Methods: A comprehensive collection of HIV-1 pol sequences from individuals diagnosed with HIV in Victoria, Australia, between January 1st 2000 and December 31st 2020 were deidentified and used as the basis of our assessment. These sequences were subtyped and surveillance drug resistance mutations (SDRMs) identified, before definition of transmission groups was performed using HIV-TRACE (0.4.4). Phylodynamic methods were applied using BEAST (2.6.6), assessing effective reproductive numbers for large groups, and additional demographic data were integrated to provide a high resolution view of HIV transmission in Victoria on a decadal time scale. Findings: Based on standard settings for HIV-TRACE, 70% (2438/3507) of analysed HIV-1 pol sequences were readily assigned to a transmission group. Individuals in transmission groups were more commonly males (aOR 1.50), those born in Australia (aOR 2.13), those with probable place of acquisition as Victoria (aOR 6.73), and/or those reporting injectable drug use (aOR 2.13). SDRMs were identified in 375 patients (10.7%), with sustained transmission of these limited to a subset of smaller groups. Informative patterns of epidemic growth, stabilisation, and decline were observed; many transmission groups showed effective reproductive numbers (R e ) values reaching greater than 4.0, representing considerable epidemic growth, while others maintained low R e values. Interpretation: This study provides a high resolution view of HIV transmission in Victoria, Australia, and highlights the potential of molecular epidemiology to guide and enhance public health responses in this setting. This informs ongoing discussions with community groups on the acceptability and place of molecular epidemiological approaches in Australia. Funding: National Health and Medical Research Council, Australian Research Council.

Non-SARS-CoV-2 respiratory viral detection and whole genome sequencing from COVID-19 rapid antigen test devices: a laboratory evaluation study.

BACKGROUND: There has been high uptake of rapid antigen test device use for point-of-care COVID-19 diagnosis. Individuals who are symptomatic but test negative on COVID-19 rapid antigen test devices might have a different respiratory viral infection. We aimed to detect and sequence non-SARS-CoV-2 respiratory viruses from rapid antigen test devices, which could assist in the characterisation and surveillance of circulating respiratory viruses in the community. METHODS: We applied archival clinical nose and throat swabs collected between Jan 1, 2015, and Dec 31, 2022, that previously tested positive for a common respiratory virus (adenovirus, influenza, metapneumovirus, parainfluenza, rhinovirus, respiratory syncytial virus [RSV], or seasonal coronavirus; 132 swabs and 140 viral targets) on PCR to two commercially available COVID-19 rapid antigen test devices, the Panbio COVID-19 Ag Rapid Test Device and Roche SARS-CoV-2 Antigen Self-Test. In addition, we collected 31 COVID-19 rapid antigen test devices used to test patients who were symptomatic at The Royal Melbourne Hospital emergency department in Melbourne, Australia. We extracted total nucleic acid from the device paper test strips and assessed viral recovery using multiplex real-time PCR (rtPCR) and capture-based whole genome sequencing. Sequence and genome data were analysed through custom computational pipelines, including subtyping. FINDINGS: Of the 140 respiratory viral targets from archival samples, 89 (64%) and 88 (63%) were positive on rtPCR for the relevant taxa following extraction from Panbio or Roche rapid antigen test devices, respectively. Recovery was variable across taxa: we detected influenza A in nine of 18 samples from Panbio and seven of 18 from Roche devices; parainfluenza in 11 of 20 samples from Panbio and 12 of 20 from Roche devices; human metapneumovirus in 11 of 16 from Panbio and 14 of 16 from Roche devices; seasonal coronavirus in eight of 19 from Panbio and two of 19 from Roche devices; rhinovirus in 24 of 28 from Panbio and 27 of 28 from Roche devices; influenza B in four of 15 in both devices; and RSV in 16 of 18 in both devices. Of the 31 COVID-19 devices collected from The Royal Melbourne Hospital emergency department, 11 tested positive for a respiratory virus on rtPCR, including one device positive for influenza A virus, one positive for RSV, four positive for rhinovirus, and five positive for SARS-CoV-2. Sequences of target respiratory viruses from archival samples were detected in 55 (98·2%) of 56 samples from Panbio and 48 (85·7%) of 56 from Roche rapid antigen test devices. 98 (87·5%) of 112 viral genomes were completely assembled from these data, enabling subtyping for RSV and influenza viruses. All 11 samples collected from the emergency department had viral sequences detected, with near-complete genomes assembled for influenza A and RSV. INTERPRETATION: Non-SARS-CoV-2 respiratory viruses can be detected and sequenced from COVID-19 rapid antigen devices. Recovery of near full-length viral sequences from these devices provides a valuable opportunity to expand genomic surveillance programmes for public health monitoring of circulating respiratory viruses. FUNDING: Australian Government Medical Research Future Fund and Australian National Health and Medical Research Council.

Laboratory diagnosis of HIV: a contemporary overview in the Australian context.

Over the past decade there have been technical advances in human immunodeficiency virus (HIV) assays and updates to testing regulations that have substantially changed the landscape of laboratory testing for HIV. In addition, there have been significant changes in the epidemiology of HIV in Australia in the context of highly effective contemporary biomedical treatment and prevention strategies. Here, we provide an update on contemporary issues for the laboratory detection and confirmation of HIV in Australia. These include (1) the impact of early treatment and biological prevention strategies on the serological and virological detection of HIV; (2) the updated national HIV laboratory case definition and its interaction with testing regulations, public health and clinical guidelines; and (3) novel strategies for the laboratory detection of HIV, including the incorporation of HIV nucleic acid amplification tests (NAATs) into testing algorithms. These developments present an opportunity to develop a nationally consistent contemporary HIV testing algorithm that would result in optimisation and standardisation of HIV testing in Australia.

Laboratory evaluation of ELISA and indirect immunofluorescence assay in response to emergence of Japanese encephalitis virus genotype IV in Australia.

The unexpected recent emergence of Japanese encephalitis virus (JEV) genotype IV in multiple southern states of Australia necessitated an evaluation of JEV serological tests suitable for diagnosing acute infection and for seroprevalence studies. This study examined the analytical and clinical performance of two high-throughput JEV assays, Euroimmun immunofluorescence assay (IFA) and Euroimmun enzyme-linked immunosorbent assay (ELISA), across four cohorts; (1) surveillance of piggery workers in outbreak areas, (2) surveillance of residents in outbreak areas, (3) acute JEV infection and (4) post-JEV vaccination. ELISA and IFA IgM demonstrated minimal cross-reactivity (0-1.8%) with other endemic flaviviruses, with high sensitivity (100%) for acute JEV infection in this low endemicity setting. Differences in IgG serodynamics between the two assays suggest convalescent and paired testing with IgM are critical in diagnosing acute infection. High assay concordance was observed between ELISA and IFA when used in serosurveillance (97.4% agreement, Cohen' κ 0.74 [95% CI 0.614-0.860]) and vaccination cohorts (91.1% agreement, Cohen's κ 0.806 [95% CI 0.672-0.941]). In conclusion, this study highlights the clinical & epidemiological applications and limitations of these two commercial JEV assays.

HIV latency can be established in proliferating and nonproliferating resting CD4+ T cells in vitro: implications for latency reversal.

OBJECTIVE: To determine whether latency can be established and reversed in both proliferating and nonproliferating CD4+ T cells in the same model in vitro. METHODS: Activated CD4+ T cells were infected with either a nonreplication competent, luciferase reporter virus or wild-type full-length enhanced green fluorescent protein (EGFP) reporter virus and cultured for 12 days. The cells were then sorted by flow cytometry to obtain two distinct T-cell populations that did not express the T-cell activation markers, CD69, CD25 and human leukocyte antigen (HLA)-DR: CD69CD25HLA-DR small cells (nonblasts) that had not proliferated in vitro following mitogen stimulation and CD69CD25HLA-DR large cells (which we here call transitional blasts) that had proliferated. The cells were then reactivated with latency-reversing agents and either luciferase or EGFP quantified. RESULTS: Inducible luciferase expression, consistent with latent infection, was observed in nonblasts and transitional blasts following stimulation with either phorbol-myristate-acetate/phytohemagglutinin (3.8 ±â€Š1 and 2.9 ±â€Š0.5 fold above dimethyl sulfoxide, respectively) or romidepsin (2.1 ±â€Š0.6 and 1.8 ±â€Š0.2 fold above dimethyl sulfoxide, respectively). Constitutive expression of luciferase was higher in transitional blasts compared with nonblasts. Using wild-type full-length EGFP reporter virus, inducible virus was observed in nonblasts but not in transitional blasts. No significant difference was observed in the response to latency-reversing agents in either nonblasts or transitional blasts. CONCLUSION: HIV latency can be established in vitro in resting T cells that have not proliferated (nonblasts) and blasts that have proliferated (transitional blasts). This model could potentially be used to assess new strategies to eliminate latency.

Treatment of disseminated histoplasmosis in advanced HIV using itraconazole with increased bioavailability.

Disseminated histoplasmosis (DH), an endemic mycosis caused by the dimorphic fungus Histoplasma capsulatum, is a life-threatening infection in immunocompromised hosts. A patient with newly-diagnosed human immunodeficiency virus (HIV) infection presented with a violaceous, raised, indurated, pruritic rash over the face, arms and trunk on a background of significant weight loss, fevers with sweats, diarrhoea and worsening shortness of breath. His CD4+ T cell count was 14 cells/µl (12%). Histoplasmosis was diagnosed from histology, fungal stain and culture of skin biopsy. In addition to DH, he was found to have Pneumocystis jiroveci pneumonia and multi-resistant Salmonella choleraesuis bacteraemia. He improved with treatment with antibiotics and was commenced on conventional itraconazole, orally. Antiretroviral therapy was commenced soon after. He was unable to achieve therapeutic levels with the conventional formulation due to gastrointestinal side effects and had ongoing fevers. A newer formulation of oral itraconazole with improved bioavailability was commenced. He achieved therapeutic drug levels and had no further intolerance. His fevers settled and the rash improved. He has now completed one year of treatment and is well. To our knowledge this is the first case of moderate DH in an advanced HIV patient treated successfully with oral itraconazole with improved bioavailability.

Predictors of chronic kidney disease and utility of risk prediction scores in HIV-positive individuals.

OBJECTIVE: The current study aimed to validate existing risk prediction scores and identify predictors of chronic kidney disease (CKD) in the setting of HIV. DESIGN AND METHODS: A retrospective cohort study of HIV-positive individuals (n = 748) with baseline estimated glomerular filtration rate (eGFR) more than 60 ml/min was conducted at the Alfred Hospital, Melbourne, Australia. Multivariable regression analysis was performed to determine factors associated with development of CKD, defined as two consecutive measurements of eGFR less than 60 ml/min. The performance of CKD risk scores proposed by the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group and Scherzer and colleagues were estimated by the area under the receiver operator curve (AUROC). RESULTS: CKD developed in 37 individuals (5.0%), at a median of 4.7 (interquartile range 2.2, 6.2) years. Older age [odds ratio (OR) 3.03, 95% confidence interval (CI): 1.20, 7.65, P = 0.02] and lower baseline eGFR (OR 10.39, 95% CI: 4.73, 22.83, P < 0.001) were associated with the development of CKD. Neither current, nor cumulative tenofovir disoproxil fumarate (TDF) use was associated with progression to CKD [current TDF hazard ratio (HR) 1.05, 95% CI: 0.54, 2.07, P = 0.88; cumulative TDF HR 1.03, 95% CI: 0.86, 1.24, P = 0.75]. The short D:A:D and Scherzer scores were well calibrated, with the short D:A:D score demonstrating superior discrimination (short D:A:D AUROC 0.85, Scherzer AUROC 0.78, P = 0.02). CONCLUSION: Older individuals and those with a lower baseline eGFR are at higher risk for CKD. Risk prediction tools may be useful in identifying those at greatest risk, who may benefit from aggressive management of risk factors.