To B or not to B: how the hepatitis B surveillance case definition can misdirect public health actions.

Abstract: Surveillance case definitions are utilised to understand the epidemiology of communicable diseases and to inform public health actions. We report a case of hepatitis B infection that meets the case definition for newly acquired infection. However, further investigation revealed that this was most likely past resolved hepatitis B infection with subsequent reactivation secondary to immunosuppression, rather than a newly acquired infection. This case highlights the importance of thorough case and clinician interviews, in combination with detailed assessment of pathology results in collaboration with treating clinicians, to determine the most appropriate public health actions.

Predictors of liver disease progression in people living with HIV-HBV co-infection on antiretroviral therapy.

BACKGROUND: In people living with HIV-HBV, liver fibrosis progression can occur even with suppressive antiretroviral therapy (ART). We investigated the relationship between liver fibrosis and biomarkers of inflammation, apoptosis, and microbial translocation. METHODS: In this observational cohort study adults living with HIV-HBV already on effective ART were recruited in Australia and Thailand and followed for 3 years including 6 monthly clinical review and blood tests and annual transient elastography. Differences in clinical and laboratory predictors of liver fibrosis progression were tested followed by regression analysis adjusted for CD4+ T-cells at study entry. A linear mixed model was fitted to longitudinal data to explore changes over time. FINDINGS: 67 participants (85% male, median age 49 y) were followed for 175 person-years. Median duration of ART was 10 years (interquartile range (IQR) 8-16 years). We found 11/59 (19%) participants during 3-years follow-up (6/100 person-years) met the primary endpoint of liver disease progression, defined as increased Metavir stage from baseline to final scan. In regression analysis, progressors compared to non-progressors had higher levels of high mobility group box 1 protein (HGMB1), (median (IQR) 3.7 (2.6-5.0) and 2.4 ng/mL (1.5-3.4) respectively, adjusted relative risk 1.47, 95% CI [1.00, 2.17]) and lower nadir CD4+ T-cell percentage (median 4% (IQR 2-8) and 11% (4-15) respectively (relative risk 0.93, 95% CI [0.88, 0.98]). INTERPRETATION: Progression in liver fibrosis occurs in people with HIV-HBV on suppressive ART. Fibrosis progression was associated with higher HMGB1 and lower percentage nadir CD4+ T-cell count, highlighting the importance of early initiation of HBV-active ART. FUNDING: This work was supported by NHMRC project grant 1101836; NHMRC practitioner fellowship 1138581 and NHMRC program grant 1149990. The funder had no role in study design, data collection, data analysis, interpretation, writing of this manuscript or decision to submit for publication.

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.

Effective CMV prophylaxis with high-dose valaciclovir in allogeneic hematopoietic stem-cell recipients at a high risk of CMV infection.

BACKGROUND: Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. METHODS: We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400 IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2 g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. RESULTS: In the SD-VALA cohort (n = 27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n = 35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p < .0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p = .0005). CONCLUSIONS: In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.

Invasive pulmonary aspergillosis in critically ill patients with COVID-19 in Australia: implications for screening and treatment.

We report four cases of invasive pulmonary aspergillus co-infection in patients with coronavirus disease 2019 (COVID-19) infection and acute respiratory distress syndrome requiring intensive care unit (ICU) admission. Aspergillus fumigatus and Aspergillus terreus were isolated, with early infection onset following ICU admission. Clinicians should be aware of invasive pulmonary aspergillosis in ICU patients with COVID-19 infection, particularly those receiving dexamethasone. We propose screening of these high-risk patients with twice-weekly fungal culture from tracheal aspirate and, if feasible, Aspergillus polymerase chain reaction. Diagnosis is challenging and antifungal treatment should be considered in critically ill patients who have new or worsening pulmonary changes on chest imaging and mycological evidence of infection.

Cytomegalovirus in primary immunodeficiency.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. RECENT FINDINGS: PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. SUMMARY: We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

Successful Implementation of an Increased Viral Risk Donor Waiting List for Preconsented Kidney Transplant Candidates in Victoria, Australia.

Increased viral risk donors (IVRDs) with increased risk behaviors for blood-borne virus infection and negative nucleic acid testing have a low absolute risk of "window period" infection. Utilization and allocation of IVRD organs differ between jurisdictions. METHODS: We examined the characteristics and utilization of deceased donor IVRD kidneys and recipient outcomes within a 2-y period (July 31, 2018-July 31, 2020) postimplementation of a new opt-in allocation pathway for preconsented recipients in Victoria, Australia. RESULTS: Fifty-six kidneys from 31 IVRDs were utilized, comprising 13% of donors. Preconsent rate to accept IVRD kidneys increased to 41% of the waitlist in the 2 y postimplementation, and IVRDs having no kidneys utilized reduced to 0%. Compared with non-IVRD kidneys, kidney offer declines >10 per donor were less likely from IVRDs (3% vs 19%; P < 0.05). IVRDs were younger (median age 36 [IQR 30-44] vs 51 [35-60] y; P < 0.0001), with lower kidney donor profile index (25% [13-40%] vs 57% [29-75%]; P < 0.0001), and less hypertension (0% vs 22%; P < 0.01). Estimated glomerular filtration rate 3 mo post-transplant was superior (P < 0.01). Injecting drug use (61%) was the most common increased risk behavior. 29% of IVRDs were hepatitis C antibody positive but nucleic acid testing negative. No active infection was detected in any recipient post-transplant. CONCLUSIONS: The described opt-in system permits efficient allocation and utilization of kidneys from IVRDs, with superior quality and graft function. Education is crucial to facilitate informed consent and equity of access to this donor pool.

Hepatitis B related dilemmas in the renal unit.

Testing for hepatitis B in dialysis patients is routine, but newer and more sensitive detection methods mean that there is sometimes confusion around viral loads and occult infection. There are frequently difficult choices surrounding isolation and treatment. Here we describe the use of HBV serology and DNA testing in decisions around patients with end-stage renal disease. We also suggest isolation decisions based on our current understanding of the virus and its infectivity.

Microelimination of Hepatitis C Among People With Human Immunodeficiency Virus Coinfection: Declining Incidence and Prevalence Accompanying a Multicenter Treatment Scale-up Trial.

BACKGROUND: Gay and bisexual men (GBM) are a key population affected by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection. We aimed to measure HCV treatment effectiveness and to determine the population impact of treatment scale-up on HCV prevalence and incidence longitudinally among GBM. METHODS: The co-EC Study (Enhancing Care and Treatment Among HCV/HIV Coinfected Individuals to Eliminate Hepatitis C Transmission) was an implementation trial providing HCV direct-acting antiviral treatment in Melbourne, Australia, during 2016-2018. Individuals with HCV/HIV coinfection were prospectively enrolled from primary and tertiary care services. HCV viremic prevalence and HCV antibody/viremic incidence were measured using a statewide, linked, surveillance system. RESULTS: Among 200 participants recruited, 186 initiated treatment during the study period. Sustained virological response in primary care (98% [95% confidence interval {CI}, 93%-100%]) was not different to tertiary care (98% [95% CI, 86%-100%]). From 2012 to 2019, between 2434 and 3476 GBM with HIV infection attended our primary care sites annually, providing 13 801 person-years of follow-up; 50%-60% received an HCV test annually, and 10%-14% were anti-HCV positive. Among those anti-HCV positive, viremic prevalence declined 83% during the study (54% in 2016 to 9% in 2019). HCV incidence decreased 25% annually from 1.7/100 person-years in 2012 to 0.5/100 person-years in 2019 (incidence rate ratio, 0.75 [95% CI, .68-.83]; P < .001). CONCLUSIONS: High treatment effectiveness by nonspecialists demonstrates the feasibility of treatment scale-up in this population. Substantial declines in HCV incidence and prevalence among GBM provides proof-of-concept for HCV microelimination. CLINICAL TRIALS REGISTRATION: NCT02786758.

Long-Term TDF-Inclusive ART and Progressive Rates of HBsAg Loss in HIV-HBV Coinfection-Lessons for Functional HBV Cure?

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is effective in suppressing HIV and hepatitis B virus (HBV) replication in HIV-HBV coinfection although HBV DNA can persist in some individuals on TDF-containing antiretroviral therapy (ART). We initiated a prospective longitudinal study to determine durability of HBV virological control and clinical outcomes after prolonged TDF-based ART in HIV-HBV coinfection. METHODS: Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing ART from Australia (n = 41) and Thailand (n = 52) were enrolled. Participants were followed 6-monthly for 2 years, then annually to 5 years. Laboratory and clinical assessments and a serum sample were collected at each study visit. These analyses compare follow-up at 2 and 5 years. RESULTS: 12.0% (95% confidence interval 6.8 to 20.2) of total study entry cohort (n = 92) or 15.3% (95% confidence interval: 8.8 to 25.3) of those with data to year 5 (n = 72) lost hepatitis B surface antigen (HBsAg). The only statistically significant association with HBsAg loss was lower study entry quantitative HBsAg. CD4 T-cell count increased by a median 245 cells/mm3 between the preTDF sample and 5 years of follow-up. By year 5, 98.5% of the cohort had undetectable HBV DNA (<15 IU/mL) and 91.4% had undetectable HIV RNA (<20 copies/mL). CONCLUSIONS: HBsAg loss was high and ongoing over 5 years of follow-up in HIV-HBV coinfected individuals on TDF-containing ART and undetectable HBV was almost universal. Although the pattern of HBsAg loss temporarily parallels immune reconstitution, we could not identify predictive immune markers. The high rate of HBsAg loss in HIV-HBV coinfection may offer valuable insights into the search for a functional HBV cure.

Increased risk of cervical dysplasia in females with autoimmune conditions-Results from an Australia database linkage study.

BACKGROUND: Autoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures. METHODS: Data linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed. RESULTS: Females with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group. CONCLUSIONS: Females with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.

Review article: prevention, diagnosis and management of COVID-19 in the IBD patient.

BACKGROUND: The current COVID-19 pandemic, caused by SARS-CoV-2, has emerged as a public health emergency. All nations are seriously challenged as the virus spreads rapidly across the globe with no regard for borders. The primary management of IBD involves treating uncontrolled inflammation with most patients requiring immune-based therapies. However, these therapies may weaken the immune system and potentially place IBD patients at increased risk of infections and infectious complications including those from COVID-19. AIM: To summarise the scale of the COVID-19 pandemic, review unique concerns regarding IBD management and infection risk during the pandemic and assess COVID-19 management options and drug interactions in the IBD population. METHODS: A literature review on IBD, SARS-CoV-2 and COVID-19 was undertaken and relevant literature was summarised and critically examined. RESULTS: IBD patients do not appear to be more susceptible to SARS-CoV-2 infection and there is no evidence of an association between IBD therapies and increased risk of COVID-19. IBD medication adherence should be encouraged to prevent disease flare but where possible high-dose systemic corticosteroids should be avoided. Patients should exercise social distancing, optimise co-morbidities and be up to date with influenza and pneumococcal vaccines. If a patient develops COVID-19, immune suppressing medications should be withheld until infection resolution and if trial medications for COVID-19 are being considered, potential drug interactions should be checked. CONCLUSIONS: IBD patient management presents a challenge in the current COVID-19 pandemic. The primary focus should remain on keeping bowel inflammation controlled and encouraging medication adherence.

Challenges and opportunities for hepatitis B cure in the setting of HIV--hepatitis B virus co-infection.

PURPOSE OF REVIEW: To examine issues specific to HIV--HBV co-infection that are relevant to the search for and achieving hepatitis B cure in this the setting RECENT FINDINGS: In HIV--HBV co-infection, high rates of hepatitis B surface antigen (HBsAg) loss early after initiation of HBV-active antiretroviral therapy (ART) have previously been reported. Between 2012 and 2016, HBsAg loss from 2.8 to 23% was reported in numerous studies, including those already on suppressive HBV-active ART. Data published in 2018-2019 show that these rates have remained fairly stable (3.0-13.9%). However, it appears that higher HBsAg loss on starting HBV-active ART in co-infection falls within a few years to levels similar to that observed in long-term treated HBV mono-infection. Immune reconstitution and CD4+ T-cell recovery are likely to play a role in high HBsAg loss rates seen in early treated co-infection, although the mechanisms driving this are yet to be fully elucidated. SUMMARY: High rates of HBsAg loss early after HBV-active ART initiation is unique to HIV--HBV co-infection, making it the ideal setting to investigate underlying mechanisms of HBV loss and develop new HBV cure strategies. This phenomenon could be used to enhance HBsAg loss with new therapeutic approaches currently being investigated; however, this is obstructed by excluding co-infection from such studies.

The QuantiFERON Monitor® assay is predictive of infection post allogeneic hematopoietic cell transplantation.

INTRODUCTION: Following allogeneic hematopoietic stem cell transplantation (alloHCT), excessive immunosuppression can be complicated by infection, while inadequate immunosuppression can result in graft-vs-host disease (GVHD). An accurate method to assess overall immune status post HCT is lacking. The QuantiFERON Monitor® (QFM) assay measures interferon gamma (IFN-γ) release from whole blood following incubation with both innate (Toll-like receptor 7, TLR7) and adaptive (CD3 antibody) stimulants and may result in a more complete assessment of the immune system. METHODS: Whole blood samples were prospectively collected from alloHCT recipients at conditioning followed by days 10, 30, 60, 90, 120, and 180 post-transplant and assayed by the QFM test. IFN-γ levels were correlated to time post HCT and episodes of infection and GVHD. RESULTS: Forty patients were enrolled in the study (68% male; median age 47 years; 58% matched related donors, 42% unrelated; 33% myeloablative). Post-stimulation IFN-γ levels rose steadily over the first 180 days post transplantation. IFN-γ levels were significantly lower in those with active infection compared to those without during the neutropenic period (P < .001). The assay was predictive of CMV reactivation (VL > 1000 copies/mL) post alloHCT (P = .001). CONCLUSION: This is a promising assay to demonstrate immune recovery and predict risk of infection after alloHCT and may allow tailoring of immunosuppression, antimicrobial treatment, and prophylaxis.

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Introduction and Immunology.

Current recommendations concerning hepatitis C virus (HBV) reactivation are limited, with nearly all guidelines focused on its occurrence in patients with hematological malignancies or some solid tumors, who are treated with immunosuppressive therapies. Few of the guidelines address reactivation in patients receiving immunosuppression with organ transplants or treatment with any of the many immunosuppressive agents in use today for the treatment of multiple different diseases, or in patients receiving the direct-acting antivirals used in the treatment of hepatitis C virus (HCV). This article covers the immunology of HBV reactivation, mechanisms of viral clearance, and recommendations for screening and prophylaxis.

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Transplant Recipients.

Organ transplantation is a lifesaving procedure for many patients. To prevent rejection or graft-versus-host disease, recipients require long-term immunosuppression. In patients who have ever been exposed to hepatitis B, it is possible for reactivation to occur; this includes patients who are anti-hepatitis B core antibody-positive only or both anti-hepatitis B core antibody-positive and hepatitis B surface antibody-positive. The susceptibility to this varies with the nature of the transplant. Hepatitis B can be transmitted from donor to recipient. It is important to assess the hepatitis B status and formulate a strategy to prevent transmission and prevent reactivation.

Screening and Prophylaxis to Prevent Hepatitis B Reactivation: Patients with Hematological and Solid Tumor Malignancies.

Patients with malignancies require chemotherapy and other immunosuppressive therapies for treatment. Because of this immunosuppression, in patients who have ever been exposed to hepatitis B it is possible for reactivation to occur. This reactivation can be fatal. Reactivation is particularly likely in patients who receive B cell-active agents such as rituximab. The occurrence of reactivation flares may also delay further chemotherapy, which can negatively affect the outcome of the underlying malignancy. Accordingly, it is important to screen patients for markers of hepatitis B and institute antiviral prophylaxis to prevent reactivation.