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.

Patient and caregiver preferences for haemophilia treatments: A discrete-choice experiment.

INTRODUCTION: An evolving haemophilia treatment landscape provides new possibilities for previously unattainable lifestyles. AIM: We sought to understand how people with haemophilia (PwH) and their caregivers value the potential benefits of novel prophylactic treatments. We conducted a discrete-choice experiment (DCE) to quantify preferences for features of haemophilia treatments among adults and caregivers of children with haemophilia. A best-worst scaling (BWS) exercise measured the perceived burden of treatment administration features. METHODS: A cross-sectional, web-based survey was administered to male adults (≥18 years) and caregivers of male children (≤17 years) living with haemophilia in the United States. Respondents evaluated eight pairs of hypothetical haemophilia treatment profiles defined by six attributes in the DCE and 15 features in the BWS. RESULTS: In the DCE, both adults with haemophilia (n = 151) and caregivers (n = 151) prioritised avoiding the risk of developing inhibitor/ anti-drug antibodies and treatments that allowed for a more active life. They placed a lower priority on reducing the number of spontaneous bleeding episodes, route and frequency of administration, and avoiding the risk of hospitalisation due to adverse events. The BWS documented the burdensomeness of IV infusions and medications that require mixing and refrigeration. CONCLUSION: PwH and caregivers prefer treatments that enable a more active lifestyle with a lower risk of inhibitor development. Both groups valued the ability to lead an active life over reducing spontaneous bleeding, with caregivers placing the most weight on this attribute. As new treatments expand possibilities, healthcare professionals and PwH should continue to share decision-making, incorporating clinical judgment and individual preferences.

Mpox Management: A Holistic Local Response to a Global Threat.

Newly formed local public health units in Victoria have been established to support a place-based approach that tailors and delivers public health initiatives and responds to public health incidents and issues. Initially, post-establishment of these units, public health activities focused on the prevention and control of communicable diseases. In 2022, mpox emerged as a global public health threat. As case numbers rose across Australia, local public health units in Victoria were engaged by the Department of Health to support a localized response to this new threat. The South East Public Health Unit, Monash Health, developed a number of targeted initiatives to control the local spread of mpox, ranging from capacity building of health professionals to increase early diagnosis, contact tracing, facilitating vaccine delivery, and community engagement. This contributed to effective local elimination within 6 months, demonstrating how LPHUs are well placed to engage with local communities and health care providers to respond rapidly to newly emerging public health threats.

Eliciting Exploratory Patient Preference Data: A Case Study in a Rare Disease.

INTRODUCTION: Qualitative and quantitative methods provide different and complementary insights into patients' preferences for treatment. OBJECTIVE: The aim of this study was to use a novel, mixed-methods approach employing qualitative and quantitative approaches to generate preliminary insights into patient preferences for the treatment of a rare disease-generalized myasthenia gravis (gMG). METHODS: We conducted a mixed-methods study to collect exploratory qualitative and quantitative patient preference information and generate informative results within a condensed timeline (about 4 months). Recruitment was facilitated by an international health research firm. Study participants first reviewed a brief document describing six treatment attributes (to facilitate more efficient review of the material during the focus groups) and were then provided a link to complete an online quantitative survey with a single risk threshold task. They then participated in online focus groups, during which they discussed qualitative questions about their experience with gMG treatment and completed up to three quantitative threshold tasks, the first of which repeated the threshold task from the online survey. RESULTS: The study elicited both quantitative data on 18 participants' risk tolerance and qualitative data on their treatment experience, additional treatment attributes of importance, the reasoning behind their preferences, and the trade-offs they were willing to make. Most participants (n = 15) chose the same hypothetical treatment in the first threshold task in the online survey and the focus groups. Focus group discussions provided insights into participants' choices in the threshold tasks, confirmed that all the attributes were relevant, and helped clarify what was important about the attributes. CONCLUSIONS: Patient preference information can be collected using a variety of approaches, both qualitative and quantitative, tailored to fit the research needs of a study. The novel mixed-methods approach employed in this study efficiently captured patient preference data that were informative for exploratory research, internal decision making, and future research.

Patient Preferences for Lung Cancer Interception Therapy.

Importance: Interception therapy requires individuals to undergo treatment to prevent a future medical event, but little is known about preferences of individuals at high risk for lung cancer and whether they would be interested in this type of treatment. Objective: To explore preferences of individuals at high risk for lung cancer for potential interception therapies to reduce this risk. Design, Setting, and Participants: This survey study used a discrete-choice experiment and included hypothetical lung cancer interception treatments with 4 attributes: reduction in lung cancer risk over 3 years, injection site reaction severity, nonfatal serious infection, and death from serious infection. Respondents were assigned to a baseline lung cancer risk of 6%, 10%, or 16% over 3 years. The discrete-choice experiment was administered online (July 13 to September 6, 2022) to US respondents eligible for lung cancer screening according to US Preventive Services Task Force guidelines. Participants included adults aged 50 to 80 years with at least a 20 pack-year smoking history. Statistical analysis was performed from September to December 2022. Main Outcomes and Measures: Attribute-level preference weights were estimated, and conditional relative attribute importance, maximum acceptable risks, and minimum acceptable benefits were calculated. Characteristics of respondents who always selected no treatment were also explored. Results: Of the 803 survey respondents, 495 (61.6%) were female, 138 (17.2%) were African American or Black, 55 (6.8%) were Alaska Native, American Indian, or Native American, 44 (5.5%) were Asian or Native Hawaiian or Other Pacific Islander, 104 (13.0%) were Hispanic, Latin American, or Latinx, and 462 (57.5%) were White, Middle Eastern or North African, or a race or ethnicity not listed; and mean (SD) age was 63.0 (7.5) years. Most respondents were willing to accept interception therapy and viewed reduction in lung cancer risk as the most important attribute. Respondents would accept a greater than or equal to a 12.0 percentage point increase in risk of nonfatal serious infection if lung cancer risk was reduced by at least 20.0 percentage points; and a greater than or equal to 1.2 percentage point increase in risk of fatal serious infection if lung cancer risk was reduced by at least 30.0 percentage points. Respondents would require at least a 15.4 (95% CI, 10.6-20.2) percentage point decrease in lung cancer risk to accept a 12.0 percentage point increase in risk of nonfatal serious infection; and at least a 23.1 (95% CI, 16.4-29.8) percentage point decrease in lung cancer risk to accept a 1.2 percentage point increase in risk of death from serious infection. Respondents who were unwilling to accept interception therapy in any question (129 [16.1%]) were more likely to be older and to currently smoke with no prior cessation attempt, and less likely to have been vaccinated against COVID-19 or examined for skin cancer. Conclusions and Relevance: In this survey study of individuals at high risk of lung cancer, most respondents were willing to consider interception therapy. These results suggest the importance of benefit-risk assessments for future lung cancer interception treatments.

Treatment preferences among patients with mild-to-moderate atopic dermatitis.

Study purpose: New treatments for atopic dermatitis (AD) are emerging; however, little is known about the treatment preferences of patients with mild-to-moderate AD. To measure patients' preferences, a cross-sectional, web-based discrete choice experiment (DCE) survey was developed and administered to 300 adults in the United States with a self-reported physician diagnosis of mild-to-moderate AD.Materials and methods: In the DCE, respondents evaluated pairs of hypothetical AD treatment profiles defined by efficacy, risk, and mode and frequency of administration attributes. The DCE data were analyzed using a random parameters logit model. Subgroup analysis was used to investigate preference heterogeneity.Results: The results revealed achieving clear or almost clear skin within 3-4 months of treatment was the most important attribute relative to all other study attributes. The results indicated that a topical cream applied twice daily was preferred to systemic treatments. Subgroup analysis revealed that respondents with lower self-assessed disease burden were more likely to choose topical over systemic treatments and less averse to the risk of pain, burning, and/or stinging from the medicine (all other treatment features remaining equal) than respondents with higher self-assessed disease burden.Conclusion: The results of this study can help inform shared decision-making to manage mild-to-moderate AD.

Favipiravir in early symptomatic COVID-19, a randomised placebo-controlled trial.

Background: Well tolerated antivirals administered early in the course of COVID-19 infection when the viremia is highest could prevent progression to severe disease. Favipiravir inhibits SARS-CoV-2 viral replication in vitro with evidence of clinical benefit in open label trials. Placebo controlled studies of people with early symptomatic COVID-19 with regular assessments of SARS-CoV-2 viral load can determine if it has an antiviral effect and improves clinical outcomes. Methods: People with PCR-confirmed COVID-19 and 5 days or less of symptoms were randomised 1:1 to favipiravir 1800 mg on day 1, then 800 mg twice daily or matched placebo for 14 days. SARS-CoV-2 viral load was quantitated from second daily self-collected nose-throat swabs while receiving study drug. The primary endpoint was time to virological cure defined as 2 successive swabs negative for SARS-CoV-2 by PCR and secondary outcomes were progression of disease severity, symptom resolution and safety. Findings: Between 31 July 2020 and 19 September 2021, 200 people were enrolled (199 in the community, 1 in hospital) with 190 receiving one or more doses of drug (modified intention to treat [mITT] population). There was no difference in time to virological cure (Log-rank p=0.6 comparing Kaplan Meier curves), progression to hospitalisation (14 favipiravir, 9 placebo; p=0.38), time to symptom resolution (cough, fever, sore throat) and there were no deaths. 51 people related an adverse event that was possibly drug related, but these were evenly distributed (n=24 favipiravir, n=27 placebo). Sensitivity analyses where the definition of virological cure was changed to: a single negative PCR, exclude datapoints based on the presence or absence of human DNA in the swab, a SARS-CoV-2 viral load < 300 copies/mL being considered negative all demonstrated no difference between arms. Interpretation: Favipiravir does not improve the time to virological cure or clinical outcomes and shows no evidence of an antiviral effect when treating early symptomatic COVID-19 infection. Funding: The study was supported in part by grants from the Commonwealth Bank Australia, the Lord Mayor's Charitable Foundation, Melbourne Australia and the Orloff Family Charitable Trust, Melbourne, Australia. JHM is supported by the Medical Research Future Fund, AYP, JT are supported by the Australian National Health and Medical Research Council.

Protocol for an HIV Pre-exposure Prophylaxis (PrEP) Population Level Intervention Study in Victoria Australia: The PrEPX Study.

Background: Pre-exposure prophylaxis (PrEP) is the use of HIV anti-retroviral therapy to prevent HIV transmission in people at high risk of HIV acquisition. PrEP is highly efficacious when taken either daily, or in an on-demand schedule. In Australia co-formulated tenofovir-emtricitabine is registered for daily use for PrEP, however, this co-formulation is not listed yet on the national subsidized medicines list. We describe a study protocol that aims to demonstrate if the provision of PrEP to up to 3800 individuals at risk of HIV in Victoria, Australia reduces HIV incidence locally by 25% generally and 30% among GBM. Methods: PrEPX is a population level intervention study in Victoria, Australia in which generic PrEP will be delivered to 3800 individuals for up to 36 months. Study eligibility is consistent with the recently updated 2017 Australian PrEP guidelines. Participants will attend study clinics, shared care clinics, or outreach clinics for quarterly HIV/STI screening, biannual renal function tests and other clinical care as required. Study visits and STI diagnoses will be recorded electronically through the ACCESS surveillance system. At each study visit participants will be invited to complete behavioral surveys that collect demographics and sexual risk data. Diagnosis and behavioral data will be compared between PrEPX participants and other individuals testing within the ACCESS surveillance system. A subset of participants will complete in depth surveys and interviews to collect attitudes, beliefs and acceptability data. Participating clinics will provide clinic level data on implementation and management of PrEPX participants. The population level impact on HIV incidence will be assessed using Victorian HIV notification data. Discussion: This study will collect evidence on the real world impact of delivery of PrEP to 3800 individuals at risk of acquiring HIV in Victoria. This study will provide important information for the broader implementation of PrEP planning upon listing of the tenofovir-emtricitabine on the national subsidized list of medicines. The study is registered on the Australian New Zealand Clinical Trials Registry (ACTRN12616001215415).

Dolutegravir with tenofovir disoproxil fumarate-emtricitabine as HIV postexposure prophylaxis in gay and bisexual men.

OBJECTIVES: Completion rates for HIV postexposure prophylaxis (PEP) are often low. We investigated the adherence and safety of dolutegravir (DTG; 50 mg daily) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC; 300/200 mg, respectively) as three-drug PEP in gay and bisexual men. DESIGN: Open-label, single-arm study at three sexual health clinics and two emergency departments in Australia. METHODS: In total, 100 HIV-uninfected gay and bisexual men requiring PEP received DTG and TDF-FTC for 28 days. The primary end point was PEP failure (premature PEP cessation or primary HIV infection through week 12). Additional end points were adherence by self-report (n = 98) and pill count (n = 55), safety, and plasma drug levels at day 28. RESULTS: PEP completion was 90% (95% confidence interval 84-96%). Failures (occurring at a median 9 days, interquartile range 3-16) comprised loss to follow-up (9%) and adverse event resulting in study drug discontinuation (headache, 1%). No participant was found to acquire HIV through week 12. Adherence to PEP was 98% by self-report and in the 55 participants with corresponding pill count data. The most common clinical adverse events were fatigue (26%), nausea (25%), diarrhoea (21%), and headache (10%). There were only four grade 3-4 subjective adverse events. The most common laboratory adverse event was raised alanine aminotransferase (22%), but there was no case of clinical hepatitis. At day 28, the mean estimated glomerular filtration rate decrease was 14 ml/min/1.73m (SD 17, P = 0.001); an estimated glomerular filtration rate of less than 60 ml/min/1.73m occurred in 3%. CONCLUSIONS: DTG with TDF-FTC is a well tolerated option for once-daily PEP.

Comparing non-occupational post-exposure prophylaxis drug regimens for HIV: insights from a linked HIV surveillance system.

Background International non-occupational post-exposure prophylaxis (NPEP) guidelines recommend routine use of three drug NPEP regimens, despite absence of evidence for greater prevention efficacy compared with two drug regimens. This study examines the potential for excess HIV seroconversions among high-risk men who have sex with men (MSM) reporting receptive anal intercourse with a source of unknown HIV serostatus (RAIU) following a two-drug versus a three-drug NPEP regimen. METHODS: Data for MSM in the Victorian NPEP service database between 10 August 2005 and 31 December 2012 were linked with all Victorian HIV notifications up to 31 December 2013. The primary outcome was NPEP failure following NPEP presentation among MSM reporting RAIU, stratified by the number of drugs prescribed. RESULTS: Among 1482 MSM reporting 2002 episodes of RAIU and prescribed two- or three-drug NPEP, 70 seroconverted to HIV, but only 19 were considered possible NPEP failures. HIV diagnosis incidence among men reporting RAIU was 1.2/100 person years (PY) (95%CI=1.0-1.6); 1.1/100 PY (95%CI=0.8-1.4) among MSM prescribed two drugs and 2.2/100 PY (95%CI=1.4-3.7) among MSM prescribed three drugs (P<0.01). Of the 19 possible NPEP failures, 13 (0.7%) were prescribed two drugs and six (2.7%) three drugs (P<0.001). CONCLUSIONS: This study suggests that two-drug NPEP regimens do not result in excess seroconversions compared with three-drug regimens when used following RAIU. Clinical services should carefully consider their use of three drug NPEP and whether resources might be better invested in other prevention strategies, particularly pre-exposure prophylaxis (PrEP).

Single-Tablet Emtricitabine-Rilpivirine-Tenofovir as HIV Postexposure Prophylaxis in Men Who Have Sex With Men.

BACKGROUND: Completion rates for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) are low. We investigated the adherence and safety of coformulated emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) as a 3-drug, single-tablet regimen for PEP in men who have sex with men (MSM). METHODS: In an open-label, single-arm study at 2 public sexual health clinics and 2 hospital emergency departments in urban Australia, 100 HIV-uninfected MSM requiring 3-drug PEP received single-tablet FTC-RPV-TDF once daily for 28 days. The primary endpoint was premature PEP cessation or primary HIV infection through week 12. Additional endpoints were adherence (by self-report of doses missed or not ingested with a meal, by pill count, and by plasma concentrations of tenofovir and FTC at week 4); and safety (clinical and laboratory adverse events [AEs]). RESULTS: PEP completion was 92% (95% confidence interval, 85%-96%); premature cessation resulted from loss to follow-up (6%), AEs (1%), or study burden (1%). No participant was found to acquire HIV through week 12. Adherence was 98.6% (standard deviation [SD], 2.4) by pill count and 98.5% (SD, 2.7) by self-report; 86% reported taking all doses with food, and 88% of the subset tested had plasma tenofovir levels suggesting full adherence (>40 ng/mL). Eighty-eight participants experienced at least 1 clinical AE; 4 had grade 3 AEs or higher, possibly attributable to study drug. Fifty-six participants experienced at least 1 laboratory AE; 4 had AEs of grade 3 or higher, possibly attributable to study drug. CONCLUSIONS: A single-tablet regimen of FTC-RPV-TDF was well tolerated as once-daily PEP, with high levels of adherence and completion. CLINICAL TRIALS REGISTRATION: NCT01715636.

Developing an evidence-based guideline for the management of exposure to hepatitis B at a Victorian tertiary hospital.

OBJECTIVE: To develop a guideline for the management of potential exposures to hepatitis B virus (HBV) at The Alfred Hospital, based on results of clinical audit, database analysis and literature review. METHODS: i) Retrospective record review of all histories of patients who received HBV immunoglobulin (HBIG) at The Alfred between 1/1/2007 and 30/9/2011. ii) Analysis of HBV serological results of men who have sex with men (MSM) on Victorian NPEP Service (VNPEPS) database between 10/8/2005 and 31/12/2011. iii) Literature review to determine risks of HBV transmission and best practice for prevention of HBV transmission. RESULTS: A total of 48 patients were potentially exposed to HBV and given HBIG, with sexual exposure the most common indication (n=20). The source was reported to be HBsAg positive in one case only. Of the MSM on the VNPEPS database, 63% were immune to HBV, and only 0.5% of patients tested had evidence of chronic HBV infection. The recommendations for use of HBIG in The Australian Immunisation Guidelines are ambiguous and differ from other international guidelines. CONCLUSION: This audit at a tertiary referral hospital identified problems with the management of those potentially exposed to HBV. In those non-immune patients exposed to HBV, the combination of HBIG plus vaccination provides the best protection against infection. The risk of transmission of HBV is highly variable; rates of chronic HBV in PWID and MSM in Australia are low and do not warrant use of HBIG unless the source is known to be HBsAg positive.

Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected individuals on cART via inhibition of telomerase activity. METHODS: Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART. RESULTS: Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 µM. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47; P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11; P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01). CONCLUSIONS: NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected individuals on cART.

Adherence to HIV treatment guidelines for comorbid disease assessment and initiation of antiretroviral therapy.

BACKGROUND: There are limited data on adherence to HIV treatment guidelines. We assessed adherence to US Department of Health and Human Services guidelines with Australian Commentary for adults initiating antiretroviral therapy (ART). METHODS: Data were recorded regarding "when to start", "what to start" and pre-ART comorbid disease assessment for consecutive adults initiating ART at primary care and hospital clinics in Sydney and Melbourne from 2004 through 2008. Independent predictors of adherence to guidelines were calculated by stepwise logistic regression. RESULTS: For the 500 subjects (95.9% male, mean 40.2 years, median CD4 count 270 cells/µL) "when to start" adherence was 87.6%, and was less likely with initiation in a clinical trial [0.25 (95% CI: 0.13 to 0.49); P < 0.0001] and previous, short-term nontherapeutic antiretroviral exposure [0.08 (0.03 to 0.25); P < 0.0001]. "What to start" adherence was 69.0% for guideline-"preferred" regimens (85.8% for guideline-"preferred" or "alternative" regimens) and more likely with ART initiated in 2008 versus pre-2008 [OR: 2.69 (1.64 to 4.61); P = 0.0001]. Median comorbid disease assessment adherence was 56.8%, ranging from 25.6% for urinalysis to 99.2% for white blood cell count, and was more likely in patients with AIDS, and initiating ART in hospital or in a clinical trial. Hospital clinics were more likely to perform antiretroviral resistance testing (71.2% vs. 46.4%, P < 0.0001), to use "preferred" ART regimens (76.8% vs. 62.2%, P = 0.0002) but less likely to promote healthy diet and lifestyle (63.4% vs. 36.4%, P < 0.0001). CONCLUSIONS: "When to start" and "what to start" guidelines have been largely adhered to in Australia, but pre-ART comorbid disease assessment requires greater attention.

HIV seroconversions among male non-occupational post-exposure prophylaxis service users: a data linkage study.

BACKGROUND: Despite widespread prescription of non-occupational post-exposure prophylaxis (NPEP) in Victoria, little is known about subsequent HIV acquisition among NPEP users. We linked the Victorian NPEP Service (VNPEPS) database and the Victorian HIV Surveillance Registry to determine the number, incidence rate and predictive factors of HIV seroconversions among users of the VNPEPS. METHODS: Records from male patients that received NPEP in the VNPEPS database (n = 1420) between January 2001 and February 2008 were linked with all entries in the Victorian HIV Surveillance Registry up to May 2008. RESULTS: Sixty-one men who presented to the VNPEPS were identified as HIV seropositive; 16 of these were diagnosed at initial presentation for NPEP. The incidence of HIV seroconversion in males who were HIV seronegative at first presentation for NPEP was 1.27 (95% confidence interval 0.95-1.70) per 100 person-years. There was no association between HIV seroconversion and number of NPEP presentations or age. The median age of seroconversion was 34.6 years. CONCLUSION: The incidence of HIV infection among men presenting to the VNPEPS is slightly lower than the HIV incidence in NPEP users in a recent Australian cohort study of men who have sex with men, but higher than HIV incidence in general gay male populations. Frequency of NPEP use was not associated with risk of HIV seroconversion. Examination of risk behaviour before and after NPEP use in this population is required to further assess the impact of NPEP availability and use on HIV incidence rates and risk behaviour in Australia.