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Backgrounds: Anal cancer is an uncommon condition, occurring at higher rates in specific subpopulations. Clinical experience is limited and substantial changes have recently occurred in our understanding of this condition. We, therefore, set out to characterize patients presenting with anal cancer and investigate whether there have been any changes over the past 20 years. Methods: Retrospective audit of cases identified from pathology and clinical databases during the period 1 January 2000 to 31 December 2019. Results: Two hundred and sixteen patients had anal squamous cell carcinomas, comprising 160 (74%) males and 56 (26%) females. Mean age at initial diagnosis was 55.1 ± 11.20 for males and 60.6 ± 15.18 for females (P = 0.02). At initial diagnosis, HIV‐positive cases were significantly younger than HIV negative cases (mean 52.2 ± 9.35 vs. 62.8 ± 11.61, P < 0.001); 46% of cases were classified as intra‐anal, 29% perianal and 25% both; 52% were > 2 cm at diagnosis. At presentation, intra‐anal cases were larger and more advanced than perianal cases (P = 0.049). Compared with the period 2000–2009, anal cancers presented more commonly in 2010–2019 (148 vs. 76), were more likely to occur in HIV‐negative people and to be diagnosed at a similar stage. Conclusion: The number of anal cancer cases almost doubled over the study period and people living with HIV presented 10 years younger than others. Perianal cases presented earlier than those originating in intra‐anal locations. Together with the large size at diagnosis, this suggests the potential value of screening, particularly for intra‐anal cancers in those at high risk. [ABSTRACT FROM AUTHOR]

Australian State governments have maintained overseas trade and diplomatic engagements, a practice known as 'paradiplomacy' for well over a century. In 2020 the Federal Government abruptly moved to restrict the practice, establishing oversight and creating a Ministerial veto power. Why did this sudden shift occur? This article reviews the under-studied history and contemporary practice of paradiplomacy in Australia. It explains and analyses the 2020 shift as a response to fears of weaponised interdependence within an evolving strategic environment. The article shows the legislation has advantages yet is insufficient to resolve the political challenges and reflects an unprecedented desire for control. The article then argues the lack of scholarship on paradiplomacy reflects a prevailing 'methodological nationalism' and argues this should be re-considered to help think through how the new strategic environment is shaping Australia's national institutions and policies. [ABSTRACT FROM AUTHOR]

Background Overseas-born people who are ineligible for government-subsidised health care experience barriers to accessing HIV pre-exposure prophylaxis (PrEP) in Australia. This study aimed to assess a program providing free PrEP to overseas-born adults at risk of acquiring HIV. Methods Medicare-Ineligible Expanded Implementation in Communities (MI-EPIC) was a single-arm, open-label trial of daily tenofovir disoproxil fumarate/emtricitabine as PrEP. Six clinics recruited Medicare-ineligible adults who met HIV risk criteria in New South Wales, Australia. We recorded data on HIV and sexually transmitted infection (STI) diagnoses, and PrEP dispensing from July 2019 to June 2020. PrEP adherence as a medication possession ratio (MPR) was calculated as pills dispensed divided by days. We administered an optional survey on behaviours and attitudes to PrEP and sexual health. Results The 221 participants (206 men; 93.2%) had a median age of 29years (IQR 26-34). Participants were mostly born in Asia (53.4%), Latin America or the Caribbean (25.3%), or Europe (10.9%). Adherence was high; 190 participants (86.0%) had an MPR of >60%. Of 121 survey participants, 42 (34.7%) completed the survey in a language other than English. Of participants who had not used PrEP in the 6months before enrolment (n=45, 37.2%), the most common reasons were cost (n=22, 48.9%), and lack of knowledge about accessing PrEP (n=20, 44.4%). Conclusions Medicare-ineligible people at risk of HIV demonstrate high adherence when given access to free PrEP and translated information. Increasing PrEP awareness and reducing barriers to accessing PrEP in this high-risk population should be priorities in HIV prevention. [ABSTRACT FROM AUTHOR]

Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods. [ABSTRACT FROM AUTHOR]

Background A substantial minority of patients living with HIV refuse or cease antiretroviral therapy (ART), have virological failure (VF) or develop an AIDS-defining condition (ADC) or serious non-AIDS event (SNAE). It is not understood which socioeconomic and psychosocial factors may be associated with these poor outcomes.Methods: Thirty-nine patients with poor HIV treatment outcomes, defined as those who refused or ceased ART, had VF or were hospitalised with an ADC or SNAE (cases), were compared with 120 controls on suppressive ART. A self-report survey recorded demographics, physical health, life stressors, social supports, HIV disclosure, stigma or discrimination, health care access, treatment adherence, side effects, health and treatment perceptions and financial and employment status. Socioeconomic and psychosocial covariates significant in bivariate analyses were assessed with conditional multivariable logistic regression, adjusted for year of HIV diagnosis.Results: Cases and controls did not differ significantly with regard to sex (96.2% (n = 153) male) or age (mean (± s.d.) 51 ± 11 years). Twenty cases (51%) had refused or ceased ART, 35 (90%) had an HIV viral load >50 copies mL-1, 12 (31%) were hospitalised with an ADC and five (13%) were hospitalised with a new SNAE. Three covariates were independently associated with poor outcomes: foregoing necessities for financial reasons (adjusted odds ratio (aOR) 3.1, 95% confidence interval (95% CI) 1.3-7.6, P = 0.014), cost barriers to accessing HIV care (aOR 3.1, 95% CI 1.0-9.6, P = 0.049) and lower quality of life (aOR 3.8, 95% CI 1.5-9.7, P = 0.004).Conclusions: Despite universal health care, socioeconomic and psychosocial factors are associated with poor HIV outcomes in adults in Australia. These factors should be addressed through targeted interventions to improve long-term successful treatment. [ABSTRACT FROM AUTHOR]

PrELUDE study evaluated daily pre-exposure prophylaxis (PrEP) in high-risk individuals in Australia. This open-label, single-arm study tested participants for HIV/STI and collected behavioural information three-monthly. We report trends over 18 months in medication adherence, side-effects, HIV/STI incidence and behaviour. 320 gay/bisexual men (GBM), 4 women and 3 transgender participants, followed on average 461 days, reported taking seven pills/week on 1,591 (88.5%) occasions and 4-6 pills/week on 153 (8.5%) occasions. No HIV infections were observed. STI incidence was high and stable, while gonorrhoea infections declined from 100.0 to 25.8/100 person-years between 6 and 15 months (p < 0.001). The number of HIV-positive and unknown-status sex partners, and condomless anal intercourse, significantly increased. In this high-risk cohort of mainly GBM, increases in risk behaviours and high STI incidence were not accompanied by HIV infections due to high adherence to daily PrEP. The study informed policy and further PrEP implementation among Australian GBM. [ABSTRACT FROM AUTHOR]

Background and purpose -- The number of shoulder registries increases. We assessed international trends in use of shoulder arthroplasty, and described the current state of procedure selection and outcome presentation as documented in national and regional joint registries. Methods -- Published reports from 9 population-based shoulder arthroplasty registries (country/region: Norway, Sweden, New Zealand, Denmark, California, Australia, Emilia-Romagna, Germany, and United Kingdom) were analyzed. Data were extracted on age, sex, disease indication, type of surgical procedure, surgical volume, and outcomes. Results -- Shoulder arthroplasty incidence rate in 2012 was 20 procedures/105 population with a 6-fold variation between the highest (Germany) and lowest (United Kingdom) country. The annual incidence rate increased 2.8-fold in the past decade. Within the indications osteoarthritis, fracture, and cuff-tear arthropathy variations in procedure choice between registries were large. Outcomes evaluation focused on revision in all registries, but different measures and strata were used. Only Australia provided revision rates for prosthesis brands stratified by both indication and procedure. Finally, in 2 registries with available data surgeons performed on average 10-11 procedures yearly. Interpretation -- Annual incidence rates of shoulder arthroplasty have almost tripled over the past decade. There is wide variation in procedure selection for the major indications, a low average surgeon volume, a substantial number of brands with small annual volume, and large variation in outcome presentation. The internationally increasing registry activity is an excellent basis for improving the so far weak evidence in shoulder arthroplasty. [ABSTRACT FROM AUTHOR]

One of the most widely-endorsed norms in Australian politics is the requirement for bipartisanship in the management of defence and security policy. This norm is assumed to lead to good policy creation, foster political unity, and protect those who implement national policy (particularly the military). The paper argues that evidence for all three of these claims is overstated. In addition, the effects of the norm are often counter-productive and even harmful to the conduct and management of Australian policy. The paper concludes by arguing that the norm of bipartisanship for Australian defence and security policy should be abandoned. [ABSTRACT FROM AUTHOR]

Background: Missing more than one tablet of contemporary antiretroviral therapy (ART) per month increases the risk of virological failure. Recent studies evaluating a comprehensive range of potential risk factors for suboptimal adherence are not available for high-income settings. Methods: Adults on ART with undetectable viral load (UDVL) were recruited into a national, multi-centre cohort, completing a comprehensive survey assessing demographics, socio-economic indicators, physical health, well-being, life stressors, social supports, HIV disclosure, HIV-related stigma and discrimination, healthcare access, ART regimen, adherence, side effects, costs and treatment beliefs. Baseline data were assessed, and suboptimal adherence was defined as self-reported missing ≥1 ART dose/month over the previous 3-months; associated factors were identified using bivariate and multivariate binary logistic regression. Results: We assessed 522 participants (494 [94.5%] men, mean age = 50.8 years, median duration UDVL = 3.3 years [IQR = 1.2–6.8]) at 17 sexual health, hospital, and general practice clinics across Australia. Seventy-eight participants (14.9%) reported missing ≥1 dose/month over the previous three months, which was independently associated with: being Australian-born (AOR [adjusted odds ratio] = 2.4 [95%CI = 1.2–4.9], p = 0.014), not being in a relationship (AOR = 3.3 [95%CI = 1.5–7.3], p = 0.004), reaching the “Medicare safety net” (capping annual medical/pharmaceutical costs) (AOR = 2.2 [95%CI = 1.1–4.5], p = 0.024), living in subsidised housing (AOR = 2.5 [95%CI = 1.0–6.2], p = 0.045), receiving home-care services (AOR = 4.4 [95%CI = 1.0–18.8], p = 0.046), HIV community/outreach services linkage (AOR = 2.4 [95%CI = 1.1–5.4], p = 0.033), and starting ART following self-request (AOR = 3.0 [95%CI = 1.3–7.0], p = 0.012). Conclusions: In this population, 15% reported recent suboptimal ART adherence at levels associated in prospective studies with subsequent virological failure, despite all having an undetectable viral load. Associations were with social/economic/cultural/patient engagement factors, but not ART regimen/clinical factors. These associations may help identify those at higher risk of future virological failure and guide patient education and support. [ABSTRACT FROM AUTHOR]

The article highlights foreign policy issues in Australia from January-June 2016. Topics discussed include reasons the 2016 Defence White Paper (2016 DWP) is an important document to consider in relation to Australia's foreign policy, four priority areas for Australian foreign policy as integral to the achievement of the Strategic Defence Objectives, and debate over the proper relationship between foreign and defence policy.

This paper examines the Australian federal government's use of regional engagement to stop irregular migration. It shows that Australia's policy elites have long debated whether regional cooperation is useful or necessary for stopping irregular migration. The debate among policy elites bears little relationship to the academic and ideological controversy over Australia's "engagement" with Asia. Rather, this controversy is defined by pragmatism and operates akin to a pendulum, with an action- reaction cycle occurring where governments seek alternative approaches to what they perceive as the failures of their predecessors. This paper shows that the governments who have championed Asian engagement have been no more willing to seek a regional approach to irregular migration than those who seem to downplay engagement. Differing perspectives on regional cooperation is an important and largely under-examined aspect of Australia's broader national debate about irregular migration. Given the significance of this issue to Australian politics, it also serves as an important case study in the wider context of Australia's relationship with and attitudes towards the Asia-Pacific. [ABSTRACT FROM AUTHOR]

The Indian Ocean is a region of increasing importance, with booming economic opportunities, shifting power dynamics and rising geopolitical competition. To manage this transition some Australian policy-makers are advocating the practice of defence diplomacy as a mechanism to help mould cooperative practices and to build regional trust while dissipating potential or ongoing regional flashpoints. Australia's 2013 Defence White Paper identified Australia as an agent who can play a critical part in the emergence of certain types of norms as a means of conflict prevention and crisis management in the Indo-Pacific region. This paper explores the use of defence diplomacy as a means for seeking regional influence. It uses an innovative new framework of norm entrepreneurship to examine the choices facing Australian policy-makers in increasingly complex security environment. This paper argues that while Australia should aim to promote defence diplomacy as a central part of rising security dialogue and practice with ‘like-mined’ countries, there must also be careful reflection to ensure that this objective is a constructive use of a middle power's limited resources and influence. [ABSTRACT FROM PUBLISHER]

The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV−) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS ≥ 0.5) based on the local norms was best at discriminating between the two groups (HIV− = 14.3 % vs. HIV+ = 53.3 %; p < 0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV− = 4.1 % vs. HIV+ = 14.7 %; p = 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living ( p ≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performance-based (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors. [ABSTRACT FROM AUTHOR]

This article examines whether Australia is a middle power. It identifies the three most popular approaches to defining a middle power: by a country's position, behaviour and identity. The article tests each definition against Australia, highlighting the strengths and weaknesses of each. Highlighting an earlier systemic approach to defining states, an alternative ‘systemic impact’ definition for middle powers is proposed. This approach, it is argued, provides a more comprehensive manner for identifying whether a country like Australia is a middle power, along with the implications for international security. [ABSTRACT FROM PUBLISHER]

One of the most effective rhetorical punches thrown by the Coalition during its period in Opposition was the (accurate) claim that Australia's defence spending had slipped to the lowest levels since 1938. In turn the Coalition nominated a target of spending two per cent of Australia's gross domestic product on Defence, should it win the 2013 election. This promise was later echoed by the Labor Government. This article explores how the 1938 comparison emerged, how it morphed into a two per cent of GDP policy target and argues that this debate has been unhelpful for Australia's security. It argues that the Coalition, now in office, should abandon the two per cent target and return to a more orthodox approach to funding defence. [ABSTRACT FROM AUTHOR]

Background: Since 2005, Australian clinicians were advised to undertake quarterly syphilis testing for all sexually active HIV-positive men who have sex with men (MSM). We describe differences in syphilis testing frequency among HIV-positive MSM by clinic testing policies since this recommendation. Methods: Three general practices, two sexual health clinics and two hospital HIV outpatient clinics provided data on HIV viral load and syphilis testing from 2006–2010. Men having ≥1 viral load test per year were included; >95% were MSM. We used Chi-2 tests to assess changes in syphilis testing frequency over time, and differences by clinic testing policy (opt-out, opt-in and risk-based). Results: The proportion of men having HIV viral loads with same-day syphilis tests increased from 37% in 2006 to 63% in 2007 (p<0.01) and 68–69% thereafter. In 2010, same-day syphilis testing was highest in four clinics with opt-out strategies (87%, range:84–91%) compared with one clinic with opt-in (74%, p = 0.121) and two clinics with risk-based strategies (22%, range:20–24%, p<0.01). The proportion of men having ≥3 syphilis tests per year increased from 15% in 2006 to 36% in 2007 (p<0.01) and 36–38% thereafter. In 2010, the proportion of men having ≥3 syphilis tests in a year was highest in clinics with opt-out strategies (48%, range:35–59%), compared with opt-in (39%, p = 0.121) and risk-based strategies (8.4%, range:5.4–12%, p<0.01). Conclusion: Over five years the proportion of HIV-positive men undergoing syphilis testing at recommended frequencies more than doubled, and was 5–6 times higher in clinics with opt-out and opt-in strategies compared with risk-based policies. [ABSTRACT FROM AUTHOR]

Abstract [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including Australia's 2016 defence white paper, role of public consultation, and farewell to editor Peter Dean.

An introduction is presented in which the editor discusses various reports within the issue on topics including establishment of an international uranium enrichment facility in Australia, State of Play report on non-proliferation and disarmament and Australian forces' nuclear-powered submarine.

Introduction: Severe cutaneous adverse reactions (SCAR) are a group of T cell-mediated hypersensitivities associated with significant morbidity, mortality and hospital costs. Clinical phenotypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP). In this Australasian, multicentre, prospective registry, we plan to examine the clinical presentation, drug causality, genomic predictors, potential diagnostic approaches, treatments and long-term outcomes of SCAR in Australia and New Zealand., Methods and Analysis: Adult and adolescent patients with SCAR including SJS, TEN, DRESS, AGEP and another T cell-mediated hypersensitivity, generalised bullous fixed drug eruption, will be prospectively recruited. A waiver of consent has been granted for some sites to retrospectively include cases which result in early mortality. DNA will be collected for all prospective cases. Blood, blister fluid and skin biopsy sampling is optional and subject to patient consent and site capacity. To develop culprit drug identification and prevention, genomic testing will be performed to confirm human leukocyte antigen (HLA) type and ex vivo testing will be performed via interferon-γ release enzyme linked immunospot assay using collected peripheral blood mononuclear cells. The long-term outcomes of SCAR will be investigated with a 12-month quality of life survey and examination of prescribing and mortality data., Ethics and Dissemination: This study was reviewed and approved by the Austin Health Human Research Ethics Committee (HREC/50791/Austin-19). Results will be published in peer-reviewed journals and presented at relevant conferences., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12619000241134)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease., Methods: RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing., Findings: 29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (<1%) were transgender, with a median age of 44·3 years (IQR 36·2-51·3) at baseline. As of Dec 31, 2019, 14 000 (47·7%) of 29 340 participants had been exposed to an INSTI. During a median follow-up of 6·16 years (IQR 3·87-7·52; 160 252 person-years), 748 (2·5%) individuals had a cardiovascular disease event (incidence rate of 4·67 events [95% CI 4·34-5·01] per 1000 person-years of follow-up). The crude cardiovascular disease incidence rate was 4·19 events (3·83-4·57) per 1000 person-years in those with no INSTI exposure, which increased to 8·46 events (6·58-10·71) per 1000 person-years in those with more than 0 months to 6 months of exposure, and gradually decreased with increasing length of exposure, until it decreased to similar levels of no exposure at more than 24 months of exposure (4·25 events [2·89-6·04] per 1000 person-years among those with >24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44-2·39]; >6 to 12 months of exposure: 1·19 [0·84-1·68]; >12 to 24 months of exposure: 1·46 [1·13-1·88]; >24 to 36 months of exposure: 0·89 [0·62-1·29]; and >36 months of exposure: 0·96 [0·69-1·33]; p<0·0001)., Interpretation: Although the potential for unmeasured confounding and channelling bias cannot fully be excluded, INSTIs initiation was associated with an early onset, excess incidence of cardiovascular disease in the first 2 years of exposure, after accounting for known cardiovascular disease risk factors. These early findings call for analyses in other large studies, and the potential underlying mechanisms explored further., Funding: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands National Observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences., Competing Interests: Declaration of interests JMM reports a personal 80:20 research grant from Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–22, and consulting honoraria or research grants from AbbVie, Angelini, Contrafect, Genentech, Gilead Sciences, Jansen, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare. CS reports payment or honoraria from Gilead for educational presentations. FW reports consulting fees from ViiV Healthcare. JJV reports grants or contracts from Merck, Gilead, Pfizer, Astellas Pharma, Basilea, German Centre for Infection Research (DZIF), German Federal Ministry of Education and Research, Deutsches Zetrum für Luft- und Raumfahrt, University of Bristol, and Rigshospitalet Copenhagen; consulting fees from Pfizer, Gilead, and Shionogi; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Merck, Gilead, Pfizer, Astellas Pharma, Basilea, DZIF, University Hospital Freiburg/Congress and Communication, Academy for Infectious Medicine, University Manchester, German Society for Infectious Diseases (DGI), Ärztekammer Nordrhein, University Hospital Aachen, Back Bay Strategies, German Society for Internal Medicine (DGIM), Shionogi, Molecular Health, Netzwerk Universitätsmedizin, Janssen, and NordForsk. AS reports grants from Gilead Sciences (payment to institution) and GSK (payment to institution); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Merck. ACar reports grants from ViiV Healthcare and MSD; consulting fees from Gilead Sciences, ViiV healthcare, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events Gilead Sciences; and support for attending meetings or travel from Gilead Sciences, MSD. HG owns stock in GSK and is an employee of ViiV Healthcare. FR is an employee of and has stock options in Gilead Sciences. HG reports grants or contracts from Swiss National Science Foundation (payment made to institution), Yvonne Jacob Foundation (payment made to institution), Gilead Sciences (COVID-19 program; payment made to institution); and participation a Data Safety Monitoring Board or Advisory Board for Merck, Gilead Sciences, Janssen, ViiV Healthcare, and Novartis. LDR reports payment for conference fee, transport, and accommodation, and participation at meetings held by, Takeda, MSD, Gilead Sciences, and GSK. MvdV reports grants or contracts with ViiV Healthcare (payment made to institution) and Gilead Sciences (payment made to institution); consulting fees from Merck (payment made to institution), ViiV Healthcare (payment made to institution), and Gilead Sciences (payment made to institution); and being a board member for Amsterdam Dinner foundation (unpaid). AM reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from ViiV Healthcare and Gilead Sciences; payment for expert testimonial from Eiland and Bonnin; and support for attending meetings and travel from ViiV Healthcare. AP-M reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background Overseas-born people who are ineligible for government-subsidised health care experience barriers to accessing HIV pre-exposure prophylaxis (PrEP) in Australia. This study aimed to assess a program providing free PrEP to overseas-born adults at risk of acquiring HIV. Methods Medicare-Ineligible Expanded Implementation in Communities (MI-EPIC) was a single-arm, open-label trial of daily tenofovir disoproxil fumarate/emtricitabine as PrEP. Six clinics recruited Medicare-ineligible adults who met HIV risk criteria in New South Wales, Australia. We recorded data on HIV and sexually transmitted infection (STI) diagnoses, and PrEP dispensing from July 2019 to June 2020. PrEP adherence as a medication possession ratio (MPR) was calculated as pills dispensed divided by days. We administered an optional survey on behaviours and attitudes to PrEP and sexual health. Results The 221 participants (206 men; 93.2%) had a median age of 29years (IQR 26-34). Participants were mostly born in Asia (53.4%), Latin America or the Caribbean (25.3%), or Europe (10.9%). Adherence was high; 190 participants (86.0%) had an MPR of >60%. Of 121 survey participants, 42 (34.7%) completed the survey in a language other than English. Of participants who had not used PrEP in the 6months before enrolment (n=45, 37.2%), the most common reasons were cost (n=22, 48.9%), and lack of knowledge about accessing PrEP (n=20, 44.4%). Conclusions Medicare-ineligible people at risk of HIV demonstrate high adherence when given access to free PrEP and translated information. Increasing PrEP awareness and reducing barriers to accessing PrEP in this high-risk population should be priorities in HIV prevention.

Background: In 2015, New South Wales (Australia) removed patient co-payments for ART of HIV. We hypothesized the policy change would reduce overall out-of-pocket (OOP) healthcare expenditure, improve ART adherence, and better maintain HIV suppression., Methods: Using data from a national, 2-year prospective study of adults with HIV on ART (n=364) (2013-2017), we compared OOP healthcare expenditure, ART adherence, and virological failure (VF) in participants subject to the co-payment policy change with participants from other jurisdictions who never paid, and who always paid, co-payments. We used fixed effects regression models to compare outcomes, and incidence rates for VF., Results: Although ART co-payments declined, there was no significant change in total OOP healthcare expenditure in participants ceasing co-payments compared to those who continued (adjusted coefficient 0.09, 95% CI -0.31 to 0.48). Co-payment removal did not significantly reduce suboptimal ART adherence (from 17.5% to 16.3%) or VF (from 5.0 to 3.7 episodes per-100-person-years). Participants in the lowest income group but not receiving concessional government benefits incurred a non-significant increase in total OOP healthcare expenses; while concessional participants experienced a significant increase in non-ART HIV healthcare costs after the policy changed., Conclusion: In this population, ART co-payments represented a small proportion of OOP healthcare expenditure. Its removal did not materially impact ART adherence or VF, although the study was not powered to detect these., Competing Interests: Conflicts of Interest EL, LM, JdW and JR have no conflicts to declare; AC has received research funding from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD and ViiV Healthcare; KJS has received travel sponsorship from Gilead Sciences., (Copyright © 2021. Published by Elsevier B.V.)

Objectives: To examine the safety of an agonist-type treatment, lisdexamfetamine (LDX), at 250 mg/day among adults with methamphetamine (MA) dependence., Design: A dose-escalating, phase-2, open-label, single-group study of oral LDX at two Australian drug treatment services., Setting: The study was conducted at two Australian stimulant use disorder treatment clinics., Participants: There were 16 participants: at least 18 years old, MA dependent for at least the preceding 2 years using ICD-10 criteria, reporting use of MA on at least 14 of the preceding 28 days., Interventions: Daily, supervised LDX of 100-250 mg, single-blinded to dose, ascending-descending regimen over 8 weeks (100-250 mg over 4 weeks; followed by 4-week dose reduction regimen, 250-100 mg). Participants were followed through to week 12., Outcomes: Primary outcomes were safety, drug tolerability and regimen completion at the end of week 4. Participants were followed to week 12. Secondary outcomes included: change in MA use; craving; withdrawal; severity of dependence; risk behaviour; change in other substance use; medication acceptability; potential for non-prescription use; adherence and neurocognitive functioning., Results: Fourteen of 16 participants (87.5%) completed escalation to 250 mg/day. Two participants withdrew from the trial in the first week: one relocated away from the study site, the other self-withdrew due to a possible, known side effect of LDX (agitation). There was one serious adverse event of suicidal ideation which resolved. All other adverse events were mild or moderate in severity and known side effects of LDX. No participant was withdrawn due to adverse events. MA use decreased from a median of 21 days (IQR: 16-23) to 13 days (IQR: 11-17) over the 4-week escalation period (p=0.013)., Conclusions: LDX at a dose of up to 250 mg/day was safe and well tolerated by study participants, warranting larger trials as a pharmacotherapy for MA dependence., Trial Registration Number: ACTRN12615000391572., Competing Interests: Competing interests: NE and AC are employed by St Vincent’s Hospital Sydney, a public health service funded by the NSW Ministry of Health. BC is employed by St Vincent’s Health Australia and has no conflicts to declare. AD is employed by Hunter New England Local Health District, a public health service funded by NSW Health and reports research and travel support from Braeburn/Camurus, research support from Indivior, and has served on an advisory board for Mundipharma, all for unrelated work. RB has received investigator-initiated untied educational grants from Reckitt Benckiser/Indivior for the development of an opioid-related behaviour scale and a study of opioid substitution therapy uptake among chronic non-cancer pain patients. RB has received an untied educational grant from Mundipharma for a postmarketing study of reformulated oxycodone. AC has received research funding from Bristol-Myers Squibb, Gilead Sciences, and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD and ViiV Healthcare, all of which are unrelated to this present study. ZL is employed by UNSW and has no competing interests to declare. KJS is employed by UNSW and has received unrelated travel sponsorship from Gilead Sciences. NL is employed by South East Sydney Local Health District, a public health service funded by the NSW Ministry of Health; he has received research funding from Camurus, and has served on Advisory Boards for Mundipharma, Camurus and Indivior for work unrelated to this study., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

PrELUDE study evaluated daily pre-exposure prophylaxis (PrEP) in high-risk individuals in Australia. This open-label, single-arm study tested participants for HIV/STI and collected behavioural information three-monthly. We report trends over 18 months in medication adherence, side-effects, HIV/STI incidence and behaviour. 320 gay/bisexual men (GBM), 4 women and 3 transgender participants, followed on average 461 days, reported taking seven pills/week on 1,591 (88.5%) occasions and 4-6 pills/week on 153 (8.5%) occasions. No HIV infections were observed. STI incidence was high and stable, while gonorrhoea infections declined from 100.0 to 25.8/100 person-years between 6 and 15 months (p < 0.001). The number of HIV-positive and unknown-status sex partners, and condomless anal intercourse, significantly increased. In this high-risk cohort of mainly GBM, increases in risk behaviours and high STI incidence were not accompanied by HIV infections due to high adherence to daily PrEP. The study informed policy and further PrEP implementation among Australian GBM.

Objective: To compare the effects of switching tenofovir disoproxil fumarate (TDF) or treatment with an intravenous bisphosphonate on bone mineral density (BMD) in HIV-positive adults with low bone mass., Design: Two-year, randomized, open-label study at 10 sites in Australia and Spain., Participants: Of 112 adults on TDF-based antiretroviral therapy (ART) screened, 87 with low BMD (T-score < -1.0 at hip or spine by dual-energy X-ray absorptiometry) and undetectable plasma HIV viral load were randomized to either switch TDF to another active antiretroviral drug or to continue TDF-based ART and receive intravenous zoledronic acid (ZOL) 5 mg annually for 2 years., Primary Outcome Measure: Change in lumbar spine BMD at 24 months by intention-to-treat analysis. Secondary outcomes included changes in femoral neck and total hip BMD, fractures, safety, and virological failure., Results: Forty-four participants were randomized to TDF switch and 43 to ZOL, mean age 50 years (SD 11), 96% men, mean TDF duration 5.9 years (SD 3.1), and mean spine and hip T-scores -1.6 and -1.3, respectively. At 24 months, mean spine BMD increased by 7.4% (SD 4.3%) with ZOL vs. 2.9% (SD 4.5%) with TDF-switch (mean difference 4.4%, 95% CI 2.6-6.3; P < 0.001). Mean total hip BMD increased by 4.6 (SD 2.6%) and 2.6% (SD 4%), respectively (mean difference 1.9%, 95% CI 0.5-3.4; P = 0.009). There was one fracture in the ZOL group vs. seven fractures in four TDF-switch participants. Virological failure occurred in one TDF-switch participant. Other safety endpoints were similar., Conclusion: ZOL is more effective than switching TDF at increasing BMD in HIV-positive adults with low bone mass.

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.

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., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Both antiretroviral treatment interruption (TI) and cessation have been strongly discouraged since 2006. We describe the incidence, duration, and risk factors for TI and loss-to-follow-up (LTFU) rates across 13 countries. All 4689 adults (76% men) in two large HIV cohorts in Australia and Asia commencing combination antiretroviral therapy (ART) to March 2010 were included. TI was defined by ART cessation >30 days, then recommencement, and loss to follow-up (LTFU) by no visit since 31 March 2009 and no record of death. Survival analysis and Poisson regression methods were used. With median follow-up of 4.4 years [interquartile range (IQR):2.1-6.5], TI incidence was 6.7 per 100 person years (PY) (95% CI:6.1-7.3) pre-2006, falling to 2.0 (95% CI:1.7-2.2) from 2006 (p<0.01). LTFU incidence was 3.5 per 100 PY (95% CI:3.1-3.9) pre-2006, and 4.1 (95% CI:3.5-4.9) from 2006 (p=0.22). TIs accounted for 6.4% of potential time on ART pre-2006 and 1.2% from 2006 (p<0.01), and LTFU 4.7% of potential time on ART pre-2006 and 6.6% from 2006 (p<0.01). Median TI duration was 163 (IQR: 75-391) days pre-2006 and 118 (IQR: 67-270) days from 2006 (p<0.01). Independent risk factors for the first TI were: Australia HIV Observational Database participation; ART initiation pre-2006; ART regimens including stavudine and didanosine; three nucleoside analogue reverse transcriptase inhibitors; ≥7 pills per day; and ART with food restrictions (fasting or with food). In conclusion, since 2006, 7.8% of patients had significant time off treatment, which has the potential to compromise any 'test and treat' policy as during the interruption viral load will rebound and increase the risk of transmission.

Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomized to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline and months 4 and 12; BMD at the spine (dual-energy X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared with the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p ≤ 0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, whereas increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months., (Copyright © 2013 American Society for Bone and Mineral Research.)

Objective: Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV). Our study aims to project the life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments., Methods: Patient antiretroviral treatment data were sourced from an observational cohort of 3434 predominantly male (94.2%) PLHIV in Australia over the period 1997-2010. These data were analyzed in a computer simulation model to calculate the distribution of time until exhaustion of all treatment options and expected effect on mortality. Standardized mortality ratios were used to simulate expected survival before and after treatment exhaustion., Results: We estimated that the median time until exhaustion of currently available treatment options is 45.5 years [interquartile range (IQR) 34.0-61.0 years]. However, 10% of PLHIV are expected to exhaust all currently available cART options after just 25.6 years. PLHIV who start currently available cART regimens at age 20 years are expected to live to a median age of 67.4 (IQR 53.2-77.7) years. This is a substantial improvement on no cART [27.7 (IQR 23.8-32.0) years] but is still substantially less than the median general population mortality age [82.2 (IQR 74.0-87.8) years]. The life expectancy gap between PLHIV and the general population is greatest for those infected at younger ages., Conclusion: As treatment options are exhausted, a substantial difference in life expectancy between PLHIV and the general population could be expected even in resource-rich settings, particularly for people who acquire HIV at a younger age or who are currently highly treatment experienced.

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.

Background: Asymptomatic ischaemic heart disease (IHD) in HIV-infected patients has not been studied., Methods: Resting, 12-lead electrocardiograms (ECG) were evaluated for asymptomatic IHD (Q-wave and/or ST segment depression) at baseline from HIV-infected participants with no known IHD enrolling in the SMART study. The ECG recordings were standardized and centrally analysed. Factors associated with asymptomatic IHD were identified by logistic regression, sequentially adjusted for demographics, clinical history, metabolic risk factors and type and duration of antiretroviral therapy (ART)., Results: Of 4831 participants with an evaluable, baseline ECG and no prior IHD, mean age was 44 years (SD, 9.3); 28.4% were female; 6.6% had diabetes; 16.5% were receiving antihypertensive therapy; and 95.4% were ART experienced. ECG evidence of IHD was detected in 526 (10.9%) [Q-wave in 283 (5.9%), ST segment depression in 264 (5.5%)]; 16.7% in those 60 years or older. Variables independently associated with these abnormalities were older age [age > or= 60 versus < 40 years: odds ratio (OR), 2.2; 95% confidence interval (CI), 1.5-3.2; P < 0.001], current antihypertensive therapy (OR, 1.5; 95% CI, 1.1-1.9; P = 0.003) and recruitment in Europe (OR, 1.4; 95% CI, 1.1-1.7; P = 0.004) or Asia (OR, 1.6; 95% CI, 1.0-2.6; P = 0.05), both compared with North America. Diabetes was borderline significant (OR, 1.4; 95% CI, 1.0-2.0; P = 0.06)., Conclusions: ECG evidence of asymptomatic IHD was common in this large cohort of HIV-infected adults and more common than a history of symptomatic IHD. Traditional factors were the predominant determinants of risk. No clear association between ART type or duration and asymptomatic IHD was noted.