Prevalence, frequency, and motivations for alkyl nitrite use among gay, bisexual and other men who have sex with men in Australia.

BACKGROUND AND AIMS: Gay, bisexual and other men who have sex with men (GBM) use alkyl nitrites ('poppers') at higher rates than other populations to functionally enhance sexual experiences. Their use has been associated with HIV sexual risk behaviours including receptive anal sex. We investigate the prevalence, frequency, and motivations for poppers use and their relationship with HIV risk. We also discuss the implications of the recent scheduling changes to poppers by the Australian Therapeutic Goods Administration. METHODS: Data were drawn from the Following Lives Undergoing Change (Flux) study, a prospective observational study of licit and illicit drug use among GBM. Between 2014 and 2018, 3273 GBM enrolled in the study. In 2018, 1745 GBM provided data relating to frequency of and motivations for poppers use and were included in this analysis. RESULTS: Median age was 33 years (IQR 25-46) and 801 GBM (45.9%) had used poppers in the previous six months ('recent use'). Among these men, 195 (24.3%) had used them weekly or more frequently. Most recent users (77.4%) reported using poppers for a 'buzz' during sex or to facilitate receptive anal intercourse (60.8%). The majority (57.7%) of HIV-negative men reporting recent poppers use were concurrently taking HIV pre-exposure prophylaxis. Recent poppers use was independently associated with receptive anal intercourse with casual partners (aOR 1.71; 95%CI 1.35-2.16) and chemsex (aOR 4.32; 95%CI 3.15-5.94). Poppers use was not associated with anxiety, depression, or drug-related harms. Only 15.4% of current users indicated they would stop using poppers if they were criminalised; 65.0% said they would 'find other ways' to obtain them. CONCLUSIONS: Poppers are commonly used by Australian GBM to functionally enhance sexual experiences, particularly to facilitate receptive anal intercourse. Few men experienced drug-related harms from poppers use. Regulatory changes must ensure potential harms from popper use are minimised without increasing barriers to access or perpetuating stigma.

Program implementation gaps and ethical issues in the prevention of HIV infection among infants, children, and adolescents in sub-Saharan Africa.

Strategies for HIV prevention among infants, children, and adolescents have evolved significantly over the past 20 years. These include the global scale-up of simplified multidrug HIV regimens for pregnant women, leading to impressive reductions in new child HIV infections. However, significant gaps remain, especially in high HIV-burden sub-Saharan African countries. For example, many pregnant women living with HIV (WLHIV) are unable to access and sustain HIV testing and treatment partly due to low agency and harmful gender norms. Among pregnant WLHIV, adolescent girls face an additional layer of societal and health-system barriers in accessing care for themselves and their exposed infants. Legal and structural barriers limit access to HIV prevention-related sexual and reproductive health services among high-risk adolescents, including girls and young men who have sex with men. Key ethical issues underlying HIV prevention gaps for infants, children, and adolescents prevail. This narrative review explores these issues and highlights counter-measures for programming and policy, including gender empowerment, improving access to and appropriateness of critical health services, rights-based policy and legislation, closing research gaps, and considering the values and preferences of young people for HIV prevention and treatment services.

Predictors of Daily Adherence to HIV Pre-exposure Prophylaxis in Gay/Bisexual Men in the PRELUDE Demonstration Project.

Adequate adherence to pre-exposure prophylaxis (PrEP) is critical to prevent HIV infection, but accurately measuring adherence remains challenging. We compared two biological [blood drug concentrations in plasma and peripheral blood mononuclear cells (PBMC)] and two self-reported measures (facilitated recall to clinicians and self-report in online surveys) and identified predictors of daily PrEP adherence among gay and bisexual men (GBM) in their first 12 months on PRELUDE, an open-label, single-arm PrEP demonstration project in New South Wales, Australia. 327 participants were enrolled; 263 GBM attended their 12-month follow-up visit (81% retention). Overall, 91% of blood samples had plasma drug concentrations indicative of taking 7 pills/week, and 99% had protective drug concentrations (≥ 4 pills/week). Facilitated recall to clinicians identified 99% of participants with protective adherence as measured by PBMC drug concentrations. Daily adherence measured by facilitated recall was associated with behavioural practices including group sex (aOR 1.33, 95% CI 1.15-1.53, p < 0.001). Retained participants maintained high adherence to daily PrEP over 12 months, confirmed by four different measures. Facilitated recall to clinicians is a suitable measure for assessing PrEP adherence in populations engaged in care where there is established trust and rapport with patients. Trial registration: ClinicalTrials.gov NCT02206555.

Validation of participant eligibility for pre-exposure prophylaxis: Baseline data from the PRELUDE demonstration project.

BACKGROUND: In Australia, pre-exposure prophylaxis (PrEP) is targeted to individuals at high risk for HIV infection. We describe the HIV risk profile and characteristics of PRELUDE participants, and evaluate the population validity of the sample in representing high-risk gay and bisexual men (GBM) eligible for PrEP. METHODS: PRELUDE is an on-going, open-label, single-arm observational study. Participants were identified in clinics and screened for eligibility using a paper-based risk assessment tool which followed the New South Wales (NSW) PrEP guidelines. Selection was validated using an independent online behavioural survey, completed by study participants upon enrolment. Demographic information was analysed using descriptive statistics, and kappa tests were used to determine agreement between reporting of high-risk practices in the risk assessment and behavioural survey. RESULTS: During 2014-15, 471 individuals were targeted for enrolment; 341 were assessed for PrEP eligibility and 313 were enrolled. Of these, 303 (97%) identified as GBM. Overall, 85% of GBM met at least one high-risk criterion; 68% reported receptive intercourse with an HIV-positive or unknown status casual male partner, and 37% reported methamphetamine use in the three months preceding enrolment. The remaining 15% were enrolled based on medium-risk behaviours, or at the clinicians' discretion. We found an 82% total agreement between self-reported high-risk behaviour and clinicians' categorisation of GBM as being at high risk for HIV based on PrEP eligibility criteria. CONCLUSIONS: Behavioural eligibility criteria used by clinicians successfully identified individuals at high risk for HIV infection. This targeted approach ensures that the greatest public health and HIV prevention benefits can be derived in a setting without universal access to PrEP.

Undue inducement, or unfair exclusion: considering a case study of pregnancy in an HIV prevention trial.

In their recent paper'Undue inducement: a case study in CAPRISA 008', Mngadi et al conclude that a participant in an HIV prevention study who deliberately concealed her pregnancy was not 'unduly induced' to participate by the offer of an experimental product. This paper argues that while the authors' conclusion is sound, the framing of this case study is consistent with the preoccupation in research ethics with the concept of undue inducement, coupled with a highly risk-averse attitude to pregnancy (regardless of whether those risks may be willingly assumed by pregnant women themselves). We suggest that the critical research ethics question raised by Mngadi et al's case study is not 'undue inducement', but the exclusion of pregnant women from research studies where the risks are acceptable to the potential participant, and benefits likely. We also suggest that current regulatory paradigms regarding pregnancy are both overly paternalistic and value the fetus over the mother. In order to ensure timely provision of new HIV prevention agents, we argue that there is a need for expeditious testing of proven effective agents in pregnancy, with due consideration given to situations where preliminary efficacy data exist but fall short of licensure standards. This requires a paradigm shift from researchers, funders, regulators and ethical review bodies towards practices that critically examine the legitimacy of the exclusion of pregnant women on a study-by-study basis.

'They say God punishes people with HIV': experiences of stigma and discrimination among adults with HIV in Dili, Timor-Leste.

Little is known about the experiences of people with HIV in the small island nation of Timor-Leste. This study explored the HIV-related stigma experiences of adults aged between 18 and 40 living with HIV in Dili, Timor-Leste. Participants were interviewed on topics related to living with HIV, both as key informants describing the experience of others with HIV known to them, and also with respect to their own personal experiences. Findings suggest that people with HIV in Timor-Leste face stigma and discrimination in various contexts. In this predominantly Catholic country, perceptions of HIV and attitudes towards people with HIV appear to be commonly shaped by religious beliefs. In families and communities, participants encountered gossip, social exclusion and threats of violence. In health settings, participants experienced discrimination from health providers in the form of failing to maintain confidentiality and inappropriate treatment. The impact of stigma was profoundly negative and influenced participants' decision to disclose their status to others. Participants attributed stigma to a lack of information about HIV among the general public. Unless stigma reduction interventions also address the Church's role in shaping perceptions of HIV, education campaigns are unlikely to be effective in reducing HIV-related stigma.

Baseline Preferences for Daily, Event-Driven, or Periodic HIV Pre-Exposure Prophylaxis among Gay and Bisexual Men in the PRELUDE Demonstration Project.

INTRODUCTION: The effectiveness of daily pre-exposure prophylaxis (PrEP) is well established. However, there has been increasing interest in non-daily dosing schedules among gay and bisexual men (GBM). This paper explores preferences for PrEP dosing schedules among GBM at baseline in the PRELUDE demonstration project. MATERIALS AND METHODS: Individuals at high-risk of HIV were enrolled in a free PrEP demonstration project in New South Wales, Australia, between November 2014 and April 2016. At baseline, they completed an online survey containing detailed behavioural, demographic, and attitudinal questions, including their ideal way to take PrEP: daily (one pill taken every day), event-driven (pills taken only around specific risk events), or periodic (daily dosing during periods of increased risk). RESULTS: Overall, 315 GBM (98% of study sample) provided a preferred PrEP dosing schedule at baseline. One-third of GBM expressed a preference for non-daily PrEP dosing: 20% for event-driven PrEP, and 14% for periodic PrEP. Individuals with a trade/vocational qualification were more likely to prefer periodic to daily PrEP [adjusted odds ratio (aOR) = 4.58, 95% confidence intervals (95% CI): (1.68, 12.49)], compared to individuals whose highest level of education was high school. Having an HIV-positive main regular partner was associated with strong preference for daily, compared to event-driven PrEP [aOR = 0.20, 95% CI: (0.04, 0.87)]. Participants who rated themselves better at taking medications were more likely to prefer daily over periodic PrEP [aOR = 0.39, 95% CI: (0.20, 0.76)]. DISCUSSION: Individuals' preferences for PrEP schedules are associated with demographic and behavioural factors that may impact on their ability to access health services and information about PrEP and patterns of HIV risk. At the time of data collection, there were limited data available about the efficacy of non-daily PrEP schedules, and clinicians only recommended daily PrEP to study participants. Further research investigating how behaviours and PrEP preferences change correspondingly over time is needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02206555. Registered 28 July 2014.

Critical role of ethics in clinical management and public health response to the West Africa Ebola epidemic.

The devastation caused by the Ebola virus disease (EVD) outbreak in West Africa has brought to the fore a number of important ethical debates about how best to respond to a health crisis. These debates include issues related to prevention and containment, management of the health care workforce, clinical care, and research design, all of which are situated within the overarching moral problem of severe transnational disadvantage, which has very real and specific impacts upon the ability of citizens of EVD-affected countries to respond to a disease outbreak. Ethical issues related to prevention and containment include the appropriateness and scope of quarantine and isolation within and outside affected countries. The possibility of infection in health care workers impelled consideration of whether there is an obligation to provide health services where personal protection equipment is inadequate, alongside the issue of whether the health care workforce should have special access to experimental treatment and care interventions under development. In clinical care, ethical issues include the standards of care owed to people who comply with quarantine and isolation restrictions. Ethical issues in research include appropriate study design related to experimental vaccines and treatment interventions, and the sharing of data and biospecimens between research groups. The compassionate use of experimental drugs intersects both with research ethics and clinical care. The role of developed countries also came under scrutiny, and we concluded that developed countries have an obligation to contribute to the containment of EVD infection by contributing to the strengthening of local health care systems and infrastructure in an effort to provide fair benefits to communities engaged in research, ensuring that affected countries have ready and affordable access to any therapeutic or preventative interventions developed, and supporting affected countries on their way to recovery from the impact of EVD on their social and economic lives.

Preexposure prophylaxis-related stigma: strategies to improve uptake and adherence - a narrative review.

Despite high levels of efficacy, the implementation of preexposure prophylaxis (PrEP) as a strategy to prevent new HIV infection has been slow. Studies show that PrEP works so long as it is taken, making adherence one of the great challenges of effective PrEP implementation alongside issues of access and uptake. Given that effective PrEP use requires ongoing self-administration of pills by people at high risk of HIV acquisition, it is a strategy best understood not as simply biomedical, but as biobehavioral or biopsychosocial, meaning that that social, psychological, cultural, and structural factors all contribute to the success or failure of the intervention. The willingness of people at risk of HIV to take up and adhere to PrEP depends greatly upon social understandings - whether it is seen as effective, as a healthy option, and a socially acceptable strategy for preventing HIV. Stigma - unfavorable associations - can negatively influence the implementation of PrEP. Because it is associated with high-risk sexual activity, PrEP risks multiple stigmas that can differ according to specific cultural conditions. This includes the stigma of being related to HIV (which may also relate to other stigmas, such as homosexuality, sex work, and/or drug use) and the stigma of PrEP being an alternative to condoms (as condom use is associated with responsible sexual activity). PrEP-related stigma has emerged as a significant social harm that can arise from PrEP research participation, reported by trial participants from a range of different trial sites, different trial populations, and spanning different continents. Social marketing needs to redress PrEP-related stigmas through health promotion campaigns aimed at clinicians, HIV-affected communities, and people at high risk of HIV who might benefit from PrEP access. PrEP access needs to be reframed as a positive and responsible option to help people remain HIV-negative.

Standards and guidelines for HIV prevention research: considerations for local context in the interpretation of global ethical standards.

While international standards are important for conducting clinical research, they may require interpretation in particular contexts. Standard of care in HIV prevention research is now complicated, given that there are now two new biomedical prevention interventions - 'treatment-as-prevention', and pre-exposure prophylaxis--in addition to barrier protection, counselling, male circumcision and treatment of sexually transmissible infections. Proper standards of care must be considered with regard to both normative guidance and the circumstances of the particular stakeholders--the community, trial population, researchers and sponsors. In addition, the special circumstances of the lives of participants need to be acknowledged in designing trial protocols and study procedures. When researchers are faced with the dilemma of interpretation of international ethics guidelines and the realities of the daily lives of persons and their practices, the decisions of the local ethics committee become crucial. The challenge then becomes how familiar ethics committee members in these local settings are with these guidelines, and how their interpretation and use in the local context ensures the respect for persons and communities. It also includes justice and the fair selection of study participants without compromising data quality, and ensuring that the risks for study participants and their community do not outweigh the potential benefits.

Development of guidelines for the conduct of HIV research monitoring by ethics committees in Nigeria.

Nigerian research ethics committees are charged with the responsibility to monitor ongoing research to ensure compliance with ethical standards. Recent evidence from qualitative studies on research conduct however, indicate that many research studies fail to implement their protocols as written, and that this is not reported due to a failure of comprehensive monitoring. As Nigeria is in many respects a highly suitable country in which to conduct HIV biomedical prevention research, we argue there is a need to reprioritise the strengthening of the monitoring capacity of ethics committees so that such vital and ethically complex research can be conducted with confidence. We identify the need for (i) improved resourcing and training of ethics committee members, and (ii) comprehensive planning of research monitoring as part of the ethics committee protocol review process. We also highlight the significance of community collaboration and the establishment of a central pool of national monitors, as essential components for reinvigorating monitoring capacity.

Ethics of ancillary care in clinical trials in low income countries: a Nigerian case study.

The ethical conduct of HIV prevention researchers is subject to scrutiny. Many clinical trials take place in low and middle income countries where HIV incidence is high, but the benefits of research are often first enjoyed in high income countries. The provision of ancillary care--medical care provided to clinical trial participants during a trial, which is not related to the research question--is one way in which trial participants can receive direct benefits from their participation in research. We argue that such care is a legitimate benefit of research participation. This care does not constitute 'undue inducement' if the research study itself involves minimal risk and is subject to ethical and regulatory oversight. We also argue that research teams working with populations who have sub-optimal healthcare access have a duty to provide ancillary care within agreed limits. These limits should be negotiated to ensure that the research remains feasible and economically viable.

The seventh (and last?) International Microbicides Conference: from discovery to delivery.

The most recent estimates indicate that in 2011, 34 million people were living with HIV, the majority in sub-Saharan Africa. Even though the estimated number of new infections is decreasing, there remains an urgent need for new prevention technologies, particularly those controlled by women and men who have receptive sex. Microbicides are products designed to be applied vaginally or rectally to prevent acquisition of HIV and other sexually transmissible infections and, as such, provide a great hope for female-controlled HIV prevention. Oral prevention drugs are a more recent development that also has great potential. The field changed radically in 2010-2011 with the first trials demonstrating effectiveness of a microbicide and oral prevention drugs. The seventh biannual Microbicides conference, which took place in Sydney, Australia, in April 2012, was the first conference in this series since these new results and represented a transition from the discovery phase of research to considerations of implementation. Researchers, advocates, community representatives, funders and the media came together over 3 days to talk about the realities of implementation, particularly in regard to challenges in adherence and funding, and also examined early findings for new prevention technologies. This report of the 2012 International Microbicides Conference provides a summary of recent developments and ongoing challenges in the field of microbicides research.

Ethics of medical care and clinical research: a qualitative study of principal investigators in biomedical HIV prevention research.

In clinical research there is a tension between the role of a doctor, who must serve the best interests of the patient, and the role of the researcher, who must produce knowledge that may not have any immediate benefits for the research participant. This tension is exacerbated in HIV research in low and middle income countries, which frequently uncovers comorbidities other than the condition under study. Some bioethicists argue that as the goals of medicine and those of research are distinct, it is a mistake for researchers to assume therapeutic responsibilities while engaging in research. Others propose that there is a duty of care, but disagree as to how this is limited and specified. In this qualitative study, principal investigators from HIV prevention trials discuss their experience of providing medical benefits to participants within the context of conducting research into HIV biomedical prevention technologies. They describe the limitations imposed at times by funders and at times by infrastructure constraints, and canvass the importance of ancillary care provision and capacity building in trial communities. The views of the principal investigators are compatible with the perspective that there is a duty of care, limited by the nature of the research, the depth of the relationship between research and participant, and the capacity of the research site. The therapeutic orientation in HIV prevention trial appears to be indivisible from competent research practise by making concrete and appropriate benefits available to trial participants and their communities that support rather than compete with local infrastructure.

Because we can: clashes of perspective over researcher obligation in the failed PrEP trials.

This article examines the relationship between bioethics and the therapeutic standards in HIV prevention research in the developing world, focusing on the closure of the pre-exposure prophylaxis (PrEP) trials in the early 2000s. I situate the PrEP trials in the historical context of the vertical transmission debates of the 1990s, where there was protracted debate over the use of placebos despite the existence of a proven intervention. I then discuss the dramatic improvement in the clinical management of HIV and the treatment access movement, and consider how these contexts have influenced research practice. I argue that as HIV prevention trials oblige researchers to observe the rate at which vulnerable people under their care acquire HIV, there is an obligation to provide antiretroviral treatment to seroconverters and other health care benefits that fall within the scope of researchers' entrustment, both to avoid exploitation and to enact reciprocal justice. I argue against propositions that the obligations to provide specific benefits are vague, fall only upon researchers and sponsors, and create injustices by privileging the few over the many. Finally, I contend that the realisation of a broader standard of care in HIV prevention research broadens the role of research from being a simple tool to produce knowledge to a complex intervention that can play a part in the reduction of health disparities.