The Cost of Dying Exhibition: public, professional and political reactions to a visual exhibition depicting experiences of poverty at the end of life.

Public health approaches to palliative care are internationally endorsed for their potential to improve the social determinants of dying such as energy costs, transport and housing. Enhancing public understanding of inequities in end of life experiences, which exist even in economically advanced countries, is vital if the value of public health approaches are to be endorsed and invested in. Visual exhibitions have a strong tradition of raising awareness and influencing public health discourse. The UK-based Cost of Dying exhibition (April-August 2023) presented real examples of how financial hardship and deprivation intersect with end of life experience through professional portraits, photovoice imagery taken by individuals at the end of their lives, and digital stories co-produced with bereaved relatives. Three iterations of the exhibition were displayed at public venues and a health conference. Evaluation methods comprised anonymous feedback cards (n=208), panel discussions and social media reactions. Thematic analysis was used to identify themes within the feedback. The emotional resonance of the exhibition was a key theme, with attendees expressing sadness, anger, empathy and hope. Visitors found the exhibition thought-provoking and expressed that it countered existing stereotypes about what it means to experience financial hardship at the end of life. The exhibition spurred calls for change, with some attendees questioning in what capacity they could help. Individuals with expertise in end of life care reported that the imagery validated their professional experiences. In conclusion, the Cost of Dying exhibition made visible the struggles endured by individuals confronting financial hardship and material deprivation at the end of life. Such exhibitions can challenge the traditional view of dying as a swift process taking place sequestered in institutions, revealing that it often unfolds over time and individuals may continue to live at home in the community, struggling with unmet needs and unresponsive state services.

"The great escape": how an incident of elopement gave rise to trauma informed palliative care for a patient experiencing multiple disadvantage.

BACKGROUND: This case report from Scotland, UK illustrates how unresolved traumatic experiences across the life course can affect a patient's engagement with palliative care and offers insights into the flexibility and adaptations necessary for taking a trauma informed approach to care for an individual experiencing multiple disadvantage. Trauma informed care is a cornerstone in the pursuit of equitable palliative care, particularly for those facing multiple disadvantage, as it acknowledges the impact of past traumas on current healthcare experiences, and fosters an environment of understanding, acceptance, and tailored support to alleviate suffering in the final stages of life. CASE PRESENTATION: "M" was a veteran with a history of homelessness, living with end stage anal cancer and symptoms consistent with post-traumatic stress disorder, although he never received a formal diagnosis. M exhibited complex behaviours perceived to be related to his history of trauma, including his decision to elope from the hospice, reluctance to accept personal care from nurses, and unpredictability. These behaviours posed a significant challenge to his palliative care team, both in the hospice and at home. An individualised and flexible approach to care delivery was eventually adopted, which included a 'safety-netting' approach and care delivery outside of the hospice. M was ultimately supported to remain at home until a week before he died. CONCLUSION: M's case underscores the necessity of adopting a trauma informed approach to palliative care, particularly for patients with a history of trauma and multiple disadvantage. The case highlights the importance of understanding and respecting a patient's past traumas, promoting safety and autonomy, and ensuring flexibility in care delivery.

Dying at home for people experiencing financial hardship and deprivation: How health and social care professionals recognise and reflect on patients' circumstances.

Background: International palliative care policy often views home as the most desirable location for end-of-life care. However, people living in more deprived areas can worry about dying in poor material circumstances and report more benefits from hospital admission at the end of life. There is increasing recognition of inequities in the experience of palliative care, particularly for people living in more deprived areas. Promoting an equity agenda in palliative care means building healthcare professionals' capacity to respond to the social determinants of health when working with patients near the end of their life. Objectives: The purpose of this article is to present data which reveal how some health and social care professionals view home dying for people experiencing financial hardship and deprivation. Design: This work was framed by social constructionist epistemology. Methods: Semi-structured qualitative interviews (n = 12) were conducted with health and social care professionals who support people at the end of life. Participants were recruited from one rural and one urban health board area in Scotland, UK. Data collection occurred between February and October 2021. Analysis: Thematic analysis was used to analyse the interview data. Discussion: Our findings suggest that healthcare staff relied on physical clues in the home environment to identify if people were experiencing financial hardship, found discussions around poverty challenging and lacked awareness of how inequities intersect at the end of life. Health professionals undertook 'placing' work to try and make the home environment a suitable space for dying, but some barriers were seen as insurmountable. There was recognition that increased partnership working and education could improve patient experiences. We argue further research is needed to capture the perspectives of individuals with direct lived experience of end-of-life care and financial hardship.

The viability and appropriateness of using visual methods in end of life research to foreground the experiences of people affected by financial hardship and deprivation.

BACKGROUND: Visual methods have been used extensively in social research to explore people's experiences of structural disadvantage. This indicates that they may provide a useful research approach to understanding equity-related concerns within palliative care. However, little has been published regarding the use of visual methods with people at the end of life. PURPOSE OF THE PAPER: In this article we draw on our experiences of using visual methods to illuminate the end of life experiences of people experiencing financial hardship and deprivation in Scotland's largest city. EVIDENCE USED TO SUPPORT THE INFORMATION PRESENTED: We present evidence from the published literature, as well as our own experiences of using visual methods to explore dying at home for people experiencing financial hardship and deprivation. Our analysis draws on two specific visual methods: photovoice and professional photography. Photovoice is a participatory visual method which involves enabling participants to take and discuss their own images and present them to different audiences to try to enact social change. We report our experiences as researchers, as well as those of our participants and recruitment partners. KEY LEARNING POINTS: To successfully use visual methods, researchers need to invest significant time and resource in building a strong rapport with participants. There are also key ethical, practical and representational challenges to consider. A participatory framework should be adopted which ensures agency for participants in terms of image creation and public dissemination. Participants reported value in using visual methods in terms of legacy building and self-representation. Using photovoice (insider's view) and professional photography (outsider's view) together offered complementary perspectives, enabling a rich layering of stories and meaning. Our findings indicate visual methods can illuminate aspects of the end of life experience not captured by other research methods.

Medicalisation, suffering and control at the end of life: The interplay of deep continuous palliative sedation and assisted dying.

Medicalisation is a pervasive feature of contemporary end of life and dying in Western Europe and North America. In this article, we focus on the relationship between two specific aspects of the medicalisation of dying: deep continuous palliative sedation until death and assisted dying. We draw upon a qualitative interview study with 29 health professionals from three jurisdictions where assisted dying is lawful: Flanders, Belgium; Oregon, USA; and Quebec, Canada. Our findings demonstrate that the relationship between palliative sedation and assisted dying is often perceived as fluid and complex. This is inconsistent with current laws as well as with ethical and clinical guidelines according to which the two are categorically distinct. The article contributes to the literature examining health professionals' opinions and experiences. Moreover, our findings inform a discussion about emergent themes: suffering, timing, autonomy and control - which appear central in the wider discourse in which both palliative sedation and assisted dying are situated, and which in turn relate to the wider ideas about what constitutes a 'good death'.

The impact of poverty and deprivation at the end of life: a critical review.

This critical review interrogates what we know about how poverty and deprivation impact people at the end of life and what more we need to uncover. While we know that people in economically resource-rich countries who experience poverty and deprivation over the life course are likely to die younger, with increased co-morbidities, palliative care researchers are beginning to establish a full picture of the disproportionate impact of poverty on how, when and where we die. This is something the Covid-19 pandemic has further illustrated. Our article uses a critical social science lens to investigate an eclectic range of literature addressing health inequities and is focused on poverty and deprivation at the end of life. Our aim was to see if we could shed new light on the myriad ways in which experiences of poverty shape the end of people's lives. We start by exploring the definitions and language of poverty while acknowledging the multiple intersecting identities that produce privilege. We then discuss poverty and deprivation as a context for the nature of palliative care need and overall end-of-life circumstances. In particular, we explore: total pain; choice at the end of life; access to palliative care; and family caregiving. Overall, we argue that in addressing the effects of poverty and deprivation on end-of-life experiences, there is a need to recognise not just socio-economic injustice but also cultural and symbolic injustice. Too often, a deficit-based approach is adopted which both 'Others' those living with poverty and renders invisible the strategies and resilience they develop to support themselves, their families and communities. We conclude with some recommendations for future research, highlighting in particular the need to amplify the voices of people with lived experience of poverty regarding palliative and end-of-life care.

Assisted dying and palliative care in three jurisdictions: Flanders, Oregon, and Quebec.

BACKGROUND: An increasing number of jurisdictions around the world are legalizing assisted dying. This creates a particular challenge for the field of palliative care, which often precludes producing premature death by the injection or self-administration of lethal medications upon a patient's voluntary request. A 2019 systematic scoping review of the literature about the relationship between palliative care and assisted dying in contexts where assisted dying is lawful, found just 16 relevant studies that included varied and combined stances ranging from complete opposition, to collaboration and integration. Building on that review, the present study was conducted in Quebec (Canada), Flanders (Belgium), and Oregon (USA), with the objective of exploring the relationship between palliative care and assisted dying in these settings, from the perspective of clinicians and other professionals involved in the practice. METHODS: Semi-structured in-depth qualitative interviews were conducted with 29 professionals from Oregon [10], Quebec [9] and Flanders [10]. Participants were involved in the development of policy, management, or delivery of end of life care services in each of the jurisdictions. Data was analyzed thematically and followed a procedure of data immersion, and the construction of a thematic and interpretive account. RESULTS: Three themes were identified from each of the locations. Flanders: the integrated approach; discontents in palliative care; concerns about liberalization of assisted dying laws. Oregon: the role of hospice; non-standardized protocols and policies; concerns about access to medications and care. Quebec: a contested relationship; the special situation of independent hospice; lack of knowledge about and access to palliative care. CONCLUSIONS: No clear and uniform relationship between palliative care and assisted dying can be identified in any of the three locations. The context and practicalities of how assisted dying is being implemented alongside access to palliative care need to be considered to inform future laws. We seek a better understanding of whether and in what ways assisted dying presents a threat to palliative care.

A critical rejoinder to "Life's End: Ethnographic Perspectives".

This article stands as a response to Goodwin-Hawkins and Dawson's (2018) article "Life's End: Ethnographic Perspectives" which was published in this journal as an Introduction to a Special Issue of ethnographies about end of life. We address three interwoven fallacies promoted in "Life's End." First, we begin by challenging the authors' central contention that there is no "rigorous body of anthropological work on the issue of dying." We then problematize the authors' conflation of anthropology and ethnography. Finally, we deconstruct their argument that there is an "anthropological aversion" to the study of dying stemming from the inherent "intimacy" of ethnographic methods, as well as their assumption that there is something uniquely emotionally challenging about studying dying. We argue that in framing their Introduction to ethnographies of dying as largely one of absence, Goodwin-Hawkins and Dawson ignore a rich history and diversity of research. In challenging the authors' obfuscation of our subdiscipline, we offer as a corrective a wide range of examples taken from a substantive canon of ethnographic research spanning almost 70 years. We conclude with a broader call for slow academia to ensure that important scholarly contributions are not erased from memory and history rewritten.

What is the cultural value of dying in an era of assisted dying?

Assisted dying is now a lawful and integral component of many societies 'death system', orienting individual and collective encounters with death and dying. While only a very small number of people living with terminal illness in these societies will opt for an assisted death, the choice, nevertheless, exists for those who satisfy the legal criteria. Theoretically, in these jurisdictions, this turns dying into an optional part of the human life cycle; a final phase of life that, until now, seemed a universal feature of life except in instances of sudden death. As anthropologists specialising in death and dying, we pose the question of how the various cultural scripts that have sought to give meaning to dying in post-industrial Western societies since the mid-20th century might be affected by the advent of assisted dying. We begin by building on both medical and social science literature to construct a working definition of 'dying'. We then identify four dominant cultural scripts: psychological growth, preparation for death, the suffering experience and the caring experience. After outlining each script, we discuss how it may (or may not) be affected by the increase in assisted dying legislation. We propose that it is the 'caring' script; the notion of affective, intergenerational bonds created through the experience of caring for people specifically in the last few months or weeks of their life, which are likely to be most affected. However, we find that access to these cultural scripts is already limited because of the widespread reluctance to recognise and name 'dying', and the challenges of doing so. Consequently, the various cultural scripts we identify are negated not by the increase in assisted dying, but rather by a combination of medical advances and institutional orthodoxies which limit opportunity for people to experience themselves, or others, as 'dying'.

The Relationship of Palliative Care With Assisted Dying Where Assisted Dying is Lawful: A Systematic Scoping Review of the Literature.

CONTEXT: A central approach of palliative care has been to provide holistic care for people who are dying, terminally ill, or facing life-limiting illnesses while neither hastening nor postponing death. Assisted dying laws allow eligible individuals to receive medically administered or self-administered medication from a health provider to end their life. The implementation of these laws in a growing number of jurisdictions therefore poses certain challenges for palliative care. OBJECTIVES: To analyze the research literature about the relationship of assisted dying with palliative care, in countries where it is lawful. METHODS: A five-stage scoping review process was adapted from the Joanna Briggs Institute. Data sources searched through October 2018 were MEDLINE, CINAHL, PsychINFO, SCOPUS, and ProQuest dissertations and theses, with additional material identified through hand searching. Research studies of any design were included, but editorials or opinion articles were excluded. RESULTS: After reviewing 5778 references from searches, 105 were subject to full-text review. About 16 studies were included: from Belgium (n = 4), Canada (n = 1), Switzerland (n = 2), and the U.S. (n = 9). We found that the relationship between assisted dying and palliative care practices in these locations took varied and sometimes combined forms: supportive, neutral, coexisting, not mutually exclusive, integrated, synergistic, cooperative, collaborative, opposed, ambivalent, and conflicted. CONCLUSION: The studies in this review cast only partial light on challenges faced by palliative care when assisted dying is legal. There is pressing need for more research on the involvement of palliative care in the developing practices of assisted dying, across a growing number of jurisdictions.

A moment for compassion: emerging rhetorics in end-of-life care.

Compassion is an emotional response to the suffering of others. Once felt, it entails subsequent action to ameliorate their suffering. Recently, 'compassion' has become the flagship concept to be fostered in the delivery of end-of-life care, and a rallying call for social action and public health intervention. In this paper, we examine the emerging rhetorics of compassion as they relate to end-of-life care and offer a critique of the expanding discourse around it. We argue that, even where individuals 'possess' compassion or are 'trained' in it, there are difficulties for compassion to flow freely, particularly within Western society. This relates to specific sociopolitical structural factors that include the sense of privacy and individualism in modern industrialised countries, highly professionalised closed health systems, anxiety about litigation on health and safety grounds, and a context of suspicion and mistrust within the global political scenario. We must then ask ourselves whether compassion can be created intentionally, without paying attention to the structural aspects of society. One consequence of globalisation is that countries in the global South are rapidly trying to embrace the features of modernity adopted by the global North. We argue that unrealistic assumptions have been made about the role of compassion in end-of-life care and these idealist aspirations must be tempered by a more structural assessment of potential. Compassion that is not tied to to realistic action runs the risk of becoming empty rhetoric.

Interventions at the end of life - a taxonomy for 'overlapping consensus'.

Context: Around the world there is increasing interest in end of life issues. An unprecedented number of people dying in future decades will put new strains on families, communities, services and governments.  It will also have implications for representations of death and dying within society and for the overall orientation of health and social care. What interventions are emerging in the face of these challenges? Methods: We conceptualize a comprehensive taxonomy of interventions, defined as 'organized responses to end of life issues'. Findings: We classify the range of end of life interventions into 10 substantive categories: policy, advocacy, educational, ethico-legal, service, clinical, research, cultural, intangible, self-determined. We distinguish between two empirical aspects of any end of life intervention: the 'locus' refers to the space or spaces in which it is situated; the 'focus' captures its distinct character and purpose. We also contend that end of life interventions can be seen conceptually in two ways - as 'frames' (organized responses that primarily construct a shared understanding of an end of life issue) or as 'instruments' (organized responses that assume a shared understanding and then move to act in that context). Conclusions: Our taxonomy opens up the debate about end of life interventions in new ways to provide protagonists, activists, policy makers, clinicians, researchers and educators with a comprehensive framework in which to place their endeavours and more effectively to assess their efficacy. Following the inspiration of political philosopher John Rawls, we seek to foster an 'overlapping consensus' on how interventions at the end of life can be construed, understood and assessed.

Assisted Suicide as a Remedy for Suffering? The End-of-Life Preferences of British "Suicide Tourists".

The highly charged debate about the moral status of assisted suicide features regularly in the news media in medically advanced countries. In the United Kingdom, the debate has been dominated in recent years by a new mode of death: assisted suicide in Switzerland, so-called suicide tourism. Drawing on in-depth interviews with people who were actively planning on 'going to Switzerland,' alongside participant-observation at a do-it-yourself self-deliverance workshop, I discuss how participants arrived at their decision to seek professionalized assistance. In doing so, I explore the constituent elements of people's suffering, examining how participants justified, rationalized, or sought authentication from a doctor for their decision to die in light of their own belief systems and aesthetic preferences for a good death.

Awareness contexts revisited: indeterminacy in initiating discussions at the end-of-life.

AIMS: To explore if and how information about a transition to a palliative care approach was communicated to patients recently discharged from hospital and who fulfilled standardized criteria for palliative care need. BACKGROUND: Palliative care philosophy and, more recently, UK palliative care policy, endorse a context of 'open' awareness, where all parties openly acknowledge that the patient's death is approaching. The perceived benefits of making the patient aware of their prognosis encompass a variety of planning activities, which mean that death, when it occurs, is arguably more in keeping with the wishes of the patient. DESIGN: A qualitative inductive interview study conducted in 2010-2011. METHODS: Fifteen semi-structured interviews were conducted with 15 patients and 3 family carers. All patients were identified as having palliative care needs according to standardized criteria, 3-6 months after discharge from hospital. A thematic analysis was undertaken. FINDINGS: Contrary to the professed ideal of 'open' awareness, some participants were only partially aware and others wholly unaware that they were likely to be approaching the end-of-life. Those identified as unaware were over 85. Participants displayed a reluctance to acquire knowledge which would require them to face the imminence of death. CONCLUSION: Philosophy and policy aside, people do not always conform to the autonomy paradigm of a self-directed life followed by a self-directed death.

The nature of, and reasons for, 'inappropriate' hospitalisations among patients with palliative care needs: a qualitative exploration of the views of generalist palliative care providers.

BACKGROUND: Recent studies have concluded that there is significant potential to reduce the extent of 'inappropriate' hospitalisations among patients with palliative care needs. However, the nature of, and reasons for, inappropriate hospitalisations within a palliative care context is under-explored. AIM: To explore the opinions of 'generalist' palliative care providers regarding the nature of, and reasons for, inappropriate admissions among hospital inpatients with palliative care needs. DESIGN: Qualitative study with data collected via individual interviews and focus groups. SETTING/PARTICIPANTS: Participants (n = 41) comprised 'generalist' palliative care providers working in acute hospital and community settings. SETTING: One District Health Board in an urban area of New Zealand. RESULTS: The majority of participants discussed 'appropriateness' in relation to their own understanding of a good death, which typically involved care being delivered in a 'homely' environment, from known people. Differing attitudes among cultural groups were also evident. The following reasons for inappropriate admissions were identified: family carers being unable to cope, the 'rescue culture' of modern medicine, the financing and availability of community services and practice within aged residential care. CONCLUSIONS: On the basis of our findings, we recommend a shift to the term 'potentially avoidable' admission rather than 'inappropriate admission'. We also identify an urgent need for debate regarding the role of the acute hospital within a palliative care context. Interventions to reduce hospital admissions within this population must target societal understandings of death and dying within the context of medicalisation, as well as take into account cultural and ethnic diversity in attitudes, if they are to be successful.

Exploring education and training needs among the palliative care workforce.

OBJECTIVES: Education and training are seen as 'absolutely essential parts of providing palliative care'. As part of a larger study to explore the extent of palliative care need in two acute hospital settings, we report the perceptions of healthcare professionals regarding their training and educational needs. METHODS: In Phase 1, we undertook eight focus groups and four individual interviews with 58 health professionals from general practice, specialist palliative care and acute hospitals, exploring perceived education and training priorities. Phase 2 of the study involved a survey of palliative care need at two hospitals in England. Hospital based doctors and nurses completed questionnaires to identify patients with palliative care needs and to respond to questions about their training and education needs. RESULTS: Various barriers exist to the provision and management of palliative care, not least a need for more education and training. Focus group participants felt they were not adequately trained to address prognosis and goals of care with patients and their families. In Phase 2 of the study, 171 nursing staff and 81 medical staff completed the questionnaire and two-thirds of our sample felt they required additional training in palliative care. CONCLUSIONS: Although important, the use of standardised care pathways alongside the provision of education and training for healthcare professionals alone will not improve quality of care. More work is needed to examine and clarify the interplay of: behaviour change, setting, the 'cure' orientation approach, type of health professional and nature of any educational intervention in order to effect sustained behavioural change.

Fatigue and beyond: patterns of and motivations for illicit drug use among long-haul truck drivers.

OBJECTIVES: The present study aimed to investigate the illicit drug use patterns of long-distance truck drivers. This population is considered to be a special interest group in terms of drug-driving research and policy due to high rates of use, involvement of drugs in truck accidents, and the link between drug use and work-related fatigue. METHODS: Qualitative interview data were collected from 35 long-haul truck drivers in Southeast Queensland and analyzed through grounded theory techniques. Interviews were conducted at truck stops and loading facilities in both metropolitan and regional cites throughout Queensland. RESULTS: High rates of licit and illicit drug use (particularly amphetamines) were reported by the majority of the sample. However, unlike previous studies that focus on fatigue, this research found overlapping and changing motivations for drug use during individual lifetimes. Becker's model of a drug use "career" was utilized to reveal that some drivers begin illicit drug use before they commence truck driving. As well as fatigue, powerful motives such as peer pressure, wanting to fit the trucking "image," socialization, relaxation, and addiction were also reported as contributing factors to self-reported drug driving. CONCLUSIONS: The results indicate that these additional social factors may need to be considered and incorporated with fatigue factors when developing effective drug prevention or cessation policies for truck drivers.

GW433908/ritonavir once daily in antiretroviral therapy-naive HIV-infected patients: absence of protease resistance at 48 weeks.

OBJECTIVES: To investigate the emergence of resistance to GW433908 (908), a protease inhibitor (PI) with demonstrated antiviral efficacy, safety and tolerability, when administered once daily (q.d.) with low dose ritonavir (908/r). DESIGN: A 48-week Phase III open-label study (SOLO, APV30002) in which antiretroviral therapy-naive patients (n = 649) were treated with 908/r, (1400 mg/200 mg, q.d.) or nelfinavir [1250 mg, twice daily (b.i.d.)] with two nucleoside reverse transcriptase inhibitors (NRTI), abacavir (300 mg, b.i.d.) and lamivudine (150 mg, b.i.d.). METHODS: Viral genotype and phenotype were analysed at baseline and on treatment up to 48 weeks and beyond. RESULTS: Emergence of genotypic resistance was significantly different between the 908/r q.d. and the nelfinavir b.i.d. treatment arms for both PIs (0 versus 50%; P < 0.001) and the NRTI (13% versus 69%; P < 0.001) received. In the nelfinavir arm the key protease mutations D30N and/or L90M were frequently observed. The absence of protease resistance mutations and reduced incidence of NRTI resistance mutations in the 908/r q.d. arm was confirmed by phenotyping, which showed a lack of PI cross-resistance. CONCLUSIONS: The absence of resistance to 908 or cross-resistance to other PIs, and reduced NRTI resistance, following a 908/r q.d. regimen supports the use of this boosted PI early in therapy.

HIV-1 reverse transcriptase and protease resistance mutations selected during 16-72 weeks of therapy in isolates from antiretroviral therapy-experienced patients receiving abacavir/efavirenz/amprenavir in the CNA2007 study.

OBJECTIVE: To determine HIV-1 reverse transcriptase (RT) and protease (PRO) mutations selected in isolates from antiretroviral therapy (ART)-experienced patients receiving an efavirenz/abacavir/amprenavir salvage regimen. METHODS: Open-label, single arm of abacavir, 300 mg twice daily, amprenavir, 1200 mg twice daily and efavirenz, 600 mg once daily, in ART-experienced patients of which 42% were non-nucleoside reverse transcriptase inhibitor-naive. The virology population examined consisted of all patients who took at least 16 weeks of study drugs (n=74). Plasma population sequencing was carried out at baseline and last time point at which patients were still taking the three study drugs + other ART. The median follow-up was 48 weeks (range week 16-72). RESULTS: Baseline (n=73) and on-therapy (n=49) genotypes were obtained. By 48 weeks, 51% of isolates had > or = 3 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations. NNRTI mutations selected on therapy were K103N (51%), substitutions at position 190 (17/49, 35%): G to A (n=11) / S (n=4) / E (n=1) and T (n=1); L100I (37%) and V1081 (20%) mutations. P225H was not observed in this study. L100I and G190A/S/E/T mutations were rarely detected in the same viral population and baseline Y181C favoured the G190 mutations (OR=8.9, P<0.001), rather than the L100I. The NRTI mutations selected were in accordance with abacavir known resistance profile, no new TAMs were observed, new L74V or I mutations developed in 39 and 16% of isolates, respectively, however, new M184V mutations were only detected in isolates from two patients, one of whom had added lamivudine + didanosine. M184V was common at baseline (55%) and maintained in 22/27 (81%) isolates (five of these 22 added lamivudine or didanosine, or both). The PRO mutations selected were in accordance with the distinct resistance profile of amprenavir compared with other protease inhibitors. Mutations D30N, G48V, N88D/S, L90M and 154V were de-selected, and mutations I50V, I or V to 54M/L, I84V, M46I/L, L33F, I47V as well mutations at position 10 were observed in 20/49 (41%) isolates. CONCLUSION: Prior NNRTI and NRTI therapy influences the pathway of resistance to efavirenz. In this study, the prevalence of mutations selected by efavirenz were different from those described in less ART-experienced patients. Baseline Y181C was associated with the development of mutations at position 190, but not L100I or K103N. In this patient population, abacavir with efavirenz preferentially selected for L74V but not for thymidine analogue mutations. M184V was rarely selected and was maintained in only 77% of patients who did not add lamivudine or didanosine. Finally, amprenavir-specific mutations were selected in the background of other primary protease inhibitor mutations, confirming the distinct resistance profile of amprenavir.

Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro.

Human immunodeficiency virus type 1 (HIV-1) Gag protease cleavage sites (CS) undergo sequence changes during the development of resistance to several protease inhibitors (PIs). We have analyzed the association of sequence variation at the p7/p1 and p1/p6 CS in conjunction with amprenavir (APV)-specific protease mutations following PI combination therapy with APV. Querying a central resistance data repository resulted in the detection of significant associations (P < 0.001) between the presence of APV protease signature mutations and Gag L449F (p1/p6 LP1'F) and P453L (p1/p6 PP5'L) CS changes. In population-based sequence analyses the I50V mutant was invariably linked to either L449F or P453L. Clonal analysis revealed that both CS mutations were never present in the same genome. Sequential plasma samples from one patient revealed a transition from I50V M46L P453L viruses at early time points to I50V M46I L449F viruses in later samples. Various combinations of the protease and Gag mutations were introduced into the HXB2 laboratory strain of HIV-1. In both single- and multiple-cycle assay systems and in the context of I50V, the L449F and P453L changes consistently increased the 50% inhibitory concentration of APV, while the CS changes alone had no measurable effect on inhibitor sensitivity. The decreased in vitro fitness of the I50V mutant was only partially improved by addition of either CS change (I50V M46I L449F mutant replicative capacity approximately 16% of that of wild-type virus). Western blot analysis of Pr55 Gag precursor cleavage products from infected-cell cultures indicated accumulation of uncleaved Gag p1-p6 in all I50V viruses without coexisting CS changes. Purified I50V protease catalyzed cleavage of decapeptides incorporating the L449F or P453L change 10-fold and 22-fold more efficiently than cleavage of the wild-type substrate, respectively. HIV-1 protease CS changes are selected during PI therapy and can have effects on both viral fitness and phenotypic resistance to PIs.