Arnaud Buchs
email: arnaud.buchs@sciencespo-grenoble.fr

Iratxe Calvo-Mendieta
email: iratxe.calvo-mendieta@univ-littoral.fr

Olivier Petit
email: olivier.petit@univ-artois.fr

Philippe Roman
email: philippe.roman@ichec.be

Challenging the Ecological Economics of Water: Social and political perspectives

Keywords: water policy, interdisciplinarity, ecological economics of water, research agenda

This paper introduces the special section entitled 'Ecological Economics of Water: social and political perspectives', which brings together articles published in successive issues of the journal in 2020 and 2021. By discussing the literature, we review contemporary issues and controversies surrounding water management and water policies to highlight the importance of the social and political dimensions that an ecological economics of water should address. We promote comprehensive and reflective approaches that consider seriously institutions and institutional change, e.g. to discuss the role of water-related indicators in water policies. We demonstrate the relevance of this special section that come after two water-related special issues already published in Ecological Economics. Finally, we introduce each of the articles of this special section, which we believe can help shape a new avenue of research among ecological economists of water.

1. Contemporary issues and controversies in water governance: why do socio-political dimensions matter?

Over the last decades, controversies about water management have abounded. They were fuelled both by real-world events and trends (privatization of water supply services in several cities all around the world, water 'wars' over who governs water treatment and supply and for whom, implementation of water markets, etc.), by institutional discussions (water as an 'economic good' or as a human right, etc.) and by scientific progress (performance indicators of water supply services, neoinstitutional analyses of 'optimal' water governance, etc.). Some of the hottest topics regarding water management remain the same today as the ones that prevailed by the end of the 20 th century: is water an economic good? Should it be managed accordingly and what does it mean? What is the best mix of market and non-market policy tools? Is there (still) a place (and in what circumstances?) for big hydraulic infrastructure development? Should demand-side management be always promoted first? etc. Similarly, questions about valuation are still alive: should economics value water with 'standard' 2 economic valuation tools (hedonic valuation, travel cost method, contingent valuation, etc.)? Should any monetary valuation ever be made? Such crucial issues are still open to debate and we argue that ecological economists could make a difference in stepping into the conversation and in emphasizing socio-political dimensions. Such discussions are developed in the journal Ecological Economics since three decades and can be enriched from a cross-disciplinary dialogue with other fields of study, as done by [START_REF] Kallis | To value or not to value? That is not the question[END_REF] who have developed such a dialogue with Political Ecology.

Water crises are looming large

Water issues have been widely put to the fore in the scientific and policymaking arenas over the last decades. Water crises have been looming increasingly large, and they are currently recognized as one of the main threats to human development and security, not least for business (World Economic Forum, 2015). As environmental factors become increasingly important among the top risks reported in the Global Risk Report 2020, the 'water crises' item consistently ranks high. And no doubt that water issues, among which water stress, will only be accentuated with climate change. This is therefore no surprise that two of the 17 UN Sustainable Development Goals (SDG) are devoted to water (goal 6 on clean water and sanitation and goal 14 on life below water).

Several disciplines needed to document these crises

A steadily growing body of work has documented these current and future water crises and put various management issues into question [START_REF] Allouche | The water-food-energy nexus. Power, politics and Justice[END_REF][START_REF] Boelens | Water Justice[END_REF]La Jeunesse and Larrue, 2019;Dumont et al., 2021, among many others). Beyond hydrology, (hydro)geology and other natural sciences, several disciplines have helped characterize the multifaceted water scarcity and water crises: environmental history [START_REF] Paavola | Water Quality as Property: Industrial Water Pollution and Common Law in the Nineteenth Century United States[END_REF], environmental sociology [START_REF] Poupeau | The making of water policy in the American southwest: Environmental sociology and its tools[END_REF], political ecology [START_REF] Boelens | Hydrosocial territories: a political ecology perspective[END_REF], critical geography (Norman et al., 2015), gender studies [START_REF] Ahlers | The water question in feminism: Water control and gender inequities in a neo-liberal era[END_REF], (water) economics [START_REF] Garrick | Rethinking the economics of water: an assessment[END_REF], environmental economics [START_REF] Garrick | Valuing water for sustainable development[END_REF] and ecological economics [START_REF] Brouwer | Integrated Hydro-economic modelling: Approaches, key issues and future research directions[END_REF][START_REF] Calvo-Mendieta | Common Patrimony: A Concept to Analyze Collective Natural Resource Management. The Case of Water Management in France[END_REF] among many others. Critical approaches, mainly in the social sciences, have significantly contributed in understanding of the topic: unveiling the power asymmetries that very often lie behind scarcity and crises; describing in a fine-grained fashion the variegated actors and logics that induce and produce scarcity and crises; identifying those who predominantly bear the burden of scarcity and crises. Such issues have thus been, to a large extent, denaturalized and replaced into their socio-political context [START_REF] Mollinga | Knowledge, context and problemsheds: a critical realist method interdisciplinary water studies[END_REF].

Political and intellectual controversies are still alive

At a more normative level, multi-level, decentralized and polycentric governance have been advocated [START_REF] Pahl-Wostl | A conceptual framework for analysing adaptive capacity and multi-level learning processes in resource governance regimes[END_REF], especially when water is considered as a common pool resource [START_REF] Villamayor-Tomas | Polycentricity in the water-energy nexus: A comparison of polycentric governance traits and implications for adaptive capacity of water user associations in Spain[END_REF]. According to some water experts, great leaps forward have been made at the policy level with the recognition of water as an economic good [START_REF] Rogers | Water is an economic good: How to use prices to promote equity, efficiency, and sustainability[END_REF] and as a human right [START_REF] Salman | The Human Right to Water: Legal and Policy Dimensions[END_REF], and more integrated and participative management practices have been advocated around the globe. By the end of the 20 th century, Integrated Water Resources Management (IWRM) has taken precedence over state-led water management [START_REF] Biswas | Integrated Water Resources Management: A Reassessment[END_REF][START_REF] Merrey | Integrating ''livelihoods'' into integrated water resources management: taking the integration paradigm to its logical next step for developing countries[END_REF][START_REF] Medema | From premise to practice: a critical assessment of integrated water resources management and adaptive management approaches in the water sector[END_REF][START_REF] Petit | Integrated Water Resources Management: From General Principles to its Implementation by the State. The case of Burkina Faso[END_REF].

But decades of reform of the water agenda have not delivered good quality nor sufficient quantity to all those in need (UN Water, 2020). So, there is no 'end of history' in water management. The field is probably as lively, evolving, and fraught with controversies as three decades ago. Management fads like IWRM or the 'nexus' approaches have come to be challenged, both by practitioners and by scientists (see recent debates in Water Alternatives Forum, 20201 ). This enduring and heated debate does include the social sciences, but probably too little. Similarly, some ecological economists have taken part in these debates, but arguably in a pretty infrequent and sparse fashion. And we argue that their contribution has seldom relied on approaches rooted in the social sciences. This begs a critical question regarding the current situation: given the broadly acknowledged fact that social sciences could (and some say, should) have played a greater role in these debates and that power and inequality issues have been sidelined in favour of technocratic methodologies, the need for an ecological economic approach investigating the social and political dimensions of water management is certainly of peculiar relevance now.

As a matter of fact, big questions regarding water management and water crises are far from being settled. The very nature, or ontology, of water, has fuelled heated debates: is it a basic good? A human right? A common good? All these dimensions at the same time? Socio-political struggles on the ground ('luchas por el agua', battles against water commodification, privately managed water services, enclosures or water grabbing, etc., in developing as well as developed countries) have, to a certain extent, mirrored academic debates on the scope and limits of water markets and private water services [START_REF] Meinzen-Dick | Beyond panaceas in water institutions[END_REF][START_REF] Bel | Is private production of public services cheaper than public production? A meta-regression analysis of solid waste and water services[END_REF][START_REF] Grafton | On the Marketisation of Water: Evidence from the Murray-Darling Basin, Australia[END_REF][START_REF] Mcdonald | The New Water Wars: Struggles for Remunicipalisation[END_REF][START_REF] Garrick | Rethinking the economics of water: an assessment[END_REF][START_REF] Marques | Revisiting the Comparison of Public and Private Water Service Provision: An Empirical Study in Portugal[END_REF].

'Valuations are always with us' [START_REF] Myrdal | Institutional Economics[END_REF] Valuation issues are still generating lively debates [START_REF] Garrick | Valuing water for sustainable development[END_REF]. How should the environment be valued? Since the seminal paper by [START_REF] Costanza | The value of the world's ecosystem services and natural capital[END_REF] and the subsequent debates about the economic valuation of ecosystem services (ES) or the effectiveness of payments for ecosystem services (PES), most questions posed then remain today: links between ES and human well-being, importance of governance dynamics, equity and justice issues, etc. Value and valuation methods are still largely discussed and debated: should valuation be limited to monetary valuation? Should we use more qualitative and multi-criteria methods? What are the most satisfactory participatory dynamics? Debates in ecological economics, even if they have not reached a unified explanatory framework, have contributed to a more integrated approach to ecological valuation and valuation of damages, risks and services.

The institutions of water management have also sparked a great amount of research and controversy, while fashionable concepts and policy frameworks followed each other. While the widely adopted Integrated Water Resources Management (IWRM) approach has proved versatile and has delivered limited results [START_REF] Tortajada | The rapidly changing global water management landscape[END_REF], what are the current alternatives? The 'nexus' approach (the 'water-energy-food nexus' most notably) has recently gained currency in academic and policy circles with its focus on interrelatedness of issues and its capacity to go beyond the river basin and beyond 'water' as the overarching actor. It has been praised for being more coherent than the IWRM paradigm [START_REF] Muller | The 'nexus' as a step back towards a more coherent water resource management paradigm[END_REF] but it has also proved problematic and short of expectations: little real transdisciplinary work and policies have been implemented under the heading of the nexus, and of notable relevance for the present paper, over-reliance on quantitative tools and little use of social science methods have been recorded [START_REF] Albrecht | The Water-Energy-Food Nexus: a systematic review of methods for nexus assessment[END_REF]. This certainly makes room for ecological economists stepping into the debate. Similar shortage of social science inputs/insights has been highlighted regarding 'environmental flows' [START_REF] Anderson | Understanding rivers and their social relations: A critical step to advance environmental water management[END_REF]. By the way, the whole practice of determining environmental flows is challenged as they are most often determined in a technocratic top-down way, raising concerns about whose interests such guaranteed flows serve. While it had been widely considered common knowledge and good practice that the most appropriate scale of analysis and action was river basin, such popular belief has also been put under critical scrutiny over the last decades [START_REF] Waterbury | Between unilateralism and comprehensive accords: Modest steps toward cooperation in international river basins[END_REF][START_REF] Graefe | River Basins as new Environmental Regions? The depolitization of water management[END_REF]Norman et al., 2015). Rather than a silver bullet to water management, this has proven a complex institutional journey with sizeable amounts of failure (see, e.g., [START_REF] Abers | Practical Authority. Agency and Institutional Change in Brazilian Water Politics[END_REF].

The impetus for and fate of such concepts as IWRM and the nexus testify to the need to find integrative approaches to complex, context-specific water issues that can offer transdisciplinary guidance. In this respect, we believe ecological economics has a role to play. Numerous limitations relative to most currently implemented and worked out frameworks point to a lack of recognition of plural interests and values, or overly technocratic, deterministic and positivist stances [START_REF] Mollinga | Knowledge, context and problemsheds: a critical realist method interdisciplinary water studies[END_REF][START_REF] Kellner | The controversial debate on the role of water reservoirs in reducing water scarcity[END_REF]. These concerns straightforwardly echo some of the guiding principles of ecological economics like value pluralism and incommensurability, post-normal science or participative deliberation.

New approaches and their limitations

While water controversies have kept on running along old issues and new fads, the water research field has also been seized 'from the outside' by new concepts, theories and narratives. Among them, naturebased solutions, planetary boundaries and the circular economy stand out as dominant frameworks. We argue that they would benefit from strengthening their socio-political outlook too.

'Working with nature', 'innovating with nature', 'renaturing cities', 'nature-positive business solutions'… the concept of 'nature-based solutions' (NBSs) has emerged in the 2010s to address global challenges such as climate change, human well-being and biodiversity, while enhancing synergies among the SDGs [START_REF] Seddon | Grounding nature-based climate solutions in sound biodiversity science[END_REF](Seddon et al., , 2020b)). For water resources, NBSs are increasingly seen as innovative and lowcost alternatives to tackle these challenges, while generating multiple benefits (UN Water, 2018;[START_REF] Nika | Nature-based solutions as enablers of circularity in water systems: A review on assessment methodologies, tools and indicators[END_REF]. Even though the European Commission and the UN are promoting the concept and funding research, NBSs remain underdefined [START_REF] Krauze | From classical water-ecosystem theories to nature-based solutions -Contextualizing nature-based solutions for sustainable city[END_REF]). EU's definition ('solutions that are inspired and supported by nature, which are cost-effective, simultaneously provide environmental, social and economic benefits and help build resilience. Such solutions bring more, and more diverse, nature and natural features and processes into cities, landscapes and seascapes, through locally adapted, resource-efficient and systemic interventions') seems to suffer from the same weaknesses as the concept of sustainable development [START_REF] Lélé | Sustainable Development: A Critical Review[END_REF]. Focusing on objectives and aims, concrete criteria are missing and this leaves ample room for interpretation. If some authors see NBSs as the opportunity to 'refocu[s] solutions from technological strategies to socio-ecological principles such as human well-being and community-based governance models' [START_REF] Gulsrud | Innovative urban forestry governance in Melbourne?: Investigating "green placemaking" as a nature-based solution[END_REF]), EU's ambition is 'to invest in nature and nature-based solutions which can deliver new products and services (…) to stimulate a market for nature-based solutions' [START_REF] De Boissezon | European Commission (Head of Unit 'Sustainable Management of Natural Resources' -DG RTD 'Climate Action and Resource Efficiency' Directorate)[END_REF]. The risk of continuing to do business as usual with new packaging seems real. If NBS are sometimes seen as 'undisputable answers to challenged urban landscapes and societies globally' [START_REF] Lafortezza | Nature-based solutions: Settling the issue of sustainable urbanization[END_REF], it seems necessary to clarify the concept (Gómez-Martin et al., 2020;[START_REF] Bridgewater | Whose nature? What solutions? Linking Ecohydrology to Nature-based solutions[END_REF]. Recent research shows that trade-offs and negative effects can be important [START_REF] Lin | Hydro-dam -A nature-based solution or an ecological problem: The fate of the Tonlé Sap Lake[END_REF] and that NBSs need key factors to achieve their potential: analysing institutional frameworks, fostering participation and co-creation process, using transdisciplinary approaches [START_REF] Kumar | Towards an operationalisation of nature-based solutions for natural hazards[END_REF][START_REF] Giordano | Enhancing nature-based solutions acceptance through stakeholders' engagement in co-benefits identification and trade-offs analysis[END_REF] or even specific and more important funding [START_REF] Faivre | Nature-based solutions in the EU: innovating with nature to address social, economic and environmental challenges[END_REF]. To avoid perverse effects of NBSs, policies need to be grounded in a holistic approach, with integrated and not sectoralised forms of governance and within an interdisciplinary economic approach (Seddon et al., 2020a).

In recent years, research on 'planetary boundaries' has come to provide the dominant narrative about the state of Planet Earth and its most pressing ecological issues [START_REF] Rockström | A safe operating space for humanity[END_REF]. It has been endorsed by both 'renegade' economists [START_REF] Raworth | Doughnut Economics: Seven Ways to Think Like a 21st-Century Economist[END_REF] and mainstream environmental economists [START_REF] Barbier | Natural Resource Economics, Planetary Boundaries and Strong Sustainability[END_REF]. But concerns have been voiced regarding the potential technocratic and homogenizing content of such a global approach [START_REF] Pickering | Democratising planetary boundaries: experts, social values and deliberative risk evaluation in Earth system governance[END_REF]. Among the nine identified planetary boundaries, 'water' is arguably the one that fuelled greatest controversy [START_REF] Heistermann | A planetary boundary on freshwater use is misleading[END_REF], which prompted boundaries scholars to revise the framework [START_REF] Gleeson | The Water Planetary Boundary: Interrogation and Revision[END_REF]. Adapting water planetary boundaries to regional and local scales is a highly challenging issue [START_REF] Zipper | Integrating the Water Planetary Boundary With Water Management From Local to Global Scales[END_REF]. In addition, the concept has been criticized on grounds of political impacts and governance: 'Moving parameters of earth system governance from policy targets to planetary boundaries hence implies a shift in responsibility, and political power, from the policy-maker to the expert' (Biermann and Kim, 2020: 503).

Much more rooted in business practices than in Earth sciences is the circular economy approach. It has recently gained prominence in governmental institutions, business governance and academia thanks to its simple narrative of 'circularizing linear flows' of matter and energy and its relatively operational orientation. But it has also been criticized for its scientific blind spots [START_REF] Korhonen | Circular Economy: The Concept and its Limitations[END_REF] as well as for its technocratic and apolitical leanings [START_REF] Genovese | The Circular Economy at a Crossroads: Technocratic Eco-Modernism or Convivial Technology for Social Revolution?[END_REF]. The framework has been used in the context of water conservation as a win-win approach (see, e.g., [START_REF] Sartal | Bringing the circular economy closer to small and medium enterprises: Improving water circularity without damaging plant productivity[END_REF], which corresponds to the usual narrative around the circular economy (in particular the one promoted by the Ellen McArthur Foundation). Such 'faith' in the benefits of the circular economy has recently been labelled by two prominent ecological economists a 'policy legend' [START_REF] Giampietro | From elite folk science to the policy legend of the circular economy[END_REF].

Current environmental and socio-economic challenges justify the development of an interdisciplinary approach to water politics, considering both lessons from 'hard science' and contributions from critical social science, avoiding narrow economic approaches. To be sure, ecological economics would benefit from stepping aside and looking at what other disciplines have to say about its core topics, among which water scarcity and governance, but at the same time a stronger voice of ecological economists would be of significant value to tackle contemporary issues and controversies in water governance.

2. What place for social and political issues in the ecological economics of water?

How does the journal Ecological Economics address water issues?

This special section is the third topical collection published in Ecological Economics to specifically address water issues. The first special section, published in 2008 and entitled 'Integrated Hydro-Economic Modelling for Effective and Sustainable Water Management' (edited by Roy Brouwer and Marjan Hofkes) postulated that: 'the complexity of interactions between water and the economy can be captured through formal, mathematical models linking relevant hydrological and biogeochemical processes to economic "laws" of supply and demand underlying the provision of scarce water services'. (Brouwer and Hofkes, 2008: 16). The papers selected in this issue develop three types of models: (i) holistic, (ii) modular and (iii) Computable General Equilibrium (CGE), the third type being considered as allowing to capture more precisely the economy-wide impacts of water policy. The social and political dimensions of water were considered as parameters through the baseline and policy scenarios (i.e. structure of water allocation rights, introduction of new water trade systems and the modification of existing economic instruments like water bills, pollution permits, etc.). These dimensions were considered as the context (and the constraints), and constitute one module that interacts with the hydrological system.

The second special section published in Ecological Economics, entitled 'Participation and evaluation for sustainable river basin governance', was edited in 2009 by Paula Antunes, Giorgos Kallis, Nuno Videira and Rui Santos. Like the previous one, the starting point of this special section is also methodological, it identifies gaps that it tries to fill, but its approach is quite different as it affirms the need to develop new multi-dimensional, inclusive and plural approaches to water resource management (ibid: 931).

Here, the pluralism of perspectives (and therefore of values, not limited to economic value) and the complexity of uncertainties imply 'inclusive' governance schemes (ibid: 932). The political dimension of the issues at stake (and of the discourses related to them) is claimed and justifies the use of participation (in the broad sense) to account for divergent interests related to water (private, civil society, government, social movements). The inherent complexity of each system (hydrological cycles and biological systems) is reinforced by the pluralism of values and interests. For example, the influence of plural individual values conditions the scope and meaning of willingness to pay (ibid: 936). From this point of view, the present special section is probably closer to this second special section than to the first one. The integrated dimension conditions the very definition of the objects that are apprehended thanks to a conceptual model articulating three dimensions: process, information and evaluation. These three dimensions are themselves framed by the institutional, political and socio-economic context in which basin governance takes place. A conceptualization of integration is suggested, namely 'Integrated Deliberative Decision Process (IDDP)', which identifies two levels of integration: between the deliberative processes supporting decision-making (three deliberative methods are analysed in the special issue: participatory modelling, deliberative visioning and social multi-criteria); between deliberative activities and the rest of the decision-making process, i.e. 'its non-deliberative political part, or its normal science part' (Antunes et al., 2009: 937).

How should ecological economics of water shed socio-political light on the debates?

By developing pluri-or interdisciplinary approaches crossing several disciplines in humanities and social sciences and natural sciences, or even transdisciplinary approaches at the crossroads of disciplines and citizen knowledge [START_REF] Baumgärtner | Relating the philosophy and practice of ecological economics: The role of concepts, models, and case studies in inter-and transdisciplinary sustainability research[END_REF][START_REF] Borderon | Réflexivité et registres d'interdisciplinarité. Une boussole pour la recherche entre natures et sociétés[END_REF], published research in the field of ecological economics of water is primarily dedicated to management, governance, policy and decisionmaking. This is shown by the content analysis performed in [START_REF] Buchs | Can social ecological economics of water reinforce the 'Big Tent'?[END_REF]: most articles addressing water issues published in the journals Ecological Economics, Environmental Policy and Governance (EPG) and Environmental Values (considered as representative of the field) address these issues (37.1% of the segments of abstracts over a corpus made up of 701 abstracts refer to these issues). It is worth noticing that among the three sources, the journal Ecological Economics is relatively less representative of this type of concern compared to the other two (notably EPG). Ecological Economics is more oriented towards water use issues (especially agriculture water use), monetary valuation and quantitative metrics.

Thus, research in ecological economics seems to be very relevant to feed reflections on the political and social dimensions related to water. We would like to highlight three aspects of this work that we consider relevant and likely to guide future research: comprehensive and reflexive approaches; a critical appraisal of water-related indicators; research that considers institutions seriously.

Promoting comprehensive and reflexive approaches

Decision making presupposes first having a knowledge of phenomena in their complexity. Therefore, the first aspect we wish to emphasise relies upon the relevance of comprehensive and reflexive approaches, i.e. approaches that attempt to propose a post factum explanation (and not only hypothetical, sometimes tautological). For example, for water scarcity, two types of approaches may be distinguished [START_REF] Aguilera-Klink | The social construction of scarcity. The case of water in Tenerife (Canary Islands)[END_REF]: scarcity may be considered as a starting point (i.e. as an exogenous phenomenon, once observed, scarcity is mainly reduced to its physical component) or an arrival point for the analysis. The second type of approach considers that scarcity has geo-physical determinants and is also, to a large extent, a geographically and historically located phenomenon. Preventing and adapting to water scarcity supposes first characterizing and understanding the phenomenon. Here, scarcity is an endogenous and complex phenomenon (articulation between social and physical systems), with a pronounced anthropic dimension, i.e. water scarcity is also a social construct [START_REF] Becker | It never rains in California": Constructions of drought as a natural and social phenomenon[END_REF][START_REF] Buchs | La pénurie en eau est-elle inéluctable ? Une approche institutionnaliste de l'évolution du mode d'usage de l'eau en Espagne et au Maroc[END_REF][START_REF] Buchs | Can social ecological economics of water reinforce the 'Big Tent'?[END_REF].

Influencing public policies requires a critical appraisal of water-related indicators

Numerous papers published in the field of water management are based on the analysis of indicators, as tools aiming at better capturing the issues at stake. While we agree with the importance of measuring stocks and flows, it is important to continue developing a critical appraisal of these indicators, because their interpretation is also the reflection of different -and sometimes opposingways to understand water management issues. Once again, the attempt to quantify water availability and the interpretation of such figures as a problem of water scarcity is not neutral. [START_REF] Beltran | How does virtual water flow in Palestine? A political ecology analysis[END_REF] refer to a political ecology approach to combine an analysis of virtual water flows in Palestine with the power relationships which help explain the socio-political aspects of these flows. More broadly, it is important to keep in mind the necessity to develop a critical appraisal of water-related indicators, since these indicators often contribute to shape policies [START_REF] Molle | Water Poverty Indicators: Conceptual Problems and Policy Issues[END_REF].

Considering institutions seriously

If we wish to enhance a science that, on the one hand, considers the political and social dimensions of water resources and uses, and on the other hand allows us to have a grip on reality to encourage sustainability, it is necessary to take institutions into account seriously. Indeed 'sustainability demands changes in both political and economic institutions' [START_REF] Vatn | Institutions for sustainability-Towards an expanded research program for ecological economics[END_REF].

In this respect, an ecological economics of water should be based on conceptual tools that account for institutional dimensions. Firstly, at the ontological level, characterizing human-environment interactions requires a clear conceptual framework, and we argue the latter should be deeply anchored in institutional thinking. Several relevant approaches can be put to work: the Environmental governance systems (EGS) framework [START_REF] Vatn | Environmental Governance. Institutions, Policies and Actions[END_REF]), Ostrom's IAD and SES frameworks [START_REF] Cole | The Utility of Combining the IAD and SES Frameworks[END_REF], the Institutional resource regimes (IRR) [START_REF] Gerber | Institutional Resource Regimes: Towards sustainability through the combination of property-rights theory and policy analysis[END_REF], the Water use mode [START_REF] Buchs | La pénurie en eau est-elle inéluctable ? Une approche institutionnaliste de l'évolution du mode d'usage de l'eau en Espagne et au Maroc[END_REF] etc. Secondly, there is a theoretical necessity to develop tools that help understand institutional change: how to understand the articulation between behaviours, rules (institutions) and values? What are the relevant levers to shape them in a more sustainable perspective? On this issue, the perspectives differ [START_REF] Hall | Political Science and the Three New Institutionnalisms[END_REF][START_REF] Dimaggio | The New Institutionalisms: Avenue of Collaboration[END_REF][START_REF] Nielsen | Institutionalist Approaches in the Social Sciences: Typology, Dialogue, and Future Challenges[END_REF]: are institutions the result of past power relations as suggested by proponents of an approach based on historical institutionalism (old institutionalism, [START_REF] Dupuy | Analyzing Socio-Environmental Conflicts with a Commonsian Transactional Framework: Application to a Mining Conflict in Peru[END_REF]regulation theory, Zuindeau, 2007)? Are they partially the result of strategic choices, as considered by proponents of rational choice institutionalism (as for New institutional economics, [START_REF] Paavola | Institutional Ecological Economics[END_REF]? Are they fundamentally dependent on values, as for sociological institutionalism [START_REF] Centemeri | Reframing problems of incommensurability in environmental conflicts through pragmatic sociology: from value pluralism to the plurality of modes of engagement with the environment[END_REF] or on habits, following evolutionist approaches [START_REF] Hodgson | Darwinian coevolution of organizations and the environment[END_REF]?

While deciding what option is most relevant according to the topic and context is beyond the scope of the present article, we consider that if it is to be in touch with reality and transformative, an ecological economics of water must be based on an institutional theory.

A mutual enrichment to further develop the theoretical and methodological toolkit of the ecological economics of water

Recent contributions published at the occasion of the 30 th anniversary of the institutionalization of the ecological economics field (mobilizing both the journal and the society) have stressed the necessity to better anchor Ecological Economics in its historical roots and to engage a dialogue with other fields of study which have emerged during the past decades, especially in the social sciences (social ecological systems, commons, degrowth, etc.). Ecological economics, as a field of study, has traditionally been interested in engaging interdisciplinary dialogues with boundary objects and especially 'Grand concepts' [START_REF] Lundgren | The Grand Concepts of Environmental Studies Boundary objects between disciplines and policymakers[END_REF] such as sustainable development, ecosystem services or resilience. In the field of water, other Grand concepts mentioned in the first section of this paper (IWRM, the nexus approaches, and more recently nature-based solutions) need to be mobilized, criticized and overcome by ecological economists. It is all the more important since, according to Wironen and Erickson (2020: 4), 'to date, ecological economics has given less attention to the social and political as opposed to the economic and ecological.' Indeed, these Grand concepts, which are commonly used in the political discourse, must be carefully scrutinized and this is the reason why ecological economists also need to further develop a critical inquiry of water management issues.

Several approaches developed by social scientists can help strengthen a critical inquiry of water management issues in the field of ecological economics. Sources of inspiration can come from specific journals dealing with water management issues (Water Alternatives for instance) or dealing with a wide range of issues, in a critical way, such as Geoforum. Ecological economists should be aware of the evolution of theories, methods and ideas developed in these journals, to enrich their own work. The journal Ecological Economics can also become the locus of new and ground-breaking ideas, methodologies and approaches, just as exemplified in a recent paper published in the journal on rooted water collectives [START_REF] Vos | Rooted Water Collectives. Towards an Analytical Framework[END_REF].

At the same time, ecological economists interested in water resource management should be able to develop a discussion platform to foster dialogue and controversies, between scholars and professionals dealing with water-related issues, within the field of ecological economics and beyond. Opening the theoretical and methodological waterscape can bring new ideas from the fields of political ecology [START_REF] Kallis | To value or not to value? That is not the question[END_REF][START_REF] Linton | The Hydrosocial cycle: defining and mobilizing a relational-dialectical approach to water[END_REF], transboundary water resource management and hydropolitics [START_REF] Zeitoun | Hydro-hegemony: A framework for analysis of transboundary water conflicts[END_REF][START_REF] Zeitoun | Transboundary water interaction I: Reconsidering conflict and cooperation[END_REF], cultural political economy [START_REF] Mollinga | Cultural Political Economy and critical water studies: An introduction to the special themed section[END_REF][START_REF] Ioris | Socioecological economics of water development in the Brazilian Amazon: Elements for a critical reflection[END_REF] in this special section), or socio-hydrology [START_REF] Wesselink | Socio-hydrology and hydrosocial analysis: Toward dialogues across disciplines[END_REF][START_REF] Konar | Expanding the Scope and Foundation of Sociohydrology as the Science of Coupled Human-Water Systems[END_REF].

This double movement -openness to what is happening outside of the field of ecological economics and ability to host controversies within the field and beyond -is, according to us, a necessary step to continue developing political and social issues in water management and thus challenging the ecological economics of water. We remain convinced that a scientific field, such as ecological economics, can only develop and diffuse ground-breaking ideas through a cross-fertilization process.

3. The special section 'Ecological economics of water: social and political perspectives': a brief overview This special section displays common features with the two previous ones presented before. It is related to the collective nature of the issue. This special section follows the session entitled 'Towards an Ecological Economics of Water' the authors of the present paper organized during the ESEE 2017 conference held in Budapest. Among the papers presented there, some succeeded in being published. As this special section is far from covering all the issues (ontological, methodological, theoretical), it is much more the beginning of a discussion than the end of a research cycle. Below, we briefly sketch out the papers published under the umbrella of this special section. Our purpose is to invite the reader to have a closer look at them by stressing the main messages contained in the papers. They are presented chronologically, following their date of publication in the journal.

The first paper by Arnaud Buchs, Olivier Petit and Philippe Roman (2020) takes an introspective look at the water-related literature in ecological economics, addressing the importance of social and political dimensions and questioning the degree of pluralism in this field. On the basis of [START_REF] Spash | The shallow or the deep ecological economics movement?[END_REF] reference typology (which identifies three groups of researchers in the field of ecological economics: 'new resource economists', 'new environmental pragmatists' and 'social ecological economists'), the authors focus on social ecological economics and its imprint in water research. Two methods of content analysis are developed: first, the tenets and limits of Spash's typology are examined using selected papers published in Ecological Economics. Then, the authors perform a textual analysis of a large corpus of articles' abstracts in the fields of i) ecological economics and ii) environmental and resource economics. The authors show that, in the field of ecological economics of water, Spash's groups are not easily distinguishable and clear-cut boundaries are difficult to find. Moreover, Ecological Economics appears at the interface between mainstream approaches and more critical ones. An alternative representation of the field is suggested 'in the form of a triangle where each approach constitutes a vertex, and where what distinguishes approaches in pairwise comparisons is (1) the kind of metrics used, (2) the transformative nature of science, and (3) theoretical consistency'. In order to strengthen pluralism within the field of ecological economics of water, the authors provide an overview of what a social ecological economics of water should look like: the ontological particularity of water; value pluralism, power relations; pluralistic, interdisciplinary and reflexive methodology; articulation between theory and field-work.

The second paper [START_REF] Colby | Acquiring environmental flows: ecological economics of policy development in western U[END_REF] focuses on the western US to analyse, from two complementary theoretical approaches (social ecological economics of water and punctuated equilibrium theory), how environmental flows in rivers and aquifers have been addressed by public policy instruments. More specifically, the paper considers the implementation of water markets and applies its analytical framework to two case studies: Edwards Aquifer in Texas and the Colorado River Delta. The analysis highlights the importance of power issues in the implementation of these water markets and emphasizes the importance of recognizing water as a common patrimony [START_REF] Calvo-Mendieta | Common Patrimony: A Concept to Analyze Collective Natural Resource Management. The Case of Water Management in France[END_REF]. In addition, the paper highlights the need to design innovative public policy instruments to consider a variety of competing issues. It proposes to move away from a stigmatizing vision of water markets, sometimes criticized for dogmatic reasons, and offers avenues for the future development of this type of instrument in the western US, as well as in other places around the world.

The diversity of approaches within the 'big tent' of ecological economics may be illustrated by the paper proposed by Sahar Daghagh Yazd, Sarah Ann Wheeler and Alec Zuo [START_REF] Yazd | Understanding the impacts of water scarcity and socioeconomic demographics on farmer mental health in the Murray-Darling Basin[END_REF]. Authors address political and social consequences of climate change and water scarcity through farmer's health in the Murray Darling Basin (Australia), and more particularly their effect on mental health. They model farmers' mental health by merging several databases, including the longitudinal survey 'Household, Income and Labour Dynamics in Australia' (HILDA, 14 waves from 2001 to 2015, period that includes the 'Millennium drought') and various climate and water databases. Climate change impacts the variability of rainfalls, increasing uncertainty over water allocations of farmers. The paper reveals that water scarcity increases psychological distress for Australian farmers, worsening psychological distress already induced by financial difficulties (farmer suicide rates are up to two times higher than the general population's rate). To encourage farmers' resilience to address 'hotter and drier future', the authors suggest that policies must focus on long-term, preventative approaches, rather than current short-term, reactive approaches. These policies may, for example, enhance agro-ecological practices. As livelihood is positively linked to farmer mental health, the authors suggest to secure earnings, by recognising the role of agriculture for the provision of environmental/ecological services. The paper invites to question the relevance of the current ultra-competitive agricultural production system. loris (2020) addresses the issue of development and modernisation in the Brazilian Amazon region through hegemonic water development and dam construction. Doing so, he vindicates the usefulness of a socioecological economics of water: 'Among many positive attributes, socioecological economics can help us to understand the impact of mainstream developmental ideologies and associated discourses, as well as to comprehend the complexity of the interface between economic and morethan-economic practices.' (p. 5) Ioris' specific take on how socioecological economics of water could contribute to understanding water management practices is to put to the fore the ideas of resignification and cultural political economy. In his opinion, more attention should be paid to cultural dimensions, in particular the politics of identity and recognition.

The paper by Özge Can Dogmus and Jonas Østergaard Nielsen on corruption in the hydropower sector in Bosnia and Herzegovina is a good example of how approaches that fall under (integrative) geography or political ecology may address political aspects linked to water policy. As such, this article provides a way to bridge complementary approaches to ecological economics ones. The authors focus on the hydropower boom in Bosnia and Herzegovina, with a particular emphasis on small-scale hydropower plants. They show that most projects were aborted or still remain on paper, some for more than 10 years (in 2017, the number of planned hydropower projects was almost 300, 251 of which were smallscale projects, and only 19 of which were actually under construction). Endemic corruption in the sector in particular and in the country in general is one of the main reasons for this situation. Through an empirical study, the authors present the administrative structuring that encourages this corruption. While the literature on the links between hydropower and corruption in developing and transition countries is substantial, it focuses on mega projects. A blind spot remains regarding small-scale units and this paper aims at filling this gap.

The paper by Elena Lopez-Gunn et al. aims to analyse the difficulties of integrating nature-based solutions into the range of public policy instruments in the fields of water and biodiversity. Starting from the Spanish case, whose imaginary about water is strongly marked by the need to build new infrastructures to cope with resource scarcity (hydraulic paradigm), the authors examine the case of the Medina del Campo aquifer and analyse the discourses of the actors, to identify the instruments that could appear to be the most appropriate, if one aims to go beyond this hydraulic paradigm. Drawing on an institutional analysis borrowed from new institutional economics (Williamson and Ostrom in particular) and the political science work of Paul Sabatier, the authors develop an analytical grid based on several layers, allowing them to highlight the evolution of values and political frameworks. Nature-based solutions are then presented as natural assurance schemes, where the preservation of ecosystem services other than productive services appears hierarchically more important. This vision is compatible with the recognition of water as an eco-social asset, or even a common patrimony, and is thus closer to the principles of social ecological economics.

Concluding remarks

We are convinced that the seeds for social and political approaches of water resources already exist, within and beyond the ecological economics community, and some of them make up this special section. Still, efforts remain to be made to upscale socio-politically oriented work on water topics in ecological economics and bridges remain to be built between ecological economists of water and social science, human geography and political ecology critical scholars. We argue that sharing, collectively developing and refining institutionalist frameworks specifically devised for the understanding of water issues might play a key role in shaping a community of ecological economists seriously engaged with the social and political dimensions of water. It would bring significant scientific benefits and contribute to a more critical and transformative ecological economics of water. The special section 'Ecological Economics of Water: Social and Political Perspectives' offers alternative pathways to contribute to this vision, and we hope that more research will come to feed the debate.

http://www.water-alternatives.org/index.php/blog/nexus


Eva Teruel

Marie-Anne Vandenhende

Didier Neau

Estibaliz Lazaro

Pierre Duffau

Marc-Olivier Vareil

Charles Cazanave

Adélaïde Perrier

Fabien Le Marec

Olivier Leleux

Fabrice Bonnet
email: fabrice.bonnet@chu-bordeaux.fr

Dr Linda Wittkop
email: linda.wittkop@u-bordeaux.fr

Fabrice Pr

Bonnet

Statin use and risk of severe bacterial infection in a population living with HIV: prospective cohort study of the ANRS CO3 Aquitaine Cohort 2000-2018

Keywords: Statins, bacterial infections, HIV

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Since the introduction of antiretroviral therapies (ART), people living with HIV (PLHIV) in developed countries are less likely to suffer from AIDS-related opportunistic diseases and their life expectancy is similar to the non-infected HIV population [START_REF] Lewden | All-cause mortality in treated HIV-infected adults with CD4 >=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration[END_REF][START_REF] Trickey | Survival of HIVpositive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies[END_REF][START_REF] Deeks | The end of AIDS: HIV infection as a chronic disease[END_REF]. However, PLHIV are highly affected by non-AIDS co-morbidities, including bacterial infections, which remain more frequent among PLHIV [START_REF] Marec | Incidence and risk factors for severe bacterial infections in people living with HIV. ANRS CO3 Aquitaine Cohort 2000-2012[END_REF][START_REF] Barry | Invasive pneumococcal disease in a cohort of HIV-infected adults: incidence and risk factors, 1990-2003[END_REF][START_REF] Kohli | Bacterial pneumonia, HIV therapy, and disease progression among HIV-infected women in the HIV Epidemiologic Research (HER) Study[END_REF][START_REF] Sogaard | Hospitalization for pneumonia among individuals with and without HIV Infection, 1995-2007: A Danish population-based, nationwide cohort study[END_REF][START_REF] Domingo | Bacterial meningitis in HIV-1-infected patients in the era of highly active antiretroviral therapy[END_REF]. Severe bacterial infections (SBI) represents the second cause of hospitalization in HIV adults and the first cause of hospitalization in HIV children worldwide and in all geographical regions [START_REF] Ford | Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis[END_REF]. The severity of these infections in this population also appears to be greater than in the general population, accounting for 10% and more of non-AIDS deaths among PLHIV [START_REF] Lewden | All-cause mortality in treated HIV-infected adults with CD4 >=500/mm3 compared with the general population: evidence from a large European observational cohort collaboration[END_REF][START_REF] Morlat | Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000[END_REF] in northern countries and up to 20% in Africa [START_REF] Farahani | Prevalence and distribution of non-AIDS causes of death among HIV-infected individuals receiving antiretroviral therapy: a systematic review and meta-analysis[END_REF]. In this context, improving the primary prevention of bacterial infections in PLHIV seems necessary.

Statins, whose primary indication is the treatment of hypercholesterolemia, also appear to have beneficial immunomodulatory and anti-inflammatory effects [START_REF] Palinski | Immunomodulation: a new role for statins?[END_REF][START_REF] Mach | Statins as immunomodulators[END_REF][START_REF] Marz | HMG-CoA Reductase Inhibition: Anti-Inflammatory Effects beyond Lipid Lowering?[END_REF]. Although the mode of action has not yet been established, statins seems to be able to advantageously modulate inflammatory responses to severe infections, and also have a direct influence on the infectivity and proliferation of a wide range of microorganisms [START_REF] Palinski | Immunomodulation: a new role for statins?[END_REF]. Observational studies have shown a decreased risk of infection among statin-users in the general population and immunosuppressed populations such as people with diabetics or kidney failure [START_REF] Gupta | Statin use and hospitalization for sepsis in patients with chronic kidney disease[END_REF][START_REF] Tleyjeh | Statins for the prevention and treatment of infections: A systematic review and meta-analysis[END_REF][START_REF] Björkhem-Bergman | Statin treatment and mortality in bacterial infections -A systematic review and meta-analysis[END_REF][START_REF] Khan | The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis[END_REF]. However, the potential protective effect of statins on the risk of infection remains controversial. A meta-analysis of seven clinical trials reanalyzed for this specific purpose does not support the hypothesis that statins reduce the risk of infection at least on the short term duration of a therapeutic trial [START_REF] Van Den Hoek | Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials[END_REF]. However, a large randomized clinical trial, which evaluated the effect of statins on many types of infections, showed slight decreases in the risk of pneumoniae, soft tissue and gynecological infections among statin-users [START_REF] Novack | The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial[END_REF]. The association between statin use and SBI has not been studied in PLHIV, a population with an increased risk of SBI.

The aim of this study was to evaluate the effect of statin use on the occurrence of a first episode of SBI in PLHIV in the era of ART in the French Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine cohort, in southwestern France, between 2000 and 2018.

Methods

Study design and population

The ANRS CO3 Aquitaine cohort was created in 1987 at the Bordeaux University hospital that is the sponsor of the study. It is an open, prospective and multicentric hospital-based cohort of PLHIV [START_REF] Marec | Incidence and risk factors for severe bacterial infections in people living with HIV. ANRS CO3 Aquitaine Cohort 2000-2012[END_REF]. Participants are recruited in 16 medical centers from 11 public hospitals in southwestern France. All patients, aged 18 years or older attending a participating hospital in the study could be included in the cohort if their HIV-1 infection had been confirmed by a Western blot testing. All patients included in this cohort provided written informed consent.

The study protocol was approved by the French Ethics committee (Comité de protection des personnes Sud-Ouest et Outre Mer III).

Data is collected at each consultation or hospitalization of the subject using an electronical case report form. A total of 10,695 patients were included in the cohort as of December 31, 2018. Within the ANRS CO3 Aquitaine cohort, subjects who had at least two follow-up visits between January 1, 2000 and December 31, 2018 were included for the purpose of the present study.

Outcomes: First episode of SBI and Severe pulmonary bacterial infection (SPBI)

A bacterial infection was defined as a clinical diagnosis associated with one of the codes of the 10th revision of the International Classification of Diseases (ICD10) representing a bacterial infection [21]. It was considered severe when it resulted in a hospitalization of at least 48 hours or death. Initial diagnoses of SBI recorded in the database were systematically reassessed by a physician who reviewed each patient's file and classified SBI cases as definite, probable, possible or excluded. Definite, probable and possible SBI were retained in this present study to improve specificity of SBI classification. Severe pulmonary bacterial infections (SPBI) were considered in secondary analyses.

Principal exposure: the use of statins

Statin use was assessed using the Anatomy, Therapeutic and Chemical (ATC) classification used to classify drugs. All treatments characterized by a C10AA/C10BA codes, were considered as statin therapies. For each individual, at each follow-up visit, investigators recorded information regarding statin type, dosing, statin discontinuations and the duration of treatment.

Confounding factors

Potential confounding factors in the relationship between statin use and the occurrence of SBI were identified: route of HIV acquisition, history of cancer and cardiovascular disease, co-infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), age, gender, stage of HIV infection (Stage A, B, C), ART history, diabetes, alcohol and tobacco consumption, HIV-1 viral load, CD4 and CD8 T-lymphocytes count. The route of HIV acquisition, age and gender were recorded at the inclusion in the cohort. All other confounding variables were time dependent. Co-infection with hepatitis C virus was defined as the presence of HCV antibody or HCV ribonucleic acid; HBV co-infection was defined as the presence of HBsAg or HBV DNA. The use and type of ART was also collected at inclusion and at each follow-up visit.

The HIV-1 viral load (measured in copies/mL), CD4+ and CD8+ lymphocyte counts (measured in cells/mm3) were measured at each blood test.

Statistical analyses

Characteristics of the study population were described according to the status of statin use.

Annual incidence rates of SBI and SPBI were computed by dividing the number of first SBI or SBPI by the total number of person-years. The confidence intervals (CI) were calculated using the exact Poisson method. The cumulative incidence curves were calculated with the Aalen-Johansen estimator to take death into account as a competitive risk upon the occurrence of a first episode of SBI.

Main analysis

Only complete cases were included. Subjects were considered to be on statins between the date of statin initiation and the end of their follow-up even if they stopped treatment, to be close to an intention to treat analysis. Survival times were the time between inclusion in the study and the date of the occurrence of SBI, death, the last follow-up visit or December 31, 2018, whichever occurred first. In order to take into account the problem of time-dependent confusion, Cox marginal structural model were performed with the method of stabilized inverse probability weighting (SIPW) [START_REF] Hernan | Causal Inference[END_REF][START_REF] Hernán | Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease[END_REF][START_REF] Robins | Marginal structural models and causal inference in epidemiology[END_REF]. For each subject, SIPW numerator was the probability of being on statin conditionally on his history of statin use and his baseline confounding and the SIPW denominator was the probability of being on statins conditionally to his history of statin use, his baseline and time-dependent confounding. The effect of statin use on the occurrence of SBI and SPBI was then estimated by an unadjusted cause-specific Cox model weighted by SIPW. The risk proportionality hypothesis was verified using Schönefeld residues.

Sensitivity analyses

Classical Cox models [START_REF] Cox | Regression Models and Life-Tables[END_REF] (unadjusted and time-dependent adjusted) were also performed in order to compare results with those to Cox marginal structural model. In a second analysis, subjects were censored at the end date of statin treatment when information was available in the patient's follow-up, in order to be close to an "as treated" analysis [START_REF] Hernán | Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease[END_REF]. Cox marginal structural models were then performed using the same method as for the main analysis, but in this case SIPW were multiplied by the inverse of the probability of being censored. In order to verify the validity of the results obtained in the Cox marginal structural model and in particular the plausibility of the exchangeability hypothesis, two other models were carried out by calculating SIPW using other sets of variables. In a first model, total cholesterol was added to the confounding variables because it was strongly related to statin use. In another model, instead of the number of CD4 and CD8, the CD4/CD8 ratio was used because it is strongly associated with SBI [START_REF] Marec | Incidence and risk factors for severe bacterial infections in people living with HIV. ANRS CO3 Aquitaine Cohort 2000-2012[END_REF]. Protease inhibitors and Integrase strand transfer inhibitors can have markedly different effects on lipids. Thus, patients with a protease inhibitors based regimen might have a higher probability of being treated with statins. Therefore, we did sensitivity analyses adjusting the analysis with an ART variable distinguishing between no treatment, PI-based regimens, INSTI-based regimens, other cART and monotherapy. At last, since lipophilic statins exert more immunomodulatory effects that hydrophilic, we performed stratified analysis including lipophilic and hydrophilic statins on the risk of SBI.

In order to manage missing data, presence of diabetes, HIV-1 viral load, number of CD4, number of CD8, HCV co-infection, HBV co-infection, alcohol and tobacco consumptions were imputed using Multivariate Imputation by Chained Equations (MICE) [START_REF] Azur | Multiple imputation by chained equations: what is it and how does it work?[END_REF]. Imputation was performed on five datasets that were then grouped together for analysis. The variables used to predict missing values were sex, age, mode of HIV infection, stage of HIV infection, history of cancer and cardiovascular disease, ART, statin use and occurrence of SBI. All analyses were done using R-3.5.2 and R Studio 1.2.1335 [START_REF] Robins | Marginal structural models and causal inference in epidemiology[END_REF].

Results

Population description

Of the 10,695 individuals included in the cohort as of December 31, 2018, 7,313 subjects met the inclusion criteria, representing 66,142 person-years of follow-up (figure).

The characteristics of patients of the ANRS CO3 Aquitaine Cohort at inclusion, five and ten years of follow-up are included in the table 1. The characteristics of patients taking statins and not taking statins are described in the table 2.

The overall incidence of a first episode of SBI (including SPBI) was 12.4/1000 person-years (95%CI: 11.6-13.3). The probability of developing a SBI was 7.0% in the first 5 years of the study, 11.7% in the first 10 years of the study and 15.1% in the first 15 years of the study.

The overall incidence of a first episode of SPBI was 6.7/1 000 person-years (95%CI: 11.6-13.3) with a decrease of the incidence from 18,6/1 000 person-years in 2000-2002 to 0.6/1 000 person-years in 2017-2018. The probability of developing a SPBI was 3.3% in the first 5 years of the study, 6.1% in the first 10 years of the study and 8.3% in the first 15 years of the study.

Association between statin use and occurrence of SBI and SPBI

According to the results of the main analysis, no significant difference in risk of SBI and SPBI was observed between statin-users and non-statin-users. If the entire population would have been treated with statins, the instant risk of a first episode of SBI would have been 3% lower than the instant risk that would have been observed if the same population had not been treated with statins (Hazard ratio (HR)=0.97; 95%CI: 0.75-1.25; p=0.82). The results were similar for all sensitivity analyses performed and after MICE imputations (table 3). If the entire population would have been treated with statins, the instant risk of a first episode of SPBI would have been 8% lower than the instant risk that would have been observed if the same population had been treated with statins (HR=0.92; 95%CI: 0.67-1.28). The results were similar for all sensitivity analyses performed and after MICE imputations (table 4).

No protective effect of statins on the risk of SBI was observed with either the crude Cox model, the adjusted Cox model, artificial censorship of subjects who stopped the statins, adding total cholesterol to the calculation of SIPW or replacing the number of CD4 and CD8 with the CD4/CD8 ratio (table 3). The same results were observed when we considered the effect of statins on the risk of SPBI (table 4).

In stratified analysis the effect of statins on SPI was not modified by the type (lipophilic and hydophilic) of statin used (data not shown).

Complementary analysis adjusting for ACE inhibitors and angiotensin II receptors blocker use had no impact of our overall results (data not shown).

Discussion

Although the association between statin use and the occurrence of infections has been widely discussed in the literature, this study is the first to focus on this association in PLHIV, a population with a documented increased risk of SBI. The number of events observed was sufficient due to a large sample, long follow-up (19 years) and few people lost to follow-up.

All analyses done in this study showed no statistically significant effects of statin use on the risk of occurrence of SBI in PLHIV.

Unlike our study, a large number of observational studies have shown a protective effect of statin use on the risk of infection and published meta-analyses have also concluded in this regard [START_REF] Tleyjeh | Statins for the prevention and treatment of infections: A systematic review and meta-analysis[END_REF][START_REF] Khan | The role of statins in prevention and treatment of community acquired pneumonia: a systematic review and meta-analysis[END_REF]. However, the majority of studies were retrospective and statin status was not updated during follow-up. In our study, we attempted to approximate the effects that would have been observed if the study would have been a randomized clinical trial. Our results were identical to those observed in a meta-analysis of clinical trials done by van den Hoek et al. in 2011, where no effect of statin use on the risk of infection was found [START_REF] Van Den Hoek | Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials[END_REF]. But in the randomized trial of Novack et al. 2012 [START_REF] Novack | The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial[END_REF], statin use was associated with a slightly decrease of pneumonia we have not confirmed in our larger observational study. Of note, this randomized trial was not designed to show an effect of statins on the risk of SBI and the target population was at low risk of SBI, far from our HIV population.

Statin therapy, like other preventive therapies, is known to be a potential source of "healthy user" bias. Individuals initiating preventive therapy are more aware of their health and have better medical follow-up. This may therefore lead to a systematic difference in risk between the two treatment strategies, with a reduced risk of infection among statin-users, unrelated to the therapeutic virtues of the treatment. However, in our context, HIV infection requires regular medical follow-up in all cases, which has minimized the presence and impact of this bias. Assessing the effectiveness of a treatment in an observational study can lead to biased results, particularly because the assignment to treatment groups is not random and the reasons for receiving a certain level of exposure are likely to be associated with the individual characteristics. This problem has been well considered here by using an analytical strategy adapted for the obtention of causal effects in observational studies by taking into account time-dependent confounding bias.

During this study, although every effort was made to minimize potential sources of error, several limitations were identified. First, the selection of the population resulted in the exclusion of 2515 subjects from the cohort. Excluded individuals had more unfavorable characteristics than included subjects (supplementary material). These differences suggested that the sample actually used may not be representative of the target population.

A significant number of data were missing, resulting in the loss of one-third of the initial sample. Nevertheless, the analyses after imputation showed results similar to the complete case analysis. Exposure to statins was defined using the information we had in the patient follow-up sheets based on ATC classification which is important for obtaining accurate information regarding drug use. After a treatment initiation, it happened that no information was available during several follow-up visits. In these cases, subjects were considered statinusers until we had a date of treatment discontinuation. This could have led to errors in exposure classification. Nevertheless, this had no impact on the study's principal analyses in which, after statin initiation, subjects were considered under treatment throughout their follow-up. Unlike a clinical trial where treatment levels are well defined in the protocol, in an observational study, there may be several "versions" of the same level of exposure. We showed no effect of lipophilic or hydrophilic statins on the risk of SBI, but according to the imbalance of the prescriptions in favor of the hydrophilic statins less likely to induce drugdrug interactions with antiretrovirals, we can not exclude a specific effect of lipophilic statins on the risk of SBI.

Figure :

 : Figure: Flow of participants through the study, ANRS CO3 Aquitaine Cohort, 2000-2018.

Table 1 :

 1 Time-dependent characteristics at inclusion, 5 years, 10 years and 15 years after inclusion in the study. ANRS CO3 Aquitaine cohort, 2000

Table 2 :

 2 Characteristics of individuals at the time of statin intake for subjects who initiated statin therapy during their follow-up and inclusion in the study for subjects who did not take statins during follow-up, ANRS CO3 cohort, Aquitaine, 2000-2018 Hemophilia, transfusion between 01/01/1978 and 01/08/1985, maternal-fetal contamination, accident of exposure to the risk of HIV transmission * Protease inhibitor or nucleoside and nucleoside reverse transcriptase inhibitors or non-nucleoside reverse transcriptase inhibitors or integrase inhibitors or maturation inhibitors or fusion inhibitors or not classified † Taking oral/injectable antidiabetic therapy or having blood glucose levels at any time of day > 2g/dL ♦ Presence of HCV antibody or HCV ribonucleic acid

	Statin users (N=1590)	Non-statins users (N=5723)

Ø Presence of HBs antigen or HBV DNA

Funding: This work was supported by the CHU de Bordeaux and the French National Agency against HIV and hepatitis (ANRS) Author's Contribution: ET, FB and LW designed the study. MAV, DN, EL, PD, MOV, CC collected the data and interpreted the results of the analysis. ET, AP, FLM, OL perform the management and the analysis of the data. All authors' have read and approved the manuscript.

SBI are still very common among PLHIV and finding a protective effect of statins could have significantly improved the health of this population. Unfortunately, statins appear to be ineffective in the primary prevention of SBI and SPBI in PLHIV. In a previous study on the same database between 2000 and 2007 we showed that smoking cessation dramatically reduced the risk of bacterial pneumonia independently of other factors [START_REF] Benard | Bacterial pneumonia among HIV-infected patients: decreased risk after tobacco smoking cessation. ANRS CO3 Aquitaine Cohort, 2000-2007[END_REF].

The reduction of the incidence of SBI/SPBI in PLHIV will have to be done by considering other options than statins such as tobacco quitting and generalization of influenza and pneumococcal vaccination.

Conflict of