Keywords: Islamophobia, Religious intolerance, Racism, Cultural Racism, Enemy image, Islam Islamophobia, Islam, racism, cultural racism, religious intolerance, enemy image

This paper contributes to the debate on the meaning of the term "Islamophobia". It proposes an examination of the early twentieth century approaches to Islamophobia, both the term and the phenomenon. The aim is to show that the phenomenon had already been identified at the end of the nineteenth century and that it had been defined by the beginning of the twentieth. That definition could throw some light on the current debate about the meaning of the term.

The recent history of the term Islamophobia begins in the United Kingdom somewhere around the late 1980s / early 1990s, when the term began to be used to signal rejection of and discrimination against the resident Muslim population in the "West" (Allen 2006, pp. 1-23). However, following the publication of the Runnymede Trust report (1997), and particularly in the post 9/11 period, the term became a 'contested concept in the public space' [START_REF] Allen | Islamophobia: contested concept in the public space[END_REF], not only in the United Kingdom but also in much of Europe. Not only was the pertinence of the term debated, but also the very existence of a phenomenon that merited such a name [START_REF] Malik | Islamophobia myth[END_REF]. Some authors tried to discredit the term by stating that it had been invented by the Islamists to condemn any criticism of Islam (Fourest and [START_REF] Bruckner | Le chantage à l'islamophobie[END_REF]. Meanwhile, those who were in favour of the term being used were unable to agree as to what phenomenon it should be applied to.

The main problem -then and even now-concerned the why and the wherefore of this phenomenon: were Muslims being rejected and discriminated against owing to their skin colour, their ethnic origin or their religion? Or was it a mixture of all these elements? It is the response to these questions that has engendered perception of Islamophobia as a form of religious intolerance, or, conversely, a form of racism or what has been called 'new racism' [START_REF] Barker | The new racism: conservatives and the ideology of the tribe[END_REF] or 'cultural racism' (Modood 1997a). 1 At the same time, the pertinence of the term Islamophobia for referring to rejection of and discrimination against Muslims was conditioned by the nature of this phenomenon. Towards the end of the 1990s, some authors began to discuss the suitability of the term Islamophobia for designating rejection based on what they considered not so much a "phobia" of the Islamic religion, but rejection on an ethno-cultural basis. If, then, rejection of Islam was not the main source of this discrimination against Muslims, why speak of Islamophobia?

In 1997, for example, Tariq Modood, qualified the term Islamophobia as 'somewhat misleading' because, according to him, the rejection and discrimination against Muslims 'is more a form of racism than a form of religious intolerance, though it may perhaps be best described as a form of cultural racism, in recognition of the fact that the target group, the Muslims, are identified in terms of their non-European descent, in terms of their not being white, and in terms of their perceived culture' (Modood 1997b). Along these same lines, Fred Halliday argued that 'anti-Muslimism' was a more appropriate term because 'the attack now is against not Islam as a faith but Muslims as a people, the latter grouping 3 together all, especially immigrants, who might be covered by the term' (Halliday 1999, emphasis in original).

Hence, some authors have tended to deny that there is any relationship between Islamophobia and religious intolerance [START_REF] Bunzl | Between anti-Semitism and Islamophobia: some thoughts on the new Europe[END_REF]. Others believed that, more than religious intolerance, Islamophobia would denote intolerance towards religion in general or a certain fear of the growing presence of religion in the public sphere. Vincent Geisser, for example, sees Islamophobia as a form of 'religiophobia' (Geisser 2003, p. 12). Along these same lines, Pnina Werbner argued that in Islamophobia, Islam conjures up the archetype -or 'folk devil'of the Grand Inquisitor because what is at stake 'is not the battle between Christendom and Islam, as many Muslims believe. What is scary about Islam is the way it evokes the spectre of puritanical Christianity, a moral crusade, European sectarian wars, the Crusaders, the Inquisition, the attack on the permissive society' (Werbner 2005). Islamophobia, then, is identified with a certain secularized and laicist elite. This perspective nonetheless fails to account for profoundly religious forms of Islamophobia, some of its exponents even calling out for an increased presence of religion in the public sphere. [START_REF] Verkhovsky | Who is the enemy now? Islamophobia and antisemitism among Russian Orthodox nationalists before and after September 11[END_REF][START_REF] Stockdale | Citizens of Heaven» versus «the Islamic Peril»: the anti-Islamic Rhetoric of Orlando's Holy Land Experience since September 11, 2001[END_REF], Cimino 2005, Bravo López 2009a).

Conversely, other authors considered that both race and religion were mixed up in Islamophobia, engendering a form of cultural racism [START_REF] Nieuwkerk | Veils and wooden clogs don't go together[END_REF], Werbner 2005[START_REF] Meer | The politics of voluntary and involuntary identities: are Muslims in Britain an ethnic, racial or religious minority[END_REF][START_REF] Meer | A sociological comparison of anti-Semitism and anti-Muslim sentiment in Britain[END_REF][START_REF] Meer | Refutations of racism in the «Muslim question[END_REF][START_REF] Cesari | Securitization and religious divides in Europe. Muslims in Western Europe After 9/11: Why the term islamophobia is more a predicament[END_REF]). These authors contend that the Islamic identity has been subject to a process of racialization whereby this identity is now defined on the basis of the individual's ethnic origin rather than exclusively on the basis of his beliefs. In Identification of Islamophobia with racism or cultural racism has led some of these authors to compare it with anti-Semitism, with the aim of demonstrating that a religious minority can be racialized and fall prey to racism even though the religious identity is theoretically voluntary. Anti-Semitism would be proof of this [START_REF] Meer | The politics of voluntary and involuntary identities: are Muslims in Britain an ethnic, racial or religious minority[END_REF][START_REF] Meer | Refutations of racism in the «Muslim question[END_REF][START_REF] Meer | A sociological comparison of anti-Semitism and anti-Muslim sentiment in Britain[END_REF]. But this perspective also raises problems. It is doubtful that anti-Semitism can be considered as a form of racism or cultural racism. Indeed, the relationship between anti-Semitism and racism has been -and still is-the subject of a longstanding debate in literature on anti-Semitism. Within this debate, there is a strong tendency to deny that anti-Semitism is a form of racism without denying that there is a union between the two in certain contexts. [START_REF] Katz | Misreadings of Anti-Semitism[END_REF][START_REF] Levy | Antisemitism in the modern world: an anthology of texts[END_REF], pp. 4-5, Langmuir 1996, pp. 311-314, Lindemann 1997, pp. 95-96, Pulzer 2005[START_REF] Volkov | Germans, Jews, and Antisemites[END_REF], pp. 75-79, Bravo López 2009b, pp. 191-220).

Racism, according to this literature, played an adjacent role, not a necessary one, in anti-Semitism. Some anti-Semites embraced racial theories, others did not.

Some anti-Semites identified Jews on the basis of their ancestry, and therefore believed that once a Jew always a Jew. Other anti-Semites continued to identify Jews on the basis of their religion, believing that a Jew could stop being a Jew through conversion, "reform", assimilation or abandonment of religion. This did not, however, enhance their image of the Jews that continued to be Jews, or of their role in society.

Anti-Semites differed in a great many respects. Some were Catholics, others Evangelists, others atheists. Some were left wing, others right wing; some racist, were a threat to their wellbeing and even to their very survival.

Meer, Noorani and Modood are therefore right to point out that a religious minority such as Muslims can be the object of a rejection similar to that suffered by the Jews. But they are probably not right to consider that this is because both Islamophobia and anti-Semitism are forms of racism or cultural racism.

Today one type of Islamophobia can be likened to liberal, Catholic and Protestant anti-Semitism. Although it is still fiercely anti-Islam and anti-Muslim, it does concede -in theory at least-that Muslims can stop being Muslims or "reform" and become "good citizens" (Bravo López 2009b, pp. 349-470). 2 And we also come across instances of Islamophobia targeting minorities such as converts to Islam (Özyürek 2009). But it would be highly problematic to identify these forms of Islamophobia as forms of racism or cultural racism insofar as they are devoid of any of the biological or cultural determinism inherent therein. As George M. Fredrickson puts it, 'if conversion or assimilation is a real possibility, we have religious or cultural intolerance but not racism' (Fredrickson 2002, p. 170). In this case, Ali Rattansi would be right on stating that '"Islamophobia" or any other kind of hostility to Islam and Muslims is not necessarily racist, but in many contexts can take a relatively "strong" or "hard" racist form' (Rattansi 2007, p. 111, emphasis in original).

Determinism is a key feature in the case of the anti-Semites who embraced racial theories, and yet it is difficult to encounter in Islamophobia. It is difficult to find Islamophobes prepared to affirm -like some anti-Semites did regarding the Jews-that the evil Islam has inoculated in Muslims cannot be removed because 2006, Commission on British Muslims andIslamophobia 2004, p. 7). Some, as Christopher Allen notes, have even tried to take credit for coining the term themselves (Allen 2006, pp. 5-6). And yet the term is at least a hundred years old.

Dinet and Ibrahim's approach

The only early twentieth century work that has been occasionally cited in the course of the present debate on Islamophobia is L'Orient vu de l'Occident by Étienne Dinet (1861Dinet ( -1929) ) and Slimane ben Ibrahim (1870Ibrahim ( -1953)), considered by some to be the first authors to use the term [START_REF] Gresh | L'utilisation du mot «islamophobie[END_REF][START_REF] Cesari | Securitization and religious divides in Europe. Muslims in Western Europe After 9/11: Why the term islamophobia is more a predicament[END_REF], Allen 2006, p. 3).

Despite its title, L'Orient vu de l'Occident is not a book dealing with the vision (or better still, visions) of the East as seen from the West, but rather limits itself to studying a handful of authors, not all of whom receive the same treatment. More 1925, pp. 44-48). Dinet and Ibrahim simply believed that Casanova was mistaken and they therefore limit themselves to contradicting his point of view and leave it at that.

The term "Islamophobia" was therefore used merely to criticize the work of just one of the authors analysed in L'Orient vu de l'Occident: Henri Lammens.

Dinet and Ibrahim contend that some of the remarks made in certain works by underlying idea here -one so prominent in the discourses of French Africanists of the time-is that the Islamicized black populations were not really Muslims because they 'practised a "bastardised" form of Islam' [START_REF] Harrison | France and Islam in West Africa, 1860-1960[END_REF], p. 2, 94-117, Jonckers 2006). Hence Quellien's concern with the 'growing Islamization' of West Africa: 'This matter is of the utmost importance in terms of the future of our possessions as we may one day find ourselves facing populations that are entirely Muslim in name and in deed' (Quellien 1910, p. 191).

The concern Quellien expresses regarding this burgeoning Islamization would appear to contradict his earlier statements concerning Islam. West African Islam would apparently have to be differentiated from Islam in general if it were to be spared the Islamophobic accusations, deserved in the case of Islam overall or so

Quellien would have us believe. However, it was shortly afterwards that he went on to say that the Islamized black populations had become more civilized thanks to . So perhaps Islamization was not such a bad thing after all… In all events, Quellien's stand can be summed up a follows: 'Muslims are neither little saints nor brigands ' (ibid. p. 195).

The Islamophobic authors cited by Quellien apparently thought that although Islam certainly represented a step forward in relation to paganism, Islamization would turn the Islamized populations into "our" enemies because Islam had 'always been hostile to our penetration ' (ibid. p. 195). From this perspective, this hostility would be embedded in the very nature of the Islamic religion, in its teachings as reflected in the Qur'an. This, says Quellien, was the view held by the German missionary Karl Wilhelm Kumm (1874Kumm ( -1930)), who stated that: It was this Islamophobia ascribed to the aforementioned authors that would lead them to 'advocate a policy of persecution with regard to Islam' (ibid. p. 208).

This persecution policy would consist of a series of measures designed to help reduce the influence of Islam among the population, measures that were effectively implemented both in North and West Africa [START_REF] Ageron | Les Algériens musulmans et la France (1871-1919[END_REF], Weil 2006[START_REF] Harrison | France and Islam in West Africa, 1860-1960[END_REF][START_REF] Triaud | Politiques musulmanes de la France en Afrique subsaharienne à l'époque coloniale[END_REF]. The Word and the thing It is hardly surprising that it was precisely between the late nineteenth and early twentieth century that the first approximations to Islamophobia appeared. As Christopher Harrison explains, 'there was then a perception of a struggle which opposed Christian Europe against the Muslim "Orient"' (Harrison 1988, p. 29). It was at this time that studies of this perception of Islam and Muslims began to appear, before the word "Islamophobia" even began to be used.

The existence of this fear of Islam and Muslims had been detected well before Quellien tackled Islamophobia. In 1891, the French writer Jules-Hippolyte Percher, alias Harry Alis (1857-1895) -from whom Quellien was to borrow a few ideas-warned of the existence in his day of a series of anti-Muslim 'axioms', the principal one being that 'the Muslim is the natural irreconcilable enemy of the Christian'' (Percher 1891, pp. 203-204, emphasis in original).

More exhaustively, the director of the Africa Department at the French colonial ministry in the period 1902-1906 (Harrison 1988, p. 32), Louis Gustave Binger 17 against this over substantiated judgement that Muslims were and always will be our enemies' (Binger 1906, p. 6).

Binger says that this feeling of hostility towards Islam had become more entrenched owing to the engagement of French colonial troops with their Muslim adversaries during these years. These long, hard and costly battles ignited a resurgence among the French population of old anti-Islamic stereotypes that held

Islam responsible for all this opposition to colonial penetration (ibid. p. 18).

Contrary to those who held this opinion, Binger points out that it was not only Muslims who opposed colonial penetration. Pagan and even Christian populations offered similar resistance (ibid. pp. 19-20). Binger concedes that Islam does sometimes exert a certain influence on these opposition movements, but that in these instances Islam is being used as tool to satisfy personal ambitions (ibid. p.

21).

There is no doubt that Binger's ideas largely inspired those later expounded by Quellien, who cites his countryman repeatedly.

The images of Islam conveyed by certain authors are not therefore justified, says Binger. Discussions of how peoples subject to colonial power resist it sometimes amount to instances of bad faith and dual morality. Attitudes that would be viewed patriotic among Europeans are considered to denote fanaticism and barbarism on the part of Muslims. As Binger notes in a passage that deserves to be cited in full:

If the Muslim defends his country, his home, his independence, his liberties, he is neither a patriot nor a man sacrificing himself for the sake of a noble and lofty sentiment, he would be a fanatic. 18 Do we find him reading his Qur'an, the only book he possesses? He must also be a fanatic.

Does he refuse to serve your interests? That would be fuelled by fanaticism.

Does he meet his co-religionists to discuss the Pentateuch or the Gospel, perhaps simply to learn to read his prayers properly? This is for the purpose of later exercising his fanaticism.

Has he allied himself with other Muslims in a war? This will always be driven by fanaticism and hatred of Christians.

In a word, all the Muslim's actions, especially those that run counter to our policy or our interests, can be ascribed to fanaticism. And stranger still, we at home would consider most of these hostile acts inspired by this so-called fanaticism as highly commendable qualities, as highly patriotic acts, or even as highly political acts. If Vercingetorix were to appear among the Muslims, we would treat him as a fanatic. (ibid. pp. 31-32)

The stand taken by authors such as Binger, Quellien and Delafosse should lead us to appreciate the pluralism that characterized the European discourse regarding Islam. Even during the colonial period, far from encountering monolithic rejections of Islam, we come across authors positioning themselves against blatantly Islamophobic viewpoints, and identifying and discussing them.

In addition to all the aforementioned authors, there were others who used the term Islamophobia in the 1920s, but none of those that have been identified

actually tried to define it [START_REF] Marty | L'islam en Guinée[END_REF], p. 119, Cook 1924[START_REF] Bernard | L'islam et l'Afrique du nord', L'islam et la politique contemporaine[END_REF]. In their wake, the term has been used on few occasions. It does not, for example, appear in any of the reference works on the image of Islam as perceived in Europe throughout history. Neither Norman Daniel (1966Daniel ( , 1993)) -neither in the original nor the revised edition (1997)-, although he did later on (Said 1985).

Before this, in 1968, the Spanish historian and philologist Américo Castro used the term in a fragment of one of his essays. He stated that Islamophobia and anti-Semitism had engendered in Spain 'an elusive historiography' that had covered up the Jewish and Islamic influences in the history of Spain (Castro 1985, p. 98). The Tunisian historian Hichem Djaït also used it before Said, but curiously to argue that in France in the 1970s, old Islamophobia had been replaced by Arabophobia (Djaït 1978, p. 60), which could be construed as meaning that rejection based on the "other's" religion had been replaced by rejection based on the "other's" ethnic origin.

And so it was not until the late 1990s and the beginning of the twenty-first century that the term was once again used more frequently, more frequently even than when it started being used at the beginning of the twentieth century. The post 9/11 context has doubtless contributed to this.

Conclusion

Islamophobia is not a new term. Between the end of the nineteenth and beginning of the twentieth century, various authors detected the presence in Europe of an attitude towards Islam and Muslims that some of them designated with the term "Islamophobia". Although the present debate on Islamophobia has hitherto ignored their contributions, these were important and are still useful.

These authors, particularly Quellien, not only used the term but also tried to define it. it is not the sine qua non of its existence.

The same holds true for the relationship between Islamophobia and racism or cultural racism: they may be elements worth considering in certain instances of Islamophobia, but again, they are not the sine qua non of its existence.

Islamophobia can effectively be confounded with a form of racism or cultural racism because it occasionally targets minorities that are effectively racialized.

But it is the perception of Islam as a threat that engenders the racialization of the Islamic identity. It is the need to identify the threat, to identify the Islam incarnate in Muslims, that causes the Islamic identity to be transformed into an involuntary identity: the Muslim will be identified not on the basis of his beliefs but rather on the basis of his origin, his ancestry and a series of ethno-cultural traits.

It is equally true, however, that these minorities can fall prey to racism or cultural racism without the Islamic reference coming into play. This therefore should not be described as Islamophobia, but simply as racism or cultural racism.

It is when Islamophobia is used to reject or discriminate against Muslims who are identified as such on the basis of a series of ethnic features -rather than their beliefs-that confusion sets in. Because in these cases, unless an explicit motive exists, it is never clear whether this rejection stems from the Muslim being identified with the "Islamic threat" or because he is identified as a foreigner, a In short, approaches to the term and the phenomenon in the early twentieth century leave no doubt that the term "Islamophobia" should only be applied to denote a hostile attitude towards Islam and Muslims based on the image of Islam as the enemy and as a vital, irrefutable and absolute threat to "our" wellbeing and even to "our" existence, irrespective of how Muslims are identified, whether on the basis of religious or ethnic criteria.

F

  Towards a definition of Islamophobia: approximations of the early twentieth centuryIntroduction: what is Islamophobia?

  the Islamic identity -in principle religious and therefore voluntary-becomes involuntary as soon as Muslims are racialized.

  But consensus did exist in one fundamental respect: Judaism and Jews

  not intend to provide an exhaustive study of how the term Islamophobia was used in the early twentieth century, but rather to try and salvage a number of approximations to Islamophobia that have not received the attention they deserve. The aim is to analyse how these authors understood the phenomenon and in what sense they used the term Islamophobia, and finally, to demonstrate the relevance of these texts to the present debate. It should become clear that the definition some of these authors applied to Islamophobia could still be useful.

  specifically, most of the book is devoted to criticizing the work of two authors: the Belgian Orientalist who joined the Society of Jesus, Henri Lammens(1862- 1937), and the French Arabist Paul Casanova. Both, according to Dinet and Ibrahim, had equally mistaken visions of Islam and particularly of its prophet Mohammed. But they were not mistaken for the same reasons or to the same extent.Paul Casanova apparently committed an error of appreciation. In his Mohammed et la fin du monde(Paris, 1911), Casanova allegedly made the his attention to certain stories that had been handed down by Islamic tradition instead of concentrating on other more secure sources, mistakenly concluding that Mohammed was awaiting the end of the world before his own death which is why he failed to appoint a successor (Dinet and Ibrahim

  Lammens are an example of 'the degree of aberration to which Islamophobia can lead a learned man' (ibid. p. 26). For Dinet and Ibrahim, the manner in which Lammens tackled certain subjects bespeaks Islamophobia. It is not simply that his vision of Islam and Mohammed is mistaken, there is more: they contend that his entire interpretation of Islamic traditions is made in bad faith and based on a biased selection of the traditions that conform more easily to Lammens' preconceived image of Islam. Lammens paints an unfair portrait of Mohammed, branding him as disloyal and as a coward, a glutton and a sleepyhead, without providing any documentary evidence to uphold his claims and twisting the meaning of certain passages in the main texts from the Islamic tradition. Moreover, while denigrating the figure of Mohammed, he simultaneously paints a kindly and sympathetic portrait of all his enemies. In short, as far as Dinet and Ibrahim were concerned, Lammens was embarked on a 'pseudo-scientific crusade in the hope of bringing Islam down once and for all' (ibid. p. 20).

F

  past and what it will probably engender in the future. The citations we find there can be summed up as follows: «Fight the infidel, reduce him to slavery or slay him.» If we can win over to Christianity the pagan tribes of central Sudan among which the white man's prestige is presently considerable, we will establish an effective bastion against the Muslim religion. (ibid. p. 202) These texts were supposedly designed to convince the colonial authorities that Islam was effectively the eternal and implacable enemy of Christianity and Europe and that they should therefore change their disposition towards the Christian missions in the Islamic world: they should support them more resolutely. For these authors, Christianity was the only barrier capable of countering the 'grave dangers European possessions will face as a result of their complete Islamization' (ibid. p. 204). Like Dinet and Ibrahim after him, Quellien identifies the most radically Islamophobic authors as highly confessional authors linked with various Christian churches, and especially with some engaged in proselytizing among the Muslim population.

(

  , published in 1906 a work entirely devoted to this type of representation of Islam and Muslims as a threat: Le péril de l'Islam.Up to a point, the aim of this book and the subjects it deals with call to mind recent works such as The Islamic threat: myth or reality?[START_REF] Esposito | The Islamic threat: myth or reality? 3rd ed[END_REF], works that have tried to dismantle certain myths created by adherents to a discourse based on the threatening image of Islam. In his work Binger lists the accusations most commonly levelled against Islam -a list that is broadly taken up again by Quellien: holy war, slavery, polygamy, fanaticism. In giving his opinion of each accusation, Binger always tends to play down the importance of Islam in terms of each charge. But this work goes further than dismantling the myths concerning Islam, its main aim -according to Binger himself-being to 'warn the public

  Arab. Using Quellien's definition, however, it is only in the first case that the term "Islamophobia" would apply.

  erroneous representations of Islam, however far from the truth, do not amount to Islamophobia. Nor do degrading or humiliating representations of Islam and the Prophet constitute Islamophobia per se. Islamophobia is on the other hand the motivation underpinning these types of misrepresentation of lslam and its prophet.What, then, is Islamophobia for Dinet and Ibrahim?No explicit reply to this question is to be found in their book, but if we were to hazard an opinion, we might suggest that if the aim of Lammens' behaviour is, as , who they claim sounded a 'call for war against Islam' in the sense of launching a Christian proselytizing offensive that Dinet and Ibrahim say was doomed to failure(ibid. pp. 183-184).Despite this small and primitive attempt at making a typological classification of Islamophobia, the authors do not provide any explicit definition. However, judging from the words they used to analyse the case of Henri Lammens, it follows that they perceived Islamophobia as a hostile attitude towards Islam, a desire to do away with it, and consideration of Islam as an enemy to be fought. Those who most ardently wish to see us leave the country -and there certainly are those who feel this way-do so not because we are not of their faith, but simply because we are not of their race, their mentality or their land, because we are foreigners. (...) Islamophobia therefore has no raison d'être in West Africa, where Islamophilia in the sense of granting preference to Muslims, would create a We are therefore duty-bound to strive to maintain the status quo and remain absolutely neutral with regard to all religions in the interests of European domination and of course in the interests of the natives. (Delafosse 1910, emphasis in original, Delafosse 1912, vol. 3, pp. 211-212) The second work was a PhD thesis written by Alain Quellien, a functionary in the French colonial ministry, and it is entitled La politique musulmane dans Prejudice against Islam has always been widespread among the people of Western and Christian civilization and still is. For some, the Muslim is the natural and irreconcilable enemy of the Christian and the European; Islam is the negation of civilization, and barbarism, bad faith and cruelty are the best one can expect from the Mohammedans. (ibid. p. 133) Further on, Quellien again points to the indissoluble union between fear and dislike of Islam and fear and dislike of those who are its most obvious incarnation:Islam would appear to be slightly exaggerated; the Muslim is not the European's natural born enemy but he can become [this enemy] as a result of local circumstances and notably when he resists armed conquest.' (ibid. p. 135) Islamophobia would not therefore consist of a merely critical or negative attitude towards Islam. Islamophobia would be an attitude towards Islam based on the belief that Islam -and Muslims as the incarnation thereof-is an implacable and absolute enemy. For Quellien, Islamophobes consider Muslims their enemies because they identify them with a religion that they perceive as an enemy, rather than identifying them in "racial" or ethnic terms. Consequently, discussing and criticizing Islamophobia consists of denying or relativizing the importance of the Islamic religion in each of the accusations levelled by the Islamophobes against Islam and the Muslims. Islamophobia does not make sense, Quellien seems to be saying, because Islam is not the cause of what Muslims are accused of.

	o r F o r o r numerous. F o r F o r polygamous. The existence of polygamy is therefore a social rather than a religious issue' (ibid. p. 146). Fourth is fatalism, which Quellien ascribes more to the allegedly passive character of black populations rather than to Islam per se (ibid. pp. 150-152). This is an example of how in a colonial context, racism against a black population -which also happens to be Muslim-could appear on the part of people who were openly against Islamophobia. In this last respect, Quellien's opinion is diametrically opposed to the opinion of those who level F r o (1867-1952)F feeling of distrust among the non-Muslim populations, who are more nonetheless no doubt that all black peoples, whether Muslims or fetishists, are tranquillity and a serious advantage for our security' (ibid. p. 190). The
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	influence, but that this could generally be narrowed down to instances of referring sometimes appears to share the very fear of Islam he ascribes to others. He
	to religion to satisfy personal ambitions (ibid. p. 138). occasionally appears to ascribe the tolerant nature of Islam in French West Africa
	10 11 13 14

Dinet and Ibrahim put it, 'to bring down Islam once and for all', it follows that Islamophobia consists of a hostile attitude towards Islam and a desire to do away with it altogether. Islamophobia would, in short, mean considering Islam as an enemy that must be fought. Years later Dinet and Ibrahim returned to this subject. In their work Le pèlerinage à la maison sacrée d'Allah, they devote several pages to 'Europe's hostility towards Islam', establishing what may well be the first typology of Islamophobia (Dinet and Ibrahim 1930, pp. 173-184). Dinet and Ibrahim distinguish between two types of Islamophobia, one 'pseudo-scientific' and the other 'clerical'. Pseudo-scientific Islamophobia would be the kind ascribed to certain Orientalists. However, beyond singling out erroneous translations of the Qur'an and certain initiatives to encourage the writing of Arabic with Latin letters, the authors fail to provide any examples of what this 'pseudo-scientific' Islamophobia might consist of (ibid. pp. 176-183). Clerical Islamophobia was allegedly engaged in by certain Evangelical missionaries bent on converting Muslims to Christianity. In this respect, the two authors are mainly referring to the American missionary Samuel M. Zwemer Alain Quellien's approach Dinet and Ibrahim were not the first to use the term Islamophobia, which appeared earlier in at least two works on the subject of West Africa under French colonial rule, both dated 1910. The first one is an article by the French Africanist Maurice Delafosse (1870-1926) entitled 'L'état actuel de l'islam dans l'Afrique occidentale française'. Towards the end of this article, Delafosse makes a few recommendations concerning the way in which the French colonial authorities should wrestle with Islam. He says: Whatever those for whom Islamophobia is a principle of indigenous administration may say, France has no more to fear from Muslims in West Africa than from non-Muslims. (…) l'Afrique occidentale française. In it, Quellien devotes an entire epigraph to Islamophobia, providing what we might consider a first explicit definition of the term. For Quellien, Islamophobes are 'all the authors who consider Islam an implacable enemy of the Europeans' (Quellien 1910, p. 135). Islamophobia therefore springs from the notion that Islam is the implacable enemy of the Europeans, which would clearly denote a hostile attitude towards Islam and the Muslims. For Quellien, considering Islam as an implacable enemy and considering Muslims as implacable enemies are one and the same. Summing up Islamophobia in just a few sentences, Quellien says: According to Quellien, then, Islamophobia is based on a series of accusations.

First is the 'holy war' accusation, apparently based on the notion that Islam was the sole cause of the string of armed conflicts pitting Muslim populations against colonial armies in the nineteenth century. Quellien contends that this armed

The second accusation used to justify Islamophobia is slavery (ibid. pp. 141-146), followed by polygamy, in which respect Quellien notes that 'there is these accusations. Quellien believes that Islam has 'assuredly fuelled the progress of the populations it has converted, it has provided them with a moral force they hitherto lacked and, through the idea that good deeds will be rewarded, it has greatly encouraged the good instincts of human nature

' (ibid. p. 152)

. Contrary to the assertions of the Islamophobic authors Quellien cites, Islam does not breed fanaticism and intolerance and far less so in French-controlled West Africa where 'the Muslim shows great tolerance towards Christianity' (ibid. p. 153).

Notwithstanding these considerations, Quellien warns of the existence of certain dangers threatening European hegemony in Islamic countries, dangers embodied in Sufi brotherhoods or tariqahs, pan-Islamism and certain Mahdi movements. According to Quellien, these dangers -while real enough-are not as significant as they were often held to be

(ibid. pp. 158-169, 178-179, 184-188)

.

to the fact that it is professed by a "race" with a 'naturally mild-natured, indolent and peaceful' character, which he qualifies as 'a sure guarantee of their

  Nor did Edward Said used it inOrientalism (1979) or in Covering Islam

	(1962), nor Maxime Rodinson (1980), nor, more recently, John Tolan (2002) used
	the term.
	F o r
	P
	e
	e r
	R
	e
	v i e
	w
	O n l
	y
	, nor Richard Southern
	19

  And through criticism and analysis, they also tried to understand what with this name consisted of. These authors used the term to refer to the belief that Islam and Muslims were the implacable, absolute and eternal enemies of Christianity, Christians, Europe and Europeans. An enemy image cannot consist only in feelings of dislike or antipathy; it always involves the possibility of violence and destruction. It is a matter of existence and survival.'(Luostarinen 1989, emphasis in original). In this case, Islamophobia would be a hostile attitude towards Islam and Muslims based on the image of Islam as an enemy, as a threat to "our" wellbeing and even to Islam effectively represented a threat to Europe and the Europeans, but not because it defended theological truths that differed from the tenets of Christianity, but because it might serve as a vehicle for political mobilization against the European colonial presence. In short, although religious intolerance can be an element that should be taken into consideration in certain cases of Islamophobia,

	the phenomenon designated Islamophobia engendered, nurtured and conveyed an 'enemy image' of Islam and
	Muslims, insofar as they are perceived as the incarnation of Islam.
	According to Luostarinen, an 'enemy image' is 'a belief held by certain group
	F o r P e e r R that its security and basic values are directly and seriously threatened by some F o r P e e r other group. "our" survival. R
	e Islamophobia, then, would be neither a form of religious intolerance nor a form e
	v i e w of racism or cultural racism, although in certain circumstances it could be mixed v i e with these other forms of rejection. The authors studied here show that Islamophobia can be shared by many people irrespective of ideology or religious w
	O n l y beliefs. These authors show that being racist does not necessarily mean being Islamophobic, just as being Islamophobic does not necessarily imply being racist. O n l Delafosse, Quellien and Binger could be racists without being Islamophobes and y
	at the same time, other authors they criticized as Islamophobes were not
	necessarily racists. This hold true particularly in the case of some Evangelical
	missionaries who, even when they had an image of Islam as the enemy, believed
	that Muslims would no longer represent a threat to Europeans if they converted to
	Christianity. But the same can be said of more secularized individuals, for whom
	20 21

  The nationalist Serbian intellectuals and islam: defining and eliminating a Muslim community', in QURESHI, E. & SELLS, M. A. (eds) The new Crusades: constructing the Muslim enemy. New York: Columbia University Press, pp. 314-352. CIMINO, R. 2005 '«No God in common»: American Evangelical discourse on Islam after 9/11', Review of Religious Research, vol. 47, no. 2, pp. 162-174. Islam and the West: the making of an image. Oxford: Oneworld Pub. [1st ed. Edinburgh, 1960]. DELAFOSSE, M. 1910 'L'état actuel de l'islam dans l'Afrique occidentale française', Revue du Monde Musulman, vol. 11, no. 5, pp. 32-53.---1912 Haut-Sénégal-Niger (Soudan français). 3 vols. Paris: E. Larose. DINET, É. & IBRAHIM, S. B. 1925 L'Orient vu de l'Occident: essai critique. Le statut des musulmans en Algérie coloniale: une nationalité française dénaturée', in ARKOUN, M. & LE GOFF, J. (eds) Histoire de l'islam et des musulmans en France du Moyen Âge à nos jours. Paris: Albin Michel, pp. Anthropology Today, vol. 21, no. 1, pp. 5-9. FERNANDO BRAVO LÓPEZ is member of the Workshop on International Mediterranean Studies (TEIM), Universidad Autónoma de Madrid. He is currently working on a book based on his PhD thesis, devoted to the comparison between Islamophobia and anti-Semitism. ADDRESS: Taller de Estudios Internacionales Mediterráneos (TEIM), Facultad de Filosofía y Letras, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049, Madrid (Spain). Email: fernandobravolopez@yahoo.es

	o r F o r than an explanation'. Submission to the Changing Landscape of Citizenship and Security, 6th PCRD of European Commission, 1 June, http://www.libertysecurity.org/IMG/pdf_Challenge_Project_report.pdf (accessed 20 May 2010). o r F o r F o r F o r F r o CIGAR, N. 2003 'F WEIL, P. 2006 '548-561. WERBNER, P. 2005 'Islamophobia: incitement to religious hatred -legislating for a new fear?' Page 29 of 29
	P P P P P P P
	e e e e e e e
	e r e r e r e r e r e r e r
	R R R R R R R
	e e e e e e e
	v i e v i e v i e v i e v i e v i e v i e
	w w w w w w w
	O n l O n l O n l O n l O n l O n l O n l
	y y y y y y y
	24 29

COMMISSION ON BRITISH MUSLIMS AND ISLAMOPHOBIA 2004 Islamophobia: Issues, challenges and action. Stoke on Trent, UK & Sterling, USA: Trentham Books. COOK, S. A. 1924 'Chronicle. The history of religions', Journal of Theological Studies, no. 25, pp. 101-109. DANIEL, N. 1966 Islam, Europe and Empire. Edinburgh: Edinburgh University Press. ---1993 Paris: H. Piazza. ---1930 Le pèlerinage à la maison sacrée d'Allah. Paris: Hachette. URL: http://mc.manuscriptcentral.com/rers ethnic@surrey.ac.uk Ethnic and Racial Studies

URL: http://mc.manuscriptcentral.com/rers ethnic@surrey.ac.ukEthnic and Racial Studies

Acknowledgements

This article was made possible through the R&D project "Immigration and Religious Pluralism" (PAI08-0159-2339), directed by Miguel Hernando de Larramendi and funded by the Junta de Comunidades de Castilla-La Mancha (Spain). The author would like to thank Caroline Haslett, who translated into English the original Spanish text of this article.


Dr Kathryn J Rolfe
email: kathryn.rolfe@addenbrookes.nhs.uk

M D Curran

G J M Alexander

T Woodall

N Andrews

H E Harris

Univariable Multivariable Factor Level Non-Viraemic/Total (%) RR (95% CI), p-value RR* (95% CI), p-value

Keywords: clearance, genotype, hepatitis C, spontaneous, serotype

Table II: Univariable and multivariable analyses of those individuals for whom genotyping and serotyping data was available (N=280) and for all those included in the study with and without typing data (N=321). * Relative risks obtained using binomial regression with a log link. ** Note that using logistic regression rather than binomial regression with a log-link gives OR=3.03 (1.53-6.00), P=0.002 for type-1 and OR = 2.75 (0.84-9.02), P=0.10 for types 2, 4, 5 and 6. Infecting HCV type was identified by genotyping (viraemic) or serotyping (nonviraemic). Binomial regression analysis investigated the independent effect of HCV type on spontaneous loss of HCV-RNA from serum by comparing the two groups.

Ninety one per cent of patients were found to be either genotype 1 or genotype 3.

The prevalence of type 1 infection was greater among non-viraemic (64.5%) than viraemic individuals (45%). After controlling for the effects of potential confounding factors, multivariable analyses showed that individuals with type 1 infections were more likely to be non-viraemic than genotype 3 infections (RR=2.07; 95%CI: 1.25, 3.43; P=0.005). Individuals infected at an older age were also less likely to become HCV-RNA negative spontaneously (RR=0.42 comparing those infected at >=20 years of age against those infected at <20 years of age, 95%CI: 0.25, 0.72; P=0.002). In conclusion, the results suggest that HCV genotype 1 infections are more likely than genotype 3 infections to become spontaneously non-viraemic, as are infections acquired at younger age.

Introduction

Spontaneous resolution of HCV infection, defined by normalisation of liver function tests (LFTs) and loss of HCV-RNA from serum, occurs in 26 -36% of HCV-infected individuals (Santantoni et al, 2003[START_REF] Carreño | Occult hepatitis C virus infection: a new form of hepatitis C[END_REF][START_REF] Micallef | Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies[END_REF]. This group is of particular interest since an understanding of the mechanisms associated with spontaneous loss of HCV-RNA from serum may aid vaccine development. A number of factors are linked to spontaneous loss of HCV-RNA from serum including clinical factors such as symptomatic infection [START_REF] Gerlach | Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance[END_REF], HBV co-infection [START_REF] Piasecki | Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population[END_REF] and host factors including female gender [START_REF] Alric | Study of host-and virus-related factors associated with spontaneous hepatitis C virus clearance[END_REF][START_REF] Micallef | Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies[END_REF]) and white ethnicity [START_REF] Piasecki | Influence of alcohol use, race, and viral coinfections on spontaneous HCV clearance in a US veteran population[END_REF][START_REF] Thomas | The natural history of hepatitis C virus infection: host, viral, and environmental factors[END_REF].

Innate and host immune responses to HCV are likely to play an important role in spontaneous loss of HCV-RNA from serum, which has been linked in some, but not all studies with: genetic polymorphisms that modify IL-10, TNF-α or IFN-γ production [START_REF] Kusumoto | Interleukin-10 or tumor necrosis factor-alpha polymorphisms and the natural course of hepatitis C virus infection in a hyperendemic area of Japan[END_REF][START_REF] Lio | IL-10 and TNFalpha polymorphisms and the recovery from HCV infection[END_REF][START_REF] Mangia | IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection[END_REF][START_REF] Minton | Clearance of hepatitis C virus is not associated with single nucleotide polymorphisms in the IL-1, -6, or -10 genes[END_REF]; polymorphisms in interferon-induced genes [START_REF] Knapp | Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR[END_REF] and HLA class II alleles [START_REF] Minton | Association between MHC Class II alleles and clearance of circulating Hepatitis C virus[END_REF]. Recent studies have demonstrated a significant association between a single polymorphism upstream of the IL28B gene (which encodes the type III interferon IFN-λ3) and both spontaneous [START_REF] Thomas | Genetic variation in IL28B and spontaneous clearance of hepatitis C virus[END_REF] and treatment-induced [START_REF] Ge | Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance[END_REF] HCV resolution. In a large cohort of women infected with HCV from a single source, HLA-B27 allele was present more frequently in non-viraemic individuals compared to those with viraemia [START_REF] Mckiernan | Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source[END_REF].

Viral factors have also been reported to influence spontaneous loss of HCV-RNA from serum. A prospective study of 92 anti-HCV positive males with a history of with 7% of type 1) [START_REF] Lehmann | High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection[END_REF]. Infection with genotype 1, specifically subtype 1b, has been linked to chronic infection [START_REF] Amoroso | Correlation between virus genotype and chronicity rate in acute hepatitis C[END_REF][START_REF] Hwang | Hepatitis C viral genotype influences the clinical outcome of patients with acute posttransfusion hepatitis C[END_REF]. Conversely, in a large study, Harris and colleagues (2007) suggested that HCV genotype 1 infection was more likely to be associated with spontaneous loss of HCV-RNA from serum than non-1 genotype infection. A recent meta-analysis of 31

longitudinal studies with 675 study subjects concluded that the only factors significantly associated with loss of HCV-RNA from serum were female gender and acute symptomatic HCV infection [START_REF] Micallef | Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies[END_REF].

The aim of this study was to describe the prevalent HCV genotypes in a cohort of patients presenting to the hepatology service at Addenbrooke's Hospital, Cambridge and to investigate whether spontaneous loss of HCV-RNA from serum was linked to infecting HCV genotype.

Materials and Methods

Study sample

Consecutive patients presenting as new referrals to the Hepatology clinic at and time since exposure (calculated as the date of sample minus the reported date of exposure). Sufficient residual sera were available for further testing in 321 of these individuals (219 viraemic and 102 non-viraemic patients) which were subjected to investigation as below.

HCV typing

For viraemic patients, HCV genotype was identified using an improved Taqman HCV genotyping assay [START_REF] Rolfe | A real-time Taqman method for hepatitis C virus genotyping[END_REF][START_REF] Rolfe | A real-time Taqman method for hepatitis C virus genotyping and methods for further subtyping of isolates[END_REF]. For non-viraemic patients, the infecting viral type was ascertained by serotyping using the Murex HCV Serotyping kit (Abbott Diagnostics, Berkshire), following manufacturers' guidelines. Further tests were carried out on all non-viraemic samples to exclude the possibility that these might be HCV-RNA positive but at levels below the sensitivity of the HCV quantitation assay.

One ml of serum was ultracentrifuged (25,000 xg for 60 min) prior to extraction to concentrate any virus particles. The pellet was then re-suspended in 350 µl of ultra-PURE™ water. Nucleic acid was extracted on the BioRobot MDx workstation (Qiagen, Crawley UK) and amplified using the HCV quantitation assay. HCV-RNA remained undetectable in all sera ultracentrifuged prior to extraction; the internal control (which detects amplification inhibition) was amplified in these samples within the acceptable range.

Statistical analysis

For statistical analysis, age at exposure was examined as a categorical variable (<20 years vs. >= 20 years). As 91% of infections were found to be either genotype 1 or

Results

Of the 321 specimens, 37 were untypable, 4 were mixed genotypes, 138 were type 1, 118 were type 3, and 24 were other types. For the primary analysis those that were untypable or of mixed type were not included, leaving 280 typed specimens of which 62 were from non-viraemic patients (Table I). The univariable analyses demonstrated that spontaneous loss was more likely in those who were UK born, who were younger at acquisition and who were infected with type 1 virus (Table II). In the multivariable analysis the effect of type 1 remained similar with a RR compared to type 3 of 2.07 (95% CI; 1.25, 3.43). Genotypes 2, 4, 5, and 6 showed some evidence of having a higher spontaneous loss than type 3 (RR 2.94), although this was based on small numbers (n=24) and was not significant when using logistic regression II). In the multivariable analysis, likelihood of spontaneous loss remained significantly associated with those born in the UK and those who were <20 compared to >=20 years old at acquisition (RR 0.42; 95% CI 0.25, 0.72, for >=20 versus <20) (Table II).

Further analyses on all individuals initially included in the study (n=321), which took into account the 41 that were non-typable or of mixed type, were undertaken (Table II). Age at exposure and country of birth remained significantly associated with spontaneous loss of HCV-RNA from serum with broadly similar RR estimates.

Additionally, excess alcohol was associated with a reduced likelihood of spontaneous loss of HCV RNA in this group (RR 0.61; 95% CI 0.43, 0.85). Genotype could not be assessed in this analysis since those that were non-typable (with one exception)

were non-viraemic.

Discussion

Early treatment of HCV can prevent chronic infection. However, antiviral therapy for HCV infection has substantial side effects and is costly. Spontaneous loss of HCV-RNA from serum occurs in around twenty to thirty per cent of people with acute HCV infection [START_REF] Santantonio | Natural course of acute hepatitis C: a long-term prospective study[END_REF][START_REF] Micallef | Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies[END_REF]. It would be advantageous to identify these people prior to therapy. Spontaneous loss of HCV-RNA from serum occurs within 3 months of infection [START_REF] Gerlach | Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance[END_REF][START_REF] Santantonio | Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance[END_REF], so delaying treatment of individuals to target only those who remain HCV-RNA positive is feasible [START_REF] Santantonio | Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy[END_REF]. For the strategy of delayed treatment to be possible, it would be helpful to identify factors, host or viral, that predict spontaneous loss of HCV-RNA from serum. In this study, those without viraemia were defined as negative for HCV-RNA on a number of occasions. It is presently unclear whether spontaneous loss of HCV-RNA from serum is associated with complete eradication of the virus including the liver, or whether low-level viral replication persists but is controlled by cellular and humoral immune responses.

Several small studies suggest that HCV-RNA can be consistently undetectable in serum or plasma by laboratory assays, but be identifiable in serum and peripheral blood mononuclear cells (PBMCs) by molecular tests with enhanced sensitivity, in patients thought to have loss of HCV-RNA from serum [START_REF] Pham | Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C[END_REF][START_REF] Radkowski | Evidence for viral persistence in patients who test positive for anti-hepatitis C virus antibodies and have normal alanine aminotransferase levels[END_REF]. Increasing the sensitivity of HCV-RNA detection is possible by ultracentrifugation of the serum prior to nucleic acid extraction (Bartolomé et al, 2007;[START_REF] Forman | Increased sensitivity of the Roche COBAS AMPLICOR HCV test, version 2.0, using modified extraction techniques[END_REF][START_REF] Mchutchison | Ultracentrifugation and concentration of a large volume of serum for HCV RNA during treatment may predict sustained and relapse response in chronic HCV infection[END_REF]. The HCV quantitation assay utilised in this study, demonstrated good sensitivity (25 IU/mL), comparable to commercial assays. HCV-RNA was not detected in any of those HCV-RNA negative in serum despite ultracentrifugation prior to extraction.

Thirty seven isolates (36.3%) were negative by HCV serotyping, which was probably due to degradation of HCV-specific antibodies during storage. Serotyping failure could also be a result of loss of antibody response with time in resolved infection, especially in individuals with a long time period between exposure and subsequent testing. The assay should not exhibit different genotype sensitivity which might have resulted in bias. The possibility of bias was investigated by examining the optical density (OD) readings of all serotyped isolates. No significant difference in OD was observed between genotype 1 and type non-1 isolates. However, the possibility of over-representation of a particular serotype amongst those which failed cannot be completely ruled out. Despite the steps taken to ensure that samples were HCV-RNA negative, the possibility of occult HCV infection in individuals presumed to have cleared the virus cannot be ruled out. Occult HCV infection has been recently reported and is defined as the presence of HCV-RNA in the liver without serum HCV-RNA [START_REF] Castillo | Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown[END_REF]. It has been reported in two clinical situations: in anti-HCV negative, serum HCV-RNA negative patients with abnormal LFTs and in anti-HCV positive subjects with normal LFTs without serum HCV-RNA (Carreno et al, 2006). In a small study on twelve patients who were anti-HCV positive, serum HCV-RNA negative with normal LFTs, 83% of these individuals had both genomic and anti-genomic HCV-RNA strands detected in the liver, demonstrating HCV replication in the majority of these patients (Carreno et al, 2006a). Interestingly, all the infections were found to be with subtype 1b. Recently a study examining liver biopsies from HCV non-viraemic individuals found evidence of an ongoing immune response in the liver, which also often demonstrated fibrosis, supporting the view that HCV persists in the liver of most serum HCV-RNA negative individuals [START_REF] Hoare | Histological changes in HCV antibody-positive, HCV RNA-negative subjects suggest persistent virus infection[END_REF]. These findings suggest that the term 'spontaneous clearance' must be used with care, as these individuals may still have genomic HCV-RNA in liver tissue.

The findings of the present study support those of Harris and colleagues (2007). In their study, the infecting type was ascertained in a large cohort of individuals who were viraemic (n = 508) or had spontaneous loss of HCV-RNA from serum (n = 96).

That study showed that the prevalence of genotype 1 in those who were HCV-RNA negative in serum was 69% and in those that had remained viraemic was 51%, suggesting that individuals with HCV genotype 1 infection were more likely to become HCV-RNA negative (OR 0.47, 95% CI 0.29-0.78, P = 0.003). The study Programme and had acquired their infection on a known date via transfusion of infected blood (prior to routine HCV screening) [START_REF] Harris | The HCV National Register: towards informing the natural history of hepatitis C infection in the UK[END_REF]. The population group in the present study is very different. Unlike the aforementioned study, many of the patients in this study would have been identified by virtue of their clinical symptoms and referred to the Hepatology clinic for further investigation post-testing.

As such, cohorts of patients from tertiary referral centres are more likely to be biased towards symptomatic disease [START_REF] Sweeting | Estimated progression rates in three United Kingdom hepatitis C cohorts differed according to method of recruitment[END_REF]. Also, in contrast to the study by Harris and colleagues, 'date of infection' was often a crude estimate, as high risk activities, like intravenous drug use, gave an uncertain date for HCV acquisition.

The results from the present study strengthen the evidence that patients with genotype 1 infections are more likely to become spontaneously HCV-RNA negative in serum. Infecting genotype was significantly associated with non-viraemia in both univariable and multivariable statistical analyses. Individuals who had type 1 infections were more than twice (2.07x) as likely to become HCV-RNA negative.

Over 91% of HCV infections in this study were genotype 1 or 3, which reflects UK epidemiology (Health Protection Agency, 2009) This study also demonstrated that genotypes 2, 4, 5 and 6 were associated with non-viraemia (RR 2.94) although due to the low numbers of these genotypes, the finding was not significant when using logistic regression (p=0.10). Additionally those who acquired their infections at an older age were less likely to become HCV-RNA negative, with a RR of 0.42 for those infected at >=20 years of age compared to <20 years of age. The suggestion that genotype 1 infections are more likely to spontaneously lose HCV-RNA from serum than type 3 infections is contrary to certain other studies [START_REF] Amoroso | Correlation between virus genotype and chronicity rate in acute hepatitis C[END_REF][START_REF] Hwang | Hepatitis C viral genotype influences the clinical outcome of patients with acute posttransfusion hepatitis C[END_REF][START_REF] Lehmann | High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection[END_REF]. Although spontaneous loss of HCV-RNA from serum may be more likely in genotype 1 infection, it is thought that, in those individuals with a chronic genotype 1 infection, disease may be more severe [START_REF] Harris | Does the clinical outcome of hepatitis C infection vary with the infecting hepatitis C virus type?[END_REF][START_REF] Lopez-Labrador | Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma[END_REF][START_REF] Nousbaum | Hepatitis C virus type 1b (II) infection in France and Italy[END_REF][START_REF] Pozzato | Different genotypes of hepatitis C virus are associated with different severity of chronic liver disease[END_REF][START_REF] Tanaka | Hepatitis C virus 1b(II) infection and development of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma: a case-control study in Japan[END_REF]. It is plausible that genotype 1 infections might be more aggressive and therefore more likely to provoke an immune response leading to resolution, but if the immune response fails then the disease may be more severe. The association between younger age at exposure and spontaneous loss of HCV-RNA from serum demonstrated in this study has been reported in haemophiliacs [START_REF] Messick | Hepatitis C viral clearance and antibody reactivity patterns in persons with haemophilia and other congenital bleeding disorders[END_REF][START_REF] Zhang | Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia[END_REF] and in childhood HCV infection [START_REF] Yeung | Spontaneous clearance of childhood hepatitis C virus infection[END_REF]. Older age at exposure is thought to be linked to increased risk of progression to cirrhosis [START_REF] Minola | Age at infection affects the long-term outcome of transfusionassociated chronic hepatitis C[END_REF]. It is pertinent to mention that in the study described, the age of exposure was, for the majority, a crude estimate which relied on each individual's recollection of risk incident. For those, such as intravenous drug users, who are involved continually in risk behaviour, the date of infection may be inaccurate. The association between younger age at exposure and increased likelihood of spontaneous non-viraemia is not surprising as the immune system is more responsive and able to fight infection at a young age and degenerates during the ageing process.

This study has demonstrated that age at exposure and HCV genotype are both associated with loss of HCV-RNA from serum. Thus, younger patients with acute genotype 1 HCV infection may be less likely to need antiviral treatment.

  factors have been associated with spontaneous loss of hepatitis C virus (HCV-)RNA from serum, including infecting HCV type, although results are conflicting. This study aimed to investigate further whether infecting HCV type was linked to spontaneous loss of HCV-RNA. Serum samples from 321 untreated HCV antibody positive patients presenting at the Hepatology clinic at Addenbrooke's Hospital, Cambridge between 2004 and 2007 were tested. These individuals were classified either as HCV antibody and HCV-RNA positive (viraemic, n=219) or HCV antibody positive and repeatedly HCV-RNA negative (non-viraemic, n=102).

  demonstrated a greater prevalence of genotype 3 in individuals who cleared HCV-RNA from serum spontaneously (86% of type 3 cleared compared

  patients enrolled in the UK HCV National Register and most of these patients (90%) had been traced during the National HCV Lookback

Table I :

 I Results of HCV genotyping and serotyping (excluding mixed genotypes and serotyping failures).

		Not-known	7/67 (10.4)	0.29 (0.14-0.59), 0.001		4/64 (6.3)	0.23 (0.88-0.62), 0.004
	Alcohol	Safe alcohol	71/195 (36.4)	Baseline	Baseline	38/161 (23.6)	Baseline	Baseline
	consumption	Excess	29/117 (24.8)	0.68 (0.47-0.98), 0.04	0.61 (0.43-0.85), 0.004	22/110 (20)	0.85 (0.53-1.35), 0.49	0.72 (0.50-1.05), 0.09
		alcohol
		Not-known	2/9 (22.2)	0.61 (0.18-2.1), 0.43	0.98 (0.28-3.48), 0.98	2/9 (22.2)	0.94 (0.27-3.30), 0.93	0.92 (0.24-3.56), 0.90
	Genotype	Type-3				16/118 (13.6)	Baseline	Baseline
		Type-1				40/138 (29.0)	2.14 (1.26-3.61), 0.005	2.07 (1.25-3.43), 0.005**
		Type-2,4,5,6				6/24 (25.0)	1.84 (0.08-4.23), 0.15	2.94 (1.74-4.97),
								<0.001**
	Age at exposure	<20 years	46/94 (48.9)	Baseline	Baseline	32/80 (40.0)	Baseline	Baseline
		>20 years	36/117 (30.8)	0.63 (0.45-0.88), 0.008	0.67 (0.49-0.93), 0.015	14/95 (14.7)	0.37 (0.21-0.64), <0.001	0.42 (0.25-0.72), 0.002
		Not-known	20/110 (18.2)	0.37 (0.24-0.58), <0.001	0.45 (0.28-0.70), <0.001	16/105 (15.2)	0.38 (0.23-0.64), <0.001	0.43 (0.25-0.73), 0.002
	Time since	<20 years	27/78 (34.6)	Baseline		17/68 (25.0)	Baseline
	exposure
		>20 years	55/133 (41.4)	1.19 (0.83-1.72), 0.34		29/107 (27.1)	1.08 (0.65-1.82), 0.76
		Not-known	20/110 (18.2)	0.53 (0.32-0.87), 0.01		16/105 (15.2)	0.61 (0.33-1.12), 0.11

Acknowledgements and Disclosures

This research was funded in part by the Health Protection Agency. None of the authors have any financial or other conflicts of interest.


Dean Bryant

Nirmala Rai

Gareth Lloyd Rowlands

Sam Hibbitts

Joanne Jones

Amanda Tristram

Alison Fiander

Dr Ned Powell
email: powellng@cf.ac.uk

Alison Tristram

Ned Fiander

Powell

Human Papillomavirus type distribution in Vulval Intraepithelial Neoplasia determined using PapilloCheck DNA microarray

Keywords: HPV, Human papillomavirus, VIN, Vulval intraepithelial neoplasia, Papillocheck HPV, Human papillomavirus, VIN, Vulval intraepithelial neoplasia, Papillocheck 38

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

INTRODUCTION 39

Vulval intraepithelial neoplasia is frequently a painful, distressing condition, and a 40 precursor lesion of invasive vulval carcinoma. In recent decades the incidence of 41 vulval intraepithelial neoplasia has increased, while the mean age of patients has 42 decreased. The incidence of vulval cancer rose by 17% between 197917% between and 200117% between 43 [MacLean, 2004]], with 996 new cases registered in England in 2000 [MacLean, 44 2006]. 45 Human Papillomavirus (HPV) positivity in vulval intraepithelial neoplasia lesions is 46 reported in international meta-analyses as 84% with most cases attributable to HPV 47 type 16 [START_REF] Vuyst | 241 Prevalence and type distribution of human papillomavirus in carcinoma and 242 intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis[END_REF]. The most likely explanation for the increased 48 incidence of vulval intraepithelial neoplasia is the substantial rise in HPV infections 49 of the lower genital tract [START_REF] Peto | The cervical cancer epidemic that 287 screening has prevented in the UK[END_REF]; the lifetime risk of HPV infection being 50 estimated at up to 79% [START_REF] Syrjanen | Prevalence, incidence, and estimated life-time risk of 296 cervical human papillomavirus infections in a nonselected Finnish female 297 population[END_REF]. 51

The aim of this investigation was to identify HPV types present in vulval 52 intraepithelial neoplasia, confirmed histologically, using the Greiner Bio-One 53 (associated with lichen sclerosis) [START_REF] Sideri | Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, 290 ISSVD Vulvar Oncology Subcommittee[END_REF]. However, the existence of 79 differentiated vulval intraepithelial neoplasia is disputed, and in practice this diagnosis 80 is rarely made [START_REF] Mccluggage | Recent developments in vulvovaginal pathology[END_REF] HPV infection was identified using the Greiner Bio-One Papillocheck ® assay (Greiner 88 Bio-One GmbH, Frickenhausen, Germany), which enables simultaneous detection and 89 typing of 24 different HPV types in a single reaction (HPV 16,18,31,33,35,39,45,90 51,52,53,56,58,59,66,68,70,73,82,6,11,40,42,43 & 44) . The assay uses 91 multiplex PCR with fluorescent primers to amplify a 350bp fragment of the E1 gene. 92

The PCR product is then hybridised to a PapilloCheck ® DNA array, comprising 28 93 probes, each in 5 replicate spots. To identify false negatives the assay includes 94 amplification of the human ADAT1 gene. Hybridization is assessed using the 95 CheckScanner™ array reader. Amplification, hybridization, detection and 96 interpretation were performed according to the manufacturer's instructions. A valid 97 result was defined as one which passed all of the PapilloCheck ® internal controls 98 (including DNA adequacy, sample inhibition, and hybridisation). 99

Previous studies have confirmed the analytical [START_REF] Dalstein | Analytical 238 evaluation of the PapilloCheck test, a new commercial DNA chip for detection 239 and genotyping of human papillomavirus[END_REF]Jones et al., 100 2009] and clinical validity [START_REF] Halfon | 253 Comparison of the clinical performance of carcinogenic HPV typing of the 254 Linear Array and Papillocheck((R)) HPV-screening assay[END_REF]Hesselink et al., 2009] were: 3 cases with HPV 16 and 33; 2 cases with HPV 16 and 6; and one case each of 119 (16,18), (33, 42), (16, 31, 33), (16, 51). In the 5 cases where only LR types were 120 present, 3 were HPV 6 (histology: two cases of vulval intraepithelial neoplasia grade 121 3, and one vulval intraepithelial neoplasia grade 3 with well-differentiated carcinoma 122 and viral warts), 1 was HPV 40 (vulval intraepithelial neoplasia 1) and 1 contained 123 HPV 42 (vulval intraepithelial neoplasia 1). 124 or worse. This was slightly lower in HPV negative lesions, where 9/11 (81.8%) 134 showed vulval intraepithelial neoplasia grade 2 or worse, but this difference was not 135 significant (Fisher's P = 0.266). 136

There was no significant correlation between HPV type and histological grade; 137 however it was noticeable that all of the HPV 16 positive cases were associated with 138 vulval intraepithelial neoplasia 2 or worse, while a high risk type (HPV 18) was 139 identified in only 1/5 vulval intraepithelial neoplasia grade 1 cases with valid HPV 140 results. 141 Slides were available for pathology review for 54/59 cases. 52/54 cases were "Usual 142 vulval intraepithelial neoplasia"; 2/54 cases were "Probable Differentiated vulval 143 intraepithelial neoplasia". Both cases of probable Differentiated vulval intraepithelial 144 neoplasia were in HPV negative patients: one an 82 year old woman with vulval 145 intraepithelial neoplasia 3, the other a 61 year old woman with vulval intraepithelial 146 neoplasia 1 (but with a history of vulval cancer). Among the cases with valid HPV 147 results, 42/49 cases of usual vulval intraepithelial neoplasia were HPV positive 148 (85.7% 95%CI: 73.3-92.9%). 149 This is the largest UK series of vulval intraepithelial neoplasia in which HPV type has 151 been determined. The main limitation of this study was the use of a self selected 152 sample, i.e. women attending a specialist vulval intraepithelial neoplasia clinic. This 153 might bias the sample towards women with persistent or recurrent disease, which 154 might possibly result in some over-representation of more persistent types (HPV 16). 155

A further limitation was the use of separate biopsies for pathology and HPV analysis; 156 in practice both biopsies were immediately adjacent and cases were only included if 157 both biopsies were part of the same macroscopically visible lesion. It is however 158 theoretically possible that the research biopsy may not be representative of the 159 diagnostic biopsy. 160 161 Several studies have investigated HPV prevalence in vulval intraepithelial neoplasia 162 in the UK and estimate HPV positivity at 37.5 to 100%, with the proportion of HPV 163 positive cases containing HPV 16 varying from 37.5 to 93.3% [Abdel-Hady et al., 164 2001;[START_REF] Baldwin | Vaccinia-expressed human papillomavirus 16 and 18 e6 and e7 as a 228 therapeutic vaccination for vulval and vaginal intraepithelial neoplasia[END_REF][START_REF] Daayana | 235 Phase II trial of imiquimod and HPV therapeutic vaccination in patients with 236 vulval intraepithelial neoplasia[END_REF][START_REF] Fiander | Prime-boost vaccination strategy in women with 246 high-grade, noncervical anogenital intraepithelial neoplasia: clinical results 247 from a multicenter phase II trial[END_REF]Gasco et al., 165 2002;[START_REF] Todd | The effects of 5% imiquimod cream on 299 high-grade vulval intraepithelial neoplasia[END_REF][START_REF] Tristram | Clinical responses to Cidofovir applied topically to 301 women with high grade vulval intraepithelial neoplasia[END_REF][START_REF] Woo | The use of HPV Linear 306 Array Assay for multiple HPV typing on archival frozen tissue and DNA 307 specimens[END_REF]. The sample 166 size in these studies ranged from 8-29 cases. The sample size for the current study is 167 larger, and the findings are more consistent with the overall results of a recent 168 international meta-analysis, in which 84.0% of vulval intraepithelial neoplasia cases 169 tested HPV positive (67.5% were HPV 16, 7.7% were HPV 33, and 4.6% were HPV 170 18) [START_REF] Vuyst | 241 Prevalence and type distribution of human papillomavirus in carcinoma and 242 intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis[END_REF]. The corresponding proportions in the current study were 171 overall HPV positivity of 79.6% (61.1 % were positive for HPV 16, 14.8% for HPV 172 33, and 3.7% for HPV 18). These are also similar to a separate meta-analysis which 173 (HPV 16 present in 71.2%, HPV33 in 7.7% and HPV 18 in 5.5% [START_REF] Smith | Human 292 papillomavirus type-distribution in vulvar and vaginal cancers and their 293 associated precursors[END_REF]). 175

Patients who tested positive for HPV infection were significantly younger (by over 11 176 years on average) than those testing negative. This is consistent with HPV associated 177 disease being more common in younger women and vulval intraepithelial neoplasia 178 associated with lichen sclerosis being more common in older patients [Bonvicini et 179 al., 2005]. 180

The finding that 85.7% of usual vulval intraepithelial neoplasia were HPV positive is 181 in accord with data previously reviewed [START_REF] Van De Nieuwenhof | Review of squamous 304 premalignant vulvar lesions[END_REF]. The 7 HPV 182 negative usual vulval intraepithelial neoplasia patients represent an interesting group; 183 it is not clear whether these patients are accounted for by mis-diagnosis of 184 differentiated vulval intraepithelial neoplasia (possibly due to sampling error), or 185 whether there is a subset of usual vulval intraepithelial neoplasia that is truly HPV 186 negative. 187 188 Three cases showing vulval intraepithelial neoplasia grade 2 or worse were associated 189 with a low risk HPV type alone (HPV6). One of these cases showed vulval 190 intraepithelial neoplasia grade 3 with well differentiated squamous cell carcinoma and 191 viral warts; it is possible that the warts were associated with the HPV 6 but the vulval 192 intraepithelial neoplasia and carcinoma were not. This apparent association between 193 high grade vulval intraepithelial neoplasia and LR HPV types runs contrary to the 194 suggestion that LR types cause only warts and low grade lesions. However an 195 association between LR HPV types and high grade disease was observed in the De 196

Vuyst meta analysis [START_REF] Vuyst | 241 Prevalence and type distribution of human papillomavirus in carcinoma and 242 intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis[END_REF] which reported approximately 5% of 197 vulval intraepithelial neoplasia 2/3 as linked to HPV 6. 198 HPV associated vulval intraepithelial neoplasia is most common in women in their 200 30's and 40's [START_REF] Hart | Vulvar intraepithelial neoplasia: historical aspects and current status[END_REF]. The incidence of VIN is approximately 5 per 100,000 201 women per year and is increasing [START_REF] Joura | Epidemiology, diagnosis and treatment of vulvar intraepithelial 271 neoplasia[END_REF]. HPV infection is endemic in the UK 202 with almost 30% of women in the 20-25 year age range now infected with a high risk 203 anogenital HPV type [START_REF] Hibbitts | Human papillomavirus prevalence in women attending 264 routine cervical screening in South Wales, UK: a cross-sectional study[END_REF]. Hence, in the short term, the number of 204 women affected by vulval intraepithelial neoplasia is likely to continue increasing. 205

HPV vaccination has been shown to be 100% effective in prevention of vulval 206 epithelial neoplasia 2/3 associated with HPV 16/18 in a per protocol population [Joura 207 et al., 2007]

  PapilloCheck ® DNA chip assay and determine the proportion of vulval intraepithelial 54 neoplasia potentially preventable by HPV prophylactic vaccination. comprised women attending a specialist vulval intraepithelial 59 neoplasia clinic at the University Hospital of Wales, Cardiff, UK between 2003 and 60 2009, with vulval intraepithelial neoplasia confirmed histologically, who gave written 61 informed consent for a biopsy to be taken for research purposes. The study was 62 approved by South Wales LREC (SMKW/EL/03/5178). 59 cases were investigated, 63 with an age range of 22-82 years, and a mean age of 45.8 years. There were six cases 64 of vulval intraepithelial neoplasia grade 1, two of vulval intraepithelial neoplasia 65 grade 2, and fifty one cases of vulval intraepithelial neoplasia grade 3. 66 67 Sample collection and processing. 68 Separate biopsies were taken for histology and research use. The research biopsy was 69 immediately placed in liquid based cytology medium (which fixed cells and preserved 70 DNA). DNA was extracted from the research biopsy using the Qiagen QIAamp kit 71 (QIAGEN GmbH, Hilden, Germany) according to the manufacturer's instructions. 72 73 Pathology review 74 A recent review of vulval intraepithelial neoplasia histopathology recommended 75 replacement of the vulval intraepithelial neoplasia 1/2/3 subdivisions with two 76 categories reflecting the putative aetiology of the disease: usual vulval intraepithelial 77 neoplasia (HPV-associated); and differentiated vulval intraepithelial neoplasia 78

  were aged 22-81 with a mean of 43.4 years. HPV negative cases 127 were aged 33-82 years with a mean of 54.9 years. The means of these groups were 128 significantly different (t test p = 0significant correlation between HPV positivity and grade of lesion. Of 132 the HPV positive cases, 40/43 (93.0%) showed vulval intraepithelial neoplasia grade 2 133

  HPV positivity of 80.4% for vulval intraepithelial neoplasia 2/3 174

Table I .

 I . In the UK vaccination of 12-13 year old girls against HPV 16/18 208 infection began in 2008. Hence it is likely to be 20 to 30 years before the effects of 209 this intervention become apparent in reduced incidence of vulval intraepithelial 210 neoplasia. Ultimately however, as HPV 16/18 were present in 63.0% of vulval 211 intraepithelial neoplasia, our data suggest that greater than half of vulval 212 intraepithelial neoplasia cases could be potentially prevented by vaccination. HPV type distribution within histological grade. There were 10 cases showing multiple infection, hence the number of types identified is greater that the number of cases. Percentages indicate the proportion of cases that tested positive for a given type. *the HPV 44 probe cross-hybridizes to HPV 55, hence these types are reported together.

					HPV Type
	Histology	16 18 31	33 51	6 40 42 44/55*
	VIN 1	0	1	0	0	0	0	1	2	1
	VIN 2	1	0	0	0	0	1	0	0	0
	VIN 3	32	1	1	8	1	4	0	1	0
	Total	33	2	1	8	1	5	1	3	1
	%	61.1 3.7 1.9 14.8 1.9	9.3 1.9 5.6	1.9
		F o r F o r F o r F o r
			P P P P
				e e e e
				e r e r e r e r
	213 214					R R R R e e e e v i e v i e v i e v i e
									w w w w

Acknowledgements

DB is grateful for support by a Cancer Research Wales Studentship Award. 216 Funding: The consumables for this study were provided free of charge by Greiner 217 Bio-One GmbH, Frickenhausen, Germany.