MD Julie Bottero
email: julie.bottero@aphp.fr

Anders Boyd

Joël Gozlan

Fabrice Carrat

Maud Lemoine

Hayette Rougier

Brigitte Varsat

Nicolas Boo

Cécile Charlois-Ou

Anne Collignon

Olivier Cha

Pauline Campa

Philippe Dhotte

Pierre-Marie Girard

Karine Lacombe

BSc Matthew Banks

Effectiveness of Hepatitis B rapid tests towards linkage to care: results of a randomized, multicenter study

Keywords: HBV, HBsAg testing, missed opportunities, screening, risk factors, Rapid test

Objectives: Worldwide, many infected individuals are unaware of their hepatitis B virus (HBV) status. We evaluated the effectiveness of HBV rapid-testing in promoting linkage-to-care.

Methods

: In 2012, volunteers were recruited from five Parisian centers. Participants were randomized 1:1 to receive standard serology (S) or rapid-testing (VIKIA®-HBsAg/Quick ProfileTM-anti-HBsAb) with confirmatory serology (R+S). Primary endpoint was percentage of individuals with appropriate linkage-to-care (non-immunized individuals starting vaccination or HBsAg-positive individuals receiving medical evaluation). Secondary outcomes were percentage receiving HBV-test results and performance of HBV rapid-tests.

Results: In total, 995 individuals were screened. Among HBV-infection groups included in the primary endpoint (n=409), 20 (4.9%) received appropriate linkage-to-care, with no difference between S and R+S groups (5.7% vs 4.1%, p=0.5). Two of 8 HBsAg-positive participants had a medical visit (1/6 and 1/2 in the S and R+S groups, respectively) and 18/401 (4.5%) nonimmunized participants initiated . Factors tending to be associated with linkage-to-care were female-gender, birth country of high HBV-prevalence and extended medical stay. Test results were not obtained in 4.7% of participants, which was significantly higher in the S arm (p=0.02). Sensitivity and specificity were both 100% for the VIKIA®-HBsAg rapid-test and 94.4% and 80.8%, respectively, for the anti-HBsAb Quick Profile™ rapid-test.

Conclusions: Despite a higher proportion of participants obtaining their results in the R+S arm and better performance of anti-HBsAb rapid-tests than previously described, we found no evidence that HBV-screening based initially on rapid-tests leads to increased HBV-vaccination rates or medical evaluation. This strategy needs evaluation in more hard-to-reach populations.

TEXT BACKGROUND

With more than 15 million infected persons and 38,000 attributed deaths each year in the United States [START_REF] Weinbaum | Recommendations for identification and public health management of persons with chronic hepatitis B virus infection[END_REF] and Europe [START_REF] Hatzakis | The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*[END_REF], hepatitis B virus (HBV) is one of the most frequent chronic infectious diseases, with a higher prevalence than human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. More than two-thirds of HBV-infected persons in Europe and the United States are unaware of their infection status [START_REF] Elpa | Report on hepatitis patient self-help in Europe[END_REF][START_REF]Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C[END_REF].These persons do not benefit from adequate medical care and constitute a reservoir of HBV transmission, which could be a source of new infections, such as the case for HIV [START_REF] Coates | Behavioural strategies to reduce HIV transmission: how to make them work better[END_REF].

In France, HBV prevalence was estimated at 0.65% in 2004, representing 281,000 individuals with positive hepatitis B surface antigen (HBsAg). In addition, 7.3%, or 3.2 million, were anti-Hepatitis B core antibody (anti-HBcAb) positive, indicating previous exposure to HBV [START_REF] Meffre | Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors[END_REF]. Among chronic carriers of HBsAg, 55% (155,000) were unaware of their HBV status. Since 1994, France's HBV immunization policy has focused on two broad aims: identifying, testing, and vaccinating persons high at-risk of HBV-exposure; and vaccinating all individuals during infancy, childhood or adolescence [START_REF] Dhumeaux | Prise en charge des personnes infectées par les virus de l'hépatite B ou de l'hépatite C[END_REF]. Despite these recommendations, vaccine coverage rates remained inadequate among infants until 2007 [START_REF] Dhumeaux | Prise en charge des personnes infectées par les virus de l'hépatite B ou de l'hépatite C[END_REF][START_REF] Invs | Couverture vaccinale hépatite B « 1 dose » à l'âge de 6 mois selon l'année de naissance, 2004-2014[END_REF] and were less than 50% in high at-risk groups [START_REF] Sclafer | Évolution de la couverture vaccinale contre l'hépatite B chez les patients vus à la consultation de médecine générale d'un centre de référence pour toxicomanes[END_REF][START_REF] Jauffret-Roustide | A national cross-sectional study among drug-users in France: epidemiology of HCV and highlight on practical and statistical aspects of the design[END_REF][START_REF] Bottero | Testing for Hepatitis B Virus (HBV) alone does not increase vaccine coverage in non-immunized persons[END_REF].

HBV-testing is essential for several reasons. It confirms whether individuals have been vaccinated or effectively acquired anti-hepatitis B surface antibodies (anti-HBsAb), identifies persons at-need of HBV vaccination, and provides a gateway to necessary care for infected persons, especially at early stages of disease [START_REF] Weinbaum | Recommendations for identification and public health management of persons with chronic hepatitis B virus infection[END_REF]. A number of recommendations are currently available, insisting upon increased HBV testing and turnaround time in returning results [START_REF] Weinbaum | Recommendations for identification and public health management of persons with chronic hepatitis B virus infection[END_REF][START_REF]Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C[END_REF][START_REF] Dgs | Plan national de lutte contre les hépatites B et C[END_REF].

HBV tests are usually based on standard enzyme-linked immunoabsorbant assays (ELISA), which require long periods of time to process. With the recent development of HBV rapid tests, results with high sensitivity and specificity can be given within minutes [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF]. Consequently, tested persons would no longer need to collect their test results at a later time [START_REF] Hutchinson | A meta-analysis of the effectiveness of alternative HIV counseling and testing methods to increase knowledge of HIV status[END_REF][START_REF] Has | Dépistage de l'infection par le VIH en France[END_REF] and more appropriate patient counseling could be delivered at first consultation. However, no study to-date has formally evaluated the effectiveness of rapid testing interventions as a means to increase linkage-to-care among persons unaware of their HBV-status.

The main objective of the Optiscreen B II study was to determine the usefulness of incorporating HBV rapid tests during screening in order to more adequately provide care for those tested. To this end, we conducted a randomized, multicenter trial determining if appropriate care was given when either rapid tests with confirmatory ELISA or standard ELISA was used.

METHODS

Study design and participants

The Optiscreen-B II study was a multi-center, parallel-group, randomized trial comparing the use of standard HBV tests to rapid tests. The study was approved by the Hôtel-Dieu Hospital Ethics Committee (Paris, France) in accordance with the Helsinki Declaration.

Volunteers were recruited from five study centers in the Paris metropolitan region, which actively participate in HBV screening, vaccination, and care -two STD clinics, one primary health care center, one general screening center, and one travel clinic. From 29 February 2012 to 05 July 2012, participants were included if seeking care at any of the participating centers, ≥18 years old, and could be available for further contact and medical follow-up at a single university teaching hospital.

Only persons eligible for HBV-screening were invited to participate. In a pre-randomization phase, participants were asked questions on potential risk factors associated with HBVtransmission during a face-to-face interview with a clinical research associate. This questionnaire (16) was based on screening/vaccination recommendations from the United States Centers of Disease Control and Prevention (CDC) (1) and the French council that determines immunization policies [START_REF] Hcsp | Calendrier des vaccinations et recommandations vaccinales 2011 selon l'avis du Haut conseil de la santé publique[END_REF]. If a participant did not have any one of the criteria recommending HBV-testing, they were not included in the study. Second, since one major factor steering the decision to test in practice is complete certainty of prior HBV-infection or vaccination status, participants with a confirmed HBsAg-positive, anti-HBsAb-positive, or anti-HBcAb-positive test (requiring irrefutable proof of result) were deemed ineligible for HBV-screening.

Participants were not included if they were unwilling to participate, already participated in the Optiscreen-B I validation study [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF], or were not covered under the national health care system. Signed written informed consent was obtained for all eligible participants prior to randomization.

Study interventions

Eligible participants were randomized 1:1 to receive one of two possible interventions: standard HBV test (S) or rapid HBV test with confirmatory ELISA (R+S). The central data management center (Inserm U707, Paris, France) was responsible for randomization. A computerized random number generator was used to select random permuted block sizes of 3 and 6 within each center.

The randomization list was concealed from investigators, who assigned participants to testing groups through a Web site after validating eligibility criteria.

In the S arm, approximately 10 mL of blood was drawn and then tested for HBsAg, anti-HBsAb, and anti-HBcAb. Serostatus was determined using a commercially-available ELISA assay (MONOLISA AgHBs Ultra, anti-HBs plus, anti-hepatitis B core antibody-anti-HBc-plus, BIORAD, Hercules, USA). Results were given 7-14 days after testing and, depending on the study center, were either mailed to participants or left at the study center for collection.

In the R+S arm, a 10 mL blood draw was collected. Before the blood sample coagulated, a few drops were immediately taken and applied to a rapid test determining HBsAg (VIKIA® Biomérieux, Marcy-L'Etoile, France) and anti-HBsAb status (Quick ProfileTM, Lumiquick, Santa Clara, CA, USA). Rapid tests were performed and interpreted per manufacturer's instructions by a trained clinical research associate, as previously detailed [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF]. Due to the poor sensitivity and negative predictive value of the rapid anti-HBsAb test [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF], the remaining blood sample was further tested using standard ELISA (as described in the S arm above). A presumptive diagnosis was made during the study visit based on results from the two rapid tests (Table 1). All participants were asked to obtain their ELISA results available 7-14 days after rapid testing.

For both arms, we established HBV-infection groups using ELISA results and defined them as follows: HBsAg-positive, resolved infection, isolated anti-HBc Ab+, vaccinated, and nonimmunized.

Study end-points

The primary outcome was the percentage of participants appropriately seeking care if needed.

Since this only applied to infection groups that required a medical intervention, analysis was restricted to HBsAg-positive and non-immunized individuals. Considering that follow-up recommendations for isolated anti-HBcAb-positive patients were unclear [START_REF] Weinbaum | Recommendations for identification and public health management of persons with chronic hepatitis B virus infection[END_REF][START_REF]EASL Clinical Practice Guidelines: management of chronic hepatitis B[END_REF], we decided not to evaluate the primary end-point in this HBV-infection group. However, the treating physician could recommend further evaluation.

HBsAg-positive persons were given instructions to schedule a comprehensive medical exam at Saint-Antoine Hospital, in accordance with European recommendations [START_REF] Easl | EASL clinical practice guidelines: Management of chronic hepatitis B virus infection[END_REF]. Appropriate care was then determined if a full evaluation of HBV-disease was performed 6 months after screening.

Non-immunized persons were contacted at most three times 4 to 6 months after screening via telephone by a clinical research associate. These participants were asked if they had been vaccinated and, if so, the date of first HBV vaccination. Appropriate care was then determined if HBV vaccination was initiated between screening and the time of telephone interview.

Participants unable to be contacted were considered as non-vaccinated in analysis

The secondary outcome was percentage of participants receiving their HBV-test result. For those study centers where HBV-test results were mailed, all participants were considered to have obtained their results (n=567). For those centers where HBV-test results were not mailed out, participants were considered as receiving their result if they returned to the clinic to obtain printed results (S and R+S arms) or had a reliable rapid test result that did not necessarily require ELISA (R+S arm, Table 1). In order to evaluate the effect of bias from mailing results, we performed subgroup analysis including only centers where the test result was not mailed.

Statistical analysis

Power calculations were performed to detect a >15% difference in immediate linkage-to-care and vaccination [START_REF]Surveillance and prevention of hepatitis B and C in Europe[END_REF]. Since virtually no data were available before the start of this study, discussions from an expert panel of clinicians concluded that an estimated 30% of participants would have appropriate care with a standard HBV test. Assuming Type 1 error of 0.05 and 80% power, a minimum 152 participants for each group would be needed. As roughly 40% of the population would be either non-immunized or HBsAg-positive from previous epidemiological studies [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF], a minimum of 375 participants for each group would be required.

Outcomes were compared using Pearson's χ² or Fisher's Exact test. In order to understand the reasons for not obtaining HBV-test results and for seeking appropriate care, we used randomeffects logistic regression to determine the univariable association between each outcome and a variety of demographic and HBV-transmission risk factors, while accounting for within-center correlation. Risk factors with a p≤0.2 in univariate analysis and study arm were retained and used to create a predictive, multivariable model.

In patients randomized to the R+S arm, we evaluated the performance of HBsAg and anti-HBsAb rapid tests compared to ELISA. Sensitivity (Se), specificity (Sp), positive and negative predictive values (PPV and NPV, respectively), and area under the receiving operator characteristic curves (AUROC) were estimated for each rapid test, without taking into account indeterminate results.

All statistical analysis were performed using STATA (v12.1, College Station, TX) and significance was determined using a p-value <0.05. This trial is registered at ClinicalTrials.gov (NCT01767597).

RESULTS

Study participants

Figure 1 illustrates the flow of study participation. A total of 2061 participants were initially screened for eligibility, of whom 1000 (48.5%) were randomized to receive either S or R+S testing. Among them, five did not fully complete study intervention. Thus, a total of 995 participants were included in analysis.

Half of participants were male with an average age of 40.4 (SD=15.8) years. A slight minority of participants were born in country of intermediate or high HBV-prevalence (HBsAg-positive 2.0-8.0%: n=253, 25.4%; and HBsAg-positive>8.0%: n=175, 17.6%, respectively). Almost 6% of participants lived in difficult social situations. No significant differences were observed between study groups (Table 2), yet there was a higher proportion of participants who had received tattoos in the R+S than S arm (p=0.04).

HBV-infection status

Overall, there were 8 participants with HBsAg-positive serology (R+S group: n=2, S group: n=6), giving an HBsAg-positive prevalence of 0.8% (95%CI: 0.3-1.6). All other participants had resolved infection (n=124, 12.5%), isolated anti-HBcAb (n=34, 3.4%), were vaccinated (n=428, 43.0%) or non-immunized (n=401, 40.3%). No difference between randomization groups and HBV-infection status was observed (p>0.09).

Performance of HBsAg and anti-HBsAb rapid tests in the R+S arm

Table 3 gives the classification probabilities of both rapid tests compared to standard serology for participants randomized to the R+S arm. While considering the very low prevalence of HBsAgpositive serology, the VIKIA® rapid HBsAg test had perfect Se, Sp, PPV, NPV. While including only patients with definitive anti-HBsAb results from standard serology (N=443), the QUICK PROFILE TM anti-HBsAb test had high Se, with moderately high Sp, PPV, and NPV.

Obtaining HBV test results

Of the 995 participants, 95.3% acquired their test results, while this proportion was fairly similar across HBV-infection groups (p=0.15, Figure 2). Among the participants included in centers where results were not mailed (n=428), 381 (89.0%) received their HBV-test result, while a significant difference was observed between S and R+S groups (85.4% and 92.6%, respectively, p=0.02). In multivariable analysis (data not shown), the only significant risk factor associated with failure to obtain results was the S study arm after adjusting for age, parents from a country of high HBV-prevalence, and HBV-infection status.

Appropriate care for HBV-infection groups in need of medical intervention

Among those HBV-infection groups in need of medical intervention (n=409), 20 (4.9%) received appropriate care, with no difference between study arms (p=0.5, Figure 2). Two of 8 (25.0%) HBsAg-positive participants came for medical consultation to ascertain their HBV-disease status (1/6 and 1/2 in the S and R+S groups respectively, p=0.3) and 18 of 401 (4.5%) nonimmunized participants initiated HBV vaccination (11/205 and 7/196 in the S and R+S groups respectively, p=0.5). Even when excluding patients who were unable to be reached by telephone, there was no difference in vaccination rates between S (n=12, 6.6%) and R+S (n=8, 4.9%) interventions (N=346, p=0.5).

In multivariable analysis (data not shown), males were borderline significantly less likely than women to receive appropriate HBV-care (p=0.05). Participants from high HBV-endemic countries and those who had an extended stay at a medical facility tended to receive more adequate care (p=0.08 and p=0.07, respectively).

DISCUSSION

To the best of our knowledge, this is the first randomized study that directly evaluates whether additional HBsAg and anti-HBsAb rapid testing has any benefit compared to confirmatory ELISA.

There was a higher proportion of participants obtaining their results in the rapid testing arm, yet there was no evidence that rapid testing led to increased HBV vaccination rates or "linkage-tocare". Even though no clear determinant was observed for more appropriate care, tendencies were indeed noted with female-gender, originating from a high HBV-endemic countries, and prolonged stay at a medical facility.

Among HBsAg-positive participants, no association between randomized groups and linkage-tocare was observed. This finding could be attributed to the low prevalence of HBV infection, in particular, compared to a previous evaluation among individuals without national healthcare (0.8% versus 2.1% respectively) [START_REF] Bottero | Current state of and needs for hepatitis B screening: results of a large screening study in a low-prevalent, metropolitan region[END_REF]. With higher HBsAg-prevalence, the benefit of rapid testing would probably be more readily observed in specific sub-populations at-risk for HBV-infection (i.e. immigrants, intra-venous drug users, men who have sex with men, etc.) [START_REF] Meffre | Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors[END_REF][START_REF] Bottero | Current state of and needs for hepatitis B screening: results of a large screening study in a low-prevalent, metropolitan region[END_REF][START_REF] Spenatto | Hepatitis B screening: Who to target? A French sexually transmitted infection clinic experience[END_REF][START_REF] Meffre | Prévalence des hépatites B et C en France en[END_REF], as has been suggested for HIV [START_REF] Lorente | Expanding access to nonmedicalized community-based rapid testing to men who have sex with men: an urgent HIV prevention intervention (the ANRS-DRAG study)[END_REF][START_REF] Champenois | ANRS-COM'TEST: description of a community-based HIV testing intervention in non-medical settings for men who have sex with men[END_REF] and/or HCV [START_REF] Drobnik | Public health implications of rapid hepatitis C screening with an oral swab for community-based organizations serving high-risk populations[END_REF][START_REF] Bottero | Simultaneous HIV-VHB-HCV pointof-care tests improve the screening outcomes[END_REF]. The most notable of them are "hard-to-reach" populations (i.e. those with difficult access to care). )As all participants came to a medical center on their own initiative and were required to have some form of health insurance, individuals with barriers to healthcare were not well represented.

Rapid tests also failed to demonstrate any effect on HBV-vaccination rates, which were largely inadequate [START_REF] Bottero | Testing for Hepatitis B Virus (HBV) alone does not increase vaccine coverage in non-immunized persons[END_REF][START_REF] Launay | Impact of free on-site vaccine and/or healthcare workers training on hepatitis B vaccination acceptability in high-risk subjects: a pre-post cluster randomized study[END_REF]. This finding might reflect a general problem with vaccination coverage in France [START_REF] Dhumeaux | Recommandations sur la prise en charge des personnes infectées par les virus de l'hépatite B ou de l'hépatite C[END_REF]. However, it needs to be stressed that, as a major limitation, the Quick Profile TM anti-HBsAb rapid test could not be used to confirm non-immunized HBV-status [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF]. Since this rapid test had poor sensitivity, a definitive result at the initial visit could not be given to participants with a negative anti-HBsAb rapid test. This problem prevented us from providing appropriate counseling on HBV vaccination without resorting to serological testing, thus making it difficult to evaluate the potential impact of anti-HBsAb rapid testing. Unfortunately, no other alternative rapid test with high classification probabilities was available, specifically one that has been evaluated apart from the manufacture [START_REF] El-Ghitany | Evaluation of commercialized rapid diagnostic testing for some Hepatitis B biomarkers in an area of intermediate endemicity[END_REF]. However, we did observe somewhat satisfactory performance of the anti-HBsAb rapid test, contrary to our earlier report [START_REF] Bottero | Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France[END_REF]. The test used in our previous evaluation was a dual HBsAg Interestingly, our results resonate with the "cascade" of care, which has been well-established in HIV [START_REF] Mugavero | The state of engagement in HIV care in the United States: from cascade to continuum to control[END_REF] and HCV infection [START_REF] Holmberg | Hepatitis C in the United States[END_REF]. In such a framework, specific steps of healthcare involvement, starting from identifying those infected via testing to those receiving adequate care, are evaluated at each level. In our study, we demonstrate encouraging findings on the proportion of participants receiving test results, thus allowing infected individuals to be identified. However, this effect depended on the reliability of rapid test results (i.e. no need to obtain serological results after rapid testing), which was less the case among non-immunized individuals. The distribution of HBV status groups needs to be considered when comparing our results to others. In any case, infection awareness has provided a major step towards linkage-to-care in the past [START_REF] Gardner | The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection[END_REF][START_REF] Hsieh | HIV Care Continuum for HIV-Infected Emergency Department Patients in an Inner-City Academic Emergency Department[END_REF]), yet, there was a substantial drop-off in the proportion of patients adequately seeking care in our study.

Further research would be needed to determine if this finding is due to the low-risk of HBV-related disease perceived by participants, laxness of HBV-related care by the physician, or a combination of both.

One limitation of our study relates to the conditions under which serological results were obtained. Blood samples were immediately drawn after the study visit, contrary to routine practice where participants would have to test at a clinical laboratory located at a different facility.

This may have increased the proportion of patients obtaining HBV test results. Second, participants could have had a strong preference to receive rapid testing and when allocated to the S arm, would have been disappointed and even less likely to obtain screening results. However, such a bias, likely to favor the R+S arm, appeared to be minimal considering no difference between randomized arms was observed.

Notwithstanding these limitations, our study adds novel insight in the use of rapid tests during routine care. This is the first study to evaluate the clinical impact of adding rapid testing by randomizing participants to a specific intervention. While at the same time, we used a composite end-point reflecting healthcare interventions that affect both the individual (i.e. protection against HBV-infection, assessing the need for HBV-specific care) and the population (i.e. vaccination coverage). Finally, we demonstrate the complexity of evaluating interventions conditional on the status of HBV infection, which should be considered in future testing campaigns.

CONCLUSION

In conclusion, rapid testing for HBV with confirmatory ELISA might not increase vaccination for non-immunized and linkage-to-care for infected individuals when compared to standard practice. However, the lack of reliable anti-HBsAb tests may have compromised any advantage with rapid testing, stressing the usefulness of tests with higher sensitivity and specificity in identifying nonimmunized individuals. Furthermore, rapid testing should be evaluated in populations with higher HBsAg-seroprevalence. Seeing that these individuals are also at high risk of exposure to HIV and HCV, algorithms incorporating simultaneous rapid testing for these viruses are warranted. arms. The proportion of participants who were informed of their HBV-status (i.e. received their test results) are then given for each HBV-infection group, while assuming that mailed results were received and read by the participant. Finally, the primary end-point of appropriate care is illustrated in the shaded box below, with no significant difference between intervention arms for HBsAg-positive (p=0.3) or non-immunized (p=0.5) individuals (combined groups, p=0.5).

TABLES

  and anti-HBsAb test (Ref 71069-1, Lot No 10081601 and Lot No 11052410), whereas the one used herein was a different, single anti-HBsAb test from the same manufacture (Ref 71006, Lot No 12021401). As no further laboratory analysis was done, we cannot offer any other technical explanations for the discrepancies between these tests.

Figure 1 Figure 2 .

 12 Figure 1. Study Flow Diagram

Table 1 . Interpretation of HBV rapid tests and results needed to declare obtention HBV Rapid Test Presumptive diagnosis

 1

	Tests results
	needing to be
	obtained**

**Combination of results needed from rapid test (R) and/or serological test (S) in order to be considered as successfully obtaining test results. All participants listed as R did not necessarily need confirmation with ELISA (diagnosis from rapid test was considered reliable). All participants listed as R+S required confirmation with ELISA (diagnosis from rapid test was considered unreliable).

Table 2 . Description of the study population per intervention arm

 2 All numbers above represent n (%), except for age where mean (SD) is given. *Statistical comparison between arms was performed using Pearson's χ² test or Fisher's exact test for categorical variables and Student's t test for continuous variables.Couverture médicale universelle, health insurance coverage that is given to persons living in precarious social situations (i.e. unemployed, poverty, etc.).

	Intervention Arm	p*
	Standard test	Rapid test
	(n=496)	(n=499)

2

Table 3 . Classification probabilities comparing rapid HBsAg and anti-HBsAb tests to ELISA

 3 B surface antigen; anti-HBsAb, anti-Hepatitis B surface antibodies; ELISA, enzyme-linked immuno-assay; AUC, area under the curve; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value. *n=56 patients were excluded because they had intermediate results from the ELISA test.

		HBsAg serology ELISA	AUC (95% CI)	Se	Sp	PPV NPV
		Positive	Negative
	VIKIA®	(n=2)	(n=497)	1.000 (-)	100 100 100	100
	Positive	2	0
	Negative	0	497
		HBsAb serology ELISA
		Positive	Negative*
	QUICK PROFILE (n=285)	(n=158)	0.876 (0.844-	94.4 80.8 88.1 90.5
				0.908)
	Positive	251	15
	Negative	34	143
	HBsAg, hepatitis

ACKNOWLEDGMENTS

We wish to thank all study participants as well as all medical and paramedical centers participating in the study, Tabassome Simon and nurses from the URC-Est and the data management center especially Frederic Chau, Frederic Fotre, Sylvain Bitschine, Isabelle Goderel and Gregory Pannetier. We also acknowledge Samia Hicham, Julie Lamarque, and Christelle Pauleau for their extraordinary effort in data collection at various sites.

This study was made possible by funds from the Agence Nationale de Recherche contre le Sida et les Hépatites (grant n°2010-334), Gilead Sciences and Roche and material support from the Mairie de Paris. AB was awarded a post-doctoral fellowship from the ANRS.


M Chbiki

T Da

Silva Botelho

J G Bauzin

N Laraqi
email: nlaraqi@u-paris10.fr

J.-F Jarno

Thermal effect on the thermomechanical behavior of contacts in a Traveling Wave Tube (TWT)

Keywords: Thermal effect, Traveling Wave Tubes, Thermomechanical behavior, Coating, Plasticity

A new thermo-elasto-plastic study of the contact between the helix and the rods of the delay line of Traveling Waves Tubes (TWT) was realized. Our study is focused on the analysis of the hot lines shrinking phenomenon. In the studied case, unlike brazed configuration, the contact areas are not perfect, resulting in a diminution of the heat transfer process. In order to maximize the contact area and to homogenize the contact pressure, a soft thermal conductive material is coated on the helix: copper was chosen for this study. In the present work, an analytical model is used to identify the properties of the copper coating at a given temperature. We focused on the mechanical properties in order to improve the assembly process with a better numerical study. Experimental study have been made to validate the proposed model. The first comparison results seem to indicate that the model represents the reality with a good agreement. It is very clearly shown that the temperature decreases the mechanical properties. (Young's modulus, yield strength, tensile strength…). And the thickness of the coating increases the contact area. This last point is less important at room temperature (6% of increase) than at 140°C (22%).

Introduction

Traveling-Wave Tubes (TWT) are hyper frequency (up to 50 GHz) vacuum tubes used as power amplifier. TWT consist of three parts (Fig. 1), known as an electron gun (1), a transmission line (2) and a collector [START_REF] Johnson | Contact Mechanics[END_REF]. The high frequency wave is injected at the electron gun side of the vacuum tube, containing a helix wire. This wave is then amplified by interaction with the electron beam. During this process, the helix materials experience a strong thermal dissipation that may cause damage. Therefore, it is required that such materials have a high thermal conductivity together with a quite strong electrical insulation. In addition, its geometry is quite complex due to the necessary interaction between the input wave and the electron beam for amplification.

In a previous work [START_REF] Chbiki | Thermal analysis of a transmission line of Traveling Wave Tube (TWT)[END_REF] an analytical modeling of thermal steady-state behavior of the TWT was proposed. In that work, each individual component thermal resistivity was first evaluated and then the global assembly thermal resistivity was determined as a function of individual resistivities and geometries. That global modeling allowed a parametric study of the TWT thermal resistivity.

Given the small dimensions of the TWT, the study of the thermo-mechanical behavior of interfaces is of major interest. Varied processes are used to assemble TWT, leading to varied interface qualities. In the present work we focus on a specific contact between the helix and barrel (Fig. 2). The thermal conductivity of that contact depends on the contact area and contact pressure, resulting from the assembling technique. In order to maximize the contact area and to homogenize the contact pressure, a soft, thermal conductive material is coated on the helix. In that application, copper was chosen. The shrinking technique used to assemble the helix together with the rods is known to provoke large plastic deformation of the copper coating, leading to an augmentation of the contact area and a homogenization of the contact pressure.

Such a thermo-mechanical analysis can be performed numerically, using finite elements for example. But to achieve realistic results, one has to know adequate temperature-dependent mechanical properties of the constitutive materials of that assembly. More specifically, the properties of the copper coating are of major interest. Some performing techniques are available to access these mechanical properties, based on instrumented micro indentation tests [START_REF] Pharr | Nanoindentation of soft films on hard substrates: experiments and finite elements simulations[END_REF][START_REF] Vlassak | Indentation plastic displacement field: part I, the case of soft films on hard substrates[END_REF][START_REF] Tunvisut | Use of scaling functions to determine mechanical properties of thin coatings from microindentation tests[END_REF] but the use of such instrumented devices make it difficultif possibleto measure the coating properties with temperature, due to the limited access to samples and sensitivity of sensors. Some results are available on the temperature dependent properties of thin copper sheets of 12 µm to 0.2 mm [START_REF] Khatibi | Temperature dependent elastic and thermal properties of thin copper foils[END_REF]. Another technique is then used to access these temperature dependent mechanical properties [START_REF] Silva Botelho | Analytical and experimental elastoplastic spherical indentations of a layered half-space[END_REF][START_REF] Silva Botelho | Identification inverse des propriétés élastoplastiques de revêtements antifretting pour les alliages de titane[END_REF]. This technique is also based on indentation, but instead of measuring the charge-discharge indentation curve, the analysis is focused ond the measurement of the residual imprint. Since no sensor (else than temperature) is needed during the test, a wide range of temperatures is possible. An analytical model is then used to identify the properties of the copper coating at a given temperature.

Modeling of the contact

The real helix/spacer contact is sphere/plan like, which justifies the use of a spherical indentation experimental technique (Fig. 2). This model gives then an analytical relationship between the contact radius (a) and the normal static load (W N ). The geometric description of the problem is given in Fig. 3, where solids 1 and 2 are respectively the indenter and the substrate and solid 3 is the copper coating. Their respective Young's moduli and Poisson ratio are E 1 , E 2 , E 3 , ν 1 , ν 2 , ν 3 . The elastic limit of the coating is denoted Re 3 . The elasto-plastic behavior of the copper is represented schematically in Fig. 4.The plastic part of the curve is characterized by a tangent modulus (E II3 ), related with Young's Modulus as in (Eq.1).

II 3 3 EE   (Eq.1)
The model needs only two constants to describe the plastic part of the coating behavior: Re 3 and E II3 .

The full resolution of the contact problem has been given by Da Silva Botelho et al. [START_REF] Silva Botelho | Analytical and experimental elastoplastic spherical indentations of a layered half-space[END_REF]. The main results of this work are summarized as follows. In case of elasto-plastic behavior of the coating, the relation between the normal load and the contact radius is given by (Eq.2):

2 4 N 0 eq 2 a 1 a W W 1 ( 1 ) 1 Re 1a a               (Eq.2)
With the following constants and scaling values:

4 4 3 12 0 3 eq E 9h W 4 4( 3 4 ) R E        (Eq.3)
eq eq 2 0 eq 2Rh Re E aE  (Eq.4) (Eq.6)

1 3 2 3 2 3 eq 3 3 2 33 23 EE 2 Re Re 1 1 1 1 1 EE                            (Eq.7) 1 33 22 II 3 3 2 II 3 2 33 33 22 3 3 2 II 3 2 R E E E E 1 2 1 2 11 11 E E E E E                                  (Eq.8)
In these equations, Re eq represents the equivalent yield stress on the contact, including the behaviors of the substrates and the soft coating and λ includes the boundary conditions of adhesion at the interface coating/substrate.

The contact radius given by these equations is then used to evaluate the thermal contact resistance using references [START_REF] Laraqi | Thermal constriction resistance of coated solids -static and sliding contacts[END_REF][START_REF] Laraqi | Asperities eccentricity effect on the thermal constriction resistance of static or sliding contact[END_REF][START_REF] Laraqi | Theory of thermal resistance between solids with randomly sized and located contacts[END_REF].

Experimental and analytical results

To determine the mechanical constants of the copper elastoplastic behavior, a reverse engineering process is performed, using (Eq.2-8). An experimental campaign is then set up on tungsten wires with copper coating but with a flat geometry instead of helix one to avoid the structural contribution of the helix in the experimental results. The dimensions of the wire were 2 mm width and 0.4 mm thick. The coating was performed using a classical electrolysis technique. The wire width was 1 mm and the copper thicknesses were 3 µm and 6 µm.

A specific indenter (developed at LISMMA Laboratory) was used to perform indentation tests on copper coated helix wires. The indenter kinematic diagram is presented in Fig. 5. The normal load, W N , is applied using weights and the dimensions of the contact area are measured after total unloading. Fig. 6 gives an overview of the test bench and the geometry of the wire.

The indenter represents the rod material and was 1mm diameter. Its initial microgeometry was controlled before the tests using a confocal surfometer. A balancing weight was used to compensate the own weight of the moving parts of the bench. A quasi-static loading is then performed, to avoid inertial effects. 7 successive loadings were performed at a given load to set up the dispersion of the results. Each imprint is the result of a unique test and a minimum distance between the imprints has been met (6 times the indenter diameter). The contact was maintained for 15 seconds (a previous study showed that the time while kept in charge didn't affect the results [START_REF] Silva Botelho | Analytical and experimental elastoplastic spherical indentations of a layered half-space[END_REF]).

The tested loads varied from 100 g to 3 kg. The lower boundary corresponds to the minimum load at which an imprint was detected and the upper boundary comes from the bench limitations. Tests were performed at room temperature and at 140°C. A portable heater was used to apply the temperature and a thermocouple was used to monitor the wire temperature during the test Fig. 6. For each tested temperature and each coating thickness, analysis of the contact radius vs. normal load curves were then exploited. Fig. 7 shows the influence of copper thickness on the evolution of contact radius with load. For the two tested thicknesses, the evolution of contact radius with load is quite similar. Despite the experimental dispersion, the two curves are clearly separated. For a given load, a thicker coating enables a larger contact radius. Unless for the two first points, the difference between the two curves is about 6%. The two first points, especially for 6 µm, differ from the global evolution. This experimental fact is related to the experimental apparatus: at low load, a transversal sliding component occurs, due to the apparatus kinematics Fig. 8. Fig. 9 exhibits the influence of temperature on the contact radius for a 3 µm thick coating. The higher the temperature, the larger the contact radius, which can be explained by the sensitivity of copper Young's modulus and yield strength with temperature [START_REF] Arnaud | Propriétés du cuivre et de ses alliages[END_REF]. Indeed, it is known that the mechanical properties decreases quickly above 100°C, which explains that at a given load, the contact radius is larger when temperature is larger and that residual imprint can be measured at lower load when test temperature was higher. The two curves are well separated until about 17 N of normal load. After that value, both curves are similar, denoting a saturation effect, related to the indenter radius and the penetration depth. That saturation can be considered as a limitation of the assumptions of the analytical model at 140°C. At room temperature, such a saturation will occur at higher load, due to stronger mechanical properties. 9 but with a 6 µm thick coating. The very same conclusions can be drawn except for the saturation effect. In fact, the coating is thick enough to avoid the saturation at such loads. The saturation will most probably occur at higher load. Fig. 11 compares the evolution of contact radius for the two thicknesses at 140°C. The two thicknesses have a similar evolution, but the difference between them is more pronounced at 140°C than at room temperature. The difference between the two curves is about 22% (mean value). At room temperature, the difference was only about 6%. This evolution is to be compared to the evolution of mechanical properties of copper between room temperature and 140°C. From all these results, it is quite clear that to promote a larger contact radius, one has to select, among the operating conditions tested, the thickest coating and the highest temperature.

Once these experimental data established, next step is to compare them with the analytical model to identify mechanical constants. Analyzing the comparison between results for 3 µm at 140°C and analytical data (Fig. 12), it seems that experimental data exhibits a transition from one analytical curve to the other, from the smoother one to the harder one. The very same conclusion can be drawn for 6 µm at 140°C (Fig. 13). For the 6 µm thick coating, the transition from copper properties to tungsten substrate properties is even clearer.

At room temperature, such a transition is not so clear, because of the lack of experimental data at low load. These comparisons bring out some information. One is to set the validity limit of our analytical model to normal loads less than 5N for reverse engineering of experimental data. At higher load, the tungsten substrate becomes dominant on the copper coating, due to the not so small penetration depth compared to the coating thickness and indenter radius.

Conclusion

This study allowed us to propose an analytical identification of the copper coating properties. It allows us to notice that the coating study cannot be separated from the substrate study, even if it is much stiffer than the substrate.

The contact area increases with increasing thickness of the coating and that tendency is magnified by the effect of temperature: at room temperature, doubling the coating thickness increases the contact area by 6% for a given load whereas at 140°C doubling the thickness results in an increase of the contact area by 22%. This effect is to be related to the evolution of mechanical properties of copper with temperature.

This study pointed out the influence of the temperature and the thickness of the coating on the evolution of the contact radius, which is a key feature for the thermal contact resistance. These results are to be used in a heat transfer study of a transmission line of traveling wave tubes.

Fig. 1 :

 1 Fig.1: Traveling-Wave Tube (TWT) scheme

Fig. 2 :

 2 Fig.2: Transmission line

Fig. 3 :

 3 Fig.3: Modeling of the soft coated contact problem[START_REF] Silva Botelho | Analytical and experimental elastoplastic spherical indentations of a layered half-space[END_REF]

Fig. 4 :

 4 Fig.4: Representation of the elasto-plastic behavior of the coating with linear hardening

Fig. 5 :Fig. 6 :

 56 Fig.5: Kinematic diagram of the indenter

Fig. 7 :

 7 Fig. 7: Influence of the coating thickness at room temperature.

Fig. 8 .

 8 Fig.8.: Transversal sliding

Fig. 9 :

 9 Fig.9: Influence of temperature on the variation of contact radius against normal load of a 3 µm coating.

Fig. 10 :

 10 Fig.10: Influence of temperature on the variation of contact radius against normal load of a 6 µm coating.

Fig. 12 Fig. 13

 1213 Fig.13present the experimental data at respectively 3 µm and 6 µm and the analytical model for various mechanical constants, expressed in terms of yield strength (Re) and tensile strength (Rm).

Fig. 11 :

 11 Fig.11: Influence of coating thickness at 140 °C.

Fig. 12 :

 12 Fig.12: Comparison of experimental data and analytical model for the coating of 3 µm thick.

Acknowledgements

The authors wish to express their gratitude to Thales Electron Devices (TED) and l'Association Nationale de la Recherche et de la technologie (ANRT) for the technical and financial support granted to this study.