Estimating prevalence from dried blood spots without using biological cut-offs: application of a novel approach to hepatitis C virus in drug users in France (ANRS-Coquelicot survey).

Seroprevalence estimation using cross-sectional serosurveys can be challenging due to inadequate or unknown biological cut-off limits of detection. In recent years, diagnostic assay cut-offs, fixed assay cut-offs and more flexible approaches as mixture modelling have been proposed to classify biological quantitative measurements into a positive or negative status. Our objective was to estimate the prevalence of anti-HCV antibodies among drug users (DU) in France in 2011 using a biological test performed on dried blood spots (DBS) collected during a cross-sectional serosurvey. However, in 2011, we did not have a cut-off value for DBS. We could not use the values for serum or plasma, knowing that the DBS value was not necessarily the same. Accordingly, we used a method which consisted of applying a two-component mixture model with age-dependent mixing proportions using penalised splines. The component densities were assumed to be log-normally distributed and were estimated in a Bayesian framework. Anti-HCV prevalence among DU was estimated at 43.3% in France and increased with age. Our method allowed us to provide estimates of age-dependent prevalence using DBS without having a specified biological cut-off value.

Fifteen years of Nucleic Acid Testing in France: Results and lessons.

Of the 40 million donations screened with Nucleic acid testing (NAT) between July 2001 and December 2015 in France, 20 HIV-positive, 13 HCV-positive and 17 HBV (HBV-NAT was initiated in 2005 and extended to the whole country in 2010) donations were discarded thanks to NAT. The main benefit in terms of discarded donations is related to HBV with a yield of 0.88 per million donations, which is 12.5 and 1.8 times higher than for HCV and HIV respectively. The main risk factor found in these donors during the post donation interview was having sex with men for males (n=11, all repeat blood donors), having a partner HCV positive (n=6) or at-risk partner (originated from endemic area or HBV positive) for HBV (n=8) for HIV, HCV and HBV, respectively. Although the mean viral load was high for HIV (5.6 log copies/mL) and HCV (7 log IU/mL), HBV cases show low level of DNA (1.8 log IU/mL) demonstrating the need of a highly sensitive NAT assay. Overall, the clinical benefit for recipients remains those related to the prevention of HIV contaminations since HCV avoided transmissions are extremely rare (only one case in the last 5 years thanks to NAT) and the potential infectivity of HBV-NAT only positive cases is questionable due to the low level of HBV DNA and the presence of anti-HBs in more than a half of DNA positive/HBsAg and anti-HBc negative donors.

Hepatitis B virus in drug users in France: prevalence and vaccination history, ANRS-Coquelicot Survey 2011-2013.

People who use drugs (PWUD) are a key population for hepatitis B virus (HBV) vaccination and screening. We aimed to estimate the seroprevalence of HBs antigen (HBsAg) and self-reported HBV vaccination history in French PWUD attending harm reduction centres using data from the ANRS-Coquelicot multicentre survey conducted in 2011-2013 in 1718 PWUD. Self-fingerprick blood samples were collected on dried blood spots to detect the presence of HBsAg. HBsAg seroprevalence was estimated at 1·4% [95% confidence interval (CI) 0·8-2·5]. It varied between PWUD born in high (7·6%, 95% CI 2·7-19·1), moderate (2·2%, 95% CI 0·8-5·7) and low (0·7%, 95% CI 0·3-1·5) endemic zones. Factors independently associated with HBsAg carriage were being born in a moderate or high endemic zone or reporting precarious housing. Self-reported HBV vaccination history varied from 47·4% in high endemic zones, to 59·3% and 62·6% for moderate and low endemic zones, respectively. Our results suggest that drug use plays a small and substantial role, respectively, in HBsAg carriage in PWUD born in high/moderate and low endemic zones.

Age- and time-dependent prevalence and incidence of hepatitis C virus infection in drug users in France, 2004-2011: model-based estimation from two national cross-sectional serosurveys.

Hepatitis C virus (HCV) infection is a public health issue worldwide. Injecting drug use remains the major mode of transmission in developed countries. Monitoring the HCV transmission dynamic over time is crucial, especially to assess the effect of harm reduction measures in drug users (DU). Our objective was to estimate the prevalence and incidence of HCV infection in DU in France using data from a repeated cross-sectional survey conducted in 2004 and 2011. Age- and time-dependent HCV prevalence was estimated through logistic regression models adjusted for HIV serostatus or injecting practices. HCV incidence was estimated from a mathematical model linking prevalence and incidence. HCV prevalence decreased from 58·2% [95% confidence interval (CI) 49·7-66·8] in 2004 to 43·2% (95% CI 38·8-47·7) in 2011. HCV incidence decreased from 7·9/100 person-years (95% CI 6·4-9·4) in 2004 to 4·4/100 person-years (95% CI 3·3-5·9) in 2011. HCV prevalence and incidence were significantly associated with age, calendar time, HIV serostatus and injecting practices. In 2011, the highest estimated incidence was in active injecting DU (11·2/100 person-years). Given the forthcoming objective of generalizing access to new direct antiviral agents for HCV infection, our results contribute to decision-making and policy development regarding treatment scale-up and disease prevention in the DU population.

Hepatitis C virus and HIV seroprevalences, sociodemographic characteristics, behaviors and access to syringes among drug users, a comparison of geographical areas in France, ANRS-Coquelicot 2011 survey.

BACKGROUND: People who use drugs (PWUDs) are at a high risk for hepatitis C virus (HCV) and human immunodeficiency virus (HIV), but they have different characteristics depending on the local context. In France, seroprevalence, sociodemographic, and behavior information have only been studied at a national level rather than at a local level. The aim of this study was to describe and examine profile and drug use practice differences in seven French cities and departments and to assess whether these differences can explain HCV and HIV seroprevalence variations between French geographical areas. METHODS: Data were collected from the cross-sectional ANRS-Coquelicot survey conducted for the second time in 2011 among drug users having injected or snorted drugs at least once in their life. Professional interviewers administrated a face-to-face questionnaire in six different areas in France: Paris, Marseille, Bordeaux, Lille, Strasbourg and the Seine-Saint-Denis department (Paris suburbs). Participants were asked to self-collect a fingerpick blood sample in order to search for the presence of anti-HIV and anti-HCV antibodies and to estimate seroprevalence in PWUDs. RESULTS: Overall, HCV and HIV seroprevalence was 44% [95% CI: 39.6-47.9] and 10% [95% CI: 7.5-12.6] respectively. The highest HCV seroprevalence was 56% in Marseille and the lowest was 24% in Bordeaux and for HIV the highest was 18% in Seine-Saint-Denis and the lowest was 0% in Lille. The population's age differed between areas and could mostly explain HCV seroprevalence variation but not exclusively. Profiles and practices, different in each area, can also explain this variation. In multivariate analysis, HCV seroprevalence was lower in Bordeaux (prevalence ratio [PR]=0.64), Strasbourg (PR=0.76), and Seine-Saint-Denis (PR=0.8) than in Paris. Nearly one-third of injectors declared having had difficulties to obtain syringes in the 6 previous months, but disparities existed between areas. CONCLUSION: HCV risk exposure in PWUDs remains high in France and varies between different areas. Innovative harm reduction strategies including educative programs about safe injecting and supervised consumption rooms need to be developed.

[Relevance of safety measures to avoid HTLV transmission by transfusion in 2014]. / Pertinence des mesures sécuritaires transfusionnelles vis-à-vis du HTLV en 2014.

In high-income countries, the safety of blood transfusion related to viruses has reached a very high level, especially thanks to the implementation of multiple measures aimed at reducing the transfusion risk. The cost-effectiveness of these preventive measures is frequently discussed due to global financial resources, which are more and more limited. Hence, the revision of safety strategies is a key issue, especially when these strategies are redundant, as those implemented to avoid Human T-cell Lymphotropic Virus (HTLV) transmission, which are based on both antibodies screening and leucoreduction of blood products. The residual risk of the transmission of HTLV by transfusion has been recently estimated at 1 in 20 million donations (2010-2012) in France (excluding overseas territories). This estimation did not take into account the leucoreduction, which appears to be a very efficient preventive measure as the virus is strictly intra-cellular. To help decision-making, we have evaluated some parameters related to HTLV blood transmission. Firstly, the probability that an incident occurring during the leucoreduction process affects a HTLV-positive blood donation has been estimated at 1 in 178 million. Estimation of clinical consequences of HTLV-positive transfusions would affect 1 to 2 transfused-patients without leucoreduction, and one recipient every 192 years in case of 10% failures of the filtration method. Obviously, despite a risk, which appears to be controlled, HTLV screening will be disputed as soon as the efficiency of leucoreduction to totally prevent virus blood transmission will be proven and when pathogen inactivation methods are generalized to all blood cellular products.

[Assessment of a transfusion emergent risk: the case of HEV]. / Estimation d'un risque transfusionnel émergent: l'exemple du VHE.

BACKGROUND: The risk assessment for blood transfusion is an essential step that must precede any screening strategy of a pathogen transmitted by transfusion. After several cases of HEV transmission by transfusion in France, a risk assessment for this virus was performed. METHODS: We used a method based on the prevalence of HEV-RNA in plasmas collected for the preparation of SD-plasma. To estimate the rate of HEV-RNA positive among all blood donations, data on SD-plasma were adjusted on the following HEV risk factors: gender, age group and region of residence. We assumed that HEV risk factors were the same in plasma donors and whole blood donors. RESULTS: Among 57,101 plasma donations tested for HEV-RNA in 2013, 24 were positive (crude rate of 4.2 per 10,000 donations). After adjustment, the total number of HEV-RNA positive blood donations was estimated at 788, accounting for a rate of 2.65 per 10,000 donations (95% CI: 1.6-3.7) or 1 in 3800 donations (1 in 6,200-1 in 2,700). This rate was 12 times higher in men than in women, increased with age, and varied according to region of residence. CONCLUSION: The risk of blood donation contamination by HEV has been estimated to be 1 in 3800 donations in 2013. An essential input is still missing to assess now the risk in recipients: the minimum infectious dose. Furthermore, the risk in recipients has to be analyzed according to characteristics of transfused patients: presence of anti-HEV immunity, existence of chronic liver disease or immunodeficiency.

[Factsheets: support in the analysis of recipients' adverse reactions]. / Fiches techniques: aide à l'analyse des effets indésirables receveurs.

In order to help the analysis of adverse effects of transfusion, factsheets have been written by working groups of the French agency for the safety of health products ANSM. Each factsheet deals with a blood transfusion side effect and is composed of five parts, including pathophysiological mechanisms, diagnostic criteria, management recommendations, etiologic investigations and rules for filing the notification form to ANSM. Since 2006, 11 factsheets have been published on the French haemovigilance network website. The major characteristics of the two last sheets published "post-transfusion purpura" and "non erythrocyte incompatibility reaction" are presented, followed by the updated card for "allergy". These factsheets give relevant guidelines allowing better evaluation of recipients' adverse reactions, particularly their diagnosis, severity and accountability. They also could initiate studies among European and international haemovigilance networks.

Deferral from donating blood of men who have sex with men: impact on the risk of HIV transmission by transfusion in France.

BACKGROUND: In France, men who have sex with men (MSM) are permanently excluded from blood donation. This policy is felt to be discriminatory by MSM activists. Furthermore, the policy is not fully respected because some MSM do not report their sexual behaviour before donating. METHODS: We estimated the fraction of the current risk of HIV attributed to MSM. We then constructed a model based on data obtained from behavioural and epidemiological surveys to assess the impact of a new strategy in which MSM would only be deferred if they report more than one sexual partner in the last 12 months. RESULTS: Thirty-one HIV seroconversions occurred among repeat donors between 2006 and 2008, giving a risk of one in 2 440 000 donations. Fifteen of these seroconversions (48%) were MSM. If all MSM had abstained from donating blood, the risk would have been 1 in 4 700 000 donations, half the current risk. The new strategy would result in an overall HIV risk of between 1 in 3 000 000 (close to the current risk) to 1 in 650 000 donations (3·7 times higher than the current risk). CONCLUSIONS: Changing the current MSM deferral policy may increase the risk of transfusion-transmission of HIV. However, this does not take into account a possible better compliance with MSM with a less stringent policy that would be perceived as more equitable. Conversely, relaxing the policy could encourage some MSM to seek an HIV test in blood centres. Thus, further qualitative study is needed to assess possible changes in compliance linked to a new policy.

[Access to blood donation of men who have sex with men and impact on the risk of HIV transmission by transfusion: international overview]. / Accès au don du sang des hommes ayant des relations sexuelles avec des hommes et impact sur le risque de transmission du VIH par transfusion: tour d'horizon international.

As far back as 1983, in many countries, men who have sex with men were permanently excluded from blood donation because of their high risk of HIV infection. Since the implementation of HIV screening of blood donations in 1985, there has been a remarkable improvement in the viral safety of the blood supply due to improvements in donor selection and continuous progress in screening assays, including nucleic acid amplification testing. Despite, these improvements and the strong pressure of certain associations of the civil society, only few countries reduced the deferral duration for men who have sex with men. Studies that have assessed the impact of a modification of the permanent deferral measure on the HIV residual risk showed that a reduction in the deferral duration generates an additional risk. Even if this risk is tiny, is it acceptable to expose the blood product recipients to an additional risk? Nevertheless, these studies do not take into account an important parameter that is the probable better compliance of men who have sex with men with a temporary exclusion. The most recent studies agree to conclude that an alternative to the permanent exclusion of all men who have sex with men could consist in authorizing the donation from 12-month abstinent men who have sex with men, as some countries did already. This measure would allow covering widely the window period for the men having recently taken risks or for those whose partners would have taken risks, under the essential condition of an improvement of the donor compliance.

[Health alert management and emerging risk]. / Gestion des alertes sanitaires et risque émergent.

Following health crisis that have occurred in the nineties (contaminated blood, mad cow, asbestos, etc.) and more recently those generated by the heat wave in 2003 or by emerging infectious pathogens (SARS, West Nile, Chikungunya, H5N1, H1N1…), a real health vigilance system has been progressively developed in France. After a brief historical overview of the health alert system, this article will give the guiding principles of its current organization in France and will present two examples of recent health alerts (Chikungunya in the Reunion Island in 2005-2006 and hepatitis A outbreak in the Côtes-d'Armor in August 2007), that have needed the implementation of preventive measures regarding the blood donor selection. These two examples have shown that the position of the alert in the French health vigilance system needs to be very close to the event. In that case, health alert is a very useful tool for decision making especially when measures have to be taken to prevent transfusion-transmitted pathogens.

Recently acquired HIV infection in men who have sex with men (MSM) in France, 2003-2008.

An increase in the number of new HIV diagnoses among men who have sex with men (MSM) has been observed in several countries in the early 2000s. In this article, we explore the trends in MSM in France between 2003 and 2008. To estimate the number of MSM newly diagnosed with HIV, we take into account the reporting delay, underreporting and missing data for HIV case notification. To identify recent infections (RI) (acquired an average of six months before diagnosis), we used an enzyme immunoassay for recent HIV-1 infections (EIA-RI) which has been performed routinely for new HIV diagnoses since 2003. Multivariate analysis was used to identify factors associated with RI. We estimate that between 1,900 and 2,400 MSM have been newly diagnosed with HIV every year: the proportion of MSM among all newly diagnosed with HIV cases has increased from 25.2% (95% confidence interval (CI): 23.3-27.1) in 2003 to 37.0% (95% CI: 35.2-38.7) in 2008 and was stable during the period 2006-2008. In 2008, the rate of newly diagnosed HIV cases per 10,000 MSM living in France was 72.5. The proportion of non-B subtypes of HIV-1 among cases diagnosed in MSM was 11.7% (2003-2008). The assessment of RI was performed for 4,819 MSM newly diagnosed with HIV in 2003-2008. Of these, 47.6% (95%CI = 46.2-49.0) (2,295 cases) were shown to have been recently infected. The risk of RI was greater for those of French nationality (adjusted odds ratio (aOR) =1.6 [95% CI: 1.4-1.9]), those with high economic status (aOR =1.4 [95% CI: 1.2-1.8]), those tested after a risk exposure (aOR =1.6[95% CI: 1.3-1.8]) or after presenting with clinical symptoms or abnormal biological markers (aOR =1.8 [95% CI: 1.5-2.0]), those who had tested for HIV three or more times during their life-time (aOR =4.2 [95% CI: 3.4-5.2]) and those living in the Paris area (aOR =1.2 [95% CI: 1.0-1.3]). The risk of RI decreased with age. The HIV situation among MSM living in France is a cause of concern, despite the prevention campaigns dedicated to this highly educated sub-population.

[Quantitative estimate of the risk of blood donation contamination by infectious agents]. / Estimation quantitative du risque de contamination d'un don de sang par des agents infectieux.

The occurrence of asymptomatic penetration of certain infectious agents in blood presents a risk of transmission of one of these agents during blood transfusion. Although well controlled for some infectious agents (HIV, HTLV, HCV, HBV), this risk is nevertheless neither documented nor quantified for other pathogens that are responsible for serologically unscreened or undetectable infections at the time of blood donation. This risk is generally low in endemic situations, although it increases for particular time periods and locations when clustered cases or outbreaks occur. Prevention measures may then be implemented (interruption of blood collection, quarantined donations, etc.). These measures can have an important impact, particularly by limiting the supply of blood products to health care facilities. It is therefore important for these measures to be adapted to the risk of transmission through blood transfusion. Quantitative risk estimates of blood donation contamination can therefore contribute to guiding those measures. In this context, in early 2005, the French Public Health Institute (InVS) started a project with the aim of obtaining a priori quantitative risk estimates of contamination of a blood donation by infectious agents for various scenarios in terms of incidence and time-space distribution. The objective of this article is to update the last estimates of residual risks of the major transfusion-transmitted viral infections (HIV, HTLV, HCV and HBV) and to present the work realized by the working group << Quantitative estimate of the risk of blood donation contamination by infectious agents>>.

Blood safety strategies for human T-cell lymphotropic virus in Europe.

BACKGROUND: To prevent the blood transmission of human T-cell lymphotropic virus (HTLV), different countries have introduced anti-HTLV blood screening. Furthermore, leucoreduction of blood components has been implemented to preclude the transmission of infectious agents present in white blood cells. STUDY DESIGN AND METHODS: To evaluate the current European strategies adopted to ensure the blood safety for HTLV, a European investigation spanning a period from 2003 to 2008 was carried out. RESULTS: In 2003, of the 23 included countries, 11 performed anti-HTLV screening, four of which (Scandinavian countries) only did it on first-time donors. Norway and Finland stopped it in 2007 and 2008, respectively. Two groups may be defined according to increasing prevalence rates per 10 000 donations in first-time donors: Scandinavia and Ireland (0 to 0.17), France, the Netherlands and UK (0.45 to 0.48); Romania was clearly apart from all other participating countries (5.33). HTLV-positive donors (88.6%) either come from endemic areas (82.3%) or declare to have a sexual partner coming from endemic areas (6.3%). Of the 283 HTLV-positive donations that could be characterized, 6.6% were HTLV-II. Fourteen of 22 countries currently use systematic leucoreduction, at least in cellular blood components. Six countries perform both universal anti-HTLV screening and blood cell leucoreduction. CONCLUSION: The implementation of leucoreduction did not modify the blood HTLVscreening policy, except for Norway and Finland. Several screening strategies in low endemic countries performing leucoreduction were discussed. However, the withdrawal of anti-HTLV screening should be decided after assessing the remaining HTLV transfusion risk.

Four years of surveillance of recent HIV infections at country level, France, mid 2003 - 2006: experience and perspectives.

New systems of surveillance to better monitor the dynamics of HIV are needed. A national surveillance of new HIV diagnoses which included the collection of dried serum spots (DSS) to identify recent infections (<6 months) using an EIA-RI assay was implemented in 2003 in France. The collection of DSS is based on the voluntary participation by both patients and microbiologists. Multivariate analysis was used to identify factors associated with recent infection (RI). Between July 2003 and December 2006, 14,155 cases newly diagnosed for HIV were reported. A minority of patients refused the collection of DSS (3.3%) and the rate of participation of laboratories was 80%. The test was performed for 10,855 newly diagnosed HIV cases, the overall proportion of RI was 23.1% (95% CI, 22.3%-23.9%). The proportion of RI was higher among men who have sex with men (MSM) (42.8%) than among heterosexuals (16.3%). Among heterosexuals, it varied by current nationality: 27% among French versus 8.4% among Africans. The risk of RI was greater for MSM (aOR=1.8), those of French nationality (aOR=3.9), those with high-economic status (aOR=1.2), those tested after a risk exposure (aOR=1.4), those tested for HIV three or more times during their lifetime (aOR=2.5). The risk of RI decreased with age. A nation-wide implementation of RI monitoring is feasible. The information on RI is very useful for renewing prevention messages, particularly among population in which HIV transmission is on going, such as MSM.

Principles and uses of HIV incidence estimation from recent infection testing--a review.

Since the 1990s, the development of laboratory-based methods has allowed to estimate incidence of human immunodeficiency virus (HIV) infections on single samples. The tests aim to differentiate recent from established HIV infection. Incidence estimates are obtained by using the relationship between prevalence, incidence and duration of recent infection. We describe the principle of the methods and typical uses of these tests to characterise recent infection and derive incidence. We discuss the challenges in interpreting estimates and we consider the implications for surveillance systems. Overall, these methods can add remarkable value to surveillance systems based on prevalence surveys as well as HIV case reporting.The assumptions that must be fulfilled to correctly interpret the estimates are mostly similar to those required in prevalence measurement. However, further research on the specific aspect of window period estimation is needed in order to generalise these methods in various population settings.

Differential improvement in survival among patients with AIDS after the introduction of HAART.

We explored changes in the survival of patients with AIDS (PWA) according to the availability of antiretroviral drugs (1994-2002). We tested whether changes in the hazard ratio of progression to death (HR) have been homogeneous among various groups of PWA. We included 4158 PWA diagnosed in Paris, notified to the French National Surveillance Institute by 2002. Four calendar periods were defined: monotherapy (1994-95), bitherapy-HAART transition (1996), early HAART (1997-99), late HAART (2000-October 2002). HR were calculated with Cox models, including the calendar period, modelled as a time dependent covariate. Models were stratified by age, transmission category, CD4 cell count, and AIDS-defining illnesses (ADI) group. Cumulative survival at 60 months increased from 44.0% (before July 1996) to 75.6% (after July 1996) and median survival increased from 31.9 months to >76 months. Adjusted HR reached a minimum in the late HAART period (HR 0.22, 95% CI: 0.19-0.26). No difference in the decrease of the HR has been found by age. HR decreased and was marked during the late HAART period across all HIV transmission categories, including intravenous drug use. HR decreased significantly for all ADIs groups, including tumours. Among PWA diagnosed with tuberculosis, the HR decreased significantly only in the late HAART period. HR decrease was stronger for PWA with a CD4 cell count < or =200/mm(3). Substantial improvements in survival after the introduction of HAART were found for all PWA but varied by specific ADIs and the degree of immunosuppression.

[Modes of hepatitis C virus transmission: methodological approaches]. / Les modes de transmission du virus de l'hépatite C : approches méthodologiques.

Since the mid-1990s, hepatitis C virus (HCV) transmission through blood transfusion has become very rare in western countries. Better understanding of the current modes of transmission is needed. However, risk factors have been mainly estimated on prevalent HCV infections. In this paper we describe the methods of the main case-control studies and their contribution to the knowledge on modes of HCV transmission. We also report the results of a case-control study of incident HCV infections recently carried out in France which confirms the continuing major role of IV drug use and suggests that transmission related to invasive care remained a potential source of new HCV infection between 1995 and 2001.