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.

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.

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.

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.

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>>.

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.

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.

[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.

Trends in risk of transfusion-transmitted viral infections (HIV, HCV, HBV) in France between 1992 and 2003 and impact of nucleic acid testing (NAT).

Monitoring trends in residual risk of transfusion-transmitted viral infections is important to assess improvements in blood safety and to adapt the risk reduction policies. These trends were analysed in France over 4 periods of 3 years (1992-1994, 1995-1997, 1998-2000 and 2001-2003). The 2001-2003 estimates were compared to the results of HIV-1 and HCV NAT implemented on all blood donations in July 2001. Due to improvements in donor recruitment and selection, continuing progress in screening assays, and preventive measures taken in the community to control infections, a significant decrease was observed in residual risks for HIV, HCV and HBV between 1992 and 2003. The residual risk is currently extremely low: for the 2001-2003 period, this risk was estimated at 1 in 3.15 million donations for HIV, at 1 in 10 million for HCV and at 1 in 640,000 for HBV. Of the 6.14 million donations screened with NAT between July 2001 and December 2003 in France, 2 HIV-positive and 3 HCV-positive donations were discarded thanks to NAT, representing a yield of 1 in 3.07 million for HIV and 1 in 2.05 million for HCV. These results show the limited benefit of NAT and suggest that its cost-effectiveness is poor.

[Epidemiological surveillance of blood donors and residual risk of blood-borne infections in France, 2001 to 2003]. / Surveillance épidémiologique des donneurs de sang homologues et risque résiduel en France entre 2001 et 2003.

The national surveillance of French blood donors is performed by the Institut de Veille Sanitaire and the National Reference Center for Hepatitis B and C in transfusion in collaboration with the Etablissement Français du Sang and the Army blood center. The main objectives of this surveillance are to evaluate trends in prevalence and incidence rates of blood-borne infections in the blood donor population, to identify routes of contamination and to assess residual risk. This exhaustive surveillance also contributes to evaluate the blood donor selection and the impact of measures taken to prevent infections in the general population. The analyse of the database of all blood donations obtained from 2001 to 2003 has shown that prevalence rates were stable in the study period (0.60 per 10(4) donors for HIV, 8.0 per 10(4) donors for HCV, 1.8 per 10(4) first-time donors for HBs Ag and 0.56 per 10(4) donors for HTLV), The incidence rate of HIV and HBV (1 per 10(5) person-years) was three-times higher than for HCV (0.35 per 10(5) person-years) and eleven times higher than for HTLV (0.09 per 10(5) person-years). At least, the residual risk of transfusion-transmitted viral infections is very low: 1/3,150,000 donations for HIV, 1/10,000,000 donations for HCV and 1/640,000 donations for HBV. The yield of Nucleic Acid Testing (NAT) is limited since only 2 donations for HIV and 3 for HCV which were negative for antibodies were discarded thank to the NAT.

[Evaluation of the organization of pre and post transfusion screening of viral infection markers in blood recipients in France in 2001]. / Evaluation de l'organisation du dépistage sérologique pré- et post-transfusionnel en France en 2001.

In France, data collection related to blood recipient's viral infectious disease markers pre and post-transfusion is a legal requirement for hospitals. Our study aimed to evaluate the actual modalities of this extensive screening in 2001, six years after the Ministry of health issued recommendations. A questionnaire was sent to the haemovigilance correspondents in hospitals having transfused labile blood products (LBP) in 2001. A total of 1463 hospitals having transfused 85% of LBP in France responded. 82.4% of hospitals have written guidelines for pre-transfusion screening of viral markers, mainly for HIV and hepatitis C. A frozen repository storage is held by 23.9% of hospitals with storage durations between 1 to 40 years. 84% of hospitals have written guidelines for post-transfusion screening. The test prescriptions are mostly done by physicians from clinical services and they include in more than 80% of cases, HIV and HCV markers. Only 12% of hospitals recontact the patient in case of a no show. Even though 77.5% of responding hospitals have labile blood products recipients follow up processes, their effectiveness remains quite low, only 16% of recipients having test results available at the hospital.

Increasing diversity of HIV-1M serotypes in French blood donors over a 10-year period (1985-1995). Retrovirus Study Group of the French Society of Blood Transfusion.

OBJECTIVE: Phylogenetic analysis of gene sequences of HIV-1 has led to the classification of isolates into a major group (M) of viruses, itself divided into subtypes (A to I), and a minor group (O) of rare isolates. Subtype B viruses are the most prevalent in Western countries but little is known about the dynamics of diffusion of the other subtypes in these regions. The prevalence of B subtypes and non-B subtypes in French blood donors between 1985 and 1995 was evaluated. METHODS: A retrospective study was conducted in 490 blood donors, identified as positive for antibody to HIV-1, by twelve French blood banks between 1985 and 1995. Serological subtyping was performed with a subtype-specific enzyme immunoassay, the reliability for genotyping of which has been demonstrated previously. RESULTS: Of 450 typable samples, 48 (10.7%) were non-B subtypes. Non-B reactive samples were found in all of the regions. An increasing prevalence of individuals infected by non-B viruses was observed, from approximately 4% in the early period to more than 20% in 1994-1995 (P = 0.0004). Non-B viruses did not appear to be restricted to patients with direct or indirect epidemiological links to non-European populations. CONCLUSION: We observed an increasing diversity of HIV-1 strains in the population of blood donors residing in France. This stresses the necessity to broaden the surveillance of HIV-1 diversity in order to improve measures to prevent HIV-1 infections.

Seroepidemiology of HTLV-I/II in universal screening of blood donations in France.

OBJECTIVE: To evaluate the serological and epidemiological characteristics of HTLV-I/II-positive blood donors in continental France during the first 6 months of universal screening of blood donations (n = 1,816,927). METHOD: A collaborative investigation of all confirmed anti-HTLV-I/II-positive samples reported by blood transfusion centres was performed. Seventy-three out of 77 reported samples were retested at two reference laboratories. Epidemiological data on risk factors were compiled. RESULTS: Of the 73 retested samples, 66 were confirmed to be HTLV-I-positive and one to be HTLV-II-positive; six samples were designated false-positive, mainly because of non-specific reactivity to recombinant gp21 in Western blot. The overall prevalence of HTLV-I/II in continental France is 0.039 per thousand. The main risk factor identified for HTLV-I infection was directly (origin) or indirectly (heterosexual contact) linked to endemicity in the Caribbean. The cost per case of avoided contamination in the 6-month period of this study was 1.36 million French francs. CONCLUSIONS: Sixty-two per cent of HTLV-I/II-infected blood donations would not have been discarded through the previous targeted HTLV screening or through other mandatory tests, including anti-hepatitis B core. To avoid false-positive results, we propose a new algorithm of diagnosis.

Record-linkage between two anonymous databases for a capture-recapture estimation of underreporting of AIDS cases: France 1990-1993. The Clinical Epidemiology Group from Centres d'Information et de Soins de l'Immunodéficience Humaine.

OBJECTIVE: To estimate the completeness of the French mandatory AIDS surveillance system (Declaration Obligatoire DO) over the 1990-1993 period using a capture-recapture approach, by matching the mandatory reports with the AIDS cases present in the French Hospital Database on HIV infection (FHDH). METHODS: An anonymous record-linkage algorithm was developed to identify those cases common to both anonymous surveillance systems. The linkage was based on sex, date of birth, and infection risk group, all strictly matched, and on the dates of AIDS diagnosis and of death, the places of diagnosis and residence, and the AIDS-defining diseases at diagnosis. The total number of AIDS cases and completeness of both surveillance systems were estimated using a capture-recapture approach, assuming independence of the ascertainment sources. RESULTS: The completeness of the mandatory reporting was estimated at 83.6% (95% CI: 82.9-84.3), and that of the FHDH at 47.6% (95% CI: 46.9-48.3) for the surveillance of AIDS cases diagnosed among adults in France between 1990 and 1993. The completeness of the system based on FHDH increased over the study period as more hospitals joined the project, while the completeness of the DO surveillance system remained stable. CONCLUSION: This approach was useful in estimating the underreporting of AIDS cases in France. Regularly performed, it will allow the impact of underreporting to be monitored over time.

Screening of viral markers for HIV HBV and HCV infections in blood donors in France and residual risk of viral transmission by blood transfusion.

The first part of this article presents the results of screening tests for antibodies to human immunodeficiency virus (HIV) and hepatitis C virus (HCV) and for hepatitis B surface antigen (HBsAg) from 1986 to 1996. The second part presents the most recent