A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Primary resistance of hepatitis B virus to nucleoside and nucleotide analogues.

Nucleoside and nucleotide analogues (NUCs) targeting hepatitis B virus are capable of selecting resistant viruses upon long-term administration as monotherapies. The prevalence of resistance-associated substitutions (RASs) and fitness-associated substitutions at baseline of NUC therapy and their impact on treatment responses remain unknown. A total of 232 treatment-naïve patients chronically infected with hepatitis B virus (HBV) consecutively referred for the first time to one of French reference centres were included. The nearly full-length HBV reverse transcriptase was sequenced by means of deep sequencing, and the sequences were analysed. RASs were detected in 25% of treatment-naïve patients, generally representing low proportions of the viral quasispecies. All amino acid positions known to be associated with HBV resistance to currently approved NUCs or with increased fitness of resistant variants were affected, except position 80. RASs at positions involved in lamivudine, telbivudine and adefovir resistance were the most frequently detected. All patients with RASs detectable by next-generation sequencing at baseline who were treatment-eligible and treated with currently recommended drugs achieved a virological response. The presence of pre-existing HBV RASs has no impact on the outcome of therapy if potent drugs with a high barrier to resistance are used.

Molecular epidemiology and mechanisms of resistance of azithromycin-resistant Neisseria gonorrhoeae isolated in France during 2013-14.

OBJECTIVES: The objective of this study was to determine the prevalence and mechanisms of azithromycin resistance of Neisseria gonorrhoeae French isolates from 2013 to 2014. METHODS: N. gonorrhoeae samples isolated in a network of laboratories were tested for susceptibility to azithromycin between April 2013 and March 2014. Fifty-four isolates that were non-susceptible to azithromycin and 18 susceptible isolates were characterized for molecular mechanisms of resistance by PCR/sequencing and genotyped using N. gonorrhoeae multiantigen sequence typing (NG-MAST). RESULTS: Among the 970 N. gonorrhoeae isolates, 54 (5.56%) were non-susceptible to azithromycin, 9 (1%) were resistant and 45 (4.6%) showed intermediate resistance. Azithromycin-non-susceptible isolates harboured a C2599T mutation in the rrl gene encoding the 23S rRNA alleles (5.5%), a C substitution in the mtrR promoter (5.5%), an A deletion in the mtrR promoter (53.7%) and mutations in the L4 ribosomal protein (14.8%) and in the MtrR repressor (25.9%). No isolates showed an L22 mutation or carried an erm, ere, mef(A)/(E) or mphA gene. Thirty different STs were highlighted using the NG-MAST technique. The predominant genogroups non-susceptible to azithromycin were G21 (31%), G1407 (20%) and G2400 (15%). Genogroup G2400 (15%) was revealed to be a novel cluster prevalent in the south of France and resistant to azithromycin, ciprofloxacin and tetracycline. CONCLUSIONS: Our study highlights that the prevalence of resistance of N. gonorrhoeae to azithromycin in France is low and essentially due to multiple genetic mutations. Its dissemination occurs through three major genogroups including a novel one in France (G2400).

Burden of HIV and hepatitis C co-infection: the changing epidemiology of hepatitis C in HIV-infected patients in France.

BACKGROUND & AIMS: To better evaluate the HIV-HCV co-infection burden in the context of new effective HCV treatment. METHODS: We reviewed all the epidemiological data available on HCV-related disease in HIV-infected patients in France. Sources of data have been selected using the following criteria: (i) prospective cohorts or cross-sectional surveys; (ii) conducted at a national level; (iii) in the HIV-infected population; (iv) able to identify HCV co-infection and chronic active hepatitis C (HCV RNA positive); and (v) conducted during the period 2003-2012. RESULTS: The overall prevalence of HIV-HCV co-infection has decreased from 22-24% to 16-18%. This prevalence decreased from 93% to 87% among injecting drug users while it increased from 4% to 6% among men who have sex with men. The characteristics of patients have changed: decrease in the proportion of patients with chronic active hepatitis C (HCV RNA positive) from 77% to 63% and in the genotypes 2 and 3 HCV infection; increase in the proportion of HCV genotype 1 (from 45-50% to 58%) and genotype 4 (from 15% to 22%). The proportion of patients treated with highly active antiretroviral therapy increased from 76% to 95%, with higher rates of undetectable HIV viral load (47% in 2004 vs. 85% in 2012). CONCLUSION: The decreasing prevalence and the change in patients profile in HIV-HCV co-infection underline the importance of continuing efforts to educate physicians and patients. This should increase the benefit of viral risk reduction policies and increase the access of co-infected patients to HCV treatment.

Characteristics of patients recently infected with HIV-1 non-B subtypes in France: a nested study within the mandatory notification system for new HIV diagnoses.

The presence of HIV-1 non-B subtypes in Western Europe is commonly attributed to migration of individuals from non-European countries, but the possible role of domestic infections with non-B subtypes is not well investigated. The French mandatory anonymous reporting system for HIV is linked to a virological surveillance using assays for recent infection (<6 months) and serotyping. During the first semester of years 2007 to 2010, any sample corresponding to a non-B recent infection was analyzed by sequencing a 415-bp env region, followed by phylogenetic analysis and search for transmission clusters. Two hundred thirty-three recent HIV-1 infections with non-B variants were identified. They involved 5 subtypes and 7 circulating recombinant forms (CRFs). Ninety-two cases (39.5%) were due to heterosexual transmissions, of which 39 occurred in patients born in France. Eighty-five cases (36.5%) were identified in men having sex with men (MSM). Forty-three recent non-B infections (18.5%) segregated into 14 clusters, MSM being involved in 11 of them. Clustered transmission events included 2 to 7 cases per cluster. The largest cluster involved MSM infected by a CRF02_AG variant. In conclusion, we found that the spread of non-B subtypes in France occurs in individuals of French origin and that MSM are particularly involved in this dynamic.

HIV prevalence and sexual risk behaviors associated with awareness of HIV status among men who have sex with men in Paris, France.

A cross-sectional survey, using self-sampled finger-prick blood on blotting paper and anonymous behavioral self-administrated questionnaires was conducted in Paris in 2009 among MSM attending gay venues. Paired biological results and questionnaires were available for 886 participants. HIV seroprevalence was 17.7 % (95 % CI: 15.3-20.4). Four groups were identified according to their knowledge of their HIV biological status. Among the 157 found to be seropositive, 31 (19.7 %) were unaware of their status and reported high levels of sexual risk behaviors and frequent HIV testing in the previous 12 months. Among the 729 MSM diagnosed HIV-negative, 183 were no longer sure whether they were still HIV-negative, or had never been tested despite the fact that they engaged in at-risk sexual behaviors. This study provides the first estimate of HIV seroprevalence among MSM in Paris and underlines the specific need for combined prevention of HIV infection in this MSM population.

Missed opportunities for HIV testing in newly-HIV-diagnosed patients, a cross sectional study.

BACKGROUND: In France, 1/3 HIV-infected patients is diagnosed at an advanced stage of the disease. We describe missed opportunities for earlier HIV testing in newly-HIV-diagnosed patients. METHODS: Cross sectional study. Adults living in France for ≥1 year, diagnosed with HIV-infection ≤6 months earlier, were included from 06/2009 to 10/2010. We collected information on patient characteristics at diagnosis, history of HIV testing, contacts with healthcare settings, and occurrence of HIV-related events 3 years prior to HIV diagnosis. During these 3 years, we assessed whether or not HIV testing had been proposed by the healthcare provider upon first contact in patients notifying that they were MSM or had HIV-related conditions. RESULTS: 1,008 newly HIV-diagnosed patients (mean age: 39 years; male: 79%; MSM: 53%; diagnosed with an AIDS-defining event: 16%). During the 3-year period prior to HIV diagnosis, 99% of participants had frequented a healthcare setting and 89% had seen a general practitioner at least once a year. During a contact with a healthcare setting, 91/191 MSM (48%) with no HIV-related conditions, said being MSM; 50 of these (55%) did not have any HIV test proposal. Only 21% (41/191) of overall MSM who visited a healthcare provider received a test proposal. Likewise, 299/364 patients (82%) who sought care for s had a missed opportunity for HIV testing. CONCLUSIONS: Under current screening policies, missed opportunities for HIV testing remain unacceptably high. This argues in favor of improving risk assessment, and HIV-related conditions recognition in all healthcare facilities.

Hepatitis B knowledge, perceptions and practices in the French general population: the room for improvement.

BACKGROUND: Little is known about the knowledge, perceptions and prevention practices of the French general population with respect to Hepatitis B virus (HBV) infection. This article describes this population's knowledge of HBV, their perceptions of the disease, and associated screening and vaccination practices. It compares these indicators with those observed in the same population for HIV, an infection with a chronic course and transmission modes resembling those of HBV. METHODS: A module on hepatitis B was added into the HIV KABP (Knowledge, Attitudes, Beliefs and Practices) survey which was carried out telephonically in 2010 among a random sample of 9,014 individuals aged between 18-69 and living in metropolitan France. RESULTS: Compared with HIV, the general population was less aware that needle exchange during intravenous drug use and sexual relationships are HBV transmission modes (HBV: 89.9% and 69.7%; HIV: 99.1% and 99.4%). The fear of both illnesses was similar at 20.3%. The individual perceived risk of infection was higher for HBV than for HIV with, respectively, 60.8% and 40.3% of respondents believing they had an equal or greater risk of being infected than the average person. However, the percentage of those reporting HBV screening during their lifetime (27.4%) was half that for HIV screening (61.4%). In multivariate analysis, HBV screening was reported more often by individuals born in areas with high HBV endemicity (OR = 2.1 [95% CI: 1.5-2.9]) than by those born in low HBV endemicity areas, and more often by those who reported they had taken drugs intravenously during their lifetime (OR = 2.2 [95% CI: 1.2-4.2]) than those who did not report such behavior. Almost one in two respondents (47%) reported HBV vaccination. The intermediate or high endemicity groups did not report vaccination more often than those born in low endemicity areas nor did those reporting intravenously drug use compared with those who did not. CONCLUSIONS: This study highlights very contrasting levels of knowledge, perceptions and practices regarding HBV and HIV in the French general population. Our results demonstrate the need to improve the general and high-risk populations' knowledge of HBV, in particular concerning sexual transmission, in order to improve screening and vaccination practices.

First cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections in France, investigations and implications for the prevention of human-to-human transmission, France, May 2013.

In May 2013, Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection was diagnosed in an adult male in France with severe respiratory illness, who had travelled to the United Arab Emirates before symptom onset. Contact tracing identified a secondary case in a patient hospitalised in the same hospital room. No other cases of MERS-CoV infection were identified among the index case's 123 contacts, nor among 39 contacts of the secondary case, during the 10-day follow-up period.

Global HIV epidemiology: specific patterns of the epidemic in the North and South.

Thirty years after the identification of the first cases of AIDS, it was estimated that 34 million of people were living with HIV worldwide in 2011. The incidence is declining but remains high, with 2.5 million of new HIV infections per year. Africa is the region of the world most heavily affected, accounting for three-quarters of the global burden of HIV infection and the same proportion for new infections. The incidence declines in most parts of the world while heterosexual transmission remains the dominant mode of HIV acquisition followed by homosexual transmission. Intravenous drug use continues to drive the epidemic in Eastern Europe and parts of Asia. Condom use remains the cornerstone of prevention of sexual transmission. Male medical circumcision has now been proven an effective public health intervention to prevent sexual transmission. Antiretroviral treatment may reduce sexual transmission at population level while improving the conditions of life and survival of those harbouring the virus. Harm-reduction together with blood safety prevent blood transmission. The prevention of mother-to-child transmission is now moving its global objective to elimination by the end of 2015. At least 20 years will be necessary for achieving HIV control at the worldwide level with currently available interventions.

Continuous spread of HIV-1 subtypes D and CRF01_AE in France from 2003 to 2009.

Among 61 and 35 patients who were infected in France by viruses of the rare clades D and CRF01_AE, respectively, approximately half of them originated from areas where HIV-1 is endemic, but the data showed that both clades have spread in the French indigenous population, particularly in men having sex with men (MSM).

The spectrum of malignancies in HIV-infected patients in 2006 in France: the ONCOVIH study.

Since no large descriptive studies of incident cancers in HIV-infected patients are available in France, the nationwide cross-sectional ONCOVIH study aimed to prospectively report new malignancies diagnosed in HIV-infected patients in cancer centers and HIV/AIDS centers. We estimated the number of cancers in France for the year 2006 using the capture-recapture methods with two sources: ONCOVIH and the FHDH ANRS-CO4 cohort, as well as the completeness of the sources. Incidence and relative risks (RR) to the general population were estimated. In 2006, 672 new malignancies in 668 patients were reported in ONCOVIH; the most common were non Hodgkin's lymphoma (NHL, 21.5%), Kaposi's sarcoma (KS, 16.0%), lung cancer (9.4%), anal cancer (8.2%), Hodgkin's lymphoma (7.6%), skin cancers excluding melanoma (6.8%), and liver cancer (5.6%). Based on the capture-recapture approach, the estimated number of malignancies was 1320 and non-AIDS-defining malignancies (NADM) represented 68% of cases. The overall ascertainment of malignancies were 53%, and 59%, in the ONCOVIH study, and the FHDH ANRS-CO4 cohort, respectively. The estimated incidence of cancer among HIV-infected patients was 14 per 1000 person-years. Compared with the general population, the estimated RR in HIV-infected patients was 3.5 (95%CI 3.3-3.8) in men and 3.6 (95%CI 3.2-4.0) in women, and was particularly elevated in younger patients. Even in the era of combined antiretroviral therapy, the incidence of cancer is higher in HIV-infected persons than in the general population. A large variety of malignancies were diagnosed, and the majority were NADM.

Emerging role of hepatocellular carcinoma among liver-related causes of deaths in HIV-infected patients: The French national Mortalité 2005 study.

BACKGROUND/AIMS: Longer exposure to hepatitis C (HCV) or B virus (HBV) and the increased use of hepatitis treatment might have an impact on liver-related deaths in patients co-infected with the Human Immunodeficiency Virus (HIV). We describe the proportion of liver-related deaths among HIV-infected patients in 2005 compared with 2000. METHODS: In a nationwide survey (341 hospital departments involved in HIV management), all deaths of HIV-infected patients were prospectively reported. Deaths from either cirrhosis, hepatocellular carcinoma or fulminant hepatitis were defined as liver-related deaths. RESULTS: Of the 898 deaths reported in 2005, liver-related causes accounted for 15.4%; this is compared to 13.4% in 2000. Among liver-related deaths, hepatocellular carcinoma increased from 15% to 25% (p=0.04). Among hepatocellular carcinoma-related deaths: in 2000, 10% were HCV-infected; in 2005, 25% were HCV-infected (p=0.03). Half of the HCV-related deaths had been treated for HCV but 98% remained HCV-RNA positive at time of death. The proportion of HBV-related deaths remained stable between 2000 and 2005. CONCLUSIONS: Liver-related deaths, mainly liver cancers, have increased in HIV-infected patients in France despite wide access to HCV treatment. The stability of HBV-related deaths might be explained by the use of dually active antiretroviral drugs in co-infected patients.

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.

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.

Prevalence of HIV-2 and HIV-1 group O infections among new HIV diagnoses in France: 2003-2006.

French national surveillance of new HIV diagnoses included the collection of dried serum spots to identify HIV serotypes. Between January 2003 and June 2006, 10,184 new diagnoses were reported. The proportions of HIV-2 and HIV-1 group O infections were 1.8 and 0.1%, respectively. Most of these cases occurred in patients infected through heterosexual contact and originated from the corresponding endemic areas. Three cases of HIV-2 infections were reported in non-African men having sex with men.

Rectal lymphogranuloma venereum surveillance in France 2004-2005.

Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) caused by Chlamydia trachomatis strains belonging to the L1, L2 or L3 genotype. An alert about an outbreak of LGV among MSM in the Netherlands was published in January 2004. The first cases of rectal LGV in France were retrospectively diagnosed in March 2004 and sentinel surveillance for LGV was implemented in April 2004. Most of the participating centres were located in the cities of Paris and Bordeaux. Only confirmed rectal LGV cases were included in the surveillance. Rectal specimens from men that were found to be positive for C trachomatis by PCR were sent to the National Reference Centre for Chlamydia infection for genotyping. Simple epidemiological data provided by clinicians and genotyping results were sent to the Institut de Veille Sanitaire (InVS) where data were anonymously recorded. A total of 328 C. trachomatis rectal strains isolated in men were genotyped by the end of December 2005. Of these, 244 (74%) were LGV strains belonging to the L2 genotype. No L1 or L3 C. trachomatis genotype was found. Diagnosis was made retrospectively for 46 cases. The median age of patients with LGV was 39 years. HIV status was known for 96 patients: 82/96 (85%) were HIV-infected. Most LGV cases were diagnosed in the Paris area (92%). Among the remaining 26% C. trachomatis strains, genotypes Da and G were the most frequent. As with syphilis in recent years, the emergence of LGV in Europe is mainly affecting HIV-infected MSM. The screening and treatment of STIs should be included in the clinical follow-up of all HIV-infected MSM.

[Epidemiology of HIV infection in the world and in France]. / Epidémiologie de l'infection par le VIH dans le monde et en France.

All continents are affected by HIV at various degrees and the situation of Africa is certainly one of the most serious with HIV prevalence over 20% in Austral Africa, and accounting for half of all HIV cases in the world. Eastern Europe has been recently affected by HIV mainly among IDU. In Asia, the spread of epidemic on general population follows HIV transmission linked to drug use and commercial sex. Similar trends have been observed in Western Europe: relapse of safer sex among men wich have sex with men (MSM) with new HIV contamination, decrease of HIV transmission among drug users and increase of new HIV diagnosis among heterosexuals originating from countries with high prevalence of HIV/AIDS, notably sub-Saharan Africa. Since the introduction of potent anti-retroviral agents in 1996, the numbers of AIDS cases and mortality due to AIDS have sharply decreased in Western Europe. The number of new HIV diagnosis in 2004 is around 7 000 cases in France. The two mostly affected populations in 2003-2004 are homosexuals and sub-Saharan Africans. The harm reduction policies conducted has markedly reduced HIV transmission among injecting drug users.