Christine Larsen

European recommendations for the management of healthcare workers occupationally exposed to hepatitis B virus and hepatitis C virus

Exposure prevention is the primary strategy to reduce the risk of occupational bloodborne pathogen infections in healthcare workers (HCW). HCWs should be made aware of the medicolegal and clinical relevance of reporting an exposure, and have ready access to expert consultants to receive appropriate counselling, treatment and follow-up. Vaccination against hepatitis B virus (HBV), and demonstration of immunisation before employment are strongly recommended. HCWs with postvaccinal anti-HBs levels, 1-2 months after vaccine completion, >10 mIU/mL are considered as responders. Responders are protected against HBV infection: booster doses of vaccine or periodic antibody concentration testing are not recommended. Alternative strategies to overcome non-response should be adopted. Isolated anti-HBc positive HCWs should be tested for anti-HBc IgM and HBV-DNA: if negative, anti-HBs response to vaccination can distinguish between infection (anti-HBs >50 mUI/ml 30 days after 1st vaccination: anamnestic response) and false positive results(anti-HBs >10 mUI/ml 30 days after 3rd vaccination: primary response); true positive subjects have resistance to re-infection. and do not need vaccination The management of an occupational exposure to HBV differs according to the susceptibility of the exposed HCW and the serostatus of the source. When indicated, post-exposure prophylaxis with HBV vaccine, hepatitis B immunoglobulin or both must be started as soon as possible (within 1-7 days). In the absence of prophylaxis against hepatitis C virus (HCV) infection, follow-up management of HCV exposures depends on whether antiviral treatment during the acute phase is chosen. Test the HCW for HCV-Ab at baseline and after 6 months; up to 12 for HIV-HCV co-infected sources. If treatment is recommended, perform ALT (amino alanine transferase) activity at baseline and monthly for 4 months after exposure, and qualitative HCV-RNA when an increase is detected.

Introduction of SARS in France, March–April, 2003

We describe severe acute respiratory syndrome (SARS) in France. Patients meeting the World Health Organization definition of a suspected case underwent a clinical, radiologic, and biologic assessment at the closest university-affiliated infectious disease ward. Suspected cases were immediately reported to the Institut de Veille Sanitaire. Probable case-patients were isolated, their contacts quarantined at home, and were followed for 10 days after exposure. Five probable cases occurred from March through April 2003; four were confirmed as SARS coronavirus by reverse transcription–polymerase chain reaction, serologic testing, or both. The index case-patient (patient A), who had worked in the French hospital of Hanoi, Vietnam, was the most probable source of transmission for the three other confirmed cases; two had been exposed to patient A while on the Hanoi-Paris flight of March 22–23. Timely detection, isolation of probable cases, and quarantine of their contacts appear to have been effective in preventing the secondary spread of SARS in France.

Treatment of acute hepatitis C in human immunodeficiency virus–infected patients: The HEPAIG study

Acute hepatitis C continues to be a concern in men who have sex with men (MSM), and its optimal management has yet to be established. In this study, the clinical, biological, and therapeutic data of 53 human immunodeficiency virus (HIV)‐infected MSM included in a multicenter prospective study on acute hepatitis C in 2006‐2007 were retrospectively collected and analyzed. The mean hepatitis C virus (HCV) viral load at diagnosis was 5.8 ± 1.1 log10 IU/mL (genotype 4, n = 28; genotype 1, n = 14, genotype 3, n = 7). The cumulative rates of spontaneous HCV clearance were 11.0% and 16.5% 3 and 6 months after diagnosis, respectively. Forty patients were treated, 38 of whom received pegylated interferon and ribavirin. The mean duration of HCV therapy was 39 ± 17 weeks (24 ± 4 weeks in 14 cases). On treatment, 18/36 (50.0%; 95% confidence interval 34.3‐65.7) patients had undetectable HCV RNA at week 4 (RVR), and 32/39 (82.1%; 95 confidence interval 70.0‐94.1) achieved sustained virological response (SVR). SVR did not correlate with pretreatment parameters, including HCV genotype, but correlated with RVR (predictive positive value of 94.4%) and with effective duration of HCV therapy (64.3% for 24 ± 4 weeks versus 92.0% for longer treatment; P = 0.03). Conclusion: The low rate of spontaneous clearance and the high SVR rates argue for early HCV therapy following diagnosis of acute hepatitis C in HIV‐infected MSM. Pegylated interferon and ribavirin seem to be the best option. The duration of treatment should be modulated according to RVR, with a 24‐week course for patients presenting RVR and a 48‐week course for those who do not, irrespectively of HCV genotype. (HEPATOLOGY 2010)

Gaining Greater Insight into HCV Emergence in HIV-Infected Men Who Have Sex with Men: The HEPAIG Study

Objectives The HEPAIG study was conducted to better understand Hepatitis C virus (HCV) transmission among human immuno-deficiency (HIV)-infected men who have sex with men (MSM) and assess incidence of HCV infection among this population in France. Methods and Results Acute HCV infection defined by anti-HCV or HCV ribonucleic acid (RNA) positivity within one year of documented anti-HCV negativity was notified among HIV-infected MSM followed up in HIV/AIDS clinics from a nationwide sampling frame. HIV and HCV infection characteristics, HCV potential exposures and sexual behaviour were collected by the physicians and via self-administered questionnaires. Phylogenetic analysis of the HCV-NS5B region was conducted. HCV incidence was 48/10 000 [95% Confidence Interval (CI):43–54] and 36/10 000 [95% CI: 30–42] in 2006 and 2007, respectively. Among the 80 men enrolled (median age: 40 years), 55% were HIV-diagnosed before 2000, 56% had at least one sexually transmitted infection in the year before HCV diagnosis; 55% were HCV-infected with genotype 4 (15 men in one 4d-cluster), 32.5% with genotype 1 (three 1a-clusters); five men were HCV re-infected; in the six-month preceding HCV diagnosis, 92% reported having casual sexual partners sought online (75.5%) and at sex venues (79%), unprotected anal sex (90%) and fisting (65%); using recreational drugs (62%) and bleeding during sex (55%). Conclusions This study emphasizes the role of multiple unprotected sexual practices and recreational drugs use during sex in the HCV emergence in HIV-infected MSM. It becomes essential to adapt prevention strategies and inform HIV-infected MSM with recent acute HCV infection on risk of re-infection and on risk-reduction strategies.

Cost-effectiveness of HIV post-exposure prophylaxis in France.

ObjectiveTo assess the cost-effectiveness of HIV post-exposure prophylaxis (PEP) in France. MethodsWe used a decision tree to evaluate, from a societys perspective, the cost of PEP per quality-adjusted life-year (QALY) saved. We used 1999–2003 PEP surveillance data and literature-derived data on per event transmission probabilities, PEP efficacy and quality of life with HIV. HIV prevalence and lifetime cost of HIV/AIDS management in the HAART era were derived from French studies. We assumed that mean life expectancy in full health was 65 years among uninfected individuals and that the mean survival time after HIV infection was 22.5 years. The costs of PEP drugs and follow-up were derived from the French public sector. A 3% annual rate was used to discount future costs and effects. ResultsDuring 1999–2003, PEP was prescribed to 8958 individuals (heterosexual sex: 47.6%; homosexual sex: 28.4%; occupational exposure: 23.4%; drug injection: 0.6%); of those, 2143 were exposed to a known HIV-infected source. PEP was estimated to prevent 7.7 infections and saved 64.5 QALY at a net cost of &U20AC;5.7 million, resulting in an overall cost-effectiveness ratio of &U20AC;88 692 per QALY saved. PEP was cost saving for 4.4% of cases and cost effective (< &U20AC;50 000 per QALY) in a further 11.3% of cases. In contrast, 72 and 52% of prescriptions had a cost-effectiveness ratio exceeding &U20AC;200 000 and &U20AC;2 millions, respectively, per QALY saved. ConclusionOverall, the French PEP programme is only moderately cost effective. PEP guidelines should be revised to target high-risk exposures better.

Post-Exposure Prophylaxis of HIV Infection in Healthcare Workers: Recommendations for the European Setting

The European Commission funded a project for the standardisation of the management of occupational exposures to HIV/blood-borne infections and antiretroviral post-exposure prophylaxis (PEP) in Europe. Within this project, the following recommendations and rationale were formulated by experts representative of participating countries. Based on assessment of the exposure, material, and source characteristics, PEP should be started as soon as possible with any triple combination of antiretrovirals approved for the treatment of HIV-infected patients; initiation is discouraged after 72 hours Rapid HIV testing of the source could reduce inappropriate PEP. HIV testing should be performed at baseline, 4, 12, and 24 weeks, with additional clinical and laboratory monitoring of adverse reactions and potential toxicity at week 1 and 2. HIV resistance tests in the source and direct virus assays in the exposed HCW are not recommended routinely. These easy-to-use recommendations seek to maximise PEP effect while minimising its toxicity and inappropriate use.

The undiagnosed chronically-infected HCV population in France. Implications for expanded testing recommendations in 2014.

Background Recent HCV therapeutic advances make effective screening crucial for potential HCV eradication. To identify the target population for a possible population-based screening strategy to complement current risk-based testing in France, we aimed to estimate the number of adults with undiagnosed chronic HCV infection and age and gender distribution at two time points: 2004 and 2014. Methods A model taking into account mortality, HCV incidence and diagnosis rates was applied to the 2004 national seroprevalence survey. Results In 2014, an estimated 74,102 individuals aged 18 to 80 were undiagnosed for chronic HCV infection (plausible interval: 64,920-83,283) compared with 100,868 [95%CI: 58,534-143,202] in 2004. Men aged 18-59 represented approximately half of the undiagnosed population in 2014. The proportion of undiagnosed individuals in 2004 (43%) varied from 21.9% to 74.1% in the 1945-1965 and 1924-1944 birth cohorts. Consequently, age and gender distributions between the chronically-infected (diagnosed and undiagnosed) and undiagnosed HCV populations were different, the 1945-1965 birth cohort representing 48.9% and 24.7%, respectively. Conclusions Many individuals were still undiagnosed in 2014 despite a marked reduction with respect to 2004. The present work contributed to the 2014 recommendation of a new French complementary screening strategy, consisting in one-time simultaneous HCV, HBV and HIV testing in men aged 18-60. Further studies are needed to assess the cost-effectiveness and feasibility of such a strategy. We also demonstrated that data on the undiagnosed HCV population are crucial to help adapt testing strategies, as the features of the chronically-infected HCV population are very distinct.

Hepatitis C virus genotype 3 and the risk of severe liver disease in a large population of drug users in France

Although risk factors for cirrhosis in chronic hepatitis C virus (HCV) infection have been identified, the role of HCV‐genotype 3 remains controversial, and limited data are available in drug users. The aim of the study was to assess risk factors for severe liver disease (cirrhosis/hepatocellular carcinoma) in HCV‐infected drug users between 2001 and 2007 in France. Patients who reported drug use and who had been referred for HCV infection to hepatology centers from a national surveillance system were identified. The severity of liver disease was assessed clinically and histologically (Metavir score). Factors associated with severe liver disease were analyzed after estimating missing values by multiple imputation (MI). Of the 4,065 drug users naive to anti‐HCV treatment who were referred to the 26 participating centers, 8.0% had severe liver disease, 25.7% were infected with HCV‐genotype 3. Factors associated independently with an increased risk of severe liver disease were HCV‐genotype 3 (adjusted odds ratio, multiple imputation (aORMI) = 1.6, [95% confidence interval, 95% CI: 1.2–2.1]), HIV infection (aORMI = 1.8, [1.2–2.8]), male sex (aORMI = 2.0, [1.4–2.8]), age over 40 years (aORMI = 2.1, [1.6–2.9]), history of excessive alcohol consumption (aORMI = 2.8, [2.1–3.7]), and duration of infection ≥18 years (aORMI = 2.9, [2.0–4.3]). This analysis shows that HCV‐genotype 3 is associated with severe liver disease in drug users, independently of age, sex, duration of infection, alcohol consumption, and co‐infection with HIV. These results are in favor of earlier treatment for drug users infected with HCV‐ genotype 3 and confirm the need for concomitant care for excessive alcohol consumption. J. Med. Virol. 82:1647–1654, 2010. 2010 Wiley‐Liss, Inc.

Practical considerations for sensitivity analysis after multiple imputation applied to epidemiological studies with incomplete data

BackgroundMultiple Imputation as usually implemented assumes that data are Missing At Random (MAR), meaning that the underlying missing data mechanism, given the observed data, is independent of the unobserved data. To explore the sensitivity of the inferences to departures from the MAR assumption, we applied the method proposed by Carpenter et al. (2007).This approach aims to approximate inferences under a Missing Not At random (MNAR) mechanism by reweighting estimates obtained after multiple imputation where the weights depend on the assumed degree of departure from the MAR assumption.MethodsThe method is illustrated with epidemiological data from a surveillance system of hepatitis C virus (HCV) infection in France during the 2001–2007 period. The subpopulation studied included 4343 HCV infected patients who reported drug use. Risk factors for severe liver disease were assessed. After performing complete-case and multiple imputation analyses, we applied the sensitivity analysis to 3 risk factors of severe liver disease: past excessive alcohol consumption, HIV co-infection and infection with HCV genotype 3.ResultsIn these data, the association between severe liver disease and HIV was underestimated, if given the observed data the chance of observing HIV status is high when this is positive. Inference for two other risk factors were robust to plausible local departures from the MAR assumption.ConclusionsWe have demonstrated the practical utility of, and advocate, a pragmatic widely applicable approach to exploring plausible departures from the MAR assumption post multiple imputation. We have developed guidelines for applying this approach to epidemiological studies.

Impact of hepatitis C triple therapy availability upon the number of patients to be treated and associated costs in France: a model-based analysis

Objective The combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor (PI) has been approved in summer 2011 for the treatment of genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially improved efficacy. The aim of this study was to estimate the number of G1 patients to be treated in France in 2012 and associated costs. Methods A published model of HCV and data on PEG-IFN sales were used to estimate patients needing treatment using three scenarios. (1) HCV screening rate unchanged versus 2010; proportion of treated F0–F1 patients unchanged, proportion of treated F2–F4 patients increased to the current proportion of treated F2–F4 G2/3 patients. (2) Scenario 1 but the proportion of treated F0–F1 patients increased to the current proportion of treated F0–F1 G2/3 patients. (3) Scenario 2 but a 5% increase in the HCV screening rate. To estimate cost, treatment duration was multiplied by drug unit cost. Probabilities corresponding to treatment duration were estimated based on liver fibrosis stage, treatment-naive or experienced status of the patient and virological response kinetics on treatment. Results Compared with the 5100 G1 patients treated in 2010, the number of G1 patients receiving treatment in 2012 would be 15 000 in scenario 1, 18 300 in scenario 2 and 19 400 in scenario 3, among whom 2.5–3.7% may receive PEG-IFN/RBV and 96.3–97.5% PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638 million Euros. Conclusion These model-based estimates indicate that new anti-HCV treatments may result in a three- to fourfold increase in the number of G1 patients to be treated in France in 2012.