Fabrice Carrat

Time lines of infection and disease in human influenza: a review of volunteer challenge studies.

The dynamics of viral shedding and symptoms following influenza virus infection are key factors when considering epidemic control measures. The authors reviewed published studies describing the course of influenza virus infection in placebo-treated and untreated volunteers challenged with wild-type influenza virus. A total of 56 different studies with 1,280 healthy participants were considered. Viral shedding increased sharply between 0.5 and 1 day after challenge and consistently peaked on day 2. The duration of viral shedding averaged over 375 participants was 4.80 days (95% confidence interval: 4.31, 5.29). The frequency of symptomatic infection was 66.9% (95% confidence interval: 58.3, 74.5). Fever was observed in 37.0% of A/H1N1, 40.6% of A/H3N2 (p = 0.86), and 7.5% of B infections (p = 0.001). The total symptoms scores increased on day 1 and peaked on day 3. Systemic symptoms peaked on day 2. No such data exist for children or elderly subjects, but epidemiologic studies suggest that the natural history might differ. The present analysis confirms prior expert opinion on the duration of viral shedding or the frequency of asymptomatic influenza infection, extends prior knowledge on the dynamics of viral shedding and symptoms, and provides original results on the frequency of respiratory symptoms or fever.

Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study

BACKGROUND Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study. METHODS 19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohns disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40). FINDINGS At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkins lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. INTERPRETATION Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. FUNDING Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

Regulatory T-Cell Responses to Low-Dose Interleukin-2 in HCV-Induced Vasculitis

BACKGROUND Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy. METHODS We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis. RESULTS No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E(max) (maximum value)÷baseline value×100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators. CONCLUSIONS The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.).

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.

BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France. METHODS We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries. RESULTS Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio [HR], 5.9; 95% confidence interval [CI], 2.1-16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3-12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05-1.11; P < .0001). CONCLUSIONS Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening.

Liver biopsy: The best, not the gold standard

Fibrosis, the hallmark of chronic liver diseases, is one of the major deleterious processes associated with chronic hepatitis C. Staging of fibrosis relies on an evaluation of several histological features including assessment of extent of the extracellular matrix deposit, the localization of the deposits within the liver lobule and changes in lobular architecture. These features are then integrated into a semiquantitative scoring system. Histological staging of fibrosis has gained acceptance as a major element in evaluation of liver damage in hepatitis C. Indeed, staging mirrors the natural evolution of chronic hepatitis, predicts evolution toward development of cirrhosis and end-stage liver complications, contributes to predicting a sustained response to antiviral treatment. This is crucial as cirrhosis, the end-point of fibrosis, is the main cause of morbidity and mortality in chronic liver diseases [1–4]. Because fibrosis implies morphological damage, liver biopsy has come to be the natural gold standard for staging the disease. However, the high prevalence of chronic hepatitis C in addition to the cost and constraints generated by this procedure has triggered an intensive search for alternative methods for staging the disease. How to evaluate the performance of these surrogates and how the inherent limits of the biopsy influ-

Effect of influenza vaccination of nursing home staff on mortality of residents: a cluster-randomized trial.

OBJECTIVES: To evaluate the effect of staff influenza vaccination on all‐cause mortality in nursing home residents.

Towards an HBV cure: state-of-the-art and unresolved questions—report of the ANRS workshop on HBV cure

HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis ‘HBV Cure’ programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.

Evaluation of Clinical Case Definitions of Influenza: Detailed Investigation of Patients During the 1995–1996 Epidemic in France

Using clinical predictors, we evaluated clinical case definitions of influenza during the 1995-1996 outbreak in France. Thirty-five general practitioners collected virological specimens and clinical data. Predictors of influenza virus infection were selected with logistic regression models. The results varied with the influenza virus subtype: temperature of >38.2 degrees C, stiffness or myalgia, rhinorrhea, and cough were predictive of influenza A/H3N2, whereas fatigue, lacrimation or conjunctival injection, and the absence of stiffness or myalgia were predictive of influenza A/H1N1. On the basis of this analysis and data from the literature, 12 clinical case definitions were evaluated for their abilities to diagnose influenza virus infection. They were associated with positive predictive values of 27% to 40% and negative predictive values of 80% to 91%. We conclude that focused studies evaluating clinical case definitions of influenza with use of subsets of patients should accompany population-based disease surveillance for optimal estimates of the disease burden associated with influenza epidemics.

Usefulness of co-treatment with immunomodulators in patients with inflammatory bowel disease treated with scheduled infliximab maintenance therapy

Background and aims Concomitant use of immunosuppressants (IS) with scheduled infliximab (IFX) maintenance therapy for Crohns disease (CD) or ulcerative colitis (UC) is debated. The aim of this study was to assess whether IS co-treatment is useful in patients with inflammatory bowel disease (IBD) on scheduled IFX infusions. Methods 121 consecutive patients with IBD (23 UC, 98 CD) treated by IFX and who received at least 6 months of IS co-treatment (azathioprine (AZA) or methotrexate (MTX)) were studied. In each patient, the IFX treatment duration was divided into semesters which were independently analysed regarding IBD activity. Results Semesters with IS (n=265) and without IS (n=319) were analysed. IBD flares, perianal complications and switch to adalimumab were less frequently observed in semesters with IS than in those without IS (respectively: 19.3% vs 32.0%, p=0.003; 4.1% vs 11.8%, p=0.03; 1.1% vs 5.3%, p=0.006). Maximal C-reactive protein (CRP) level and IFX dose/kg observed during the semesters were lower in semesters with IS. Within semesters with IS, IBD flares and perianal complications were less frequently observed in semesters with AZA than in those with MTX. In multivariate analysis, IS co-treatment was associated with a decreased risk of IBD flare (OR 0.52; 95% CI 0.35 to 0.79) Conclusion In patients with IBD receiving IFX maintenance therapy, IS co-treatment is associated with reduced IBD activity, IFX dose and switch to adalimumab. In this setting, co-treatment with AZA seems to be more effective than co-treatment with MTX. Benefit of such a combination treatment has to be balanced with potential risks, notably infections and cancers.