Françoise Lunel-Fabiani

Polyarteritis Nodosa and Hepatitis C Virus Infection

Excerpt To the editors:Markers of hepatitis B virus (HBV) infection have been reported in 20% to 40% of patients with polyarteritis nodosa, suggesting that HBV could be an etiologic factor (1-3). I...

Risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus-coinfected patients during interferon plus ribavirin-based therapy.

Objective:To evaluate the incidence, clinical features, and risk factors for symptomatic mitochondrial toxicity in HIV/hepatitis C virus (HCV)-coinfected patients receiving anti-HCV therapy. Methods:All cases of symptomatic mitochondrial toxicity reported in 416 patients participating in an open, randomized trial of peg-interferon α-2b plus ribavirin vs. interferon α-2b plus ribavirin for 48 weeks were reviewed. Associations with antiretroviral treatments and with clinical and laboratory findings were sought by univariate and multivariate analysis. Results:Eleven of the 383 patients who received at least 1 dose of anti-HCV treatment developed symptomatic mitochondrial toxicity (symptomatic hyperlactatemia and pancreatitis in 6 and 5 patients, respectively). All cases occurred in patients being treated for HIV infection, and the incidence of symptomatic mitochondrial toxicity was 47.5 per 1000 patient-years. In multivariate analysis, symptomatic mitochondrial toxicity was significantly associated with didanosine-containing antiretroviral regimens (odds ratio 46; 95% CI, 7.4 to infinity; P < 0.001), but not with stavudine or with nucleoside reverse transcriptase inhibitor regimens not containing didanosine. The incidence of symptomatic mitochondrial toxicity was 200.2 per 1000 patient-years in patients receiving didanosine. Demographic characteristics were not associated with symptomatic mitochondrial toxicity. Conclusions:Coadministration of ribavirin with didanosine should be avoided. If unavoidable, patients should be monitored closely for mitochondrial toxicity. Didanosine should be suspended if clinical signs or symptoms of mitochondrial toxicity occur.

Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy.

The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95–0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7–5.0; P < 0.01), absence of HIV co‐infection (OR: 2.08; 95% CI = 1.2–3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2–2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0–2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1–3.8; P = 0.03). In conclusion, among difficult‐to‐treat genotypes, the subtype 1a is associated with a lower response to anti‐HCV therapy than subtypes 1b, 4a, and 4d. J. Med. Virol. 81:2029–2035, 2009.

Spontaneous Hepatic Decompensation in Patients Coinfected with HIV and Hepatitis C Virus during Interferon-Ribavirin Combination Treatment

Spontaneous hepatic decompensation was observed in 7 of 383 patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving treatment with interferon and ribavirin. Multivariate analysis identified the following risk factors: didanosine use (odds ratio [OR], 8.8; 95% confidence interval [CI], 1.2-102.3; P < .02), cirrhosis, (OR, 8.8; 95% CI, 1.2-104.2; P<.02), and elevated total bilirubin level (OR, 7.9; 95% CI, 1.08-93.3; P<.03). Didanosine should thus not be given to patients with cirrhosis, particularly when treatments for HCV and HIV infections have to be administered concomitantly.

Prevalence, risk factors, and molecular epidemiology of hepatitis B and hepatitis delta virus in pregnant women and in patients in Mauritania.

No recent data are available on hepatitis B virus (HBV) and hepatitis Delta virus (HDV) prevalence in Mauritania. One thousand twenty pregnant women and 946 patients visiting for routine checkups were screened for HBV and HDV infection. Demographic, epidemiological, ethnic, clinical, and biological data were recorded. HBV and HDV genotypes were determined by sequencing and phylogenetic analyses. In the pregnant women and patients cohorts, respectively, the prevalence of HBsAg (10.7% and 18.3%) and anti‐HBcAb (66.3% and 76.5%) indicated high HBV endemicity. In pregnant women, exposure to HBV was significantly associated in multivariate analysis with education level, ethnicity, blood transfusion, and occupation. HDV antibodies (HDVAb) were found in 14.7% of pregnant women. In patients, HBsAg was found less frequently in females than in males. Again in multivariate analysis, exposure to HBV was significantly correlated with gender (males), and HDVAb positivity with age and gender. The HBV DNA viral load was >3 log IU/ml in only 10.1% of pregnant women and in 17.3% of patients. HDV‐RNA was detectable in 21 (67.7%) of the 31 patients positive for HDVAb, and in 11 of the 16 pregnant women positive for HDVAb (68.8%). The most frequent HBV genotypes were: HBV/D, 53%; HBV/E, 35%; and HBV/A, 12%. Sub‐genotyping revealed HBV/D1,/D7, and the recently described/D8. HDV genotypes were: HDV‐1, 90.3% and HDV‐5, 9.7%. This study confirms the high prevalence of HBV and HDV infections in Mauritania and demonstrates the high genetic diversity of HBV in this country. J. Med. Virol. 84: 1186–1198, 2012.

IL-34 and macrophage colony-stimulating factor are overexpressed in hepatitis C virus fibrosis and induce profibrotic macrophages that promote collagen synthesis by hepatic stellate cells

Chronic hepatitis C virus (HCV) infection is characterized by progressive hepatic fibrosis, a process dependent on monocyte recruitment and accumulation into the liver. The mediators expressed in chronically injured liver that control the differentiation of human monocytes into profibrotic macrophages (Mφ) remain poorly defined. We report that chronically HCV‐infected patients with high fibrosis stages have higher serum levels of macrophage colony‐stimulating factor (M‐CSF) and interleukin (IL)−34 than HCV‐infected patients with lower fibrosis stages and healthy subjects. Immunohistochemistry reveals an intense expression of IL‐34 and M‐CSF by hepatocytes around liver lesions. In addition, HCV infection and inflammatory cytokines enhance the in vitro production of IL‐34 and M‐CSF by hepatocytes. We next analyzed the acquisition of profibrotic properties by Mφ generated with M‐CSF (M‐CSF‐Mφ) or IL‐34 (IL‐34‐Mφ). M‐CSF and IL‐34 up‐regulate the expression, by differentiating monocytes, of chemokine (C‐C motif) ligand (CCL)2, CCL4, C‐C chemokine receptor (CCR)1, and CCR5, which are involved in monocyte recruitment/Mφ accumulation in liver lesions. M‐CSF‐Mφ and IL‐34‐Mφ also express the hepatic stellate cell (HSC) activators, platelet‐derived growth factor, transforming growth factor beta, and galectin‐3. IL‐34‐Mφ and M‐CSF‐Mφ induce type I collagen synthesis by HSCs, the main collagen‐producing cells in liver fibrosis. IL‐13, whose expression correlates with the fibrosis stage in HCV‐infected patients, decreases the expression of the collagenase, matrix metalloproteinase 1, by IL‐34‐Mφ and M‐CSF‐Mφ, thereby enhancing collagen synthesis. By inhibiting the production of interferon‐gamma (IFN‐γ) by activated natural killer cells, IL‐34‐Mφ and M‐CSF‐Mφ prevent the IFN‐γ‐induced killing of HSCs. Conclusion: These results identify M‐CSF and IL‐34 as potent profibrotic factors in HCV liver fibrosis. (Hepatology 2014;60:1878–1889)

Multicenter Quality Control for the Detection of Hepatitis C Virus RNA in Seminal Plasma Specimens

ABSTRACT The discrepant results available in the literature about the presence of hepatitis C virus (HCV) RNA in seminal plasma of men chronically infected by this agent are related, at least in part, to the molecular techniques used and particularly to the wide range of protocols dedicated to RNA extraction. In order to evaluate these protocols and to standardize the method of detection of HCV RNA in this fluid, a panel of coded specimens was tested blindly in 12 French laboratories; it included 14 seminal plasma specimens and four water controls spiked with HCV RNA ranging from 10 to 20,000 IU/ml and two HCV-negative seminal plasma specimens. The extraction step was performed according to methods using either silica beads (NucliSens [Organon Teknika S.A., Fresnes, France]; RNA viral kit [Qiagen, Courtaboeuf, France]) or guanidinium thiocyanate (Amplicor HCV assay; Roche Diagnostics, Meylan, France), preceded or not by a centrifugation of the seminal plasma. For the amplification step, all the laboratories performed the same reverse transcription-PCR technique (Amplicor HCV Cobas assay). The percentage of correct results ranged from 53.3 to 100, the poorest results being obtained when no centrifugation step preceded the Amplicor extraction protocol. The rate of correct results was significantly higher in laboratories using a preliminary centrifugation of the specimen (P = 0.034 by chi-square test). By contrast, the overall number of correct results was not correlated to the initial volume of sample used for the test. These results allowed us to validate standardized techniques adapted to the performance of this test on a routine basis, especially in men infected with HCV and involved in programs of medically assisted reproduction.

A national French survey on the use of growth factors as adjuvant treatment of chronic hepatitis C

We conducted a national retrospective survey on hospital practitioners to evaluate the magnitude of erythropoietin (EPO) or granulocyte colony‐stimulating factor (G‐CSF) prescriptions in patients treated for chronic hepatitis C. Four hundred seventy‐one questionnaires were sent, and 274 practitioners (58.2%) responded. Forty‐six percent of practitioners used EPO, and 31% used G‐CSF. The total number of HCV‐infected patients receiving antiviral therapy per year was estimated at 6,630 patients, of whom 8.8% and 4% received EPO and G‐CSF, respectively. EPO‐β was the main EPO molecule prescribed at a median dose of 30,000 IU/wk (range: 2,000‐80,000). The indications for prescribing EPO varied greatly, including “fragile patients” (34%), “low” Hb level (8‐11 g/dL) (19%), “rapid decline” in Hb level (2‐5 g/dL during the first month of therapy) (12%), and symptomatic anemic patients (7%). G‐CSF was mainly prescribed for a “low” level of neutrophils ranging from 400 to 750 neutrophils/mm3. In multivariate analysis, independent predictors of EPO and G‐CSF prescription were age of practitioner less than 45 years (EPO: OR = 1.96, P = 0.03; G‐CSF: OR = 2.27, P = 0.004), practice in university hospital (EPO: OR = 5.89, P < 0.0001; G‐CSF: OR = 2.39, P = 0.003), and the high number of CHC treated/year (EPO: OR = 6.18, P < 0.0001; G‐CSF: OR = 2.58, P = 0.002). Conclusion: Our survey reveals an important rate of EPO and G‐CSF prescriptions but with considerable disparity in the schedule of injections, the molecules used, and above all the indications. The suitable role of EPO and G‐CSF as complements to HCV therapy urgently needs to be clarified. (HEPATOLOGY 2007;45:377–383.)

IL-26 is overexpressed in chronically HCV-infected patients and enhances TRAIL-mediated cytotoxicity and interferon production by human NK cells

Objective Interleukin-26 (IL-26) is a member of the IL-10 cytokine family, first discovered based on its peculiar expression by virus-transformed T cells. IL-26 is overexpressed in chronic inflammation (rheumatoid arthritis and Crohn’s disease) and induces proinflammatory cytokines by myeloid cells and some epithelial cells. We thus investigated the expression and potential role of IL-26 in chronic HCV infection, a pathology associated with chronic inflammation. Design IL-26 was quantified in a cohort of chronically HCV-infected patients, naive of treatment and its expression in the liver biopsies investigated by immunohistochemistry. We also analysed the ability of IL-26 to modulate the activity of natural killer (NK) cells, which control HCV infection. Results The serum levels of IL-26 are enhanced in chronically HCV-infected patients, mainly in those with severe liver inflammation. Immunohistochemistry reveals an intense IL-26 staining in liver lesions, mainly in infiltrating CD3+ cells. We also show that NK cells from healthy subjects and from HCV-infected patients are sensitive to IL-26. IL-26 upregulates membrane tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) expression on CD16− CD56bright NK cells, enabling them to kill HCV-infected hepatoma cells, with the same efficacy as interferon (IFN)-α-treated NK cells. IL-26 also induces the expression of the antiviral cytokines IFN-β and IFN-γ, and of the proinflammatory cytokines IL-1β and TNF-α by NK cells. Conclusions This study highlights IL-26 as a new player in the inflammatory and antiviral immune responses associated with chronic HCV infection.

Systemic diseases and biotherapies: Understanding, evaluating, and preventing the risk of hepatitis B reactivation

Hepatitis B virus (HBV) reactivation can occur in chronic carriers of the HBV surface antigen (HBsAg) and constitutes a well-known complication of immunosuppressive therapy. HBV reactivation has also been reported after contact with the HBV. The increasing use of biological agents (TNFα antagonists, rituximab, abatacept, and tocilizumab) to treat systemic diseases has resulted in numerous publications about the risk of HBV reactivation. The relevant scientific societies have issued recommendations designed to prevent HBV reactivation. The main measures consist of screening for markers indicating chronic HBV infection (HBsAg) or HBV infection in the distant past (antibodies to the HBV core antigen) before initiating biological therapies, vaccinating marker-negative patients, and considering close follow-up or antiviral treatment before immunosuppressive treatment initiation or in the event of HBV reactivation. Here, we discuss the pathophysiological mechanisms underlying HBV reactivation during biological treatments, most notably in patients with occult HBV infection or markers for remote HBV infection, whose hepatocyte nuclei may contain a resistance form of HBV DNA known as covalently closed circular DNA (cccDNA). Assessment of the risk of reactivation relies on the HBV status, drugs used, and data from the literature. Finally, we discuss the various recommendations and modalities for HBV vaccination, preemptive treatment, and patient management, according to the level of risk and to the circumstances in which reactivation occurs.