Louis D'Alteroche

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.

Sustained virologic response with ribavirin in chronic hepatitis E virus infection in heart transplantation

Hepatitis E virus (HEV) is an emerging problem amongst transplant recipients. We report a patient with chronic HEV hepatitis after a heart transplant. The patient received a 3-month course of oral ribavirin (17 mg/kg/day). HEV RNA became undetectable in the serum after 1 month of treatment and remained undetectable in serum and stool samples until the last follow-up, 2 months after completion of ribavirin therapy. The values of liver function indicators returned to normal reference ranges. The main ribavirin-induced side effect was a significant but well-tolerated anemia. We confirmed that ribavirin may induce a sustained virologic response (4 months after ribavirin cessation) in heart transplant patients with chronic HEV infection. Liver cytolysis is rather common in patients after heart transplantation. Rapid evolution to liver fibrosis lesions and available anti-viral therapy highlight the need to look for HEV infection in heart transplant recipients with unexplained hepatitis.

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme

Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real‐world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization.

Sequence and Functional Analysis of the Envelope Glycoproteins of Hepatitis C Virus Variants Selectively Transmitted to a New Host

ABSTRACT Hepatitis C virus (HCV) remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hypervariable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from nontransmitted variants in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetent host may thus be more complex than those suggested by mouse models. Human antibodies directed against HCV envelope effectively cross-neutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.

Thrombopénie auto-immune associée à une réactivation virale B (séroréversion HBs) après autogreffe de moelle

We report a case of autoimmune thrombocytopenia associated with acute reverse seroconversion of hepatitis B in a patient who was initially hepatitis B virus surface antigen negative and hepatitis B virus surface antibody positive. Reactivation occurred 9 months after chemotherapy with anti-CD 20 monoclonal antibodies and autologous hematopoietic stem cell transplantation for lymphoma had been performed. After non specific polyglobulin injections and treatment with adefovir dipivoxil, thrombocytopenia and viral replication were controlled. Seroconversion for both HBe and HBs occurred at 5 months. Adefovir was stopped 4 months later with no relapse during fifteen months of follow-up. This case shows that patients who have had previous contact with hepatitis B virus should be monitored if they become immunosuppressed, even if anti-HBs were initially present.

Viral sequence variation in chronic carriers of hepatitis C virus has a low impact on liver steatosis.

Most clinical studies suggest that the prevalence and severity of liver steatosis are higher in patients infected with hepatitis C virus (HCV) genotype 3 than in patients infected with other genotypes. This may reflect the diversity and specific intrinsic properties of genotype 3 virus proteins. We analyzed the possible association of particular residues of the HCV core and NS5A proteins known to dysregulate lipid metabolism with steatosis severity in the livers of patients chronically infected with HCV. We used transmission electron microscopy to quantify liver steatosis precisely in a group of 27 patients, 12 of whom were infected with a genotype 3 virus, the other 15 being infected with viruses of other genotypes. We determined the area covered by lipid droplets in liver tissues and analyzed the diversity of the core and NS5A regions encoded by the viral variants circulating in these patients. The area covered by lipid droplets did not differ significantly between patients infected with genotype 3 viruses and those infected with other genotypes. The core and NS5A protein sequences of the viral variants circulating in patients with mild or severe steatosis were evenly distributed throughout the phylogenic trees established from all the collected sequences. Thus, individual host factors seem to play a much greater role than viral factors in the development of severe steatosis in patients chronically infected with HCV, including those infected with genotype 3 viruses.

Peritoneovenous Shunt After Failure of Octreotide Treatment for Chylous Ascites in Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown origin, affecting almost exclusively middle-aged women, characterized by abnormal smooth muscle proliferation in the lung, lymphatics, and mediastinal, lower cervical, and abdominal nodes [1]. Chylous ascites is an extrapulmonary manifestation of the disease, which may be difficult to control and has had justified different attempts of medical treatment [1–3]. Treatment with octreotide is a rising alternative to surgery for numerous causes of chylous ascites [4, 5]. We report the case of a patient with chylous ascites revealing LAM successfully treated by peritoneovenous shunting after failure of medical therapy.

Neutropénie et thrombopénie auto-immunes sévères associées à une hépatite chronique C: effet du traitement antiviral.

Resume Nous rapportons le cas d’un malade de 45 ans hospitalise pour thrombopenie et neutropenie severes d’origine auto-immune associees a une hepatite chronique virale C. Apres echec d’un traitement par immunoglobulines polyvalentes et corticotherapie, un traitement antiviral par interferon alpha et ribavirine etait effectue pendant 1 an. La thrombopenie s’ameliorait au cours du traitement puis s’aggravait de nouveau a l’arret. La neutropenie s’ameliorait progressivement au cours du traitement. Deux ans apres l’arret du traitement, la recherche de l’ARN du virus de l’hepatite C etait positive dans le serum, la numeration plaquettaire etait a 77 G/L et la numeration des polynucleaires neutrophiles etait a 1,6 G/L. En conclusion, notre observation suggere qu’un traitement antiviral peut avoir un effet benefique dans certains cas de cytopenies auto-immunes severes associees a une infection par le virus de l’hepatite C.

Rupture d’un kyste du cholédoque au cours de la grossesse

ne femme âgée de 26 ans, enceinte de 36 semaines et demi ’aménorrhée, primipare, était hospitalisée en décembre 995 pour une violente douleur de l’hypochondre droit vec nausées et vomissements. Il n’existait pas d’ictère et a patiente était apyrétique. Les tests hépatiques usuels taient normaux. L’échographie abdominale montrait une asse kystique sous-hépatique de dix centimètres de diaètre, distincte de la vésicule biliaire. Il existait un panchement intrapéritonéal de faible abondance. Une ésarienne était réalisée en urgence donnant naissance à n enfant de sexe masculin de 3,2 kg, Apgar 10. Au cours de a césarienne, l’exploration abdominale mettait en évidence n volumineux kyste du cholédoque. Il existait un épancheent bilieux sous-hépatique et dans la gouttière pariétoolique droite. Un drainage sous-hépatique était laissé en lace et la patiente était opérée à nouveau deux jours plus ard. Il existait une diffusion de bile à travers une paroi choédocienne kystique sans rupture franche de sa continuité. a cholangiographie montrait un volumineux kyste du choléoque associé à une dilatation du canal hépatique gauche : il ’agissait d’un type IVa de la classification de Todani. Il était éalisé une cholécystectomie et une résection de la voie iliaire principale avec respect de la convergence biliaire n amont et tunnelisation de la portion intrapancréatique e la voie biliaire principale jusqu’à l’abouchement dans le anal commun bilio pancréatique qui était présent. Il était éalisé une anastomose hépaticojéjunale sur une anse en Y n transmésocolique. L’examen anatomopathologique de la ièce opératoire montrait une cholécystite chronique avec holestérolose, une paroi kystique avec des remaniements nflammatoires aigus et des petits foyers de dysplasie épihéliale légère. Les suites opératoires étaient simples. La atiente était revue deux ans plus tard ; elle était asymptoatique et l’échographie hépatique était normale.

12 Weeks of a Ribavirin‐Free Sofosbuvir and Nonstructural Protein 5A Inhibitor Regimen Is Enough to Treat Recurrence of Hepatitis C After Liver Transplantation

Sofosbuvir (SOF) combined with nonstructural protein 5A (NS5A) inhibitors has demonstrated its efficacy in treating a recurrence of hepatitis C virus (HCV) after liver transplantation (LT). However, the duration of treatment and need for ribavirin (RBV) remain unclear in this population. Our aim was to determine whether LT recipients could be treated with an SOF + NS5A inhibitor‐based regimen without RBV for 12 weeks post‐LT. Between October 2013 and December 2015, 699 LT recipients experiencing an HCV recurrence were enrolled in the multicenter ANRS CO23 CUPILT cohort. We selected patients receiving SOF and NS5A inhibitor ± RBV and followed for at least 12 weeks after treatment discontinuation. The primary efficacy endpoint was a sustained virological response 12 weeks after the end of treatment (SVR12). Among these 699 patients, 512 fulfilled the inclusion criteria. Their main characteristics were: 70.1% genotype 1, 18.2% genotype 3, 21.1% cirrhosis, and 34.4% previously treated patients. We identified four groups of patients according to their treatment and duration: SOF + NS5A without RBV for 12 (156 patients) or 24 (239 patients) weeks; SOF + NS5A + RBV for 12 (47 patients) or 24 (70 patients) weeks. SVR12 values reached 94.9%, 97.9%, 95.7%, and 92.9%, respectively (P = 0.14). Only 20 patients experienced a treatment failure. Under multivariate analysis, factors such as fibrosis stage, previous treatment, HCV genotype, and baseline HCV viral load did not influence SVR12 rates in the four groups (P = 0.21). Hematological adverse events (AEs) were more common in the RBV group: anemia (P < 0.0001) and blood transfusion (P = 0.0001). Conclusion: SOF + NS5A inhibitors without RBV for 12 weeks constituted reliable therapy for recurrent HCV post‐LT with an excellent SVR12 whatever the fibrosis stage, HCV genotype, and previous HCV treatment. (Hepatology 2018; 00:000‐000).