Philippe Sultanik

Brief communication: case reports of ribavirin treatment for chronic hepatitis E.

BACKGROUND There is currently no accepted treatment of chronic hepatitis E virus (HEV) infection. OBJECTIVE To report 2 patients in whom ribavirin therapy seemed to alter the natural history of chronic HEV infection. DESIGN Case reports. SETTING Hepatology unit of a tertiary care center in France. PATIENTS A kidney and pancreas transplant recipient and a patient with idiopathic CD4(+) T lymphocytopenia, both with biopsy-proven chronic HEV infection. INTERVENTION Patients received oral ribavirin, 12 mg/kg of body weight daily for 12 weeks. MEASUREMENTS Liver function tests, detection of HEV RNA (viremia and stool shedding) by reverse transcriptase polymerase chain reaction, and anti-HEV IgM and IgG antibodies. RESULTS Both patients had normalized liver function test results after 2 weeks of treatment and cleared HEV after 4 weeks of treatment. Hepatitis E virus RNA remained undetectable in the serum and stools throughout follow-up (3 months and 2 months for the first and second patient, respectively). Side effects were considered mild. LIMITATION Given the relatively short follow-up, the achievement of HEV eradication could not be claimed. CONCLUSION Ribavirin is a potentially effective treatment of HEV infection and should be evaluated in patients with chronic HEV infection. PRIMARY FUNDING SOURCE None.

Regression of an HCV-associated disseminated marginal zone lymphoma under IFN-free antiviral treatment.

To the editor: Hepatitis C virus (HCV) is prevalent in B-cell–associated lymphomas, including marginal zone and diffuse large B-cell lymphomas.[1][1] A stepwise model of lymphomagenesis induced by chronic antigenic stimulation and/or a direct pro-oncogenic effect of intracellular HCV proteins is

Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients

Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8+ T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8+ T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8+ T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection. DOI: http://dx.doi.org/10.7554/eLife.07916.001

Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies

Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL101–77 from the NH2‐truncated CXCL103–77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103–77 concentration, a reciprocal increase in CXCL101–77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors.

Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors‐based therapy

Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated‐interferon/ribavirin (PR) and HCV non‐structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment‐experienced cirrhotic patients from the ANRS CUPIC cohort.

The relationship between liver stiffness measurement and outcome in patients with chronic hepatitis C and cirrhosis: a retrospective longitudinal hospital study.

There is a relationship between liver stiffness measurement (LSM) and outcome of HCV patients.

HIV‐associated obliterative portopathy (HIV‐OP) underlies cryptogenic liver disease in HIV‐seropositive patients

Dinh et al. have reported that, in a single centre, eight of 115 HIV-infected patients (6.9%) had unexplained noncirrhotic portal hypertension (NCPH) [1]. Their report provides further evidence that NCPH in HIV-positive patients is a vascular disease of the liver. It also highlights the potential severity of the syndrome and underlines how important it is to develop early screening strategies. Dr Dinh’s group is the tenth team worldwide to report cases of NCPH in HIV-positive patients. Undoubtedly, NCPH is an emerging disease in HIV-infected patients. Our group currently follows 21 similar patients. All were referred to our unit for unexplained abnormal liver function tests with or without portal hypertension. As did Dr Dinh, we found that the Fibroscan s was inappropriate to diagnose NCPH in HIV-positive patients. The median Fibroscan s value in our cohort was 8.3 kPa [interquartile

Patients With Chronic Hepatitis B Should Be Screened for Hepatocellular Carcinoma Regardless of Liver Stiffness Measurement

Kim and colleagues report that a high liver stiffness value ( 13 kPa) is an independent risk factor for hepatocellular carcinoma in patients with treated and untreated chronic hepatitis B viral infection. The problem is that the liver stiffness value is a function of fibrosis and necroinflammation and that liver stiffness may decrease when the latter is controlled. In our center, 627 patients with chronic hepatitis B viral infection underwent liver stiffness measurement between 2006 and 2014 and 16 (2.5%) developed hepatocellular carcinoma after a median follow-up of 35 (interquartile range 17-65) months. Considering the entire cohort, the liver stiffness value was correlated to hepatocellular carcinoma development with an area under the receiver operating characteristic curve of 0.87 (P < 0.0001). Nevertheless, a 13-kPa threshold for prediction of hepatocellular carcinoma had a sensitivity and specificity at 31% and 95%, respectively. Among patients under treatment, the sensitivity and specificity for the same threshold were 36% and 91%, respectively, corresponding to seven patients with a median liver stiffness value of 7.4 (interquartile range 5.4-9) kPa before the development of hepatocellular carcinoma. Moreover, three (43%) of them had overt cirrhosis or biopsy-proven “occult” cirrhosis at the time of hepatocellular carcinoma. It is likely that a growing number of clinicians will perform serial liver stiffness measurements in their patients with chronic hepatitis B viral infection, including those under treatment, and that evidence-based proven management of these patients will be inferred from such measurements. At the individual level, the liver stiffness value does not accurately predict the risk of hepatocellular carcinoma and liver stiffness measurement should not be used as a follow-up tool. Patients at risk of hepatocellular carcinoma should comply with recommended follow-up.

Impact of IL28B , APOH and ITPA Polymorphisms on Efficacy and Safety of TVR- or BOC-Based Triple Therapy in Treatment-Experienced HCV-1 Patients with Compensated Cirrhosis from the ANRS CO20-CUPIC Study

Background Human genetic factors influence the outcome of pegylated interferon and ribavirin hepatitis C therapy. We explored the role of IL28B, APOH and ITPA SNPs on the outcomes of triple therapy including telaprevir or boceprevir in patients with compensated cirrhosis chronically infected with HCV-1. Patients and Methods A total of 256 HCV-1 Caucasian treatment-experienced patients with compensated cirrhosis from the ANRS CO20-CUPIC cohort were genotyped for a total of 10 candidate SNPs in IL28B (rs12979860 and rs368234815), APOH (rs8178822, rs12944940, rs10048158, rs52797880, rs1801689 and rs1801690) and ITPA (rs1127354 and rs7270101). We tested the association of IL28B and APOH SNPs with sustained virological response and of ITPA SNPs with anemia related phenotypes by means of logistic regression assuming an additive genetic model. Results None of the six APOH SNPs were associated with sustained virological response. The favorable alleles of the IL28B SNPs rs12979860 and rs368234815 were associated with sustained virological response (rs12979860: OR = 2.35[1.50–3.70], P = 2x10-4). Refined analysis showed that the effect of IL28B SNPs on sustained virological response was restricted to prior PegIFN/RBV relapse (OR = 3.80[1.82–8.92], P = 8x10-4). We also confirmed the association between ITPA low activity alleles and protection against early hemoglobin decline in triple therapy (P = 2x10-5). Conclusion Our results suggest that the screening of rs12979860 may remain interesting for decision making in prior relapse HCV-1 Caucasian patients with compensated cirrhosis eligible for a telaprevir- or boceprevir-based therapy.

Baseline sensitivity of T cells to alpha-IFN correlates with sustained virological response to IFN-based triple therapy in HCV infection

Chronic infection with HCV is a public health problem with approximately 170 million people infected worldwide. Interferon alpha (IFNα) sensitivity in liver and IL28B genotype has been identified as important determinants of HCV clearance in the setting of pegylated interferon/ribavirin treatment. Herein, we explored IFNα sensitivity in PBMC from 21 healthy donors and 21 HCV‐infected patients treated with pegylated interferon/ribavirin and HCV nonstructural protein‐3 inhibitors (i.e. telaprevir/boceprevir). We explored phospho‐STAT1 level as read‐out for IFN signalling pathway activation in PBMC, T cells and monocytes and correlated results with virological response. We found that PBMC from healthy donors are desensitized to IFNα after priming and challenged with IFNα, with a subsequent decrease of phospho‐STAT1 and interferon‐stimulated genes. Furthermore, we show that CD3+ T cells, but not monocytes, become desensitized after 4 weeks of treatment, with a significant decrease of phospho‐STAT1 after ex vivo IFNα stimulation. Finally, we identified baseline phospho‐STAT1 level in CD3+ T cells as a potential biomarker of sustained virological response, regardless of the IL28B genotype. In the upcoming costly era of IFN‐sparing regimen, baseline IFNα sensitivity could act as biomarker to define cost‐effectiveness strategies of treatment by identifying patients who will or will not respond to IFN‐based treatments.