Christian Trepo

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.

Pneumococcal pneumonia in HIV-infected patients by antiretroviral therapy periods

To ascertain the relationship between periods of various antiretroviral therapies and the incidence of first community‐acquired pneumococcal pneumonia (CAPP) among HIV‐1 infected patients.

A randomized trial of viral hepatitis prevention among underprivileged people in the Lyon area of France

BACKGROUNDnWe compared the efficacy of two viral hepatitis B and C (VHBC) screening strategies, relative to no intervention, among underprivileged people (UP) living in shelters in the Lyon area.nnnMETHODSnEighteen of 37 shelters were randomly sampled after stratification based on the accommodation capacity and the screening centres/shelters distance. Through randomization, the S0 strategy (no intervention), the S1 strategy [group information (GI) and referral for screening] and the S2 strategy (GI and in situ screening) were each applied in six shelters. A standardized questionnaire was offered to each participant. Follow-up of positive cases was organized via the reference centre of VHBC of Lyon.nnnRESULTSnThe screening completion rate (SCR) among 1276 included subjects in S0, S1 and S2 was 1.5, 42.8 and 59.7%, respectively (P < 10(-6)). This rate was higher in S2 regardless of the sociodemographic variable considered. Odds ratios (OR) of screening completion (SC) was significantly higher in S1 versus S0, OR = 49.8 [95% confidence interval (CI): 26.1-102.1], in S2 versus S0, OR = 98.5 (95% CI: 51.9-200.8) and in S2 versus S1, OR = 2.0 (95% CI: 1.3-2.9). Age, country of birth and professional inactivity were independently associated with SC.nnnCONCLUSIONSnHealth authorities must ensure widespread screening of UP, which is more effective when conducted in shelters than in screening centres.

First presentation for care of HIV-infected patients with low CD4 cell count in Lyon, France: risk factors and consequences for survival.

Abstract To identify the risk factors associated with presentation for care with CD4 cell count ≤200 cells/mm3 and death in HIV-infected patients in Lyon, France. Data were analyzed on participants from mid-1992 to December 2006 in the Lyon section of the French Hospital Database on HIV Infection. Patients were stratified into two categories according to CD4 cell count at first presentation for care in University of Lyon hospitals: Group 1 (Gr1) patients with CD4 ≤200 cells/mm3 and Group 2 (Gr2) patients with CD4 >200 cells/mm3. Multivariate logistic regression assessed the risk factors associated with first presentation for care with CD4 ≤200 cells/mm3. Survival was analyzed according to the Cox regression model. Among 3569 eligible patients (838 females and 2731 males, mean age: 36.3±10.3 years), 1139 (31.9%) were categorized as Gr1. The factors associated with first presentation for care with CD4 ≤200 cells/mm3 were: older age, male gender, route of HIV transmission, migrant populations, geographical areas other than Rhône-Alpes, and access to care in 1992–1997. Overall mortality was higher in Gr1 than in Gr2 (24.4% [278/1139] vs. 4.1% [101/2430]; p<0.001). The risk of death was 5.81 [4.61–7.32] in Gr1 compared to Gr2. In addition to CD4 cell count, age and enrollment periods for care were factors independently related to death. Despite public health efforts in Lyon, one-third of HIV-infected patients reach the health care system with CD4 cell count ≤200 cells/mm3, which was linked with higher mortality.

Traitement de l'hépatite B: progrès attendus

Despite the development of new anitiviral agents, the treatment of chronic hepatitis B remains a major clinical challenge. Major achievements have been made with the rationale use of antivirals exhibiting a complementary cross resistance profile to prevent antiviral drug resistance. The current concept of modern antiviral therapy of chronic hepatitis B relies on a precise virologic monitoring and early treatment adaptation to prevent drug resistance. The difficulty of achieving viral clearance and the risk of drug resistance development are major arguments to continue research in the field of antivirals and to identify new targets for therapy. The development of true combination therapy is highly desirable to fulfil the objective of long-term viral suppression, clearance of viral cccDNA and infected cells and ultimately cure of the disease.

Diversity of Hepatocellular Carcinoma Clones Bearing Hematopoietic Malignancies‐Related Chromosomal Translocation

Interpatient heterogeneity of hepatocellular carcinoma has been in‐depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV‐associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFβs proproliferative effect on all clones were observed. TGFβ, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially β‐catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E‐cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling‐defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies. J. Cell. Biochem. 115: 666–677, 2014.