How to improve access to therapy in hepatitis B patients

Despite the availability of a preventive vaccine and active antiviral treatments that stop disease progression and reduce the risk of hepatocellular carcinoma, hepatitis B is still a major public health problem. Only an estimated 10% of the 257 million people living with HBV have been diagnosed and as few as 1% are being adequately treated. Barriers to diagnosis and treatment include: (i) limited awareness and lack of knowledge about HBV infection and HBV-related diseases; (ii) under-diagnosis with insufficient screening and referral to care; (iii) limited treatment due to drug availability, costs, reimbursement policies and the need for long-term or life-long therapy. These barriers and the actions needed to improve access to treatment are strongly influenced by the prevalence of infection and affect middle-high vs low-middle income countries differently, where most HBV carriers are found. In high-prevalence regions and low-to middle-income countries, the main challenges are availability and cost while in low-prevalence regions and middle-to high-income countries low screening rates, public awareness, social stigma and discrimination play an important role. Overcoming these challenges on a global scale is a complex clinical and public health challenge and multilateral commitment from pharmaceutical companies, governments, funders and the research community is lacking. The new WHO 2016 Global Health Sector Strategy on viral hepatitis targets testing and treatment, suggesting that important but strong actions are needed from advocacy groups, scientific societies and funding agencies to foster awareness and access to cure

Comparison and analysis of the efficacy of drug therapy for liver cancer

Hepatocellular carcinoma (HCC) is a poor prognosis tumor when not accessible to potentially curative treatments such as surgical resection, thermal ablations or liver transplantation. Systemic cytotoxic chemotherapies have shown inconsistent clinical benefit. In 2007, sorafenib, a tyrosine kinase inhibitor (TKI), was the first systemic therapy able to significantly improve the outcome of HCC patients non-eligible for curative or loco-regional therapies, despite a modest tolerance and low tumor objective response rate (ORR). Among the newer TKIs approved after 2017, lenvatinib was the first to show a striking ORR and demonstrate non-inferiority vs. sorafenib in the first-line setting. Furthermore, phase 3 trials showed the benefit of other TKIs, regorafenib and cabozantinib, and the anti-angiogenic ramucirumab monoclonal antibody, in systemic second-line therapy. Immune checkpoint inhibitors targeting PD1, achieved striking tumor shrinkage in some patients in monotherapy, seeming to be associated with exciting outcomes. Unfortunately, this occurred in too few patients to improve the median overall survival. More recently, the combination of anti-angiogenic drugs targeting the liver microenvironment with PD-1/PD-L1 inhibitors, such as the combination of bevacizumab and atezolizumab, proved to be substantially effective in phase 3, and other combinations of PD-1/PD-L1 and CTLA-4 inhibitors or TKIs have raised a lot of hopes for the systemic treatment of HCC

Predictors of liver fibrosis in patients with non-alcoholic fatty liver disease. The role of metabolic syndrome, insulin-resistance and inflammation [Predittori di fibrosi epatica in pazienti con steatosi epatica non-alcolica. Il ruolo della sindrome metabolica, dell'insulino-resistenza e dell'infiammazione]

NAFLD (non-alcoholic fatty liver disease) reaches an high prevalence in the general population, and it is closely related to metabolic syndrome (MetS). The entity of metabolic abnormalities and the chronic inflammation seem to play a main role in the development of liver fibrosis. The aim of our study is to determine whether subjects with NAFLD and MetS have higher liver fibrosis degree when compared with NAFLD subjects without MetS, and to investigate the relations between fibrosis, MetS and its single components and inflammation. We considered 24 patients with NAFLD. Those who had viral- and alcohol- related liver disease were excluded. MetS was diagnosed according to NCEP ATP III criteria; inflammatory status was determined through C-reactive protein (PCR) assay. The peripheral insulin-resistance was assessed by calculating HOMA ir. Liver fibrosis was measured by transient elastography (Fibroscan®). Subjects with MetS had higher HOMA ir, PCR and Fibroscan® score (log value: 0.92±0.24 KPa vs 0.73±0.2 KPa; p=0.047). The linear correlation analysis showed that Fibroscan® score was related to MetS, number of MetS components, waist circumference, HOMA ir and PCR. However the multivariate regression analysis showed that only HOMA ir (B=0.077; 95%CI: -0.002- 0.157; p=0.05) and PCR (B=0.152; 95% CI: 0.006 - 0.299; p=0.006) were independent predictors of higher Fibroscan® score. MetS is associated to higher liver fibrosis degree in subjects with NAFLD. The insulin-resistance and inflammation seem to be the main determinants

Interaction between Toll-Like Receptor 9-CpG Oligodeoxynucleotides and Hepatitis B Virus Virions Leads to Entry Inhibition in Hepatocytes and Reduction of Alpha Interferon Production by Plasmacytoid Dendritic Cells

International audienceWe previously reported that Toll-like receptor 9 (TLR9)-CpG oligonucleo-tides could inhibit the establishment of hepatitis B virus (HBV) infections in hepato-cytes. Our aim was to uncover the underlying mechanisms of this inhibition. HepaRG cells, RPMI-B lymphoblastoma cells, and primary plasmacytoid dendritic cells (pDCs) exposed to HBV and TLR9 ligands/agonists in various configurations were used. We observed an inhibition of HBV infection upon TLR9 stimulations only when agonist was applied during inoculation. This inhibition was independent of interleukin-6 (IL-6)/interferon-inducible protein 10 (IP-10) production as well as of TLR9 expression in hepatocytes. We further demonstrated an entry inhibition mechanism by showing a noncovalent binding of TLR9 agonist to HBV particles. Besides inhibiting HBV entry into hepatocytes, this biophysical interaction between HBV virions and TLR9 agonist was responsible for a reduction of alpha interferon (IFN-) expression by pDCs. Interestingly , subviral particles composed of only HBsAg were able to genuinely inhibit the TLR9 pathway, without titrating TLR9 ligands. To conclude, our data suggest that synthetic TLR9-CpG oligonucleotides can strongly inhibit HBV entry by " coating " HBV virions and thereby preventing their interaction with cellular receptor. This titration effect of TLR9 agonist is also artifactually responsible for the inhibition of TLR9 engagement in pDCs, whereas a genuine inhibition of this innate pathway was confirmed with HBsAg subviral particles. H epatitis B virus (HBV) chronically infects 240 million people worldwide and represents one of the major etiologies for cirrhosis and hepatocellular carcinoma (1, 2). The progression rate of chronicity is tightly linked with the maturity of the immune system, since 90 to 95% of infected newborns become chronic carriers, whereas only 5 to 10% of adults do (3). As HBV long-term persistence is characterized by subversion of both innate and adaptive immunity (4, 5), a better understanding of the underlying cellular and molecular mechanisms of this escape should help in defining new therapeutic strategies to reactivate the host immune system and control viral replication. Current front-line therapies include the use of nucleoside analogues to specifically inhibit viral reverse transcription and/or pegylated interferon alpha 2a or 2b (Peg-IF

Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis

Summary: Bacterial infections are the most frequent precipitating event in patients with acute decompensation of cirrhosis (AD) and are associated with high mortality. Early diagnosis is challenging due to cirrhosis-related systemic inflammation. Here we investigated the potential of circulating microRNAs to diagnose bacterial infections and predict survival in cirrhotic patients with AD. High throughput profiling of circulating microRNAs was performed using the Nanostring technology in 57 AD patients and 24 patients with compensated cirrhosis (CC). Circulating miRs profiling showed that: (a) miRs differentially detected in AD vs. CC were mostly down-regulated; (b) a composite score including absolute neutrophil count, C reactive protein and miR-362-3p could diagnose bacterial infection with an excellent performance (AUC of 0.825 [95% CI = 0.671–0.980; p < 0.001]); (c) a composite score including miR-382-5p, miR-592 and MELD-Na improved 6-month survival prediction. Circulating miRs are strongly dysregulated in patients with AD and may help to improve bacterial infection diagnosis and survival prediction

Effect of Peg-IFN on the viral kinetics of HDV infected patients treated with bulevirtide

International audienceBackground &amp; AimsBulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with Peg-IFN are unknown.MethodsWe used mathematical modeling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks.ResultsThe efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, while Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (&gt;2 log of decline or undetectability) at week 48 of 86.9% (95% PI = [79.7;95.0]), compared to 56.1% (95% PI = [46.4;66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5;13.2]) with bulevirtide compared to 18.8% (95% PI = [11.6;29.0]) with bulevirtide+Peg-IFN. Mathematical modeling suggests that after 144 weks of treatment, the rates of viral cure could be 42.1% (95% PI= [33.3;52.6]) with bulevirtide and 66.7% (95% PI= [56.5;76.8]) with bulevirtide+Peg-IFN.ConclusionsIn this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment.Impact and ImplicationBulevirtide has been approved for Chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of peg-IFN and bulevirtide in CHD patients. Clinical trials are now warranted to confirm those predictions

Treatment With Bulevirtide in HIV Infected patients With chronic Hepatitis Delta. ANRS HD EP01 BULEDELTA & Compassionate Cohort

International audienceBackground and AimsIn France, Bulevirtide (BLV) was available in September 2019 through an early access program to treat patients with hepatitis Delta virus (HDV). The aim of this analysis was to evaluate the efficacy and safety of BLV in HIV patients with HDV coinfection.Patients and methodsPatients received BLV 2 mg +/- pegylated interferon (pegIFNα) according to the physician’s decision. The primary endpoint (per-protocol analysis) was the virological response rate at week 48, defined as the proportion of patients with undetectable serum HDV-RNA or HDV-RNA decline > 2 log10 IU/mL from baseline.ResultsCharacteristics of the 38 patients were as follow: 28 male, mean age 47.7 years, mean baseline HDV-RNA viral load 5.7 ± 1.2 log10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30 - 65) cp/ml and 566 ± 307/mm3, respectively. Eight patients stopped treatment before week 48. At W48, 10 of 19 patients (52.6%) in the 2 mg BLV group, and 5 of 7 patients (71.4%) in the 2 mg BLV + pegIFNα group had reached virological response (no HDV-RNA available in 4 patients). At W48, 7/19 patients in the 2 mg BLV group, and 3/6 patients in the 2 mg BLV + pegIFNα group had combined response (virological response and normal ALT level).ConclusionAdults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNα showed a strong virological response