A novel treatment of patients with chronic hepatitis C.

OBJECTIVES: Interferon alpha-2b therapy for Chronic Hepatitis C patients has been unsatisfactory. Recombinant Granulocyte Macrophage Colony-Stimulating Factor has been shown to have anti-viral effects in vivo and in vitro via cytokines release. Recently its effects on chronic hepatitis B and possibly chronic hepatitis C were reported. We, decided to conduct a pilot study to evaluate the anti-viral effects of recombinant human GM-CSF mono-therapy in patients with chronic hepatitis C and to assess its side effects. METHODS: A total of 10 patients (male/female: 5/5) (age: 34-60, mean: 45) seen in our center between 2/95 to 2/96 were randomly selected to receive recombinant human Granulocyte Macrophage Colony-Stimulating-Factor at 125 ug/m2 subcutaneously daily for two weeks followed by three times weekly for another 8 weeks. Biochemical (ALT) and viral (HCV-RNA) responses were measured prior to treatment and at weeks four and eight. Side effects were recorded. RESULTS: Six out of the ten patients treated had significant viral reduction but none became negative. Eight out the ten patients treated showed biochemical improvement and three out of the eight had normalized liver enzymes. Age, sex, stage of the disease did not influence the response but there seems to be a tendency for patients with higher pre-treatment viral level to respond virally. Side effects are minimal and well-tolerated. CONCLUSION: Recombinant human Granulocyte Macrophage Colony-Stimulating-Factor in the dose used has anti-viral effects in the majority of the chronic hepatitis C patients studied. Side effects are minimal and well tolerated. Further study with higher doses and longer duration is needed to prove its clinical efficacy in treating patients with chronic hepatitis C

Changes in gastrointestinal microbial communities influence HIV-specific CD8+ T-cell responsiveness to immune checkpoint blockade.

ObjectivesThe aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB).DesignThirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed.MethodsBacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed.ResultsFusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB.ConclusionThe gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure