Role of interferon lambda 4 and ALT levels in optimising treatment of HCV for patients with low-stage fibrosis

The use of new anti-HCV drugs is currently limited by high costs and dual therapy; pegylated interferon and ribavirin (peg-IFN+RBV) still represents the only affordable treatment in patients with low-stage fibrosis. We evaluated the role of Interferon lambda4 (IFNL4) polymorphisms and its combination with on-treatment alanine transaminase (ALT) modification in predicting sustained virological response (SVR) in HCV genotype 1 and 4 patients with low-stage fibrosis. We retrospectively analysed 124 patients with Metavir ≤F2, who received dual therapy at our centre. Genotyping for IFNL4 polymorphisms was assessed at baseline, as well as ALT levels (baseline and week 2, 4, 12 and 24 of therapy). Thirty patients (24%) were TT/TT, 74 (60%) TT/DG and 20 (16%) DG/DG. The SVR rate was significantly higher in TT/TT genotype compare to TT/DG and DG/DG (97% vs. 53% and 50%, respectively, p=0.001). Patients that achieved a 60% reduction of ALT baseline value after 4 weeks of therapy had a significantly higher SVR rate (94% vs. 52%, p<0.001). Factors significantly associated with SVR were TT/TT genotype (p=0.029), RVR (p=0.019) and 60% ALT reduction at 4 week of therapy (p=0.005). The absence of both TT/TT genotype and 60% ALT reduction were negative predictors of SVR (p<0.001). In conclusion, the combined use of IFNL4 polymorphisms and ALT reduction at 4 week of treatment is able to optimize candidates’ selection for peg-IFN+RBV, discriminating those that could still benefit from dual therapy from the ones that need the new regimen

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

Background Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. Methods and Findings KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. Conclusions The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1

Human Leukocyte Antigen Complex and Other Immunogenetic and Clinical Factors Influence Susceptibility or Protection to SARS-CoV-2 Infection and Severity of the Disease Course. The Sardinian Experience

Aim: SARS-CoV-2 infection is a world-wide public health problem. Several aspects of its pathogenesis and the related clinical consequences still need elucidation. In Italy, Sardinia has had very low numbers of infections. Taking advantage of the low genetic polymorphism in the Sardinian population, we analyzed clinical, genetic and immunogenetic factors, with particular attention to HLA class I and II molecules, to evaluate their influence on susceptibility to SARS-CoV-2 infection and the clinical outcome. Method and Materials: We recruited 619 healthy Sardinian controls and 182 SARS-CoV-2 patients. Thirty-nine patients required hospital care and 143 were without symptoms, pauci-symptomatic or with mild disease. For all participants, we collected demographic and clinical data and analyzed the HLA allele and haplotype frequencies. Results: Male sex and older age were more frequent in hospitalized patients, none of whom had been vaccinated during the previous seasonal flu vaccination campaignes. Compared to the group of asymptomatic or pauci-symptomatic patients, hospitalized patients also had a higher frequency of autoimmune diseases and glucose-6-phosphate-dehydrogenase (G6PDH) deficiency. None of these patients carried the beta-thalassemia trait, a relatively common finding in the Sardinian population. The extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 [OR 0.1 (95% CI 0–0.6), Pc = 0.015] was absent in all 182 patients, while the HLA-C*04:01 allele and the three-loci haplotype HLA-A*30:02, B*14:02, C*08:02 [OR 3.8 (95% CI 1.8–8.1), Pc = 0.025] were more frequently represented in patients than controls. In a comparison between in-patients and home care patients, the HLA-DRB1*08:01 allele was exclusively present in the hospitalized patients [OR &gt; 2.5 (95% CI 2.7–220.6), Pc = 0.024]. Conclusion: The data emerging from our study suggest that the extended haplotype HLA-A*02:05, B*58:01, C*07:01, DRB1*03:01 has a protective effect against SARS-CoV-2 infection in the Sardinian population. Genetic factors that resulted to have a negative influence on the disease course were presence of the HLA-DRB1*08:01 allele and G6PDH deficiency, but not the beta-thalassemic trait. Absence of influenza vaccination could be a predisposing factor for more severe disease

Can antiretroviral therapy modify the clinical course of HDV infection in HIV positive patients?

Background: Infection with hepatitis delta virus (HDV) affects approximately 6-14.5% of patients coinfected with HIV-1 and HBV, showing a more aggressive clinical course compared with an HIV-negative population. There is no universally approved treatment for chronic hepatitis D (CHD) in HIV-infected patients. Antiretroviral therapy (ART) containing tenofovir has been recently associated with HDV suppression. Our aim was to evaluate whether the outcome of CHD in HIV-infected patients can be favourably influenced by ART including reverse transcriptase inhibitors. Methods: The clinical course of four HBV/HDV/HIV-coinfected patients receiving ART were retrospectively examined. Results: HDV RNA became undetectable in all patients after a variable period of ART along with the disappearance of hepatitis B surface antigen in two of them, and an increase in CD4+ T-cell count. In all patients, virological changes were associated with improved liver function tests and clinical features. Conclusions: We suggest that ART regimens including drugs active against HBV could have beneficial effects on the clinical course of CHD in patients with HIV-1 by favouring immunological reconstitution

HCV treatment in Sardinian HIV-HCV coinfected patients: a real-life perspective study on safety, efficacy, and immune reconstitution

Background HIV-HCV co-infected patients have long been considered difficult-to-treat. The introduction of direct-acting antivirals (DAAs) changed this paradigm.We evaluated the efficacy and safety of DAA-based regimens and the impact of DAAs-induced HCV clearance on the immunological status in HIV-HCV co-infected patients. Research design and methods HIV patients starting HCV treatment with DAAs were included. Sustained virological response at 12 weeks after DAAs treatment (SVR12) was assessed. CD4+ and CD8+ blood cell count and CD4+/CD8+ ratio were recorded at baseline and six months post DAA treatment. We enrolled 201 patients, 76.1% males, median age 54 years, the most common genotypes 3 (29.8%) and 1a (29.4%), 40.3% with cirrhosis, 32.3% with prior interferon-based treatment. All patients were on antiretroviral treatment, 24.4% on methadone maintenance therapy and 22.6% on psychotropic drugs. Results SVR12 was 98.4%, the most common side effects were pruritus (8.4%), headache (7.4%) and fatigue (5.9%). An increase in CD4+ and CD8+ cell count was observed six months after completion of DAAs treatment, in particular in patients with low CD4+ cell count at baseline. Conclusions DAAs treatment resulted in high SVR12 rates, was well tolerated and Increased CD4+ and CD8+, especially in patients with low CD4+ cell count at baseline