Escaping High Viral Load Exhaustion: CD8 Cells with Altered Tetramer Binding in Chronic Hepatitis B Virus Infection

Deletion, anergy, and a spectrum of functional impairments can affect virus-specific CD8 cells in chronic viral infections. Here we characterize a low frequency population of CD8 cells present in chronic hepatitis B virus (HBV) infection which survive in the face of a high quantity of viral antigen. Although they do not appear to exert immunological pressure in vivo, these CD8 cells are not classically “tolerant” since they proliferate, lyse, and produce antiviral cytokines in vitro. They are characterized by altered HLA/peptide tetramer reactivity, which is not explained by TCR down-regulation or reduced functional avidity and which can be reversed with repetitive stimulation. CD8 cells with altered tetramer binding appear to have a specificity restricted to envelope antigen and not to other HBV antigens, suggesting that mechanisms of CD8 cell dysfunction are differentially regulated according to the antigenic form and presentation of individual viral antigens

Suboptimal SVR rates in African patients with atypical genotype 1 subtypes: Implications for global elimination of hepatitis C.

BACKGROUND & AIMS: HCV subtypes which are unusual in Europe are more prevalent in the African region, but little is known of their response to direct-acting antivirals (DAAs). These include non-1a/1b/ non-subtypeable genotype 1 (G1) or non-4a/4d (G4). In this report we aimed to describe the genotype distribution and treatment outcome in a south London cohort of African patients. METHODS: We identified all patients born in Africa who attended our clinic from 2010-2018. Information on HCV genotype, treatment regimen and outcome were obtained. Non-subtypeable samples were analysed using Glasgow NimbleGen next-generation sequencing (NGS). Phylogenetic analysis was carried out by generating an uncorrected nucleotide p-distance tree from the complete coding regions of our sequences. RESULTS: Of 91 African patients, 47 (52%) were infected with an unusual subtype. Fourteen novel, as yet undesignated subtypes (G1*), were identified by NGS. Three individuals were infected with the same subtype, now designated as subtype 1p. Baseline sequences were available for 22 patients; 18/22 (82%) had baseline NS5A resistance-associated substitutions (RASs). Sustained virological response (SVR) was achieved in 56/63 (89%) overall, yet only in 21/28 (75%) of those with unusual G1 subtypes, with failure in 3/16 G1*, 1/2 G1p and 3/3 in G1l. Six treatment failures occurred with sofosbuvir/ledipasvir compared to 1 failure on a PI-based regimen. The SVR rate for all other genotypes and subtypes was 35/35 (100%). CONCLUSIONS: Most individuals in an unselected cohort of African patients were infected with an unusual genotype, including novel subtype 1p. The SVR rate of those with unusual G1 subtypes was 75%, raising concern about expansion of DAAs across Africa. Depending on the regimen used, higher failure rates in African cohorts could jeopardise HCV elimination. LAY SUMMARY: Direct-acting antiviral medications are able to cure hepatitis C in the majority of patients. The most common genotype of hepatitis C in Europe and the United States is genotype 1a or 1b and most clinical trials focused on these genotypes. We report that in a group of African patients, most of them had unusual (non-1a/1b) genotype 1 subtypes, and that the cure rate in these unusual genotypes was lower than in genotypes 1a and 1b

Hepatitis C virus (HCV) tends to associate preferentially with high- density lipoproteins by standard ultracentrifugal fractionation of plasma from patients with chronic HCV infection

Because hepatitis C virus (HCV) has an unusually low buoyant density in plasma, we have determined whether HCV-RNA associates with specific lipoprotein classes by conventional NaCl-NaBr density solutions and whether the association is affected by viraemia. We studied 12 consecutive patients with chronic HCV and obtained four plasma lipoprotein fractions using sequential, isopycnic ultracentrifugation: very-low plus intermediate-density lipoproteins (VLDL/IDL; ρ<1.019 g ml−1), low-density lipoproteins (LDL; ρ 1.019–1.063 g ml−1), high-density lipoproteins (HDL; ρ 1.063–1.21 g ml−1) and very-high-density lipoproteins (ρ>1.21 g ml−1, which also include bulk plasma proteins). HCV-RNA was determined in each fraction, and after two successive 10-fold dilutions, using a nested PCR of the 5′ non-coding region. In 10 patients, HCV-RNA was detected in all samples, in one patient in only the HDL, and in the remaining patient in all fractions except LDL. This study confirms that HCV in plasma has a relatively low density and that much is lipoprotein associated. Moreover, we found that in most patients (9/12; 75%) the HDL fraction had the richest, or equal richest, concentration of HCV-RNA. Nevertheless, the virion clearly distributed heterogeneously in plasma, although no obvious relationship was noted between distribution patterns and either the level of viraemia or ongoing antiviral treatment. Whether this preference for association with HDL is mediated by the lipid or protein constituents of the HCV particle remains to be established

Reply to: “Is resistance to direct-acting antivirals in sub-Saharan Africa a threat to HCV elimination? Recommendations for action”

No abstract available

High patient acceptability for a hepatitis C mobile outreach service targeting ‘vulnerable’ homeless communities - an important component for elimination?

Background and Aims: Given the HCV elimination agenda, finding and treating ‘seldom heard’ communities such as the homeless is critical. Such populations do not interface well with traditional models of care. In 2018, King’s College Hospital, in collaboration with The Hepatitis C Trust, commissioned a mobile clinic to screen and treat homeless people in Lambeth, Lewisham and Southwark for HCV. The ‘HCV Mobile Outreach Service’ includes point-of-care finger prick HCV screening (InTec anti-HCV antibody) and confirmatory testing (Cepheid finger GeneXpert prick HCV RNA), non-invasive liver assessment by Fibroscan (Echosens), a multidisciplinary medical team (including peer) and needle and syringe programme provision. The aim of this study was to measure the patients’ acceptability of the service model (overall service, finger prick testing and peer). Method: Patient acceptability was assessed using a theoretical framework of acceptability (TFA) survey (Sekhon et al, 2017) which considers cognitive and emotional responses to an intervention. It is formed of seven distinct constructs (affective attitude, burden, ethicality, perceived effectiveness, intervention coherence, self– efficacy and opportunity cost). Each construct is measured by a 5- point Likert scale. Question 1 (Q1) indicates overall performance and either a score (out of 35) for Q2-8 or a composite be calculated. At Q6, patients were asked to elaborate further about their views allowing qualitative insight. A paper survey was administered to patients using a purposive sampling strategy. Consent was received verbally. Results: Demographics - 35 patients (60% Male, 40% Female), Intravenous drug use (34% current, 26% past use, 40% never), HCV status (11% past infection, 40% current infection, 45% never infected). The results suggest patient acceptability for all components were high. Few chose to elaborate further, (response rates: overall service (37%), finger prick testing (37%) and Peer Navigator (20%)). Most comments were positive describing the benefit of not having to attend appointments at the hospital and a preference for engaging with a Peer. Although patients found the finger prick testing less acceptable than other components of the service, feedback suggests it is more acceptable than venepuncture. Distribution of the patients’ TFA score and composite mean. Conclusion: The HCV Mobile Outreach Service is considered a highly acceptable intervention by this community and could contribute to HCV elimination efforts, linkage to other facets of care is currently being evaluated