METHODS: Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and phenotypic alterations in CD4+ T cells including circulating Tfh cells, CD8+ T cells, and TCR iVα7.2+ MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based on markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-α, IFN-γ) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression.
RESULTS: The activation marker CD69 was significantly increased in CD4+hi T cells, while CD8+ MAIT cells producing IFN-γ were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-α+CD4+lo T cells, CD69+CD8+ T cells, CD69+CD4+ MAIT cells, PD-1+CD4+hi T cells, PD-1+CD8+ T cells, and Ki67+CD4+ MAIT cells, were independently associated with decelerating the plasma viral load (PVL). TNF-α levels showed a positive correlation with increase in cytokine levels and decrease in PVL.
CONCLUSION: Chronic viral infection negatively impacts the quality of peripheral MAIT cells and Tfh cells via differential expression of both activating and inhibitory receptors.
METHODS: Retrospective data pertaining to 713 patients from January 2009 to December 2013 were retrieved from hospital and disease notification records for analysis. The risk factors for hepatitis C virus (HCV) infection were grouped into IVDU and non-IVDU risk factors for analysis using multiple logistic regression.
RESULTS: Of the hepatitis C patients included in this study, the most common age group was 31 to 40 years (30.2%), and male patients (91.2%) made up the overwhelming majority. Ethnic Malays constituted approximately 80.4% of the patients, and IVDU was the main risk factor (77.8%) for HCV infection. Multiple logistic regression showed that male patients were 59 times more likely to have IVDU as a risk factor for HCV infection. Single patients were 2.5 times more likely to have IVDU as a risk factor. Patients aged ≥71 years were much less likely than patients aged ≤30 years to have IVDU as a risk factor for HCV infection.
CONCLUSIONS: IVDU was found to be an important risk factor for HCV infection among patients in the KS district. The factors associated with IVDU included age, sex, and marital status. Appropriate preventive measures should be developed to target the groups in which IVDU is most likely to be a risk factor for HCV infection.
METHODS: We established a multi-country cross-sectional dataset of first available quantitative HCV RNA linked to demographic and clinical data. We excluded individuals on HCV treatment. We analyzed the distribution of HCV RNA and determined critical thresholds for detection of HCV viraemia. We then performed logistic regression to evaluate factors associated with LLV, and derived relative sensitivities for significant covariates.
RESULTS: The dataset included 66,640 individuals with HCV viraemia from Georgia (44.4%), Canada (40.9%), India (8.1%), Cambodia (2.6%), Egypt (1.6%), Pakistan (1.3%), Cameroon (0.4%), Indonesia (0.2%), Thailand (0.2%), Vietnam (0.1%), Malaysia (0.05%), and Mozambique (0.02%). The 97% LOD was 1,318 IU/mL (95% CI 1298.4, 1322.3). Factors associated with LLV were younger age 18-30 vs. 51-64 years (OR 2.56 95% CI 2.19, 2.99), female vs. male sex (OR 1.32, 95% CI 1.18, 1.49), and advanced fibrosis stage F4 vs. F0-1 (OR 1.44, 95%CI 1.21, 1.69). Only the younger age group had a decreased relative sensitivity below 95% at 93.3%.
CONCLUSIONS: In this global dataset, a test with an LOD of 1,318 IU/mL would identify 97% of viraemic HCV infections among almost all populations. This LOD will help guide manufacturers in the development of affordable POC diagnostics to expand HCV testing and linkage to care in LMICs.
LAY SUMMARY: We created and analyzed a dataset from 12 countries with 66,640 participants with chronic hepatitis C virus infection. We determined that about 97% of those with viraemic infection had 1300 International Units/mL or more of circulating virus at the time of diagnosis. While current diagnostic tests can detect as little as 12 International Units/mL of virus, our findings suggest that increasing the level of detection closer to 1300 would maintain good test accuracy and will likely allow for more affordable portable tests to be developed for use in low and middle income countries.
RESULTS: cSC binds > 0.06 μg/ml of purified human and mouse pIgA with negligible cross-reactivity against IgM and IgA. Virus-specific pIgA was significantly higher in serum of acute HAV (n = 6) and HEV (n = 12) patients than uninfected samples (HEV: p
METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183.
FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment.
INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality.
FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.