Validation of the Performance of A1HPV6, a Triage Blood Test for the Early Diagnosis and Prognosis of SARS-CoV-2 Infection.

BACKGROUND AND AIMS: Apolipoprotein A1 (A1) and haptoglobin (HP) serum levels are associated with the spread and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We have constructed and validated a multivariable risk calculator (A1HPV6) integrating A1, HP, alpha2-macroglobulin, and gamma glutamyl transferase to improve the performances of virological biomarkers. METHODS: In a prospective observational study of hospitalized patients with nonsevere SARS-CoV-2 infection, A1HPV6 was constructed in 127 patients and validated in 116. The specificity was assessed in 7482 controls representing the general population. The primary diagnostic endpoint was the area under the receiver operating characteristic curve in patients with positive SARS-CoV-2 PCR. The primary prognostic endpoint was the age-and sex-adjusted risk of A1HPV6 to predict patients with WHO-stage > 4 (W > 4) severity. We assessed the kinetics of the A1HPV6 components in a nonhuman primate model (NHP), from baseline to 7 days (D7) after SARS-CoV-2 infection. RESULTS: The area under the receiver operating characteristic curve for A1HPV6 was 0.99 (95% CI 0.97-0.99) in the validation subset, which was not significantly different from that in the construction subset, 0.99 (0.99-0.99; P = .80), like for sensitivity 92% (85-96) vs 94% (88-97; P = .29). A1HPV6 was associated with W > 4, with a significant odds ratio of 1.3 (1.1-1.5; 0.002). In NHP, A1 levels decreased (P < .01) at D2 and normalized at D4; HP levels increased at D2 and peaked at D4. In patients, A1 concentration was very low at D2 vs controls (P < .01) and increased at D14 (P < .01) but was still lower than controls; HP increased at D2 and remained elevated at D14. CONCLUSION: These results validate the diagnostic and prognostic performances of A1HPV6. Similar kinetics of apolipoprotein A1, HP, and alpha-2-macroglobulin were observed in the NHP model. ClinicalTrials.gov number, NCT01927133.

External validation of LCR1-LCR2, a multivariable HCC risk calculator, in patients with chronic HCV.

BACKGROUND & AIMS: The Liver Cancer Risk test algorithm (LCR1-LCR2) is a multianalyte blood test combining proteins involved in liver cell repair (apolipoprotein-A1 and haptoglobin), known hepatocellular carcinoma (HCC) risk factors (sex, age, and gamma-glutamyl transferase), a marker of fibrosis (alpha2-macroglobulin) and alpha-fetoprotein (AFP), a specific marker of HCC. The aim was to externally validate the LCR1-LCR2 in patients with chronic HCV (CHC) treated or not with antivirals. METHODS: Pre-included patients were from the Hepather cohort, a multicentre prospective study in adult patients with CHC in France. LCR1-LCR2 was assessed retrospectively in patients with the test components and AFP, available at baseline. The co-primary study outcome was the negative predictive value (NPV) of LCR1-LCR2 for the occurrence of HCC at 5 years and for survival without HCC according to the predetermined LCR1-LCR2 cut-offs. The cut-offs were adjusted for risk covariables and for the response to HCV treatment, and were quantified using time-dependent proportional hazards models. RESULTS: In total, 4,903 patients, 1,026 (21.9%) with baseline cirrhosis, were included in the study. Patients were followed for a median of 5.7 (IQR 4.2-11.3) years. A total of 3,788/4,903 (77.3%) patients had a sustained virological response. There were 137 cases of HCC at 5 years and 214 at the end of follow-up. HCC occurred at 5 years in 24/3,755 patients with low-risk LCR1-LCR2 compared with 113/1,148 patients with high-risk LCR1-LCR2. The NPV was 99.4% (95% CI 99.1-99.6). Similar findings (hazard ratio, 10.8; 95% CI, 8.1-14.3; p <0.001) were obtained after adjustment for exposure to antivirals, age, sex, geographical origin, HCV genotype 3, alcohol consumption, and type 2 diabetes mellitus. CONCLUSIONS: The results showed that LCR1-LCR2 can be used to successfully identify patients with HCV at very low risk of HCC at 5 years. LAY SUMMARY: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide and the fastest growing cause of cancer death in many countries. We constructed and internally validated a new multianalyte blood test to assess this Liver Cancer Risk (LCR1-LCR2). This study confirmed the performance of LCR1-LCR2 in patients with chronic HCV in the national French cohort Hepather, and its ability to identify patients at a very low risk of HCC at 5 years. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT01953458).

Multicenter comparison of the new Cobas 6800 system with Cobas Ampliprep/Cobas TaqMan and Abbott RealTime for the quantification of HIV, HBV and HCV viral load.

BACKGROUND: The new Roche Cobas 6800 platform (C6800) has been recently introduced for viral load (VL) measurement. OBJECTIVES: Comparing C6800 to Cobas Ampliprep/Cobas TaqMan v2.0 (CAP/CTM) for the quantification of HIV, HBV and HCV viremia, and to the Abbott RealTime assay (ABB) for HCV quantification. STUDY DESIGN: We analysed 121 samples for HBV, and 139 for HIV-1 including 2 groupO and 137 group M viruses (36.5% subtype B, 27.0% CRF02_AG, 22.6% from other clades, and 14% subtype not available). For the 100 HCV samples compared with CAP/CTM, 42% were genotype 1 and 17% were genotype 4. For the 68 HCV samples compared with ABB, 52.9% were genotype 1 and 22.1% were genotype 4. RESULTS: C6800 results correlated well with those of CAP/CTM for all three viruses (R2: 0.97-0.99). However, C6800 can yield different viraemia results: higher for HIV (mean difference: +0.11 log10copies/mL, p<0.0001), and lower for HBV (mean difference:-0.11 log10 IU/mL, p<0.0001). Differences exceeded 0.5 log10 for 6.5% of HIV-1 samples and 7.4% of HBV samples. For HCV quantification, C6800 gave mostly lower values than the other assays towards the bottom of the range, and higher values in the upper part of the range, especially in comparisons with ABB, for which 28% of differences exceeded 0.5 log10 IU/mL. No particular HCV genotype was identified as responsible for these differences. CONCLUSION: Overall, the comparison tests between C6800 and CAP/CTM systems are satisfactory for the three viruses. Frequent discrepancies were observed between C6800 and ABB for HCV.

Hepatitis E infection in patients with severe alcoholic hepatitis: is there a place for systematic screening?

BACKGROUND: One study has suggested that markers of acute hepatitis E virus (HEV) infection are present in 3.6% of patients with severe alcoholic hepatitis (AH). However, validation of these preliminary results is lacking, as well as the impact of HEV infection on the 6-month survival. AIMS: The aims of this study were to evaluate the prevalence of HEV infection markers in an external cohort of patients with histologically proven severe AH and to assess the impact of markers of acute HEV infection on the 6-month survival and the need for liver transplantation (LT). PATIENTS AND METHODS: Patients admitted for severe AH from January 2008 to June 2014 were analysed. HEV serology (IgM and IgG) was retrospectively performed. RESULTS: Ninety-three patients were analysed (male sex 77.4%, age 53±9 years, Maddrey discriminant function 65±32, MELD score 24±6). Six patients (6.5%) had markers of acute HEV infection (IgM+and IgG+), 11 (11.8%) of past HEV infection (IgG+and IgM-) and 76 (81.7%) had a negative serology (IgM- and IgG-). Initial presentation and biological characteristics were not different between IgM+ and IgM- patients, except for the aspartate aminotransferase level (P<0.001). Markers of acute HEV infection had no impact on response to corticosteroids, 1-, 3- or 6-month survival, and the need for LT. Three patients showed symptomatic acute HEV at onset of acute AH: two were treated with ribavirin during the acute phase: one patient died and one patient underwent LT. CONCLUSION: Markers of acute HEV infection were present in 6.5% of patients in our cohort of cirrhotics with histologically proven severe AH, without any impact on short-term or long-term outcome. Whether systematic screening of acute HEV infection in this population should be performed remains an unsolved question.

A two adenine insertion polymorphism in the 3' untranslated region of factor VII gene is associated with peripheral arterial disease but not with venous thrombosis. Results of case-control studies.

Polymorphic variants of genes encoding blood coagulation proteins have been extensively studied as risk factors for venous or arterial thrombosis A variation in the 3' untranslated region (UTR) involved in the post-transcriptional regulation of factor VII (FVII) gene has been recently identified, a two adenine insertion/deletion at nucleotide 11293. In this study, we investigated its effect on the risk of thrombosis in the frame of two case-control studies, including patients suffering from peripheral arterial disease (PAD) or venous thromboembolic (VTE) disease. The 3'UTR FVII gene polymorphism was investigated i) in 181 patients who had symptomatic atherosclerotic disease of the lower limbs, ii) in 178 patients who had had at least one episode of objectively diagnosed deep venous thrombosis and iii) in controls matched for age and sex. Plasma FVII antigen (FVII: Ag) levels were lower in the presence of the 3'UTR 2A insertion (68.4 +/- 12.3%, 81.3 +/- 14.5% and 89.5 +/- 13.7% in 2A/2A, 2A/0 and 0/0 subjects respectively, p < 0.0001). No significant relationship was found with VTE disease. In the contrary we observed a lower risk of PAD for the 2A/2A compared to the 0/0 genotype after adjustment for traditional risk factors (hypercholesterolemia, smoking status, diabetes and hypertension), with an OR of 0.24 [95% CI 0.06-0.99]. In conclusion, the 2 adenine insertion in the 3'UTR of FVII gene, related to lower plasma FVII levels, is a genetic variation that may contribute to reduce the risk of PAD.