Hepatitis virus (HCV) diagnosis and access to treatment in a UK cohort

Abstract

Background: As direct acting antiviral (DAA) therapy is progressively rolled out for patients with hepatitis C virus (HCV) infection, careful scrutiny of HCV epidemiology, diagnostic testing, and access to care is crucial to underpin improvements in delivery of treatment, with the ultimate goal of elimination.

Methods: We retrospectively studied microbiology records from a large UK teaching hospital in order to compare the performance of HCV screening and diagnostic tests (antibody, antigen and HCV RNA detection). Having described a local cohort of adults with active HCV infection, we investigated the proportion who attended hospital appointments, were prescribed direct acting antiviral (DAA) therapy, and cleared HCV RNA following treatment.

Results: Over a total time period of 33 months between 2013 and 2016, we tested 38,509 individuals for HCV infection and confirmed a new diagnosis of active HCV infection (HCV-Ag + and/or HCV RNA+) in 353 (positive rate 0.9%). Our in-house HCV-Ab screening test had a positive predictive value of 87% compared to repeat HCV-Ab testing in a reference laboratory, highlighting the potential for false positives to arise using this test. HCV-Ag had 100% positive predictive value compared to detection of HCV RNA. There was a strong correlation between quantitative HCV-Ag and HCV RNA viral load (p < 0.0001). Among the cases of infection, genotype-1 and genotype-3 predominated, the median age was 37 years, 84% were male, and 36% were in prison. Hepatology review was provided in 39%, and 22% received treatment. Among those who received DAA therapy with 12 weeks of follow-up, 93% achieved a sustained virologic response (SVR₁₂).

Conclusions: HCV-Ag performs well as a diagnostic test compared to PCR for HCV RNA. Active HCV infection is over-represented among men and in the prison population. DAA therapy is successful in those who receive it, but a minority of patients with a diagnosis of HCV infection access clinical care. Enhanced efforts are required to provide linkage to clinical care within high risk populations.

Keywords: Antibody; Antigen; Cure; DAA; Diagnosis; Epidemiology; Ethnicity; Genotype; HCV; Prison; Screening; Sustainable development goals; Treatment.

Fig. 1

Algorithms describing HCV screening and diagnosis in a UK teaching hospital laboratory in 2014 (Group 1) and 2016 (Group 2). ^aThe total positive rate for Group 1 is defined as the number of samples that were HCV RNA positive (n = 191) divided by the total number of samples screened (n = 19,226). ^bThe total positive rate for Group 2 is defined as samples that were deemed positive for active HCV infection based on interpretation of combined results (this includes HCV-Ag positive and not further screened (n = 34), plus any sample that was HCV-RNA positive irrespective of the HCV-Ag result (n = 128, comprising 121 HCV-Ag positive, and 7 HCV-Ag negative samples), divided by the total number of samples screened (n = 19,283). The lower limit of quantification for HCV RNA was 12 iU/ml. There was no case of detectable HCV RNA below the limit of quantification. Full metadata for this cohort can be found in the supporting data-file: 10.6084/m9.figshare.5355097

Fig. 2

Distribution of HCV genotypes in a UK cohort. a Data for an extended cohort of 250 individuals for whom HCV genotyping was undertaken in our laboratory between 2014 and 2016 (includes the 186 individuals represented in panel b, plus an additional 64 individuals who had genotyping undertaken within this time period but were not captured within Group 1 or Group 2). b Data for 186 individuals for whom genotype was determined from among the cohort of 353 new HCV diagnoses within Group 1 and Group 2 of this study. There was no enrichment of a specific genotype in the prison population (prison population accounted for 30/84 geno-1 infections, and 34/80 geno-3 infections; p = 0.4 Fisher’s Exact Test)

Fig. 3

False positive HCV IgG antibody results according to ethnic origin in a UK cohort. Ethnicity was estimated using Onolytics software [26, 27]. Data shown are for a cohort recruited starting in 2014 (designated Group 1), screened using an in-house HCV-Ab (ADVIA Centaur automated immunoassay; Bayer) and confirmed using two further ELISA tests (Ortho and BioRad). ‘False positives’ are defined as those screening positive on ADVIA but subsequently negative, ‘true positives’ are defined as samples positive on all three tests. P-values obtained by Fishers Exact Test; *** p < 0.0005

Fig. 4

Relationship between HCV Antigen test and quantitative PCR for HCV RNA viral load. a Range of HCV RNA viral loads for samples testing HCV-Ag positive (n = 121) and HCV-Ag negative (n = 74). Median and interquartile range shown. P-values by Mann-Whitney U test; ***p < 0.0001. b Relationship between between HCV-Ag and HCV RNA viral load for all samples testing HCV-Ag positive (n = 121). Dashed lines represent threshold for detection for HCV RNA (12 IU/ml) and HCV-Ag (3 fmol/L). Solid line represents linear regression analysis; R² = 0.3, p < 0.0001. c Percentage of samples testing false-negative for HCV-Ag according to HCV RNA viral load. P-value by Fisher’s Exact test ***p < 0.0001. Data are shown for 128 samples for which both HCV RNA and HCV-Ag testing was undertaken. HCV-Ag was falsely negative (< 3 fmol/L) in 5/13 cases with HCV RNA < 10⁴ IU/ml, and in 2/115 cases with HCV RNA > 10⁴ IU/ml

Fig. 5

Graphical representation of the disparity between the number of individuals diagnosed with active HCV infection and those who access clinical review, treatment, and achieve SVR₁₂. Summary of outcomes for the entire cohort is shown in Table 5. The percentages quoted in this figure represent the proportion of patients in each category from the total denominator of 353. Individuals diagnosed in prison were significantly less likely to attain an SVR₁₂ endpoint (SVR₁₂ was documented for 5/127 individuals in prison vs. 61/226 not in prison, p < 0.0001, Fisher’s Exact test)