Diagnosis of Acute HCV Infection and Estimated Incidence
Diagnosis of Acute HCV Infection and Estimated Incidence
The diagnosis of acute hepatitis C virus (HCV) infection is not straightforward; few people exhibit clinical symptoms and genome/antigen detection techniques do not indicate when infection had occurred. Here, a strategy to detect HCV RNA in the absence of antibody ('window-period') for diagnosis of acute infection is assessed. The sentinel surveillance of hepatitis testing study was used to retrospectively identify anti-HCV negative samples from high-risk individuals (2002–2003), for testing singly for HCV RNA. Additional samples were identified prospectively (2005) and tested in pools for HCV RNA. Positive samples were genotyped. Incidence and costs of adopting the pooling strategy were estimated. In the retrospective study, 8/390 (2.1%) samples were confirmed HCV RNA positive, anti-HCV negative. Prospectively, 3237 samples were tested in 325 pools. Five positive pools identified four confirmed HCV RNA positive patients (one false positive). Estimated incidence was 12.9 per 100 person-years in injecting drug users (IDUs) (retrospective study) and 3.7 per 100 person-years among drug/alcohol services and prison attendees (prospective study). Estimated costs were £850 per positive sample, in areas of higher risk. The yield from a window-period strategy depends upon the population tested. Pooled HCV RNA testing of anti-HCV negative samples from the current IDUs is realistic and relatively inexpensive to identify recently infected individuals.
Most individuals infected with hepatitis C virus (HCV) fail to clear virus at the acute stage, becoming chronically infected, with consequent significant risks of progressive liver disease, cirrhosis and hepatocellular carcinoma. Treatment of chronic HCV with combination pegylated-interferon (PEG-IFN) and ribavirin achieves sustained virological response (SVR) rates of 42-52% of patients infected with HCV genotype 1 and 76-82% of those with genotype 2/3. In contrast, much higher SVR rates (e.g. >97%) have been reported when treating acute HCV infection with PEG-IFN, irrespective of the infecting genotype. It would thus seem preferable to treat HCV infection at the acute stage rather than waiting for the infection to become chronic.
The problem is that diagnosis of acute HCV infection is not straightforward. Detection of anti-HCV IgM does not distinguish acute from chronic infection. Genome or antigen detection techniques provide information on the current infection status of an individual, but do not indicate when infection may have taken place. One possible laboratory approach to diagnosis of acute infection would be to demonstrate sero- or genoconversion in serial samples, but practically, it is difficult to obtain regular repeat samples in high-risk individuals such as injecting drug users (IDUs). Clinical approaches to diagnosis are also flawed. Only a small minority of acute infections are symptomatic. Even in patients presenting with acute hepatitis C, the majority of whom are already anti-HCV positive, one cannot be certain that illness is due to recent infection with HCV rather than another inter-current cause in a chronically infected patient.
Incidence of hepatitis C can be estimated through cohort studies, where high-risk individuals are followed up over a period of time and serial samples are tested for seroconversion. This approach has a number of limitations, including the length of time required for follow-up, high costs and practicalities of following-up a typically hard to reach group. In the UK, HCV incidence varies according to population and geography, being low among blood donors (K. Davison, personal communication) and high among current IDUs. Incidence can also be estimated using data from cross-sectional studies, by identifying samples from individuals during the window-period, i.e. where anti-HCV antibody is negative but HCV RNA positive. This approach uses assumptions about the duration of the window-period, from detection of HCV RNA to seroconversion to HCV antibody.
The sentinel surveillance of hepatitis testing study began in 2002 and collects data on people tested for hepatitis A, B or C, electronically direct from laboratory information systems. The study aims to monitor trends in testing and the characteristics of people being tested and to provide a sampling frame for additional testing, to supplement routine national surveillance. Study procedures were established during the pilot phase involving eight laboratories (2002-2003); the study has since expanded to include 24 laboratories covering approximately one third of the English population. Data were gathered prospectively from the time each laboratory joined the study, with retrospective data to January 2002 collected where possible. In this paper the study was used as a sampling frame to identify samples for additional testing.
Here we assess a strategy for diagnosis of acute infection based on the presence of HCV RNA in the absence of HCV antibody -'window period' diagnosis. Our study was performed in two stages. Sera from high-risk individuals, known to be anti-HCV negative were screened retrospectively for HCV RNA. As a consequence of identifying samples retrospectively, we conducted a prospective study using serum samples sent for routine HCV diagnostic tests, using a protocol of pooling samples in batches of 10 prior to HCV RNA testing. These data were then used to estimate HCV incidence in high- and low-risk populations.
Summary and Introduction
Summary
The diagnosis of acute hepatitis C virus (HCV) infection is not straightforward; few people exhibit clinical symptoms and genome/antigen detection techniques do not indicate when infection had occurred. Here, a strategy to detect HCV RNA in the absence of antibody ('window-period') for diagnosis of acute infection is assessed. The sentinel surveillance of hepatitis testing study was used to retrospectively identify anti-HCV negative samples from high-risk individuals (2002–2003), for testing singly for HCV RNA. Additional samples were identified prospectively (2005) and tested in pools for HCV RNA. Positive samples were genotyped. Incidence and costs of adopting the pooling strategy were estimated. In the retrospective study, 8/390 (2.1%) samples were confirmed HCV RNA positive, anti-HCV negative. Prospectively, 3237 samples were tested in 325 pools. Five positive pools identified four confirmed HCV RNA positive patients (one false positive). Estimated incidence was 12.9 per 100 person-years in injecting drug users (IDUs) (retrospective study) and 3.7 per 100 person-years among drug/alcohol services and prison attendees (prospective study). Estimated costs were £850 per positive sample, in areas of higher risk. The yield from a window-period strategy depends upon the population tested. Pooled HCV RNA testing of anti-HCV negative samples from the current IDUs is realistic and relatively inexpensive to identify recently infected individuals.
Introduction
Most individuals infected with hepatitis C virus (HCV) fail to clear virus at the acute stage, becoming chronically infected, with consequent significant risks of progressive liver disease, cirrhosis and hepatocellular carcinoma. Treatment of chronic HCV with combination pegylated-interferon (PEG-IFN) and ribavirin achieves sustained virological response (SVR) rates of 42-52% of patients infected with HCV genotype 1 and 76-82% of those with genotype 2/3. In contrast, much higher SVR rates (e.g. >97%) have been reported when treating acute HCV infection with PEG-IFN, irrespective of the infecting genotype. It would thus seem preferable to treat HCV infection at the acute stage rather than waiting for the infection to become chronic.
The problem is that diagnosis of acute HCV infection is not straightforward. Detection of anti-HCV IgM does not distinguish acute from chronic infection. Genome or antigen detection techniques provide information on the current infection status of an individual, but do not indicate when infection may have taken place. One possible laboratory approach to diagnosis of acute infection would be to demonstrate sero- or genoconversion in serial samples, but practically, it is difficult to obtain regular repeat samples in high-risk individuals such as injecting drug users (IDUs). Clinical approaches to diagnosis are also flawed. Only a small minority of acute infections are symptomatic. Even in patients presenting with acute hepatitis C, the majority of whom are already anti-HCV positive, one cannot be certain that illness is due to recent infection with HCV rather than another inter-current cause in a chronically infected patient.
Incidence of hepatitis C can be estimated through cohort studies, where high-risk individuals are followed up over a period of time and serial samples are tested for seroconversion. This approach has a number of limitations, including the length of time required for follow-up, high costs and practicalities of following-up a typically hard to reach group. In the UK, HCV incidence varies according to population and geography, being low among blood donors (K. Davison, personal communication) and high among current IDUs. Incidence can also be estimated using data from cross-sectional studies, by identifying samples from individuals during the window-period, i.e. where anti-HCV antibody is negative but HCV RNA positive. This approach uses assumptions about the duration of the window-period, from detection of HCV RNA to seroconversion to HCV antibody.
The sentinel surveillance of hepatitis testing study began in 2002 and collects data on people tested for hepatitis A, B or C, electronically direct from laboratory information systems. The study aims to monitor trends in testing and the characteristics of people being tested and to provide a sampling frame for additional testing, to supplement routine national surveillance. Study procedures were established during the pilot phase involving eight laboratories (2002-2003); the study has since expanded to include 24 laboratories covering approximately one third of the English population. Data were gathered prospectively from the time each laboratory joined the study, with retrospective data to January 2002 collected where possible. In this paper the study was used as a sampling frame to identify samples for additional testing.
Here we assess a strategy for diagnosis of acute infection based on the presence of HCV RNA in the absence of HCV antibody -'window period' diagnosis. Our study was performed in two stages. Sera from high-risk individuals, known to be anti-HCV negative were screened retrospectively for HCV RNA. As a consequence of identifying samples retrospectively, we conducted a prospective study using serum samples sent for routine HCV diagnostic tests, using a protocol of pooling samples in batches of 10 prior to HCV RNA testing. These data were then used to estimate HCV incidence in high- and low-risk populations.