- Email: [email protected]
Hepatitis C virus screening to reveal a better picture of infection
Science & Society
Hepatitis C virus screening to reveal a better picture of infection Maria Cristina Medici1, Claudio Galli2, and Adriana Calderaro1 1
Unit of Microbiology and Virology, Department of Clinical and Experimental Medicine, Faculty and Medicine and Surgery, University of Parma, Italy, Viale Antonio Gramsci, 14-43126 Parma, Italy 2 Scientific Affairs, Abbott Diagnostics, via Amsterdam, 125-00144 Roma, Italy
Antiviral therapy for hepatitis C virus (HCV) infection will be the next revolution in clinical virology. Sensible planning for treatment is needed, starting with populationscreening policies ideally using the HCV core antigen. This will result in a more defined picture of the silent spread of HCV.
A breakthrough in the diagnosis of HCV infection The impact of HCV on the healthcare system has been dramatic: a prospective evaluation carried out in the USA estimated that, even if a 24% decrease in prevalence from 2005 to 2021 is foreseen, the mortality for HCV-related chronic liver disease will increase due to the aging of HCVinfected subjects and the subsequent development of clinical disease [1,2]. Furthermore, unlike hepatitis B virus (HBV) infection, there is no conclusive evidence for protective immunity against HCV and, therefore, the likelihood of a prophylactic vaccine is slim. To identify and proactively treat HCV infections, comprehensive screening of at-risk populations should be undertaken. As a result of this, a systematic, population-wide screening for HCV has been proposed in the USA [3] based on three assumptions: (i) the burden of HCV infection relies mostly on the ‘baby boomers’, because people born in 1945– 1965 account for more than two-thirds of infected individuals [3,4]; (ii) screening this target population for specific antibodies (anti-HCV) and viral nucleic acid (HCV RNA) will enable the identification of the majority of infected individuals and prioritization of therapeutical interventions aimed at reducing the future impact of HCV-related chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1,5]; and (iii) over the next couple of years, specific antiviral drugs (direct-acting antiviral drugs; DAA) whose efficacy for the complete eradication of HCV has been reported to be as high as 95%, will become available [6]. One of such drugs (sofosbuvir) was cleared in 2014 by the US FDA and in the EU and evaluated either in association with ribavirin or inhibitors of nonstructural protein 5A (NS5A; daclatasvir or ledipasvir). Two other formulations, one based on multiple DAAs, including an inhibitor of the NS3/4 protease (paritaprevir) and the NS5A replication complex (ombitasvir), plus ritonavir and a Corresponding author: Calderaro, A. ([email protected]). Keywords: population screening; hepatitis C virus; testing algorithms. 0966-842X/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2015.02.007
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Trends in Microbiology, June 2015, Vol. 23, No. 6
non-nucleoside NS5B polymerase inhibitor (dasabuvir) were approved at the end of 2014 in the USA and in January 2015 in the EU. Other DAAs, such as simeprevir, an inhibitor of the NS3/4A protease, have already undergone clinical trials for registration purposes [6]. The first assumption of the proposed systematic screening in the USA is not valid in all countries. This is due to different routes of transmission and to other population variables, which means that the target population for screening policies aimed at the identification of potentially curable HCV infections will not be the same in all settings. In all instances, the basic question for cost–benefit analysis and for therapeutic planning is: how many chronically infected subjects do we expect to find? Finding the actual burden of HCV infection in apparently healthy individuals is challenging. In Europe, information on this as well as other major diseases comes from the European Centre for Disease Prevention and Control (ECDC). The latest report available [7] depicts a scattered picture and underlines the lack of reliable data due to different surveillance systems, mostly passive, and to different criteria used for diagnosis, given that some countries simply report anti-HCV-positive cases, whereas others indicate only viremic patients as being HCV infected. The latter option is better because only active infections bear the risk of developing into chronic liver disease and eventually cirrhosis or hepatocellular carcinoma, and these are the life-threatening consequences that we wish to prevent. In any case, the overall incidence of HCV in Europe is low: in 2012, less than one case of acute, symptomatic HCV infection per 100 000 inhabitants was reported in Italy, while the incidence ranged from 0.4% to 1.6% in the other countries [7]. Of note, in some European countries the surveillance systems capture only acute symptomatic infections, which account for only a fraction of all new cases of HCV [1], while, for instance, HCV prevalence in Italy has been reported to be as high as 2.6% in the general population [8], corresponding to almost 1.5 million people. So, while the figures of HCV incidence bear only a pale resemblance with those of a few decades ago, the actual prevalence and the burden of chronic infections are both difficult to estimate. Regardless of the target population to be screened, a testing strategy for HCV infections should guarantee the highest possible accuracy for the identification of active infection, for example, the best combination of sensitivity and specificity. The recent guidelines from the US Centers for Disease Control and Prevention (CDC) indicate a sequential algorithm, with the initial testing for anti-HCV
Science & Society followed by the determination of the eventual presence of the viral genome (HCV RNA) on antibody-positive samples [3]. Is this the best option for HCV screening? Maybe not: HCV testing is not implemented in all hospitals or community-based settings, and brings additional complexity due to the need for specialized personnel. In addition, the cost per result is higher because, on average, HCV RNA is more expensive than the serology [9]. Furthermore, as the CDC indicated and all population surveys confirmed [5,10,11], a substantial fraction of antibody-positive individuals are no longer infected, due to a spontaneous clearance of HCV [5,10,11]. Given that the real target of any interventional screening is the identification of subjects with an active infection [12], the combination of anti-HCV testing followed by HCV RNA testing on antibody-positive subjects may then be suboptimal. Recently, a new option for testing with a single serological assay that enables the identification of the HCV core antigen (HCVAg) has become available. The first demonstration for diagnostic purposes of HCVAg in the circulation of infected hosts was reported shortly after HCV genomic RNA characterization was completed [13]. HCVAg is detectable in acute HCV infection almost at the same time as HCV RNA [14] and, therefore, some weeks earlier than antibodies; in addition, it persists during all phases of infection. Given that HCVAg is present in both circulating virions and immune complexes with anti-HCV antibodies, a pre-analytical lysis step is necessary to release the antigen from these complexes; modern automated assays include a pretreatment step for this purpose [14]. A potential drawback for HCVAg testing is that the assay sensitivity corresponds approximately to 1000 IU/mL HCV RNA [14]. While this may cause problems if it is used in the monitoring of treated patients instead of a highly sensitive assay for HCV RNA, which is the recommended assay [12], this will not represent an issue in chronic, untreated individuals, who usually show levels in excess of that value [11,15]. Serological assays (HCVAb and HCVAg) are fully automated, do not require specialized personnel, and are also suited for high-volume testing on immunochemistry analyzers. Molecular testing is more technically demanding and high volumes may be processed only at sites that carry out blood-donation screening. Antibody testing (HCVAb) is available almost everywhere and HCV RNA assays are available in specialized laboratories, whereas the routine use of HCVAg utilization is still limited. Direct costs estimates are difficult, because prices vary locally depending on the test volumes: in general, HCVAg and HCV RNA assays are more expensive than those for HCVAb [9,12]. From a clinical standpoint, HCVAg and HCV RNA are able to identify acute infections and chronic active infections, while HCVAb appear only after 10 weeks from exposure [12], and are also detectable in patients who have cleared the virus. A first glimpse of the potential utility of HCVAg testing for population screening has been provided by Kuo et al. [15], who demonstrated a nearly absolute specificity and 96% sensitivity when a positive HCVAg result was coupled with high-level antibody reactivity. From our perspective, a single marker screening strategy, similar to what has been historically done with the
Trends in Microbiology June 2015, Vol. 23, No. 6
Selecon of the target populaon on the basis of clinical evaluaon: subjects with the clinical suspicion of acve HCV infecon
Test for HCV angen to diagnose HCV acve infecon
Subjects with posive HCVAg test: clinical assessment to evaluate therapy HCV RNA test including genotyping to administer anviral treatment Monitor efficacy of the anviral treatment
TRENDS in Microbiology
Figure 1. Proposed algorithm for hepatitis C virus (HCV) screening aimed at the identification of active infections for therapeutical interventions with the new direct-acting antiviral drugs (DAA) drugs. The monitoring of treatment efficacy could also be based on HCV core antigen (HCVAg) testing 12–24 weeks after the end of treatment.
HBV surface antigen (HBsAg) for the detection of HBV active infection, would be preferred. Using HCVAg as a marker will represent a significant step in the process of more clearly understanding the actual burden of HCV infection and disease and will enable design of a simpler and faster screening strategy (Figure 1) for therapeutic interventions. This approach will also bring clear advantages from an operating and economic standpoint: for the former, the assay results may be available within 1 hour from sampling; for the latter, testing for HCVAg instead of HCV RNA will result in a cost reduction per individual screen of US$85, mostly related to the decrease in personnel cost [9]. Concluding remarks We are on the verge of a major breakthrough in healthcare because HCV, currently a major cause of chronic disease and mortality, may eventually be cured. The upsurge in public interest in the spread, dynamics, and consequencies of HCV infection, for which a vaccine is not yet available, provides yet another opportunity to reinforce the role of clinical virologists as primary players in healthcare, not only with sophisticated molecular techniques, but also with a sound and sensible application of modern screening tools. References 1 Kershenobich, D. et al. (2011) Applying a system approach to forecast the total hepatitis C virus infected population size: model validation using US data. Liver Int. 31 (Suppl. 2), 4–17 2 Ly, K. et al. (2012) The growing burden of mortality from viral hepatitis in the US, 1999–2007. Ann. Intern. Med. 156, 271 3 Smith, B.D. et al. (2012) Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945– 1965. MMWR 61, 1–32 4 Ward, J.W. (2013) The epidemiology of chronic hepatitis C and onetime hepatitis C virus testing of persons born during 1945 to 1965 in the United States. Clin. Liver Dis. 17, 1–11 5 Poynard, T. et al. (2003) Viral hepatitis C. Lancet 362, 2095–2100 325
Science & Society 6 Cortez, K.J. and Kottilil, S. (2015) Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C. Ther. Adv. Chronic Dis. 6, 4–14 7 European Centre for Disease Prevention and Control (2014) Hepatitis B and C surveillance in Europe, 2012, ECDC 8 Valcavi, P. et al. (1999) Prevalence of hepatitis C virus antibodies in a clinical-based group of Italians from one geographical area. Clin. Infect. Dis. 5, 125–129 9 Cresswell, F.V. et al. (2015) Hepatitis C core antigen testing: a reliable, quick and potentially cost-effective alternative to Hepatitis C polymerase chain reaction in diagnosing acute Hepatitis C virus infection. Clin. Infect. Dis. 60, 263–266 10 Hahne´, S.J.M. et al. (2013) Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening. BMC Infect. Dis. 13, 181
326
Trends in Microbiology June 2015, Vol. 23, No. 6 11 Guadagnino, V. et al. (2013) Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: evidence for a vanishing infection. Dig. Liver Dis. 45, 403–407 12 Kamili, S. et al. (2012) Laboratory diagnostics for hepatitis C virus infection. Clin. Infect. Dis. 55, S43–S48 13 Takahashi, K. et al. (1992) Demonstration of a hepatitis C virus– specific antigen predicted from the putative core gene in the circulation of infected hosts. J. Gen. Virol. 73, 667–672 14 Medici, M.C. et al. (2011) Hepatitis C virus core antigen: Analytical performances, correlation with viremia and potential applications of a quantitative, automated immunoassay. J. Clin. Virol. 51, 260– 265 15 Kuo, Y.H. et al. (2012) Is hepatitis C virus core antigen an adequate marker for community screening? J. Clin. Microbiol. 50, 1989– 1993
Hepatitis C virus screening to reveal a better picture of infection Maria Cristina Medici1, Claudio Galli2, and Adriana Calderaro1 1
Unit of Microbiology and Virology, Department of Clinical and Experimental Medicine, Faculty and Medicine and Surgery, University of Parma, Italy, Viale Antonio Gramsci, 14-43126 Parma, Italy 2 Scientific Affairs, Abbott Diagnostics, via Amsterdam, 125-00144 Roma, Italy
Antiviral therapy for hepatitis C virus (HCV) infection will be the next revolution in clinical virology. Sensible planning for treatment is needed, starting with populationscreening policies ideally using the HCV core antigen. This will result in a more defined picture of the silent spread of HCV.
A breakthrough in the diagnosis of HCV infection The impact of HCV on the healthcare system has been dramatic: a prospective evaluation carried out in the USA estimated that, even if a 24% decrease in prevalence from 2005 to 2021 is foreseen, the mortality for HCV-related chronic liver disease will increase due to the aging of HCVinfected subjects and the subsequent development of clinical disease [1,2]. Furthermore, unlike hepatitis B virus (HBV) infection, there is no conclusive evidence for protective immunity against HCV and, therefore, the likelihood of a prophylactic vaccine is slim. To identify and proactively treat HCV infections, comprehensive screening of at-risk populations should be undertaken. As a result of this, a systematic, population-wide screening for HCV has been proposed in the USA [3] based on three assumptions: (i) the burden of HCV infection relies mostly on the ‘baby boomers’, because people born in 1945– 1965 account for more than two-thirds of infected individuals [3,4]; (ii) screening this target population for specific antibodies (anti-HCV) and viral nucleic acid (HCV RNA) will enable the identification of the majority of infected individuals and prioritization of therapeutical interventions aimed at reducing the future impact of HCV-related chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma [1,5]; and (iii) over the next couple of years, specific antiviral drugs (direct-acting antiviral drugs; DAA) whose efficacy for the complete eradication of HCV has been reported to be as high as 95%, will become available [6]. One of such drugs (sofosbuvir) was cleared in 2014 by the US FDA and in the EU and evaluated either in association with ribavirin or inhibitors of nonstructural protein 5A (NS5A; daclatasvir or ledipasvir). Two other formulations, one based on multiple DAAs, including an inhibitor of the NS3/4 protease (paritaprevir) and the NS5A replication complex (ombitasvir), plus ritonavir and a Corresponding author: Calderaro, A. ([email protected]). Keywords: population screening; hepatitis C virus; testing algorithms. 0966-842X/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tim.2015.02.007
324
Trends in Microbiology, June 2015, Vol. 23, No. 6
non-nucleoside NS5B polymerase inhibitor (dasabuvir) were approved at the end of 2014 in the USA and in January 2015 in the EU. Other DAAs, such as simeprevir, an inhibitor of the NS3/4A protease, have already undergone clinical trials for registration purposes [6]. The first assumption of the proposed systematic screening in the USA is not valid in all countries. This is due to different routes of transmission and to other population variables, which means that the target population for screening policies aimed at the identification of potentially curable HCV infections will not be the same in all settings. In all instances, the basic question for cost–benefit analysis and for therapeutic planning is: how many chronically infected subjects do we expect to find? Finding the actual burden of HCV infection in apparently healthy individuals is challenging. In Europe, information on this as well as other major diseases comes from the European Centre for Disease Prevention and Control (ECDC). The latest report available [7] depicts a scattered picture and underlines the lack of reliable data due to different surveillance systems, mostly passive, and to different criteria used for diagnosis, given that some countries simply report anti-HCV-positive cases, whereas others indicate only viremic patients as being HCV infected. The latter option is better because only active infections bear the risk of developing into chronic liver disease and eventually cirrhosis or hepatocellular carcinoma, and these are the life-threatening consequences that we wish to prevent. In any case, the overall incidence of HCV in Europe is low: in 2012, less than one case of acute, symptomatic HCV infection per 100 000 inhabitants was reported in Italy, while the incidence ranged from 0.4% to 1.6% in the other countries [7]. Of note, in some European countries the surveillance systems capture only acute symptomatic infections, which account for only a fraction of all new cases of HCV [1], while, for instance, HCV prevalence in Italy has been reported to be as high as 2.6% in the general population [8], corresponding to almost 1.5 million people. So, while the figures of HCV incidence bear only a pale resemblance with those of a few decades ago, the actual prevalence and the burden of chronic infections are both difficult to estimate. Regardless of the target population to be screened, a testing strategy for HCV infections should guarantee the highest possible accuracy for the identification of active infection, for example, the best combination of sensitivity and specificity. The recent guidelines from the US Centers for Disease Control and Prevention (CDC) indicate a sequential algorithm, with the initial testing for anti-HCV
Science & Society followed by the determination of the eventual presence of the viral genome (HCV RNA) on antibody-positive samples [3]. Is this the best option for HCV screening? Maybe not: HCV testing is not implemented in all hospitals or community-based settings, and brings additional complexity due to the need for specialized personnel. In addition, the cost per result is higher because, on average, HCV RNA is more expensive than the serology [9]. Furthermore, as the CDC indicated and all population surveys confirmed [5,10,11], a substantial fraction of antibody-positive individuals are no longer infected, due to a spontaneous clearance of HCV [5,10,11]. Given that the real target of any interventional screening is the identification of subjects with an active infection [12], the combination of anti-HCV testing followed by HCV RNA testing on antibody-positive subjects may then be suboptimal. Recently, a new option for testing with a single serological assay that enables the identification of the HCV core antigen (HCVAg) has become available. The first demonstration for diagnostic purposes of HCVAg in the circulation of infected hosts was reported shortly after HCV genomic RNA characterization was completed [13]. HCVAg is detectable in acute HCV infection almost at the same time as HCV RNA [14] and, therefore, some weeks earlier than antibodies; in addition, it persists during all phases of infection. Given that HCVAg is present in both circulating virions and immune complexes with anti-HCV antibodies, a pre-analytical lysis step is necessary to release the antigen from these complexes; modern automated assays include a pretreatment step for this purpose [14]. A potential drawback for HCVAg testing is that the assay sensitivity corresponds approximately to 1000 IU/mL HCV RNA [14]. While this may cause problems if it is used in the monitoring of treated patients instead of a highly sensitive assay for HCV RNA, which is the recommended assay [12], this will not represent an issue in chronic, untreated individuals, who usually show levels in excess of that value [11,15]. Serological assays (HCVAb and HCVAg) are fully automated, do not require specialized personnel, and are also suited for high-volume testing on immunochemistry analyzers. Molecular testing is more technically demanding and high volumes may be processed only at sites that carry out blood-donation screening. Antibody testing (HCVAb) is available almost everywhere and HCV RNA assays are available in specialized laboratories, whereas the routine use of HCVAg utilization is still limited. Direct costs estimates are difficult, because prices vary locally depending on the test volumes: in general, HCVAg and HCV RNA assays are more expensive than those for HCVAb [9,12]. From a clinical standpoint, HCVAg and HCV RNA are able to identify acute infections and chronic active infections, while HCVAb appear only after 10 weeks from exposure [12], and are also detectable in patients who have cleared the virus. A first glimpse of the potential utility of HCVAg testing for population screening has been provided by Kuo et al. [15], who demonstrated a nearly absolute specificity and 96% sensitivity when a positive HCVAg result was coupled with high-level antibody reactivity. From our perspective, a single marker screening strategy, similar to what has been historically done with the
Trends in Microbiology June 2015, Vol. 23, No. 6
Selecon of the target populaon on the basis of clinical evaluaon: subjects with the clinical suspicion of acve HCV infecon
Test for HCV angen to diagnose HCV acve infecon
Subjects with posive HCVAg test: clinical assessment to evaluate therapy HCV RNA test including genotyping to administer anviral treatment Monitor efficacy of the anviral treatment
TRENDS in Microbiology
Figure 1. Proposed algorithm for hepatitis C virus (HCV) screening aimed at the identification of active infections for therapeutical interventions with the new direct-acting antiviral drugs (DAA) drugs. The monitoring of treatment efficacy could also be based on HCV core antigen (HCVAg) testing 12–24 weeks after the end of treatment.
HBV surface antigen (HBsAg) for the detection of HBV active infection, would be preferred. Using HCVAg as a marker will represent a significant step in the process of more clearly understanding the actual burden of HCV infection and disease and will enable design of a simpler and faster screening strategy (Figure 1) for therapeutic interventions. This approach will also bring clear advantages from an operating and economic standpoint: for the former, the assay results may be available within 1 hour from sampling; for the latter, testing for HCVAg instead of HCV RNA will result in a cost reduction per individual screen of US$85, mostly related to the decrease in personnel cost [9]. Concluding remarks We are on the verge of a major breakthrough in healthcare because HCV, currently a major cause of chronic disease and mortality, may eventually be cured. The upsurge in public interest in the spread, dynamics, and consequencies of HCV infection, for which a vaccine is not yet available, provides yet another opportunity to reinforce the role of clinical virologists as primary players in healthcare, not only with sophisticated molecular techniques, but also with a sound and sensible application of modern screening tools. References 1 Kershenobich, D. et al. (2011) Applying a system approach to forecast the total hepatitis C virus infected population size: model validation using US data. Liver Int. 31 (Suppl. 2), 4–17 2 Ly, K. et al. (2012) The growing burden of mortality from viral hepatitis in the US, 1999–2007. Ann. Intern. Med. 156, 271 3 Smith, B.D. et al. (2012) Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945– 1965. MMWR 61, 1–32 4 Ward, J.W. (2013) The epidemiology of chronic hepatitis C and onetime hepatitis C virus testing of persons born during 1945 to 1965 in the United States. Clin. Liver Dis. 17, 1–11 5 Poynard, T. et al. (2003) Viral hepatitis C. Lancet 362, 2095–2100 325
Science & Society 6 Cortez, K.J. and Kottilil, S. (2015) Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C. Ther. Adv. Chronic Dis. 6, 4–14 7 European Centre for Disease Prevention and Control (2014) Hepatitis B and C surveillance in Europe, 2012, ECDC 8 Valcavi, P. et al. (1999) Prevalence of hepatitis C virus antibodies in a clinical-based group of Italians from one geographical area. Clin. Infect. Dis. 5, 125–129 9 Cresswell, F.V. et al. (2015) Hepatitis C core antigen testing: a reliable, quick and potentially cost-effective alternative to Hepatitis C polymerase chain reaction in diagnosing acute Hepatitis C virus infection. Clin. Infect. Dis. 60, 263–266 10 Hahne´, S.J.M. et al. (2013) Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening. BMC Infect. Dis. 13, 181
326
Trends in Microbiology June 2015, Vol. 23, No. 6 11 Guadagnino, V. et al. (2013) Hepatitis C virus infection in an endemic area of Southern Italy 14 years later: evidence for a vanishing infection. Dig. Liver Dis. 45, 403–407 12 Kamili, S. et al. (2012) Laboratory diagnostics for hepatitis C virus infection. Clin. Infect. Dis. 55, S43–S48 13 Takahashi, K. et al. (1992) Demonstration of a hepatitis C virus– specific antigen predicted from the putative core gene in the circulation of infected hosts. J. Gen. Virol. 73, 667–672 14 Medici, M.C. et al. (2011) Hepatitis C virus core antigen: Analytical performances, correlation with viremia and potential applications of a quantitative, automated immunoassay. J. Clin. Virol. 51, 260– 265 15 Kuo, Y.H. et al. (2012) Is hepatitis C virus core antigen an adequate marker for community screening? J. Clin. Microbiol. 50, 1989– 1993