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The diagnosis of acute hepatitis C virus infection during seroconversion: an important therapeutic opportunity
Journal of Infection (2004) 49, 165–168
www.elsevierhealth.com/journals/jinf
CASE REPORT
The diagnosis of acute hepatitis C virus infection during seroconversion: an important therapeutic opportunity R. McMullana,*, P.V. Coylea, S. Feeneya, C. McCaugheya, W. Greggb, N. McDougallc a
Northern Ireland Regional Virus Laboratory, Royal Victoria Hospital, Belfast, UK Addiction Service, Holywell Hospital, Antrim, UK c Gastroenterology Unit Antrim Area Hospital, Antrim, UK b
Accepted 22 January 2004 Available online 3 March 2004
Case A 29-year-old male intravenous drug user of 6 years, with a previous history of affective disorder and deliberate self harm had been under the ongoing care of an addiction team for heroin addiction. His medication had recently been changed from buprenorphine to methadone and routine-screening tests had revealed significant elevation of liver transaminases although he was asymptomatic. Based on his deranged liver function tests (LFTs) he was referred to an acute hospital for further assessment. The only clinical sign elicited at this time was tenderness on palpation of the right hypochondrium. No organomegaly was detectable; this was confirmed by normal abdominal ultrasonography. Elevated liver transaminases, particularly alanine aminotransferase (ALT), were noted (Table 1); these continued to rise over the following few days. The patient admitted to having taken approximately *Corresponding author. Address: Medical Microbiology, Kelvin Laboratories, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK. Tel.: þ44-2890-240-503x3410; fax: þ44-2890311-416. E-mail address: [email protected]
12 g of paracetamol during a 24 h period 3 weeks previously. Based on the clinical history and LFTs there was a high index of suspicion for acute hepatitis C. Although there was no known exposure to a definite HCV positive contact, this man had a 6-year history of needle-sharing intravenous drug use, had undergone tatooing and had two recent episodes of unprotected sexual intercourse. On the day of presentation to hospital (day 7, Fig. 1) a specimen of blood examined for hepatitis C virus (HCV) screening IgG antibody (Ab) was negative. However, a further specimen taken on day 11 was positive, although a supplementary assay, the recombinant immunoblot assay-3 (RIBA3), was negative. On day 15 another specimen was examined; HCVAb remained positive. At this time, the RIBA-3 had also become positive. Retrospective real-time, quantitative, polymerase chain reaction (PCR) amplification of RNA extracted from all of the specimens referred to above was carried out (Fig. 1). Furthermore, a specimen which had been taken 6 days prior to hospital admission (day 1, Fig. 1), also negative for HCVAb, was included. Of note, PCR positivity 10 days prior to seroconversion was observed in this
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.01.009
166
R. McMullan et al.
Table 1 Trend in laboratory indices over time
Serum ALT (IU/ml) Antibody status OD/CO RIBA status RIBA antigen results C100 C22 C33 NS5 Viral load (copies £ 1000/ml)
Day 1
Day 7
Day 11
Day 15
Day 19
Day 29
Day 31
338 – 0.33 nt nt
2490 – 0.5 nt nt
3340 þ 1.44 –
2711 þ 5.95 þ
1366
1106 þ 11.13 nt nt
– – – – 1327
– þ þþ – 81
1350
3383
1.3
1693
Day 45
Day 49
Day 77
þ 11.59 þ
þ 31.13 þ
þ 17.37 nt nt
– þþ þþ – 34
– þ þþ þ þþ þ – 12.9
69
Equiv.
Day of presentation to acute hospital. þ , Positive test result; –, negative test result; nt, not tested; OD/CO, ratio of optical density of antibody test to positive cut-off value. Equiv ¼ test equivocal: PCR positive in 25% of specimens examined.
case; unfortunately no further previous specimens were available for retrospective viral load assessment. The rise and fall in HCV viral load is evident, however, an unexpected rise at day 29 is noteworthy (Fig. 1). This virus was found to be genotype 3a. The patient was followed up at an outpatient clinic and after 8 weeks of remaining HCV RNA positive it was decided that he should receive combination antiviral therapy with pegylated interferon and ribavirin.
Discussion Hepatitis C virus infection is usually diagnosed in its chronic phase. Acute infection is not usually clinically apparent, with as few as 10% of episodes being associated with jaundice.1 Chronic infection has major implications for the individual since up to 30% of infected persons may ultimately develop cirrhosis and those with cirrhosis have a 1–7% risk per year of developing a hepatocellular carcinoma.1,2
Figure 1 Viral load and serum ALT over time.
Diagnosis of hepatitis C seroconversion
Approximately 60% of chronic liver disease in the US has been attributed to chronic HCV infection.3,4 Although much of this may be traced to the receipt of blood products, which is now unlikely following donor screening, new cases associated with injecting drug behaviour are increasingly recognised. Therefore, prevention of progression to chronic infection may, potentially, avoid the major attributable burden of disease to both the individual and society. Few studies have addressed the issue of treatment for acute hepatitis C, largely due to the small proportion of patients presenting with an acute illness. Jaeckel et al.5 reported an excellent response rate to interferon monotherapy but no studies have thoroughly assessed the role of combination therapy with pegylated interferon and ribavirin—the current gold standard in therapy for chronic hepatitis C. Early diagnosis and treatment is, therefore, potentially of great value to the individual. In the context of intravenous drug users (ivdu), early detection would also provide an opportunity for public health intervention to other individuals who may have been infected at the same time. This would require the establishment of a contact tracing infrastructure to identify, test and treat, needle-sharing contacts of viraemic patients. Hence, reliable detection of early infection also has the potential to impact on the spread of HCV infection in the wider community. Serological tests in common use at present are limited by both the inability to distinguish acute from chronic infection and the variable ‘window’ period between infection and seroconversion which, in the general population, requires at least 5 – 6 weeks.6 However, this may be much longer in certain risk groups such as haemodialysis patients and intravenous drug users (ivdu).7,8 Beld et al. demonstrated this seroconversion window ranging from 2 – 94 months following detection of viraemia among 12 intravenous drug users.7 They remarked that, independent of HIV status, the immune system of ivdu appears to be unable to respond to low levels of HCV RNA for prolonged periods. Therefore, since it is possible to obtain falsenegative results with such serological tests, we recommend that improved communication between laboratories and clinicians should be pursued. This is particularly so in patients at risk in whom clinical suspicion of HCV infection is high. Clinician-awareness of the limits of screening serology should prompt discussion with virology colleagues when dealing with seronegative, but suspect, cases of HCV. Such discussion would allow further examination of specimens by PCR. Addition-
167
ally, data demonstrating the utility of nonmolecular HCV core antigen testing has been encouraging,9,10 with Peterson reporting a mean lag-time of only one day following PCR-positivity.11 In this case, it was serendipitous that the patient had several encounters with healthcare providers who had a high index of suspicion, allowing the initially negative HCV screening test to be repeated. Of interest, the confirmatory RIBA was negative when the screening HCVAb was first positive. Hence, although one might regard such as a false-positive HCVAb result, the possibility of this pattern being a feature of HCV seroconversion ought to be considered when dealing with any patient in a HCV risk group. A RIBA-indeterminate or negative pattern has been reported as a characteristic of late disease in a cohort of Irish women infected with contaminated anti-D immunoglobulin.12 Of note, however, such RIBA patterns were observed only in PCR-negative individuals. The patient’s viral load data look to be in keeping with a good cellular response to the initial infection in view of the overall reduction, however, persistence of viraemia until at least day 49 (or day 77, depending on how the equivocal result is interpreted) indicated failure to clear the infection which contributed towards the decision to initiate treatment. In spite of this, early control of replication may imply the likelihood of a successful response to interferon therapy. A critical, unanswered, question in this area is how to select those patients with acute infection who should be offered treatment and when. Firstly, an estimate of likelihood of compliance must be made. It seems probable that individuals whose lives are chaotic (such as continuing ivdu) would not complete therapy; therefore, commencing treatment would be unwise. Secondly, the potential for spontaneous complete resolution of the acute infection, reported to be as high as 30% in one study,13 should be borne in mind. Two studies that have looked at this area suggested that the following factors are associated with reduced likelihood of a favourable outcome: absence of jaundice with the acute illness, younger age and persistence of viraemia for more than 7 – 12 weeks.13,14 In this case the patient met the first two criteria and, after being presented with relevant information and waiting 8 weeks, a decision to commence therapy was made. The increasing availability of viral load assays has the potential to confuse this decision unless interpreted cautiously. Fluctuating viral load is one of the recognised patterns associated with acute infection.15 This patient appeared to have a rapidly falling viral load, however, it rose sharply
168
for a second time (Fig. 1); this may encourage prolonged watchful waiting among patients in whom qualitative PCR would give persistently positive results and prompt treatment sooner. However, combination therapy is expensive and further studies are needed to help define in more precise terms who to treat, how to treat and how long to wait before starting such therapy. In conclusion, since testing for hepatitis C virus is undergoing change, in view of the deficiencies of conventional serology we recommend early discussion with the virology laboratory when dealing with patients who are seronegative in the face of high suspicion or risk of HCV infection.
References 1. Booth JCL, O’Grady J, Neuberger J. Clinical guidelines on the management of hepatitis C. Gut 2001;49(Suppl. 1):i1—i21. 2. Esteban JI, Genesca J, Alter HJ. Hepatitis C: molecular biology, pathogenesis, epidemiology, clinical features and prevention. Prog Liver Dis 1992;10:253—282. 3. Gross Jr B. Clinician’s guide to hepatitis C. Mayo Clin Proc 1998;73:355—361. 4. Alter MJ. The epidemiology of acute and chronic hepatitis C. Clin Liver Dis 1997;1:559—568. 5. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. Lancet 2001;345: 1452—1457. 6. Krajden M. Hepatitis C virus diagnosis and testing. Can J Pub Health 2000;91(Suppl. 1):S34—S39.
R. McMullan et al.
7. Beld M, Penning M, vanPutten M, et al. Low levels of hepatitis C virus in serum, plasma and peripheral blood mononuclear cells of injecting drug users during long antibody-undetectable periods before seroconversion. Blood 1999;94:1183—1191. 8. Schroter M, Feucht HH, Schafer P, Zollner B, Laufs R. High percentage of seronegative HCV infections in haemodialysis patients: the need for PCR. Intervirology 1997;40:277—278. 9. Icardi G, Ansaldi F, Bruzzone BM. Novel approach to reduce the hepatitis C window period: clinical evaluation of a new enzyme-linked immunosorbent assay for HCV core antigen. J Clin Microbiol 2001;39:3110—3114. 10. Aoyagi K, Iida K, Ohue C, et al. Performance of a conventional enzyme immunoassay for hepatitis C virus core antigen in the early phases of hepatitis C infection. Clin Lab 2001;47:119—127. 11. Peterson J, Green G, Iida K, et al. Detection of hepatitis C core antigen in the antibody negative window phase of hepatitis C infection. Vox Sanguinis 2000;72:80—85. 12. Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort. Gut 2001;49:423—430. 13. Santantonio T, Sinisi E, Guastadisegni A, et al. Natural course of acute hepatitis C: a long-term prospective study. Dig Liver Dis 2003;35:104—113. 14. Hofer H, Watkins-Riedel T, Janata O, et al. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. Hepatology 2003;37:60—64. 15. Beld M, Penning M, McMorrow M, et al. Different hepatitis C virus RNA load profiles following seroconversion among injecting drug users without correlation with HCV genotype and serum alanine aminotransferase levels. J Clin Microbiol 1998;36:872—877.
www.elsevierhealth.com/journals/jinf
CASE REPORT
The diagnosis of acute hepatitis C virus infection during seroconversion: an important therapeutic opportunity R. McMullana,*, P.V. Coylea, S. Feeneya, C. McCaugheya, W. Greggb, N. McDougallc a
Northern Ireland Regional Virus Laboratory, Royal Victoria Hospital, Belfast, UK Addiction Service, Holywell Hospital, Antrim, UK c Gastroenterology Unit Antrim Area Hospital, Antrim, UK b
Accepted 22 January 2004 Available online 3 March 2004
Case A 29-year-old male intravenous drug user of 6 years, with a previous history of affective disorder and deliberate self harm had been under the ongoing care of an addiction team for heroin addiction. His medication had recently been changed from buprenorphine to methadone and routine-screening tests had revealed significant elevation of liver transaminases although he was asymptomatic. Based on his deranged liver function tests (LFTs) he was referred to an acute hospital for further assessment. The only clinical sign elicited at this time was tenderness on palpation of the right hypochondrium. No organomegaly was detectable; this was confirmed by normal abdominal ultrasonography. Elevated liver transaminases, particularly alanine aminotransferase (ALT), were noted (Table 1); these continued to rise over the following few days. The patient admitted to having taken approximately *Corresponding author. Address: Medical Microbiology, Kelvin Laboratories, Royal Victoria Hospital, Grosvenor Road, Belfast BT12 6BA, UK. Tel.: þ44-2890-240-503x3410; fax: þ44-2890311-416. E-mail address: [email protected]
12 g of paracetamol during a 24 h period 3 weeks previously. Based on the clinical history and LFTs there was a high index of suspicion for acute hepatitis C. Although there was no known exposure to a definite HCV positive contact, this man had a 6-year history of needle-sharing intravenous drug use, had undergone tatooing and had two recent episodes of unprotected sexual intercourse. On the day of presentation to hospital (day 7, Fig. 1) a specimen of blood examined for hepatitis C virus (HCV) screening IgG antibody (Ab) was negative. However, a further specimen taken on day 11 was positive, although a supplementary assay, the recombinant immunoblot assay-3 (RIBA3), was negative. On day 15 another specimen was examined; HCVAb remained positive. At this time, the RIBA-3 had also become positive. Retrospective real-time, quantitative, polymerase chain reaction (PCR) amplification of RNA extracted from all of the specimens referred to above was carried out (Fig. 1). Furthermore, a specimen which had been taken 6 days prior to hospital admission (day 1, Fig. 1), also negative for HCVAb, was included. Of note, PCR positivity 10 days prior to seroconversion was observed in this
0163-4453/$30.00 Q 2004 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2004.01.009
166
R. McMullan et al.
Table 1 Trend in laboratory indices over time
Serum ALT (IU/ml) Antibody status OD/CO RIBA status RIBA antigen results C100 C22 C33 NS5 Viral load (copies £ 1000/ml)
Day 1
Day 7
Day 11
Day 15
Day 19
Day 29
Day 31
338 – 0.33 nt nt
2490 – 0.5 nt nt
3340 þ 1.44 –
2711 þ 5.95 þ
1366
1106 þ 11.13 nt nt
– – – – 1327
– þ þþ – 81
1350
3383
1.3
1693
Day 45
Day 49
Day 77
þ 11.59 þ
þ 31.13 þ
þ 17.37 nt nt
– þþ þþ – 34
– þ þþ þ þþ þ – 12.9
69
Equiv.
Day of presentation to acute hospital. þ , Positive test result; –, negative test result; nt, not tested; OD/CO, ratio of optical density of antibody test to positive cut-off value. Equiv ¼ test equivocal: PCR positive in 25% of specimens examined.
case; unfortunately no further previous specimens were available for retrospective viral load assessment. The rise and fall in HCV viral load is evident, however, an unexpected rise at day 29 is noteworthy (Fig. 1). This virus was found to be genotype 3a. The patient was followed up at an outpatient clinic and after 8 weeks of remaining HCV RNA positive it was decided that he should receive combination antiviral therapy with pegylated interferon and ribavirin.
Discussion Hepatitis C virus infection is usually diagnosed in its chronic phase. Acute infection is not usually clinically apparent, with as few as 10% of episodes being associated with jaundice.1 Chronic infection has major implications for the individual since up to 30% of infected persons may ultimately develop cirrhosis and those with cirrhosis have a 1–7% risk per year of developing a hepatocellular carcinoma.1,2
Figure 1 Viral load and serum ALT over time.
Diagnosis of hepatitis C seroconversion
Approximately 60% of chronic liver disease in the US has been attributed to chronic HCV infection.3,4 Although much of this may be traced to the receipt of blood products, which is now unlikely following donor screening, new cases associated with injecting drug behaviour are increasingly recognised. Therefore, prevention of progression to chronic infection may, potentially, avoid the major attributable burden of disease to both the individual and society. Few studies have addressed the issue of treatment for acute hepatitis C, largely due to the small proportion of patients presenting with an acute illness. Jaeckel et al.5 reported an excellent response rate to interferon monotherapy but no studies have thoroughly assessed the role of combination therapy with pegylated interferon and ribavirin—the current gold standard in therapy for chronic hepatitis C. Early diagnosis and treatment is, therefore, potentially of great value to the individual. In the context of intravenous drug users (ivdu), early detection would also provide an opportunity for public health intervention to other individuals who may have been infected at the same time. This would require the establishment of a contact tracing infrastructure to identify, test and treat, needle-sharing contacts of viraemic patients. Hence, reliable detection of early infection also has the potential to impact on the spread of HCV infection in the wider community. Serological tests in common use at present are limited by both the inability to distinguish acute from chronic infection and the variable ‘window’ period between infection and seroconversion which, in the general population, requires at least 5 – 6 weeks.6 However, this may be much longer in certain risk groups such as haemodialysis patients and intravenous drug users (ivdu).7,8 Beld et al. demonstrated this seroconversion window ranging from 2 – 94 months following detection of viraemia among 12 intravenous drug users.7 They remarked that, independent of HIV status, the immune system of ivdu appears to be unable to respond to low levels of HCV RNA for prolonged periods. Therefore, since it is possible to obtain falsenegative results with such serological tests, we recommend that improved communication between laboratories and clinicians should be pursued. This is particularly so in patients at risk in whom clinical suspicion of HCV infection is high. Clinician-awareness of the limits of screening serology should prompt discussion with virology colleagues when dealing with seronegative, but suspect, cases of HCV. Such discussion would allow further examination of specimens by PCR. Addition-
167
ally, data demonstrating the utility of nonmolecular HCV core antigen testing has been encouraging,9,10 with Peterson reporting a mean lag-time of only one day following PCR-positivity.11 In this case, it was serendipitous that the patient had several encounters with healthcare providers who had a high index of suspicion, allowing the initially negative HCV screening test to be repeated. Of interest, the confirmatory RIBA was negative when the screening HCVAb was first positive. Hence, although one might regard such as a false-positive HCVAb result, the possibility of this pattern being a feature of HCV seroconversion ought to be considered when dealing with any patient in a HCV risk group. A RIBA-indeterminate or negative pattern has been reported as a characteristic of late disease in a cohort of Irish women infected with contaminated anti-D immunoglobulin.12 Of note, however, such RIBA patterns were observed only in PCR-negative individuals. The patient’s viral load data look to be in keeping with a good cellular response to the initial infection in view of the overall reduction, however, persistence of viraemia until at least day 49 (or day 77, depending on how the equivocal result is interpreted) indicated failure to clear the infection which contributed towards the decision to initiate treatment. In spite of this, early control of replication may imply the likelihood of a successful response to interferon therapy. A critical, unanswered, question in this area is how to select those patients with acute infection who should be offered treatment and when. Firstly, an estimate of likelihood of compliance must be made. It seems probable that individuals whose lives are chaotic (such as continuing ivdu) would not complete therapy; therefore, commencing treatment would be unwise. Secondly, the potential for spontaneous complete resolution of the acute infection, reported to be as high as 30% in one study,13 should be borne in mind. Two studies that have looked at this area suggested that the following factors are associated with reduced likelihood of a favourable outcome: absence of jaundice with the acute illness, younger age and persistence of viraemia for more than 7 – 12 weeks.13,14 In this case the patient met the first two criteria and, after being presented with relevant information and waiting 8 weeks, a decision to commence therapy was made. The increasing availability of viral load assays has the potential to confuse this decision unless interpreted cautiously. Fluctuating viral load is one of the recognised patterns associated with acute infection.15 This patient appeared to have a rapidly falling viral load, however, it rose sharply
168
for a second time (Fig. 1); this may encourage prolonged watchful waiting among patients in whom qualitative PCR would give persistently positive results and prompt treatment sooner. However, combination therapy is expensive and further studies are needed to help define in more precise terms who to treat, how to treat and how long to wait before starting such therapy. In conclusion, since testing for hepatitis C virus is undergoing change, in view of the deficiencies of conventional serology we recommend early discussion with the virology laboratory when dealing with patients who are seronegative in the face of high suspicion or risk of HCV infection.
References 1. Booth JCL, O’Grady J, Neuberger J. Clinical guidelines on the management of hepatitis C. Gut 2001;49(Suppl. 1):i1—i21. 2. Esteban JI, Genesca J, Alter HJ. Hepatitis C: molecular biology, pathogenesis, epidemiology, clinical features and prevention. Prog Liver Dis 1992;10:253—282. 3. Gross Jr B. Clinician’s guide to hepatitis C. Mayo Clin Proc 1998;73:355—361. 4. Alter MJ. The epidemiology of acute and chronic hepatitis C. Clin Liver Dis 1997;1:559—568. 5. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. Lancet 2001;345: 1452—1457. 6. Krajden M. Hepatitis C virus diagnosis and testing. Can J Pub Health 2000;91(Suppl. 1):S34—S39.
R. McMullan et al.
7. Beld M, Penning M, vanPutten M, et al. Low levels of hepatitis C virus in serum, plasma and peripheral blood mononuclear cells of injecting drug users during long antibody-undetectable periods before seroconversion. Blood 1999;94:1183—1191. 8. Schroter M, Feucht HH, Schafer P, Zollner B, Laufs R. High percentage of seronegative HCV infections in haemodialysis patients: the need for PCR. Intervirology 1997;40:277—278. 9. Icardi G, Ansaldi F, Bruzzone BM. Novel approach to reduce the hepatitis C window period: clinical evaluation of a new enzyme-linked immunosorbent assay for HCV core antigen. J Clin Microbiol 2001;39:3110—3114. 10. Aoyagi K, Iida K, Ohue C, et al. Performance of a conventional enzyme immunoassay for hepatitis C virus core antigen in the early phases of hepatitis C infection. Clin Lab 2001;47:119—127. 11. Peterson J, Green G, Iida K, et al. Detection of hepatitis C core antigen in the antibody negative window phase of hepatitis C infection. Vox Sanguinis 2000;72:80—85. 12. Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort. Gut 2001;49:423—430. 13. Santantonio T, Sinisi E, Guastadisegni A, et al. Natural course of acute hepatitis C: a long-term prospective study. Dig Liver Dis 2003;35:104—113. 14. Hofer H, Watkins-Riedel T, Janata O, et al. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. Hepatology 2003;37:60—64. 15. Beld M, Penning M, McMorrow M, et al. Different hepatitis C virus RNA load profiles following seroconversion among injecting drug users without correlation with HCV genotype and serum alanine aminotransferase levels. J Clin Microbiol 1998;36:872—877.