Identified cases of acute hepatitis C from computerized laboratory database: A hospital-based epidemiological and clinical study

Journal of Infection (2008) 56, 274e280

www.elsevierhealth.com/journals/jinf

Identified cases of acute hepatitis C from computerized laboratory database: A hospital-based epidemiological and clinical study Chao-Hung Hung a, Sheng-Nan Lu a,b, Jing-Houng Wang a, Shu-Fen Hung a, Chien-Hung Chen a, Tsung-Hui Hu a, Chuan-Mo Lee a, Chi-Sin Changchien a,* a

Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial HospitaleKaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Niao Sung 833, Kaohsiung, Taiwan b Xiamen Chang Gung Hospital, Fujian, PR China Accepted 29 January 2008 Available online 17 March 2008

KEYWORDS Acute hepatitis C; Anti-HCV titer; Seroconversion; Epidemiology; antiviral therapy

Summary Objective: Diagnosis of acute hepatitis C (AHC) relies on documented positiveseroconversion of antibody to hepatitis C virus (anti-HCV) that is infrequently encountered. To clarify the epidemiology and clinical course of AHC, we tried to find more AHC patients from a computerized laboratory database by using a supplemental criterion of rising anti-HCV titer. Methods: All the computerized laboratory databases of anti-HCV and alanine aminotransferase (ALT) were reviewed. Candidates for AHC were identified by either anti-HCV positive seroconversion, rise of anti-HCV titer (signal to cut-off ratio (S/CO) ratio <40 to 40), or spontaneous HCV RNA clearance. AHC cases and their matched chronic hepatitis C controls were interviewed by a caseecontrol study concerning risk factors. Results: AHC was identified in 123 patients (68 men and 55 women; median age: 48.4  13.9 years), who had higher rates of recent surgery (p Z 0.037) and frequent injection therapy (p Z 0.036) compared to controls. Self-limited AHC was observed in 18 (19.1%, 95% confidence interval: 12.3e25.9%) of 94 AHC patients who had been followed for 6 months, with a higher bilirubin level (2 vs. <2, p Z 0.007) compared to those evolved to chronic infection. Conclusions: Screening of a laboratory database for anti-HCV and ALT might uncover more AHC candidates to disclose the epidemiology and clinical course of AHC. ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ886 7 731 7123x8301; fax: þ886 7 732 2402. E-mail addresses: [email protected], [email protected] (C.-S. Changchien). 0163-4453/$34 ª 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2008.01.049

Acute hepatitis C

Introduction Hepatitis C virus (HCV) is a leading cause of chronic liver disease, with over 170 million people infected worldwide.1 Approximately 50e84% of patients infected develop acute chronic hepatitis, and may have a significant long-term risk of liver cirrhosis and hepatocellular carcinoma.2e9 Acute hepatitis C (AHC) is infrequently diagnosed because most patients do not have symptoms9e11 and no etiologic marker has been proven useful to identify AHC and to distinguish between AHC and acute exacerbation of chronic hepatitis C.12e14 Moreover, the diagnosis of AHC is of clinical importance since early intervention with interferon (IFN)-based therapies during the acute phase significantly reduces evolution to chronic hepatitis.15,16 In addition to the receipt of blood and blood products prior to widespread screening, more than two-thirds of the new infections in Western countries are associated with the sharing of contaminated equipment between injecting drug users (IDU); however, in up to 40% of cases, the exact mode of HCV transmission remains undefined.17,18 The epidemiology of HCV infection in developing countries might be different. It is hard to trace the route of infection in most chronic HCV infection due to its insidious onset and chronic course, whereas it might be much easier to do so for AHC cases if they are identified early enough. If the risk factors could be accurately assessed, proper education targeted at harm minimization and other necessary control measures might avoid continuous spread of HCV. The demonstration of seroconversion to anti-HCV positivity remains the only means of identifying AHC to date. However, the documented seroconversion cases has decreased because the sensitivity and specificity of second- or third-generation anti-HCV assays has improved remarkably and shortened the window period.19,20 Previously we demonstrated that increasing the titer of anti-HCV (AxSYM, version 3.0; Abbott, Chicago, IL, USA) might be used as a supplemental diagnostic criterion for AHC in those without documented seroconversion.14 In that study, serial signal/cutoff (S/CO) ratios of third-generation anti-HCV assays were analyzed in 18 patients with a clinical diagnosis of AHC. Of them, the initial S/CO values on the first visit were less than 40 in 14 (78%) patients, and 12 (86%) of them showed a rising pattern of S/CO values (40) thereafter. The other two cases (14%) with spontaneous viral clearance had a persistently low S/CO ratio. On the contrary, the S/CO ratio was persistently high (40) in chronic hepatitis C cases with acute exacerbation. Accordingly, an initial S/CO value <40 with a rising pattern (40) might be the most common change of serial anti-HCV in those with suspected AHC infection without documented seroconversion. Most studies on AHC have investigated the infection resulting from transfusion or from needlestick exposure among health care workers since these were the commonest identified modes of transmission for HCV.9,21e23 As compared with post-transfusion hepatitis, community-acquired AHC may differ regarding size of the inoculum, as well as mode of transmission and patient characteristics. So far, studies on the community-acquired AHC are still limited.9,24,25 Therefore, we conducted the present study to clarify the epidemiology and clinical course of AHC in

275 southern Taiwan by screening the computerized laboratory database of anti-HCV and alanine aminotransferase (ALT) to find candidates for AHC.

Patients and methods Study design to find the candidates for AHC Identification of candidates for AHC was based on the assumption derived from previous studies in that a low S/ CO value <40 with a subsequent rise (40) is the most common change of serial anti-HCV in suspected AHC patients without documented seroconversion.14 We therefore screened the computerized databases of anti-HCV and ALT in our hospital from January 1999 to December 2004. Our hospital is a 2200-bed medical center that is a non-profit and service-oriented institution and is the largest tertiary referral center in southern Taiwan. Most of our patients came from Kaohsiung City and Kaohsiung County, including several HCV hyperendemic areas, where medical resources were still insufficient in some rural areas and medical injections were found to be the main mode of spreading HCV infection.26e28 The medical records were reviewed and the necessary laboratory tests were completed using stored samples from the serum bank, including antiHCV, qualitative detection and genotyping of HCV. The Human Research and Ethics Committee (Institutional Review Board) approved the study and informed consent was obtained from each patient involved in the study.

Epidemiology of HCV AHC is considered to run a course of approximately 6 months.24 A self-limited course of AHC was defined as permanent (>6 months) loss of HCV RNA in serum and normalization of ALT.24 The term chronic hepatitis C is applied if the patients had transient loss or persistence of serum HCV RNA beyond 6 months after the onset of symptoms.24 A structured questionnaire was performed by an interviewer to evaluate the risk factors for HCV, including history of blood transfusion, surgery, habitual injection therapy, dental procedure, tattooing, acupuncture, body piercing, IDU, and sexual transmission in AHC cases and their individual age- and sex- matched chronic hepatitis C controls, who were selected from our outpatient clinic during the same period (from January 1999 to December 2004). The risk factors were assessed during the episode of AHC (<6 months) or recent half a year in chronic hepatitis C cases. Questionnaire also elicited basic demographic information of respondents including place of residence, age, level of education, year of diagnosis, and duration of attendance at the liver clinic.

Antiviral therapy An assessment was performed on antiviral therapy of the cases under study to assess the response to therapy. Early treatment was defined as therapy initiation during the acute episode (<3 months); whereas delayed treatment was initiated after 3 months of the onset of AHC. Sustained

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virological response (SVR) was defined as normalization of ALT level together with negative HCV RNA at 6 months after completion of antiviral therapy.

Laboratory investigations Anti-HCV was detected by third-generation enzyme immunoassays (AxSYM, version 3.0; Abbott, Chicago, IL, USA). The presence of anti-HCV can be expressed as a signal to cut-off ratio (S/CO). An S/CO ratio of 1.0 was interpreted as reactive, within the gray zone if 0.8  S/CO < 1.0, and non-reactive if <0.8. Qualitative detection of HCV RNA was performed by a standardized qualitative RTePCR assay (Amplicor, Roche Diagnostics, Branchburg, NJ, USA), using biotinylated primers for the 50 noncoding region. The lowest detection limit of this assay was 100 copies/ml (50 IU/ml). Genotyping of HCV was done by reverse hybridization assay (InnoLiPA HCV II; Innogenetics N.V., Gent, Belgium) in the HCV-Amplicor products.

Statistical analysis The ManneWhitney U-test was used to compare continuous variables between the two groups. Differences between binominal variables were evaluated with Chi square analysis or Fisher’s exact test depending on the size of the sample. All analysis was carried out using SPSS software version 11.0 (SPSS Inc., Chicago, IL). A p-value of less than 0.05 was considered statistically significant.

Results Identification of AHC cases Fig. 1 shows the diagnostic algorithm with AHC in this study. A total of 639,649 ALT data and 117,091 events of anti-HCV

were collected. Seroconversion of anti-HCV was observed in 183 persons. There were 4485 events of anti-HCV <40. Of them, 216 patients had both anti-HCV <40 and ALT 10 times the upper limit of normal (i.e. 400 U/L); and the other 102 patients had ALT <400 U/L along with a rising anti-HCV titer (<40 to 40). In Table 1, among the 216 patients with both anti-HCV <40 and ALT 400 U/L, 138 patients were suspected to have AHC based on the presence of HCV RNA by reverse transcriptionepolymerase chain reaction (RTePCR) in the first serum sample and/or clinical and biochemical criteria (acute onset of hepatitis in individuals without pre-existing liver disease, exclusion of other coexisting infections). Those who have low titer of anti-HCV such as late phase of viral clearance (past infection or sustained response to antiviral therapies) and possible false-positive results were also excluded.26,27 Besides the 14 patients with concomitant anti-HCV seroconversion, 82 were defined as confirmed AHC cases. Of them, 72 patients had a rise of anti-HCV titer from 19.9  12.3 (<40) to 91.6  42.3 (40) during a median period of 88 days. The remaining 10 patients had spontaneous HCV RNA clearance (8 with persistent low S/CO ratio, and 2 with decrease of antiHCV titer (S/CO 40 to <40), with a median interval of 242 days between the initial and the last examination of anti-HCV. We defined the other 42 patients who had initial anti-HCV titer <40 without serial follow-up as probable AHC cases that were excluded at the final analysis. Among the 102 patients with ALT <400 U/L and a rising anti-HCV titer, only 8 who had a positive HCV RNA in the first serum sample were confirmed AHC cases. Table 2 shows the 183 patients with seroconversion of anti-HCV. Among them, 63 patients had immunodeficiency status such as end-stage renal disease, which was frequently followed during routine examination. Thirty-three patients who had a positive HCV RNA in the serum were considered as having a new acquired HCV infection. Of them, only 12 patients had hepatitis C viremia concomitant

ALT data N=639649 (events)

Anti-HCV titer N=117091 (events)

Anti-HCV<40 N=4485 (events)

ALT<400 (U/L) 40 Anti-HCV<40 N=102 (persons)

Confirmed AHC (N=8)

400>ALT>200 IU/L (N=6)

Not AHC (N=94)

ALT<200 IU/L (N=2)

ALT≥ 400 (U/L) & Anti-HCV< 40 N=216 (persons)

Probable AHC (N=42)

Not rising titer, HCV- RNA clearance (N=10)

Confirmed AHC (N=82)

Rising titer (N=72)

14 combined

Not AHC (N=78)

ALT>400 IU/L (N=23)

Anti-HCV seroconversion N=183 (persons)

Confirmed AHC (N=33)

400>ALT>200 IU/L (N=5)

Not AHC (N=150)

ALT<200 IU/L (N=5)

Figure 1 Diagnostic algorithm with acute hepatitis C: a large-scale screening of the computerized database of anti-HCV and ALT laboratory from 1999 January to December 2004.

Acute hepatitis C

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Table 1 Diagnosis of acute hepatitis C based on low antiHCV titer (S/CO ratio<40) and hepatitis C viremia ALT 400 U/L & anti-HCV S/CO ratio <40

Cases (n Z 216)

Combined seroconversion

14

a

Confirmed AHC Rise of anti-HCV titer (S/CO ratio <40 to 40) Persistent low anti-HCV titer (S/CO <40) with spontaneous HCV RNA clearance Decrease of anti-HCV titer (S/CO ratio 40 to<40) with spontaneous HCV RNA clearance

82 72

Probable AHC Low anti-HCV titer (S/CO <40) without serial follow-up

42

Not AHC Possible false-positive or past infectionb Sustained response to antiviral therapyb Immunodeficiency status Undeterminedc

78 51 11 3 13

ALT <400 U/L & anti-HCV S/CO ratio <40 to 40

Cases (n Z 102)

Confirmed AHCa Not AHC Possible false-positive or past infectionb Immunodeficiency status Undetermined

8

Table 2 Anti-HCV seroconversion in 183 patients between January 1999 and December 2004 at our hospital No. of cases Documented acute hepatitis C Peak ALT 400 U/L Peak ALT 200 & <400 U/L Peak ALT <200 U/L

33a 23 5 5

Immunodeficiency statusb Possible false-positive or past infectionc Undeterminedd

63 60 27

a

2

Twelve patients had anti-HCV positive seroconversion during acute phase of AHC infection; while the other 21 patients had a previous data of negative anti-HCV. b End staged renal disease accounted for the majority of immunodeficiency status. c Low anti-HCV titer <10 without HCV viremia and/or serial ALT change. d No available stored serum to evaluate.

during AHC was 1000 U/L (range: 66e2820 U/L), and 4.6 mg/dl (range: 0.4e26.6 mg/dl), respectively. Thirtyone (25.2%) patients had no evident jaundice (total bilirubin <2 mg/dl). As shown in Fig. 2, the incidence of AHC was gradually decreased from 1999 to 2004.

8 94 54 22 18

a Diagnosis based on the presence of HCV RNA by RTePCR in the first serum sample. b S/CO ratio <40 and high ALT level did not occur at the same time. c No available stored serum to evaluate.

Table 3 Baseline characteristics of 123 confirmed acute hepatitis C cases Variables Diagnosis Rise of anti-HCV titer or spontaneous HCV RNA clearance Anti-HCV seroconversion Age (years)

with anti-HCV positive seroconversion during acute phase of AHC infection, while the other 21 patients had a previous data of negative anti-HCV. Among the 123 confirmed AHC patients, only 9 (7.3%) had been reported to the Centers for Disease Control of Taiwan as AHC cases.29

Baseline characteristics of AHC cases Table 3 shows the baseline characteristics of 123 confirmed AHC cases (90 based on low anti-HCV titer with hepatitis C viremia and 33 based on anti-HCV positive seroconversion with hepatitis C viremia). They were 68 men and 55 women, 19e80 years old, with a median age of 48.4  13.9 years. Ten patients (8.7%, 10/115) were also positive for hepatitis B surface antigen (HBsAg). Fifty-five patients (44.7%) were infected with genotype 1 whereas 42 (34.1%) were infected with genotype 2, and 5 (4.0%) with genotype 3 or mixed type. The median of peak ALT level and total bilirubin level

Gender Male Female HBsAg(þ) Peak ALT (U/L) Peak bilirubin (mg/dl) <2 2, <5 5 Not available

Median (range) or number (%) 90 (73.2%) 33 (26.8%) 48.4 (19e80) 68 (55.3%) 55 (44.7%) 10/115 1000 4.6 31 30 56 6

(8.7%) (66e2820) (0.4e26.6) (25.2%) (24.3%) (45.5%) (4.9%)

HCV genotyping 1 2 1þ2 3 Undetermined/not available

55 42 3 2 21

Antiviral therapy Early treatment (<3 months) Delayed treatment (3 months)

19 (15.4%) 3 (2.4%) 16 (13.0%)

(44.7%) (34.1%) (2.4%) (1.6%) (17.1%)

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Questionnaire interviewing on the transmission routes of acute hepatitis C by caseecontrol design A caseecontrol study was performed to evaluate the risk factors for HCV in 123 AHC cases, and a total of 107 patients (87%) responded effectively. As shown in Table 4, AHC cases had a higher ratio of history of surgery in recent 6 months (11.3% vs. 3.9%, p Z 0.037) and frequent (three or more times per month) medical injection therapy (38.3% vs. 21.6%, p Z 0.036) compared to chronic hepatitis C controls. The history of blood transfusion, frequent dental procedure, IDU, sex exposure, acupuncture, tattoo and needle injury were not significantly different between these two groups.

Natural course None of the subjects in this study died during AHC course. Ninety-seven of the 123 AHC patients had been followed beyond 6 months after the onset of AHC. After excluding three cases receiving antiviral therapy immediately (<3 months), self-limited AHC were observed in 18/94 (19.1%, 95% confidence interval (CI): 12.3e25.9%) patients. As shown in Table 5, patients with self-limited AHC and those who developed chronic hepatitis did not significantly differ with regard to age, sex, underlying hepatitis B infection, HCV genotype and peak ALT level. However, self-limited AHC patients had a significantly higher bilirubin level (2 vs. <2, p Z 0.007) compared to those who evolved to chronic infection.

Response to antiviral therapy In this cohort, 19 (15.4%) received IFN-based antiviral therapies, which were given during the acute episode (<3 months) in 3 patients. Therapy was initiated after a median of observation period of 8 months (range: 0e39 months) after the onset of AHC. The median of treatment period was 24 weeks (range: 8e48 weeks). Patients were treated with IFN-a therapy (3e5 million units subcutaneously thrice weekly) in combination with ribavirin (n Z 12) and pegylated-IFN in combination with ribavirin (n Z 7). Three patients receiving early treatment and 13 of the 16 patients with delayed treatment achieved an SVR.

35

AHC Cases

25

22

22

20 15

15

15

2003

2004

15 10 5 1999

2000

2001

2002

(year)

Figure 2

Variables

AHC (n Z 107) CHC (n Z 107) p-Value

Age 52.6  12.8 Gender (M/F) 49/58 Blood transfusion 4/104 (4%) Surgery 12/106 (11%) Injection therapy 70/98 (71%) Frequent injection 28/73 (38%) therapya Dental procedure 40/91 (44%) 9/68 (13%) Frequent dental procedurea Injecting drug 3/103 (3%) users Possible sex 6/106 (6%) exposure Acupuncture 8/105 (8%) Tattoo or pierce 0/106 (0%) Needle injury 1/107 (1%)

52.6  12.7 49/58 0/104 (0%) 4/103 (4%) 50/81 (62%) 11/51 (22%)

0.061 0.037 0.112 0.036

38/88 (43%) 7/68 (10%)

0.519 0.395

1/102 (1%)

0.314

4/107 (4%)

0.368

3/102 (3%) 1/107 (1%) 0/107 (0%)

0.116 0.502 0.500

Risk factors assessed during episode of AHC (<6 months) or recent half a year in CHC cases. a Frequent therapy: episode 3 times per month.

Discussion As compared with hepatitis A and B which are both easily diagnosed and can be preventable, AHC lacks a reliable serologic tag and cannot be prevented by vaccination. The diagnosis of AHC relies on the documented seroconversion to anti-HCV; however, it is infrequently encountered because of the detection of seroconversion at an earlier stage by second or third generation anti-HCV enzyme immunoassays.12e14 Previous study has shown that detection of HCV-RNA by a sensitive test without anti-HCV is strongly indicative of AHC.10 In clinical practice this sequence of events is quite rare, unless patients at risk are prospectively followed. We previously demonstrated that a low S/CO ratio <40 with a subsequent rising titer might be used as a supplemental diagnostic criterion for AHC in

Table 5 Characteristics in self-limited and chronic course of acute hepatitis C

34

30

0

Table 4 Questionnaire of risk factor assessment for hepatitis C in acute hepatitis C cases and age-, sex- matched chronic hepatitis C controls

Secular trend of AHC occurrence.

Variables

Chronic (n Z 76)

Self-limited (n Z 18)

p-Value

Age Gender (M/F) HBsAg(þ/) Genotype (1/non-1) Peak ALT (U/L) <400 vs. 400 Peak T-bil (mg/dl) <2 vs. 2

47.3  14.4 41/35 8/63 33/29 990  662 15/61 6.4  6.2 26/45

49.6  14.0 9/9 2/14 12/3 1222  713 1/17 8.0  5.8 1/17

0.507 0.483 0.587 0.052 0.208 0.135 0.125 0.007

Ninety-seven of the 123 AHC patients had been followed beyond 6 months after the onset of AHC. Three cases receiving antiviral therapy immediately (<3 months) were also excluded for analysis.

Acute hepatitis C patients without documented seroconversion.14 In this study, we extended this methodology to screen the computerized laboratory databases of anti-HCV and ALT in our hospital to find more candidates for AHC in southern Taiwan. Based on this supplemental criterion, we successfully collected 90 AHC patients who did not meet the traditional criteria of AHC. This study design might find more AHC patients to avoid a statistical insignificance due to the small number in disclosing the epidemiology and clinical course of AHC. Our present data clarifying the characteristics of 123 AHC patients in southern Taiwan represents one of the largest single-center cohort studies to date. The low S/CO ratios may represent the early phase of AHC infection, the late phase of viral clearance, or the true false-positive results.30e35 Nevertheless, presence of HCVRNA may distinguish the former from the other two conditions. Furthermore, recombinant immunoblot assay (RIBA) is a useful tool to differentiate the late phase of viral clearance from a false-positive result by detecting the C22 antibody, which is regarded as the most durable antibody in spontaneous recovery from AHC or after successful antiviral treatment.32,33 Additionally, reduced S/CO ratios might be associated with immunodeficiency status such as human immunodeficiency virus infection or organ transplant requiring immunosuppression.34 Moreover, AHC patients with persistent low HCV titer might have a self-limited course, in which the following HCV-RNA should have negative seroconversion significantly different from that in immunodeficiency status. Several HCV hyperendemic areas with an anti-HCV prevalence of up to 58% have been found in southern Taiwan, where medical injections were found previously to be the main mode of spreading HCV infection.26e28 Our data showed that AHC cases had a higher ratio of recent history of surgery and frequent medical injection therapy compared to chronic hepatitis C controls, suggesting that iatrogenic medical procedures with contaminated insults were still the main mode to sustain the persistent endemic state of HCV infection in southern Taiwan, where medical resources were still insufficient in some rural areas and habitual medical injection therapy was found in low socioeconomic strata.26e28 The likely mode of transmission is through inadequately sterilized medical equipment including needles and syringes. By contrast, IDU, tattooing and skin penetration such as body piercing and acupuncture reported as transmission risks have a minor role in our study population. The median age of our AHC patients was 48 years, which was higher than that in a recent study showing that young adults with IDU were the predominant community-acquired AHC patients in a Western country.24 Accordingly, appropriate education targeted at risk reduction should be performed sufficiently in our high-risk group consisting of middle-aged persons who a had history of habitual medical injection therapy. However, the incidence of reported AHC has gradually decreased over time, indicating that public health education has been improving. Some factors potentially associated with recovery from AHC infection have been reported, such as female gender, symptomatic disease, HCV genotype, and the host immune response.3,7,9,24,36,37 Recently, a meta-analysis that included nine studies of post-transfusion hepatitis, 19 of acute clinical hepatitis, and three of seroincident cases

279 showed that the proportion with spontaneous viral clearance following AHC infection ranged from 0.0 to 0.8, with a weighted mean of 0.26 (95% CI: 0.22e0.29).9 In our cohort, self-limited AHC was observed in less than 20% of 94 patients who had been followed beyond 6 months after the onset of AHC. These data were much lower than those in a recent study from a Western country that showed 52% of community-acquired AHC patients having spontaneous recovery.24 The patients with self-limited AHC and those evolving to chronic hepatitis C did not differ with regard to age, sex, underlying hepatitis B infection, HCV genotype and peak ALT level. However, self-limited AHC patients had a significantly higher bilirubin level (2 vs. <2, p Z 0.007) compared to those who evolved to chronic infection, suggesting that severity of AHC appeared to influence spontaneous resolution. Previous studies have demonstrated that early antiviral treatment of AHC is much more effective than treatment of chronic hepatitis C infection.15,16 Jaeckel and co-workers published their uncontrolled cohort study reporting an outstanding SVR rate of 98% in patients with AHC.15 In our study, the SVR rate was particularly high (100%) in patients receiving immediate antiviral therapy during the acute episode (<3 months). Although our case number is too small to reach a firm conclusion, it is worth further study as to whether early treatment (<3 months) in AHC reduces evolution to chronic infection in a meta-analysis. In a recent randomized controlled trial, short-term IFN therapy leads to an SVR rate significantly higher in the early-intervention group than in the late-intervention group.16 Further studies are necessary to define the optimal timing of start of treatment, the duration of treatment, and the dose of antiviral drugs. In conclusion, a large-scale screening of the computerized laboratory database of anti-HCV and ALT might help us find more candidates for AHC. In view of the high percentage of developing chronic disease in our study cohort, early intervention with antiviral therapy should be considered for AHC infection in southern Taiwan.

Acknowledgements This study was supported by National Science Council (Republic of China, Taiwan), grant number: NSC93-2314B182-048 to SN Lu. We have nothing to disclose and have no financial relationship with commercial entities.

Supplementary data Supplementary data associated with this article can be found, in the online version, at doi: 10.1016/j.jinf.2008. 01.049.

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