Skip Navigation

Improving the Diagnosis of Acute Hepatitis C Virus Infection with Expanded Viral Load Criteria

  1. Barbara H. McGovern1,2,
  2. Christopher E. Birch1,5,6,
  3. Melinda J. Bowen6,7,
  4. Laura L. Reyor3,6,
  5. Ellen H. Nagami1,5,6,
  6. Raymond T. Chung3,4, and
  7. Arthur Y. Kim4,5,6
  1. 1Lemuel Shattuck Hospital, Jamaica Plain
  2. 2Tufts Medical School, Boston
  3. 3Gastrointestinal Unit, Massachusetts General Hospital, Boston
  4. 4Harvard Medical School, Boston
  5. 5Harvard University Center for AIDS Research, Boston
  6. 6Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University (formerly known as Partners AIDS Research Center), Charlestown
  7. 7University of Massachusetts Medical School, Worcester, Massachusetts
  1. Reprints or correspondence: Dr. Barbara McGovern, Lemuel Shattuck Hospital, Div of Infectious Diseases, 170 Morton St, Jamaica Plain, MA 02130 (bmcgovern{at}tuftsmedicalcenter.org).
 
Next Section

Abstract

Background.The diagnosis of acute hepatitis C virus (HCV) infection is imprecise because antibody testing does not differentiate between acute and chronic infection. Although virologic features, such as viral load fluctuations and low levels of viremia, have been noted to be characteristic of acute HCV infection, these parameters have not been used for diagnosis.

Methods.We validated the use of these novel parameters (ie, viral load fluctuations >1 log and HCV RNA levels <100,000 IU/mL) in a cohort of acute HCV seroconverters. We then applied standard diagnostic criteria for acute HCV infection in a cohort of high-risk injection drug users entering prison with suspected acute HCV infection (n=37). We subsequently assessed whether these novel virologic parameters, measured serially over a 10-week period, could enhance the diagnosis of acute infection.

Results.Low-level viremia and viral load fluctuations were highly prevalent in our cohort of acute seroconverters (81% and 86%, respectively), whereas low-level viremia occurred in only 13% of control patients with chronic infection. With use of standard criteria, 37 inmates received a diagnosis of acute HCV infection. Among the 35 patients with HCV RNA detectable at baseline, we found low-level viremia to be highly prevalent (n=27; 77%); among patients with a minimum of 2 HCV RNA samples, we demonstrated viral fluctuations in more than one-third (n=9; 36%).

Conclusions.The diagnosis of acute infection in HCV-seropositive patients is strengthened by the use of virologic parameters that are uncommon in chronic disease. Viral load fluctuations and low levels of HCV RNA should be incorporated into standard diagnostic criteria.

The diagnosis of acute hepatitis C virus (HCV) infection is problematic because antibody testing does not differentiate between acute and chronic infection and seroconversion is often not documented [1, 2]. Physicians have traditionally made clinical judgements on the basis of the presence of symptoms, viremia, abnormal aminotransferase levels, and a history of prior seronegativity [3]. Accurate identification of acutely infected individuals is important, because early antiviral therapy can lead to higher sustained virologic response rates [4-6].

Many persons who are newly infected with HCV are asymptomatic and do not present for medical evaluation [7]. The diagnosis of HCV infection includes arbitrary thresholds for defining severe hepatitis; yet patients may be identified either early or late in the course of their acute infection when aminotransferase levels may be minimally abnormal [8]. In this clinical scenario, the diagnosis can be missed or mistaken for chronic infection. Conversely, aminotransferase levels may be markedly increased because of a variety of other causes, including alcohol abuse, drug toxicity, or cocaine intoxication [9-11]; in any of these scenarios, a patient with chronic HCV infection and elevated aminotransferase levels may be misclassified with newly acquired infection. Thus, symptoms, signs, and laboratory testing all have their inherent limitations in clinical practice.

Some individuals are diagnosed because of their history of risk. This is particularly true of health care workers who report a precisely defined exposure with subsequent confirmation of seroconversion [12]. Although they account for a small portion of acute infections, health care workers are often well-represented in studies of acute HCV infection because of their prospective identification [4]. Injection drug users often acquire HCV infection within 6–12 months of initiation of sharing drug paraphernalia [13, 14] but rarely seek medical attention [4, 5, 15, 16]. They are also unlikely to have documentation of prior serologic testing because of a lack of health care-seeking behaviors and fragmented care [17, 18]. Since the median time from initial viremia to seroconversion is ∼1 month [3], the majority of patients are already seropositive during the early stages of infection.

Without knowledge of prior serologic testing, differentiating acute from chronic infection in injection drug users is difficult; therefore, other distinguishing features are needed to improve diagnostic accuracy. Chronically infected patients have stable HCV RNA levels that vary by ∼0.5 log [19–22]. An individual's viral set point is maintained over time in the absence of other modifying factors (eg, concomitant human immunodeficiency virus (HIV) infection) [23]. In contrast, in acute HCV infection, viral-host interactions lead to marked variations in viremia until the ultimate clinical outcome (ie, spontaneous clearance or viral persistence) is established [24–26].

Another helpful diagnostic parameter is the magnitude of the HCV RNA levels. In a study of 2472 chronically infected patients, only 8.9% had a viral load <5.0 log 10 IU/mL [27]. Another retrospective study of 1550 patients with chronic infection demonstrated that only 13% had a viral load <400,000 IU/mL [28]. In contrast, studies of acute HCV infection have demonstrated that many patients have low levels of viremia, which may reflect either viral decline immediately prior to spontaneous clearance or transient immunologic control [16, 25, 29-35].

Although viral load fluctuations and low-level viremia have been noted in multiple reports of acute HCV infection, these parameters have never been applied as part of a diagnostic approach. In this report, we provide data on 37 individuals with recent onset of injection drug use who were diagnosed with acute/early HCV infection shortly after being incarcerated; we use criteria endorsed by the Centers for Disease Control and Prevention (CDC). We demonstrate that viral load fluctuations of >1 log and/or low levels of viremia (<105IU/mL) were highly prevalent in these patients. We also show that these virologic parameters were highly prevalent in a cohort of patients with documented seroconversion; in contrast, low-level viremia was distinctly uncommon in our control patients who had chronic HCV infection. We propose that the diagnosis of acute HCV infection can be well determined by initial risk ascertainment followed by observation of serial changes in viral load. These parameters are particularly helpful in assessing patients without prior serologic testing.

Previous SectionNext Section

Methods

Patient population. In our prison-based pilot study, we identified 21 recently incarcerated inmates with acute HCV infection during a 30-month period with use of referrals for symptoms of hepatitis and/or elevated aminotransferase levels [36]. We demonstrated that serial monitoring of HCV RNA levels at baseline, 4 weeks, and 10 weeks differentiated patients who developed persistent viremia from those who attained spontaneous resolution.

Our subsequent study (the basis of this report) was designed to identify acute HCV infection cases on the basis of high-risk behaviors through systematic screening of 3248 newly incarcerated inmates from October 2006 through December 2007. Questionnaires were administered by health care providers on intake into the correctional system; questionnaires screened for a history of HCV testing and new-onset injection drug use or sharing of drug paraphernalia within 12 months before incarceration. Fifty-four high-risk patients without a self-reported history of HCV infection were screened serologically and invited to enroll in an observational study.

The duration of infection was calculated using the number of months between estimated inoculation and enrollment. Laboratory tests included measurement of HCV RNA (Versant HCV RNA v3.0 assay bDNA; Bayer Diagnostics) and aminotransferase levels and analysis of hepatitis A and B serologies. Regardless of whether aminotransferase levels were abnormal, patients underwent screening for HCV RNA and aminotransferase levels at baseline, 4 weeks, and 10 weeks, depending on risk. Those with confirmed hepatitis were seen at the subspecialty clinic for medical evaluation.

Diagnostic criteria. We adopted 2 approaches to the diagnosis of acute hepatitis C. Most studies of acute HCV infection have required prior negative HCV antibody serologic test results within 6 months before presentation, detectable HCV RNA, and abnormal aminotransferase levels, ranging from 2–20 times the upper limit of normal (ULN) [37]. For our standard approach, we used an alanine aminotransferase (ALT) level >7× the ULN as our diagnostic threshold, as recommended by the CDC [38]. Patients with recent onset of high-risk behaviors were categorized in terms of probability of acute HCV infection as follows: (1) seronegative patients with HCV RNA detectable at baseline and subsequent seroconversion had “definite” acute HCV infection; (2) HCV-seropositive patients with a documented seronegative status within 6 months and an ALT level >7× the ULN also had “definite” acute HCV infection; (3) those without documentation of prior testing within 6 months who were HCV seropositive with detectable HCV RNA and an ALT level >7× the ULN had “probable” infection; and (4) those without documentation of prior testing within 6 months who were HCV-seropositive with detectable HCV RNA and an ALT level <7× the ULN had “possible” infection.

For our novel diagnostic approach, we determined whether serial monitoring of HCV RNA could better define the probability of acute infection in patients who did not have documentation of prior serologic testing. In this dynamic model, patients with recent onset of high-risk behaviors were categorized in terms of probability of acute HCV infection as follows: (1) patients who had spontaneous clearance were classified as having “definite” acute HCV infection; (2) patients with HCV RNA fluctuations >1 log were defined as having “high probability” acute HCV infection; (3) patients with HCV RNA fluctuations <1 log were classified as having “moderate” or “low probability” acute HCV infection, depending on whether their peak ALT level was greater or less than 7× the ULN; (4) patients with any single measurement of HCV RNA level <105IU/mL were defined as having a “high probability” of acute infection.

HCV RNA levels in patients with chronic infection. We conducted retrospective chart reviews of incarcerated patients who were evaluated for chronic HCV infection during this same study period to determine the viral set point in a parallel cohort. The same HCV testing methodology used in the acutely infected patients was applied. Exclusion criteria included HIV infection.

Virologic parameters in “definite” acute HCV cohort. We retrospectively assessed the prevalence of low-level viremia and viral load fluctuations within a separate cohort of community/incarcerated patients with a diagnosis “definite” acute HCV infection who presented to Lemuel Shattuck Hospital or Massachusetts General Hospital, partially reported in Table 1and elsewhere [31, 36].

Ethical issues. All study subjects provided written informed consent. Consent was waived for the deidentified chart review of viral loads from chronically infected individuals. These protocols conform to the 1975 Helsinki guidelines for the conduct of human research and were approved by each hospital's institutional review board. The Lemuel Shattuck Hospital Institutional Review Board includes a prisoner advocate. Patient consent forms included contact information for a second prisoner advocate (not involved in this research) to address any concerns of the participants.

Statistical analysis. Comparison of binary features between groups was performed with 2-tailed χ2testing or Fisher's exact test. Comparison of continuous variables between groups was performed with a Mann-Whitney test or a Student's t test. For comparison of viral loads between chronically and acutely infected individuals, mean values were compared, because >1 measurement was available from certain individuals during the study. The sensitivity, specificity, and likelihood ratio of proposed diagnostic criteria was calculated with nonparametric methods. Figures were generated and analyses were performed using GraphPad Prism-4 (GraphPad Software).

Previous SectionNext Section

Results

Identification of acute HCV infection during intake into the correctional system. Among the 3248 inmates who were screened shortly after incarceration, 54 were determined to be “high risk”; 37 patients received a diagnosis of acute HCV infection. All patients were HIV seronegative. Sixteen patients had symptoms of hepatitis (43%), including right upper quadrant pain (n = 13), fatigue (n = 12), nausea (n = 8), vomiting (n = 4), and jaundice (n = 2). Other causes of acute hepatitis, including hepatitis A and B viruses, were ruled out; alcohol- or cocaine-related hepatitis were unlikely because of the extended period between incarceration and study enrollment (mean duration, 42 days; interquartile range [IQR], 21–51 days). Three patients reported a history of heavy alcohol use prior to incarceration.

All study patients had evidence of HCV antibodies at enrollment and reported injection drug use as a risk factor. The majority of patients (73%) had never undergone prior serologic testing. Of the patients with self-reported previous testing, only 3 could be confirmed (patients 8–10). These 3 were the only study participants who were classified as having “definite” acute HCV infection on the basis of standard definitions (see the Methods section). Two of these 3 patients had significant aminotransferase level abnormalities but no detectable HCV RNA at presentation, consistent with a recent resolution of viremia. Nineteen other patients were classified as having “probable” and 15 others as having “possible” cases of acute HCV infection on the basis of CDC guidelines.

Magnitude of viremia and viral load fluctuations in acute/chronic HCV infection. We subsequently determined whether virologic parameters, such as low-level viremia and/or viral load fluctuations may be prevalent among patients with acute infection. We first tested this concept by retrospectively determining the prevalence of these virologic parameters in a separate cohort of 21 individuals with “definite” acute HCV infection (10 of 21 reported elsewhere [31]). All HCV-seropositive subjects had either documented seroconversion within 6 months of antibody testing or had achieved spontaneous clearance of viremia; all were HIV seronegative. Within this well-defined cohort, low-level viremia <105IU/mL was present in 17 (81%) of 21 patients and viral load fluctuations were noted in 18 (86%) of 21 (Table 1).

Next, we prospectively determined the prevalence of these virologic parameters in the 35 HCV RNA-seropositive incarcerated patients who did not have documented serologic testing within 6 months before presentation. Consistent with the findings from the acute seroconverter cohort, these virologic parameters were also common in our incarcerated cohort. Specifically, 27 case patients (77%) had documentation of at least 1 HCV RNA measurement <105IU/mL (mean, 17,581 IU/mL; range, 682–86,315 IU/mL) (Table 2). In contrast, only 13% of 623 control patients with chronic HCV infection had an HCV RNA level <105IU/mL (Figure 1). Using this cut off, a detectable HCV viral load with a value <105IU/mL showed a sensitivity of 60% and a specificity of 87% for detection of acute/early HCV infection, with a likelihood ratio of 4.7 (receiver operating characteristic area under the curve, 0.84). Furthermore, of the 25 patients who underwent serial HCV RNA level testing, the prevalence of viral load fluctuations >1 log was 36% (Table 2and Figure 2). The latter was found to be less frequent in the incarcerated cohort, compared with the acute HCV seroconverter group (P=.002, by χ2test) (Table 3). Whether this may be related to the timing of their diagnosis relative to their onset of infection is unclear. Patients in the incarcerated cohort presented later in the course of infection (median, 5.0 months; IQR, 2–7 months), compared with those with documented seroconversion, for whom the median estimated duration of infection was only 3.0 months (IQR, 1–5 months) (Table 3). Incarcerated patients also had a lower rate of symptomatic disease, which may have resulted from our systematic risk-based approach (43% vs 86%; P < .05).

Figure 1
View larger version:
Figure 1

The distribution of hepatitis C virus (HCV) RNA levels, representing 698 values from 623 chronically infected individuals (black bars ) and 97 values from 35 individuals with suspected acute infection (gray bars ). Each bar represents a range of 0.25 log 10 IU/mL; values along the x axis are the upper end of each range. Seventy-seven percent of the incarcerated cohort had documentation of at least 1 HCV RNA level measurement <105IU/mL (mean, 17,581 IU/mL; range, 682–86,315 IU/mL). In contrast, only 13% of the control group, tested during the same time period with identical methodology, had an HCV RNA level <105IU/mL.

Figure 2
View larger version:
Figure 2

Serial hepatitis C virus (HCV) RNA (black circles ) and alanine aminotransferase (ALT) (black squares ) levels in 6 representative individuals with acute hepatitis C infection. The horizontal dotted line represents the cut off for low viral load, defined as 105log 10 IU/mL.

With use of the criterion of low-level viremia, 22 (63%) of 35 patients had an HCV RNA level <105IU/mL on their initial screening. The utility of serial monitoring as a guide to diagnosis was most apparent in 3 patients, 1 with “probable” and 2 with “possible” acute HCV infection according to CDC criteria (patients 1, 5, and 13), who presented with normal aminotransferase levels at baseline. Two of these patients had low levels of viremia (<105IU/mL) with subsequent virologic clearance; 1 was lost to follow-up (Figure 3).

We also carefully examined the subset of patients with persistent viremia who did not meet the CDC guidelines for ALT abnormality (eg, ALT level <7× the ULN). Of these 11 patients, the median HCV RNA level was 44,025 IU/mL (range, 682-810,000 IU/mL; 9 patients had evidence of HCV RNA levels <105IU/mL). One of these patients also had evidence of viral load fluctuations of 1.6 log.

In summary, with serial monitoring, we were able to reclassify the vast majority of the patients with “possible” or “probable” acute HCV infection as having “definite” (n = 8), “high probability” (n=20), “moderate probability” (n = 5), and “low probability” (n = 2) acute HCV infection with use of these novel virologic parameters (Table 2). The veracity of these findings is reflected by the high sustained virologic response rates achieved in those who accepted therapy [39].

Figure 3
View larger version:
Figure 3

Serial alanine aminotransferase (ALT) (black squares ) and hepatitis C virus (HCV) RNA (black circles ) levels in 3 individuals with normal aminotransferase levels at baseline. Follow-up testing documented marked increases of aminotransferase levels and the presence of viremia. The panels for patients 1 and 5 are representative of the clinical courses of patients who achieved spontaneous clearance of viremia. Patient 13 was lost to follow-up before the clinical outcome could be determined.

Figure 4
View larger version:
Figure 4

A dynamic algorithm for the diagnosis of acute hepatitis C virus (HCV) infection based on risk factors, serial monitoring of alanine aminotransferase (ALT) levels, and HCV RNA parameters. ULN, upper limit of normal.

Table 1
View larger version:
Table 1

Diagnostic Parameters of the Acute Hepatitis C Virus (HCV) Seroconverter Cohort

Table 2
View larger version:
Table 2

Diagnostic Parameters of the Incarcerated Acute Hepatitis C Virus (HCV) Infection Cohort

Table 3
View larger version:
Table 3

Summary of Demographic and Virologic Characteristics of Patients with Acute Hepatitis C Virus (HCV) Infection

Previous SectionNext Section

Discussion

We have adopted a novel approach to the diagnosis of acute HCV infection that exploits 2 virologic parameters that are distinctly uncommon among patients with longstanding disease. Several studies involving chronically infected patients have demonstrated that HCV RNA levels are relatively stable over long periods of follow-up, varying by <0.5 log in the majority of infected persons [19-22]. In contrast, studies of acute HCV pathogenesis have highlighted marked virologic fluctuations in early infection [24, 25, 26], which were observed in over one-third of our patients. Interestingly, we observed that subjects identified in the seroconverter cohort were more likely to demonstrate viral load fluctuations than were their prison counterparts, possibly because of their earlier identification during their infection. Variations in viral load are likely related to immunologic control exerted by T cells in early virus-host interactions [8, 40].

Second, we demonstrate that low levels of viremia were also frequently observed in our study participants; in contrast, low HCV RNA levels were seen in a minority of our controls with chronic infection, consistent with other reports [27]. Low levels of HCV RNA may reflect transient immunologic control, early ramp-up of viremia, or viral decline preceding spontaneous clearance, depending on when the patient is evaluated during their disease course. Over time, studies have shown that HCV RNA levels will tend to remain stable or increase as infected individuals enter the chronic phase of infection [21].

Although low levels of HCV RNA and viral load fluctuations have been demonstrated in multiple reports of patients with acute HCV infection, these laboratory parameters have not been integrated into diagnostic criteria [16, 25, 29-31]. In our well-defined cohort of “definite” seroconverters, we have demonstrated the validity of applying these virologic parameters as supportive laboratory criteria. We propose that standard diagnostic criteria for acute HCV infection should be expanded to include these virologic parameters, which perform at least as well as ALT level increases and may be even more specific. We view the diagnosis of acute HCV infection as a dynamic process, best determined by serial monitoring of HCV RNA levels over a 10–12-week period. This approach was particularly useful in patients without prior HCV antibody testing. A threshold of ALT level >7× the ULN as major criteria for the diagnosis of acute HCV infection would have missed 15 patients in the prison cohort (including 4 who spontaneously cleared infection), which demonstrates the insensitivity of this criterion. In contrast, of patients with persistent viremia and ALT levels <7× the ULN, the majority exhibited either viral load fluctuations or low levels of viremia.

The vast majority of injection drug users with suspected acute hepatitis C can be classified with a high level of confidence on the basis of this straightforward approach, which incorporates ascertainment of risk and serial laboratory monitoring (Figure 4). Thirteen of 15 patients with “possible” acute HCV infection on presentation were reclassified as having “definite” or “high probability” acute infection on the basis of either virologic clearance, viral load fluctuations >1 log, or low levels of viremia (<105IU/mL). The validity of this approach is supported by 3 lines of evidence: (1) the high prevalence of these virologic parameters in our cohort of documented seroconverters and in other published studies; (2) the low prevalence of these parameters in other studies of chronically infected individuals and in our control group of chronically HCV-infected patients; and (3) preliminary data demonstrating high sustained virologic response in the inmates who have completed HCV therapy for persistent viremia [39]. The application of these proposed criteria would have the greatest impact on patients with persistent viremia, who should be promptly referred for treatment. These criteria may also help improve acute HCV infection surveillance programs on a local or national level.

We propose the creation of an expanded diagnostic scoring system, using weighted points for the various factors that we have considered in our model. This classification system would be based on virologic outcomes, changes in viremia (HCV RNA fluctuations of greater than or less than 1 log), levels of viremia (greater than or less than 105IU/mL), and aminotransferase level testing. This system would particularly enhance the diagnosis of HCV-seropositive patients without prior testing and would facilitate timely therapeutic interventions. However, this approach needs to be validated in larger cohorts.

Our data are limited by a lag in initial laboratory testing in some participants, such that their initial viremia was not captured because of spontaneous clearance prior to testing. Furthermore, we may have overestimated the proportion of patients who spontaneously cleared infection, because of the lower limits of HCV RNA detection associated with our assays (Versant lower limit of detection, <615 IU/mL; Amplicor [Roche] lower limit of detection, <600 IU/mL). In addition, we suspect that our case finding was not optimal because of a lack of universal screening of inmates entering the 2 intake sites. Despite this limitation, we identified 37 patients with acute hepatitis C infection within 15 months of screening through risk assessment.

In conclusion, in injection drug users with recent onset of risk-taking behaviors, we suggest serial HCV RNA monitoring to assess viral load fluctuations and level of viremia as useful parameters in the diagnosis of acute HCV infection. This approach is particularly helpful in those patients who do not have baseline HCV antibody testing, which is common among injection drug users.

Previous SectionNext Section

Acknowledgments

We thank the individuals who consented to take part in this study. We acknowledge Warren Ferguson and Arthur Brewer of the University of Massachusetts Correctional Health and the providers at MCI-Framingham and MCI-Concord for their support.

Financial support. National Institutes of Health and National Institute of Allergy and Infectious Diseases (Hepatitis C Cooperative Center U19 AI066345; K23 AI054379 to A.Y.K.; Harvard University Center for AIDS Research P30 AI060354).

Potential conflicts of interest. B.H.M. is on the speaker's bureau of Roche Pharmaceuticals and on the advisory boards of Merck and Vertex Pharmaceuticals. R.T.C. receives research grant support from Roche Labs and Schering-Plough. All other authors: no conflicts

  • Received February 24, 2009.
  • Accepted May 16, 2009.
Previous Section
 

References

  1. ↵
    1. Alberti A,
    2. Boccato S,
    3. Vario A,
    4. Benvegnu L
    . Therapy of acute hepatitis C. Hepatology 2002;36:195-200.
    CrossRefMedlineWeb of Science
  2. ↵
    1. Strader DB,
    2. Wright TL,
    3. Thomas DL,
    4. Seeff LB
    . Diagnosis, management, and treatment of hepatitis C. Hepatology 2004;39:1147-71.
    CrossRefMedlineWeb of Science
  3. ↵
    1. Orland JR,
    2. Wright TL,
    3. Cooper S
    . Acute hepatitis C. Hepatology 2001;33:321-7.
    CrossRefMedlineWeb of Science
  4. ↵
    1. Jaeckel E,
    2. Cornberg M,
    3. Wedemeyer H,
    4. et al
    . Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001;345:1452-7.
    CrossRefMedlineWeb of Science
  5. ↵
    1. Gerlach JT,
    2. Diepolder HM,
    3. Zachoval R,
    4. et al
    . Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003;125:80-8.
    CrossRefMedlineWeb of Science
  6. ↵
    1. Wiegand J,
    2. Buggisch P,
    3. Boecher W,
    4. et al
    . Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology 2006;43:250-6.
    CrossRefMedlineWeb of Science
  7. ↵
    1. Chung RT
    . Acute hepatitis C virus infection. Clin Infect Dis 2005;41(Suppl1):14-7.
    CrossRef
  8. ↵
    1. Rehermann B,
    2. Nascimbeni M
    . Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215-29.
    CrossRefMedlineWeb of Science
  9. ↵
    1. Sorbi D,
    2. Boynton J,
    3. Lindor KD
    . The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999;94:1018-22.
    CrossRefMedlineWeb of Science
    1. Kaplowitz N
    . Drug-induced liver injury. Clin Infect Dis 2004;38(Suppl 2):44-8.
    CrossRef
  11. ↵
    1. Zimmerman HJ,
    2. West M
    . Serum enzyme levels in the diagnosis of hepatic disease. Am J Gastroenterol 1963;40:387.
    MedlineWeb of Science
  12. ↵
    1. Kamal S,
    2. Moustafa KN,
    3. Chen J,
    4. et al
    . Duration of peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology 2006;43:923-31.
    CrossRefMedlineWeb of Science
  13. ↵
    National Institutes of Health. Management of Hepatitis C. Washington, DC: National Institutes of Health; 2002. Consensus Development Conference Statement.
  14. ↵
    1. Hahn JA,
    2. Page-Shafer K,
    3. Lum PJ,
    4. et al
    . Hepatitis C virus seroconversion among young injection drug users: relationships and risks. J Infect Dis 2002;186:1558-64.
    Abstract/FREE Full Text
  15. ↵
    1. Santantonio T,
    2. Sinisi E,
    3. Guastadisegni A,
    4. et al
    . Natural course of acute hepatitis C: a long-term prospective study. Dig Liver Dis 2003;35:104-13.
    CrossRefMedlineWeb of Science
  16. ↵
    1. Hofer H,
    2. Watkins-Riedel T,
    3. Janata O,
    4. et al
    . Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. Hepatology 2003;37:60-4.
    CrossRefMedlineWeb of Science
  17. ↵
    1. Hagan H,
    2. Campbell J,
    3. Thiede H,
    4. et al
    . Self-reported hepatitis C virus antibody status and risk behavior in young injectors. Public Health Rep 2006;121:710-9.
    MedlineWeb of Science
  18. ↵
    1. Garfein RS,
    2. Golub ET,
    3. Greenberg AE,
    4. et al
    . A peer-education intervention to reduce injection risk behaviors for HIV and hepatitis C virus infection in young injection drug users. AIDS 2007;21:1923-32.
    CrossRefMedline
  19. ↵
    1. Nguyen TT,
    2. Sedghi-Vaziri A,
    3. Wilkes LB,
    4. et al
    . Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients with chronic HCV infection. J Viral Hepat 1996;3:75-8.
    MedlineWeb of Science
    1. Gordon SC,
    2. Dailey PJ,
    3. Silverman A,
    4. Khan BA,
    5. Kodali VP,
    6. Wilber JC
    . Sequential serum hepatitis C viral RNA levels longitudinally assessed by branched DNA signal amplification. Hepatology 1998;28:1702-6.
    CrossRefMedlineWeb of Science
  21. ↵
    1. Fanning L,
    2. Kenny-Walsh E,
    3. Levis J,
    4. et al
    . Natural fluctuations of hepatitis C viral load in a homogeneous patient population: a prospective study. Hepatology 2000;31:225-9.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Kuramoto IK,
    2. Moriya T,
    3. Schoening V,
    4. Holland PV
    . Fluctuation of serum HCV-RNA levels in untreated blood donors with chronic hepatitis C virus infection. J Viral Hepat 2002;9:36-42.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Daar ES,
    2. Lynn H,
    3. Donfield S,
    4. et al
    . Relation between HIV-1 and hepatitis C viral load in patients with hemophilia. J Acquir Immune Defic Syndr 2001;26:466-72.
    MedlineWeb of Science
  24. ↵
    1. Cox AL,
    2. Netski DM,
    3. Mosbruger T,
    4. et al
    . Prospective evaluation of community-acquired acute-phase hepatitis C virus infection. Clin Infect Dis 2005;40:959-61.
    FREE Full Text
  25. ↵
    1. Kaplan DE,
    2. Sugimoto K,
    3. Newton K,
    4. et al
    . Discordant role of CD4 T-cell response relative to neutralizing antibody and CD8 T-cell responses in acute hepatitis C. Gastroenterology 2007;132:654-66.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Mosley JW,
    2. Operskalski EA,
    3. Tobler LH,
    4. et al
    . The course of hepatitis C viraemia in transfusion recipients prior to availability of antiviral therapy. J Viral Hepat 2008;15:120-8.
    CrossRefMedlineWeb of Science
  27. ↵
    1. Ticehurst JR,
    2. Hamzeh FM,
    3. Thomas DL
    . Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis. J Clin Microbiol 2007;45:2426-33.
    Abstract/FREE Full Text
  28. ↵
    1. Rodriguez-Torres M,
    2. Sulkowski M,
    3. Chung RT,
    4. Hamzeh FM,
    5. Jensen DM
    . Association of pretreatment and on-treatment factors with rapid virologic response in HCV genotype 1-infected patients treated with peginterferon alfa-2a/ribavirin (abstract 1305). In: Program and abstaracts of the American Association for the Study of Liver Diseases (Boston). 2007.
  29. ↵
    1. Santantonio T,
    2. Fasano M,
    3. Sinisi E,
    4. et al
    . Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatol 2005;42:329-33.
    CrossRefMedlineWeb of Science
    1. Santantonio T,
    2. Medda E,
    3. Ferrari C,
    4. et al
    . Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy. Clin Infect Dis 2006;43:1154-9.
    Abstract/FREE Full Text
  31. ↵
    1. Corey KE,
    2. Ross AS,
    3. Wurcel A,
    4. et al
    . Outcomes and treatment of acute hepatitis C virus infection in a United States population. Clin Gastroenterol Hepatol 2006;4:1278-82.
    CrossRefMedlineWeb of Science
    1. Gerlach JT,
    2. Diepolder HM,
    3. Jung MC,
    4. Gruener NH,
    5. et al
    . e. Recurrence of hepatitis C virus after loss of virus-specific CD4+T-cell response in acute hepatitis C. Gastroenterology 1999;117:933-41.
    CrossRefMedlineWeb of Science
    1. Ulsenheimer A,
    2. Lucas M,
    3. Seth NP,
    4. et al
    . Transient immunological control during acute hepatitis C virus infection: ex vivo analysis of helper T-cell responses. J Viral Hepat 2006;13:708-14.
    CrossRefMedlineWeb of Science
    1. Villano S,
    2. Vlahov D,
    3. Nelson KE,
    4. Cohn S,
    5. Thomas DL
    . Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Hepatology 1999;29:908-14.
    CrossRefMedlineWeb of Science
  35. ↵
    1. De Rosa F,
    2. Bargiacchi O,
    3. Audagnotto S,
    4. et al
    . Twelve-week treatment of acute hepatitis C virus with pegylated interferon-alfa 2b in injection drug users. Clin Infect Dis 2007;45:583-8.
    Abstract/FREE Full Text
  36. ↵
    1. McGovern B,
    2. Wurcel A,
    3. Kim AY,
    4. et al
    . Acute hepatitis C virus infection in incarcerated injection drug users. Clin Infect Dis 2006;42:1663-70.
    FREE Full Text
  37. ↵
    1. Micallef JM,
    2. Kaldor JM,
    3. Dore GJ
    . Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat 2006;13:34-41.
    CrossRefMedlineWeb of Science
  38. ↵
    1. Wasley A,
    2. Miller JT,
    3. Finelli L
    . Surveillance for Acute Viral Hepatitis—United States, 2005. MMWR Surveill Summ 2007;56:1-24.
    Medline
  39. ↵
    1. McGovern BH,
    2. Nagami EH,
    3. Birch CE,
    4. et al
    . Rate of sustained virologic response in relation to baseline hepatitis C virus (HCV) RNA level and rapid virologic clearance in persons with acute HCV infection. J Infect Dis 2009;200:877-81.
    CrossRefMedlineWeb of Science
  40. ↵
    1. Bowen DG,
    2. Walker CM
    . Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 2005;436:946-52.
    CrossRefMedline
| Table of Contents

This Article

  1. Clin Infect Dis. (2009) 49 (7): 1051-1060. doi: 10.1086/605561
  1. AbstractFree
  2. » Full Text (HTML)Free
  3. Full Text (PDF)Free

Classifications

Share

  1. Email this article

Navigate This Article

Current Issue

  1. March 1, 2012 54 (5)
  1. Clinical Infectious Diseases
  1. Alert me to new issues

Most