Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Dec 24.
Published in final edited form as: J Med Virol. 2014 Jul 8;86(10):1722–1729. doi: 10.1002/jmv.24010

Dynamics of HCV RNA levels during acute hepatitis C virus infection

Behzad Hajarizadeh 1, Jason Grebely 1, Tanya Applegate 1, Gail V Matthews 1, Janaki Amin 1, Kathy Petoumenos 1, Margaret Hellard 2, William Rawlinson 3, Andrew Lloyd 3, John Kaldor 1, Gregory J Dore 1, on behalf of the ATAHC study group
PMCID: PMC4276420  NIHMSID: NIHMS649636  PMID: 25042465

Abstract

Understanding viral dynamics during acute hepatitis C virus (HCV) infection can provide important insights into immunopathogenesis and guide early treatment. The aim of this study was investigating the dynamics of HCV RNA and alanine transaminase (ALT) levels during recent HCV infection in the Australian Trial in Acute Hepatitis C (ATAHC). ATAHC was a prospective study of the natural history of recently acquired HCV infection. Longitudinal HCV RNA and ALT levels were compared among individuals with ultimately persistent infection and spontaneous clearance outcomes. Among those with HCV persistence (n=104) and HCV clearance (n=30), median HCV RNA (5.2 vs. 4.1 log IU/mL, respectively) and ALT levels (779 vs. 1765 IU/L, respectively) were high during month two following infection, and then declined during months three and four in both groups. Among those with HCV persistence, median HCV RNA was 2.9 log IU/mL during months four, increased to 5.5 log IU/mL during month five, and remained subsequently relatively stable. Among those with HCV clearance, median HCV RNA was undetectable by month five. Median HCV RNA levels were comparable between individuals with HCV persistence and HCV clearance during month three following infection (3.2 vs. 3.5 log IU/mL, respectively; P=0.935), but markedly different during month five (5.5 vs. 1.0 log IU/mL, respectively; P<0.001). In conclusion, dynamics of HCV RNA levels in those with HCV clearance and HCV persistence diverged between months three and five following infection, with the latter time-point being potentially useful for commencing early treatment.

Keywords: Chronic, Persistent infection, Spontaneous clearance, Viral load, alanine transaminase

INTRODUCTION

Acute hepatitis C virus (HCV) infection is characterized by the appearance of virus in the blood within 2–14 days of exposure, increases in the levels of liver-associated serum enzymes particularly alanine transaminase (ALT), and gradual appearance of HCV-specific antibodies (anti-HCV antibody) within 30–60 days of exposure (reviewed in [Grebely et al., 2011; Hajarizadeh et al., 2013]).

Acute HCV infection is followed by spontaneous clearance, defined by repeated undetectable HCV RNA in the blood, in around 25% of individuals [Grebely et al., 2014; Micallef et al., 2006]; the remaining 75% progress to chronic HCV infection with potential consequences of cirrhosis, liver failure and hepatocellular carcinoma.

Understanding the patterns of change (dynamics) in HCV RNA and ALT levels during progression from acute to chronic HCV infection can provide important insights into immunopathogenesis. It may also have clinical utility in predicting spontaneous HCV clearance and hence guide in better timing for early treatment.

The dynamics of HCV RNA levels in early acute HCV (i.e. from exposure to seroconversion) have been characterised as occurring in three phases: a pre-ramp-up phase with intermittent low-level HCV RNA (from exposure to initial quantifiable HCV RNA); a ramp-up phase with exponential increase in HCV RNA levels (8–10 days); and a high-titre viremic plateau phase (45–68 days) [Glynn et al., 2005]. However, further data are needed to improve understanding of HCV RNA dynamics during progression from acute to chronic HCV infection. In addition, several studies investigating HCV RNA dynamics in acute HCV have enrolled blood product recipients [Barrera et al., 1995; Farci et al., 2000], frequent blood donors [Glynn et al., 2005; Nübling et al., 2002], haemodialysis patients [Lavillette et al., 2005; Weseslindtner et al., 2009] or health care workers [Thimme et al., 2001] where the date of exposure can be determined. However, these studies are generally limited by small sample sizes and are not representative of the most common form of HCV acquisition in developed countries (i.e. people who inject drugs). Individuals acquiring HCV through injecting drug differ in age, underlying health status, and generally less precise estimation of time of exposure.

This study sought to assess the dynamics of HCV RNA and ALT levels in recent HCV infection, with a particular focus on the transitional period during progression from acute to chronic infection, among individuals predominantly infected through injecting drug use.

MATERIALS AND METHODS

Study design & participants

The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of the natural history and treatment of recently acquired HCV infection. The ATAHC study design has been described previously in detail [Dore et al., 2010]. Individuals diagnosed with recent HCV infection (defined below) were recruited from June 2004 through November 2007. Recent infection with either acute or early chronic HCV infection was defined by the following eligibility criteria:

First positive anti-HCV antibody within six months of enrolment; and either:

  1. Acute clinical hepatitis C infection, defined as symptomatic seroconversion illness or ALT level greater than 10 times the upper limit of normal (ULN, >400 IU/L) with exclusion of other causes of acute hepatitis, at most 12 months before the initial positive anti-HCV antibody; or

  2. Asymptomatic hepatitis C infection with seroconversion, defined by a negative anti-HCV antibody within the two years prior to the initial positive anti-HCV antibody.

Participants were followed from enrolment (screening) for up to 12 weeks (baseline) to allow for spontaneous clearance, and if HCV RNA remained detectable at the baseline visit, they were offered treatment. Participants unwilling to undergo treatment and those with undetectable HCV RNA at screening or baseline continued to be followed. Participants were followed up from baseline at 12 weekly intervals for up to 144 weeks.

In the current analysis, all longitudinal HCV RNA and ALT measurements for untreated individuals (n=52) were used to assess the dynamics of HCV RNA and ALT levels. Among treated individuals (n=111), those with an estimated duration of infection <26 weeks on treatment commencement (n=29) were excluded to reduce misclassification bias due to uncertainty around subsequent spontaneous clearance without treatment. Twenty-six weeks (six months) was chosen as the cut-off given it has been shown that the large majority of individuals will spontaneously clear infection during the first six months following infection [Page et al., 2009]. Individuals treated for HCV with an estimated duration of infection ≥26 weeks were included, but only HCV RNA and ALT data up to and including the date of treatment commencement (baseline) were included in the analysis. A total number of 134 individuals were included in analysis including 52 untreated and 82 treated individuals (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Overview of ATAHC study population

All study participants provided written informed consent. The study protocol was approved by St Vincent’s Hospital, Sydney Human Research Ethics Committee (primary study committee) as well as through local ethics committees at all study sites. The study was registered with clinicaltrials.gov registry (NCT00192569).

Study definitions

Estimated date of infection

For individuals with acute clinical infection, the estimated date of infection was calculated as six weeks prior to onset of the seroconversion illness if present, or six weeks prior to the first ALT reading above 400 IU/L. For asymptomatic infection the estimated date of infection was calculated as the mid-point between the last negative anti-HCV antibody and the first positive anti-HCV antibody test result. For individuals who were anti-HCV antibody negative and HCV RNA positive at screening, the estimated date of infection was designated to be six weeks prior to screening.

Spontaneous HCV clearance

Participants with at least two undetectable qualitative HCV RNA tests (<10 IU/mL) ≥4 weeks apart following HCV infection detection.

Detection and quantification of HCV RNA

HCV RNA assessments were performed at all scheduled study visits, initially with a qualitative HCV RNA assay (TMA assay, Versant, Bayer, Pymble NSW, Australia; lower limit of detection 10 IU/mL) and if detectable repeated on a quantitative assay (Versant HCV RNA 3.0 Bayer, Pymble NSW, Australia; lower limit of detection 615 IU/mL). HCV genotyping using a commercial assay (Versant LiPa2, Bayer, Pymble NSW, Australia) was performed on all individuals with detectable HCV RNA at screening. Additional HCV genotyping using sequencing methodologies were also performed on longitudinal samples as described previously [Pham et al., 2010]. Briefly, RNA was extracted from 140 μL of sera using the QIAmp Viral RNA extraction kit (Qiagen, Hilden, Germany). The E1/HVR1 region encoding the last 171 basepairs (bp) of Core, E1, and the HVR-1 of E2 (840 bp, nucleotides 744 to 1583, with reference to HCV strain H77, GenBank accession number AF009606) was amplified by a real-time nRT-PCR using reagents and reaction conditions as described [Pham et al., 2010].

Statistical analyses

To evaluate the dynamics of HCV RNA and ALT levels during acute HCV infection, longitudinal HCV RNA and ALT levels were indexed by time since the estimated date of infection for all individuals. Population-average curves describing HCV RNA and ALT dynamics were constructed using longitudinal HCV RNA and ALT measurements. The median HCV RNA levels (log IU/mL) and ALT levels (IU/L) among all individuals were calculated in monthly intervals since estimated date of infection. To calculate monthly medians of HCV RNA and ALT, all individual measurements recorded during each one month intervals were included. All analyses were performed using Stata version 12.0 (Stata, College Station, TX, USA) and graphs were generated using GraphPad Prism (GraphPad Software, La Jolla, CA, USA).

RESULTS

A total of 134 individuals with recent HCV infection were included in this study among whom 82 received HCV treatment and 52 were untreated (Figure 1). The background and baseline characteristics of included participants are summarized in Table 1.

Table 1.

Background characteristics of ATAHC participants included in the current study, disaggregated by acute HCV infection outcome

Persistent infection
(n=104)		 Spontaneous clearance
(n=30)
Male sex, n (%) 71 (68) 20 (67)
Median age, years (IQR*) 33 (24, 41) 34 (26, 37)
Caucasian ethnicity, n (%) 95 (91) 28 (93)
Median estimated duration of infection at screening, week (IQR*) 29 (21, 45) 23 (20, 31)
Presentation of recent HCV, n (%)
 Acute clinical (symptomatic) 39 (38) 14 (47)
 Acute clinical (ALT >400 IU/L) 14 (13) 5 (17)
 Asymptomatic seroconversion 51 (49) 11 (37)
Mode of HCV acquisition, n (%)
 Injecting drug use 78 (75) 23 (77)
 Sexual intercourse 18 (17) 3 (10)
 Other 8 (8) 4 (13)
HCV genotype, n (%)
 Genotype 1 49 (47) 6 (20)
 Genotype 2 4 (4) 0 (0)
 Genotype 3 46 (44) 5 (17)
 Genotype 4 1 (1) 0 (0)
 Not available 4 (4) 19 (63)
HIV infection, n (%) 29 (28) 7 (23)
IFNL3 genotype, n (%)
 rs8099917
  GG 5 (5) 0 (0)
  GT 39 (37) 4 (13)
  TT 56 (54) 25 (83)
  Not available 4 (4) 1 (3)
 rs12979860
  CC 49 (47) 19 (63)
  CT 40 (38) 9 (30)
  TT 12 (12) 1 (3)
  Not available 3 (3) 1 (3)
Open in a new tab
*

IQR: Inter-quartile range

Dynamics of HCV RNA and ALT levels

Spontaneous HCV clearance was observed in 30 individuals, while 104 individuals had persistent HCV infection. Among those with spontaneous clearance (n=30), 18 individuals had undetectable HCV RNA at screening (indicative of spontaneous clearance prior to enrolment) and 12 individuals demonstrated spontaneous clearance during follow-up.

The dynamics of HCV RNA and ALT levels among individuals are illustrated in Figure 2 by HCV infection outcome. Median HCV RNA levels at month two following infection was 5.2 log IU/mL among those with persistent infection and was 4.1 log IU/mL among those with subsequent spontaneous clearance. Subsequent HCV RNA declines were seen in both groups, with similar median levels during month three in those with persistent infection (3.2 log IU/mL; inter-quartile range [IQR]: 2.8, 5.0) and spontaneous clearance (3.5 log IU/mL; IQR: 2.9, 5.0; P=0.935). However, the pattern of median HCV RNA levels initiated to diverge between the two groups from month three to four: a slight decline to 2.9 log IU/mL (IQR: 2.8, 6.6) in those with persistent infection compared with a marked decline to 1.9 log IU/mL (IQR: 1.0, 3.1) in those with spontaneous clearance (P=0.219 for comparison of month four levels). The divergence in median HCV RNA levels was accentuated from month four to five: a marked re-increase to 5.5 log IU/mL (IQR: 2.8, 6.4) in those with persistent infection contrasting with continued decline to undetectable level (IQR: 1.0, 2.8; P<0.001 for comparison of month five levels; Figure 2A).

Figure 2.

Figure 2

Open in a new tab

Monthly medians of HCV RNA levels (A) and ALT levels (B) in individuals with acute HCV infection from month two following infection, disaggregated by infection outcome.

Dotted horizontal line represents qualitative limits of HCV RNA detection (<10 IU/mL) in figure A and represents upper limit of normal for ALT level (40 IU/L) in figure B.

High levels of ALT were observed at month two following infection among individuals with persistent infection (779 IU/L; IQR: 557, 1624) and spontaneous clearance (1765 IU/L; IQR: 496, 2373; P=0.239) followed by sharp declines by months four and five following infection. The median ALT decline was greater in those with spontaneous clearance, and remained within the normal range from month six. In contrast, median ALT levels in those with persistent infection remained elevated throughout follow-up (Figure 2B).

Although the patterns of the median HCV RNA and ALT are clearly distinct between the groups with persistent infection and spontaneous clearance (Figure 2), there was considerable heterogeneity among individual patterns (Figures 3, 4). For instance, among individuals with spontaneous clearance, participant ID 307 had increasing HCV RNA levels up to nine months following infection but cleared infection eventually between month 12 and 18. Participant ID 635 showed spontaneous clearance with four undetectable HCV RNA assessments followed by HCV RNA recurrence 28 weeks after clearance (Figure 3). Sequencing of samples taken at enrolment and subsequent detectable HCV RNA identified HCV re-infection (recurrence with heterologous strain) in this participant. Of interest, participant ID635 had spontaneous clearance of re-infection following a single detectable HCV RNA assessment. Among those with persistent infection, participant ID 117 had two episodes of declining HCV RNA levels between months 5–8 and months 11–22 following infection, but both episodes were followed by a rebound in HCV RNA levels and progression to chronic infection. Participant ID 104 had one undetectable HCV RNA followed by HCV RNA recurrence 40 weeks after the intermittent undetectable HCV RNA (Figure 4). Sequencing of samples taken at enrolment and subsequent detectable HCV RNA identified HCV RNA intercalation (recurrence with homologous strain) in this participant.

Figure 3.

Figure 3

Open in a new tab

Longitudinal HCV RNA and ALT levels in six representative individuals with HCV spontaneous clearance.

Longitudinal HCV RNA levels (black triangles and grey shade) and ALT levels (black circles and solid line) levels in six representative individuals of individuals with HCV spontaneous clearance who had detectable HCV RNA at enrolment representing the patterns of HCV RNA and ALT levels in spontaneous HCV clearance. Dotted horizontal lines represent quantitative (<630 IU/mL) and qualitative (<10 IU/mL) limits of HCV RNA detection. Participant ID 635 experienced re-infection after spontaneous HCV clearance.

Figure 4. Longitudinal HCV RNA and ALT levels in six representative individuals with persistent HCV infection.

Figure 4

Open in a new tab

Longitudinal HCV RNA levels (black triangles and grey shade) and ALT levels (black circles and solid line) levels in six representative individuals of un-treated individuals with persistent HCV infection representing the patterns of HCV RNA and ALT levels in persistent HCV infection. Dotted horizontal lines represent quantitative (<630 IU/mL) and qualitative (<10 IU/mL) limits of HCV RNA detection. Participant ID 104 experienced HCV RNA intercalation after spontaneous HCV suppression (one undetectable qualitative HCV RNA test).

DISCUSSION

This prospective study characterized the dynamics of HCV RNA and ALT levels among individuals with recent HCV infection and indicated that median HCV RNA levels among those with subsequent spontaneous clearance and persistent infection diverged between months three and five following infection onset. In those with spontaneous clearance, a continuous decline in HCV RNA was observed between months two and five following infection as compared to an initial decline followed by an increase in HCV RNA among those with persistent infection. HCV RNA changes during this period may be useful in guiding early therapeutic intervention. However, the degree of heterogeneity in HCV RNA and ALT patterns among individuals with persistent infection and spontaneous clearance makes these inadequate as sole measures to guide therapy. Other factors, including polymorphism in the interferon lambda 3 (IFNL3; formerly called interleukin 28) gene region [Grebely et al., 2011; Grebely et al., 2014; Grebely et al., 2010] or the newly discovered interferon lambda 4 (IFNL4) gene region [Prokunina-Olsson et al., 2013], should be considered in therapeutic decision-making.

The virologic patterns demonstrated in this study, with evidence of enhanced virological control between month two and three in individuals with persistent infection and spontaneous clearance, and subsequent loss of control between month three and four in those with persistent infection, is consistent with a recent study that utilised next generation sequencing to evaluate early HCV viral evolution. In that study reductions in both HCV RNA levels and genetic diversity were identified within 100 days of infection (a “bottleneck” effect) irrespective of infection outcome, with subsequent increased HCV RNA levels and diversity in those with persistent infection [Bull et al., 2011]. Early virologic patterns have been evaluated previously as predictors of outcome. Thomson et al reported that spontaneous clearance was associated with a 2.2 log drop in HCV RNA levels within 100 days following infection in a large cohort of individuals with HIV co-infection [Thomson et al., 2011].

Despite clearly divergent overall patterns in HCV RNA levels between those with persistent infection and spontaneous clearance, considerable heterogeneity was documented among individual cases. This variance included cases with relatively high HCV RNA levels during acute HCV infection, with spontaneous clearance beyond six months infection, and cases with large HCV RNA declines during acute HCV infection, without subsequent spontaneous clearance. Fluctuation in HCV RNA levels has been reported as a hallmark of the viral dynamics in the early stages of HCV infection, and was described by some investigators as a ‘yo-yo’ pattern [Aberle et al., 2006; Smith et al., 2010]. Various studies have reported that a wide range (37% to 86%) of individuals with acute HCV experienced significant viral load fluctuations (generally defined as ≥1 log HCV RNA change) [Loomba et al., 2011; McGovern et al., 2009; Smith et al., 2010; Thomson et al., 2011]. Larger datasets of individuals with acute HCV infection are required to more fully characterise early virologic patterns, and to evaluate predictive models for spontaneous clearance. Such models may incorporate virologic features (HCV RNA level [Liu et al., 2012], early viral load decline [Thomson et al., 2011], and HCV genotype [Grebely et al., 2014]), demographic features (age [Garten et al., 2008; Zhang et al., 2006], gender [Grebely et al., 2014; Micallef et al., 2006; Page et al., 2009]), and host genetic (IFNL3 [Grebely et al., 2014; Grebely et al., 2010; Tillmann et al., 2010], IFNL4 [Prokunina-Olsson et al., 2013], HLA DQB1*03:01 [Duggal et al., 2013]) and biomarkers (IP-10 [Grebely et al., 2013a]), as all these factors have been associated with spontaneous clearance.

This study has some limitations. Most of the individuals with detectable HCV RNA at enrolment had an estimated duration of infection more than one month hence the very early dynamics of the HCV RNA levels were therefore missed. Further, estimated date of infection might not have been accurate for some individuals, particularly for asymptomatic individuals with a long period between their last HCV negative and first HCV positive tests. Although the number of individuals is relatively large for an acute HCV infection study, many individuals had relatively infrequent HCV RNA assessments. Thus, some monthly time-points had small numbers of HCV RNA measurements available. As mentioned previously, larger sample populations combining individuals from acute HCV cohorts is required to further characterise early viral dynamics. The International Collaboration of Incident hepatitis C in Injecting drug user Cohorts (InC3) has been established recently, with nine acute HCV cohorts (including ATAHC). Epidemiological studies are underway through InC3 to meet this objective [Grebely et al., 2013b].

In conclusion, the current data suggested that HCV RNA dynamics in those with HCV clearance and HCV persistence diverged between months three and five following infection, with the latter time-point being potentially useful for timing of early therapeutic intervention.

Acknowledgments

This study was funded by the National Institutes of Health grant RO1 DA 15999-01. This publication was funded by the Australian Government, Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. The Kirby Institute is affiliated with the Faculty of Medicine, UNSW Australia. Roche Pharmaceuticals supplied financial support for pegylated IFN-alfa-2a/ribavirin. BH is an Australian Postgraduate Award PhD scholar. JG is supported by a National Health and Medical Research Council Career Development Fellowship. GJD and AL were supported by National Health and Medical Research Council Practitioner Research Fellowships. MH was supported by a National Health and Medical Research Council Career Development Award and a VicHealth Senior Research Fellowship. JK was supported by National Health and Medical Research Council Research Fellowships.

Footnotes

None of the authors has commercial relationships that might pose a conflict of interest in connection with this manuscript

References

  1. Aberle JH, Formann E, Steindl-Munda P, Weseslindtner L, Gurguta C, Perstinger G, Grilnberger E, Laferl H, Dienes HP, Popow-Kraupp T, Ferenci P, Holzmann H. Prospective study of viral clearance and CD4+ T-cell response in acute hepatitis C primary infection and reinfection. J Clin Virol. 2006;36:24–31. doi: 10.1016/j.jcv.2005.12.010. [DOI] [PubMed] [Google Scholar]
  2. Barrera JM, Bruguera M, Ercilla MG, Gil C, Celis R, Gil MP, Del Onorato MV, Rodés J, Ordinas A. Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C. Hepatology. 1995;21:639–644. [PubMed] [Google Scholar]
  3. Bull RA, Luciani F, McElroy K, Gaudieri S, Pham ST, Chopra A, Cameron B, Maher L, Dore GJ, White PA, Lloyd AR. Sequential bottlenecks drive viral evolution in early acute hepatitis C virus infection. PLoS Pathog. 2011;7:e1002243. doi: 10.1371/journal.ppat.1002243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dore GJ, Hellard M, Matthews GV, Grebely J, Haber PS, Petoumenos K, Yeung B, Marks P, van Beek I, McCaughan G, White P, French R, Rawlinson W, Lloyd AR, Kaldor JM. Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. Gastroenterology. 2010;138:123–135. doi: 10.1053/j.gastro.2009.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Duggal P, Thio CL, Wojcik GL, Goedert JJ, Mangia A, Latanich R, Kim AY, Lauer GM, Chung RT, Peters MG, Kirk GD, Mehta SH, Cox AL, Khakoo SI, Alric L, Cramp ME, Donfield SM, Edlin BR, Tobler LH, Busch MP, Alexander G, Rosen HR, Gao X, Abdel-Hamid M, Apps R, Carrington M, Thomas DL. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann Intern Med. 2013;158:235–245. doi: 10.7326/0003-4819-158-4-201302190-00003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Farci P, Shimoda A, Coiana A, Diaz G, Peddis G, Melpolder JC, Strazzera A, Chien DY, Munoz SJ, Balestrieri A, Purcell RH, Alter HJ. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science. 2000;288:339–344. doi: 10.1126/science.288.5464.339. [DOI] [PubMed] [Google Scholar]
  7. Garten RJ, Lai SH, Zhang JB, Liu W, Chen J, Yu XF. Factors influencing a low rate of hepatitis C viral RNA clearance in heroin users from Southern China. World J Gastroentero. 2008;14:1878–1884. doi: 10.3748/wjg.14.1878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Glynn SA, Wright DJ, Kleinman SH, Hirschkorn D, Tu Y, Heldebrant C, Smith R, Giachetti C, Gallarda J, Busch MP. Dynamics of viremia in early hepatitis C virus infection. Transfusion (Paris) 2005;45:994–1002. doi: 10.1111/j.1537-2995.2005.04390.x. [DOI] [PubMed] [Google Scholar]
  9. Grebely J, Feld JJ, Applegate T, Matthews GV, Hellard M, Sherker A, Petoumenos K, Zang G, Shaw I, Yeung B, George J, Teutsch S, Kaldor JM, Cherepanov V, Bruneau J, Shoukry NH, Lloyd AR, Dore GJ. Plasma interferon-gamma-inducible protein-10 (IP-10) levels during acute hepatitis C virus infection. Hepatology. 2013a;57:2124–2134. doi: 10.1002/hep.26263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grebely J, Matthews GV, Dore GJ. Treatment of acute HCV infection. Nat Rev Gastroentero. 2011;8:265–274. doi: 10.1038/nrgastro.2011.32. [DOI] [PubMed] [Google Scholar]
  11. Grebely J, Morris MD, Rice TM, Bruneau J, Cox AL, Kim AY, McGovern BH, Shoukry NH, Lauer G, Maher L, Lloyd AR, Hellard M, Prins M, Dore GJ, Page K, In CSG. Cohort profile: the International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC3) Study. Int J Epidemiol. 2013b;42:1649–1659. doi: 10.1093/ije/dys167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grebely J, Page K, Sacks-Davis R, van der Loeff MS, Rice TM, Bruneau J, Morris MD, Hajarizadeh B, Amin J, Cox AL, Kim AY, McGovern BH, Schinkel J, George J, Shoukry NH, Lauer GM, Maher L, Lloyd AR, Hellard M, Dore GJ, Prins M, In CSG. The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology. 2014;59:109–120. doi: 10.1002/hep.26639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grebely J, Petoumenos K, Hellard M, Matthews GV, Suppiah V, Applegate T, Yeung B, Marks P, Rawlinson W, Lloyd AR, Booth D, Kaldor JM, George J, Dore GJ, Group AS. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology. 2010;52:1216–1224. doi: 10.1002/hep.23850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroentero. 2013;10:553–562. doi: 10.1038/nrgastro.2013.107. [DOI] [PubMed] [Google Scholar]
  15. Lavillette B, Morice Y, Germanidis G, Donot P, Soulier A, Pagkalos E, Sakellariou G, Intrator L, Bartosch B, Pawlotsky JM, Cosset FL. Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection. J Virol. 2005;79:6023–6034. doi: 10.1128/JVI.79.10.6023-6034.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Liu L, Fisher BE, Thomas DL, Cox AL, Ray SC. Spontaneous clearance of primary acute hepatitis C virus infection correlated with high initial viral RNA level and rapid HVR1 evolution. Hepatology. 2012;55:1684–1691. doi: 10.1002/hep.25575. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Loomba R, Rivera MM, McBurney R, Park Y, Haynes-Williams V, Rehermann B, Alter HJ, Herrine SK, Liang TJ, Hoofnagle JH, Heller T. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment Pharm Ther. 2011;33:559–565. doi: 10.1111/j.1365-2036.2010.04549.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McGovern BH, Birch CE, Bowen MJ, Reyor LL, Nagami EH, Chung RT, Kim AY. Improving the Diagnosis of Acute Hepatitis C Virus Infection with Expanded Viral Load Criteria. Clin Infect Dis. 2009;49:1051–1060. doi: 10.1086/605561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat. 2006;13:34–41. doi: 10.1111/j.1365-2893.2005.00651.x. [DOI] [PubMed] [Google Scholar]
  20. Nübling CM, Unger G, Chudy M, Raia S, Löwer J. Sensitivity of HCV core antigen and HCV RNA detection in the early infection phase. Transfusion (Paris) 2002;42:1037–1045. doi: 10.1046/j.1537-2995.2002.00166.x. [DOI] [PubMed] [Google Scholar]
  21. Page K, Hahn JA, Evans J, Shiboski S, Lum P, Delwart E, Tobler L, Andrews W, Avanesyan L, Cooper S, Busch MP. Acute hepatitis C virus infection in young adult injection drug users: a prospective study of incident infection, resolution, and reinfection. J Infect Dis. 2009;200:1216–1226. doi: 10.1086/605947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pham S, Bull R, Bennett J, Rawlinson W, Dore G, Lloyd A, et al. Frequent multiple hepatitis C virus infections among injection drug users in a prison setting. Hepatology. 2010;52:1564–1572. doi: 10.1002/hep.23885. [DOI] [PubMed] [Google Scholar]
  23. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O’Brien TR. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–171. doi: 10.1038/ng.2521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Smith JA, Aberle JH, Fleming VM, Ferenci P, Thomson EC, Karayiannis P, McLean AR, Holzmann H, Klenerman P. Dynamic Coinfection with Multiple Viral Subtypes in Acute Hepatitis C. J Inf Dis. 2010;202:1770–1779. doi: 10.1086/657317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194:1395–1406. doi: 10.1084/jem.194.10.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Thomson EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, Smith J, McClure MO, Karayiannis P. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut. 2011;60:837–845. doi: 10.1136/gut.2010.217166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tillmann HL, Thompson AJ, Patel K, Wiese M, Tenckhoff H, Nischalke HD, Lokhnygina Y, Kullig U, Göbel U, Capka E, Wiegand J, Schiefke I, Güthoff W, Grüngreiff K, König I, Spengler U, McCarthy J, Shianna KV, Goldstein DB, McHutchison JG, Timm J, Nattermann J. A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. Gastroenterology. 2010;139:1586–1592. doi: 10.1053/j.gastro.2010.07.005. [DOI] [PubMed] [Google Scholar]
  28. Weseslindtner L, Neumann-Haefelin C, Viazov S, Haberstroh A, Kletzmayr J, Aberle JH, Timm J, Ross SR, Klauser-Braun R, Baumert TF, Roggendorf M, Thimme R, Holzmann H. Acute infection with a single hepatitis C virus strain in dialysis patients: Analysis of adaptive immune response and viral variability. J Hepatol. 2009;50:693–704. doi: 10.1016/j.jhep.2008.11.023. [DOI] [PubMed] [Google Scholar]
  29. Zhang M, Rosenberg PS, Brown DL, Preiss L, Konkle BA, Eyster ME, Goedert JJ. Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia. Blood. 2006;107:892–897. doi: 10.1182/blood-2005-07-2781. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES