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Presentation, Outcomes, and Response to Therapy Among Patients with Acute Exacerbation of Chronic Hepatitis C - spikes in ALTs in chronic infection
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Article in Press
Clinical Gastroenterology and Hepatology June 2013
Evangelista Sagnelli1,2, Mariantonietta Pisaturo1,2, Maria Stanzione3, Vincenzo Messina2,Loredana Alessio1, Caterina Sagnelli3, Mario Starace1, Giuseppe Pasquale1, Nicola Coppola1.
1: Department of Mental Health and Public Medicine, Section of Infectious Diseases, SecondUniversity of Naples, Naples, Italy2: Division of Infectious and Tropical Diseases, AORN Sant'Annae San Sebastiano di Caserta,Caserta, Italy
3: Department of Clinical and Experimental Medicine and Surgery "F. Magrassi e A. Lanzara",Second University of Naples, Naples, Italy
"acute exacerbation of chronic hepatitis C", an event characterized by a
substantial increase in serum ALT values, at times associated to an increase in bilirubin and/or to other symptoms in common with acute hepatitis"
from Editorial:
"What can we conclude from the current study? It adds to emerging evidence that ae-CHC, symptomatic or asymptomatic, is more common in genotype 2 patients. This study also confirms the previous finding that patients with ae-CHC have more rapid progression of liver disease and hence should be treated more aggressively. The IL-28B CC genotype was more common in patients with ae-CHC, and patients with ae-CHC responded favorably to the pegylated interferon/ribavirin combination therapy. Symptomatic ae-CHC usually resolves within 6 months, and this study clearly shows that it might be difficult to differentiate from acute hepatitis C. Larger studies utilizing a standardized definition of ae-CHC inclusive of both symptomatic and asymptomatic patients may better characterize the true prevalence and natural history of acute exacerbation. So when you see your next patient with acute hepatitis C with unknown history who does not develop spontaneous resolution, is this an acute C or an acute exacerbation of chronic hepatitis C?"
"In conclusion, acute exacerbation of chronic hepatitis C is a clinical event frequently associated to HCV-2 and to IL28-B CC genotype and is responsible for an unfavorable outcome in patients with chronic hepatitis C. However, the majority of patients with acute exacerbation of chronic hepatitis C obtained a SVR, most probably because of the high frequency of HCV genotype
2 and IL28-B CC genotypes in the Case group, and possibly because the reactivation of a cell-mediated immune response may favor HCV clearance.
The more rapid progression to liver cirrhosis and the risk of HCC strongly warrant the early initiation of anti-HCV therapy for acute exacerbation of chronic hepatitis C patients, who in this study showed an impressive rate of SVR to peg-IFN+ribavirin.
The comparison of liver histology in sequential LB, possible for nearly one third of the patients in each group, suggests that acute exacerbation of chronic hepatitis C frequently causes deterioration both in fibrosis and necroinflammation. In fact, a 2-score deterioration in fibrosis was observed in nearly three quarters of the patients in the Case group and in nearly one third of the Controls. Similarly, a 2-score deterioration in HAI was found in nearly 60% of patients in the Case group and 10% in the Controls. The differences were both statistically significant. The data from previous long-term follow-up studies on the progression of HCV-associated liver disease suggest that the progression of liver fibrosis is indolent for nearly two decades after acute hepatitis C and that morbidity and mortality are more likely to emerge in the third or fourth decade after infection [25]. The rate of acceleration of liver fibrosis consequent to acute exacerbation of chronic hepatitis C shown in the present study is higher than that observed in the Control group of this study and in previous investigations in patients who did not experience this clinical event and frequently showed an indolent course of the disease [25]. This underscores the profound implication of acute exacerbation of chronic hepatitis C on the progression to cirrhosis and risk of HCC."
Abstract
Background & Aims
The slow asymptomatic progression of chronic Hepatitis C can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of chronic hepatitis C.
Methods
We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of chronic hepatitis C from January 2005 through June 2010; we followed them for a median period of 36 months. These cases were HCV RNA positive, hepatitis B antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed for at least 2 years. Liver biopsies had been taken from 23 cases and 31 controls-once before enrollment in the study and once during the follow-up period.
Results
HCV genotype 2 was detected in 46.4% of cases genotype 1 in 43.9%. Among cases, the mean level of ALT was 1063±1038 IU/dL and of total bilirubin was 15.87±7.15 mg/dL. A higher percentage of cases carried the IL-28B CC genotype than controls (40.2% vs 24.4%; P <.05). Among cases, 43.5% had a steady increase in ALT (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsies, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by >2 (P <.005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necro-inflammation >2 points (P <.005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained viral response (SVR) was achieved by 26 cases (81.2%) and 23 controls (60.5%).
Conclusion
Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a SVR following treatment with pegylated interferon and ribavirin.
EXCERPTS
The stable persistence of an inactive or moderately active stage of the illness and a slow asymptomatic progression of chronic hepatitis may be interrupted by an exacerbation of the disease, named in the present paper "acute exacerbation of chronic hepatitis C", an event characterized by a substantial increase in serum ALT values, at times associated to an increase in bilirubin and/or to other symptoms in common with acute hepatitis [5-8]. Reactivation of chronic hepatitis C (CHC) was first described in 1996 and an annual incidence rate around 10% was observed in 194 patients followed up for more than 5 years [5]. More recently, acute exacerbation of chronic hepatitis C has been described as associated with HCV genotype 2 (HCV-2) [9-12], but its occurrence in patients with other HCV genotypes has also been described [10].
At present, few contributions have been published and more data are needed on clinical presentation of acute exacerbation of chronic hepatitis C. In addition, to our knowledge, there is no information on the clinical course of acute exacerbation of chronic hepatitis C and its impact on the outcome and response to treatment of CHC. This paper reports the data of a prospective investigation on 82 consecutive patients with symptomatic acute exacerbation of chronic hepatitis C and 82 pair-matched control patients who had not shown signs of acute exacerbation before being enrolled in the present study. Patients were naïve to anti-HCV treatment and most of them observed for at least two years.
The diagnosis of acute exacerbation of chronic hepatitis C was based on an increase in the ALT value of at least five-fold the previous basal values and on the detection of anti-HCV and HCV RNA, in the absence of other viral or iatrogenic factors known to induce liver damage
Clinical Outcome
Of the 82 patients in the Case group, 13 (15.8%) dropped out because of lack of compliance and 69 were followed up for at least 2 years. On the basis of the ALT profiles during and after acute exacerbation of chronic hepatitis C, 30 (43.5%) of these 69 were considered to have deteriorated, 39 (56.5%) were stationary and none improved.
Changes in the liver fibrosis and HAI scores between the two LBs are shown in Figures 1 and 2, respectively. Deterioration in liver fibrosis of at least 2 scores was observed in 18 (78.3%) of the 23 patients in the Case group and 11 (35.5%) of the 31 in the Control group (p<0.005), whereas the fibrosis scores remained stationary in 5 (21.7%) patients in the Case group and 20 (64.5%) in the Control group. Only 1 (3.2%) patient in the Control group improved (Figure 2). Deterioration of at least 2 HAI scores was obser ved in 14 (60.9%) patients in the Case group and 3 (9.6%) in the Control group, a difference significant to the statistical analysis (p<0.005). An improvement in the HAI of at least 2 scores was found only in 4 (12.9%) patients in the Control group, whereas 9 (39.1%) patients in the Case group and 24 (77.5%) in the Control group remained stationary.
For a more comprehensive understanding of the impact of acute exacerbation of chronic hepatitis C on the clinical course of CHC, the 69 patients with a long-term follow up are presented in Figure 3 and in figures 1-4 of the supplementary data.
Patient number 1 in Figure 3 was a 42-year-old man with HCV-2a, IL28-B CC, who showed a single episode of acute exacerbation and an ALT decline in less than 4 months like another 50 patients (from patient N° 5 to patient N° 54 in Figure 1A-1H of the Supplementary data). In another 6 patients (from patient N° 55 to patient N° 60), after a single episode of acute exacerbation the ALT decline lasted more than 5 months (Figure 2 of the Supplementary data). Patient number 2 in Figure 3 was a 60-year-old female with HCV- 3, IL28-B CT, who developed an acute exacerbation of chronic hepatitis C in January 2006 with ALT levels increased up to 42-fold and a peak of total bilirubin of 21 mg/dL during reactivation. Serum ALT and bilirubin returned to normal by November 2006, remained so until September 2008 when a second episode of reactivation occurred, followed, after a partial remission, by a third episode in January 2009. The 2nd and 3 rd episodes of reactivation were anicteric and of a lesser entity compared to the first.
Patient number 3 (Figure 3) was a 64-year-old male with HCV- 2, IL28-B CC, with a first episode of a-e CHC in August 2008 and two subsequent episodes of reactivation. Total bilirubin ranged from 2-4 mg/dL throughout the observation.
Another 6 patients (from patient N° 61 to patient N°66 in Figure 3 of the Supplementary data) showed a course of the disease characterized by two or more episodes of acute exacerbation (Figure 3 of the Supplementary data).
Patient number 4 in Figure 3 was an 87-year-old male with HCV-1, IL28-B CC, who until March 2006 had a clinical, biochemical and ultrasound profile consistent with the diagnosis of CHC, with the ALT value near to normal and normal bilirubin. This patient developed an acute exacerbation of chronic hepatitis C in June 2006 followed by other three episodes of reactivation of a lesser entity up to June 2009 when unequivocal biochemical and ultrasound signs of cirrhosis were documented. Also patients N° 67,68 and 69, showed a rapid transition to liver cirrhosis (Figure 4 of the Supplementary data).
Antiviral treatment
Of the 32 patients in the Case group treated with peg-INF+ribavirin, 26 (81.2%) achieved a sustained virological response (SVR) and 6 (18.8%) were non-responders. Of the 38 treated patients in the Control group, 23 (60.5%) obtained a SVR and 12 (39.5%) were non-responders. The data on the response to treatment, according to HCV genotype and IL28-B genotype, are presented in Table 2. The 17 patients with HCV-1/4 in the Case group showed a SVR more frequently (70.6%) than the 18 with the same HCV genotypes in the Control group (44.4%). Similarly, the 15 patients with HCV-2/3 in the Case group showed a SVR more frequently than the 20 with the same HCV genotypes in the Control group (93.3% vs 75%). Table 2 also shows that SVR was achieved by all 14 patients with IL28-B CC genotype in the Case group, regardless of HCV genotype, and by 8 of the 11 (73%) in the Control group. These differences between small groups or subgroups of treated patients are not significant to the statistical analysis.
CONCLUSIONS
This long-term follow-up study of 82 patients with acute exacerbation of chronic hepatitis C improves the scanty knowledge on the clinical presentation and course of symptomatic acute exacerbation of chronic hepatitis C and on the impact of this clinical event on the outcome and response to antiviral therapy.
At the time of the first observation, the mean AST values were as high as 16-fold the normal value, ALT 25-fold and bilirubin 15-fold. There was a marked variability in the clinical presentation, with ALT increased from 6- to 43-fold the normal values and serum bilirubin from 2 to 22 mg/dL. Also variable was the clinical course of acute exacerbation of chronichepatitis C, usually characterized by a single flare, but in some cases more than one flare can occur.
An acute exacerbation of CHC may occur at any age, as shown by the wide range of ages in the study, from 24 to 87 years. After reactivation, the ALT values slowly decreased in all patients and, by the end of a 2-year follow up, about half of the patients returned to their baseline values before acute exacerbation of chronic heaptitis C, whereas for the other half, the ALT values persisted at more than 2-fold.
Nearly half of the patients with an acute exacerbation of chronic hepatitis C in the present study showed HCV-2. This observation confirms the association between this clinical event and HCV-2 shown by studies from Italy [6,9,10], a country where the prevalence of this HCV genotype in patients with CHC is around 20% [19]. The reasons for this association remain unknown and warrant further investigation. The data from the present study, however, show that is frequent even in patients with HCV-1 and that it can rarely occur also in patients with other HCV genotypes.
Although unexpected, the significantly higher prevalence of IL28-B CC in the Case group may suggest a greater likelihood of developing acute exacerbation of chronic hepatitis C for patients with this genotype, an observation that deserves further consideration in more extensive studies.
Most probably acute exacerbation of chronic hepatitis C is a consequence of a reactivation of cell-mediated immune reaction to clear HCV infection [20-22], in some way in line with the well-known propensity of IL28-B CC genotype to a spontaneous or treatment-induced clearance of HCV infection [23,24].
The comparison of liver histology in sequential LB, possible for nearly one third of the patients in each group, suggests that acute exacerbation of chronic hepatitis C frequently causes deterioration both in fibrosis and necroinflammation. In fact, a 2-score deterioration in fibrosis was observed in nearly three quarters of the patients in the Case group and in nearly one third of the Controls. Similarly, a 2-score deterioration in HAI was found in nearly 60% of patients in the Case group and 10% in the Controls. The differences were both statistically significant. The data from previous long-term follow-up studies on the progression of HCV-associated liver disease suggest that the progression of liver fibrosis is indolent for nearly two decades after acute hepatitis C and that morbidity and mortality are more likely to emerge in the third or fourth decade after infection [25]. The rate of acceleration of liver fibrosis consequent to acute exacerbation of chronic hepatitis C shown in the present study is higher than that observed in the Control group of this study and in previous investigations in patients who did not experience this clinical event and frequently showed an indolent course of the disease [25]. This underscores the profound implication of acute exacerbation of chronic hepatitis C on the progression to cirrhosis and risk of HCC.
In the present study, the patients who experienced a symptomatic acute exacerbation of chronic hepatitis C showed a tendency to achieve a SVR to peg-INF+ribavirin treatment, but the high prevalence of SVR (81.2%), although impressive, deserves confirmation in more extensive multicenter studies.The frequency of patients with HCV 2 and/or IL 28-B CC most probably explains the high efficacy of peg-INF+ribavirin treatment in the Case group, but an additional reason might be found in acute exacerbation of chronic hepatitis C itself, which, being immunologically and virologically similar to acute hepatitis, could re-establish the mechanisms that induce the high response rate to interferon observed in acute hepatitis C [26,27].
In conclusion, acute exacerbation of chronic hepatitis C is a clinical event frequently associated to HCV-2 and to IL28-B CC genotype and is responsible for an unfavorable outcome in patients with chronic hepatitis C. However, the majority of patients with acute exacerbation of chronic hepatitis C obtained a SVR, most probably because of the high frequency of HCV genotype
2 and IL28-B CC genotypes in the Case group, and possibly because the reactivation of a cell-mediated immune response may favor HCV clearance.
The more rapid progression to liver cirrhosis and the risk of HCC strongly warrant the early initiation of anti-HCV therapy for acute exacerbation of chronic hepatitis C patients, who in this st udy showed an impressive rate of SVR to peg-IFN+ribavirin.
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