September 4, 2013

Study helps characterize HCV exacerbation course, outcomes

By: SHARON WORCESTER,  Oncology Report Digital Network

09/01/13

Most patients who experience an acute exacerbation of chronic hepatitis C achieve a sustained viral response after treatment with pegylated interferon and ribavirin, a long-term case-control follow-up study shows.

Of 82 consecutive patients who had an acute exacerbation of chronic hepatitis C virus (HCV) between January 2005 and June 2010, 32 were treated with peg-IFN and ribavirin, and 26 of those (81.2%) achieved a sustained viral response (SVR); of 82 control subjects with HCV who did not experience an acute exacerbation, 38 were treated with peg-IFN and ribavirin, and 23 of those (60.5%) achieved an SVR, Dr. Evangelista Sagnelli of Second University of Naples, Italy, and her colleagues reported online April 15 ahead of print in Clinical Gastroenterology and Hepatology.

The case patients, who were a mean age of 50 years, were anti-HCV/HCV RNA positive, hepatitis B surface antigen (HBsAG)/anti-HIV–negative patients who were naive to anti-HCV therapy. HCV genotype 1 was detected in 43.9% of cases, and genotype 2 was detected in 46.4% of cases.

The patients, who were followed for a median of 36 months after a 2-month observation period, were matched to 82 controls based on age, sex, and disease genotype. The controls, who were followed for 32 months, were HBsAG-negative patients who never showed signs of symptomatic acute exacerbation; they had steady alanine aminotransferase (ALT) values at four checks per year over the prior 5 years. They also were anti-HCV therapy-naive.

More case patients than control patients carried the interleukin-28B CC genotype (40.2% vs. 24.4%).

"In several determinations over the years before reactivation, these 82 patients had been HCV RNA positive with normal or moderately increased serum alanine aminotransferase levels, suggesting an indolent, slowly progressing course of chronic hepatitis C," the investigators said.

They had a mean aspartate aminotransferase (AST) serum value of 672 IU/dL, a mean ALT serum value of 1063 IU/dL, and a total bilirubin level of 15.87 mg/dL, the investigators said (Clinical Gastroenterology and Hepatology 2013 [doi:10.1016/j.chg.2013.03.025]).

In 43.5% of cases, ALT increased steadily to at least twice the baseline value, but more than half of these (56.5%) experienced a return to baseline values prior to the acute exacerbation, they noted.

A comparison of biopsy specimens showed increasing fibrosis in 78.3% of 23 cases, compared with 38.7% of 31 controls with biopsies available. Fibrosis scores remained stationary in 21.7% of the case patients, and in 58.1% in the control group. Only one patient in the control group (3.2%) improved.

Additionally, histologic activity index (HAI) scores deteriorated by at least 2 points in 60.9% of cases, compared with 9.7% of controls.

"An improvement in the HAI of at least 2 scores was found only in 4 (12.9%) in the control group patients, whereas 9 patients (39.1%) in the case group and 24 patients (77.5%) in the control group remained stationary," the investigators said.

This study, which was designed to better characterize the clinical presentation and course of symptomatic acute exacerbation of chronic hepatitis C, as well as outcomes and response to antiviral therapy, improves "the scanty knowledge" on these topics, they said.

The findings demonstrate marked variability in the clinical presentation, with ALT levels ranging from 6- to 43-fold the normal values, and serum bilirubin increases ranging from 2 to 22 mg/dL.

The investigators also observed that although the clinical course of acute exacerbations was usually characterized by a single flare, in some cases more than one flare occurred, and that acute exacerbations can occur at any age; in this study they occurred in patients ranging in age from 24 to 87 years.

Furthermore, the observation that nearly half of the study patient with an acute exacerbation showed HCV genotype 2 confirms the association between exacerbation and genotype 2 demonstrated in previous studies, they said.

"The reasons for this association remain unknown and warrant further investigation," they said, noting that exacerbations in the current study were also common among those with HCV genotype 1, but were rare in other HCV genotypes.

The unexpectedly higher prevalence of genotype IL-28-B CC in the case patients in this study "may suggest a greater likelihood of developing acute exacerbation of chronic hepatitis C for patients with the genotype," they said, noting that this observation also deserves additional study.

"Most probably acute exacerbation of chronic hepatitis C is a consequence of a reactivation of cell-mediated immune reaction to clear HCV infection, in some ways in line with the well-known propensity of IL-28-B CC genotype to undergo a spontaneous or treatment-induced clearance of HCV infection," they said.

Another observation in this study is that acute HCV exacerbation frequently causes deterioration both in fibrosis and necroinflammation – a finding that underscores "the profound implications of acute exacerbation of chronic hepatitis C on the progression to cirrhosis and risk of hepatocellular carcinoma," they said.

"In conclusion ... acute exacerbation of chronic hepatitis is responsible for an unfavorable outcome in patients with chronic hepatitis. However, the majority of patients with acute exacerbation of chronic hepatitis C obtained an SVR, most probably because of the high frequency of HCV genotype 2 and IL-28-B CC genotypes in the case group, and possibly because the reactivation of a cell-mediated immune response may favor HCV clearance," they said, adding that "the more rapid progression to cirrhosis and the risk of hepatocellular carcinoma strongly warrant the early initiation of anti-HCV therapy for acute exacerbation of chronic hepatitis C patients."

In this study, such patients showed "an impressive rate of SVR to peg-IFN + ribavirin," they said.

This study was supported by grants from PRIN 2008, MIUR, Rome, Italy, "Ottimizzazione Della Diagnosi Eziologica dell’epatite Acuta C E Studio dei Fattori Viro-Immunologici di Guarigione, di Cronicizzazione E di Risposta Alla Terapia Con Interferone," and Tegione Campania "Progetti per il miglioramento della qualita dell’assistenza, diagnosi e terapia del paziente afetto da AIDS nei settori: immunologia, coinfezioni, informazione e prevenzione," 2008. The authors reported having no disclosures.

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