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Early-Onset Liver Fibrosis Due to Primary Hepatitis C Virus Infection Is Higher Over Time in HIV-Infected Men
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Download the PDF here
Download the PDF here
Clinical Infectious Diseases September 15 2012
Daniel S. Fierer,1 Michael P. Mullen,1
Douglas T. Dieterich,1 M. Isabel Fiel,2 and
Andrea D. Branch1
Departments of 1Medicine, and 2Pathology, Mount
Sinai School of Medicine, New York, New York
To the Editor-We were pleased to read the recent report by Vogel et al [1] of their study undertaken in response to our findings of rapid onset fibrosis during primary hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected men [2]. Their study, plus the recent publication of the liver biopsy results of Bottieau et al [3], seems to cement that this unexpected outcome is a true consequence of primary HCV infection in HIV-infected men. We disagree, however, that their results using transient elastography demonstrate a sharp decrease in the fibrosis progression rate (FPR) to a clinically unimportant level soon after the primary HCV infection period has waned.
Transient elastography measures liver stiffness, not fibrosis per se. In patients with new viral hepatitis [4] and in patients with chronic HCV infection [5], inflammation contributes significantly to the liver stiffness score. Patients with biopsies showing as little as stage 0-1 fibrosis but with higher alanine transaminase (ALT) levels had a high rate of spuriously attributed cirrhosis (stage 4) [5]. Because Vogel et al did not have liver biopsies of these patients, they could not adjust for this effect, and they thereby vastly overestimated the stage of fibrosis (and therefore the FPR) during early primary HCV infection. Then, when they calculated FPR in the subgroup of just 5 patients who were assessed at later times when inflammation and ALT were much lower, they found a much lower FPR.
To better address this issue, in continuation of our previously reported study, we performed a total of 29 liver biopsies of HIV-infected men with primary HCV infection (including the 11 reported previously [2]). Figure 1 shows a plot of histological stage against the time from first-noted ALT elevation (which coincided with the clinical presentation in >90% of cases). The results of this analysis show that higher histopathological stage of fibrosis was associated with increasing length of HCV infection (regression analysis, P = .04). These data further reinforce that in HIV-infected men there is rapid onset of fibrosis in the first 1-2 years after primary HCV infection that does not appear to resolve. Due to the same short time of follow-up as in the Vogel et al study, we cannot determine from these data the rate at which this fibrosis does or does not continue to accumulate. What happens in the subsequent 2-5 years will determine how clinically meaningful these findings end up being. But with a baseline of stage 2 fibrosis in most men immediately following the primary HCV infection, even a relatively low FPR would lead to cirrhosis more rapidly than in most clinical settings. We are optimistic that with the continued development of new HCV treatments we may be able cure nearly everyone with HCV infection within 5-10 years-but that may be too long for some of these patients. We therefore encourage Vogel and colleagues to perform long-term follow-up of their enrolled patients as we plan to do with ours so we can directly monitor liver disease progression in these patients.
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Reply to Fierer et al
Martin Vogel,1 Emma Page,2
Christoph Boesecke,1 Berit Anna Payer,3
Carolynne Schwarze-Zander,1 Stefan Mauss,4
Axel Baumgarten,5 Jan-Christian Wasmuth,1
Mark Nelson,2 Jurgen K. Rockstroh, and the
NEAT Study Group
1Department of Internal Medicine I, Bonn University,
Germany; 2Department of HIV Medicine, Chelsea and
Westminster Hospital, London, United Kingdom;
3Department of Internal Medicine III, Division of
Gastroenterology & Hepatolgy, Medical University of
Vienna, Austria; 4Center for HIV and
Hepatogastroenterology, Duesseldorf, and 5Medical
Center for Infectious Diseases, Berlin, Germany
To the Editor-We are thankful for the comments made by Fierer et al, which enrich the current discussion on the natural course of acute hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected individuals [1]. However, we do feel that the authors may have over-interpreted our data when stating that we demonstrated a "sharp decrease in the fibrosis progresssion rate (FPR) to a clinically unimportant level soon after the primary HCV infection period has waned." This statement is not correct. We showed that the calculated FPR using a linear model most likely overestimates fibrosis progression in the setting of acute HCV infection, for which only short follow-up times are available. We are happy to see that Fierer et al agree with this interpretation and no longer calculate FPRs when reporting the outcome of liver biopsies of acute HCV infections. Indeed, concordant to the current consensus statement on acute HCV infections in HIV-infected individuals, we recommended that every HIV-infected patient should be advised to consider early treatment of acute HCV infection if spontaneous clearance does not occur [2]. We fully agree that further follow-up in patients withholding treatment is warranted to detect advancing liver fibrosis early and avoid the development of significant fibrosis and/or cirrhosis and ultimately end-stage liver disease [3].
We also agree with Fierer et al that the use of transient elastography for the assessment of liver fibrosis may be confounded by liver inflammation (as high levels of aminotransferases and of bilirubin are both associated with increased results of liver stiffness); however, this was already discussed in our manuscript. Of note, this confounder was addressed accordingly by multivariate analysis; in addition, the determination of liver fibrosis by liver biopsy may also be confounded by acute liver inflammation, as has been described previously [4]. More important, however, liver biopsy as an invasive procedure cannot rule out a certain degree of confounding by indication; although overall complication rates are low, there still remains a small but not negligible risk of mortality. This may lead to a selection of high-risk patients and overestimate liver fibrosis in patients with acute HCV infection.
Current data are not definitive, and future studies are warranted. Although it is important to raise awareness of possible complications of acute HCV infection in HIV-infected individuals, we feel it is timely to inform patients and caregivers that fibrosis progression may indeed be lower than previously suggested and patients will not necessarily suffer from liver cirrhosis within a year's time. In the meantime, noninvasive assessment of liver fibrosis by transient elastography-with consideration of the limitations of the procedure in the setting of acute hepatitis-may provide healthcare providers and patients with helpful information to monitor liver fibrosis after acute HCV infection on an individual patient basis. After all, the repeatability of the elastography measurements in 6-month intervals remains one of the obvious advantages of this noninvasive method over liver biopsy.
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