Watchful waiting: role of disease progression on uncertainty and depressive symptoms in patients with chronic Hepatitis C

Journal of Viral Hepatitis

Volume 21, Issue 10, pages 727–733, October 2014

Original Article

J. P. Colagreco^1,*, D. E. Bailey², J. J. Fitzpatrick³, C. M. Musil³, N. H. Afdhal¹ and M. Lai¹

Article first published online: 7 NOV 2013

DOI: 10.1111/jvh.12207

© 2013 John Wiley & Sons Ltd

Abstract

Background and Aims: New therapies for HCV are rapidly emerging and providers are advising select patients to defer treatment and elect ‘watchful waiting’. During the watchful waiting period, patients have been shown to have high rates of illness uncertainty and depression. We sought to answer the question of whether reassuring histological data (showing minimal fibrosis or no fibrosis progression over time) is associated with less illness uncertainty and depressive symptoms.

Methods: This was a single-centre outpatient prospective cohort study to determine whether stage of fibrosis, fibrosis progression and reasons for treatment deferral were related to illness uncertainty and depressive symptoms in patients following watchful waiting.

Results: Illness uncertainty was significantly related to depressive symptoms (r = 0.49, P < 0.01). More than half of the participants (54%) had moderate levels of uncertainty. About 40% of the participants were at risk for clinical depression (21.7% at mild to moderate risk and 18.5% at high risk). Treatment naïve subjects had lower mean scores on both the CES-D (depressive symptoms measure) and the MUIS-A (illness uncertainty measure) total score, MUIS-A Ambiguity subscale and MUIS-A Inconsistency subscale than subjects who failed treatment or were interferon intolerant or ineligible. Surprisingly, liver fibrosis stage and progression were not significantly associated with overall illness uncertainty or depressive symptoms.

Conclusion: Patients with chronic hepatitis C on watchful waiting are at high risk for significant illness uncertainty and depressive symptoms. Reassuring histological data does not seem to correlate with less uncertainty or depressive symptoms.

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Study Provides More Evidence that Statins Help Slow Liver Fibrosis in Hepatitis C

Provided by HPCLive

By Marcia Frellick | May 05, 2014

New research from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial cohort indicates that continuous statin use can significantly reduce liver fibrosis progression in patients with advanced chronic hepatitis C infection.

Study results, released Sunday at Digestive Disease Week 2014 in Chicago, IL, add to evidence demonstrating that statins have anti-proliferative, anti-angiogenic, and anti-inflammatory effects on hepatic cells.
Although animal models have demonstrated that statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, effectively prevent the progression of liver fibrosis, little human data was available.

Tracey G. Simon, MD, an internist in the Gastrointestinal Unit at Massachusetts General Hospital, and Brigham and Women's Hospital in Boston, MA, and colleagues studied 547 non-cirrhotic patients with chronic hepatitis C who previously had not responded to standard interferon therapy.
The patients had Ishak Fibrosis Staging scores ≥ 3 and underwent serial liver biopsies at baseline, 1.5 years, and 3.5 years after the trial began. Inflammation was graded on an 18-point histology activity index.

Patients reported statin use as part of the comprehensive medical history taken prior to enrollment and at each follow-up visit over the length of the study. Statin users were more likely to be African American, to have lower baseline alanine transferase (ALT) levels, and to be diabetic when compared to patient who reported no statin use.

The mean change in Ishak score over the study period for those who used statins was -0.34 during 3.5 years of observation, while the mean change in the Ishak score among those in the non-statin group was +0.42 [(SE 0.07), p= 0.006] after adjustment for baseline fibrosis score.

Continuous statin use was linked with a significant decrease in time to histological progression even after adjusting for known predictors of histological outcome, including diabetes, body mass index, platelets, and hepatic steatosis (HR 0.31, 95% CI 0.10 - 0.97).

Therapies to reduce the progression of liver scarring are critical as the damage keeps the liver from performing essential functions. Slowing the progression can slow hepatic decompensation and help patients live longer. However, some clinicians have been reluctant to initiate statin therapy along with treatment for hepatitis C without more evidence that they are safe and effective for this purpose.

The HALT-C researchers said further prospective studies with a large proportion of statin users are needed to define the optimal timing for starting statins, the ideal length of therapy, and the impact on those with less severe fibrosis or other etiologies of liver disease.

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Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs - 'HIV/HCV Coinfected's Liver Disease Can Progress Quickly'

Provided by NATAP

Download The PDF Here

Hepatology
Jan 16 2014
Early View (Online Version of Record published before inclusion in an issue)

\Monica A. Konerman,1 Shruti H. Mehta,2 Catherine G. Sutcliffe,2 Trang Vu,1 Yvonne Higgins,1 Michael S. Torbenson,3 Richard D. Moore,1,2 David L. Thomas,1,2 and Mark S. Sulkowski1

From the 1Johns Hopkins Hospital/University School of Medicine, Baltimore, MD; 2Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 3Johns Hopkins Hospital Department of Pathology, Baltimore, MD.

-----------------------------

HIV/HCV Coinfected's Liver Disease Can Progress Quickly: "(34%) had progression of one or more METAVIR stages between biopsies and are referred to as "progressors......Measures of obesity (BMI, P = 0.02), diabetes (P = 0.01), and hepatic steatosis (P = 0.01) at the time of the first biopsy were associated with progression of fibrosis on the subsequent liver biopsy"....genotype 1 is identified in Table 4 below as being associated with fibrosis progression\

from Jules: many of you may recall this was presented initially as an abstractat a major conference several years ago.

"our data related to the incidence and correlates of progressive hepatic fibrosis among 282 HIV/HCV coinfected adults who underwent serial fibrosis staging resulting in 435 paired liver biopsies provide several insights into liver disease progression in HIV/HCV coinfected patients."

"In conclusion, approximately one-third of HIV/HCV coinfected patients experienced fibrosis progression of at least one METAVIR stage over a relatively short period of time, including patients with no or minimal fibrosis on first biopsy and those taking ART. Patients with persistent liver enzyme elevation, particularly of serum AST, were more likely to progress, suggesting that this simple measurement may be useful in identifying coinfected patients at greater risk for HCV disease progression. The association of obesity and its related complications with fibrosis progression underscores the potential importance of this modifiable risk factor. However, our limited ability to accurately predict progression in most patients, underscores the need for additional research to understand the basis for variable HCV disease progression in HIV-infected patients."

"The majority of coinfected patients in our prospective cohort had minimal fibrosis on initial liver biopsy. Nonetheless, over a median follow-up time of 2.5 years we observed fibrosis progression (≥1 METAVIR stage) in one-third of individual patients between the first and second liver biopsy (n = 282) and among one-third of all biopsy pairs (n = 435). While the majority of histologic change was limited to one METAVIR stage, progression of two or more stages was found in ~9% of biopsy pairs. Further,nearly 45% of patients with no evidence of hepatic fibrosis on the initial biopsy had at least stage 1 fibrosis on subsequent liver biopsy. This observed incidence of fibrosis progression over a relatively short time interval is consistent with our earlier observations and those reported in other HIV/HCV coinfected patient cohorts in which progressive disease was noted in 17% to 50% of paired histologic evaluations"

"Our finding of steatosis as a predictor of fibrosis progression is in concordance with recent investigations on this topic that have found the presence of steatosis to be strongly associated with advanced fibrosis"

"Among the 435 biopsy pairs, 149 (34%) had progression of one or more METAVIR stages between biopsies and are referred to as "progressors"(Table 3). Markers of increased hepatic inflammation measured by median AST and ALT as well as noninvasive measures of liver disease (AST-platelet ratio index [APRI] and FIB4 index) were associated with subsequent fibrosis progression.Measures of obesity (BMI, P = 0.02), diabetes (P = 0.01), and hepatic steatosis (P = 0.01) at the time of the first biopsy were associated with progression of fibrosis on the subsequent liver biopsy. Compared to nonobese patients, those with BMI >30 at the time of the initial biopsy had higher AST levels, higher prevalence of steatosis, higher histological activity indexes, and were more likely to be male "

"we did not detect an association of ART, HIV RNA suppression, or CD4 cell count with fibrosis progression. In contrast, we recently observed that the receipt of ART was independently associated with a 66% reduction in the risk of HCV-related clinical outcomes including end-stage liver disease, hepatocellular carcinoma, or liver-related death.[25] Taken together, these findings suggest that while the treatment or prevention of HIV disease may reduce liver inflammation and clinical outcomes, ART alone is not sufficient to prevent fibrosis progression in coinfected patients."

"Similar to baseline correlates, measures of hepatic inflammation were significantly different between progressors and nonprogressors between biopsies. The median AST and ALT levels between biopsies were significantly higher among biopsy pairs with fibrosis progression compared to those without fibrosis progression (P = 0.0004 for ALT and P < 0.0001 for AST). In addition, between biopsies, pairs with fibrosis progression had a significantly greater proportion of ALT and AST values >2.5 times the upper limit of normal compared with those without progression (P = 0.0002 for ALT and P < 0.0001 for AST). Time between biopsies was not associated with progression. After adjustment for baseline and between biopsy factors in multivariate analysis, the proportion of AST level >100 IU/mL between biopsies was independently associated with subsequent fibrosis progression for all biopsy pairs and for biopsy pairs restricted to those with minimal fibrosis (stage 0 or 1) (Table 4)"

-------------------------------

Fibrosis progression in human immunodeficiency virus/hepatitis C virus coinfected adults: Prospective analysis of 435 liver biopsy pairs

Monica A. Konerman,1 Shruti H. Mehta,2 Catherine G. Sutcliffe,2 Trang Vu,1 Yvonne Higgins,1 Michael S. Torbenson,3 Richard D. Moore,1,2 David L. Thomas,1,2 and Mark S. Sulkowski1 From the 1Johns Hopkins Hospital/University School of Medicine, Baltimore, MD; 2Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; 3Johns Hopkins Hospital Department of Pathology, Baltimore, MD.

ABSTRACT:

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection is associated with progressive liver disease. However, the rate of progression is variable and the ability to differentiate patients with stable versus progressive HCV disease is limited. The objective of this study was to assess the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected patients. Overall, 435 liver biopsy pairs from 282 patients without cirrhosis were analyzed. Biopsies were scored according to the METAVIR system by a single pathologist blind to biopsy sequence. Fibrosis progression was defined as an increase of at least one METAVIR fibrosis stage between paired biopsies. The majority of patients were African American (84.8%), male (67.7%), and infected with HCV genotype 1 (93.4%). On initial biopsy, no or minimal fibrosis was identified in 243 patients (86%). The median interval between biopsies was 2.5 years. Fibrosis progression was observed in 97 of 282 (34%) patients and 149 of 435 (34%) biopsy pairs. After adjustment, greater body mass index (adjusted odds ratio [aOR]: 1.04 per 1 unit increase), diabetes (aOR: 1.56), and hepatic steatosis (aOR: 1.78) at the time of initial biopsy were marginally associated with subsequent fibrosis progression. Between biopsies, elevated serum aspartate and alanine aminotransferase (AST, ALT) (aOR AST: 3.34, ALT: 2.18 for >25% values >100 U/L versus <25% values >100 U/L) were strongly associated with fibrosis progression. Conclusion: Fibrosis progression is common among HIV/HCV coinfected patients; these data suggest that progression can be rapid. Persistent elevations in serum transaminase levels may serve as important noninvasive markers to identify subsets of patients who are more likely to progress and thus warrant closer monitoring and consideration of HCV treatment.

Due to shared modes of transmission, 15%-30% of individuals with human immunodeficiency virus (HIV) infection are coinfected with hepatitis C virus (HCV).[1, 2] In the era of antiretroviral therapy (ART), chronic HCV infection leads to progressive liver disease, resulting in end-stage liver disease, hepatocellular carcinoma, and death in some, but not all coinfected patients.[3-5] While the variable progression of HCV disease is well recognized, the rate and risk factors for progressive liver disease in HIV/HCV coinfected patients are incompletely understood. Several studies conducted shortly after the availability of highly active ART suggest that effective treatment of HIV may be associated with decreased risk of liver disease progression.[6-10] However, the contributions of other potentially modifiable (e.g., obesity) and unmodifiable (e.g., age) factors to the worsening of hepatic fibrosis have not been determined. Greater understanding of such factors may have important implications for the clinical management of HIV/HCV coinfected patients. For example, current HCV treatment guidelines for HIV-infected patients recommend treatment of those patients at the greatest risk for developing liver disease.

Some, but not all, expert guidelines recommend HCV treatment for HIV-infected patients independent of biopsy stage based on an assumption of rapidly progressive disease in this population.[11-17] The identification of factors associated with progression may help to refine clinical decision-making as well as identify potentially modifiable exposures. Accordingly, the objective of this study was to determine the incidence of and risk factors for fibrosis progression in a prospective cohort of coinfected adults who underwent serial liver biopsy with the aim of identifying coinfected patients with no or minimal fibrosis who are at risk for progressive liver disease over a relatively short period of time.

Patients and Methods

Study Population

This prospective cohort study evaluated 289 HIV/HCV coinfected adults who received medical care in an urban HIV clinic in Baltimore, Maryland, from July 1993 until December 2008. Treatment for HIV and/or HCV was provided by healthcare providers according to published practice guidelines.[18, 19]Individuals with at least two liver biopsies as part of their medical care were included in the study. A total of 282 patients had an initial noncirrhotic biopsy and were assessed. Of these individuals, 124 had more than two liver biopsies including 97 patients with three biopsies, 25 with four biopsies, and two with five biopsies. In total, these 282 patients contributed 435 liver biopsy pairs to the analysis. For all patients, demographic, clinical, and laboratory data were abstracted from patient charts and a laboratory database by trained personnel. Data on injection drug use and alcohol abuse were ascertained based on physician diagnosis, chart review, and self-reports.

Laboratory Evaluations

All subjects had standard laboratory assessments performed by licensed clinical laboratories, including a complete blood cell count, serum chemistry panels, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, CD4 cell count, and plasma HIV-RNA level. HCV antibody testing was performed using a sensitive and specific enzyme immunoassay. HCV RNA and genotype testing were performed using reverse-transcriptase polymerase chain reaction.

Liver Histology

A transcutaneous liver biopsy was performed using an 18G needle. Liver tissue was fixed in 10% formalin, and paraffin-embedded sections were stained with hematoxylin-eosin and trichome stains. Biopsies were scored according to the METAVIR and the modified histological activity index scoring system by a single pathologist (M.T.) blind to biopsy sequence. The scale to classify fibrosis was as follows: F0 = no fibrosis; F1 = portal fibrosis without septa; F2 = portal fibrosis with few septa; F3 = numerous septa without cirrhosis; F4 = cirrhosis. Steatosis was scored based on the percentage of hepatocytes affected according to a 5-point scale as follows: Grade 0: none; 1: <5% fat; 2: 5%-<30% fat; 3: 30%-60% fat; 4: >60% fat.[20] All biopsies were deemed adequate for inclusion based on expert opinion by the hepatopathologist (M.T.) including assessment of size and number of portal tracts. The median length of the first biopsy of a pair was 12.0 mm (interquartile range [IQR] 10.0, 14.0 mm), while the median length of the second biopsy of a pair was 13.0 mm (IQR 10.0, 15.0 mm). The median number of portal tracts for the first biopsy of a pair was 10 (IQR 8, 13), and for the second biopsy of a pair was 11 (IQR 9, 14).

Statistical Analysis

Significant fibrosis progression was defined as an increase of at least one METAVIR stage between the biopsies. The proportion of patients who had fibrosis progression was equivalent when analyzed using the Ishak scoring system (Supporting Table 1). Subsequently, the remaining analysis was done using the METAVIR scoring system alone. To characterize changes over time, we used 435 biopsy pairs contributed by 282 individuals such that the unit of analysis was the biopsy pair and not the individual (e.g., for a patient with three biopsies, biopsy 1 -> 2 was analyzed as one pair and biopsy 2 -> 3 as a second pair).

Univariate and multivariate logistic regression with generalized estimating equation were used to assess determinants of fibrosis progression in order to account for the correlation of biopsy pairs from within the same individuals. Variables associated with fibrosis progression in univariate analysis with P < 0.15 were considered for multivariate models. Time between biopsies was included as a covariate in the models as a categorical variable (<2, 2-2.9, 3-3.9, 4+ years). Further variables that had been previously identified as predictors of progression (gender, race, and age) were forced into models regardless of statistical significance. A series of models were built, first including fixed covariates and covariates at first biopsy and then including covariates between serial biopsies. Due to colinearity, separate models were built for laboratory values measured between serial biopsies.

Predictors of interest included fixed characteristics, characteristics at the time of the first biopsy, and characteristics between the serial biopsies. Fixed characteristics included demographics, HCV genotype, and history of alcohol or injection drug use. Characteristics at the time of the first biopsy (within six months) included diabetes, body mass index (BMI), CD4 count, HIV-RNA level, ever and cumulative ART exposure up to the first biopsy, HCV-RNA level, HCV treatment before initial biopsy, cumulative HCV treatment, duration of HCV infection (estimated by age at first injection), median AST and ALT levels, hepatic steatosis, histological necroinflammatory activity, and METAVIR score. BMI was categorized according to the standard classification system as follows: normal 18.5-24.99, overweight 25-29.99, obese ≥30. The presence of diabetes was determined by clinical diagnosis.

Predictors between biopsies included any ART use between biopsies, cumulative ART use between biopsies, change in CD4 cell count and HIV viral load, HCV treatment, change in AST and ALT levels, and change in BMI. HIV viral load and CD4 cell count between biopsies were analyzed as the proportion of CD4 cell counts that were <200 cells/μL and the proportion of HIV RNA measurements that were undetectable (<400 copies/mL). ALT and AST were examined as the cumulative proportion of ALT and AST levels more than 2.5 times the upper limit of normal reference range (AST 37 U/L; ALT 40 U/L). BMI change was defined as greater than a one unit increase or decrease in BMI.

Analyses were performed using SAS v. 9.1 software (SAS Institute, Cary, NC). Approval
This study was approved by the Johns Hopkins Medicine Institutional Review Boards and written informed consent was obtained for all participants.

Results

Study Population

The demographic and clinical characteristics of the study population at initial biopsy are shown in Table 1. The median age was 44.5 years (IQR 40.5, 48.7). The majority of individuals were African American (84.8%), male (67.7%), and infected with HCV genotype 1 (93.4%). A history of injection drug use (76.6%) and alcohol abuse (48%) were frequently reported. The median BMI was 25.4 (IQR 22.5, 29.2). At the time of first biopsy most patients were receiving ART (69.2%) and had been for a median duration of 1.9 years (IQR 0, 4.3). Only 28% of patients had never received ART. The median CD4 cell count was 386 cells/μL and 15.9% had CD4 cell counts <200 cells/μL. The majority of patients (55.9%) had an HIV RNA level below the limit of detection. The median ALT and AST were 47 U/L (IQR 31, 75) and 46 U/L (IQR 33, 71), respectively. AST levels exceeding 100 U/L were observed in 14.7% (40 of 272) of patients at the time of the first biopsy and were associated with clinical history of alcohol abuse and the absence of ART (Supporting Table 2). The median HCV-RNA level was 700,000 IU/mL (IQR 500,000-1,530,000). Most patients (279 of 282, 99%) had not received HCV treatment before initial biopsy.

On initial biopsy, no or minimal fibrosis (METAVIR stage 0 or 1) was identified in 243 patients (86%), whereas 31 patients (11%) had METAVIR stage 2, and eight patients (2.8%) had METAVIR stage 3. With regard to necroinflammatory activity, 173 patients (65.8%) had a score <5 with 90 patients (34.2%) having a score of 5 or greater. Hepatic steatosis (any grade) was observed in 50 patients (12.8%).

Incidence of Fibrosis Progression

The median interval between biopsies was 2.5 years (IQR 2-3.2 years). Fibrosis progression was observed in 97 of 282 (34%) patients between their first and second liver biopsy. Among the 435 biopsy pairs, fibrosis progression was observed in 149 (34%), with 39 biopsy pairs (8.9%) demonstrating an increase of two or more METAVIR fibrosis stages. Notably, fibrosis progression was detected in 45% of 179 pairs in which the initial biopsy of the pair revealed no fibrosis (METAVIR stage 0; Table 2). While the majority of those with progression had stage 1 fibrosis on the second biopsy, 14 biopsy pairs (7.8%) had progression of two or more METAVIR fibrosis stages.

Correlates of Progression at Baseline

Among the 435 biopsy pairs, 149 (34%) had progression of one or more METAVIR stages between biopsies and are referred to as "progressors" (Table 3). Markers of increased hepatic inflammation measured by median AST and ALT as well as noninvasive measures of liver disease (AST-platelet ratio index [APRI] and FIB4 index) were associated with subsequent fibrosis progression. Measures of obesity (BMI, P = 0.02), diabetes (P = 0.01), and hepatic steatosis (P = 0.01) at the time of the first biopsy were associated with progression of fibrosis on the subsequent liver biopsy. Compared to nonobese patients, those with BMI >30 at the time of the initial biopsy had higher AST levels, higher prevalence of steatosis, higher histological activity indexes, and were more likely to be male (Supporting Table 3). The modified histological activity index was not related to fibrosis progression. Measures of biopsy quality including the length of the specimen were not associated with fibrosis progression. The median length was 12 mm among both nonprogressors (IQR 10, 14) and progressors (IQR 9, 14) with a Wilcoxon rank sum test P value of 0.13. Similarly, measures of HIV disease (CD4 cell count, HIV-RNA, ART exposure) at the time of initial biopsy were not significantly different among progressors and nonprogressors. After adjustment for baseline factors in multivariate analysis, AST level >100 IU/mL at the time of the first liver biopsy was independently associated with subsequent fibrosis progression for all biopsy pairs (adjusted odds ratio [aOR] 2.12, 95% confidence interval [CI] 1.06-4.26) but not for biopsy pairs restricted to those with minimal fibrosis (stage 0 or 1) at first biopsy (aOR 1.54, 95% CI 0.63-3.72) (Table 4).

Among pairs METAVIR stage 0 or 1 (n = 371) on initial biopsy, we also characterized the accuracy of elevated AST level (>100 U/L) at the time of the initial liver biopsy in prediction of fibrosis progression. The sensitivity of this threshold was low (13%), with a specificity of 93%. The positive predictive value of AST >100 U/L at baseline was 53%, whereas the negative predictive value was 68%.

Correlates of Progression Between Serial Biopsies

The univariate correlations of exposures between biopsies and progression were similar to those measures at baseline (Table 3). Antiretroviral therapy and suppression of HIV replication between biopsies were not associated with fibrosis progression. The change in CD4 cell count and the proportion of measured HIV-RNA values <400 copies/mL median IQR were also not statistically different between the two groups. Treatment for HCV infection with interferon plus ribavirin was prescribed in between 90 biopsy pairs, 58 (20.5%) of the nonprogressors, and 32 (21.5%) of the progressors (P = 0.81). Of the 90 biopsy pairs, HCV treatment resulted in durable or transient viral response in 17 instances (three in sustained virologic response [SVR] and 14 with relapse). None of the treated progressors achieved SVR, whereas SVR was achieved in three out of 58 treated nonprogressors (P = 0.19).

Similar to baseline correlates, measures of hepatic inflammation were significantly different between progressors and nonprogressors between biopsies. The median AST and ALT levels between biopsies were significantly higher among biopsy pairs with fibrosis progression compared to those without fibrosis progression (P = 0.0004 for ALT and P < 0.0001 for AST). In addition, between biopsies, pairs with fibrosis progression had a significantly greater proportion of ALT and AST values >2.5 times the upper limit of normal compared with those without progression (P = 0.0002 for ALT and P < 0.0001 for AST). Time between biopsies was not associated with progression. After adjustment for baseline and between biopsy factors in multivariate analysis, the proportion of AST level >100 IU/mL between biopsies was independently associated with subsequent fibrosis progression for all biopsy pairs and for biopsy pairs restricted to those with minimal fibrosis (stage 0 or 1) (Table 4). Additional sensitivity analyses were performed to assess the impact of restricting analysis to only the first biopsy in the pair, a change of at least two METAVIR stages, biopsy length, and number of portal tracts and the results were not significantly changed (Supporting Table 4).

Discussion

Effective ART has substantially reduced the incidence of acquired immune deficiency syndrome (AIDS)-related death among HIV-infected adults; among those coinfected with HCV, liver disease has emerged as an important cause of morbidity and mortality. While HIV infection has been consistently associated with more rapid progression of hepatic fibrosis, the mechanisms underlying this association are incompletely understood. In this context, our data related to the incidence and correlates of progressive hepatic fibrosis among 282 HIV/HCV coinfected adults who underwent serial fibrosis staging resulting in 435 paired liver biopsies provide several insights into liver disease progression in HIV/HCV coinfected patients.

The majority of coinfected patients in our prospective cohort had minimal fibrosis on initial liver biopsy. Nonetheless, over a median follow-up time of 2.5 years we observed fibrosis progression (≥1 METAVIR stage) in one-third of individual patients between the first and second liver biopsy (n = 282) and among one-third of all biopsy pairs (n = 435). While the majority of histologic change was limited to one METAVIR stage, progression of two or more stages was found in ~9% of biopsy pairs. Further, nearly 45% of patients with no evidence of hepatic fibrosis on the initial biopsy had at least stage 1 fibrosis on subsequent liver biopsy. This observed incidence of fibrosis progression over a relatively short time interval is consistent with our earlier observations and those reported in other HIV/HCV coinfected patient cohorts in which progressive disease was noted in 17% to 50% of paired histologic evaluations.[3, 9, 10, 21, 22] However, the precision of these prior estimates of progression was limited by small sample size.[9, 21, 22] For example, Schiavini et al.[9]calculated a rate of fibrosis progression of 50% based on analysis of 36 paired liver biopsies. Taken together, these data indicate that progression of HCV disease can occur in HIV/HCV coinfected persons with minimal fibrosis on initial staging. Since most patients had been HCV-infected for many years prior to this first biopsy, this observation suggests that fibrosis progression may be nonlinear in this patient population and underscores the need for serial monitoring in such patients (Supporting Figure 1). Importantly, among persons with minimal disease on first biopsy, the progression was generally limited to one METAVIR stage; as such, serial monitoring allows for the detection of individuals with progressive disease prior to the onset of clinical liver disease such as hepatocellular carcinoma or end-stage liver disease.

We also identified baseline and time-varying factors associated with fibrosis progression between biopsy pairs. Interestingly, HCV genotype 1 was associated with an increased risk of progression in some models. While it is possible that this reflects biological differences in disease related to HCV diversity, our cohort was relatively homogeneous with respect to patient (largely African American) and viral (largely genotype 1) characteristics. As such, this finding requires validation in other settings. Our data confirm the relationship of chronically elevated serum liver enzyme levels, namely AST and ALT levels, and fibrosis progression. While the biologic mechanism underlying the observed relationship of AST level and disease was not directly measured, elevated serum AST levels >100 U/L in our cohort were associated with alcohol abuse and failure to be on ART and may reflect the impact of these factors on disease progression. Similar to our prior study, elevated serum AST at baseline and between histologic assessment were independently associated with progression; HIV/HCV coinfected patients for whom measured AST levels were always <100 U/L were significantly less likely to have evidence of fibrosis progression on the next liver biopsy. Thus, AST level may represent an inexpensive, routinely obtained biomarker to identify persons at greater risk of progressive disease. Interestingly, we found that higher AST levels were associated with clinical history of alcohol abuse and the lack of treatment with antiretrovirals.

Although alcohol is clearly related to HCV disease pathogenesis, accurate assessment of alcohol intake in clinical cohorts may be challenging due to underreporting by patients. The observation that patients with elevated AST levels are at greater risk of progression may represent the effect of undetected alcohol exposure; novel alcohol biomarkers such as phosphatidylethanol or carbohydrate-deficient transferrin may be useful to further assess the contribution of underreported alcohol exposure.[23, 24] Despite the observation that ART exposure was associated with a lower likelihood of having high AST levels, we did not detect an association of ART, HIV RNA suppression, or CD4 cell count with fibrosis progression. In contrast, we recently observed that the receipt of ART was independently associated with a 66% reduction in the risk of HCV-related clinical outcomes including end-stage liver disease, hepatocellular carcinoma, or liver-related death.[25] Taken together, these findings suggest that while the treatment or prevention of HIV disease may reduce liver inflammation and clinical outcomes, ART alone is not sufficient to prevent fibrosis progression in coinfected patients.

We also found that markers of metabolic derangement at initial biopsy were associated with fibrosis progression, although the statistical significance did not persist in all models after multivariate analysis. The impact of obesity and its associated complications, namely hepatic steatosis and diabetes, have appropriately become focal points of investigation in the ART era during which time the metabolic profile of HIV-infected patients has shifted.[26] Our finding of steatosis as a predictor of fibrosis progression is in concordance with recent investigations on this topic that have found the presence of steatosis to be strongly associated with advanced fibrosis.[27-30] In fact, Gaslightwala and Bin[27] found in their investigation of 154 coinfected patients that fibrosis progression rates increased in a linear fashion with the grade of hepatic steatosis. Similarly, diabetes and insulin resistance are additional complications of obesity that have been identified as independent predictors of cirrhosis.[31, 32] Prospective studies are needed to investigate strategies to modify obesity and to assess the impact on the risk of fibrosis progression in HIV/HCV coinfected patients. In the absence of such prospective data, our findings suggest that measures to facilitate weight loss should be a priority in obese coinfected patients and those with a normal BMI should strive to maintain this.

While the major strength of our study is the prospective assessment of histologic disease progression in a large sample of coinfected patients, there are several limitations to our findings. First, our cohort consists primarily of African American patients infected with HCV genotype 1; our findings may not be generalizable to more diverse patient populations including those infected with other HCV genotypes. Second, our patients who underwent serial liver biopsies were engaged in medical care and were willing to undergo multiple liver biopsies; this patient population may differ from coinfected patients who were not referred for care. Noninvasive methods of fibrosis assessment such as liver elastography may be a useful tool to overcome this potential bias. Third, few HCV/HIV coinfected patients who were successfully treated for HCV underwent serial liver biopsy; while not unexpected, this limits our ability to assess the impact of HCV eradication on disease progression. Finally, studies based on liver biopsy are subject to sampling error and misclassification. To limit misclassification, biopsies were read as pairs by a single expert hepatopathologist who was blind to biopsy sequence. The criteria for adequacy of the biopsy specimen used in our cohort may also represent a limitation since we did not apply specific criteria for adequacy based on length or number of portal tracts. However, sensitivity analysis in which such criteria were applied did not change our findings. Finally, while it is possible that some patients with apparent fibrosis progression reflect sampling error, only 33 of 256 biopsy pairs with fibrosis on the first biopsy of the pair had evidence of fibrosis regression (12.8%), suggesting that misclassification was not common.

In conclusion, approximately one-third of HIV/HCV coinfected patients experienced fibrosis progression of at least one METAVIR stage over a relatively short period of time, including patients with no or minimal fibrosis on first biopsy and those taking ART. Patients with persistent liver enzyme elevation, particularly of serum AST, were more likely to progress, suggesting that this simple measurement may be useful in identifying coinfected patients at greater risk for HCV disease progression. The association of obesity and its related complications with fibrosis progression underscores the potential importance of this modifiable risk factor. However, our limited ability to accurately predict progression in most patients, underscores the need for additional research to understand the basis for variable HCV disease progression in HIV-infected patients.

Source

Treatment failure may lead to accelerated fibrosis progression in patients with chronic HCV

J Viral Hepat. 2014 Feb;21(2):111-20. doi: 10.1111/jvh.12127. Epub 2013 Aug 27.

Baran B, Gulluoglu M, Soyer OM, Ormeci AC, Gokturk S, Evirgen S, Yesil S, Akyuz F, Karaca C, Demir K, Kaymakoglu S, Besisik F.

Abstract

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01-1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81-19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

© 2013 John Wiley & Sons Ltd.

KEYWORDS: fibrosis progression, gamma-glutamyl transferase, hepatitis C, nonresponder, treatment failure

PMID: 24383924 [PubMed - in process]

Source

Progression of Liver Disease in Children with Chronic HCV Infection

Provided by NEJM Journal Watch

November 21, 2013

Atif Zaman, MD, MPH reviewing Mohan P et al. Hepatology 2013 Nov.

Histologic changes were slow overall but did include a significant increase in bridging fibrosis or cirrhosis.

The rate of liver disease progression with hepatitis C virus (HCV) infection is well characterized in adults but not in children. Although most study data from Asia and Europe suggest that liver disease progression in children with HCV infection is very slow, data from several U.S. studies indicate that it is still a risk.

In the current retrospective study, investigators compared histologic findings from repeat biopsies in 44 treatment-naive children with HCV infection who were enrolled in a larger randomized treatment trial. Data were from two biopsies taken at least 1 year apart (mean time interval, 5.8±3.5 years). HCV infection was contracted via vertical transmission in 57% of children and via blood transfusion in the rest (except for 2 participants with unknown mode of transmission). The prevalence of genotype 1 infection was 84%.

Analyses of the repeat biopsies showed the following:

• Persistent minimal inflammation in 50% of patients

• Persistent absence of fibrosis in 16% of patients

• An increase in bridging fibrosis or cirrhosis from 11% to 20% (P=0.005)

• No correlation between worsening fibrosis and mode of HCV infection acquisition or demographic, clinical, or laboratory variables

Comment

This is the largest study to date evaluating the histologic progression of hepatitis C virus infection in the pediatric population. In general, histologic progression was quite slow during a 5-year time span in the majority of patients, but, similar to the adult population, a significant minority did have histologic progression. With the advent of more-effective, better-tolerated treatment regimens for HCV infection, considering HCV treatment in the pediatric population will be important, as these patients face many decades of infection and increased risk for histologic progression without treatment.

Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex

Citation(s):

1. Mohan P et al. Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: A retrospective study. Hepatology 2013 Nov; 58:1580. (http://dx.doi.org/10.1002/hep.26519)

Source

Dietary Cholesterol Intake Is Associated With Progression of Liver Disease in Patients With Chronic Hepatitis C: Analysis of the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial

Clinical Gastroenterology and Hepatology
Volume 11, Issue 12 , Pages 1661-1666.e3, December 2013

Lei Yu, Chihiro Morishima, George N. Ioannou

published online 28 May 2013.

Abstract

Background & Aims

Little is known about whether dietary cholesterol affects disease progression in patients with chronic hepatitis C virus infection.

Methods

We analyzed data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, which included patients with advanced fibrosis and compensated cirrhosis. Cholesterol intake was determined for 608 participants on the basis of responses to food frequency questionnaires, administered at baseline and 1.8 years later. We investigated whether cholesterol intake was associated with clinical progression (death, variceal bleeding, encephalopathy, ascites, peritonitis, Child–Turcotte–Pugh score ≥7, or hepatocellular carcinoma) or histologic progression of disease (an increase in Ishak fibrosis score of 2 or more points in a second liver biopsy compared with the first).

Results

After adjustments for age, sex, race, presence of cirrhosis, body mass index, treatment with peginterferon, lifetime alcohol consumption, smoking, health status, and coffee and macronutrient intake, each higher quartile of cholesterol intake was associated with a 46% increase in the risk of clinical or histologic progression (adjusted hazard ratio [AHR], 1.46; 95% confidence interval [CI], 1.13–1.87; P for the trend = .004). Compared with patients in the lowest quartile of cholesterol intake (32–152 mg/day), those in the 3rd (224–310 mg/day; AHR, 2.83; 95% CI, 1.45–5.51) and 4th quartiles (>310 mg/day; AHR, 2.74; 95% CI, 1.22–6.16) had significantly increased risk of disease progression.

Conclusions

On the basis of analysis of data from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis trial, higher dietary cholesterol intake is associated with higher risk of disease progression in HCV-infected patients with advanced fibrosis or compensated cirrhosis.

Keywords: Diet, Cholesterol, Hepatitis C, Cirrhosis

Abbreviations used in this paper: AHR, adjusted hazard ratio, BMI, body mass index, CI, confidence interval, CTP, Child–Turcotte–Pugh,FFQ, food frequency questionnaire, HALT-C, Hepatitis C Antiviral Long-term Treatment Against Cirrhosis, HCC, hepatocellular carcinoma,HCV, hepatitis C virus, MTP, microsomal triglyceride transfer protein, TLR, Toll-like receptor

Source

Sirolimus reduces the risk of significant hepatic fibrosis after liver transplantation for hepatitis C virus: a single-center experience

Transplant Proc. 2013 Nov;45(9):3325-8. doi: 10.1016/j.transproceed.2013.04.011.

Kelly MA, Kaplan M, Nydam T, Wachs M, Bak T, Kam I, Zimmerman MA.

Division of Transplant Surgery, University of Colorado Health Sciences Center, Aurora, Colorado, USA. Electronic address: Mara.Kelly@ucdenver.edu.

Abstract

INTRODUCTION: Hepatitis C virus (HCV) recurrence following orthotopic liver transplantation is an expected outcome in all patients transplanted for a primary diagnosis of HCV. HCV recurrence has been shown to be associated with graft fibrosis and graft loss. Recent studies suggest that sirolimus (SRL) therapy may slow or inhibit hepatic fibrosis following liver transplant in patients positive for HCV at the time of transplant.

METHODS: Among 313 patients who underwent orthotopic liver transplantation for HCV between 2000 and 2009, 251 qualified for inclusion in the study. Per protocol liver biopsies were performed on all patients at 1 year following liver transplantation and/or at the time of a clinical diagnosis of HCV recurrence. Biopsies were scored for fibrosis using the Batts-Ludwig staging system (0-4); significant fibrosis was defined as fibrosis ≥ stage 2.

RESULTS: Overall, there was no difference in overall survival or graft loss in the SRL compared with the control group. Multivariate analysis revealed SRL therapy to be associated with decreased odds of significant hepatic fibrosis at year 1 postoperatively and over the study duration.

CONCLUSIONS: This retrospective, single-center study showed sirolimus-based immunosuppression to be associated with a lower risk of significant graft fibrosis, both at year 1 and throughout the study period, following liver transplantation in HCV-infected recipients.

Copyright © 2013. Published by Elsevier Inc.

PMID: 24182811 [PubMed - in process]

Source

Watchful waiting: role of disease progression on uncertainty and depressive symptoms in patients with chronic Hepatitis C

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

J. P. Colagreco^1,*,D. E. Bailey²,J. J. Fitzpatrick³,C. M. Musil³,N. H. Afdhal¹,M. Lai¹

Article first published online: 7 NOV 2013

DOI: 10.1111/jvh.12207

© 2013 John Wiley & Sons Ltd

\Article first published online: 7 NOV 2013
Manuscript Accepted: 11 SEP 2013
Manuscript Received: 10 MAY 2013

Keywords: depression; fibrosis; hepatitis C; uncertainty; watchful waiting

Summary

Background and Aims: New therapies for HCV are rapidly emerging and providers are advising select patients to defer treatment and elect ‘watchful waiting’. During the watchful waiting period, patients have been shown to have high rates of illness uncertainty and depression. We sought to answer the question of whether reassuring histological data (showing minimal fibrosis or no fibrosis progression over time) is associated with less illness uncertainty and depressive symptoms.

Methods: This was a single-centre outpatient prospective cohort study to determine whether stage of fibrosis, fibrosis progression and reasons for treatment deferral were related to illness uncertainty and depressive symptoms in patients following watchful waiting.

Results: Illness uncertainty was significantly related to depressive symptoms (r = 0.49, P < 0.01). More than half of the participants (54%) had moderate levels of uncertainty. About 40% of the participants were at risk for clinical depression (21.7% at mild to moderate risk and 18.5% at high risk). Treatment naïve subjects had lower mean scores on both the CES-D (depressive symptoms measure) and the MUIS-A (illness uncertainty measure) total score, MUIS-A Ambiguity subscale and MUIS-A Inconsistency subscale than subjects who failed treatment or were interferon intolerant or ineligible. Surprisingly, liver fibrosis stage and progression were not significantly associated with overall illness uncertainty or depressive symptoms.

Conclusion: Patients with chronic hepatitis C on watchful waiting are at high risk for significant illness uncertainty and depressive symptoms. Reassuring histological data does not seem to correlate with less uncertainty or depressive symptoms.

Source

Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

Original Article

B. Baran¹, M. Gulluoglu², O. M. Soyer¹, A. C. Ormeci¹, S. Gokturk¹, S. Evirgen¹, S. Yesil², F. Akyuz¹, C. Karaca¹, K. Demir¹, S. Kaymakoglu¹, F. Besisik^1,*

Article first published online: 27 AUG 2013

DOI: 10.1111/jvh.12127

© 2013 John Wiley & Sons Ltd

Abstract

Keywords: fibrosis progression; gamma-glutamyl transferase; hepatitis C; nonresponder; treatment failure

Summary

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01–1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81–19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.

Source

Women With Chronic Hepatitis C Virus Infection

Southern Medical Journal

Recommendations for Clinical Practice

Mary Jane Burton, MD, James B. Brock, MD, Stephen A. Geraci, MD

South Med J. 2013;106(7):422-426.

Abstract and Introduction

Abstract

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited.

Introduction

Approximately 3 million people in the United States are chronically infected with the hepatitis C virus (HCV),^[1] which is transmitted primarily through contact with the blood of an infected person. Acute infection resolves in approximately 20% of cases and the rest develop chronic infection.^[2] The major sequelae of chronic HCV infection are cirrhosis and hepatocellular carcinoma.^[2] The clinical course varies widely among individuals, with sex influencing the natural history and clinical outcomes. Understanding the unique features in women will assist clinicians in managing female patients with chronic HCV infection.

Prevalence and Natural History of HCV in Women

Since the implementation of blood product screening, injection drug use (IDU) has become the most common mode of HCV acquisition.^[1] Sex does not affect the risk of acquiring HCV. Although women in the United States historically have demonstrated a lower prevalence of HCV infection,^[3] their sex likely reflected their lower rate of IDU^[4] because sex differences in HCV prevalence are not seen in other cultures.^[5] In addition, a meta-analysis of 30 studies reported that female prison inmates are 40% more likely than are male prison inmates to be infected with HCV.^[6] Female injection drug users also exhibit higher rates of HCV infection than their male counterparts,^[7,8] a difference that is related to behavior rather than biology: Female injection drug users frequently share injection equipment and engage in unsafe sex practices,^[7,9] including having intercourse with people with whom they also inject drugs.^[10,11]

Although sex does not appear to affect the risk of HCV infection, it does influence its outcome. A systematic review of 31 longitudinal studies found that 40% of women versus 19% of men will resolve acute HCV infection.^[12] Genome-wide association studies have reported that genetic variation surrounding the interleukin-28B (IL-28B) locus is associated with enhanced response to interferon-based therapies and spontaneous resolution of HCV infection.^[13] A cohort study of Danish injection drug users noted that women with favorable IL-28B genotypes were six times as likely as women with unfavorable genotypes to spontaneously clear HCV infection;^[14] however, even when controlling for the IL-28B genotype, women remain more likely than men to spontaneously clear HCV infection.^[15]

Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure.^[16] The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis.^[17] Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies.^[18,19] This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver.^[20] Animal models suggest that estrogen suppresses hepatic fibrosis,^[21–23] and a recent in vitro study proposed that estrogen inhibits the production of HCV virions.^[24] Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause.^[25,26] In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis;^[20] however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.^[20]

Modifiable Risks for Progression of Liver Disease

Excessive alcohol intake accelerates the progression to HCV-related cirrhosis. Studies demonstrate consumption of >30 g/day increases the risk for cirrhosis in hepatitis C threefold.^[27] Current guidelines stress the importance of abstinence from alcohol for all patients with HCV.^[28] Accumulating evidence suggests that women infected with HCV are more vulnerable than their male counterparts to the effects of alcohol.^[20] A prospective study illustrated that women who consumed >20 g/day doubled their risk for increased fibrosis, whereas men required >30 g/day to reach a similar risk increment.^[29] Healthcare providers should encourage women with chronic HCV to abstain from alcohol or, alternatively, to limit intake to an equivalent of 12 g/day of ethanol.

Increased body mass index (BMI) also appears to accelerate disease progression, regardless of sex. Multiple studies have illustrated an increased risk for progression of liver disease in patients who are overweight (BMI ≥ 25 kg/m²) or obese (BMI ≥ 30 kg/m²).^[30–32] In a small prospective study of patients with chronic hepatitis C, a mean body weight reduction of 5.9 (±3) kg resulted in lower alanine aminotransferase levels and reduced levels of fibrosis on liver biopsy;^[33] thus, even modest weight loss may reduce the risk of the progression of liver disease.

Effect of Sex and Age on Treatment Response

The primary goal of treatment of HCV is the prevention of cirrhosis and hepatocellular carcinoma by eradicating the virus. The surrogate marker for viral eradication is a sustained virologic response (SVR), defined as an undetectable serum HCV viral load 6 months after completing therapy. Studies of hepatic C therapeutics that examined SVR rates by sex reported conflicting findings. Overall, men and women appear to have equal responses to pegylated interferon and ribavirin.^[34,35] When stratified by age, however, SVR rates for women dramatically decline with older age, a phenomenon that has not been observed in men^[36–38] (). Similar to their protective effects on the progression of liver disease, higher estrogen states are hypothesized to promote SVR.^[37] Studies of telaprevir or boceprevir in combination with pegylated interferon and ribavirin illustrate equivalent response rates among men and women with genotype 1 HCV^[39–42] (). These studies did not further stratify women by age, although in some studies older age was associated with overall lower rates of SVR.^[35,43]

Table 1.  Studies that stratified sustained virologic response to interferon-based therapies by sex and age

Study	Women		P	Men		P
	Age group, y	SVR, %		Age group, y	SVR, %
Hayashi et al36	<40	75	<0.0001	<40	33	<0.001
	≥40	16		≥40	25
Sezaki et al37	<50	71	0.03	<50	69	0.41
	≥50	32		≥50	63
Villa et al38	Premenopausal	68	<0.0001	<45	59	0.114
	Postmenopausal	46		≥55	50

SVR, sustained virologic response.

Table 2.  Summary of SVR rates by sex for phase III studies examining the addition of telaprevir or boceprevir to pegylated interferon and ribavirin

Study	Drug	SVR rate, women (%)	SVR rate, men (%)
Treatment naïve
ILLUMINATE39	Telaprevir	77/89 (87)	169/197 (86)
SPRINT-240	Boceprevir	181/284 (64)	294/450 (65)
Treatment experienced
REALIZE39,41	Telaprevir	103/158 (65)	247/372 (66)
RESPOND-242	Boceprevir	68/118 (60)	134/210 (63)

ILLUMINATE, Illustrating the Effects of Combination Therapy with Telaprevir; REALIZE, Retreatment of Patients with Telaprevir-based Regimen to Optimize Outcomes; RESPOND-2, Retreatment with HCV Serine Protease Inhibitor and PegIntron/Rebetol 2; SPRINT-2, Serine Protease Inhibitor Therapy-2; SVR, sustained virologic response.

Pregnancy and Breast-feeding

Women with advanced liver disease are at increased risk for complications during pregnancy, but the effects of maternal HCV infection on natal outcomes are less well defined.^[44] Recent evidence suggests that HCV infection may increase the risks for gestational diabetes, low birth weight, and neonatal intensive care unit admission.^[45,46] Modifiable risk factors, such as IDU and limited prenatal care, may be more prevalent in patients with HCV,^[41] which could confound data on maternal and fetal outcomes.

Pregnancy may improve the natural course of HCV infection. In the second and third trimesters, alanine aminotransferase levels decrease, whereas serum levels of HCV RNA increase.^[47] This could imply that decreased hepatocyte damage, possibly related to increased estrogen levels and/or placental interferon production, occurs during pregnancy. Although alanine aminotransferase and HCV RNA serum concentrations return to prepregnancy levels within several months of delivery, women with multiple gestations do exhibit slower disease progression.^[21]

Vertical transmission is the major cause of HCV infection in children.^[45] Maternal–infant transmission occurs in roughly 5% of cases in which the mother is infected with HCV,^[48] but recommendations regarding prevention are limited by insufficient high-quality data. The timing of transmission also is poorly understood; evidence exists for both in utero and transvaginal transmission.^[49] Frequently identified risk factors for vertical transmission are high maternal HCV viral load and human immunodeficiency virus (HIV) co-infection.^[50,51] Prolonged rupture of membranes (>6 hours) has been associated with more frequent perinatal transmission.^[50] In addition, some experts recommend avoiding invasive procedures that promote fetal exposure to maternal blood, such as fetal scalp monitoring.^[50,52] Elective cesarean section has been proposed to reduce the risk of vertical transmission;^[53] however, this practice is not recommended for women infected with HCV unless they are co-infected with HIV.^[52] Some studies have reported that because an elevated serum viral load increases the risk of transmission,^[50,51] women who achieve remission from HCV before conception may reduce their risk of transmitting the virus to their fetuses.

Although HCV RNA has been detected in breast milk and colostrum,^[54] breast-feeding does not appear to be a primary route of maternal–infant HCV transmission.^[50,55] Some experts believe that the quantity of virions in these bodily fluids is insufficient to result in infection and that gastric acid exerts a protective effect.^[52] Mothers infected with HCV are encouraged to breast-feed in the absence of other contraindications, such as HIV-1 co-infection, but they should be counseled that there is limited study on this topic.^[56] The Centers for Disease Control and Prevention propose temporary interruption of breast-feeding when the mother has cracked, bleeding, or traumatized nipples, which could increase exposure of the infant to HCV.^[57]

Antiviral Therapy in Women

Choosing when to initiate HCV therapy in women can be challenging, particularly with regard to maternal age and family planning. There is evidence that advanced age decreases the likelihood of an SVR in women more so than in men.^[29,30] Given the risk of vertical transmission, it may be preferable to complete treatment in women of reproductive age before they conceive. Because use of ribavirin is contraindicated in pregnancy, women of childbearing age who are considering therapy for HCV require careful counseling regarding the potential danger to a child conceived during the treatment period.

Although ribavirin has not been studied formally in human gestation, several animal studies have demonstrated significant embryocidal and teratogenic effects; as a result, ribavirin is contraindicated during pregnancy (pregnancy category X).^[58] The serum half-life of ribavirin is 12 days; the drug also is pooled in erythrocyte populations, which can result in prolonged postadministration exposure.^[59] Two forms of effective contraception are required during and 6 months following therapy with ribavirin in women capable of conception.^[58] Women who are capable of conception should be aware that if their male partners are receiving ribavirin, then the use of two forms of contraception during and 6 months after treatment is recommended. In addition, women of childbearing age should take a pregnancy test before treatment initiation and submit to monthly pregnancy tests during the treatment period.^[58] Because ribavirin has not been studied in human pregnancy, women inadvertently exposed to ribavirin 6 months before or during pregnancy should consider enrollment in the Ribavirin Pregnancy Registry (www.ribavirinpregnancyregistry.com).

The effects of interferon on the fetus are uncertain (pregnancy category C). Interferon-[alpha] does not appear to cross the placental barrier or demonstrate teratogenic effects.^[60] Case studies of pregnant women with leukemia have not demonstrated fetal malformation associated with interferon use, but intrauterine growth retardation has been observed in this setting.^[61]

Boceprevir and telaprevir have been assigned to pregnancy category B by the Food and Drug Administration; however, these medications are administered exclusively with ribavirin and pegylated interferon-[alpha], precluding any use during pregnancy. Both drugs are potent CYP3A4 substrates and inhibitors, resulting in many potentially dangerous interactions with other drugs, including oral contraceptives. Telaprevir and boceprevir may cause systemic hormonal contraceptives to be unreliable during concurrent administration.^[62,63] Drosperinone concentrations double in the presence of boceprevir, contraindicating coadministration because of concern for potentiating hyperkalemia.^[63] Barrier methods and intrauterine devices are the preferred methods of contraception in women receiving boceprevir or telaprevir in combination with pegylated interferon-[alpha] and ribavirin.^[55,56] Given the wide range of drug–drug interactions involving these agents, close review of package inserts or consultation with a clinical pharmacist is recommended in patients receiving concomitant medications during therapy.^[64]

Conclusions

The natural history of HCV infection differs between women and men. Women are more likely than men to clear acute HCV infection. With chronic HCV infection, women experience a slower progression to cirrhosis and are less likely than men to develop hepatocellular carcinoma. Accelerated disease progression occurs in postmenopausal women; older women also have lower rates than younger women of SVR to pegylated interferon and ribavirin. Infected women of childbearing age should be educated about the risks of perinatal HCV transmission and the potential teratogenicity of current treatment regimens. All women with HCV should be counseled on the effects of alcohol and obesity on the progression of liver disease.

Sidebar

Key Points

• In the absence of comorbid conditions, women with hepatitis C virus (HCV) infection experience a slower progression to cirrhosis and a lower risk of hepatocellular carcinoma.
• Following menopause, the incidence of liver damage increases and women become less responsive to interferon-based therapies for chronic HCV infection.
• Abstinence from alcohol and maintenance of a healthy weight reduce the risk of liver disease progression in patients with chronic HCV.
• Achieving a sustained virologic response before conception may reduce substantially the risk of vertical HCV transmission; however, current therapies carry risks of fetal malformation.
• Fertile women who receive pegylated interferon and ribavirin should be counseled to use two forms of contraception. Because of drug–drug interactions with estrogen-based oral contraceptives, this form of birth control is unreliable in women receiving telaprevir or boceprevir.

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