August 29, 2010

Hepatitis C and End-stage Liver Disease

Current Hepatitis Reports
DOI: 10.1007/s11901-010-0056-0
 
Diane M. Settles and Rakesh Vinayek
 
Online First™, 27 August 2010
 
Abstract
 
Cirrhosis secondary to infection with hepatitis C virus (HCV) is one of the leading causes of end-stage liver disease worldwide. The World Health Organization estimates that about 3% of the world population is chronically infected with HCV, with about 4 million infected individuals in the United States. Despite the declining US incidence of HCV, the complications of chronic HCV infection are rising rapidly. The cirrhosis can be classified as compensated or decompensated based on clinical complications. Compensated HCV-related cirrhosis can be treated safely per American Association for the Study of Liver Diseases guidelines. Treatment of decompensated HCV-related cirrhosis is challenging secondary to increased risk of complications and adverse effects during the course of antiviral therapy. The recommended treatment is the low, but accelerating dose regimen. HCV-related cirrhosis is associated with complications including ascites, variceal bleeding, renal insufficiency, hepatic encephalopathy, and hepatocellular carcinoma. Because of its poor prognosis, liver transplantation is the only definitive therapy for decompensated cirrhosis.

Keywords Hepatitis C - Cirrhosis - Portal hypertension - Complications of cirrhosis - Hepatocellular carcinoma - Variceal bleeding

Source
 
(Reprinted with kind permission from Springer Science+Business Media)
The Journal of Infectious Diseases 2010 Sept Early publication

Josiah D. Rich and Lynn E. Taylor

Brown Medical School and Miriam Hospital Immunology Center, Brown University, Providence, Rhode Island

"This group is the first to our knowledge to develop a microculture assay to detect viable HCV in small volumes of blood found in syringes. This work suggests that the duration of survival of HCV in used syringes and the amount of residual blood inside the syringe are important parameters for understanding transmission. The ability to use cultured virus to explore transmission mechanisms and develop prevention interventions has the potential to revolutionize the field. There has already been an improved understanding of the role played by biocides for HCV treatment [20].

Heimer's earlier work employed similar methods to illuminate the transmission dynamics of HIV during injection drug use [21, 22]. His group demonstrated that HIV can survive in a syringe for months. This finding, along with his team's elegant mathematical modeling studies, proved that reducing syringe circulation time could lead to reduced HIV transmission. This provided critical early evidence in support of needle exchange programs (NEPs). NEPs have had a huge impact on the reduction of HIV transmission. However, NEPs do not seem to have had as dramatic an effect on the reduction of HCV transmission among IDUs; Heimer's HCV transmission model may facilitate understanding of why this is so. It is estimated that an individual IDU injects 1000 times a year. HCV transmission remains unrestrained among IDUs, with incidence rates ranging from 16% to 42% per year [25]. This novel investigation provides robust evidence about the dynamics of viral transmission with syringes, using simulated injecting practices. More importantly, the ability to culture HCV heralds a new era in which the combination of basic laboratory, epidemiologic, and ethnographic research should allow a much more precise understanding of HCV transmission and pave the way for designing and targeting future public health interventions to prevent HCV infection."

Hepatitis C virus (HCV) infection is a staggering problem in the United States and worldwide. In the United States, HCV is responsible for 12,000 deaths each year, is the most common bloodborne pathogen, and is a leading cause of liver transplantation. Although more than 4 million people in the Unites States and 180 million worldwide (about 3%) are chronically infected, most are not aware of their diagnosis. The disease burden and mortality from HCV infection are predicted to increase in the United States 2-fold to 3-fold over the next 10-20 years as the number of persons with long duration of infection grows. This will greatly affect individual and public health and will lead to a substantial economic burden as well. Most HCV-related mortality is occurring in men <60 years of age (and disproportionately among non-Hispanic black men [1]), which makes HCV a leading infectious cause of years of potential life lost. Death due to HCV infection is the most frequent cause of non-AIDS-related death for human immunodeficiency virus (HIV)-infected persons with access to highly active antiretroviral therapy [2].

Since the discovery of a reliable test for HCV antibodies in 1990 [3], we have learned a great deal about the virus-that it leads to chronic infection in about 85% of exposures, that those who are infected have an average chance of 20% of developing cirrhosis after 20 years, and that those who consume alcohol, as well as those who are coinfected with HIV, are much more likely to progress to cirrhosis and death than others. Although HCV is curable, and antiviral HCV treatment leading to viral eradication reduces liver-related morbidity and mortality, treatment with pegylated interferon plus ribavirin is burdensome, toxic, expensive, and ineffective for half of those who attempt therapy [4-6]. Treatment initiation rates are low across varied settings [7-11]. Most patients diagnosed with chronic HCV infection have not received antiviral therapy. This is due, in part, to restrictive treatment criteria excluding patients with concomitant substance use that led to the infection in the first place [12]. The treatment landscape is on the verge of a paradigm shift with the impending launch of specifically targeted antiviral therapy for HCV (STAT-C) to inhibit HCV-specific enzymes. Along with higher anticipated cure rates will come higher costs of therapy, increased toxicity, thrice daily pill dosing, and the introduction of resistance. The lack of an HCV vaccine and limitations of treatment highlight the imperative of developing strategies to prevent HCV transmission.

Although perinatal and sexual transmission occur (including sexual transmission among HIV-infected men who have sex with men [13]), the HCV epidemic is predominantly driven by the injection of illicit drugs [14]. Before 1992, when widespread screening of the blood supply began in the United States, HCV was also commonly spread through blood transfusions and organ transplants. Testing of blood donors for HCV RNA by means of nucleic acid amplification was introduced in the United States as an investigational screening test in mid-1999 to identify donations made during the window period before seroconversion [15]. In the United States, iatrogenic transmission has been almost completely eliminated with screening of the blood supply. However, there are still incidents of transmission, such as the 2007 HCV outbreak at a freestanding private endoscopy clinic in Nevada, resulting from reuse of syringes and use of single-use medication vials on multiple patients [16, 17].

Outside of the Unites States, one of the worst iatrogenic outbreaks of HCV infection occurred in Egypt where, from the 1960s to the 1980s, a mass campaign to eradicate schistosomiasis using repeated intravenous antischistosomal therapy inadvertently infected a generation. Decades later, the overall prevalence of HCV antibody is 15%-20% of the general population [18]. Clearly, the intravenous aspect of this campaign markedly increased the transmission rate. In the absence of mass treatment campaigns using intravenous medication, similar outbreaks are not anticipated. However, acute HCV infection is typically clinically silent, and routine screening for HCV is not recommended or done, so iatrogenic transmission of HCV may be more common than we know.

During intravenous injection by injection drug users (IDUs), blood (and any bloodborne virus such as HCV) is typically drawn up into the syringe to locate the vein, thus contaminating the inside of the syringe and creating an effective tool for transmission of whatever bloodborne pathogen is then lining the syringe. IDUs often lack knowledge about safe injection practices and the need for sterility and also often lack the necessary tools (ie, sterile syringes, diluent, mixing containers [cookers], and filters [cotton]) to prevent viral transmission.

Injection drug use remains a hidden and stigmatized behavior. Addiction is a chronic relapsing disease that is highly treatable, although most people do not get the treatment that they need. Preventive efforts should focus on IDUs, but this has not transpired on the massive scale required. IDUs have been overlooked in part because of the challenges involved in working with this population, the difficulty in finding IDUs, and the underlying stigma. In the United States, society's major response to addiction in terms of resources has been to criminalize and further drive underground the behavior, often alienating people from treatment, which then leads to negative health and social consequences. Most IDUs are incarcerated at some point, and this has contributed to an unprecedented rate of incarceration. This "intervention" is expensive and ultimately ineffective. However, while we work to redirect policies and resources toward evidence-based prevention, treatment, and harm reduction, mass incarceration allows us to find IDUs and provides opportunities to address prevention, diagnosis, and treatment of addiction and HCV infection in the correctional setting.

HCV is much more prevalent than HIV among IDUs, and yet the reason for this has not been fully elucidated. Are key determinants the differences in viral viability in syringes, the concentration of the virus, the volume of blood remaining in the syringes, or other factors? The increased prevalence of HCV among IDUs certainly contributes to the difference (with a higher prevalence of HCV, a given syringe is more likely to have been used by someone infected with HCV than someone with HIV) but probably does not explain it completely. Answering these questions has, until very recently, been hampered by the inability to culture HCV and the lack of a small animal model of HCV transmission.

In this issue of the Journal, Paintsil et al [19] have contributed to our understanding of the biological mechanisms of HCV transmission by developing an experimental model of injection drug use by using cultured virus from HCV-contaminated syringes. This group is the first to our knowledge to develop a microculture assay to detect viable HCV in small volumes of blood found in syringes. This work suggests that the duration of survival of HCV in used syringes and the amount of residual blood inside the syringe are important parameters for understanding transmission. The ability to use cultured virus to explore transmission mechanisms and develop prevention interventions has the potential to revolutionize the field. There has already been an improved understanding of the role played by biocides for HCV treatment [20].

Heimer's earlier work employed similar methods to illuminate the transmission dynamics of HIV during injection drug use [21, 22]. His group demonstrated that HIV can survive in a syringe for months. This finding, along with his team's elegant mathematical modeling studies, proved that reducing syringe circulation time could lead to reduced HIV transmission. This provided critical early evidence in support of needle exchange programs (NEPs). NEPs have had a huge impact on the reduction of HIV transmission. However, NEPs do not seem to have had as dramatic an effect on the reduction of HCV transmission among IDUs; Heimer's HCV transmission model may facilitate understanding of why this is so. Furthermore, although noninjection drug use has been epidemiologically linked to HCV transmission (perhaps through the use of contaminated drug-sniffing implements [23, 24]), it is possible that noninjection drug use is really just a marker for illicit, undetected injection drug use. Using simulated laboratory studies with cultured virus should contribute to understanding the mechanism(s) and relative contribution of noninjection drug use to HCV transmission.

It is estimated that an individual IDU injects about 1000 times a year. HCV transmission remains unrestrained among IDUs, with incidence rates ranging from 16% to 42% per year [25]. This novel investigation provides robust evidence about the dynamics of viral transmission with syringes, using simulated injecting practices. More importantly, the ability to culture HCV heralds a new era in which the combination of basic laboratory, epidemiologic, and ethnographic research should allow a much more precise understanding of HCV transmission and pave the way for designing and targeting future public health interventions to prevent HCV infection.

Source
 
Also See: Survival of Hepatitis C Virus in Syringes: Implication for Transmission among Injection Drug Users
Download the PDF Here

(from Jules: again, the 2nd recent study providing I think good evidence to consider early HCV treatment)

Hepatology Sept 2010 Timothy R. Morgan1,2,*, Marc G. Ghany3, Hae-Young Kim4, Kristin K. Snow4, Mitchell L. Shiffman5, Jennifer L. De Santo6, William M. Lee7, Adrian M. Di Bisceglie8, Herbert L. Bonkovsky9, Jules L. Dienstag10, Chihiro Morishima11, Karen L. Lindsay12, Anna S. F. Lok13

"Durability of SVR: Ninety-one SVR patients had follow-up HCV R NA testing performed an average of 78.6 ± 15.9 months (range: 22.1-99.6 months) after achieving SVR, and 90 of the 91 (99%) had undetectable HCV RNA in serum"

"In summary, we found that patients with advanced chronic hepatitis C who achieved SVR had significantly lower rates of death from any cause or liver transplantation, and of liver-related morbidity and mortality, compared to patients who failed to eliminate HCV with treatment (NR). Still, patients who achieved SVR remained at risk of HCC for at least 6 years after achieving SVR. Our study also showed that patients who had temporary, but complete viral suppression (BT/R) were less likely to die or undergo liver transplantation, or to experience liver-related complications than patients in the NR group, indicating that the duration of clinical benefit may outlast the period of actual viral suppression. Importantly, laboratory tests associated with liver-disease severity (e.g., platelet count, albumin) continued to improve after patients achieved SVR. Overall, our data indicate that patients with chronic hepatitis C and advanced hepatic fibrosis who achieve SVR have a marked reduction in the risk for death or liver transplantation, or of liver-related complications, and continued improvement in laboratory markers of liver function in the 5-6 years following successful viral eradication."

"An interesting and heretofore unreported finding was the intermediate risk of clinical outcomes in the BT/R group, between the risk of that for the NR and the SVR groups. In particular, the adjusted risk of death from any cause/liver transplantation or of any liver-related outcome was significantly lower in the BT/R group than in the NR group. The risks of decompensated liver disease, HCC, and liver-related death or liver transplantation were also lower in the BT/R group than in the NR group, although these differences did not reach statistical significance. These findings suggest that complete viral suppression is associated with a reduced risk of clinical outcomes and that the benefits may outlast the period in which HCV RNA is undetectable.16"


Abstract

Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. Conclusion: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/li ver transplantation, and in liver-related morbidity/mortality, altho ugh they remain at risk for HCC.

Clinical Outcomes of SVR Patients.

Five patients who achieved SVR (3.6%) had six liver-related clinical outcomes (Table 2). One patient (patient A) had a 3-cm lesion detected on ultrasound performed for his amended study clinic visit, 7.3 years after his baseline visit and 5.8 years after achieving SVR. At entry into the HALT-C Trial, he had a liver biopsy with an Ishak fibrosis score of 4 and his platelet count was 112,000/mm3. The resected specimen revealed a well-differentiated HCC; cirrhosis was present in the nontumor liver. Another patient (patient B) who had an Ishak fibrosis score of 3 on his baseline liver biopsy was found to have a 15-cm lesion on magnetic resonance imaging performed to evaluate an elevated AFP during a routine follow-up visit 5.8 years after his baseline visit and 4.4 years after achieving SVR. Biopsy of the lesion confirmed the presence of HCC and cirrhosis in the adjacent liver. This patient died of progressive HCC 4 months later. After magnetic resonance imaging was performed, a third patient (patient G) was found to have a 1.3-cm liver mass and underwent transarterial chemoembolization twice, followed by liver transplantation, but no tumor was found in the liver explant. This patient did not meet the HALT-C Trial criteria for presumed or definite HCC. Two patients with SVR experienced variceal hemorrhage (patients E and F).

Chronic hepatitis C virus (HCV) infection is a common cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation. Follow-up studies of patients who achieved a sustained virological response (SVR) after antiviral therapy have demonstrated that the majority of patients continue to have undetectable serum HCV RNA, improvement in liver fibrosis, including reversal of cirrhosis, and a reduction in the incidence of decompensated liver disease and HCC compared with subjects who did not achieve an SVR.1-3 These studies notwithstanding, the beneficial effect of achieving an SVR on the outcome of patients with advanced chronic hepatitis C remains incompletely defined because prior studies were retrospective4-7 and included a small number of patients with cirrhosis2 and a relatively limited period of follow-up.8 In addition , few data are available on patients in the United States, because most of these studies were conducted in Japan or Europe.4-8 Furthermore, the beneficial effect of interferon and ribavirin treatment on the outcomes of patients with advanced hepatitis C who achieved viral clearance during treatment and who relapsed after discontinuation of treatment has not been established clearly.6

The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial was a multicenter study involving more than 1000 patients in the United States with advanced chronic hepatitis C and nonresponse to previous treatment with interferon-based therapy.9 During the lead-in phase of the HALT-C Trial, 1145 patients were treated with a combination of pegylated interferon and ribavirin; of these, 180 achieved SVR. Patients who did not achieve SVR entered the randomized phase of the HALT-C Trial and were followed prospectively for the development of fibrosis progression, decompensated liver disease, HCC, and death. The aim of the current study was to evaluate the effect of achieving SVR on overall mortality and on liver-related morbidity and mortality in this large, prospectively followed cohort of patients from the United States with advanced chronic hepatitis C.

DISCUSSION

We report here the results of a prospective, long-term follow-up study to evaluate the effect of achieving SVR with pegylated interferon and ribavirin treat ment on death from any cause or liver transplantation, and on liver- related morbidity and mortality, in a large cohort of patients in the United States with chronic hepatitis C and bridging fibrosis or cirrhosis. Patients who achieved SVR were compared with two groups of patients who were enrolled into the HALT-C Trial at the same time: (1) patients who failed to respond to peginterferon and ribavirin (NR) and (2) patients with virologic clearance at Week 20 but subsequent virologic breakthrough during combination antiviral therapy or relapse after completion of therapy (BT/R). In this cohort of patients with advanced chronic hepatitis C, we found that those who achieved SVR after peginterferon and ribavirin treatment had a significantly reduced risk of death from any cause/liver transplantation, and of liver-related morbidity and mortality, when compared with patients in the NR group. Importantly, achieving SVR significantly reduced the risk of developing each component of liver-related morbidity and mortality (i.e., hepatic decompensation, HCC, and liver-related death or liver transplantation) when compared with NR patients.

A strength of this study was the long duration of prospective follow-up. Patients were identified at entry into the HALT-C Trial and were followed for a median of 79 (NR) to 86 (SVR) months after starting their final course of peginterferon/ribavirin. Our findings on the effect of SVR on liver-related clinical outcomes are similar to those of retrospective, and often smaller, studies from Japan5, 7, 13-15 and Europe,6 the results of which supported an approximately 70%-90% reduction in the risk of liver-related clinical outcomes over a follow-up period of 2-6 years in patients achieving an SVR. An interesting observation in our study was the relative rapidity of the effect of achieving an SVR on hepatic decompensation; within 1 year, rates of decompensation among patients with an SVR and those with NR began to diverge. Both SVR patients in whom HCC developed had no discernable cause for ongoing liver damage . These data underscore the continued risk of HCC in patients with advanced chronic hepatitis C, even in those who achieved SVR, as has been noted previously.2, 4, 7-8, 13 Because both SVR patients in whom HCC developed were diagnosed more than 4 years (4.4 and 5.9) after achieving SVR, HCC surveillance should continue for more than 5 years after SVR, and probably for life.

Based on Cox proportional hazard analyses, we found that baseline platelet count was associated independently with all five outcomes, whereas albumin level was associated independently with four outcomes (not with HCC). Age and alkaline phosphatase were associated with the risk of HCC but not with any other outcome. This observation could suggest that the development of HCC follows a different pathway than, and is temporally independent of, the development of other complications of liver disease. In prior studies, age and sex have been associated with risk of HCC, and we reported previously that alkaline phosphatase is associated with the risk of HCC in the HALT-C Trial cohort.11

An interesting and heretofore unreported finding was the intermediate risk of clinical outcomes in the BT/R group, between the risk of that for the NR and the SVR groups. In particular, the adjusted risk of death from any cause/liver transplantation or of any liver-related outcome was significantly lower in the BT/R group than in the NR group. The risks of decompensated liver disease, HCC, and liver-related death or liver transplantation were also lower in the BT/R group than in the NR group, although these differences did not reach statistical significance. These findings suggest that complete viral suppression is associated with a reduced risk of clinical outcomes and that the benefits may outlast the period in which HCV RNA is undetectable.16

Laboratory tests commonly associated with liver disease severity, such as albumin and platelet count, improved in patients achieving an SVR but worsened in patients not achieving SVR. Of particular interest, in these patients with advanced fibrosis who achieved SVR, platelet count and albumin continued to improve between Week 72 and the final visit approximately 5.5 years later. In the only prior report of laboratory tests among SVR patients followed for 5 years, George et al.2 were unable to demonstrate improvement in laboratory tests. Therefore, improvement in liver-related blood tests after achieving an SVR in patients with advanced fibrosis is an original finding. One possible explanation for the difference between the prior report and ours is that the majority of patients followed by George and colleagues2 had mild liver fibrosis, with minimal changes in albumin and platelets that would not be expected to improve during follow-up monitoring. Overall, our data demonstrating improvement in liver-related blood tests, when combined with prior studies demonstrating reduction in liver fibrosis,1-3 suggest that liver function continues to recover in the years following an SVR in patients with advanced fibrosis/cirrhosis.

This study has several limitations. A total of 17% of patients who achieved SVR were lost to follow-up and an additional 6% declined to participate. Potentially, decompensated liver disease or HCC may have developed in these patients; therefore, our results may be an underestimate of the rate of clinical outcomes in patients who achieved SVR. We were able to determine, however, that none of the 30 patients who were lost to follow-up died according to a search of the SSDI performed at the end of amended study. Another potential limitation was the fact that the patients who achieved SVR were not monitored as closely as the BT/R and NR patients and that not all SVR patients were evaluated in person. Nevertheless, medical records with physical examination, blood tests, and/or liver imaging of the patients who were interviewed by phone were reviewed and added reliability to the ascertainment of the occurrence of decompensated liver disease or HCC as of the time of their last follow-up assessment.

In summary, we found that patients with advanced chronic hepatitis C who achieved SVR had significantly lower rates of death from any cause or liver transplantation, and of liver-related morbidity and mortality, compared to patients who failed to eliminate HCV with treatment (NR). Still, patients who achieved SVR remained at risk of HCC for at least 6 years after achieving SVR. Our study also showed that patients who had temporary, but complete viral suppression (BT/R) were less likely to die or undergo liver transplantation, or to experience liver-related complications than patients in the NR group, indicating that the duration of clinical benefit may outlast the period of actual viral suppression. Importantly, laboratory tests associated with liver-disease severity (e.g., platelet count, albumin) continued to improve after patients achieved SVR. Overall, our data indicate that patients with chronic hepati tis C and advanced hepatic fibrosis who achieve SVR have a marked reduction in the risk for death or liver transplantation, or of liver-related complications, and continued improvement in laboratory markers of liver function in the 5-6 years following successful viral eradication.

RESULTS

Demographic and Clinical Data.

Data were obtained on 140 (78%) of the 180 HALT-C Trial patients who achieved SVR. Thirty patients could not be located, and 10 declined to participate. The 40 patients who did not participate did not differ from the 140 who did at baseline or at Week 72 in demographic characteristics, baseline Ishak fibrosis score, or routine blood tests. Specifically, at Week 72 no difference was found between the SVR nonparticipants (n = 40) and participants (n = 140) for key predictors of clinical outcome such as age (49.8 ± 8.02 years versus 50.0 ± 6.12 years for nonparticipants and participants, respectively; P = 0.87), albumin (4.3 ± 0.4 versus 4.2 ± 0.4 g/dL; P = 0.26), platelet count (191 ± 56 versus 191 ± 59 x 1000/mm3; P = 0.97), AFP (3.3 ± 1.5 versus 3.3 ± 1.7 ng/mL; P = 0.88) or alkaline phosphatase (72 ± 20 versus 78 ± 20 IU/mL; P = 0 .27). Three of the 140 SVR patients had died, and copies of death certificates for two of the three were obtained. Of the 137 surviving participants, 70 were seen in clinic whereas 67 were evaluated by telephone interviews supplemented by examination of external medical records. None of the 30 patients with SVR who could not be located were listed as deceased in the online SSDI.

Baseline demographic data as well as clinical and laboratory data on the SVR group and the two comparison groups (BT/R and NR) are shown in Table 1. The three groups differed significantly in race/ethnicity, presence of cirrhosis, hepatitis C genotype, and laboratory values associated with advanced liver disease. SVR patients were more likely to be Caucasian, infected with HCV genotypes other than 1, to have fibrosis (rather than cirrhosis) on baseline biopsy and less likely to have laboratory values associated with advanced liver disease (e.g., low blood counts and albumin, or high INR and AFP) compared with patients in the BT/R and NR groups.

Durability of SVR.

Ninety-one SVR patients had follow-up HCV RNA testing performed an average of 78.6 ± 15.9 months (range: 22.1-99.6 months) after achieving SVR, and 90 of the 91 (99%) had undetectable HCV RNA in serum. The patient with reappearance of HCV RNA was presumed to have a relapse because there were no risk factors for reinfection and genotype 1b was detected at enrollment and at HCV reappearance 15 months following discontinuation of combination treatment. This patient had persistently detectable HCV RNA but no evidence of hepatic decompensation or HCC when last seen 108 months after enrollment in the lead-in phase of the HALT-C Trial.

Clinical Outcomes of SVR Patients.

Five patients who achieved SVR (3.6%) had six liver-related clinical outcomes (Table 2). One patient (patient A) had a 3-cm lesion detected on ultrasound performed for his amended study clinic visit, 7.3 years after his baseline visit and 5.8 years after achieving SVR. At entry into the HALT-C Trial, he had a liver biopsy with an Ishak fibrosis score of 4 and his platelet count was 112,000/mm3. The resected specimen revealed a well-differentiated HCC; cirrhosis was present in the nontumor liver. Another patient (patient B) who had an Ishak fibrosis score of 3 on his baseline liver biopsy was found to have a 15-cm lesion on magnetic resonance imaging performed to evaluate an elevated AFP during a routine follow-up visit 5.8 years after his baseline visit and 4.4 years after achieving SVR. Biopsy of the lesion confirmed the presence of HCC and cirrhosis in the adjacent liver. This patient died of progressive HCC 4 months later. After magnetic resonance imaging was performed, a third patient (patient G) was found to have a 1.3-cm liver mass and underwent transarterial chemoembolization twice, followed by liver transplantation, but no tumor was found in the liver explant. This patient did not meet the HALT-C Trial criteria for presumed or definite HCC. Two patients with SVR experienced variceal hemorrhage (patients E and F).

Two additional SVR patients died, one from alcohol toxicity (patient D) and the other from an unconfi rmed cause, although a family member reported that the death had occ urred after spinal surgery (patient C). These two deaths were not considered to be liver-related.

Models to Predict Clinical Outcomes.

The numbers of patients with death from any cause/liver transplantation and with liver-related outcomes in the SVR, BT/R, and NR groups are presented in Table 3. SVR patients had fewer deaths from any cause/liver transplantation (four or 2.9%) and liver-related outcomes (six outcomes in five [3.6%] patients) compared to BT/R (four or 5.2%) death from any cause/transplant; 15 liver-related outcomes in eight (10.4%) patients and NR (64 or 20.7%) death from any cause/transplant; 148 liver-related outcomes in 78 (25.2%) patients. Because the three patient groups differed in baseline severity of liver disease (e.g., Ishak fibrosis score, platelet count, albumin level; Table 1), we performed a Cox proportional hazard regression analysis (Table 4), adjusting for histological stratum (fibrosis or cirrhosis), age, race, platelet count, AST/ALT ratio, albumin, alkaline phosphatase, AFP, and treatment response (SVR, B T/R, and NR). These variables were selected because they have been associated with liver disease severity or clinical outcomes in prior HALT-C Trial analyses.11, 12 Separate multivariate models were developed to assess risk factors associated with the five outcomes analyzed in this study.

A low baseline platelet count was significantly associated with all five outcomes, whereas a low baseline albumin was a significant risk factor for all outcomes except HCC (Model 4). Age and baseline alkaline phosphatase were also sig nificant risk factors for the development of HCC (Model 4). Achievin g an SVR, when compared with nonresponders, was associated with a significantly lower hazard ratio for each of the five clinical outcomes. Patients with BT/R had a significantly lower hazard ratio for death from any cause/liver transplantation (hazard ratio [HR] = 0.29; 95% confidence interval [CI] = 0.10-0.79) and for any liver-related outcome (HR = 0.46; 95%CI = 0.22-0.96) when compared with NR. Fibrosis stage, race, and baseline AST/ALT ratio were not statistically significant risk factors in any multivariate model.

Adjusted Rates of Clinical Outcomes in SVR, BT/R, and NR Patients.

The cumulative rates of death from any cause/liver transplantation, and of liver-related morbidity and mortality, adjusted for the significant risk factors identified in the Cox models, are shown in Fig. 2 and Supporting Information Table 1. At year 7.5 from enrollment, the adjusted cumulative incidence of outcomes for the SVR, BT/R, and NR patients was, respectively, 2.2%, 4.4%, and 21.3% for death from any cause or liver transplantation (P = 0.0002); 2.7%, 8.7%, and 27.2% for any liver-related outcome (P < 0.0001); 0.9%, 4.7%, and 11.7% for decompensated liver disease (P = 0.012); 1.1%, 5.5%, and 8.8% for HCC (P = 0.077); and 0.99%, 4.1%, and 14.7% for liver-related death or liver transplantation (P = 0.005). For each of the five outcomes, the adjusted cumulative proportion of patients with outcomes was lowest for the SVR group, intermediate for the BT/R group, and highest for the NR group of patients. Although the SVR patients had fewer outcomes than the BT/R patients, the adjusted cumulative incidence was not significantly different between the SVR and the BT/R groups for any of the five outcomes (SVR versus BT/R: P = 0.44 for death or liver transplantation, P = 0.05 for any liver-related outcome, P = 0.07 for decompensated liver disease, P = 0.05 for HCC, and P = 0.13 for liver-related death or liver transplantation). The adjusted cumulative proportion with death or liver transplantation (P = 0.02) or any liver-related outcome (P = 0.04) was significantly lower for the BT/R group when compared with patients from the NR group, but the difference between these two groups was not statistically significant when decompensated liver disease (P = 0.24), HCC (P = 0.93), or liver-related death or liver transplantation (P = 0.11) were analyzed individually.

Because there was no effect of long-term peginterferon treatment on the rate of clinical outcomes,9 the Cox proportional hazard analysis and the adjusted cumulative survival analysis were repeated after including 400 patients who were randomized to the peginterferon alfa-2a (90 µg/week) arm of the HALT-C Trial and who were followed after randomization. Including these patients increased the NR group to 638 and the BT/R group to 148 individuals. All HRs and cumulative outcome analyses were essentially unchanged, except that statistical significance for SVR versus NR was stronger, the HR and adjusted survival analyses for SVR versus BT/R were significant for any liver-related outcome (P < 0.05), and the HR and adjusted survival analyses for BT/R versus NR were significant for liver-related death or liver transplantation (P < 0.05) (data not shown).

Changes in Laboratory Test Results.

Figure 3 shows changes in selected blood tests over time among patients who had blood tests performed at each of the three time points. Among the SVR patients, platelet count and albumin (shown in Fig. 3) as well as AST, ALT, and AFP (data not shown) significantly improved from baseline to the most recent values. A significant improvement in platelet count and albumin was also observed between Week 72 (Month 18), when SVR was attained, and the time of the amended study visit. In contrast, patients from the BT/R and NR groups had a significant worsening of platelet count and bilirubin between baseline and Month 72 visits, and NR patients also had deterioration in albumin and INR during the same time period.
 
Source
HCV is a leading cause of liver chronic diseases all over the world. In developed countries the highest prevalence of infection is reported among intravenous drug users and haemodialysis (HD) patients.

The present report is to identify the pathway of HCV transmission during an outbreak of HCV infection in a privately run haemodialysis (HD) unit in Italy in 2005.

Methods: Dynamics of the outbreak and infection clinical outcomes were defined through an ambi-directional cohort study. Molecular epidemiology techniques were used to define the relationships between the viral variants infecting the patients and confirm the outbreak.

Risk analysis and auditing procedures were carried out to define the transmission pathways.

Results: Of the 50 patients treated in the HD unit 5 were already anti-HCV positive and 13 became positive during the study period (AR= 28.9%). Phylogenic analysis identified that, all the molecularly characterized incident cases (10 out of 13), were infected with the same viral variant of one of the prevalent cases.

The multivariate analysis and the auditing procedure disclosed a single event of multi-dose vials heparin contamination as the cause of transmission of the infection in 11 out of the13 incident cases; 2 additional incident cases occurred possibly as a result of inappropriate risk management.DiscussionMore than 30% of all HCV infections in developed countries results from poor application of standard precautions during percutaneous procedures. Comprehensive strategy which included: educational programmes, periodical auditing on standard precaution, use of single-dose vials whenever possible, prospective surveillance for blood-borne infections (including a system of prompt notification) and risk assessment/management dedicated staff are the cornerstone to contain and prevent outbreaks in HD

Conclusions: The outbreak described should serve as a reminder to HD providers that patients undergoing dialysis are at risk for HCV infection and that HCV may be easily transmitted whenever standard precautions are not strictly applied.

Author: Simone LaniniIsabella AbbateVincenzo PuroFabrizio SosciaFrancesco AlbertoniWalter BattistiAmilcare RutaMaria CapobianchiGiuseppe Ippolito

Credits/Source: BMC Infectious Diseases 2010, 10:257

Published on: 2010-08-27
 
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Hepatitis C virus (HCV) infection is a global public health problem. Long-distance truck drivers live apart from their family for long periods of time, a lifestyle that favors at-risk behaviors such as unprotected sex with multiple partners and illicit drug use.

As data concerning HCV infection in this population are still rare, this paper aims to investigate the prevalence, genotypes/subtypes, and the factors associated with HCV infection in long-distance truck drivers in Brazil. A cross-sectional survey was carried out with 641 Brazilian long-truck drivers who were recruited at a major truck stop located at kilometer 1,296 of the BR-153 highway, which is considered to be one of the longest roads in Brazil.

All individuals were interviewed, and their serum samples were tested for the presence of antibodies to HCV (anti-HCV) by ELISA and immunoblot. Anti-HCV positive samples were tested for HCV RNA by PCR amplification of the 5'NC and NS5B regions and were genotyped using the LiPA assay and nucleotide sequencing, respectively.

Factors associated with HCV infection were identified with logistic regression. The prevalence of HCV infection was 1.4% (95% CI: 0.7-2.8).

History of blood transfusion, sharing of personal hygiene tools, illicit drug use and HBV status were factors independently associated with HCV infection in the study population. HCV RNA was detected in 8/9 anti-HCV positive samples, in which genotypes 1 (n = 3), 2 (n = 2), and 3 (n = 3) were determined by LiPA.

Using phylogenetic tree analysis of the NS5B region, subtypes 1a (n = 1), 1b (n = 2), 2b (n = 2) and 3a (n = 3) were identified. These data show that the prevalence of HCV infection among Brazilian truck drivers was similar to that observed for the general population.

History of blood transfusion, sharing of personal hygiene tools, illicit drug use and HBV status were predictors of HCV infection. The HCV genotypes/subtypes identified in the study population are consistent with those circulating in Brazil.

Author: Nara FreitasSheila TelesMarcos MatosCarmen LopesNadia ReisMarcia Espirito-SantoElisabeth LampeRegina Martins

Credits/Source: Virology Journal 2010, 7:205

Published on: 2010-08-27
 
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Therapure Biopharma Inc. (Therapure) today announced receipt of a financial contribution from the National Research Council’s Industrial Research Assistance Program (NRC-IRAP). The funding is to support Therapure’s drug delivery program for the treatment of liver cancer and hepatitis C infection.
 
Toronto, ON (Vocus) August 27, 2010

Therapure Biopharma Inc. (Therapure) today announced receipt of a financial contribution from the National Research Council’s Industrial Research Assistance Program (NRC-IRAP). The funding is to support Therapure’s drug delivery program for the treatment of liver cancer and hepatitis C infection.

Therapure’s lead product for infectious disease is a stable protein-drug conjugate of hemoglobin and ribavirin designed to selectively target the delivery of ribavirin to the liver for the treatment of hepatitis C virus (HCV) infection. Therapure’s lead cancer product is a similar conjugate of hemoglobin and floxuridine, which delivers the powerful chemotherapy drug floxuridine directly to the liver as treatment for primary liver cancer. Both products are based on a core expertise in protein chemistry and cell biology that Therapure scientists have pioneered and applied to the natural and highly specific pathway for hemoglobin metabolism as a means of treating chronic and acute liver diseases with high unmet medical need.

Both drug delivery products are in the pre-clinical stage of development. Therapure has recently completed pre-IND and pre-CTA submissions to the US FDA and Health Canada, respectively, as a key step in defining the clinical and regulatory paths for both products and advancing them products to the clinic and the treatment of patients sooner.

In addition to technical and business advisory services, the financial assistance provided by NRC-IRAP will support funding for continued pre-clinical safety and efficacy studies, and bioanalytical method development.

“Therapure is very proud to have been chosen by NRC-IRAP” said Thomas Wellner, President and CEO of Therapure. “This demonstrates the breadth of Therapure’s capabilities in Product and Method Development.”

About Therapure Biopharma Inc.:

Therapure Biopharma Inc. is an integrated biopharmaceutical company that develops, manufactures, purifies and packages therapeutic proteins. As a contract development and manufacturing organization (CDMO) Therapure Biopharma applies scientific, manufacturing, and downstream purification expertise with an intimate understanding of advanced biology, complex proteins, and regulatory processes to develop effective and innovative solutions to advance products from discovery to market for its clients. Therapure’s Health Canada licensed 130,000 sq. ft. facility, includes manufacturing, research and quality control laboratories and a cGMP warehouse, and is built to U.S. FDA, EMEA, MHRA and Health Canada standards for the aseptic handling and purification of proteins.

For more information, please visit: http://www.therapurebio.com/

Company Contacts:
Thomas Wellner, President and CEO
Therapure Biopharma Inc.
+1 905 286-6204
ceo(at)therapurebio(dot)com

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Many diagnostic and treatment options have been developed for chronic liver disease during the last 40 years, yet their influence on survival remain unclear. A new study of the prognosis for patients hospitalized for liver diseases between 1969 and 2006, and of differences in mortality and complications between patients with alcoholic and non-alcoholic liver diseases, has found that the general prognosis for patients hospitalized with chronic liver diseases has not improved.

Results will be published in the November 2010 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"The most effective changes in treatment for chronic liver disease during the last 40 years are, in my opinion, combination treatment for hepatitis C and treatment with prednisolone and azathioprine for autoimmune hepatitis," said Knut Stokkeland, an instructor in the department of medicine at Visby Hospital in Sweden and corresponding author for the study. "In addition, new diagnostic tools such as endoscopic examinations, computed tomography, MRI, and ultrasound have probably increased our possibilities to detect early disease and the development of cirrhosis."

Stokkeland added that the key difference between alcoholic and non-alcoholic liver disease is alcohol dependence (AD), which almost all patients with alcoholic liver disease have. "AD increases the risks of social problems, being a smoker, and severe psychiatric diseases," he said. "It also inhibits staying sober, which may stop disease progression."

Stokkeland and his colleagues used data from the Swedish Hospital Discharge Register and Cause of Death Register between 1969 and 2006 to both identify and follow up with a cohort of 36,462 patients hospitalized with alcoholic liver diseases and 95,842 patients hospitalized with non-alcoholic liver diseases.

"The main finding of Dr. Stokkeland's study is the much increased mortality risk of having an alcohol- versus a non-alcohol-related liver disease," observed Johan Franck, a professor of clinical addiction research at Karolinska Institutet in Sweden. "Thus, patients with alcohol-induced liver diseases should receive more attention, and they should routinely be offered treatment for their alcohol-use disorder. Presumably, the various treatment systems involved – such as hepatology versus substance-abuse care – may not be very well coordinated and this may present an area for improvement."

Stokkeland agreed. "This may be caused by the fact that hospitalized patients with [alcoholic] liver disease have such a severe liver disease that no effort may change their prognosis," he said. "I hope this study will motivate clinicians and scientists in the field of hepatology and gastroenterology to design clinical studies to see if any changes in care-taking of our patients with alcoholic liver disease may change their severe prognosis. We must also focus on treating their AD so that they may stop drinking."

"Given that alcohol doubles the risk of having a serious liver disease," added Franck, "efforts to reduce alcohol drinking will likely have a positive impact on the disease's outcome."

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Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Increased Risk of Esophageal Varices, Liver Cancer and Death in Patients with Alcoholic Liver Disease," were Fereshte Ebrahim of the National Board of Health and Welfare, and Anders Ekbom of the Department of Medicine at the Karolinksa Institutet, both of Stockholm, Sweden. The study was funded by the Bengt Ihre Foundation, the Karolinksa Institutet, and Visby Hospital. This release is supported by the Addiction Technology Transfer Center Network at http://www.attcnetwork.org/
 
Published on: 2010-08-29
 
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